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In a placebo-controlled trial in normal volunteers, the administration of two doses of sertraline did not significantly alter steady-state lithium levels or the renal clearance of lithium.



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In three separate in vivo interaction studies, sertraline was co-administered with cytochrome P450 3A4 substrates, terfenadine, carbamazepine, or cisapride under steady-state conditions. The results of these studies indicated that sertraline did not increase plasma concentrations of terfenadine, carbamazepine, or cisapride. These data indicate that sertraline’s extent of inhibition of P450 3A4 activity is not likely to be of clinical significance. Results of the interaction study with cisapride indicate that sertraline 200 mg (q.d.) induces the metabolism of cisapride (cisapride AUC and Cmax were reduced by about 35%).



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DailyMed

Label: ZYTIGA- abiraterone acetate tablet

  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: New Drug Application

Drug Label Information

Updated 05/15

If you are a consumer or patient please visit this version.

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  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use ZYTIGA safely and effectively. See full prescribing information for ZYTIGA.
    ZYTIGA ® (abiraterone acetate) Tablets
    For Oral Administration
    Initial U.S. Approval: 2011

    RECENT MAJOR CHANGES

    Dosage and Administration. (2.2) 05/2014

    INDICATIONS AND USAGE

    ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer. (1)

    DOSAGE AND ADMINISTRATION

    Recommended dose: ZYTIGA 1,000 mg (four 250 mg tablets) administered orally once daily in combination with prednisone 5 mg administered orally twice daily. ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. The tablets should be swallowed whole with water. Do not crush or chew tablets. (2.1)

    • For patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the ZYTIGA starting dose to 250 mg once daily. (2.2)
    • For patients who develop hepatotoxicity during treatment, hold ZYTIGA until recovery. Retreatment may be initiated at a reduced dose. ZYTIGA should be discontinued if patients develop severe hepatotoxicity. (2.2)

    DOSAGE FORMS AND STRENGTHS

    Tablet 250 mg (3)

    CONTRAINDICATIONS

    • ZYTIGA is contraindicated in women who are or may become pregnant. (4.1, 8.1)

    WARNINGS AND PRECAUTIONS

    • Mineralocorticoid excess: Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with LVEF < 50% or NYHA Class III or IV heart failure in Study 1 or LVEF < 50% or NYHA Class II to IV heart failure in Study 2 was not established. Control hypertension and correct hypokalemia before treatment. Monitor blood pressure, serum potassium and symptoms of fluid retention at least monthly. (5.1)
    • Adrenocortical insufficiency: Monitor for symptoms and signs of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations. (5.2)
    • Hepatotoxicity: Increases in liver enzymes have led to drug interruption, dose modification and/or discontinuation. Monitor liver function and modify, interrupt, or discontinue ZYTIGA dosing as recommended. (5.3)

    ADVERSE REACTIONS

    The most common adverse reactions (≥10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.

    The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia. (6)

    To report SUSPECTED ADVERSE REACTIONS, contact Janssen Biotech, Inc. at 1-800-526-7736 (1-800-JANSSEN) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

    DRUG INTERACTIONS

    • CYP3A4 Inducers: Avoid concomitant strong CYP3A4 inducers during ZYTIGA treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency. (2.3, 7.1)
    • CYP2D6 Substrates: Avoid co-administration of ZYTIGA with CYP2D6 substrates that have a narrow therapeutic index. If an alternative treatment cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate. (7.2)

    USE IN SPECIFIC POPULATIONS

    • Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C). (8.6)

    See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

    Revised: 5/2015

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  • FULL PRESCRIBING INFORMATION: CONTENTS*

    1 INDICATIONS AND USAGE

    2 DOSAGE AND ADMINISTRATION

    2.1 Recommended Dosage

    2.2 Dose Modification Guidelines in Hepatic Impairment and Hepatotoxicity

    2.3 Dose Modification Guidelines for Strong CYP3A4 Inducers

    3 DOSAGE FORMS AND STRENGTHS

    4 CONTRAINDICATIONS

    4.1 Pregnancy

    5 WARNINGS AND PRECAUTIONS

    5.1 Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess

    5.2 Adrenocortical Insufficiency

    5.3 Hepatotoxicity

    6 ADVERSE REACTIONS

    6.1 Clinical Trial Experience

    6.2 Post Marketing Experience

    7 DRUG INTERACTIONS

    7.1 Drugs that Inhibit or Induce CYP3A4 Enzymes

    7.2 Effects of Abiraterone on Drug Metabolizing Enzymes

    8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    8.3 Nursing Mothers

    8.4 Pediatric Use

    8.5 Geriatric Use

    8.6 Patients with Hepatic Impairment

    8.7 Patients with Renal Impairment

    10 OVERDOSAGE

    11 DESCRIPTION

    12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    12.3 Pharmacokinetics

    12.6 QT Prolongation

    13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

    13.2 Animal Toxicology and/or Pharmacology

    14 CLINICAL STUDIES

    16 HOW SUPPLIED/STORAGE AND HANDLING

    17 PATIENT COUNSELING INFORMATION

    *
    Sections or subsections omitted from the full prescribing information are not listed.
    Close
  • 1 INDICATIONS AND USAGE

    ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer.

    Close
  • 2 DOSAGE AND ADMINISTRATION

    2.1 Recommended Dosage

    The recommended dose of ZYTIGA is 1,000 mg (four 250 mg tablets) administered orally once daily in combination with prednisone 5 mg administered orally twice daily. ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken [see Clinical Pharmacology (12.3)]. The tablets should be swallowed whole with water. Do not crush or chew tablets.

    2.2 Dose Modification Guidelines in Hepatic Impairment and Hepatotoxicity

    Hepatic Impairment

    In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. A once daily dose of 250 mg in patients with moderate hepatic impairment is predicted to result in an area under the concentration curve (AUC) similar to the AUC seen in patients with normal hepatic function receiving 1,000 mg once daily. However, there are no clinical data at the dose of 250 mg once daily in patients with moderate hepatic impairment and caution is advised. In patients with moderate hepatic impairment monitor ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. If elevations in ALT and/or AST greater than 5× upper limit of normal (ULN) or total bilirubin greater than 3× ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA and do not re-treat patients with ZYTIGA [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

    Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C).

    Hepatotoxicity

    For patients who develop hepatotoxicity during treatment with ZYTIGA (ALT and/or AST greater than 5× ULN or total bilirubin greater than 3× ULN), interrupt treatment with ZYTIGA [see Warnings and Precautions (5.3)]. Treatment may be restarted at a reduced dose of 750 mg once daily following return of liver function tests to the patient's baseline or to AST and ALT less than or equal to 2.5× ULN and total bilirubin less than or equal to 1.5× ULN. For patients who resume treatment, monitor serum transaminases and bilirubin at a minimum of every two weeks for three months and monthly thereafter.

    If hepatotoxicity recurs at the dose of 750 mg once daily, re-treatment may be restarted at a reduced dose of 500 mg once daily following return of liver function tests to the patient's baseline or to AST and ALT less than or equal to 2.5× ULN and total bilirubin less than or equal to 1.5× ULN.

    If hepatotoxicity recurs at the reduced dose of 500 mg once daily, discontinue treatment with ZYTIGA. The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20× ULN and/or bilirubin greater than or equal to 10× ULN is unknown.

    2.3 Dose Modification Guidelines for Strong CYP3A4 Inducers

    Avoid concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) during ZYTIGA treatment. Although there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers, because of the potential for an interaction, if a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency to twice a day only during the co-administration period (e.g., from 1,000 mg once daily to 1,000 mg twice a day). Reduce the dose back to the previous dose and frequency, if the concomitant strong CYP3A4 inducer is discontinued [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

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  • 3 DOSAGE FORMS AND STRENGTHS

    ZYTIGA (abiraterone acetate) 250 mg tablets are white to off-white, oval-shaped tablets debossed with AA250 on one side.

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  • 4 CONTRAINDICATIONS

    4.1 Pregnancy

    ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for use in women. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations (8.1)].

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  • 5 WARNINGS AND PRECAUTIONS

    5.1 Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess

    ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1)]. In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions (6)].

    Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14)]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA.

    5.2 Adrenocortical Insufficiency

    Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions (5.1)].

    5.3 Hepatotoxicity

    In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5× ULN) were reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events.

    Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient's baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function.

    Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient's baseline or to AST and ALT less than or equal to 2.5× ULN and total bilirubin less than or equal to 1.5× ULN [see Dosage and Administration (2.2)].

    The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20× ULN and/or bilirubin greater than or equal to 10× ULN is unknown.

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  • 6 ADVERSE REACTIONS

    The following are discussed in more detail in other sections of the labeling:

    6.1 Clinical Trial Experience

    Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

    Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients.

    The most common adverse drug reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.

    The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia.

    Study 1: Metastatic CRPC Following Chemotherapy

    Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5× ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5× ULN.

    Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with ZYTIGA was 8 months.

    Table 1: Adverse Reactions due to ZYTIGA in Study 1
    ZYTIGA with Prednisone
    (N=791)    		 Placebo with Prednisone
    (N=394)
    System/Organ Class
      Adverse reaction    		 All Grades*
    %    		 Grade 3–4
    %    		 All Grades
    %    		 Grade 3–4
    %
    *
    Adverse events graded according to CTCAE version 3.0
    †
    Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness
    ‡
    Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness
    §
    Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema
    Includes all fractures with the exception of pathological fracture
    #
    Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia
    Þ
    Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively).
    ß
    Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased
    Musculoskeletal and connective tissue disorders
      Joint swelling/discomfort† 29.5 4.2 23.4 4.1
      Muscle discomfort‡ 26.2 3.0 23.1 2.3
    General disorders
      Edema§ 26.7 1.9 18.3 0.8
    Vascular disorders
      Hot flush 19.0 0.3 16.8 0.3
      Hypertension 8.5 1.3 6.9 0.3
    Gastrointestinal disorders
      Diarrhea 17.6 0.6 13.5 1.3
      Dyspepsia 6.1 0 3.3 0
    Infections and infestations
      Urinary tract infection 11.5 2.1 7.1 0.5
      Upper respiratory tract infection 5.4 0 2.5 0
    Respiratory, thoracic and mediastinal disorders
      Cough 10.6 0 7.6 0
    Renal and urinary disorders
      Urinary frequency 7.2 0.3 5.1 0.3
      Nocturia 6.2 0 4.1 0
    Injury, poisoning and procedural complications
      Fractures 5.9 1.4 2.3 0
    Cardiac disorders
      Arrhythmia# 7.2 1.1 4.6 1.0
      Chest pain or chest discomfortÞ 3.8 0.5 2.8 0
      Cardiac failureß 2.3 1.9 1.0 0.3

    Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3–4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm.

    Table 2: Laboratory Abnormalities of Interest in Study 1
    Abiraterone (N=791) Placebo (N=394)
    Laboratory Abnormality All Grades (%) Grade 3–4 (%) All Grades (%) Grade 3–4 (%)
    Hypertriglyceridemia 62.5 0.4 53.0 0
    High AST 30.6 2.1 36.3 1.5
    Hypokalemia 28.3 5.3 19.8 1.0
    Hypophosphatemia 23.8 7.2 15.7 5.8
    High ALT 11.1 1.4 10.4 0.8
    High Total Bilirubin 6.6 0.1 4.6 0

    Study 2: Metastatic CRPC Prior to Chemotherapy

    Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5× ULN and patients were excluded if they had liver metastases.

    Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥2% absolute increase in frequency compared to placebo. The median duration of treatment with ZYTIGA was 13.8 months.

    Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2
    ZYTIGA with Prednisone (N=542) Placebo with Prednisone (N=540)
    System/Organ Class
      Adverse reaction    		 All Grades*
    %    		 Grade 3–4
    %    		 All Grades
    %    		 Grade 3–4
    %
    *
    Adverse events graded according to CTCAE version 3.0
    †
    Includes terms Edema peripheral, Pitting edema, and Generalized edema
    ‡
    Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness
    General disorders
      Fatigue 39.1 2.2 34.3 1.7
      Edema† 25.1 0.4 20.7 1.1
      Pyrexia 8.7 0.6 5.9 0.2
    Musculoskeletal and connective tissue disorders
      Joint swelling/discomfort‡ 30.3 2.0 25.2 2.0
      Groin pain 6.6 0.4 4.1 0.7
    Gastrointestinal disorders
      Constipation 23.1 0.4 19.1 0.6
      Diarrhea 21.6 0.9 17.8 0.9
      Dyspepsia 11.1 0.0 5.0 0.2
    Vascular disorders
      Hot flush 22.3 0.2 18.1 0.0
      Hypertension 21.6 3.9 13.1 3.0
    Respiratory, thoracic and mediastinal disorders
      Cough 17.3 0.0 13.5 0.2
      Dyspnea 11.8 2.4 9.6 0.9
    Psychiatric disorders
      Insomnia 13.5 0.2 11.3 0.0
    Injury, poisoning and procedural complications
      Contusion 13.3 0.0 9.1 0.0
      Falls 5.9 0.0 3.3 0.0
    Infections and infestations
      Upper respiratory tract infection 12.7 0.0 8.0 0.0
      Nasopharyngitis 10.7 0.0 8.1 0.0
    Renal and urinary disorders
      Hematuria 10.3 1.3 5.6 0.6
    Skin and subcutaneous tissue disorders
      Rash 8.1 0.0 3.7 0.0

    Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3–4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm.

    Table 4: Laboratory Abnormalities in >15% of Patients in the ZYTIGA Arm of Study 2
    Abiraterone (N=542) Placebo (N=540)
    Laboratory Abnormality Grade 1–4
    %    		 Grade 3–4
    %    		 Grade 1–4
    %    		 Grade 3–4
    %
    *
    Based on non-fasting blood draws
    Hematology
      Lymphopenia 38.2 8.7 31.7 7.4
    Chemistry
      Hyperglycemia* 56.6 6.5 50.9 5.2
      High ALT 41.9 6.1 29.1 0.7
      High AST 37.3 3.1 28.7 1.1
      Hypernatremia 32.8 0.4 25.0 0.2
      Hypokalemia 17.2 2.8 10.2 1.7

    Cardiovascular Adverse Reactions:

    In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3–4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3–4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group.

    In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms.

    6.2 Post Marketing Experience

    The following additional adverse reactions have been identified during post approval use of ZYTIGA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

    Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis.

    Musculoskeletal and Connective Tissue Disorders: myopathy, including rhabdomyolysis.

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  • 7 DRUG INTERACTIONS

    7.1 Drugs that Inhibit or Induce CYP3A4 Enzymes

    Based on in vitro data, ZYTIGA is a substrate of CYP3A4.

    In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

    In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Clinical Pharmacology (12.3)].

    7.2 Effects of Abiraterone on Drug Metabolizing Enzymes

    ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3)].

    In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone (CYP2C8 substrate) was increased by 46% when pioglitazone was given together with a single dose of 1,000 mg abiraterone acetate. Therefore, patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA [see Clinical Pharmacology (12.3)].

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  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Pregnancy Category X [see Contraindications (4.1)].

    ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with ZYTIGA.

    In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6–17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients.

    8.3 Nursing Mothers

    ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

    8.4 Pediatric Use

    Safety and effectiveness of ZYTIGA in pediatric patients have not been established.

    8.5 Geriatric Use

    Of the total number of patients receiving ZYTIGA in Phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

    8.6 Patients with Hepatic Impairment

    The pharmacokinetics of abiraterone were examined in subjects with baseline mild (N=8) or moderate (N=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function.

    In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (N=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7-fold and the fraction of free drug increased 2-fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function.

    No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C). If elevations in ALT or AST >5× ULN or total bilirubin >3× ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].

    For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2), Warnings and Precautions (5.3), and Clinical Pharmacology (12.3)].

    8.7 Patients with Renal Impairment

    In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].

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  • 10 OVERDOSAGE

    Human experience of overdose with ZYTIGA is limited.

    There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function.

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  • 11 DESCRIPTION

    Abiraterone acetate, the active ingredient of ZYTIGA is the acetyl ester of abiraterone. Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate. Abiraterone acetate is designated chemically as (3β)-17-(3-pyridinyl) androsta-5,16-dien-3-yl acetate and its structure is:

    Chemical Structure

    Abiraterone acetate is a white to off-white, non-hygroscopic, crystalline powder. Its molecular formula is C26H33NO2 and it has a molecular weight of 391.55. Abiraterone acetate is a lipophilic compound with an octanol-water partition coefficient of 5.12 (Log P) and is practically insoluble in water. The pKa of the aromatic nitrogen is 5.19.

    Inactive ingredients in the tablets are colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium lauryl sulfate.

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  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    Abiraterone acetate (ZYTIGA) is converted in vivo to abiraterone, an androgen biosynthesis inhibitor, that inhibits 17 α-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis.

    CYP17 catalyzes two sequential reactions: 1) the conversion of pregnenolone and progesterone to their 17α-hydroxy derivatives by 17α-hydroxylase activity and 2) the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, respectively, by C17, 20 lyase activity. DHEA and androstenedione are androgens and are precursors of testosterone. Inhibition of CYP17 by abiraterone can also result in increased mineralocorticoid production by the adrenals [see Warnings and Precautions (5.1)].

    Androgen sensitive prostatic carcinoma responds to treatment that decreases androgen levels. Androgen deprivation therapies, such as treatment with GnRH agonists or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumor.

    ZYTIGA decreased serum testosterone and other androgens in patients in the placebo-controlled Phase 3 clinical trial. It is not necessary to monitor the effect of ZYTIGA on serum testosterone levels.

    Changes in serum prostate specific antigen (PSA) levels may be observed but have not been shown to correlate with clinical benefit in individual patients.

    12.3 Pharmacokinetics

    Following administration of abiraterone acetate, the pharmacokinetics of abiraterone and abiraterone acetate have been studied in healthy subjects and in patients with metastatic castration-resistant prostate cancer (CRPC). In vivo, abiraterone acetate is converted to abiraterone. In clinical studies, abiraterone acetate plasma concentrations were below detectable levels (<0.2 ng/mL) in >99% of the analyzed samples.

    Absorption

    Following oral administration of abiraterone acetate to patients with metastatic CRPC, the median time to reach maximum plasma abiraterone concentrations is 2 hours. Abiraterone accumulation is observed at steady-state, with a 2-fold higher exposure (steady-state AUC) compared to a single 1,000 mg dose of abiraterone acetate.

    At the dose of 1,000 mg daily in patients with metastatic CRPC, steady-state values (mean ± SD) of Cmax were 226 ± 178 ng/mL and of AUC were 993 ± 639 ng.hr/mL. No major deviation from dose proportionality was observed in the dose range of 250 mg to 1,000 mg. However, the exposure was not significantly increased when the dose was doubled from 1,000 to 2,000 mg (8% increase in the mean AUC).

    Systemic exposure of abiraterone is increased when abiraterone acetate is administered with food. In healthy subjects abiraterone Cmax and AUC0–∞ were approximately 7- and 5-fold higher, respectively, when a single dose of abiraterone acetate was administered with a low-fat meal (7% fat, 300 calories) and approximately 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a high-fat (57% fat, 825 calories) meal compared to overnight fasting. Abiraterone AUC0–∞ was approximately 7-fold or 1.6-fold higher, respectively, when a single dose of abiraterone acetate was administered 2 hours after or 1 hour before a medium fat meal (25% fat, 491 calories) compared to overnight fasting.

    Systemic exposures of abiraterone in patients with metastatic CRPC, after repeated dosing of abiraterone acetate were similar when abiraterone acetate was taken with low-fat meals for 7 days and increased approximately 2-fold when taken with high-fat meals for 7 days compared to when taken at least 2 hours after a meal and at least 1 hour before a meal for 7 days.

    Given the normal variation in the content and composition of meals, taking ZYTIGA with meals has the potential to result in increased and highly variable exposures. Therefore, no food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. The tablets should be swallowed whole with water [see Dosage and Administration (2.1)].

    Distribution and Protein Binding

    Abiraterone is highly bound (>99%) to the human plasma proteins, albumin and alpha-1 acid glycoprotein. The apparent steady-state volume of distribution (mean ± SD) is 19,669 ± 13,358 L. In vitro studies show that at clinically relevant concentrations, abiraterone acetate and abiraterone are not substrates of P-glycoprotein (P-gp) and that abiraterone acetate is an inhibitor of P-gp.

    Metabolism

    Following oral administration of 14C-abiraterone acetate as capsules, abiraterone acetate is hydrolyzed to abiraterone (active metabolite). The conversion is likely through esterase activity (the esterases have not been identified) and is not CYP mediated. The two main circulating metabolites of abiraterone in human plasma are abiraterone sulphate (inactive) and N-oxide abiraterone sulphate (inactive), which account for about 43% of exposure each. CYP3A4 and SULT2A1 are the enzymes involved in the formation of N-oxide abiraterone sulphate and SULT2A1 is involved in the formation of abiraterone sulphate.

    Excretion

    In patients with metastatic CRPC, the mean terminal half-life of abiraterone in plasma (mean ± SD) is 12 ± 5 hours. Following oral administration of 14C-abiraterone acetate, approximately 88% of the radioactive dose is recovered in feces and approximately 5% in urine. The major compounds present in feces are unchanged abiraterone acetate and abiraterone (approximately 55% and 22% of the administered dose, respectively).

    Patients with Hepatic Impairment

    The pharmacokinetics of abiraterone was examined in subjects with baseline mild (N=8) or moderate (N=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. Systemic exposure to abiraterone after a single oral 1,000 mg dose given under fasting conditions increased approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively. The mean half-life of abiraterone is prolonged to approximately 18 hours in subjects with mild hepatic impairment and to approximately 19 hours in subjects with moderate hepatic impairment.

    In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (N=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7-fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function. In addition, the mean protein binding was found to be lower in the severe hepatic impairment group compared to the normal hepatic function group, which resulted in a two-fold increase in the fraction of free drug in patients with severe hepatic impairment [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].

    Patients with Renal Impairment

    The pharmacokinetics of abiraterone were examined in patients with end-stage renal disease (ESRD) on a stable hemodialysis schedule (N=8) and in matched control subjects with normal renal function (N=8). In the ESRD cohort of the trial, a single 1,000 mg ZYTIGA dose was given under fasting conditions 1 hour after dialysis, and samples for pharmacokinetic analysis were collected up to 96 hours post dose. Systemic exposure to abiraterone after a single oral 1,000 mg dose did not increase in subjects with end-stage renal disease on dialysis, compared to subjects with normal renal function [see Use in Specific Populations (8.7)].

    Drug Interactions

    In vitro studies with human hepatic microsomes showed that abiraterone has the potential to inhibit CYP1A2, CYP2D6, CYP2C8 and to a lesser extent CYP2C9, CYP2C19 and CYP3A4/5.

    In an in vivo drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively when dextromethorphan 30 mg was given with abiraterone acetate 1,000 mg daily (plus prednisone 5 mg twice daily). The AUC for dextrorphan, the active metabolite of dextromethorphan, increased approximately 1.3 fold [see Drug Interactions (7.2)].

    In a clinical study to determine the effects of abiraterone acetate 1,000 mg daily (plus prednisone 5 mg twice daily) on a single 100 mg dose of the CYP1A2 substrate theophylline, no increase in systemic exposure of theophylline was observed.

    Abiraterone is a substrate of CYP3A4, in vitro. In a clinical pharmacokinetic interaction study of healthy subjects pretreated with a strong CYP3A4 inducer (rifampin, 600 mg daily for 6 days) followed by a single dose of abiraterone acetate 1,000 mg, the mean plasma AUC∞ of abiraterone was decreased by 55% [see Drug Interactions (7.1)].

    In a separate clinical pharmacokinetic interaction study of healthy subjects, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Drug Interactions (7.1)].

    In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone was increased by 46% when pioglitazone was given together with a single dose of 1,000 mg abiraterone acetate [see Drug Interactions (7.2)].

    In vitro, abiraterone and its major metabolites were shown to inhibit the hepatic uptake transporter OATP1B1. There are no clinical data available to confirm transporter based interaction.

    12.6 QT Prolongation

    In a multi-center, open-label, single-arm trial, 33 patients with metastatic CRPC received ZYTIGA orally at a dose of 1,000 mg once daily at least 1 hour before or 2 hours after a meal in combination with prednisone 5 mg orally twice daily. Assessments up to Cycle 2 Day 2 showed no large changes in the QTc interval (i.e., >20 ms) from baseline. However, small increases in the QTc interval (i.e., <10 ms) due to abiraterone acetate cannot be excluded due to study design limitations.

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  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

    A two-year carcinogenicity study was conducted in rats at oral abiraterone acetate doses of 5, 15, and 50 mg/kg/day for males and 15, 50, and 150 mg/kg/day for females. Abiraterone acetate increased the combined incidence of interstitial cell adenomas and carcinomas in the testes at all dose levels tested. This finding is considered to be related to the pharmacological activity of abiraterone. Rats are regarded as more sensitive than humans to developing interstitial cell tumors in the testes. Abiraterone acetate was not carcinogenic in female rats at exposure levels up to 0.8 times the human clinical exposure based on AUC. Abiraterone acetate was not carcinogenic in a 6-month study in the transgenic (Tg.rasH2) mouse.

    Abiraterone acetate and abiraterone did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay.

    ZYTIGA has the potential to impair reproductive function and fertility in humans based on findings in animals. In repeat-dose toxicity studies in male rats (13- and 26-weeks) and monkeys (39-weeks), atrophy, aspermia/hypospermia, and hyperplasia in the reproductive system were observed at ≥50 mg/kg/day in rats and ≥250 mg/kg/day in monkeys and were consistent with the antiandrogenic pharmacological activity of abiraterone [see Nonclinical Toxicology (13.2)]. These effects were observed in rats at systemic exposures similar to humans and in monkeys at exposures approximately 0.6 times the AUC in humans.

    In fertility studies in rats, reduced organ weights of the reproductive system, sperm counts, sperm motility, altered sperm morphology and decreased fertility were observed in males dosed for 4 weeks at ≥30 mg/kg/day. Mating of untreated females with males that received 30 mg/kg/day abiraterone acetate resulted in a reduced number of corpora lutea, implantations and live embryos and an increased incidence of pre-implantation loss. Effects on male rats were reversible after 16 weeks from the last abiraterone acetate administration. Female rats dosed for 2 weeks until day 7 of pregnancy at ≥30 mg/kg/day had an increased incidence of irregular or extended estrous cycles and pre-implantation loss (300 mg/kg/day). There were no differences in mating, fertility, and litter parameters in female rats that received abiraterone acetate. Effects on female rats were reversible after 4 weeks from the last abiraterone acetate administration. The dose of 30 mg/kg/day in rats is approximately 0.3 times the recommended dose of 1,000 mg/day based on body surface area.

    13.2 Animal Toxicology and/or Pharmacology

    In 13- and 26-week studies in rats and 13- and 39-week studies in monkeys, a reduction in circulating testosterone levels occurred with abiraterone acetate at approximately one half the human clinical exposure based on AUC. As a result, decreases in organ weights and toxicities were observed in the male and female reproductive system, adrenal glands, liver, pituitary (rats only), and male mammary glands. The changes in the reproductive organs are consistent with the antiandrogenic pharmacological activity of abiraterone acetate. A dose-dependent increase in cataracts was observed in rats at 26 weeks starting at ≥50 mg/kg/day (similar to the human clinical exposure based on AUC). In the 39-week monkey study, no cataracts were observed at higher doses (2 times greater than the clinical exposure based on AUC). All other toxicities associated with abiraterone acetate reversed or were partially resolved after a 4-week recovery period.

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  • 14 CLINICAL STUDIES

    The efficacy and safety of ZYTIGA in patients with metastatic castration-resistant prostate cancer (CRPC) that has progressed on androgen deprivation therapy was demonstrated in two randomized, placebo-controlled, multicenter Phase 3 clinical trials. Patients with prior ketoconazole treatment for prostate cancer and a history of adrenal gland or pituitary disorders were excluded from these trials.

    Study 1

    Patients with metastatic CRPC who had received prior docetaxel chemotherapy:

    A total of 1195 patients were randomized 2:1 to receive either ZYTIGA orally at a dose of 1,000 mg once daily in combination with prednisone 5 mg orally twice daily (N=797) or placebo once daily plus prednisone 5 mg orally twice daily (N=398). Patients randomized to either arm were to continue treatment until disease progression (defined as a 25% increase in PSA over the patient's baseline/nadir together with protocol-defined radiographic progression and symptomatic or clinical progression), initiation of new treatment, unacceptable toxicity or withdrawal.

    The following patient demographics and baseline disease characteristics were balanced between the treatment arms. The median age was 69 years (range 39–95) and the racial distribution was 93.3% Caucasian, 3.6% Black, 1.7% Asian, and 1.6% Other. Eighty-nine percent of patients enrolled had an ECOG performance status score of 0–1 and 45% had a Brief Pain Inventory-Short Form score of ≥4 (patient's reported worst pain over the previous 24 hours). Ninety percent of patients had metastases in bone and 30% had visceral involvement. Seventy percent of patients had radiographic evidence of disease progression and 30% had PSA-only progression. Seventy percent of patients had previously received one cytotoxic chemotherapy regimen and 30% received two regimens.

    The protocol pre-specified interim analysis was conducted after 552 deaths and showed a statistically significant improvement in overall survival (OS) in patients treated with ZYTIGA compared to patients in the placebo arm (Table 5 and Figure 1). An updated survival analysis was conducted when 775 deaths (97% of the planned number of deaths for final analysis) were observed. Results from this analysis were consistent with those from the interim analysis (Table 5).

    Table 5: Overall Survival of Patients Treated with Either ZYTIGA or Placebo in Combination with Prednisone in Study 1 (Intent-to-Treat Analysis)
    ZYTIGA
    (N=797)    		 Placebo
    (N=398)
    *
    p-value is derived from a log-rank test stratified by ECOG performance status score (0–1 vs. 2), pain score (absent vs. present), number of prior chemotherapy regimens (1 vs. 2), and type of disease progression (PSA only vs. radiographic).
    †
    Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio <1 favors ZYTIGA
    Primary Survival Analysis
    Deaths (%) 333 (42%) 219 (55%)
    Median survival (months) (95% CI) 14.8 (14.1, 15.4) 10.9 (10.2, 12.0)
    p-value* <0.0001
    Hazard ratio (95% CI)† 0.646 (0.543, 0.768)
    Updated Survival Analysis
    Deaths (%) 501 (63%) 274 (69%)
    Median survival (months) (95% CI) 15.8 (14.8, 17.0) 11.2 (10.4, 13.1)
    Hazard ratio (95% CI)† 0.740 (0.638, 0.859)

    Figure 1: Kaplan-Meier Overall Survival Curves in Study 1 (Intent-to-Treat Analysis)

    Figure 1

    Study 2

    Patients with metastatic CRPC who had not received prior cytotoxic chemotherapy

    In Study 2, 1088 patients were randomized 1:1 to receive either ZYTIGA at a dose of 1,000 mg once daily (N=546) or Placebo once daily (N=542). Both arms were given concomitant prednisone 5 mg twice daily. Patients continued treatment until radiographic or clinical (cytotoxic chemotherapy, radiation or surgical treatment for cancer, pain requiring chronic opioids, or ECOG performance status decline to 3 or more) disease progression, unacceptable toxicity or withdrawal. Patients with moderate or severe pain, opiate use for cancer pain, or visceral organ metastases were excluded.

    Patient demographics were balanced between the treatment arms. The median age was 70 years. The racial distribution of patients treated with ZYTIGA was 95.4% Caucasian, 2.8% Black, 0.7% Asian and 1.1% Other. The ECOG performance status was 0 for 76% of patients, and 1 for 24% of patients. Co-primary efficacy endpoints were overall survival and radiographic progression-free survival (rPFS). Baseline pain assessment was 0–1 (asymptomatic) in 66% of patients and 2–3 (mildly symptomatic) in 26% of patients as defined by the Brief Pain Inventory-Short Form (worst pain over the last 24 hours).

    Radiographic progression-free survival was assessed with the use of sequential imaging studies and was defined by bone scan identification of 2 or more new bone lesions with confirmation (Prostate Cancer Working Group 2 criteria) and/or modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria for progression of soft tissue lesions. Analysis of rPFS utilized centrally-reviewed radiographic assessment of progression.

    The planned final analysis for OS, conducted after 741 deaths (median follow up of 49 months) demonstrated a statistically significant OS improvement in patients treated with ZYTIGA compared to those treated with placebo (Table 6 and Figure 2). Sixty-five percent of patients on the ZYTIGA arm and 78% of patients on the placebo arm used subsequent therapies that may prolong OS in metastatic CRPC. ZYTIGA was used as a subsequent therapy in 13% of patients on the ZYTIGA arm and 44% of patients on the placebo arm.

    Table 6: Overall Survival of Patients Treated with Either ZYTIGA or Placebo in Combination with Prednisone in Study 2 (Intent-to-Treat Analysis)
    Overall Survival ZYTIGA
    (N=546)    		 Placebo
    (N=542)
    *
    p-value is derived from a log-rank test stratified by ECOG performance status score (0 vs. 1).
    †
    Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio <1 favors ZYTIGA
    Deaths 354 (65%) 387 (71%)
    Median survival (months)
    (95% CI)    		 34.7 (32.7, 36.8) 30.3 (28.7, 33.3)
    p-value* 0.0033
    Hazard ratio† (95% CI) 0.81 (0.70, 0.93)

    Figure 2: Kaplan Meier Overall Survival Curves in Study 2

    Figure 2

    At the pre-specified rPFS analysis, 150 (28%) patients treated with ZYTIGA and 251 (46%) patients treated with placebo had radiographic progression. A significant difference in rPFS between treatment groups was observed (Table 7 and Figure 3).

    Table 7: Radiographic Progression-free Survival of Patients Treated with Either ZYTIGA or Placebo in Combination with Prednisone in Study 2 (Intent-to-Treat Analysis)
    Radiographic Progression-free Survival ZYTIGA
    (N=546)    		 Placebo
    (N=542)
    NR=Not reached
    *
    p-value is derived from a log-rank test stratified by ECOG performance status score (0 vs. 1).
    †
    Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio <1 favors ZYTIGA
    Progression or death 150 (28%) 251 (46%)
    Median rPFS (months)
    (95% CI)    		 NR
    (11.66, NR)    		 8.28
    (8.12, 8.54)
    p-value* <0.0001
    Hazard ratio† (95% CI) 0.425 (0.347, 0.522)

    Figure 3: Kaplan Meier Curves of Radiographic Progression-free Survival in Study 2 (Intent-to-Treat Analysis)

    Figure 3

    The primary efficacy analyses are supported by the following prospectively defined endpoints. The median time to initiation of cytotoxic chemotherapy was 25.2 months for patients receiving ZYTIGA and 16.8 months for patients receiving placebo (HR=0.580; 95% CI: [0.487, 0.691], p < 0.0001).

    The median time to opiate use for prostate cancer pain was not reached for patients receiving ZYTIGA and was 23.7 months for patients receiving placebo (HR=0.686; 95% CI: [0.566, 0.833], p=0.0001). The time to opiate use result was supported by a delay in patient reported pain progression favoring the ZYTIGA arm.

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  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    ZYTIGA (abiraterone acetate) 250 mg tablets are white to off-white, oval tablets debossed with AA250 on one side. ZYTIGA 250 mg tablets are available in high-density polyethylene bottles of 120 tablets.

    NDC Number 57894-150-12

    Storage and Handling

    Store at 20°C to 25°C (68°F to 77°F); excursions permitted in the range from 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature].

    Based on its mechanism of action, ZYTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations (8.1)].

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  • 17 PATIENT COUNSELING INFORMATION

    See FDA-approved patient labeling (Patient Information)

    • Patients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician.
    • Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with ZYTIGA and prednisone.
    • Patients should be informed that ZYTIGA should not be taken with food and that no food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking ZYTIGA with food causes increased exposure and this may result in adverse reactions.
    • Patients should be informed that ZYTIGA is taken once daily and prednisone is taken twice daily according to their physician's instructions.
    • Patients should be informed that in the event of a missed daily dose of ZYTIGA or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician.
    • Patients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION.
    • Patients should be advised that their liver function will be monitored using blood tests.
    • Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA.
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  • SPL UNCLASSIFIED SECTION

    Manufactured by:
    Patheon Inc.
    Mississauga, Canada

    Manufactured for:
    Janssen Biotech, Inc.
    Horsham, PA 19044

    © Janssen Biotech, Inc. 2012
    Revised: May 2015

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  • PATIENT PACKAGE INSERT

    PATIENT INFORMATION
    ZYTIGA®     (Zye-tee-ga)
    (abiraterone acetate)
    Tablets

    Read this Patient Information that comes with ZYTIGA before you start taking it and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.

    What is ZYTIGA?

    ZYTIGA is a prescription medicine that is used along with prednisone. ZYTIGA is used to treat men with castration-resistant prostate cancer (prostate cancer that is resistant to medical or surgical treatments that lower testosterone) that has spread to other parts of the body.

    ZYTIGA is not for use in women.

    It is not known if ZYTIGA is safe or effective in children.

    Who should not take ZYTIGA?

    Do not take ZYTIGA if you are pregnant or may become pregnant. ZYTIGA may harm your unborn baby.

    Women who are pregnant or who may become pregnant should not touch ZYTIGA without protection, such as gloves.

    What should I tell my healthcare provider before taking ZYTIGA?

    Before you take ZYTIGA, tell your healthcare provider if you:

    • have heart problems
    • have liver problems
    • have a history of adrenal problems
    • have a history of pituitary problems
    • have any other medical conditions
    • plan to become pregnant. See "Who should not take ZYTIGA?"
    • are breastfeeding or plan to breastfeed. It is not known if ZYTIGA passes into your breast milk. You and your healthcare provider should decide if you will take ZYTIGA or breastfeed. You should not do both. See "Who should not take ZYTIGA?"

    Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. ZYTIGA can interact with many other medicines.

    You should not start or stop any medicine before you talk with the healthcare provider that prescribed ZYTIGA.

    Know the medicines you take. Keep a list of them with you to show to your healthcare provider and pharmacist when you get a new medicine.

    How should I take ZYTIGA?

    • Take ZYTIGA and prednisone exactly as your healthcare provider tells you.
    • Take your prescribed dose of ZYTIGA one time a day.
    • Your healthcare provider may change your dose if needed.
    • Do not stop taking your prescribed dose of ZYTIGA or prednisone without talking with your healthcare provider first.
    • Take ZYTIGA on an empty stomach. Do not take ZYTIGA with food. Taking ZYTIGA with food may cause more of the medicine to be absorbed by the body than is needed and this may cause side effects.
    • No food should be eaten 2 hours before and 1 hour after taking ZYTIGA.
    • Swallow ZYTIGA tablets whole. Do not crush or chew tablets.
    • Take ZYTIGA tablets with water.
    • Men who are sexually active with a pregnant woman must use a condom during and for one week after treatment with ZYTIGA. If their sexual partner may become pregnant, a condom and another form of birth control must be used during and for one week after treatment with ZYTIGA. Talk with your healthcare provider if you have questions about birth control.
    • If you miss a dose of ZYTIGA or prednisone, take your prescribed dose the following day. If you miss more than 1 dose, tell your healthcare provider right away.
    • Your healthcare provider will do blood tests to check for side effects.

    What are the possible side effects of ZYTIGA?

    ZYTIGA may cause serious side effects including:

    • High blood pressure (hypertension), low blood potassium levels (hypokalemia) and fluid retention (edema). Tell your healthcare provider if you get any of the following symptoms:
      • dizziness
      • fast heartbeats
      • feel faint or lightheaded
      • headache
      • confusion
      • muscle weakness
      • pain in your legs
      • swelling in your legs or feet
    • Adrenal problems may happen if you stop taking prednisone, get an infection, or are under stress.
    • Liver problems. You may develop changes in liver function blood test. Your healthcare provider will do blood tests to check your liver before treatment with ZYTIGA and during treatment with ZYTIGA.

    The most common side effects of ZYTIGA include:

    • weakness
    • joint swelling or pain
    • swelling in your legs or feet
    • hot flushes
    • diarrhea
    • vomiting
    • cough
    • high blood pressure
    • shortness of breath
    • urinary tract infection
    • bruising
    • low red blood cells (anemia) and low blood potassium levels
    • high blood sugar levels, high blood cholesterol and triglycerides
    • certain other abnormal blood tests

    Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

    These are not all the possible side effects of ZYTIGA. For more information, ask your healthcare provider or pharmacist.

    Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    How should I store ZYTIGA?

    • Store ZYTIGA at 59°F to 86°F (15°C to 30°C).

    Keep ZYTIGA and all medicines out of the reach of children.

    General information about ZYTIGA.

    Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. Do not use ZYTIGA for a condition for which it was not prescribed. Do not give your ZYTIGA to other people, even if they have the same symptoms that you have. It may harm them.

    This leaflet summarizes the most important information about ZYTIGA. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about ZYTIGA that is written for healthcare professionals.

    For more information contact Janssen Biotech, Inc. at 1-800-526-7736 (1-800-JANSSEN) or www.Zytiga.com.

    What are the ingredients of ZYTIGA?

    Active ingredient: abiraterone acetate

    Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium lauryl sulfate.

    This Patient Information has been approved by the U.S. Food and Drug Administration.

    Manufactured by:
    Patheon Inc.
    Mississauga, Canada

    Manufactured for:
    Janssen Biotech, Inc.
    Horsham, PA 19044

    © Janssen Biotech, Inc. 2012
    Revised: May 2015

    Close
  • PRINCIPAL DISPLAY PANEL

    PRINCIPAL DISPLAY PANEL - 250 mg Bottle Label

    120 TABLETS

    NDC 57894-150-12

    Zytiga®

    (abiraterone acetate)
    tablets

    250 mg

    Each tablet contains:
    abiraterone acetate 250 mg

    Warning: Women who are or may be
    pregnant should not handle ZYTIGA
    without gloves (see package insert).

    janssen

    PRINCIPAL DISPLAY PANEL - 250 mg Bottle Label
    Close
  • INGREDIENTS AND APPEARANCE
    ZYTIGA 
    abiraterone acetate tablet
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:57894-150
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    abiraterone acetate (UNII: EM5OCB9YJ6) (abiraterone - UNII:G819A456D0) abiraterone acetate 250 mg
    Inactive Ingredients
    Ingredient Name Strength
    lactose monohydrate (UNII: EWQ57Q8I5X)  
    cellulose, microcrystalline (UNII: OP1R32D61U)  
    croscarmellose sodium (UNII: M28OL1HH48)  
    povidones (UNII: FZ989GH94E)  
    sodium lauryl sulfate (UNII: 368GB5141J)  
    magnesium stearate (UNII: 70097M6I30)  
    silicon dioxide (UNII: ETJ7Z6XBU4)  
    Product Characteristics
    Color WHITE (white to off-white) Score no score
    Shape OVAL Size 16mm
    Flavor Imprint Code AA250
    Contains     
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:57894-150-12 120 in 1 BOTTLE; Type 0: Not a Combination Product
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA202379 04/28/2011
    Labeler - Janssen Biotech, Inc. (099091753)
    Establishment
    Name Address ID/FEI Business Operations
    Cambridge Major Laboratories 054452136 API MANUFACTURE(57894-150)
    Establishment
    Name Address ID/FEI Business Operations
    Cambridge Major Laboratories 961717936 API MANUFACTURE(57894-150)
    Establishment
    Name Address ID/FEI Business Operations
    Patheon, Inc. 240769596 MANUFACTURE(57894-150) , ANALYSIS(57894-150) , PACK(57894-150)
    Establishment
    Name Address ID/FEI Business Operations
    Patheon, Inc. 259484350 ANALYSIS(57894-150)
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diff --git a/war/tests/DDI-labels/7c295b64-ec39-42ec-9f02-da5b42e775e1.html b/war/tests/DDI-labels/7c295b64-ec39-42ec-9f02-da5b42e775e1.html new file mode 100644 index 0000000..80b2293 --- /dev/null +++ b/war/tests/DDI-labels/7c295b64-ec39-42ec-9f02-da5b42e775e1.html @@ -0,0 +1 @@ + DailyMed - BICALUTAMIDE- bicalutamide tablet
DailyMed

Label: BICALUTAMIDE- bicalutamide tablet

  • NDC Code(s): 16729-023-01, 16729-023-10
  • Packager: Accord Healthcare Inc
  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: Abbreviated New Drug Application

Drug Label Information

Updated 08/12

If you are a consumer or patient please visit this version.

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  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use bicalutamide safely and effectively. See full prescribing information for bicalutamide.
    Bicalutamide Tablets USP for Oral use
    Initial U.S. Approval: 1995

    INDICATIONS AND USAGE

    • Bicalutamide tablets 50 mg is an androgen receptor inhibitor indicated for use in combination therapy with a luteinizing hormone-releasing hormone (LHRH) analog for the treatment of Stage D2 metastatic carcinoma of the prostate.
    • Bicalutamide tablets 150 mg daily is not approved for use alone or with other treatments. (1)

    DOSAGE AND ADMINISTRATION

    The recommended dose for bicalutamide therapy in combination with an LHRH analog is one 50 mg tablet once daily (morning or evening). (2)

    DOSAGE FORMS AND STRENGTHS

    50 mg tablets (3)

    CONTRAINDICATIONS

    • Hypersensitivity (4.1)
    • Women (4.2)
    • Pregnancy (4.3 and 8.1)

    WARNINGS AND PRECAUTIONS

    • Severe hepatic injury and fatal hepatic failure have been observed. Monitor serum transaminase levels prior to starting treatment with bicalutamide, at regular intervals for the first four months of treatment and periodically thereafter, and for symptoms or signs suggestive of hepatic dysfunction. Use bicalutamide with caution in patients with hepatic impairment. (5.1)
    • Gynecomastia and breast pain have been reported during treatment with bicalutamide 150 mg when used as a single agent. (5.2)
    • Bicalutamide is used in combination with an LHRH agonist. LHRH agonists have been shown to cause a reduction in glucose tolerance in males. Consideration should be given to monitoring blood glucose in patients receiving bicalutamide in combination with LHRH agonists. (5.3)
    • Monitoring Prostate Specific Antigen (PSA) is recommended. Evaluate for clinical progression if PSA increases. (5.4)

    ADVERSE REACTIONS

    Adverse reactions that occurred in more than 10% of patients receiving bicalutamide plus an LHRH-A were: hot flashes, pain (including general, back, pelvic and abdominal), asthenia, constipation, infection, nausea, peripheral edema, dyspnea, diarrhea, hematuria, nocturia and anemia. (6.1)

    To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

    DRUG INTERACTIONS

    • R-bicalutamide is an inhibitor of CYP 3A4; therefore, caution should be used when bicalutamide is co-administered with CYP 3A4 substrates. (7)
    • Prothrombin times should be closely monitored in patient already receiving coumarin anticoagulants who are started on bicalutamide. (7)

    USE IN SPECIFIC POPULATIONS

    Pediatric patients: Efficacy has not been demonstrated for the treatment of familial male-limited precocious puberty (testotoxicosis). (8.4)

    See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

    Revised: 8/2012

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  • FULL PRESCRIBING INFORMATION: CONTENTS*

    1. INDICATIONS AND USAGE

    2. DOSAGE AND ADMINISTRATION

    2.1. Dosage Adjustment in Renal Impairment

    2.2. Dosage Adjustment in Hepatic Impairment

    3. DOSAGE FORMS & STRENGTHS

    4. CONTRAINDICATIONS

    4.1. Hypersensitivity

    4.2. Women

    4.3. Pregnancy

    5. WARNINGS AND PRECAUTIONS

    5.1. Hepatitis

    5.2. Gynecomastia and Breast Pain

    5.3. Glucose Tolerance

    5.4. Laboratory Tests

    6. ADVERSE REACTIONS

    6.1. Clinical Trials Experience

    6.2. Postmarketing Experience

    7. DRUG INTERACTIONS

    8. USE IN SPECIFIC POPULATIONS

    8.1. Pregnancy

    8.3. Nursing Mothers

    8.4. Pediatric Use

    8.5. Geriatric Use

    8.6. Hepatic Impairment

    8.7. Renal Impairment

    8.8. Women

    10. OVERDOSAGE

    11. DESCRIPTION

    12. CLINICAL PHARMACOLOGY

    12.1. Mechanism of Action

    12.3. Pharmacokinetics

    13. NONCLINICAL TOXICOLOGY

    13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility

    14. CLINICAL STUDIES

    14.1. Bicalutamide Tablets 50 mg Daily in Combination with an LHRH-A

    14.2. Safety Data from Clinical Studies using Bicalutamide Tablets 150 mg

    16. HOW SUPPLIED/STORAGE AND HANDLING

    16.1. Storage and Handling

    17. PATIENT COUNSELING INFORMATION

    *
    Sections or subsections omitted from the full prescribing information are not listed.
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  • 1. INDICATIONS AND USAGE

    Bicalutamide tablets 50 mg daily is indicated for use in combination therapy with a luteinizing hormone-releasing hormone (LHRH) analog for the treatment of Stage D2 metastatic carcinoma of the prostate.

    Bicalutamide tablets 150 mg daily is not approved for use alone or with other treatments [see Clinical Studies (14.2)].

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  • 2. DOSAGE AND ADMINISTRATION

    The recommended dose for bicalutamide tablets therapy in combination with an LHRH analog is one 50 mg tablet once daily (morning or evening), with or without food. It is recommended that bicalutamide tablets be taken at the same time each day. Treatment with bicalutamide tablets should be started at the same time as treatment with an LHRH analog.

    2.1. Dosage Adjustment in Renal Impairment

    No dosage adjustment is necessary for patients with renal impairment [see Use in Specific Populations(8.7)].

    2.2. Dosage Adjustment in Hepatic Impairment

    No dosage adjustment is necessary for patients with mild to moderate hepatic impairment. In patients with severe liver impairment (n=4), although there was a 76% increase in the half-life (5.9 and 10.4 days for normal and impaired patients, respectively) of the active enantiomer of bicalutamide no dosage adjustment is necessary [see Use in Specific Populations (8.6)].

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  • 3. DOSAGE FORMS & STRENGTHS

    Bicalutamide tablets 50 mg for oral administration are white to off-white, round, biconvex, film coated tablets, debossed ‘B 50’ on one side and plain on other side.

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  • 4. CONTRAINDICATIONS

    4.1. Hypersensitivity

    Bicalutamide is contraindicated in any patient who has shown a hypersensitivity reaction to the drug or any of the tablet’s components. Hypersensitivity reactions including angioneurotic edema and urticaria have been reported [see Adverse Reactions (6.2)].

    4.2. Women

    Bicalutamide has no indication for women, and should not be used in this population.

    4.3. Pregnancy

    Bicalutamide may cause fetal harm when administered to a pregnant woman. Bicalutamide is contraindicated in women, including those who are or may become pregnant. There are no studies in pregnant women using bicalutamide. If this drug is used during pregnancy, or if 1 the patient becomes pregnant while taking this drug, the patient should be appraised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

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  • 5. WARNINGS AND PRECAUTIONS

    5.1. Hepatitis

    Cases of death or hospitalization due to severe liver injury (hepatic failure) have been reported post-marketing in association with the use of bicalutamide. Hepatotoxicity in these reports generally occurred within the first three to four months of treatment. Hepatitis or marked increases in liver enzymes leading to drug discontinuation occurred in approximately 1% of bicalutamide patients in controlled clinical trials.

    Serum transaminase levels should be measured prior to starting treatment with bicalutamide, at regular intervals for the first four months of treatment, and periodically thereafter. If clinical symptoms or signs suggestive of liver dysfunction occur (e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, “flu-like” symptoms, dark urine, jaundice, or right upper quadrant tenderness), the serum transaminases, in particular the serum ALT, should be measured immediately. If at any time a patient has jaundice, or their ALT rises above two times the upper limit of normal, bicalutamide should be immediately discontinued with close follow-up of liver function.

    5.2. Gynecomastia and Breast Pain

    In clinical trials with bicalutamide 150 mg as a single agent for prostate cancer, gynecomastia and breast pain have been reported in up to 38% and 39% of patients, respectively.

    5.3. Glucose Tolerance

    A reduction in glucose tolerance has been observed in males receiving LHRH agonists. This may manifest as diabetes or loss of glycemic control in those with pre-existing diabetes. Consideration should therefore be given to monitoring blood glucose in patients receiving bicalutamide in combination with LHRH agonists.

    5.4. Laboratory Tests

    Regular assessments of serum Prostate Specific Antigen (PSA) may be helpful in monitoring the patient’s response.

    If PSA levels rise during bicalutamide therapy, the patient should be evaluated for clinical progression. For patients who have objective progression of disease together with an elevated PSA, a treatment-free period of antiandrogen, while continuing the LHRH analog, may be considered.

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  • 6. ADVERSE REACTIONS

    Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

    6.1. Clinical Trials Experience

    In patients with advanced prostate cancer treated with bicalutamide in combination with an LHRH analog, the most frequent adverse reaction was hot flashes (53%).

    In the multicenter, double-blind, controlled clinical trial comparing bicalutamide 50 mg once daily with flutamide 250 mg three times a day, each in combination with an LHRH analog, the following adverse reactions with an incidence of 5% or greater, regardless of causality, have been reported.

    Table 1. Incidence of Adverse Reactions (≥ 5% in Either Treatment Group) Regardless of Causality
    Treatment Group Number of Patients (%)
    Body System Adverse Reaction

    Bicalutamide

    Plus LHRH

    Analog

    (n=401)

    Flutamide

    Plus LHRH

    Analog

    (n=407)
    Body as a Whole
    Pain (General) 142 (35) 127 (31)
    Back Pain 102 (25) 105 (26)
    Asthenia 89 (22) 87 (21)
    Pelvic Pain 85 (21) 70 (17)
    Infection 71 (18) 57 (14)
    Abdominal Pain 46 (11) 46 (11)
    Chest Pain 34 (8) 34 (8)
    Headache 29 (7) 27 (7)
    Flu Syndrome 28 (7) 30 (7)
    Cardiovascular
    Hot Flashes 211 (53) 217 (53)
    Hypertension 34 (8) 29 (7)
    Digestive
    Constipation 87 (22) 69 (17)
    Nausea 62 (15) 58 (14)
    Diarrhea 49 (12) 107 (26)
    Increased Liver Enzyme Test 30 (7) 46 (11)
    Dyspepsia 30 (7) 23 (6)
    Flatulence 26 (6) 22 (5)
    Anorexia 25 (6) 29 (7)
    Vomiting 24 (6) 32 (8)
    Hemic and Lymphatic
    Anemia 45 (11) 53 (13)
    Metabolic and Nutritional
    Peripheral Edema 53 (13) 42 (10)
    Weight Loss 30 (7) 39 (10)
    Hyperglycemia 26 (6) 27 (7)
    Alkaline Phosphatase Increased 22 (5) 24 (6)
    Weight Gain 22 (5) 18 (4)
    Muscoloskeletal
    Bone Pain 37 (9) 43 (11)
    Myasthenia 27 (7) 19 (5)
    Arthritis 21 (5) 29 (7)
    Pathological Fracture 17 (4) 32 (8)
    Nervous System
    Dizziness 41 (10) 35 (9)
    Paresthesia 31 (8) 40 (10)
    Insomnia 27 (7) 39 (10)
    Anxiety 20 (5) 9 (2)
    Depression 16 (4) 33 (8)
    Respiratory System
    Dyspnea 51 (13) 32 (8)
    Cough Increased 33 (8) 24 (6)
    Pharyngitis 32 (8) 23 (6)
    Bronchitis 24 (6) 22 (3)
    Pneumonia 18 (4) 19 (5)
    Rhinitis 15 (4) 22 (5)
    Skin and Appendages
    Rash 35 (9) 30 (7)
    Sweating 25 (6) 20 (5)
    Urogenital
    Nocturia 49 (12) 55 (14)
    Hematuria 48 (12) 26 (6)
    Urinary Tract Infection 35 (9) 36 (9)
    Gynecomastia 36 (9) 30 (7)
    Impotence 27 (7) 35 (9)
    Breast Pain 23 (6) 15 (4)
    Urinary Frequency 23 (6) 29 (7)
    Urinary Retention 20 (5) 14 (3)
    Urinary Impaired 19 (5) 15 (4)
    Urinary Incontinence 15 (4) 32 (8)

    Other adverse reactions (greater than or equal to 2%, but less than 5%) reported in the bicalutamide-LHRH analog treatment group are listed below by body system and are in order of decreasing frequency within each body system regardless of causality.

    Body as a Whole:

    Neoplasm; Neck Pain; Fever; Chills; Sepsis; Hernia; Cyst

    Cardiovascular:

    Angina Pectoris; Congestive Heart Failure; Myocardial Infarct; Heart Arrest; Coronary Artery Disorder; Syncope

    Digestive:

    Melena; Rectal Hemorrhage; Dry Mouth; Dysphagia; Gastrointestinal Disorder; Periodontal Abscess; Gastrointestinal Carcinoma

    Metabolic and Nutritional:

    Edema; BUN Increased; Creatinine Increased; Dehydration; Gout; Hypercholesteremia

    Musculoskeletal:

    Myalgia; Leg Cramps

    Nervous:

    Hypertonia; Confusion; Somnolence; Libido Decreased; Neuropathy; Nervousness

    Respiratory:

    Lung Disorder; Asthma; Epistaxis; Sinusitis

    Skin and Appendages:

    Dry Skin; Alopecia; Pruritus; Herpes Zoster; Skin Carcinoma; Skin Disorder

    Special Senses:

    Cataract specified

    Urogenital:

    Dysuria; Urinary Urgency; Hydronephrosis; Urinary Tract Disorder

    Abnormal Laboratory Test Values:

    Laboratory abnormalities including elevated AST, ALT, bilirubin, BUN, and creatinine and decreased hemoglobin and white cell count have been reported in both bicalutamide-LHRH analog treated and flutamide-LHRH analog treated patients.

    6.2. Postmarketing Experience

    The following adverse reactions have been identified during postapproval use of bicalutamide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

    Uncommon cases of hypersensitivity reactions, including angioneurotic edema and urticaria have been seen [see Contraindications (4.1)]. Cases of interstitial lung disease (some fatal), including interstitial pneumonitis and pulmonary fibrosis, have been reported with bicalutamide. Interstitial lung disease has been reported most often at doses greater than 50 mg. A few cases of fatal hepatic failure have been reported.

    Reduction in glucose tolerance, manifesting as diabetes or a loss of glycemic control in those with pre-existing diabetes, has been reported during treatment with LHRH agonists.

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  • 7. DRUG INTERACTIONS

    Clinical studies have not shown any drug interactions between bicalutamide and LHRH analogs (goserelin or leuprolide). There is no evidence that bicalutamide induces hepatic enzymes.

    In vitro studies have shown that R-bicalutamide is an inhibitor of CYP 3A4 with lesser inhibitory effects on CYP 2C9, 2C19 and 2D6 activity. Clinical studies have shown that with co-administration of bicalutamide, mean midazolam (a CYP 3A4 substrate) levels may be increased 1.5 fold (for Cmax) and 1.9 fold (for AUC). Hence, caution should be exercised when bicalutamide is co-administered with CYP 3A4 substrates.

    In vitro protein-binding studies have shown that bicalutamide can displace coumarin anticoagulants from binding sites. Prothrombin times should be closely monitored in patients already receiving coumarin anticoagulants who are started on bicalutamide and adjustment of the anticoagulant dose may be necessary.

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  • 8. USE IN SPECIFIC POPULATIONS

    8.1. Pregnancy

    PREGNANCY CATEGORY X

    [see Contraindications (4.3)]. Based on its mechanism of action, bicalutamide may cause fetal harm when administered to a pregnant woman. Bicalutamide is contraindicated in women, including those who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

    While there are no human data on the use of bicalutamide in pregnancy and bicalutamide is not for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus.

    In animal reproduction studies, male offspring of rats receiving doses of 10 mg/kg/day (approximately 2/3 of clinical exposure at the recommended dose) and above, were observed to have reduced anogenital distance and hypospadias. These pharmacological effects have been observed with other antiandrogens. No other teratogenic effects were observed in rabbits receiving doses up to 200 mg/kg/day (approximately 1/3 of clinical exposure at the recommended dose) or rats receiving doses up to 250 mg/kg/day (approximately 2 times the clinical exposure at the recommended dose).

    8.3. Nursing Mothers

    Bicalutamide is not indicated for use in women.

    8.4. Pediatric Use

    The safety and effectiveness of bicalutamide in pediatric patients have not been established.

    Bicalutamide orodispersible tablet was studied in combination with anastrozole orodispersible tablet in an open-label, non-comparative, multi-center study that assessed the efficacy and safety of this combination regimen over 12 months in the treatment of gonadotropin-independent precocious puberty in boys with familial male-limited precocious puberty, also known as testotoxicosis. Patients were enrolled in the study if they had a baseline age ≥ 2 years and a diagnosis of testotoxicosis based on clinical features of progressive precocious puberty, symmetrical testicular enlargement, advanced bone age, pubertal levels of serum testosterone, prepubertal pattern of gonadotropin secretion following a GnRH stimulation test, and absence of other clinical and biochemical causes of testosterone excess. Thirteen out of the 14 patients enrolled completed 12 months of combination treatment (one patient was lost to follow-up). If central precocious puberty (CPP) developed an LHRH analog was to be added. Four patients were diagnosed with CPP during the 12-month study and received LHRH analog treatment and 2 additional patients were diagnosed at the end of the 12 months and received treatment subsequently. Mean ± SD characteristics at baseline were as follows: chronological age: 3.9±1.9 years; bone age 8.8±2.5; bone age/chronological age ratio: 2.06 ± 0.51; growth rate (cm/yr): 10.81 ± 4.22; growth rate standard deviation score (SDS): 0.41 ± 1.36.

    The starting bicalutamide dose was 12.5 mg. Bicalutamide was titrated in each patient until steady-state R-bicalutamide (the active isomer of bicalutamide) trough plasma concentration reached 5 to 15 mcg/mL, which is the range of therapeutic concentrations achieved in adults with prostate cancer following the administration of the currently approved bicalutamide dose of 50 mg. The starting daily dose of anastrozole was 0.5 mg. Anastrozole was independently titrated in each patient until it reached at steady-state a serum estradiol concentration of <10 pmol/L (2.7 pg/mL). The following ascending doses were used for bicalutamide: 12.5 mg, 25 mg, 50 mg, and 100 mg. For anastrozole there were two ascending doses: 0.5 mg and 1 mg. At the end of the titration phase 1 patient was on 12.5 mg bicalutamide, 8 patients were on 50 mg bicalutamide, and 4 patients were on 100 mg bicalutamide; 10 patients were on 0.5 mg anastrozole and 3 patients were on 1 mg anastrozole. In the majority of patients, steady-state trough concentrations of R-bicalutamide appeared to be attained by Day 21 with once daily dosing. Steady-state trough plasma anastrozole concentrations appeared to be attained by Day 8.

    The primary efficacy analysis of the study was to assess the change in growth rate after 12 months of treatment, relative to the growth rate during the ≥6 months prior to entering the study. Pre-study growth rates were obtained retrospectively. There was no statistical evidence that the growth rate was reduced during treatment. During bicalutamide /anastrozole treatment the mean growth rate (cm/yr) decreased by 1.6 cm/year, 95% CI (-4.7 to 1.5) p=0.28; the mean growth rate SDS decreased by 0.1 SD, 95% CI (–1.2 to 1.0) p=0.88. Table 2 shows descriptive data for growth rates for the overall population and for subgroups defined by history of previous treatment for testotoxicosis with ketoconazole, spironolactone, anastrozole or other aromatase inhibitors.

    Table 2. Growth rates
    *
    Change compared to pre-study growth rate
    †
    PT = Previous treatment for testotoxicosis with ketoconazole, spironolactone, anastrazole or other aromatase inhibitors
    ‡
    Median calculated as midpoint of 3 rd and 4 th ranked observations
    §
    NPT = no previous treatment for testotoxicosis with ketoconazole, spironolactone, anastrozole or other aromatase inhibitors
    Endpoint Analysis population Pre-study Mean Change from pre-study to 12 months % patients with growth reduction*
    Mean Median (Min, Max)
    Growth rate (cm/yr) All treated (n=13) 10.8 -1.6 -2.8 (-7.4, 8.4) 9/13 (69%)
    PT†
    (n=6)     		10.3 -0.2 -2.6‡ (-7.2, 8.4) 4/6 (67%)
    NPT§
    (n=7)    		 11.2 -2.8 -2.8 (-7.4, 1.1) 5/7 (71%)
    Growth rate
    (SD units)    		 All treated
    (n=13)     		0.4 -0.1 -0.4 (-2.7, 3.5) 9/13 (69%)
    PT†
    (n=6)     		-0.1 +0.7 -0.2‡ (-1.6, 3.5) 4/6 (67%)
    NPT §
    (n=7)    		 0.8 -0.7 -0.4 (-2.7, 0.5) 5/7 (71%)

    Total testosterone concentrations increased by a mean of 5 mmol/L over the 12 months of treatment from a baseline mean of 10 mmol/L. Estradiol concentrations were at or below the level of quantification (9.81 pmol/L) for 11 of 12 patients after 12 months of treatment. Six of the 12 patients started treatment at an estradiol concentration below the level of quantification.

    There were no deaths, serious adverse events, or discontinuations due to adverse events during the study. Of the 14 patients exposed to study treatment, 13 (92.9%) experienced at least one adverse event. The most frequently reported (>3 patients) adverse events were gynecomastia (7/14, 50%), central precocious puberty (6/14, 43%), vomiting (5/14, 36%), headache (3/14, 21%), pyrexia (3/14, 21%) and upper respiratory tract infection (3/14, 21%). Adverse reactions considered possibly related to bicalutamide by investigators included gynecomastia (6/14, 43%), central precocious puberty (2/14, 14%), breast tenderness (2/14, 14%), breast pain (1/14, 7%), asthenia (1/14, 7%), increased alanine aminotransferase [ALT] (1/14, 7%), increased aspartate aminotransferase [AST] (1/14, 7%), and musculoskeletal chest pain (1/14, 7%). Headache was the only adverse reaction considered possibly related to anastrazole by investigators. For the patient who developed elevated ALT and AST, the elevation was <3X ULN, and returned to normal without stopping treatment; there was no concomitant elevation in total bilirubin.

    8.5. Geriatric Use

    In two studies in patients given 50 or 150 mg daily, no significant relationship between age and steady-state levels of total bicalutamide or the active R-enantiomer has been shown.

    8.6. Hepatic Impairment

    Bicalutamide should be used with caution in patients with moderate-to-severe hepatic impairment. Bicalutamide is extensively metabolized by the liver. Limited data in subjects with severe hepatic impairment suggest that excretion of bicalutamide may be delayed and could lead to further accumulation. Periodic liver function tests should be considered for hepatic-impaired patients on long-term therapy [see Warnings and Precautions (5.1)].

    No clinically significant difference in the pharmacokinetics of either enantiomer of bicalutamide was noted in patients with mild-to-moderate hepatic disease as compared to healthy controls. However, the half-life of the R-enantiomer was increased approximately 76% (5.9 and 10.4 days for normal and impaired patients, respectively) in patients with severe liver disease (n=4).

    8.7. Renal Impairment

    Renal impairment (as measured by creatinine clearance) had no significant effect on the elimination of total bicalutamide or the active R-enantiomer.

    8.8. Women

    Bicalutamide has not been studied in women.

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  • 10. OVERDOSAGE

    Long-term clinical trials have been conducted with dosages up to 200 mg of bicalutamide daily and these dosages have been well tolerated. A single dose of bicalutamide that results in symptoms of an overdose considered to be life threatening has not been established.

    There is no specific antidote; treatment of an overdose should be symptomatic.

    In the management of an overdose with bicalutamide, vomiting may be induced if the patient is alert. It should be remembered that, in this patient population, multiple drugs may have been taken. Dialysis is not likely to be helpful since bicalutamide is highly protein bound and is extensively metabolized. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.

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  • 11. DESCRIPTION

    Bicalutamide tablets contain 50 mg of bicalutamide, a non-steroidal androgen receptor inhibitor with no other known endocrine activity. The chemical name is propanamide, N [4 cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-,(+-). The structural and empirical formulas are:

    bicalutamide chemical structure

    C18H14N2O4F4S

    Bicalutamide has a molecular weight of 430.37. The pKa’ is approximately 12. Bicalutamide is a fine white to off-white powder which is practically insoluble in water at 37°C (5 mg per 1000 mL), slightly soluble in chloroform and absolute ethanol, sparingly soluble in methanol, and soluble in acetone and tetrahydrofuran.

    Bicalutamide is a racemate with its antiandrogenic activity being almost exclusively exhibited by the R-enantiomer of bicalutamide; the S-enantiomer is essentially inactive.

    The inactive ingredients of bicalutamide tablets are lactose monohydrate, magnesium stearate, hypromellose E5, polyethylene glycol 400, povidone K30, sodium starch glycolate, and titanium dioxide.

    Bicalutamide tablets 50 mg meets USP Dissolution Test 2.

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  • 12. CLINICAL PHARMACOLOGY

    12.1. Mechanism of Action

    Bicalutamide is a non-steroidal androgen receptor inhibitor. It competitively inhibits the action of androgens by binding to cytosol androgen receptors in the target tissue. Prostatic carcinoma is known to be androgen sensitive and responds to treatment that counteracts the effect of androgen and/or removes the source of androgen.

    When bicalutamide is combined with luteinizing hormone releasing hormone (LHRH) analog therapy, the suppression of serum testosterone induced by the LHRH analog is not affected. However, in clinical trials with bicalutamide as a single agent for prostate cancer, rises in serum testosterone and estradiol have been noted.

    In a subset of patients who have been treated with bicalutamide and an LHRH agonist, and who discontinue bicalutamide therapy due to progressive advanced prostate cancer, a reduction in Prostate Specific Antigen (PSA) and/or clinical improvement (antiandrogen withdrawal phenomenon) may be observed.

    12.3. Pharmacokinetics

    Absorption

    Bicalutamide is well-absorbed following oral administration, although the absolute bioavailability is unknown. Co-administration of bicalutamide with food has no clinically significant effect on rate or extent of absorption.

    Distribution

    Bicalutamide is highly protein-bound (96%) [see Drug Interactions (7)].

    Metabolism/Elimination

    Bicalutamide undergoes stereospecific metabolism. The S (inactive) isomer is metabolized primarily by glucuronidation. The R (active) isomer also undergoes glucuronidation but is predominantly oxidized to an inactive metabolite followed by glucuronidation. Both the parent and metabolite glucuronides are eliminated in the urine and feces. The S-enantiomer is rapidly cleared relative to the R-enantiomer, with the R-enantiomer accounting for about 99% of total steady-state plasma levels.

    Pharmacokinetics of the active enantiomer of bicalutamide in normal males and patients with prostate cancer are presented in Table 3.

    Table 3
    Parameter Mean Standard Deviation
    Normal Males (n=30)
    Apparent Oral Clearance (L/hr) 0.320 0.103
    Single Dose Peak Concentration (μg/mL) 0.768 0.178
    Single Dose Time to Peak Concentration (hours) 31.3 14.6
    Half-life (days) 5.8 2.29
    Patients with Prostate Cancer (n=40)
    Css (μg/mL) 8.939 3.504
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  • 13. NONCLINICAL TOXICOLOGY

    13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility

    Two-year oral carcinogenicity studies were conducted in both male and female rats and mice at doses of 5, 15 or 75 mg/kg/day of bicalutamide. A variety of tumor target organ effects were identified and were attributed to the antiandrogenicity of bicalutamide, namely, testicular benign interstitial (Leydig) cell tumors in male rats at all dose levels (the steady-state plasma concentration with the 5 mg/kg/day dose is approximately 2/3 human therapeutic concentrations1) and uterine adenocarcinoma in female rats at 75 mg/kg/day (approximately 1 1/2 times the human therapeutic concentrations1). There is no evidence of Leydig cell hyperplasia in patients; uterine tumors are not relevant to the indicated patient population.

    A small increase in the incidence of hepatocellular carcinoma in male mice given 75 mg/kg/day of bicalutamide (approximately 4 times human therapeutic concentrations1) and an increased incidence of benign thyroid follicular cell adenomas in rats given 5 mg/kg/day (approximately 2/3 human therapeutic concentrations1) and above were recorded. These neoplastic changes were progressions of non-neoplastic changes related to hepatic enzyme induction observed in animal toxicity studies. Enzyme induction has not been observed following bicalutamide administration in man. There were no tumorigenic effects suggestive of genotoxic carcinogenesis.

    A comprehensive battery of both in vitro and in vivo genotoxicity tests (yeast gene conversion, Ames, E.coli, CHO/HGPRT, human lymphocyte cytogenetic, mouse micronucleus, and rat bone marrow cytogenetic tests) has demonstrated that bicalutamide does not have genotoxic activity.

    Administration of bicalutamide may lead to inhibition of spermatogenesis. The long-term effects of bicalutamide on male fertility have not been studied.

    In male rats dosed at 250 mg/kg/day (approximately 2 times human therapeutic concentrations1), the precoital interval and time to successful mating were increased in the first pairing but no effects on fertility following successful mating were seen. These effects were reversed by 7 weeks after the end of an 11-week period of dosing.

    No effects on female rats dosed at 10, 50 and 250 mg/kg/day (approximately 2/3, 1 and 2 times human therapeutic concentrations, respectively1)) or their female offspring were observed. Administration of bicalutamide to pregnant females resulted in feminization of the male offspring leading to hypospadias at all dose levels. Affected male offspring were also impotent.

    1
    Based on a maximum dose of 50 mg/day of bicalutamide for an average 70 kg patient.
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  • 14. CLINICAL STUDIES

    14.1. Bicalutamide Tablets 50 mg Daily in Combination with an LHRH-A

    In a multicenter, double-blind, controlled clinical trial, 813 patients with previously untreated advanced prostate cancer were randomized to receive bicalutamide 50 mg once daily (404 patients) or flutamide 250 mg (409 patients) three times a day, each in combination with LHRH analogs (either goserelin acetate implant or leuprolide acetate depot).

    In an analysis conducted after a median follow-up of 160 weeks was reached, 213 (52.7%) patients treated with bicalutamide -LHRH analog therapy and 235 (57.5%) patients treated with flutamide-LHRH analog therapy had died. There was no significant difference in survival between treatment groups (see Figure 1). The hazard ratio for time to death (survival) was 0.87 (95% confidence interval 0.72 to 1.05).

    bicalutamide figure 1

    Figure 1 - The Kaplan-Meier probability of death for both antiandrogen treatment groups.

    There was no significant difference in time to objective tumor progression between treatment groups (see Figure 2 ).

    Objective tumor progression was defined as the appearance of any bone metastases or the worsening of any existing bone metastases on bone scan attributable to metastatic disease, or an increase by 25% or more of any existing measurable extraskeletal metastases. The hazard ratio for time to progression of bicalutamide plus LHRH analog to that of flutamide plus LHRH analog was 0.93 (95% confidence interval, 0.79 to 1.10).

    bicalutamide figure 2

    Figure 2 - Kaplan-Meier curve for time to progression for both antiandrogen treatment groups.

    Quality of life was assessed with self-administered patient questionnaires on pain, social functioning, emotional well being, vitality, activity limitation, bed disability, overall health, physical capacity, general symptoms, and treatment related symptoms. Assessment of the Quality of Life questionnaires did not indicate consistent significant differences between the two treatment groups.

    14.2. Safety Data from Clinical Studies using Bicalutamide Tablets 150 mg

    Bicalutamide tablet 150 mg is not approved for use either alone or with other treatments.

    Two identical multicenter, randomized, open-label trials comparing bicalutamide 150 mg daily monotherapy to castration were conducted in patients that had locally advanced (T3-4, NX, MO) or metastatic (M1) prostate cancer.

    Monotherapy – M1 Group

    Bicalutamide 150 mg daily is not approved for use in patients with M1 cancer of the prostate. Based on an interim analysis of the two trials for survival, the Data Safety Monitoring Board recommended that bicalutamide treatment be discontinued in the M1 patients because the risk of death was 25% (HR 1.25, 95% CI 0.87 to 1.81) and 31% (HR 1.31, 95% CI 0.97 to 1.77) higher in the bicalutamide treated group compared to that in the castrated group, respectively.

    Locally Advanced (T3-4, NX, MO) Group

    Bicalutamide 150 mg daily is not approved for use in patients with locally advanced (T3-4, NX, M0) cancer of the prostate. Following discontinuation of all M1 patients, the trials continued with the T3-4, NX, MO patients until study completion. In the larger trial (N=352), the risk of death was 25% (HR 1.25, 95% CI 0.92 to 1.71) higher in the bicalutamide group and in the smaller trial (N=140), the risk of death was 36% (HR 0.64, 95% CI, 0.39 to 1.03) lower in the bicalutamide group.

    In addition to the above two studies, there are three other on-going clinical studies that provide additional safety information for bicalutamide 150 mg, a dose that is not approved for use. These are three multicenter, randomized, double-blind, parallel group trials comparing bicalutamide 150 mg daily monotherapy (adjuvant to previous therapy or under watchful waiting) with placebo, for death or time to disease progression, in a population of 8113 patients with localized or locally advanced prostate cancer.

    Bicalutamide 150 mg daily is not approved for use as therapy for patients with localized prostate cancer who are candidates for watchful waiting. Data from a planned subgroup analysis of two of these trials in 1627 patients with localized prostate cancer who were under watchful waiting, revealed a trend toward decreased survival in the bicalutamide arm after a median follow-up of 7.4 years. There were 294 (37.7%) deaths in the bicalutamide treated patients versus 279 (32.9%) deaths in the placebo treated patients (localized watchful waiting group) for a hazard ratio of 1.16 (95% CI 0.99 to 1.37).

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  • 16. HOW SUPPLIED/STORAGE AND HANDLING

    Bicalutamide tablets 50 mg are white to off-white, round, biconvex, film coated tablets, debossed ‘B 50’ on one side and plain on other side and supplied in bottles of 30 tablets (NDC 16729-023-10) and bottles of 100 tablets (NDC 16729-023-01).

    16.1. Storage and Handling

    “Store at 20 to 25°C (68 to 77°F) [See USP Controlled Room Temperature]”

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  • 17. PATIENT COUNSELING INFORMATION

    Patients should be informed that therapy with bicalutamide and the LHRH analog should be started at the same time and that they should not interrupt or stop taking these medications without consulting their physician.

    During treatment with bicalutamide, somnolence has been reported, and those patients who experience this symptom should observe caution when driving or operating machines.

    Patients should be informed that diabetes, or loss of glycemic control in patients with pre-existing diabetes has been reported during treatment with LHRH agonists. Consideration should therefore be given to monitoring blood glucose in patients receiving bicalutamide in combination with LHRH agonists.

    Manufactured For:
    Accord Healthcare, Inc.,
    1009, Slater Road,
    Suite 210-B, Durham, NC 27703,
    USA.

    Manufactured By:
    Intas Pharmaceuticals Limited,
    Plot No. : 457, 458,
    Village – Matoda,
    Bavla Road, Ta.- Sanand,
    Dist.- Ahmedabad – 382 210.
    India.

    10 1531 4 639197

    Issued June 2012

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  • PATIENT PACKAGE INSERT

    Patient Information

    Bicalutamide Tablets USP

    Read the Patient Information that comes with bicalutamide tablets before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical condition or your treatment.

    What are bicalutamide tablets?

    Bicalutamide is a prescription medicine called an androgen receptor inhibitor, used in combination with lutenizing hormone-releasing hormone (LHRH) medicines to treat stage D2 metatastic prostate cancer. It is not known if bicalutamide is safe and effective in children.

    Who should not take bicalutamide tablets?

    Do not take bicalutamide tablets if:

    • you are a woman.
    • you are allergic to any of the ingredients in bicalutamide tablets. See the end of this leaflet for a complete list of ingredients.

    What should I tell my healthcare provider before taking bicalutamide tablets?

    Before you take bicalutamide tablets, tell your healthcare provider about all your medical conditions including if you:

    • are a woman (see who should not take bicalutamide tablets).
    • are pregnant or think you may be pregnant.
    • have liver problems.
    • take a medicine to thin your blood. Ask your healthcare provider or pharmacist if you are not sure if your medicine is a blood thinner.
    • have diabetes (poor blood sugar control has been reported in people taking bicalutamide in combination with LHRH medicines).

    Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Bicalutamide tablets and other medicines may affect each other causing side effects. Bicalutamide tablets may affect the way other medicines work, and other medicines may affect how bicalutamide tablets works.

    Know the medicines you take. Keep a list of your medicines with you to show your healthcare providers when you get a new medicine.

    How should I take bicalutamide tablets?

    • Take bicalutamide tablets exactly as prescribed.
    • Take bicalutamide tablets at the same time everyday.
    • Your treatment with bicalutamide tablets should start at the same time as your treatment with the LHRH medicine.
    • If you miss a dose do not take an extra dose, take the next dose at your regular time. Do not take 2 doses at the same time.
    • Bicalutamide tablets can be taken with or without food.
    • If you take too much bicalutamide tablets, call your healthcare provider or Poison Control Center or go to the nearest hospital emergency room right away.
    • Do not stop taking bicalutamide tablets unless your healthcare provider tells you.
    • Your healthcare provider may do blood tests while you take bicalutamide tablets.
    • Your prostate cancer may get worse while taking bicalutamide in combination with LHRH medicines. Regular monitoring of your prostate cancer with your healthcare provider is important to determine if your disease is worse.

    What should I avoid while taking bicalutamide tablets?

    Driving and operating machinery. Do not drive, operate machinery, or do other dangerous activities until you know how bicalutamide tablets affect you.

    What are the possible side effects of bicalutamide tablets?

    Bicalutamide tablets can cause serious side effects.

    Get medical help right away, if you have:

    • Trouble breathing with or without a cough or fever. Some people who take bicalutamide tablets get an inflammation in the lungs called interstitial lung disease.
    • An allergic reaction. Symptoms of an allergic reaction include: itching of the skin, hives (raised bumps), swelling of the face, lips, tongue, throat, or trouble swallowing.
    • Yellowing of the skin and eyes (jaundice), dark urine, right upper stomach pain, nausea, vomiting, tiredness, loss of appetite, chills, fever, whole body pain. These may be symptoms of liver damage.
    • Poor blood sugar control can happen in people who take bicalutamide in combination with LHRH medicines.
    • Enlargement of breast (gynecomastia) and breast pain.

    The most common side effects of bicalutamide tablets include:

    • hot flashes, or short periods of feeling warm and sweating
    • whole body pain in your back, pelvis, stomach
    • feeling weak
    • constipation
    • infection
    • nausea
    • swelling in your ankles, legs or feet
    • diarrhea
    • blood in your urine
    • waking from sleep to urinate at night
    • a decrease in red blood cells (anemia)
    • feeling dizzy

    Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

    These are not all the possible side effects of bicalutamide tablets. For more information, ask your healthcare provider or pharmacist.

    Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    HOW SHOULD I STORE BICALUTAMIDE TABLETS?

    Store bicalutamide tablets at 20 to 25°C (68 to 77°F) [See USP Controlled Room Temperature].

    Keep bicalutamide tablets and all medicines out of the reach of children.

    General information about the safe and effective use of bicalutamide tablets.

    Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. Do not use bicalutamide tablets for a condition for which it was not prescribed. Do not give bicalutamide tablets to other people, even if they have the same symptoms that you have. It may harm them.

    This patient information leaflet summarizes the most important information about bicalutamide tablets. If you would like more information about bicalutamide tablets talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about bicalutamide tablets that is written for health professionals.

    What are the ingredients in bicalutamide tablets?

    Active ingredients include: bicalutamide.

    Inactive ingredients include: lactose monohydrate, magnesium stearate, hypromellose E5, polyethylene glycol 400, povidone K 30, sodium starch glycolate, and titanium dioxide.

    Manufactured For:
    Accord Healthcare, Inc.,
    1009, Slater Road,
    Suite 210-B, Durham, NC 27703,
    USA.

    Manufactured By:
    Intas Pharmaceuticals Limited,
    Plot No. : 457, 458,
    Village – Matoda,
    Bavla Road, Ta.- Sanand,
    Dist.- Ahmedabad – 382 210.
    India.

    10 1531 4 639197

    Issued June 2012

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  • PRINCIPAL DISPLAY PANEL

    50 mg Label

    NDC 16729 -023

    Bicalutamide

    Tablets, USP

    50 mg

    Rx Only

    Pharmacist: Dispense with a patient
    package insert.

    30 Tablets

    accord

    Bicalutamide 50 mg Label
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  • INGREDIENTS AND APPEARANCE
    BICALUTAMIDE 
    bicalutamide tablet
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:16729-023
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    BICALUTAMIDE (UNII: A0Z3NAU9DP) (BICALUTAMIDE - UNII:A0Z3NAU9DP) BICALUTAMIDE 50 mg
    Inactive Ingredients
    Ingredient Name Strength
    LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    HYPROMELLOSE 2910 (5 MPA.S) (UNII: R75537T0T4)  
    POLYETHYLENE GLYCOL 400 (UNII: B697894SGQ)  
    POVIDONE K30 (UNII: U725QWY32X)  
    SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    Product Characteristics
    Color WHITE (off-white) Score no score
    Shape ROUND Size 7mm
    Flavor Imprint Code B50
    Contains     
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:16729-023-10 30 in 1 BOTTLE
    2 NDC:16729-023-01 100 in 1 BOTTLE
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    ANDA ANDA078917 07/06/2009
    Labeler - Accord Healthcare Inc (604222237)
    Registrant - Accord Healthcare Inc (604222237)
    Establishment
    Name Address ID/FEI Business Operations
    Intas Pharmaceuticals Limited 725927649 MANUFACTURE(16729-023)
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DailyMed

Label: GILENYA- fingolimod hydrochloride capsule

  • NDC Code(s): 0078-0607-15, 0078-0607-51, 0078-0607-89
  • Packager: Novartis Pharmaceuticals Corporation
  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: New Drug Application

Drug Label Information

Updated 08/15

If you are a consumer or patient please visit this version.

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  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use GILENYA® safely and effectively. See full prescribing information for GILENYA.

    GILENYA (fingolimod) capsules, for oral use
    Initial U.S. Approval: 2010

    RECENT MAJOR CHANGES

    Warnings and Precautions (5.1, 5.4, 5.6, 5.7)

    5/2015

    Warnings and Precautions, Infections (5.2)

    7/2015

    Warnings and Precautions, PML (5.3)

    8/2015

    INDICATIONS AND USAGE

    GILENYA is a sphingosine 1-phosphate receptor modulator indicated for the treatment of patients with relapsing forms of multiple sclerosis (MS) to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability. (1)

    DOSAGE AND ADMINISTRATION

    • Recommended dose: 0.5 mg orally once-daily, with or without food (2)
    • First Dose Monitoring:
      • Observe all patients for bradycardia for at least 6 hours after first dose with hourly pulse and blood pressure measurement. Obtain electrocardiogram (ECG) prior to dosing and at end of observation period.
      • Patients who develop heart rate <45 bpm, 2nd degree or higher atrioventricular (AV) block, or in whom lowest postdose heart rate is at the end of the observation period should be monitored until resolution.
      • If symptomatic bradycardia occurs, begin continuous ECG monitoring until resolved. If pharmacological intervention is required, continue this monitoring overnight, and repeat first-dose monitoring for the second dose.
      • Patients at higher risk of symptomatic bradycardia or heart block, or prolonged QTc interval, or taking drugs with known risk of torsades de pointes should be observed overnight. (2, 7)

    DOSAGE FORMS AND STRENGTHS

    0.5 mg hard capsules (3)

    CONTRAINDICATIONS

    • Recent (within the last 6 months) myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, or Class III/IV heart failure (4)
    • History of Mobitz Type II 2nd degree or 3rd degree AV block or sick sinus syndrome, unless patient has a pacemaker (4)
    • Baseline QTc interval ≥500 msec (4)
    • Treatment with Class Ia or Class III anti-arrhythmic drugs (4)

    WARNINGS AND PRECAUTIONS

    • Bradycardia and/or atrioventricular conduction after first dose: Monitor patients. (2, 5.1)
    • Infections: GILENYA may increase the risk of infections. A recent CBC should be available before initiating treatment. Monitor for infection during treatment and for 2 months after discontinuation. Do not start in patients with active infections. (5.2)
    • Progressive multifocal leukoencephalopathy (PML); Withhold GILENYA at the first sign or symptom suggestive of PML. (5.3)
    • Macular edema: Perform an examination of the fundus including the macula before and 3–4 months after treatment initiation. Patients with diabetes mellitus or a history of uveitis are at increased risk. (5.4)
    • Posterior reversible encephalopathy syndrome (PRES): If suspected, discontinue GILENYA. (5.5)
    • Decrease in pulmonary function tests (PFT): Obtain PFT when clinically indicated. (5.6)
    • Liver injury: liver enzyme results should be available before initiation. Discontinue if significant liver injury occurs. (5.7)
    • Women of childbearing potential should use effective contraception during and for 2 months after stopping GILENYA. (5.8)
    • Blood pressure (BP): Monitor BP during treatment. (5.9)

    ADVERSE REACTIONS

    Most common adverse reactions (incidence ≥10% and > placebo): Headache, liver transaminase elevation, diarrhea, cough, influenza, sinusitis, back pain, abdominal pain, and pain in extremity (6.1)


    To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

    DRUG INTERACTIONS

    • Ketoconazole: Closely monitor during concomitant use with systemic ketoconazole. (7, 12.3)
    • Vaccines: Avoid live attenuated vaccines during, and for 2 months after stopping GILENYA treatment. (5.2, 7)

    USE IN SPECIFIC POPULATIONS

    • Pregnancy: Based on animal data, may cause fetal harm. (8.1)
    • Hepatic impairment: Closely monitor patients with severe hepatic impairment. (5.7, 8.6, 12.3)

    See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

    Revised: 8/2015

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  • FULL PRESCRIBING INFORMATION: CONTENTS*

    1     INDICATIONS AND USAGE

    2     DOSAGE AND ADMINISTRATION

    3     DOSAGE FORMS AND STRENGTHS

    4     CONTRAINDICATIONS

    5     WARNINGS AND PRECAUTIONS

    5.1     Bradyarrhythmia and Atrioventricular Blocks

    5.2     Infections

    5.3     Progressive Multifocal Leukoencephalopathy

    5.4     Macular Edema

    5.5     Posterior Reversible Encephalopathy Syndrome

    5.6     Respiratory Effects

    5.7     Liver Injury

    5.8     Fetal Risk

    5.9     Blood Pressure Effects

    5.10     Immune System Effects Following GILENYA Discontinuation

    6     ADVERSE REACTIONS

    6.1     Clinical Trials Experience

    7     DRUG INTERACTIONS

    8     USE IN SPECIFIC POPULATIONS

    8.1     Pregnancy

    8.2     Labor and Delivery

    8.3     Nursing Mothers

    8.4     Pediatric Use

    8.5     Geriatric Use

    8.6     Hepatic Impairment

    8.7     Renal Impairment

    10     OVERDOSAGE

    11     DESCRIPTION

    12     CLINICAL PHARMACOLOGY

    12.1     Mechanism of Action

    12.2     Pharmacodynamics

    12.3     Pharmacokinetics

    13     NONCLINICAL TOXICOLOGY

    13.1     Carcinogenesis, Mutagenesis, Impairment of Fertility

    13.2     Animal Toxicology and/or Pharmacology

    14     CLINICAL STUDIES

    16     HOW SUPPLIED/STORAGE AND HANDLING

    17     PATIENT COUNSELING INFORMATION

    *
    Sections or subsections omitted from the full prescribing information are not listed.
    Close
  • 1     INDICATIONS AND USAGE

    GILENYA is indicated for the treatment of patients with relapsing forms of multiple sclerosis (MS) to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability.

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  • 2     DOSAGE AND ADMINISTRATION

    Recommended Dose

    The recommended dose of GILENYA is 0.5 mg orally once-daily. Fingolimod doses higher than 0.5 mg are associated with a greater incidence of adverse reactions without additional benefit. GILENYA can be taken with or without food.

    First Dose Monitoring

    Initiation of GILENYA treatment results in a decrease in heart rate [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2)]. After the first dose of GILENYA, the heart rate decrease starts within an hour and the Day 1 nadir generally occurs within approximately 6 hours, although the nadir can be observed up to 24 hours after the first dose in some patients.

    The first dose of GILENYA should be administered in a setting in which resources to appropriately manage symptomatic bradycardia are available. In order to assess patient response to the first dose of fingolimod, observe all patients for 6 hours for signs and symptoms of bradycardia with hourly pulse and blood pressure measurement. Obtain in all patients an electrocardiogram (ECG) prior to dosing, and at the end of the observation period.

    Additional observation should be instituted until the finding has resolved in the following situations:

    • The heart rate 6 hours postdose is <45 bpm
    • The heart rate 6 hours postdose is at the lowest value postdose (suggesting that the maximum pharmacodynamic effect on the heart may not have occurred)
    • The ECG 6 hours postdose shows new onset second degree or higher atrioventricular (AV) block

    Should postdose symptomatic bradycardia occur, initiate appropriate management, begin continuous ECG monitoring, and continue observation until the symptoms have resolved.

    Should a patient require pharmacologic intervention for symptomatic bradycardia, continuous overnight ECG monitoring in a medical facility should be instituted, and the first dose monitoring strategy should be repeated after the second dose of GILENYA.

    Patients with some preexisting conditions (e.g., ischemic heart disease, history of myocardial infarction, congestive heart failure, history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, history of symptomatic bradycardia, history of recurrent syncope, severe untreated sleep apnea, AV block, sinoatrial heart block) may poorly tolerate the GILENYA-induced bradycardia, or experience serious rhythm disturbances after the first dose of GILENYA. Prior to treatment with GILENYA, these patients should have a cardiac evaluation by a physician appropriately trained to conduct such evaluation, and, if treated with GILENYA, should be monitored overnight with continuous ECG in a medical facility after the first dose. GILENYA is contraindicated in patients who in the last 6 months experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization or Class III/IV heart failure [see Contraindications (4)].

    Since initiation of GILENYA treatment results in decreased heart rate and may prolong the QT interval, patients with a prolonged QTc interval (>450 msec males, >470 msec females) before dosing or during 6 hour observation, or at additional risk for QT prolongation (e.g., hypokalemia, hypomagnesemia, congenital long-QT syndrome), or on concurrent therapy with QT prolonging drugs with a known risk of torsades de pointes (e.g., citalopram, chlorpromazine, haloperidol, methadone, erythromycin) should be monitored overnight with continuous ECG in a medical facility [see Drug Interactions (7)].

    Experience with GILENYA is limited in patients receiving concurrent therapy with drugs that slow heart rate or atrioventricular conduction (e.g., beta blockers, heart-rate lowering calcium channel blockers such as diltiazem or verapamil, or digoxin). Because the initiation of GILENYA treatment is also associated with slowing of the heart rate, concomitant use of these drugs during GILENYA initiation may be associated with severe bradycardia or heart block. The possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction should be evaluated by the physician prescribing these drugs before initiating GILENYA. Patients who cannot switch should have overnight continuous ECG monitoring after the first dose [see Drug Interactions (7)].

    Clinical data indicate effects of GILENYA on heart rate are maximal after the first dose although milder effects on heart rate may persist for, on average, 2 to 4 weeks after initiation of therapy at which time heart rate generally returns to baseline. Physicians should continue to be alert to patient reports of cardiac symptoms.

    Reinitiation of Therapy Following Discontinuation

    If GILENYA therapy is discontinued for more than 14 days, after the first month of treatment, the effects on heart rate and AV conduction may recur on reintroduction of GILENYA treatment and the same precautions (first dose monitoring) as for initial dosing should apply. Within the first 2 weeks of treatment, first dose procedures are recommended after interruption of 1 day or more; during weeks 3 and 4 of treatment first dose procedures are recommended after treatment interruption of more than 7 days.

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  • 3     DOSAGE FORMS AND STRENGTHS

    GILENYA is available as 0.5 mg hard capsules with a white opaque body and bright yellow cap imprinted with “FTY 0.5 mg” on the cap and 2 radial bands imprinted on the capsule body with yellow ink.

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  • 4     CONTRAINDICATIONS

    • Patients who in the last 6 months experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization or Class III/IV heart failure
    • History or presence of Mobitz Type II second-degree or third-degree atrioventricular (AV) block or sick sinus syndrome, unless patient has a functioning pacemaker
    • Baseline QTc interval ≥500 msec
    • Treatment with Class Ia or Class III anti-arrhythmic drugs
    Close
  • 5     WARNINGS AND PRECAUTIONS

    5.1     Bradyarrhythmia and Atrioventricular Blocks

    Because of a risk for bradyarrhythmia and atrioventricular (AV) blocks, patients should be monitored during GILENYA treatment initiation [see Dosage and Administration (2)].

    Reduction in Heart Rate

    After the first dose of GILENYA, the heart rate decrease starts within an hour. On Day 1, the maximum decline in heart rate generally occurs within 6 hours and recovers, although not to baseline levels, by 8 to 10 hours postdose. Because of physiological diurnal variation, there is a second period of heart rate decrease within 24 hours after the first dose. In some patients, heart rate decrease during the second period is more pronounced than the decrease observed in the first 6 hours. Heart rates below 40 beats per minute were rarely observed. In controlled clinical trials, adverse reactions of symptomatic bradycardia following the first dose were reported in 0.6% of patients receiving GILENYA 0.5 mg and in 0.1% of patients on placebo. Patients who experienced bradycardia were generally asymptomatic, but some patients experienced hypotension, dizziness, fatigue, palpitations, and/or chest pain that usually resolved within the first 24 hours on treatment.

    Following the second dose, a further decrease in heart rate may occur when compared to the heart rate prior to the second dose, but this change is of a smaller magnitude than that observed following the first dose. With continued dosing, the heart rate returns to baseline within 1 month of chronic treatment.

    Atrioventricular Blocks

    Initiation of GILENYA treatment has resulted in transient AV conduction delays. In controlled clinical trials, first-degree AV block after the first dose occurred in 4.7% of patients receiving GILENYA and 1.6% of patients on placebo. In a study of 697 patients with available 24-hour Holter monitoring data after their first dose (N=351 receiving GILENYA and N=346 on placebo), second-degree AV blocks (Mobitz Types I [Wenckebach] or 2:1 AV blocks) occurred in 4% (N=14) of patients receiving GILENYA and 2% (N=7) of patients on placebo. Of the 14 patients receiving GILENYA, 7 patients had 2:1 AV block (5 patients within the first 6 hours postdose and 2 patients after 6 hours postdose). All second degree AV blocks on placebo were Mobitz Type I and occurred after the first 12 hours postdose. The conduction abnormalities were usually transient and asymptomatic, and resolved within the first 24 hours on treatment, but they occasionally required treatment with atropine or isoproterenol.

    Postmarketing Experience

    In the postmarketing setting, third-degree AV block and AV block with junctional escape have been observed during the first-dose 6-hour observation period with GILENYA. Isolated delayed onset events, including transient asystole and unexplained death, have occurred within 24 hours of the first dose. These events were confounded by concomitant medications and/or preexisting disease, and the relationship to GILENYA is uncertain. Cases of syncope were also reported after the first dose of GILENYA.

    5.2     Infections

    Risk of Infections

    GILENYA causes a dose-dependent reduction in peripheral lymphocyte count to 20%–30% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues. GILENYA may therefore increase the risk of infections, some serious in nature [see Clinical Pharmacology (12.2)].

    Before initiating treatment with GILENYA, a recent CBC (i.e., within 6 months or after discontinuation of prior therapy) should be available. Consider suspending treatment with GILENYA if a patient develops a serious infection, and reassess the benefits and risks prior to reinitiation of therapy. Because the elimination of fingolimod after discontinuation may take up to 2 months, continue monitoring for infections throughout this period. Instruct patients receiving GILENYA to report symptoms of infections to a physician. Patients with active acute or chronic infections should not start treatment until the infection(s) is resolved.

    In MS placebo-controlled trials, the overall rate of infections (72%) with GILENYA was similar to placebo. However, bronchitis, herpes zoster, influenza, sinusitis, and pneumonia were more common in GILENYA-treated patients. Serious infections occurred at a rate of 2.3% in the GILENYA group versus 1.6% in the placebo group.

    Herpes Viral Infections

    In placebo-controlled trials, the rate of herpetic infections was 9% in patients receiving GILENYA 0.5 mg and 7% on placebo.

    Two patients died of herpetic infections during controlled trials. One death was due to disseminated primary herpes zoster and the other to herpes simplex encephalitis. In both cases, the patients were taking a 1.25 mg dose of fingolimod (higher than the recommended 0.5 mg dose) and had received high-dose corticosteroid therapy to treat suspected MS relapses.

    Serious, life-threatening events of disseminated varicella zoster and herpes simplex infections, including cases of encephalitis and multiorgan failure, have occurred with GILENYA 0.5 mg in the postmarketing setting. One of these events was fatal. Include disseminated herpetic infections in the differential diagnosis of patients who are receiving GILENYA and present with an atypical MS relapse or multiorgan failure.

    Cryptococcal infections

    Cryptococcal infections, including cases of cryptococcal meningitis, have been reported with GILENYA in the postmarketing setting. Patients with symptoms and signs consistent with cryptococcal meningitis should undergo prompt diagnostic evaluation and treatment.

    Prior and Concomitant Treatment with Antineoplastic, Immunosuppressive, or Immune-Modulating Therapies

    In clinical studies, patients who received GILENYA did not receive concomitant treatment with antineoplastic, non-corticosteroid immunosuppressive, or immune-modulating therapies used for treatment of MS. Concomitant use of GILENYA with any of these therapies, and also with corticosteroids, would be expected to increase the risk of immunosuppression [see Drug Interactions (7)].

    When switching to GILENYA from immune-modulating or immunosuppressive medications, consider the duration of their effects and their mode of action to avoid unintended additive immunosuppressive effects.

    Varicella Zoster Virus Antibody Testing/Vaccination

    Patients without a healthcare professional confirmed history of chickenpox or without documentation of a full course of vaccination against varicella zoster virus (VZV) should be tested for antibodies to VZV before initiating GILENYA. VZV vaccination of antibody-negative patients is recommended prior to commencing treatment with GILENYA, following which initiation of treatment with GILENYA should be postponed for 1 month to allow the full effect of vaccination to occur.

    5.3     Progressive Multifocal Leukoencephalopathy

    A case of progressive multifocal leukoencephalopathy (PML) and a case of probable PML occurred in patients with MS who received GILENYA in the post marketing setting. PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. One patient developed PML after taking GILENYA for approximately 2.5 years. The other patient developed probable PML after taking GILENYA for approximately 4 years. The diagnosis of probable PML was based on MRI findings and the detection of JCV DNA in the CSF in the absence of clinical signs or symptoms specific to PML. The patients had no other identified systemic medical conditions resulting in compromised immune system function and had not previously been treated with natalizumab, which has a known association with PML. The patients were also not taking any immunosuppressive or immunomodulatory medications concomitantly.

    At the first sign or symptom suggestive of PML, withhold GILENYA and perform an appropriate diagnostic evaluation. MRI signs may be apparent before clinical symptoms. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.

    5.4     Macular Edema

    Fingolimod increases the risk of macular edema. Perform an examination of the fundus including the macula in all patients before starting treatment, again 3–4 months after starting treatment, and again at any time after a patient reports visual disturbances while on GILENYA therapy.

    A dose-dependent increase in the risk of macular edema occurred in the GILENYA clinical development program.

    In 2-year, double-blind, placebo-controlled studies in patients with multiple sclerosis, macular edema with or without visual symptoms occurred in 1.5% of patients (11/799) treated with fingolimod 1.25 mg, 0.5% of patients (4/783) treated with GILENYA 0.5 mg and 0.4% of patients (3/773) treated with placebo. Macular edema occurred predominantly during the first 3 to 4 months of therapy. These clinical trials excluded patients with diabetes mellitus, a known risk factor for macular edema (see below Macular Edema in Patients with History of Uveitis or Diabetes Mellitus). Symptoms of macular edema included blurred vision and decreased visual acuity. Routine ophthalmological examination detected macular edema in some patients with no visual symptoms. Macular edema generally partially or completely resolved with or without treatment after drug discontinuation. Some patients had residual visual acuity loss even after resolution of macular edema. Macular edema has also been reported in patients taking GILENYA 0.5 mg in the postmarketing setting, usually within the first 6 months of treatment.

    Continuation of GILENYA in patients who develop macular edema has not been evaluated. A decision on whether or not to discontinue GILENYA therapy should include an assessment of the potential benefits and risks for the individual patient. The risk of recurrence after rechallenge has not been evaluated.

    Macular Edema in Patients with History of Uveitis or Diabetes Mellitus

    Patients with a history of uveitis and patients with diabetes mellitus are at increased risk of macular edema during GILENYA therapy. The incidence of macular edema is also increased in MS patients with a history of uveitis. In the combined clinical trial experience with all doses of fingolimod, the rate of macular edema was approximately 20% in MS patients with a history of uveitis versus 0.6% in those without a history of uveitis. GILENYA has not been tested in MS patients with diabetes mellitus. In addition to the examination of the fundus including the macula prior to treatment and at 3–4 months after starting treatment, MS patients with diabetes mellitus or a history of uveitis should have regular follow-up examinations.

    5.5     Posterior Reversible Encephalopathy Syndrome

    There have been rare cases of posterior reversible encephalopathy syndrome (PRES) reported in patients receiving GILENYA. Symptoms reported included sudden onset of severe headache, altered mental status, visual disturbances, and seizure. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, GILENYA should be discontinued.

    5.6     Respiratory Effects

    Dose-dependent reductions in forced expiratory volume over 1 second (FEV1) and diffusion lung capacity for carbon monoxide (DLCO) were observed in patients treated with GILENYA as early as 1 month after treatment initiation. In 2-year placebo-controlled trials, the reduction from baseline in the percent of predicted values for FEV1 at the time of last assessment on drug was 2.8% for GILENYA 0.5 mg and 1.0% for placebo. For DLCO, the reduction from baseline in percent of predicted values at the time of last assessment on drug was 3.3% for GILENYA 0.5 mg and 0.5% for placebo. The changes in FEV1 appear to be reversible after treatment discontinuation. There is insufficient information to determine the reversibility of the decrease of DLCO after drug discontinuation. In MS placebo-controlled trials, dyspnea was reported in 9% of patients receiving GILENYA 0.5 mg and 7% of patients receiving placebo. Several patients discontinued GILENYA because of unexplained dyspnea during the extension (uncontrolled) studies. GILENYA has not been tested in MS patients with compromised respiratory function.

    Spirometric evaluation of respiratory function and evaluation of DLCO should be performed during therapy with GILENYA if clinically indicated.

    5.7     Liver Injury

    Elevations of liver enzymes may occur in patients receiving GILENYA. Recent (i.e., within last 6 months) transaminase and bilirubin levels should be available before initiation of GILENYA therapy.

    In 2-year placebo-controlled clinical trials, elevation of liver transaminases to 3-fold the upper limit of normal (ULN) or greater occurred in 14% of patients treated with GILENYA 0.5 mg and 3% of patients on placebo. Elevations 5-fold the ULN or greater occurred in 4.5% of patients on GILENYA and 1% of patients on placebo. The majority of elevations occurred within 6 to 9 months. In clinical trials, GILENYA was discontinued if the elevation exceeded 5 times the ULN. Serum transaminase levels returned to normal within approximately 2 months after discontinuation of GILENYA. Recurrence of liver transaminase elevations occurred with rechallenge in some patients.

    Liver enzymes should be monitored in patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine. GILENYA should be discontinued if significant liver injury is confirmed. Patients with preexisting liver disease may be at increased risk of developing elevated liver enzymes when taking GILENYA.

    Because GILENYA exposure is doubled in patients with severe hepatic impairment, these patients should be closely monitored, as the risk of adverse reactions is greater [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

    5.8     Fetal Risk

    Based on animal studies, GILENYA may cause fetal harm. Because it takes approximately 2 months to eliminate GILENYA from the body, women of childbearing potential should use effective contraception to avoid pregnancy during and for 2 months after stopping GILENYA treatment.

    5.9     Blood Pressure Effects

    In MS controlled clinical trials, patients treated with GILENYA 0.5 mg had an average increase over placebo of approximately 3 mmHg in systolic pressure, and approximately 2 mmHg in diastolic pressure, first detected after approximately 1 month of treatment initiation, and persisting with continued treatment. Hypertension was reported as an adverse reaction in 8% of patients on GILENYA 0.5 mg and in 4% of patients on placebo. Blood pressure should be monitored during treatment with GILENYA.

    5.10     Immune System Effects Following GILENYA Discontinuation

    Fingolimod remains in the blood and has pharmacodynamic effects, including decreased lymphocyte counts, for up to 2 months following the last dose of GILENYA. Lymphocyte counts generally return to the normal range within 1–2 months of stopping therapy [see Clinical Pharmacology (12.2)]. Because of the continuing pharmacodynamic effects of fingolimod, initiating other drugs during this period warrants the same considerations needed for concomitant administration (e.g., risk of additive immunosuppressant effects) [see Drug Interactions (7)].

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  • 6     ADVERSE REACTIONS

    The following serious adverse reactions are described elsewhere in labeling:

    • Bradyarrhythmia and Atrioventricular Blocks [see Warnings and Precautions (5.1)]
    • Infections [see Warnings and Precautions (5.2)]
    • Progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.3)]
    • Macular Edema [see Warnings and Precautions (5.4)]
    • Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.5)]
    • Respiratory Effects [see Warnings and Precautions (5.6)]
    • Liver Injury [see Warnings and Precautions (5.7)]

    6.1     Clinical Trials Experience

    Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

    In clinical trials (Studies 1, 2, and 3), a total of 1212 patients with relapsing forms of multiple sclerosis received GILENYA 0.5 mg. This included 783 patients who received GILENYA 0.5 mg in the 2-year placebo-controlled trials (Studies 1 and 3) and 429 patients who received GILENYA 0.5 mg in the 1 year active-controlled trial (Study 2). The overall exposure in the controlled trials was equivalent to 1716 person-years. Approximately 1000 patients received at least 2 years of treatment with GILENYA 0.5 mg. In all clinical studies, including uncontrolled extension studies, the exposure to GILENYA 0.5 mg was approximately 4119 person-years.

    In placebo-controlled trials, the most frequent adverse reactions (incidence ≥10% and >placebo) for GILENYA 0.5 mg were headache, liver transaminase elevation, diarrhea, cough, influenza, sinusitis, back pain, abdominal pain, and pain in extremity. Adverse events that led to treatment discontinuation and occurred in more than 1% of patients taking GILENYA 0.5 mg were serum transaminase elevations (4.7% compared to 1% on placebo) and basal cell carcinoma (1% compared to 0.5% on placebo).

    Table 1 lists adverse reactions that occurred in ≥ 1% of GILENYA-treated patients and ≥ 1% higher rate than for placebo.

    Table 1 Adverse Reactions Reported in Studies 1 and 3 (Occurring in ≥1% of Patients and Reported for GILENYA 0.5 mg at ≥1% Higher Rate than for Placebo)
    Primary System Organ Class
    Preferred Term

    		GILENYA 0.5 mg
    N=783
    %
    		Placebo
    N=773
    %
    Infections
         Influenza 11 8
          Sinusitis 11 8
          Bronchitis 8 5
          Herpes zoster 2 1
          Tinea versicolor 2 <1
    Cardiac Disorders
          Bradycardia 3 1
    Nervous system disorders
          Headache 25 24
          Migraine 6 4
    Gastrointestinal disorders
          Nausea 13 12
          Diarrhea 13 10
          Abdominal pain 11 10
    General disorders and administration site conditions
          Asthenia 2 1
    Musculoskeletal and connective tissue disorders
          Back pain 10 9
          Pain in extremity 10 7
    Skin and subcutaneous tissue disorders
          Alopecia 3 2
          Actinic keratosis 2 1
    Investigations
          Liver transaminase elevations
          (ALT/GGT/AST)     		15 4
          Blood triglycerides increased 3 1
    Respiratory, thoracic, and mediastinal disorders
          Cough 12 11
          Dyspnea 9 7
    Eye disorders
          Vision blurred 4 2
    Vascular disorders
          Hypertension 8 4
    Blood and lymphatic system disorders
          Lymphopenia 7 <1
          Leukopenia 2 <1
    Neoplasms benign, malignant and unspecified
    (including cysts and polyps)
          Skin papilloma 3 2
          Basal cell carcinoma 2 1

    Adverse reactions of dizziness, pneumonia, eczema and pruritus were also reported in Studies 1 and 3 but did not meet the reporting rate criteria for inclusion in Table 1 (difference was less than 1%).

    Adverse reactions with GILENYA 0.5 mg in Study 2, the 1-year active-controlled (versus interferon beta-1a) study were generally similar to those in Studies 1 and 3.

    Vascular Events

    Vascular events, including ischemic and hemorrhagic strokes, and peripheral arterial occlusive disease were reported in premarketing clinical trials in patients who received GILENYA doses (1.25-5 mg) higher than recommended for use in MS. Similar events have been reported with GILENYA 0.5 mg in the postmarketing setting although a causal relationship has not been established.

    Lymphomas

    Cases of lymphoma have occurred in premarketing clinical trials and in the postmarketing setting. The relationship to GILENYA remains uncertain.

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  • 7     DRUG INTERACTIONS

    QT Prolonging Drugs

    GILENYA has not been studied in patients treated with drugs that prolong the QT interval. Drugs that prolong the QT interval have been associated with cases of torsades de pointes in patients with bradycardia. Since initiation of GILENYA treatment results in decreased heart rate and may prolong the QT interval, patients on QT prolonging drugs with a known risk of torsades de pointes (e.g., citalopram, chlorpromazine, haloperidol, methadone, erythromycin) should be monitored overnight with continuous ECG in a medical facility [see Dosage and Administration (2) and Warnings and Precautions (5.1)].

    Ketoconazole

    The blood levels of fingolimod and fingolimod-phosphate are increased by 1.7-fold when used concomitantly with ketoconazole. Patients who use GILENYA and systemic ketoconazole concomitantly should be closely monitored, as the risk of adverse reactions is greater.

    Vaccines

    GILENYA reduces the immune response to vaccination. Vaccination may be less effective during and for up to 2 months after discontinuation of treatment with GILENYA [see Clinical Pharmacology (12.2)]. Avoid the use of live attenuated vaccines during and for 2 months after treatment with GILENYA because of the risk of infection.

    Antineoplastic, Immunosuppressive, or Immune-Modulating Therapies

    Antineoplastic, immune-modulating, or immunosuppressive therapies, (including corticosteroids) are expected to increase the risk of immunosuppression, and the risk of additive immune system effects must be considered if these therapies are coadministered with GILENYA. When switching from drugs with prolonged immune effects, such as natalizumab, teriflunomide or mitoxantrone, the duration and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects when initiating GILENYA [see Warnings and Precautions (5.2)].

    Drugs That Slow Heart Rate or Atrioventricular Conduction (e.g., beta blockers or diltiazem)

    Experience with GILENYA in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction (e.g., beta blockers, digoxin, or heart rate-slowing calcium channel blockers such as diltiazem or verapamil) is limited. Because initiation of GILENYA treatment may result in an additional decrease in heart rate, concomitant use of these drugs during GILENYA initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating GILENYA. Patients who cannot switch, should have overnight continuous ECG monitoring after the first dose [see Dosage and Administration (2) and Warnings and Precautions (5.1)].

    Laboratory Test Interaction

    Because GILENYA reduces blood lymphocyte counts via redistribution in secondary lymphoid organs, peripheral blood lymphocyte counts cannot be utilized to evaluate the lymphocyte subset status of a patient treated with GILENYA. A recent CBC should be available before initiating treatment with GILENYA.

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  • 8     USE IN SPECIFIC POPULATIONS

    8.1     Pregnancy

    Pregnancy Category C

    There are no adequate and well-controlled studies in pregnant women. In oral studies conducted in rats and rabbits, fingolimod demonstrated developmental toxicity, including teratogenicity (rats) and embryolethality, when given to pregnant animals. In rats, the highest no-effect dose was less than the recommended human dose (RHD) of 0.5 mg/day on a body surface area (mg/m2) basis. The most common fetal visceral malformations in rats included persistent truncus arteriosus and ventricular septal defect. The receptor affected by fingolimod (sphingosine 1-phosphate receptor) is known to be involved in vascular formation during embryogenesis. Because it takes approximately 2 months to eliminate fingolimod from the body, potential risks to the fetus may persist after treatment ends [see Warnings and Precautions (5.8, 5.10)]. GILENYA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

    Pregnancy Registry

    A pregnancy registry has been established to collect information about the effect of GILENYA use during pregnancy. Physicians are encouraged to enroll pregnant patients, or pregnant women may register themselves in the GILENYA pregnancy registry by calling Outcome at 1-877-598-7237, sending an email to gpr@outcome.com or visiting www.gilenyapregnancyregistry.com.

    Animal Data

    When fingolimod was orally administered to pregnant rats during the period of organogenesis (0, 0.03, 0.1, and 0.3 mg/kg/day or 0, 1, 3, and 10 mg/kg/day), increased incidences of fetal malformations and embryo-fetal deaths were observed at all but the lowest dose tested (0.03 mg/kg/day), which is less than the RHD on a mg/m2 basis. Oral administration to pregnant rabbits during organogenesis (0, 0.5, 1.5, and 5 mg/kg/day) resulted in increased incidences of embryo-fetal mortality and fetal growth retardation at the mid and high doses. The no-effect dose for these effects in rabbits (0.5 mg/kg/day) is approximately 20 times the RHD on a mg/m2 basis.

    When fingolimod was orally administered to female rats during pregnancy and lactation (0, 0.05, 0.15, and 0.5 mg/kg/day), pup survival was decreased at all doses and a neurobehavioral (learning) deficit was seen in offspring at the high dose. The low-effect dose of 0.05 mg/kg/day is similar to the RHD on a mg/m2 basis.

    8.2     Labor and Delivery

    The effects of GILENYA on labor and delivery are unknown.

    8.3     Nursing Mothers

    Fingolimod is excreted in the milk of treated rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from GILENYA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

    8.4     Pediatric Use

    The safety and effectiveness of GILENYA in pediatric patients with MS below the age of 18 years have not been established.

    In a study in which fingolimod (0.3, 1.5, or 7.5 mg/kg/day) was orally administered to young rats from weaning through sexual maturity, changes in bone mineral density and persistent neurobehavioral impairment (altered auditory startle) were observed at all doses. Delayed sexual maturation was noted in females at the highest dose tested and in males at all doses. The bone changes observed in fingolimod-treated juvenile rats are consistent with a reported role of S1P in the regulation of bone mineral homeostasis.

    When fingolimod (0.5 or 5 mg/kg/day) was orally administered to rats from the neonatal period through sexual maturity, a marked decrease in T-cell dependent antibody response was observed at both doses. This effect had not fully recovered by 6-8 weeks after the end of treatment.

    8.5     Geriatric Use

    Clinical MS studies of GILENYA did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. GILENYA should be used with caution in patients aged 65 years and over, reflecting the greater frequency of decreased hepatic, or renal, function and of concomitant disease or other drug therapy.

    8.6     Hepatic Impairment

    Because fingolimod, but not fingolimod-phosphate, exposure is doubled in patients with severe hepatic impairment, patients with severe hepatic impairment should be closely monitored, as the risk of adverse reactions may be greater [see Warnings and Precautions (5.7) and Clinical Pharmacology (12.3)].

    No dose adjustment is needed in patients with mild or moderate hepatic impairment.

    8.7     Renal Impairment

    The blood level of some GILENYA metabolites is increased (up to 13-fold) in patients with severe renal impairment [see Clinical Pharmacology (12.3)]. The toxicity of these metabolites has not been fully explored. The blood level of these metabolites has not been assessed in patients with mild or moderate renal impairment.

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  • 10     OVERDOSAGE

    GILENYA can induce bradycardia as well as AV conduction blocks (including complete AV block). The decline in heart rate usually starts within 1 hour of the first dose and is maximal within 6 hours in most patients [see Warnings and Precautions (5.1)]. In case of GILENYA overdosage, observe patients overnight with continuous ECG monitoring in a medical facility, and obtain regular measurements of blood pressure [see Dosage and Administration (2)].

    Neither dialysis nor plasma exchange results in removal of fingolimod from the body.

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  • 11     DESCRIPTION

    Fingolimod is a sphingosine 1-phosphate receptor modulator.

    Chemically, fingolimod is 2-amino-2-[2-(4-octylphenyl)ethyl]propan-1,3-diol hydrochloride. Its structure is shown below:

    Fingolimod chemical structure

    Fingolimod hydrochloride is a white to practically white powder that is freely soluble in water and alcohol and soluble in propylene glycol. It has a molecular weight of 343.93.

    GILENYA is provided as 0.5 mg hard gelatin capsules for oral use. Each capsule contains 0.56 mg of fingolimod hydrochloride, equivalent to 0.5 mg of fingolimod.

    Each GILENYA 0.5 mg capsule contains the following inactive ingredients: gelatin, magnesium stearate, mannitol, titanium dioxide, yellow iron oxide.

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  • 12     CLINICAL PHARMACOLOGY

    12.1     Mechanism of Action

    Fingolimod is metabolized by sphingosine kinase to the active metabolite, fingolimod-phosphate. Fingolimod-phosphate is a sphingosine 1-phosphate receptor modulator, and binds with high affinity to sphingosine 1-phosphate receptors 1, 3, 4, and 5. Fingolimod-phosphate blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which fingolimod exerts therapeutic effects in multiple sclerosis is unknown, but may involve reduction of lymphocyte migration into the central nervous system.

    12.2     Pharmacodynamics

    Heart Rate and Rhythm

    Fingolimod causes a transient reduction in heart rate and AV conduction at treatment initiation [see Warnings and Precautions (5.1)].

    Heart rate progressively increases after the first day, returning to baseline values within 1 month of the start of chronic treatment.

    Autonomic responses of the heart, including diurnal variation of heart rate and response to exercise, are not affected by fingolimod treatment.

    Fingolimod treatment is not associated with a decrease in cardiac output.

    Potential to Prolong the QT Interval

    In a thorough QT interval study of doses of 1.25 or 2.5 mg fingolimod at steady-state, when a negative chronotropic effect of fingolimod was still present, fingolimod treatment resulted in a prolongation of QTc, with the upper boundary of the 90% confidence interval (CI) of 14.0 msec. There is no consistent signal of increased incidence of QTc outliers, either absolute or change from baseline, associated with fingolimod treatment. In MS studies, there was no clinically relevant prolongation of the QT interval, but patients at risk for QT prolongation were not included in clinical studies.

    Immune System

    Effects on Immune Cell Numbers in the Blood

    In a study in which 12 subjects received GILENYA 0.5 mg daily, the lymphocyte count decreased to approximately 60% of baseline within 4 to 6 hours after the first dose. With continued daily dosing, the lymphocyte count continued to decrease over a 2-week period, reaching a nadir count of approximately 500 cells/mcL or approximately 30% of baseline. In a placebo-controlled study in 1272 MS patients (of whom 425 received fingolimod 0.5 mg daily and 418 received placebo), 18% (N=78) of patients on fingolimod 0.5 mg reached a nadir of <200 cells/mcL on at least 1 occasion. No patient on placebo reached a nadir of <200 cells/mcL. Low lymphocyte counts are maintained with chronic daily dosing of GILENYA 0.5 mg daily.

    Chronic fingolimod dosing leads to a mild decrease in the neutrophil count to approximately 80% of baseline. Monocytes are unaffected by fingolimod.

    Peripheral lymphocyte count increases are evident within days of stopping fingolimod treatment and typically normal counts are reached within 1 to 2 months.

    Effect on Antibody Response

    GILENYA reduces the immune response to vaccination, as evaluated in 2 studies.

    In the first study, the immunogenicity of keyhole limpet hemocyanin (KLH) and pneumococcal polysaccharide vaccine (PPV-23) immunization were assessed by IgM and IgG titers in a steady-state, randomized, placebo-controlled study in healthy volunteers. Compared to placebo, antigen-specific IgM titers were decreased by 91% and 25% in response to KLH and PPV-23, respectively, in subjects on GILENYA 0.5 mg. Similarly, IgG titers were decreased by 45% and 50%, in response to KLH and PPV-23, respectively, in subjects on GILENYA 0.5 mg daily compared to placebo. The responder rate for GILENYA 0.5 mg as measured by the number of subjects with a >4-fold increase in KLH IgG was comparable to placebo and 25% lower for PPV-23 IgG, while the number of subjects with a >4 fold increase in KLH and PPV-23 IgM was 75% and 40% lower, respectively, compared to placebo. The capacity to mount a skin delayed-type hypersensitivity reaction to Candida and tetanus toxoid was decreased by approximately 30% in subjects on GILENYA 0.5 mg daily, compared to placebo. Immunologic responses were further decreased with fingolimod 1.25 mg (a dose higher than recommended in MS) [see Warnings and Precautions (5.2)].

    In the second study, the immunogenicity of Northern hemisphere seasonal influenza and tetanus toxoid vaccination was assessed in a 12-week steady-state, randomized, placebo-controlled study of GILENYA 0.5 mg in multiple sclerosis patients (n=136). The responder rate 3 weeks after vaccination, defined as seroconversion or a ≥4-fold increase in antibody directed against at least 1 of the 3 influenza strains, was 54% for GILENYA 0.5 mg and 85% in the placebo group. The responder rate 3 weeks after vaccination, defined as seroconversion or a ≥4-fold increase in antibody directed against tetanus toxoid was 40% for GILENYA 0.5 mg and 61% in the placebo group.

    Pulmonary Function

    Single fingolimod doses ≥5 mg (10-fold the recommended dose) are associated with a dose-dependent increase in airway resistance. In a 14-day study of 0.5, 1.25, or 5 mg/day, fingolimod was not associated with impaired oxygenation or oxygen desaturation with exercise or an increase in airway responsiveness to methacholine. Subjects on fingolimod treatment had a normal bronchodilator response to inhaled beta-agonists.

    In a 14-day placebo-controlled study of patients with moderate asthma, no effect was seen for GILENYA 0.5 mg (recommended dose in MS). A 10% reduction in mean FEV1 at 6 hours after dosing was observed in patients receiving fingolimod 1.25 mg (a dose higher than recommended for use in MS) on Day 10 of treatment. Fingolimod 1.25 mg was associated with a 5-fold increase in the use of rescue short acting beta-agonists.

    12.3     Pharmacokinetics

    Absorption

    The Tmax of fingolimod is 12-16 hours. The apparent absolute oral bioavailability is 93%.

    Food intake does not alter Cmax or exposure (AUC) of fingolimod or fingolimod-phosphate. Therefore GILENYA may be taken without regard to meals.

    Steady-state blood concentrations are reached within 1 to 2 months following once-daily administration and steady-state levels are approximately 10-fold greater than with the initial dose.

    Distribution

    Fingolimod highly (86%) distributes in red blood cells. Fingolimod-phosphate has a smaller uptake in blood cells of <17%. Fingolimod and fingolimod-phosphate are >99.7% protein bound. Fingolimod and fingolimod-phosphate protein binding is not altered by renal or hepatic impairment.

    Fingolimod is extensively distributed to body tissues with a volume of distribution of about 1200±260 L.

    Metabolism

    The biotransformation of fingolimod in humans occurs by 3 main pathways: by reversible stereoselective phosphorylation to the pharmacologically active (S)-enantiomer of fingolimod-phosphate, by oxidative biotransformation catalyzed mainly by the cytochrome P450 4F2 (CYP4F2) and possibly other CYP4F isoenzymes with subsequent fatty acid-like degradation to inactive metabolites, and by formation of pharmacologically inactive non-polar ceramide analogs of fingolimod.

    Inhibitors or inducers of CYP4F2 and possibly other CYP4F isozymes might alter the exposure of fingolimod or fingolimod-phosphate. In vitro studies in hepatocytes indicated that CYP3A4 may contribute to fingolimod metabolism in the case of strong induction of CYP3A4.

    Following single oral administration of [14C] fingolimod, the major fingolimod-related components in blood, as judged from their contribution to the AUC up to 816 hours post-dose of total radiolabeled components, are fingolimod itself (23.3%), fingolimod-phosphate (10.3%), and inactive metabolites [M3 carboxylic acid metabolite (8.3%), M29 ceramide metabolite (8.9%), and M30 ceramide metabolite (7.3%)].

    Elimination

    Fingolimod blood clearance is 6.3±2.3 L/h, and the average apparent terminal half-life (t1/2) is 6 to 9 days. Blood levels of fingolimod-phosphate decline in parallel with those of fingolimod in the terminal phase, yielding similar half-lives for both.

    After oral administration, about 81% of the dose is slowly excreted in the urine as inactive metabolites. Fingolimod and fingolimod-phosphate are not excreted intact in urine but are the major components in the feces with amounts of each representing less than 2.5% of the dose.

    Specific Populations

    Geriatric Patients

    The mechanism for elimination and results from population pharmacokinetics suggest that dose adjustment would not be necessary in elderly patients. However, clinical experience in patients aged above 65 years is limited.

    Gender

    Gender has no clinically significant influence on fingolimod and fingolimod-phosphate pharmacokinetics.

    Race

    The effects of race on fingolimod and fingolimod-phosphate pharmacokinetics cannot be adequately assessed due to a low number of non-white patients in the clinical program.

    Renal Impairment

    In patients with severe renal impairment, fingolimod Cmax and AUC are increased by 32% and 43%, respectively, and fingolimod-phosphate Cmax and AUC are increased by 25% and 14%, respectively, with no change in apparent elimination half-life. Based on these findings, the GILENYA 0.5 mg dose is appropriate for use in patients with renal impairment. The systemic exposure of 2 metabolites (M2 and M3) is increased by 3- and 13-fold, respectively. The toxicity of these metabolites has not been fully characterized.

    A study in patients with mild or moderate renal impairment has not been conducted. 

    Hepatic Impairment

    In subjects with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, and C), no change in fingolimod Cmax was observed, but fingolimod AUC0-∞ was increased respectively by 12%, 44%, and 103%. In patients with severe hepatic impairment (Child-Pugh class C), fingolimod-phosphate Cmax was decreased by 22% and AUC0-96 hours was decreased by 29%. The pharmacokinetics of fingolimod-phosphate was not evaluated in patients with mild or moderate hepatic impairment. The apparent elimination half-life of fingolimod is unchanged in subjects with mild hepatic impairment, but is prolonged by about 50% in patients with moderate or severe hepatic impairment.

    Patients with severe hepatic impairment (Child-Pugh class C) should be closely monitored, as the risk of adverse reactions is greater [see Warnings and Precautions (5.7)].

    No dose adjustment is needed in patients with mild or moderate hepatic impairment (Child-Pugh class A and B).

    Drug Interactions

    Ketoconazole

    The coadministration of ketoconazole (a potent inhibitor of CYP3A and CYP4F) 200 mg twice-daily at steady-state and a single dose of fingolimod 5 mg led to a 70% increase in AUC of fingolimod and fingolimod-phosphate. Patients who use GILENYA and systemic ketoconazole concomitantly should be closely monitored, as the risk of adverse reactions is greater [see Drug Interactions (7)].

    Carbamazepine

    The coadministration of carbamazepine (a potent CYP450 enzyme inducer) 600 mg twice-daily at steady-state and a single dose of fingolimod 2 mg decreased blood concentrations (AUC) of fingolimod and fingolimod-phosphate by approximately 40%. The clinical impact of this decrease is unknown.

    Other strong CYP450 enzyme inducers, e.g., rifampicin, phenytoin, phenobarbital, and St. John’s wort, may also reduce AUC of fingolimod and fingolimod-phosphate. The clinical impact of this potential decrease is unknown.

    Potential of Fingolimod and Fingolimod-phosphate to Inhibit the Metabolism of Comedications

    In vitro inhibition studies using pooled human liver microsomes and specific metabolic probe substrates demonstrate that fingolimod has little or no capacity to inhibit the activity of the following CYP enzymes: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, or CYP4A9/11 (fingolimod only), and similarly fingolimod-phosphate has little or no capacity to inhibit the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 at concentrations up to 3 orders of magnitude of therapeutic concentrations. Therefore, fingolimod and fingolimod-phosphate are unlikely to reduce the clearance of drugs that are mainly cleared through metabolism by the major CYP isoenzymes described above.

    Potential of Fingolimod and Fingolimod-phosphate to Induce its Own and/or the Metabolism of Comedications

    Fingolimod was examined for its potential to induce human CYP3A4, CYP1A2, CYP4F2, and MDR1 (P-glycoprotein) mRNA and CYP3A, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP4F2 activity in primary human hepatocytes. Fingolimod did not induce mRNA or activity of the different CYP enzymes and MDR1 with respect to the vehicle control; therefore, no clinically relevant induction of the tested CYP enzymes or MDR1 by fingolimod are expected at therapeutic concentrations. Fingolimod-phosphate was also examined for its potential to induce mRNA and/or activity of human CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A, CYP4F2, CYP4F3B, and CYP4F12. Fingolimod-phosphate is not expected to have clinically significant induction effects on these enzymes at therapeutic dose of fingolimod. In vitro experiments did not provide an indication of CYP induction by fingolimod-phosphate.

    Transporters

    Based on in vitro data, fingolimod as well as fingolimod-phosphate are not expected to inhibit the uptake of comedications and/or biologics transported by the organic anion transporting polypeptides OATP1B1, OATP1B3, or the sodium taurocholate co-transporting polypeptide (NTCP). Similarly, they are not expected to inhibit the efflux of comedications and/or biologics transported by the breast cancer resistance protein (BCRP), the bile salt export pump (BSEP), the multidrug resistance-associated protein 2 (MRP2), or P-glycoprotein (P-gp) at therapeutic concentrations.

    Oral Contraceptives

    The coadministration of fingolimod 0.5 mg daily with oral contraceptives (ethinylestradiol and levonorgestrel) did not elicit any clinically significant change in oral contraceptives exposure. Fingolimod and fingolimod-phosphate exposure were consistent with those from previous studies. No interaction studies have been performed with oral contraceptives containing other progestagens; however, an effect of fingolimod on their exposure is not expected.

    Cyclosporine

    The pharmacokinetics of single-dose fingolimod was not altered during coadministration with cyclosporine at steady-state, nor was cyclosporine steady-state pharmacokinetics altered by fingolimod. These data indicate that GILENYA is unlikely to reduce or increase the clearance of drugs cleared mainly by CYP3A4. Potent inhibition of transporters MDR1 (P-gp), MRP2, and OATP-1B1 does not influence fingolimod disposition.

    Isoproterenol, Atropine, Atenolol, and Diltiazem

    Single-dose fingolimod and fingolimod-phosphate exposure was not altered by coadministered isoproterenol or atropine. Likewise, the single-dose pharmacokinetics of fingolimod and fingolimod-phosphate and the steady-state pharmacokinetics of both atenolol and diltiazem were unchanged during the coadministration of the latter 2 drugs individually with fingolimod.

    Population Pharmacokinetics Analysis

    A population pharmacokinetics evaluation performed in MS patients did not provide evidence for a significant effect of fluoxetine and paroxetine (strong CYP2D6 inhibitors) on fingolimod or fingolimod-phosphate predose concentrations. In addition, the following commonly coprescribed substances had no clinically relevant effect (<20%) on fingolimod or fingolimod-phosphate predose concentrations: baclofen, gabapentin, oxybutynin, amantadine, modafinil, amitriptyline, pregabalin, and corticosteroids.

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  • 13     NONCLINICAL TOXICOLOGY

    13.1     Carcinogenesis, Mutagenesis, Impairment of Fertility

    Oral carcinogenicity studies of fingolimod were conducted in mice and rats. In mice, fingolimod was administered at oral doses of 0, 0.025, 0.25, and 2.5 mg/kg/day for up to 2 years. The incidence of malignant lymphoma was increased in males and females at the mid and high dose. The lowest dose tested (0.025 mg/kg/day) is less than the recommended human dose (RHD) of 0.5 mg/day on a body surface area (mg/m2) basis. In rats, fingolimod was administered at oral doses of 0, 0.05, 0.15, 0.5, and 2.5 mg/kg/day. No increase in tumors was observed. The highest dose tested (2.5 mg/kg/day) is approximately 50 times the RHD on a mg/m2 basis.

    Fingolimod was negative in a battery of in vitro (Ames, mouse lymphoma thymidine kinase, chromosomal aberration in mammalian cells) and in vivo (micronucleus in mouse and rat) assays.

    When fingolimod was administered orally (0, 1, 3, and 10 mg/kg/day) to male and female rats prior to and during mating, and continuing to Day 7 of gestation in females, no effect on fertility was observed up to the highest dose tested (10 mg/kg), which is approximately 200 times the RHD on a mg/m2 basis.

    13.2     Animal Toxicology and/or Pharmacology

    Lung toxicity was observed in 2 different strains of rats and in dogs and monkeys. The primary findings included increase in lung weight, associated with smooth muscle hypertrophy, hyperdistension of the alveoli, and/or increased collagen. Insufficient or lack of pulmonary collapse at necropsy, generally correlated with microscopic changes, was observed in all species. In rats and monkeys, lung toxicity was observed at all oral doses tested in chronic studies. The lowest doses tested in rats (0.05 mg/kg/day in the 2-year carcinogenicity study) and monkeys (0.5 mg/kg/day in the 39-week toxicity study) are similar to and approximately 20 times the RHD on a mg/m2 basis, respectively.

    In the 52-week oral study in monkeys, respiratory distress associated with ketamine administration was observed at doses of 3 and 10 mg/kg/day; the most affected animal became hypoxic and required oxygenation. As ketamine is not generally associated with respiratory depression, this effect was attributed to fingolimod. In a subsequent study in rats, ketamine was shown to potentiate the bronchoconstrictive effects of fingolimod. The relevance of these findings to humans is unknown.

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  • 14     CLINICAL STUDIES

    The efficacy of GILENYA was demonstrated in 2 studies that evaluated once-daily doses of GILENYA 0.5 mg and 1.25 mg in patients with relapsing-remitting MS (RRMS). Both studies included patients who had experienced at least 2 clinical relapses during the 2 years prior to randomization or at least 1 clinical relapse during the 1 year prior to randomization, and had an Expanded Disability Status Scale (EDSS) score from 0 to 5.5. Study 1 was a 2-year randomized, double-blind, placebo-controlled study in patients with RRMS who had not received any interferon-beta or glatiramer acetate for at least the previous 3 months and had not received any natalizumab for at least the previous 6 months. Neurological evaluations were performed at screening, every 3 months and at time of suspected relapse. MRI evaluations were performed at screening, Month 6, Month 12, and Month 24. The primary endpoint was the annualized relapse rate.

    Median age was 37 years, median disease duration was 6.7 years and median EDSS score at baseline was 2.0. Patients were randomized to receive GILENYA 0.5 mg (N=425), 1.25 mg (N=429), or placebo (N=418) for up to 24 months. Median time on study drug was 717 days on 0.5 mg, 715 days on 1.25 mg and 719 days on placebo.

    The annualized relapse rate was significantly lower in patients treated with GILENYA than in patients who received placebo. The secondary endpoint was the time to 3-month confirmed disability progression as measured by at least a 1-point increase from baseline in EDSS (0.5 point increase for patients with baseline EDSS of 5.5) sustained for 3 months. Time to onset of 3-month confirmed disability progression was significantly delayed with GILENYA treatment compared to placebo. The 1.25 mg dose resulted in no additional benefit over the GILENYA 0.5 mg dose. The results for this study are shown in Table 2 and Figure 1.

    Table 2 Clinical and MRI Results of Study 1
    All analyses of clinical endpoints were intent-to–treat. MRI analysis used evaluable dataset.
    ‡Hazard ratio is an estimate of the relative risk of having the event of disability progression on GILENYA as compared to placebo.
    GILENYA 0.5 mg N=425 Placebo N=418 p-value
    Clinical Endpoints
    Annualized relapse rate (primary endpoint) 0.18 0.40 <0.001
    Percentage of patients without relapse 70% 46% <0.001
    Hazard ratio‡ of disability progression
          (95% CI)    		 0.70
    (0.52, 0.96)    		 0.02
    MRI Endpoint
    Mean (median) number of new or newly enlarging T2 lesions over 24 months 2.5 (0) 9.8 (5.0) <0.001
    Mean (median) number of T1 Gd-enhancing lesions at Month 24 0.2 (0) 1.1 (0) <0.001
    Figure 1 Time to 3-month Confirmed Disability Progression – Study 1 (ITT population)

    Figure 1 Time to 3-Month Confirmed Disability Progression – Study 1 (ITT population)

    Study 2 was a 1-year randomized, double-blind, double-dummy, active-controlled study in patients with RRMS who had not received any natalizumab in the previous 6 months. Prior therapy with interferon-beta or glatiramer acetate up to the time of randomization was permitted.

    Neurological evaluations were performed at screening, every 3 months, and at the time of suspected relapses. MRI evaluations were performed at screening and at month 12. The primary endpoint was the annualized relapse rate.

    Median age was 36 years, median disease duration was 5.9 years, and median EDSS score at baseline was 2.0. Patients were randomized to receive GILENYA 0.5 mg (N=431), 1.25 mg (N=426), or interferon beta-1a, 30 mcg via the intramuscular route (IM) once-weekly (N=435) for up to 12 months. Median time on study drug was 365 days on GILENYA 0.5 mg, 354 days on 1.25 mg, and 361 days on interferon beta-1a IM.

    The annualized relapse rate was significantly lower in patients treated with GILENYA 0.5 mg than in patients who received interferon beta-1a IM. The key secondary endpoints were number of new and newly enlarging T2 lesions and time to onset of 3-month confirmed disability progression as measured by at least a 1-point increase from baseline in EDSS (0.5 point increase for those with baseline EDSS of 5.5) sustained for 3 months. The number of new and newly enlarging T2 lesions was significantly lower in patients treated with GILENYA than in patients who received interferon beta-1a IM. There was no significant difference in the time to 3-month confirmed disability progression between GILENYA and interferon beta-1a-treated patients at 1 year. The 1.25 mg dose resulted in no additional benefit over the GILENYA 0.5 mg dose. The results for this study are shown in Table 3.

    Table 3 Clinical and MRI Results of Study 2
    All analyses of clinical endpoints were intent-to-treat. MRI analysis used evaluable dataset.
    ‡ Hazard ratio is an estimate of the relative risk of having the event of disability progression on GILENYA as compared to control.
    GILENYA 0.5 mg N=429 Interferon beta-1a IM 30 mcg N=431 p-value
    Clinical Endpoints
    Annualized relapse rate (primary endpoint) 0.16 0.33 <0.001
    Percentage of patients without relapse 83% 70% <0.001
    Hazard ratio‡ of disability progression
          (95% CI)    		 0.71
    (0.42, 1.21)    		 0.21
    MRI Endpoint
    Mean (median) number of new or newly enlarging T2 lesions over 12 months 1.6 (0) 2.6 (1.0) 0.002
    Mean (median) number of T1 Gd-enhancing lesions at Month 12 0.2 (0) 0.5 (0) <0.001

    Pooled results of study 1 and study 2 showed a consistent and statistically significant reduction of annualized relapse rate compared to comparator in subgroups defined by gender, age, prior MS therapy, and disease activity.

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  • 16     HOW SUPPLIED/STORAGE AND HANDLING

    0.5 mg GILENYA capsules are hard gelatin capsules with a white opaque body and bright yellow cap imprinted with “FTY 0.5 mg” on the cap and 2 radial bands imprinted on the capsule body with yellow ink.

    GILENYA capsules are supplied as follows:

    Bottle of 30 capsules            NDC 0078-0607-15

    Carton of 7 capsules containing 1 blister card of 7 capsules per blister card                   NDC 0078-0607-89

    GILENYA capsules should be stored at 25ºC (77ºF); excursions permitted to 15ºC–30ºC (59ºF–86ºF). Protect from moisture.

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  • 17     PATIENT COUNSELING INFORMATION

    Advise the patient to read the FDA-approved patient labeling (Medication Guide).

    Tell patients not to discontinue GILENYA without first discussing this with the prescribing physician. Advise patients to contact their physician if they accidently take more GILENYA than prescribed.

    Cardiac Effects

    Advise patients that initiation of GILENYA treatment results in a transient decrease in heart rate. Inform patients that they will need to be observed in the doctor's office or other facility for at least 6 hours after the first dose. Advise patients that if GILENYA is discontinued for more than 14 days, effects similar to those observed on treatment initiation may be seen and observation for at least 6 hours will be needed on treatment reinitiation, and that the same precautions will be taken if treatment is interrupted for more than 1 day within the first 2 weeks of treatment, or for more than 7 days during week 3 and 4 of treatment.

    Risk of Infections

    Inform patients that they may be more likely to get infections when taking GILENYA, and that they should contact their physician if they develop symptoms of infection. Advise patients that the use of some vaccines should be avoided during treatment with GILENYA and for 2 months after discontinuation. Recommend to patients that they delay treatment with GILENYA until after VZV vaccination if they have not had chickenpox or a previous VZV vaccination. Inform patients that prior or concomitant use of drugs that suppress the immune system may increase the risk of infection.

    Progressive Multifocal Leukoencephalopathy

    Inform patients that a case of progressive multifocal leukoencephalopathy (PML) and a case of probable PML have occurred in patients who received GILENYA. Inform the patient that PML is characterized by a progression of deficits and usually leads to death or severe disability over weeks or months. Instruct the patient of the importance of contacting their doctor if they develop any symptoms suggestive of PML. Inform the patient that typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes [see Warnings and Precautions (5.3)].

    Macular Edema

    Advise patients that GILENYA may cause macular edema, and that they should contact their physician if they experience any changes in their vision. Inform patients with diabetes mellitus or a history of uveitis that their risk of macular edema is increased.

    Respiratory Effects

    Advise patients that they should contact their physician if they experience new onset or worsening of dyspnea.

    Hepatic Effects

    Inform patients that GILENYA may increase liver enzymes. Advise patients that they should contact their physician if they have any unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine.

    Fetal Risk

    Inform patients that, based on animal studies, GILENYA may cause fetal harm. Discuss with women of childbearing age whether they are pregnant, might be pregnant or are trying to become pregnant. Advise women of childbearing age of the need for effective contraception during GILENYA treatment and for 2 months after stopping GILENYA. Advise the patient that if she should nevertheless become pregnant, she should immediately inform her physician.

    Persistence of GILENYA Effects after Drug Discontinuation

    Advise patients that GILENYA remains in the blood and continues to have effects, including decreased blood lymphocyte counts, for up to 2 months following the last dose.

    T2015-127
    August 2015

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  • MEDICATION GUIDE

    GILENYA® (je-LEN-yah)
    (fingolimod)
    capsules

    Read this Medication Guide before you start using GILENYA and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your health problem or treatment.

    What is the most important information I should know about GILENYA?

    GILENYA may cause serious side effects, including:

    1.  Slow heart rate (bradycardia or bradyarrhythmia) when you start taking GILENYA. GILENYA can cause your heart rate to slow down, especially after you take your first dose. You will have a test to check the electrical activity of your heart (ECG) before you take your first dose of GILENYA.

    You will be observed by a healthcare professional for at least 6 hours after you take your first dose of GILENYA.

    After you take your first dose of GILENYA:

    • Your pulse and blood pressure should be checked every hour.
    • You should be observed by a healthcare professional to see if you have any serious side effects. If your heart rate slows down too much, you may have symptoms such as:
      • dizziness
      • tiredness
      • feeling like your heart is beating slowly or skipping beats
    • If you have any of the symptoms of slow heart rate, they will usually happen during the first 6 hours after your first dose of GILENYA. Symptoms can happen up to 24 hours after you take your first GILENYA dose.
    • 6 hours after you take your first dose of GILENYA you will have another ECG. If your ECG shows any heart problems or if your heart rate is still too low or continues to decrease, you will continue to be observed.
    • If you have any serious side effects after your first dose of GILENYA, especially those that require treatment with other medicines, you will stay in the medical facility to be observed overnight. You will also be observed for any serious side effects for at least 6 hours after you take your second dose of GILENYA the next day.
    • If you have certain types of heart problems, or if you are taking certain types of medicines that can affect your heart, you will be observed overnight after you take your first dose of GILENYA.

    Your slow heart rate will usually return to normal within 1 month after you start taking GILENYA. Call your doctor or go to the nearest hospital emergency room right away if you have any symptoms of a slow heart rate.

    If you miss 1 or more doses of GILENYA you may need to be observed by a healthcare professional when you take your next dose. Call your doctor if you miss a dose of GILENYA. See “How should I take GILENYA?”

    2.  Infections. GILENYA can increase your risk of serious infections and decrease the way vaccines work in your body to prevent certain diseases, especially the chicken pox vaccine. GILENYA lowers the number of white blood cells (lymphocytes) in your blood. This will usually go back to normal within 2 months of stopping treatment. Your doctor may do a blood test before you start taking GILENYA. Call your doctor right away if you have any of these symptoms of an infection:

    • fever
    • tiredness
    • body aches
    • chills
    • nausea
    • vomiting
    • headache accompanied by fever, neck stiffness, sensitivity to light, nausea, and/or confusion (these may be symptoms of meningitis)

    3.  Progressive multifocal leukoencephalopathy (PML). PML is a rare brain infection that usually leads to death or severe disability. If PML happens, it usually happens in people with weakened immune systems. It is important that you call your doctor right away if you have any new or worsening medical problems that have lasted several days, including problems with:

    • thinking
    • eyesight
    • strength
    • balance
    • weakness on 1 side of your body
    • using your arms and legs

    4.  A problem with your vision called macular edema. Macular edema can cause some of the same vision symptoms as an MS attack (optic neuritis). You may not notice any symptoms with macular edema. If macular edema happens, it usually starts in the first 3 to 4 months after you start taking GILENYA. Your doctor should test your vision before you start taking GILENYA and 3 to 4 months after you start taking GILENYA, or any time you notice vision changes during treatment with GILENYA. Your risk of macular edema may be higher if you have diabetes or have had an inflammation of your eye called uveitis.

    Call your doctor right away if you have any of the following:

    • blurriness or shadows in the center of your vision
    • a blind spot in the center of your vision
    • sensitivity to light
    • unusually colored (tinted) vision

    What is GILENYA?

    GILENYA is a prescription medicine used to treat relapsing forms of multiple sclerosis (MS) in adults. GILENYA can decrease the number of MS flare-ups (relapses). GILENYA does not cure MS, but it can help slow down the physical problems that MS causes.

    It is not known if GILENYA is safe and effective in children under 18 years of age.

    Who should not take GILENYA?

    Do not take GILENYA if you:

    • have had a heart attack, unstable angina, stroke or warning stroke or certain types of heart failure in the last 6 months
    • have certain types of irregular or abnormal heartbeat (arrhythmia), including patients in whom a heart finding called prolonged QT is seen on ECG before starting GILENYA
    • are taking certain medicines that change your heart rhythm

    If any of the above situations apply to you, tell your doctor.

    What should I tell my doctor before taking GILENYA?

    Before you take GILENYA, tell your doctor about all your medical conditions, including if you had or now have:

    • an irregular or abnormal heartbeat (arrhythmia)
    • a history of stroke or warning stroke
    • heart problems, including heart attack or angina
    • a history of repeated fainting (syncope)
    • a fever or infection, or you are unable to fight infections due to a disease or taking medicines that lower your immune system. Tell your doctor if you have had chicken pox or have received the vaccine for chicken pox. Your doctor may do a blood test for chicken pox virus. You may need to get the full course of the vaccine for chicken pox and then wait 1 month before you start taking GILENYA.
    • eye problems, especially an inflammation of the eye called uveitis.
    • diabetes
    • breathing problems, including during your sleep
    • liver problems
    • high blood pressure
    • Are pregnant or plan to become pregnant. GILENYA may harm your unborn baby. Talk to your doctor if you are pregnant or are planning to become pregnant.
      • Tell your doctor right away if you become pregnant while taking GILENYA or if you become pregnant within 2 months after you stop taking GILENYA.
      • If you are a female who can become pregnant, you should use effective birth control during your treatment with GILENYA and for at least 2 months after you stop taking GILENYA.

        Pregnancy Registry: There is a registry for women who become pregnant during treatment with GILENYA. If you become pregnant while taking GILENYA, talk to your doctor about registering with the GILENYA Pregnancy Registry. The purpose of this registry is to collect information about your health and your baby’s health.

        For more information, contact the GILENYA Pregnancy Registry by calling Outcome at 1-877-598-7237, by sending an email to gpr@outcome.com, or go to www.gilenyapregnancyregistry.com.

    • Are breastfeeding or plan to breastfeed. It is not known if GILENYA  passes into your breast milk. You and your doctor should decide if you will take GILENYA or breastfeed. You should not do both.

    Tell your doctor about all the medicines you take or have recently taken, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially tell your doctor if you take medicines that affect your immune system, including corticosteroids, or have taken them in the past.

    Know the medicines you take. Keep a list of your medicines with you to show your doctor and pharmacist when you get a new medicine.

    Using GILENYA and other medicines together may affect each other causing serious side effects.

    Especially tell your doctor if you take vaccines. Tell your doctor if you have been vaccinated within 1 month before you start taking GILENYA. You should not get certain vaccines, called live attenuated vaccines, while you take GILENYA and for at least 2 months after you stop taking GILENYA. If you take certain vaccines, you may get the infection the vaccine should have prevented. Vaccines may not work as well when given during GILENYA treatment.

    How should I take GILENYA?

    • You will be observed by a healthcare professional for at least 6 hours after your first dose of GILENYA. See “What is the most important information I should know about GILENYA?”
    • Take GILENYA exactly as your doctor tells you to take it.
    • Take GILENYA 1 time each day.
    • If you take too much GILENYA, call your doctor or go to the nearest hospital emergency room right away.
    • Take GILENYA with or without food.
    • Do not stop taking GILENYA without talking with your doctor first.
    • Call your doctor right away if you miss a dose of GILENYA. You may need to be observed by a healthcare professional for at least 6 hours when you take your next dose. If you need to be observed by a healthcare professional when you take your next dose of GILENYA you will have:
      • an ECG before you take your dose
      • hourly pulse and blood pressure measurements after you take the dose
      • an ECG 6 hours after your dose
    • If you have certain types of heart problems, or if you are taking certain types of medicines that can affect your heart, you will be observed overnight by a healthcare professional in a medical facility after you take your dose of GILENYA.
    • If you have serious side effects after taking a dose of GILENYA, especially those that require treatment with other medicines, you will stay in the medical facility to be observed overnight. If you were observed overnight, you will also be observed for any serious side effects for at least 6 hours after you take your second dose of GILENYA. See “What is the most important information I should know about GILENYA?”

    What are possible side effects of GILENYA?

    GILENYA can cause serious side effects.

    See "What is the most important information I should know about GILENYA?"

    Serious side effects include:

    • swelling and narrowing of the blood vessels in your brain. A condition called PRES (Posterior reversible encephalopathy syndrome) has occurred rarely in patients taking GILENYA. Symptoms of PRES usually get better when you stop taking GILENYA. However, if left untreated it may lead to a stroke. Call your doctor right away if you have any of the following symptoms:
      • sudden headache
      • confusion
      • seizures
      • loss of vision
      • weakness
    • breathing problems. Some people who take GILENYA have shortness of breath. Call your doctor right away if you have trouble breathing.
    • liver problems. GILENYA may cause liver problems. Your doctor should do blood tests to check your liver before you start taking GILENYA. Call your doctor right away if you have any of the following symptoms of liver problems:
      • nausea
      • vomiting
      • stomach pain
      • loss of appetite
      • tiredness
      • your skin or the whites of your eyes turn yellow
      • dark urine

    The most common side effects of GILENYA include:

    • headache
    • abnormal liver tests
    • diarrhea
    • cough
    • flu
    • sinusitis
    • back pain
    • abdominal pain
    • pain in arms or legs

    Tell your doctor if you have any side effect that bothers you or that does not go away.

    These are not all of the possible side effects of GILENYA. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    How do I store GILENYA?

    • Store GILENYA in the original bottle or blister pack in a dry place.
    • Store GILENYA at room temperature between 59°F to 86°F (15°C to 30°C).
    • Keep GILENYA and all medicines out of the reach of children.

    General information about GILENYA

    Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use GILENYA for a condition for which it was not prescribed. Do not give GILENYA to other people, even if they have the same symptoms you have. It may harm them.

    This Medication Guide summarizes the most important information about GILENYA. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about GILENYA that is written for healthcare professionals.

    For more information, go to www.pharma.US.Novartis.com or call 1-888-669-6682.

    What are the ingredients in GILENYA?

    Active ingredient: fingolimod

    Inactive ingredients: gelatin, magnesium stearate, mannitol, titanium dioxide, yellow iron oxide.

    This Medication Guide has been approved by the U.S. Food and Drug Administration.

    GILENYA is a registered trademark of Novartis AG.

    Manufactured by:
    Novartis Pharma Stein AG
    Stein, Switzerland

    Distributed by:
    Novartis Pharmaceuticals Corporation
    East Hanover, New Jersey 07936

    © Novartis

    T2015-128

    Revised: August 2015

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  • PRINCIPAL DISPLAY PANEL

    Package Label – 0.5 mg

    Rx Only             NDC 0078-0607-15

    GILENYA™

    (fingolimod)

    Capsules

    0.5 mg

    Equivalent to 0.56 mg fingolimod hydrochloride

    30 Capsules

    Dispense with enclosed Medication Guide.

    PRINCIPAL DISPLAY PANELGilenya0.5 mg 30 Capsules

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  • INGREDIENTS AND APPEARANCE
    GILENYA 
    fingolimod hcl capsule
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0078-0607
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    FINGOLIMOD HYDROCHLORIDE (UNII: G926EC510T) (FINGOLIMOD - UNII:3QN8BYN5QF) FINGOLIMOD 0.5 mg
    Inactive Ingredients
    Ingredient Name Strength
    GELATIN (UNII: 2G86QN327L)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    MANNITOL (UNII: 3OWL53L36A)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    FERRIC OXIDE YELLOW (UNII: EX438O2MRT)  
    Product Characteristics
    Color WHITE (white opaque body) , YELLOW (bright yellow cap) Score no score
    Shape CAPSULE Size 16mm
    Flavor Imprint Code FTY;0;5;mg
    Contains     
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:0078-0607-15 30 in 1 BOTTLE; Type 0: Not a Combination Product 09/21/2010
    2 NDC:0078-0607-51 28 in 1 CARTON; Type 0: Not a Combination Product 09/21/2010 11/30/2016
    3 NDC:0078-0607-89 7 in 1 CARTON; Type 0: Not a Combination Product 09/21/2010
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA022527 09/21/2010
    Labeler - Novartis Pharmaceuticals Corporation (002147023)
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RxNorm Names

PLAVIX (clopidogrel bisulfate) tablet, film coated
[Rebel Distributors Corp]


Category DEA ScheduleMarketing Status
HUMAN PRESCRIPTION DRUG LABELNew Drug Application
Drug Label Sections

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use
PLAVIX safely and effectively. See full prescribing information for
PLAVIX.
 
PLAVIX (clopidogrel bisulfate) tablets
Initial U.S. Approval: 1997

WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS

See full prescribing information for complete boxed warning.

  • Effectiveness of Plavix depends on activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. (5.1)
  • Poor metabolizers treated with Plavix at recommended doses exhibit higher cardiovascular event rates following acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) than patients with normal CYP2C19 function. (12.5)
  • Tests are available to identify a patient's CYP2C19 genotype and can be used as an aid in determining therapeutic strategy. (12.5)
  • Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers. (2.3, 5.1)

RECENT MAJOR CHANGES

Boxed Warning03/2010
Dosage and Administration (2.3)03/2010
Warnings and Precautions (5.1, 5.2, 5.3)03/2010

INDICATIONS AND USAGE

Plavix is a P2Y12 platelet inhibitor indicated for:

  • Acute coronary syndrome
  • Recent myocardial infarction (MI), recent stroke, or established peripheral arterial disease. Plavix has been shown to reduce the combined endpoint of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death. (1.2)

DOSAGE AND ADMINISTRATION

  • Acute coronary syndrome (2.1)
  • Recent MI, recent stroke, or established peripheral arterial disease: 75 mg once daily (2.2)

DOSAGE FORMS AND STRENGTHS

Tablets: 75 mg, 300 mg (3)

CONTRAINDICATIONS

  • Active pathological bleeding, such as peptic ulcer or intracranial hemorrhage (4.1)
  • Hypersensitivity to clopidogrel or any component of the product (4.2)

WARNINGS AND PRECAUTIONS

  • Reduced effectiveness in impaired CYP2C19 function: Avoid concomitant use with drugs that inhibit CYP2C19 (e.g., omeprazole). (5.1)
  • Bleeding: Plavix increases risk of bleeding. Discontinue 5 days prior to elective surgery. (5.2)
  • Discontinuation of Plavix: Premature discontinuation increases risk of cardiovascular events. (5.3)
  • Recent transient ischemic attack or stroke: Combination use of Plavix and aspirin in these patients was not shown to be more effective than Plavix alone, but was shown to increase major bleeding. (5.4)
  • Thrombotic thrombocytopenic purpura (TTP): TTP has been reported with Plavix, including fatal cases. (5.5)

ADVERSE REACTIONS

Bleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse reaction. (6.1)


To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

  • CYP2C19 inhibitors (e.g., omeprazole): Avoid concomitant use. (7.1)
  • Nonsteroidal anti-inflammatory drugs (NSAIDs): Combination use increases risk of gastrointestinal bleeding. (7.2)
  • Warfarin: Combination use increases risk of bleeding. (7.3)

USE IN SPECIFIC POPULATIONS

Nursing mothers: Discontinue drug or nursing, taking into consideration importance of drug to mother. (8.3)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 12/2010

Back to Highlights and Tabs

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS

1 INDICATIONS AND USAGE

1.1 Acute Coronary Syndrome (ACS)

1.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease

2 DOSAGE AND ADMINISTRATION

2.1 Acute Coronary Syndrome

2.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease

2.3 CYP2C19 Poor Metabolizers

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

4.1 Active Bleeding

4.2 Hypersensitivity

5 WARNINGS AND PRECAUTIONS

5.1 Diminished Antiplatelet Activity Due to Impaired CYP2C19 Function

5.2 General Risk of Bleeding

5.3 Discontinuation of Plavix

5.4 Patients with Recent Transient Ischemic Attack (TIA) or Stroke

5.5 Thrombotic Thrombocytopenic Purpura (TTP)

6 ADVERSE REACTIONS

6.1 Clinical Studies Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 CYP2C19 Inhibitors

7.2 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

7.3 Warfarin (CYP2C9 Substrates)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

12.5 Pharmacogenomics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Acute Coronary Syndrome

14.2 Recent Myocardial Infarction, Recent Stroke, or Established Peripheral Arterial Disease

14.3 Lack of Established Benefit of Plavix plus Aspirin in Patients with Multiple Risk Factors or Established Vascular Disease

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

17.1 Benefits and Risks

17.2 Bleeding

17.3 Other Signs and Symptoms Requiring Medical Attention

17.4 Invasive Procedures

17.5 Concomitant Medications

*
Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS

The effectiveness of Plavix is dependent on its activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19 [see Warnings and Precautions (5.1)]. Plavix at recommended doses forms less of that metabolite and has a smaller effect on platelet function in patients who are CYP2C19 poor metabolizers. Poor metabolizers with acute coronary syndrome or undergoing percutaneous coronary intervention treated with Plavix at recommended doses exhibit higher cardiovascular event rates than do patients with normal CYP2C19 function. Tests are available to identify a patient's CYP2C19 genotype; these tests can be used as an aid in determining therapeutic strategy [see Clinical Pharmacology (12.5)]. Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers [see Dosage and Administration (2.3)].

1 INDICATIONS AND USAGE

1.1 Acute Coronary Syndrome (ACS)

  • For patients with non-ST-segment elevation ACS [unstable angina (UA)/non-ST-elevation myocardial infarction (NSTEMI)], including patients who are to be managed medically and those who are to be managed with coronary revascularization, Plavix has been shown to decrease the rate of a combined endpoint of cardiovascular death, myocardial infarction (MI), or stroke as well as the rate of a combined endpoint of cardiovascular death, MI, stroke, or refractory ischemia.
  • For patients with ST-elevation myocardial infarction (STEMI), Plavix has been shown to reduce the rate of death from any cause and the rate of a combined endpoint of death, re-infarction, or stroke. The benefit for patients who undergo primary percutaneous coronary intervention is unknown.

The optimal duration of Plavix therapy in ACS is unknown.

1.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease

For patients with a history of recent myocardial infarction (MI), recent stroke, or established peripheral arterial disease, Plavix has been shown to reduce the rate of a combined endpoint of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death.

2 DOSAGE AND ADMINISTRATION

2.1 Acute Coronary Syndrome

Plavix can be administered with or without food [see Clinical Pharmacology (12.3)]

  • For patients with non-ST-elevation ACS (UA/NSTEMI), initiate Plavix with a single 300 mg oral loading dose and then continue at 75 mg once daily. Initiate aspirin (75–325 mg once daily) and continue in combination with Plavix [see Clinical Studies (14.1)].
  • For patients with STEMI, the recommended dose of Plavix is 75 mg once daily orally, administered in combination with aspirin (75–325 mg once daily), with or without thrombolytics. Plavix may be initiated with or without a loading dose [see Clinical Studies (14.1)].

2.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease

The recommended daily dose of Plavix is 75 mg once daily orally, with or without food [see Clinical Pharmacology (12.3)].

2.3 CYP2C19 Poor Metabolizers

CYP2C19 poor metabolizer status is associated with diminished antiplatelet response to clopidogrel. Although a higher dose regimen (600 mg loading dose followed by 150 mg once daily) in poor metabolizers increases antiplatelet response [see Clinical Pharmacology (12.5)], an appropriate dose regimen for this patient population has not been established in clinical outcome trials.

3 DOSAGE FORMS AND STRENGTHS

  • 75 mg tablets: Pink, round, biconvex, film-coated tablets debossed with "75" on one side and "1171" on the other
  • 300 mg tablets: Pink, oblong, film-coated tablets debossed with "300" on one side and "1332" on the other

4 CONTRAINDICATIONS

4.1 Active Bleeding

Plavix is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage.

4.2 Hypersensitivity

Plavix is contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to clopidogrel or any component of the product [see Adverse Reactions (6.2)].

5 WARNINGS AND PRECAUTIONS

5.1 Diminished Antiplatelet Activity Due to Impaired CYP2C19 Function

Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by genetic variations in CYP2C19 [see Boxed Warning] and by concomitant medications that interfere with CYP2C19. Avoid concomitant use of Plavix and drugs that inhibit CYP2C19 activity. Co-administration of Plavix with omeprazole, a proton pump inhibitor that is an inhibitor of CYP2C19, reduces the pharmacological activity of Plavix if given concomitantly or if given 12 hours apart [see Drug Interactions (7.1)].

5.2 General Risk of Bleeding

Thienopyridines, including Plavix, increase the risk of bleeding. If a patient is to undergo surgery and an antiplatelet effect is not desired, discontinue Plavix 5 days prior to surgery. In patients who stopped therapy more than five days prior to CABG the rates of major bleeding were similar (event rate 4.4% Plavix + aspirin; 5.3% placebo + aspirin). In patients who remained on therapy within five days of CABG, the major bleeding rate was 9.6% for Plavix + aspirin, and 6.3% for placebo + aspirin.

Thienopyridines inhibit platelet aggregation for the lifetime of the platelet (7–10 days), so withholding a dose will not be useful in managing a bleeding event or the risk of bleeding associated with an invasive procedure. Because the half-life of clopidogrel's active metabolite is short, it may be possible to restore hemostasis by administering exogenous platelets; however, platelet transfusions within 4 hours of the loading dose or 2 hours of the maintenance dose may be less effective.

5.3 Discontinuation of Plavix

Avoid lapses in therapy, and if Plavix must be temporarily discontinued, restart as soon as possible. Premature discontinuation of Plavix may increase the risk of cardiovascular events.

5.4 Patients with Recent Transient Ischemic Attack (TIA) or Stroke

In patients with recent TIA or stroke who are at high risk for recurrent ischemic events, the combination of aspirin and Plavix has not been shown to be more effective than Plavix alone, but the combination has been shown to increase major bleeding.

5.5 Thrombotic Thrombocytopenic Purpura (TTP)

TTP, sometimes fatal, has been reported following use of Plavix, sometimes after a short exposure (<2 weeks). TTP is a serious condition that requires urgent treatment including plasmapheresis (plasma exchange). It is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes [fragmented RBCs] seen on peripheral smear), neurological findings, renal dysfunction, and fever [see Adverse Reactions (6.2)].

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed below and elsewhere in the labeling:

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions and durations of follow up, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Plavix has been evaluated for safety in more than 54,000 patients, including over 21,000 patients treated for 1 year or more. The clinically important adverse reactions observed in trials comparing Plavix plus aspirin to placebo plus aspirin and trials comparing Plavix alone to aspirin alone are discussed below.

Bleeding

CURE

In CURE, Plavix use with aspirin was associated with an increase in major bleeding (primarily gastrointestinal and at puncture sites) compared to placebo with aspirin (see Table 1). The incidence of intracranial hemorrhage (0.1%) and fatal bleeding (0.2%) were the same in both groups. Other bleeding events that were reported more frequently in the clopidogrel group were epistaxis, hematuria, and bruise.

The overall incidence of bleeding is described in Table 1.

Table 1: CURE Incidence of Bleeding Complications (% patients)
EventPlavix
(+ aspirin)*		Placebo
(+ aspirin)*		p-value
(n=6259)(n=6303)
*
Other standard therapies were used as appropriate.
†
Life-threatening and other major bleeding.
‡
Major bleeding event rate for Plavix + aspirin was dose-dependent on aspirin: <100 mg = 2.6%; 100–200 mg = 3.5%; >200 mg = 4.9%
Major bleeding event rates for Plavix + aspirin by age were: <65 years = 2.5%, ≥65 to <75 years = 4.1%, ≥75 years = 5.9%
§
Major bleeding event rate for placebo + aspirin was dose-dependent on aspirin: <100 mg = 2.0%; 100–200 mg = 2.3%; >200 mg = 4.0%
Major bleeding event rates for placebo + aspirin by age were: <65 years = 2.1%, ≥65 to <75 years = 3.1%, ≥75 years = 3.6%
Led to interruption of study medication.
Major bleeding †3.7 ‡2.7 §0.001
  Life-threatening bleeding2.21.80.13
    Fatal0.20.2
    5 g/dL hemoglobin drop0.90.9
    Requiring surgical intervention0.70.7
    Hemorrhagic strokes0.10.1
    Requiring inotropes0.50.5
    Requiring transfusion (≥4 units)1.21.0
Other major bleeding1.61.00.005
    Significantly disabling0.40.3
    Intraocular bleeding with significant loss of vision0.050.03
    Requiring 2–3 units of blood1.30.9
Minor bleeding 5.12.4< 0.001

Ninety-two percent (92%) of the patients in the CURE study received heparin or low molecular weight heparin (LMWH), and the rate of bleeding in these patients was similar to the overall results.

COMMIT

In COMMIT, similar rates of major bleeding were observed in the Plavix and placebo groups, both of which also received aspirin (see Table 2).

Table 2: Incidence of Bleeding Events in COMMIT (% patients)
Type of bleedingPlavix
(+ aspirin)
(n=22961)		Placebo
(+ aspirin)
(n=22891)		p-value
*
Major bleeds were cerebral bleeds or non-cerebral bleeds thought to have caused death or that required transfusion.
†
The relative rate of major noncerebral or cerebral bleeding was independent of age. Event rates for Plavix + aspirin by age were: <60 years = 0.3%, ≥60 to <70 years = 0.7%, ≥70 years = 0.8%. Event rates for placebo + aspirin by age were: <60 years = 0.4%, ≥60 to <70 years = 0.6%, ≥70 years = 0.7%.
Major* noncerebral or cerebral bleeding†0.60.50.59
  Major noncerebral0.40.30.48
    Fatal0.20.20.90
Hemorrhagic stroke 0.20.20.91
  Fatal0.20.20.81
Other noncerebral bleeding (non-major)3.63.10.005
Any noncerebral bleeding3.93.40.004

CAPRIE (Plavix vs. Aspirin)

In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2.0% in those taking Plavix vs. 2.7% in those taking aspirin; bleeding requiring hospitalization occurred in 0.7% and 1.1%, respectively. The incidence of intracranial hemorrhage was 0.4% for Plavix compared to 0.5% for aspirin.

Other bleeding events that were reported more frequently in the Plavix group were epistaxis and hematoma.

Other Adverse Events

In CURE and CHARISMA, which compared Plavix plus aspirin to aspirin alone, there was no difference in the rate of adverse events (other than bleeding) between Plavix and placebo.

In CAPRIE, which compared Plavix to aspirin, pruritus was more frequently reported in those taking Plavix. No other difference in the rate of adverse events (other than bleeding) was reported.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Plavix. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

  • Blood and lymphatic system disorders: Agranulocytosis, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP)
  • Gastrointestinal disorders: Gastrointestinal and retroperitoneal hemorrhage with fatal outcome, colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis
  • General disorders and administration site condition: Fever, hemorrhage of operative wound
  • Hepato-biliary disorders: Acute liver failure, hepatitis (non-infectious), abnormal liver function test
  • Immune system disorders: Hypersensitivity reactions, anaphylactoid reactions, serum sickness
  • Musculoskeletal, connective tissue and bone disorders: Musculoskeletal bleeding, myalgia, arthralgia, arthritis
  • Nervous system disorders: Taste disorders, fatal intracranial bleeding
  • Eye disorders: Eye (conjunctival, ocular, retinal) bleeding
  • Psychiatric disorders: Confusion, hallucinations
  • Respiratory, thoracic and mediastinal disorders: Bronchospasm, interstitial pneumonitis, respiratory tract bleeding
  • Renal and urinary disorders: Glomerulopathy, increased creatinine levels
  • Skin and subcutaneous tissue disorders: Maculopapular or erythematous rash, urticaria, bullous dermatitis, eczema, toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, erythema multiforme, skin bleeding, lichen planus
  • Vascular disorders: Vasculitis, hypotension

7 DRUG INTERACTIONS

7.1 CYP2C19 Inhibitors

Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of drugs that inhibit the activity of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition. Avoid concomitant use of drugs that inhibit CYP2C19, e.g., omeprazole [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.5)].

Omeprazole

In a crossover clinical study, 72 healthy subjects were administered Plavix (300 mg loading dose followed by 75 mg per day) alone and with omeprazole (80 mg at the same time as Plavix) for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when Plavix and omeprazole were administered together. Mean inhibition of platelet aggregation was diminished by 47% (24 hours) and 30% (Day 5) when Plavix and omeprazole were administered together.

In another study, 72 healthy subjects were given the same doses of Plavix and omeprazole but the drugs were administered 12 hours apart; the results were similar, indicating that administering Plavix and omeprazole at different times does not prevent their interaction [see Warnings and Precautions (5.1)].

7.2 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Coadministration of Plavix and NSAIDs increases the risk of gastrointestinal bleeding.

7.3 Warfarin (CYP2C9 Substrates)

Although the administration of clopidogrel 75 mg per day did not modify the pharmacokinetics of S-warfarin (a CYP2C9 substrate) or INR in patients receiving long-term warfarin therapy, coadministration of Plavix with warfarin increases the risk of bleeding because of independent effects on hemostasis.

However, at high concentrations in vitro, clopidogrel inhibits CYP2C9.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Reproduction studies performed in rats and rabbits at doses up to 500 and 300 mg/kg/day, respectively (65 and 78 times the recommended daily human dose, respectively, on a mg/m2 basis), revealed no evidence of impaired fertility or fetotoxicity due to clopidogrel. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of a human response, Plavix should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

Studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from clopidogrel, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Safety and effectiveness in the pediatric population have not been established.

8.5 Geriatric Use

Of the total number of subjects in the CAPRIE and CURE controlled clinical studies, approximately 50% of patients treated with Plavix were 65 years of age and older, and 15% were 75 years and older. In COMMIT, approximately 58% of the patients treated with Plavix were 60 years and older, 26% of whom were 70 years and older.

The observed risk of thrombotic events with clopidogrel plus aspirin versus placebo plus aspirin by age category is provided in Figures 2 and 5 for the CURE and COMMIT trials, respectively [see Clinical Studies (14.1)]. The observed risk of bleeding events with clopidogrel plus aspirin versus placebo plus aspirin by age category is provided in Tables 1 and 2 for the CURE and COMMIT trials, respectively [see Adverse Reactions (6.1)]. No dosage adjustment is necessary in elderly patients.

8.6 Renal Impairment

Experience is limited in patients with severe and moderate renal impairment [see Clinical Pharmacology (12.2)].

8.7 Hepatic Impairment

No dosage adjustment is necessary in patients with hepatic impairment [see Clinical Pharmacology (12.2)].

10 OVERDOSAGE

Platelet inhibition by Plavix is irreversible and will last for the life of the platelet. Overdose following clopidogrel administration may result in bleeding complications. A single oral dose of clopidogrel at 1500 or 2000 mg/kg was lethal to mice and to rats and at 3000 mg/kg to baboons. Symptoms of acute toxicity were vomiting, prostration, difficult breathing, and gastrointestinal hemorrhage in animals.

Based on biological plausibility, platelet transfusion may restore clotting ability.

11 DESCRIPTION

Plavix (clopidogrel bisulfate) is a thienopyridine class inhibitor of P2Y12 ADP platelet receptors. Chemically it is methyl (+)-(S)-?-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate sulfate (1:1). The empirical formula of clopidogrel bisulfate is C16H16ClNO2S•H2SO4 and its molecular weight is 419.9.

The structural formula is as follows:

Chemical Structure

Clopidogrel bisulfate is a white to off-white powder. It is practically insoluble in water at neutral pH but freely soluble at pH 1. It also dissolves freely in methanol, dissolves sparingly in methylene chloride, and is practically insoluble in ethyl ether. It has a specific optical rotation of about +56°.

Plavix for oral administration is provided as either pink, round, biconvex, debossed, film-coated tablets containing 97.875 mg of clopidogrel bisulfate which is the molar equivalent of 75 mg of clopidogrel base or pink, oblong, debossed film-coated tablets containing 391.5 mg of clopidogrel bisulfate which is the molar equivalent of 300 mg of clopidogrel base.

Each tablet contains hydrogenated castor oil, hydroxypropylcellulose, mannitol, microcrystalline cellulose and polyethylene glycol 6000 as inactive ingredients. The pink film coating contains ferric oxide, hypromellose 2910, lactose monohydrate, titanium dioxide and triacetin. The tablets are polished with Carnauba wax.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Clopidogrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets.

12.2 Pharmacodynamics

Clopidogrel must be metabolized by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. This action is irreversible. Consequently, platelets exposed to clopidogrel's active metabolite are affected for the remainder of their lifespan (about 7 to 10 days). Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP.

Dose-dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of Plavix. Repeated doses of 75 mg Plavix per day inhibit ADP-induced platelet aggregation on the first day, and inhibition reaches steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg Plavix per day was between 40% and 60%. Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days.

Geriatric Patients

Elderly (≥75 years) and young healthy subjects had similar effects on platelet aggregation.

Renally-Impaired Patients

After repeated doses of 75 mg Plavix per day, patients with severe renal impairment (creatinine clearance from 5 to 15 mL/min) and moderate renal impairment (creatinine clearance from 30 to 60 mL/min) showed low (25%) inhibition of ADP-induced platelet aggregation.

Hepatically-Impaired Patients

After repeated doses of 75 mg Plavix per day for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy subjects.

Gender

In a small study comparing men and women, less inhibition of ADP-induced platelet aggregation was observed in women.

12.3 Pharmacokinetics

Clopidogrel is a prodrug and is metabolized to a pharmacologically active metabolite and inactive metabolites.

Absorption

After single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.

Effect of Food

Plavix can be administered with or without food. In a study in healthy male subjects when Plavix 75 mg per day was given with a standard breakfast, mean inhibition of ADP-induced platelet aggregation was reduced by less than 9%. The active metabolite AUC0–24 was unchanged in the presence of food, while there was a 57% decrease in active metabolite Cmax. Similar results were observed when a Plavix 300 mg loading dose was administered with a high-fat breakfast.

Metabolism

Clopidogrel is extensively metabolized by two main metabolic pathways: one mediated by esterases and leading to hydrolysis into an inactive carboxylic acid derivative (85% of circulating metabolites) and one mediated by multiple cytochrome P450 enzymes. Cytochromes first oxidize clopidogrel to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel. This metabolic pathway is mediated by CYP2C19, CYP3A, CYP2B6 and CYP1A2. The active thiol metabolite binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation for the lifespan of the platelet.

The Cmax of the active metabolite is twice as high following a single 300 mg clopidogrel loading dose as it is after four days of 75 mg maintenance dose. Cmax occurs approximately 30 to 60 minutes after dosing. In the 75 to 300 mg dose range, the pharmacokinetics of the active metabolite deviates from dose proportionality: increasing the dose by a factor of four results in 2.0- and 2.7-fold increases in Cmax and AUC, respectively.

Elimination

Following an oral dose of 14C-labeled clopidogrel in humans, approximately 50% of total radioactivity was excreted in urine and approximately 46% in feces over the 5 days post-dosing. After a single, oral dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The half-life of the active metabolite is about 30 minutes.

12.5 Pharmacogenomics

CYP2C19 is involved in the formation of both the active metabolite and the 2-oxo-clopidogrel intermediate metabolite. Clopidogrel active metabolite pharmacokinetics and antiplatelet effects, as measured by ex vivo platelet aggregation assays, differ according to CYP2C19 genotype. Genetic variants of other CYP450 enzymes may also affect the formation of clopidogrel's active metabolite.

The CYP2C19*1 allele corresponds to fully functional metabolism while the CYP2C19*2 and *3 alleles are nonfunctional. CYP2C19*2 and *3 account for the majority of reduced function alleles in white (85%) and Asian (99%) poor metabolizers. Other alleles associated with absent or reduced metabolism are less frequent, and include, but are not limited to, CYP2C19*4, *5, *6, *7, and *8. A patient with poor metabolizer status will possess two loss-of-function alleles as defined above. Published frequencies for poor CYP2C19 metabolizer genotypes are approximately 2% for whites, 4% for blacks and 14% for Chinese. Tests are available to determine a patient's CYP2C19 genotype.

A crossover study in 40 healthy subjects, 10 each in the four CYP2C19 metabolizer groups, evaluated pharmacokinetic and antiplatelet responses using 300 mg followed by 75 mg per day and 600 mg followed by 150 mg per day, each for a total of 5 days. Decreased active metabolite exposure and diminished inhibition of platelet aggregation were observed in the poor metabolizers as compared to the other groups. When poor metabolizers received the 600 mg/150 mg regimen, active metabolite exposure and antiplatelet response were greater than with the 300 mg/75 mg regimen (see Table 3). An appropriate dose regimen for this patient population has not been established in clinical outcome trials.

Table 3: Active Metabolite Pharmacokinetics and Antiplatelet Responses by CYP2C19 Metabolizer Status
DoseUltrarapid
(n=10)		Extensive
(n=10)		Intermediate
(n=10)		Poor
(n=10)
Values are mean (SD)
*
Inhibition of platelet aggregation with 5µM ADP; larger value indicates greater platelet inhibition
†
Vasodilator-stimulated phosphoprotein – platelet reactivity index; smaller value indicates greater platelet inhibition
Cmax (ng/mL)300 mg (24 h)24 (10)32 (21)23 (11)11 (4)
600 mg (24 h)36 (13)44 (27)39 (23)17 (6)
75 mg (Day 5)12 (6)13 (7)12 (5)4 (1)
150 mg (Day 5)16 (9)19 (5)18 (7)7 (2)
IPA (%)*300 mg (24 h)40 (21)39 (28)37 (21)24 (26)
600 mg (24 h)51 (28)49 (23)56 (22)32 (25)
75 mg (Day 5)56 (13)58 (19)60 (18)37 (23)
150 mg (Day 5)68 (18)73 (9)74 (14)61 (14)
VASP-PRI (%) †300 mg (24 h)73 (12)68 (16)77 (12)91 (12)
600 mg (24 h)51 (20)48 (20)56 (26)85 (14)
75 mg (Day 5)40 (9)39 (14)50 (16)83 (13)
150 mg (Day 5)20 (10)24 (10)29 (11)61 (18)

Some published studies suggest that intermediate metabolizers have decreased active metabolite exposure and diminished antiplatelet effects.

The relationship between CYP2C19 genotype and Plavix treatment outcome was evaluated in retrospective analyses of Plavix-treated subjects in CHARISMA (n=4862) and TRITON-TIMI 38 (n=1477), and in several published cohort studies. In TRITON-TIMI 38 and the majority of the cohort studies, the combined group of patients with either intermediate or poor metabolizer status had a higher rate of cardiovascular events (death, myocardial infarction, and stroke) or stent thrombosis compared to extensive metabolizers. In CHARISMA and one cohort study, the increased event rate was observed only in poor metabolizers.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

There was no evidence of tumorigenicity when clopidogrel was administered for 78 weeks to mice and 104 weeks to rats at dosages up to 77 mg/kg per day, which afforded plasma exposures >25 times that in humans at the recommended daily dose of 75 mg.

Clopidogrel was not genotoxic in four in vitro tests (Ames test, DNA-repair test in rat hepatocytes, gene mutation assay in Chinese hamster fibroblasts, and metaphase chromosome analysis of human lymphocytes) and in one in vivo test (micronucleus test by oral route in mice).

Clopidogrel was found to have no effect on fertility of male and female rats at oral doses up to 400 mg/kg per day (52 times the recommended human dose on a mg/m2 basis).

14 CLINICAL STUDIES

The clinical evidence of the efficacy of Plavix is derived from three double-blind trials involving 77,599 patients. The CAPRIE study (Clopidogrel vs. Aspirin in Patients at Risk of Ischemic Events) was a comparison of Plavix to aspirin. The CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events) and the COMMIT/CCS-2 (Clopidogrel and Metoprolol in Myocardial Infarction Trial / Second Chinese Cardiac Study) studies were comparisons of Plavix to placebo, given in combination with aspirin and other standard therapy. The CHARISMA (Clopidogrel for High Atherothrombotic Risk Ischemic Stabilization, Management, and Avoidance) study (n=15,603) also compared Plavix to placebo, given in combination with aspirin and other standard therapy.

14.1 Acute Coronary Syndrome

CURE

The CURE study included 12,562 patients with ACS without ST-elevation (UA or NSTEMI) and presenting within 24 hours of onset of the most recent episode of chest pain or symptoms consistent with ischemia. Patients were required to have either ECG changes compatible with new ischemia (without ST-elevation) or elevated cardiac enzymes or troponin I or T to at least twice the upper limit of normal. The patient population was largely Caucasian (82%) and included 38% women, and 52% patients ≥65 years of age.

Patients were randomized to receive Plavix (300-mg loading dose followed by 75 mg once daily) or placebo, and were treated for up to one year. Patients also received aspirin (75–325 mg once daily) and other standard therapies such as heparin. The use of GPIIb/IIIa inhibitors was not permitted for three days prior to randomization.

The number of patients experiencing the primary outcome (CV death, MI, or stroke) was 582 (9.3%) in the Plavix-treated group and 719 (11.4%) in the placebo-treated group, a 20% relative risk reduction (95% CI of 10%–28%; p < 0.001) for the Plavix-treated group (see Table 4).

Table 4: Outcome Events in the CURE Primary Analysis
OutcomePlavix
(+ aspirin)*		Placebo
(+ aspirin)*		Relative Risk
Reduction (%)
(95% CI)
(n=6259)(n=6303)
*
Other standard therapies were used as appropriate.
†
The individual components do not represent a breakdown of the primary and co-primary outcomes, but rather the total number of subjects experiencing an event during the course of the study.
Primary outcome
  (Cardiovascular death, MI, stroke)		582       (9.3%)719 (11.4%)20%
(10.3, 27.9)
p < 0.001
All Individual Outcome Events:†
  CV death 318       (5.1%)345 (5.5%)7%
(-7.7, 20.6)
  MI324       (5.2%)419 (6.6%)23%
(11.0, 33.4)
  Stroke75       (1.2%)87 (1.4%)14%
(-17.7, 36.6)

Most of the benefit of Plavix occurred in the first two months, but the difference from placebo was maintained throughout the course of the trial (up to 12 months) (see Figure 1).

Figure 1: Cardiovascular Death, Myocardial Infarction, and Stroke in the CURE Study

Figure

In CURE, the use of Plavix was associated with a lower incidence of CV death, MI or stroke in patient populations with different characteristics, as shown in Figure 2. The benefits associated with Plavix were independent of the use of other acute and long-term cardiovascular therapies, including heparin/LMWH, intravenous glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, lipid-lowering drugs, beta-blockers, and ACE-inhibitors. The efficacy of Plavix was observed independently of the dose of aspirin (75–325 mg once daily). The use of oral anticoagulants, non-study anti-platelet drugs, and chronic NSAIDs was not allowed in CURE.

Figure 2: Hazard Ratio for Patient Baseline Characteristics and On-Study Concomitant Medications/Interventions for the CURE Study

Figure

The use of Plavix in CURE was associated with a decrease in the use of thrombolytic therapy (71 patients [1.1%] in the Plavix group, 126 patients [2.0%] in the placebo group; relative risk reduction of 43%), and GPIIb/IIIa inhibitors (369 patients [5.9%] in the Plavix group, 454 patients [7.2%] in the placebo group, relative risk reduction of 18%). The use of Plavix in CURE did not affect the number of patients treated with CABG or PCI (with or without stenting), (2253 patients [36.0%] in the Plavix group, 2324 patients [36.9%] in the placebo group; relative risk reduction of 4.0%).

COMMIT

In patients with STEMI, the safety and efficacy of Plavix were evaluated in the randomized, placebo-controlled, double-blind study, COMMIT. COMMIT included 45,852 patients presenting within 24 hours of the onset of the symptoms of myocardial infarction with supporting ECG abnormalities (i.e., ST-elevation, ST-depression or left bundle-branch block). Patients were randomized to receive Plavix (75 mg once daily) or placebo, in combination with aspirin (162 mg per day), for 28 days or until hospital discharge, whichever came first.

The primary endpoints were death from any cause and the first occurrence of re-infarction, stroke or death.

The patient population included 28% women, 58% age ≥ 60 years (26% age ≥ 70 years), 55% patients who received thrombolytics, 68% who received ACE-inhibitors, and only 3% who underwent PCI.

As shown in Table 5 and Figures 3 and 4 below, Plavix significantly reduced the relative risk of death from any cause by 7% (p=0.029), and the relative risk of the combination of re-infarction, stroke or death by 9% (p=0.002).

Table 5: Outcome Events in the COMMIT Analysis
EventPlavix
(+ aspirin)
(N=22961)		Placebo
(+ aspirin)
(N=22891)		Odds ratio
(95% CI)		p-value
*
The difference between the composite endpoint and the sum of death+non-fatal MI+non-fatal stroke indicates that 9 patients (2 clopidogrel and 7 placebo) suffered both a non-fatal stroke and a non-fatal MI.
†
Non-fatal MI and non-fatal stroke exclude patients who died (of any cause).
Composite endpoint: Death, MI, or Stroke*2121 (9.2%)2310 (10.1%)0.91 (0.86, 0.97)0.002
Death1726 (7.5%)1845 (8.1%)0.93 (0.87, 0.99)0.029
Non-fatal MI†270 (1.2%)330 (1.4%)0.81 (0.69, 0.95)0.011
Non-fatal Stroke†127 (0.6%)142 (0.6%)0.89 (0.70, 1.13)0.33

Figure 3: Cumulative Event Rates for Death in the COMMIT Study 1

Figure

1
All treated patients received aspirin.

Figure 4: Cumulative Event Rates for the Combined End point Re-Infarction, Stroke or Death in the COMMIT Study 2

Figure

2
All treated patients received aspirin.

The effect of Plavix did not differ significantly in various pre-specified subgroups as shown in Figure 5. The effect was also similar in non-prespecified subgroups including those based on infarct location, Killip class or prior MI history (see Figure 6). Such subgroup analyses should be interpreted cautiously.

Figure 5: Effects of Adding Plavix to Aspirin on the Combined Primary Endpoint across Baseline and Concomitant Medication Subgroups for the COMMIT Study

Figure

* Three similar-sized prognostic index groups were based on absolute risk of primary composite outcome for each patient calculated from baseline prognostic variables (excluding allocated treatments) with a Cox regression model.

Figure 6: Effects of Adding Plavix to Aspirin in the Non-Prespecified Subgroups in the COMMIT Study

Figure

14.2 Recent Myocardial Infarction, Recent Stroke, or Established Peripheral Arterial Disease

CAPRIE

The CAPRIE trial was a 19,185-patient, 304-center, international, randomized, double-blind, parallel-group study comparing Plavix (75 mg daily) to aspirin (325 mg daily). The patients randomized had: 1) recent histories of myocardial infarction (within 35 days); 2) recent histories of ischemic stroke (within 6 months) with at least a week of residual neurological signs; or 3) established peripheral arterial disease. Patients received randomized treatment for an average of 1.6 years (maximum of 3 years).

The trial's primary outcome was the time to first occurrence of new ischemic stroke (fatal or not), new myocardial infarction (fatal or not), or other vascular death. Deaths not easily attributable to nonvascular causes were all classified as vascular.

Table 6: Outcome Events in the CAPRIE Primary Analysis
Plavixaspirin
Patients n=9599n=9586
Ischemic stroke (fatal or not) 438 (4.6%)461 (4.8%)
MI (fatal or not) 275 (2.9%)333 (3.5%)
Other vascular death 226 (2.4%)226 (2.4%)
Total 939 (9.8%)1020 (10.6%)

As shown in the table, Plavix was associated with a lower incidence of outcome events, primarily MI. The overall relative risk reduction (9.8% vs. 10.6%) was 8.7%, p=0.045. Similar results were obtained when all-cause mortality and all-cause strokes were counted instead of vascular mortality and ischemic strokes (risk reduction 6.9%). In patients who survived an on-study stroke or myocardial infarction, the incidence of subsequent events was lower in the Plavix group.

The curves showing the overall event rate are shown in Figure 7. The event curves separated early and continued to diverge over the 3-year follow-up period.

Figure 7: Fatal or Non-Fatal Vascular Events in the CAPRIE Study

Figure

The statistical significance favoring Plavix over aspirin was marginal (p=0.045). However, because aspirin is itself effective in reducing cardiovascular events in patients with recent myocardial infarction or stroke, the effect of Plavix is substantial.

The CAPRIE trial included a population that was randomized on the basis of 3 entry criteria. The efficacy of Plavix relative to aspirin was heterogeneous across these randomized subgroups (p=0.043). It is not clear whether this difference is real or a chance occurrence. Although the CAPRIE trial was not designed to evaluate the relative benefit of Plavix over aspirin in the individual patient subgroups, the benefit appeared to be strongest in patients who were enrolled because of peripheral vascular disease (especially those who also had a history of myocardial infarction) and weaker in stroke patients. In patients who were enrolled in the trial on the sole basis of a recent myocardial infarction, Plavix was not numerically superior to aspirin.

14.3 Lack of Established Benefit of Plavix plus Aspirin in Patients with Multiple Risk Factors or Established Vascular Disease

CHARISMA

The CHARISMA trial was a 15,603 subject, randomized, double-blind, parallel group study comparing Plavix (75 mg daily) to placebo for prevention of ischemic events in patients with vascular disease or multiple risk factors for atherosclerosis. All subjects were treated with aspirin 75–162 mg daily. The mean duration of treatment was 23 months. The study failed to demonstrate a reduction in the occurrence of the primary endpoint, a composite of CV death, MI, or stroke. A total of 534 (6.9%) patients in the Plavix group versus 573 (7.4%) patients in the placebo group experienced a primary outcome event (p=0.22). Bleeding of all severities was more common in the subjects randomized to Plavix.

16 HOW SUPPLIED/STORAGE AND HANDLING

Plavix (clopidogrel bisulfate) 75 mg tablets are available as pink, round, biconvex, film-coated tablets debossed with "75" on one side and "1171" on the other. Tablets are provided as follows:

 
NDC 21695-665-30         Bottles of 30
 
NDC 21695-665-90         Bottles of 90

Store at 25° C (77° F); excursions permitted to 15°–30° C (59°–86° F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

17.1 Benefits and Risks

  • Summarize the effectiveness features and potential side effects of Plavix.
  • Tell patients to take Plavix exactly as prescribed.
  • Remind patients not to discontinue Plavix without first discussing it with the physician who prescribed Plavix.

17.2 Bleeding

Inform patients that they:

  • will bruise and bleed more easily.
  • will take longer than usual to stop bleeding.
  • should report any unanticipated, prolonged, or excessive bleeding, or blood in their stool or urine.

17.3 Other Signs and Symptoms Requiring Medical Attention

  • Inform patients that TTP is a rare but serious condition that has been reported with Plavix and other drugs in this class of drugs.
  • Instruct patients to get prompt medical attention if they experience any of the following symptoms that cannot otherwise be explained: fever, weakness, extreme skin paleness, purple skin patches, yellowing of the skin or eyes, or neurological changes.

17.4 Invasive Procedures

Instruct patients to:

  • inform physicians and dentists that they are taking Plavix before any invasive procedure is scheduled.
  • tell the doctor performing the invasive procedure to talk to the prescribing health care professional before stopping Plavix.

17.5 Concomitant Medications

Ask patients to list all prescription medications, over-the-counter medications, or dietary supplements they are taking or plan to take, including prescription or over-the-counter omeprazole, so the physician knows about other treatments that may affect how Plavix works (e.g., warfarin and NSAIDs) [see Warnings and Precautions (5)].

Distributed by:
Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership
Bridgewater, NJ 08807

Plavix® is a registered trademark.

Repackaged by:

Rebel Distributors Cor

Thousand Oaks, CA 91320

PRINCIPAL DISPLAY PANEL - 75 mg

Plavix 75 mg

PLAVIX 
clopidogrel bisulfate tablet, film coated
Product Information
Product TypeHUMAN PRESCRIPTION DRUG LABELItem Code (Source)NDC:21695-665(NDC:63653-1171)
Route of AdministrationORALDEA Schedule    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
clopidogrel bisulfate (clopidogrel) clopidogrel75 mg
Inactive Ingredients
Ingredient NameStrength
castor oil 
hydroxypropyl cellulose 
mannitol 
cellulose, microcrystalline 
polyethylene glycol 6000 
ferric oxide red 
lactose monohydrate 
titanium dioxide 
triacetin 
carnauba wax 
Product Characteristics
ColorPINKScoreno score
ShapeROUND (biconvex) Size9mm
FlavorImprint Code 75;1171
Contains    
Packaging
#Item CodePackage Description
1NDC:21695-665-3030 in 1 BOTTLE
2NDC:21695-665-9090 in 1 BOTTLE
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
NDANDA02083901/01/1900
Labeler - Rebel Distributors Corp (118802834)
Establishment
NameAddressID/FEIBusiness Operations
Rebel Distributors Corp118802834RELABEL, REPACK

Revised: 12/2010
Document Id: 1086a7b4-b89b-4bee-8120-5f752626c046
Set id: 1086a7b4-b89b-4bee-8120-5f752626c046
Version: 1
Effective Time: 20101228
 
Rebel Distributors Corp

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WARFARIN SODIUM tablet
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HUMAN PRESCRIPTION DRUG LABELAbbreviated New Drug Application
Drug Label Sections

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use warfarin sodium safely and effectively. See full prescribing information for warfarin sodium.
Warfarin Sodium Tablets USP, for oral use
Initial U.S. Approval: 1954

WARNING: BLEEDING RISK

See full prescribing information for complete boxed warning.

•
Warfarin sodium can cause major or fatal bleeding. (5.1)
•
Perform regular monitoring of INR in all treated patients. (2.1)
•
Drugs, dietary changes, and other factors affect INR levels achieved with warfarin sodium therapy. (7)
•
Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding. (17)

RECENT MAJOR CHANGES

Contraindications (4)

10/2011

Warnings and Precautions, Use in Pregnant Women with Mechanical Heart Valves (5.5)

10/2011

INDICATIONS AND USAGE

Warfarin sodium is a vitamin K antagonist indicated for:

•
Prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism (1)
•
Prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement (1)
•
Reduction in the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction (1)

Limitation of Use

Warfarin sodium has no direct effect on an established thrombus, nor does it reverse ischemic tissue damage. (1)

DOSAGE AND ADMINISTRATION

•
Individualize dosing regimen for each patient, and adjust based on INR response. (2.1, 2.2)
•
Knowledge of genotype can inform initial dose selection. (2.3)
•
Monitoring: Obtain daily INR determinations upon initiation until stable in the therapeutic range. Obtain subsequent INR determinations every 1 to 4 weeks. (2.4)
•
Review conversion instructions from other anticoagulants. (2.8)

DOSAGE FORMS AND STRENGTHS

•
Scored tablets: 1, 2, 2-1/2, 3, 4, 5, 6, 7-1/2, or 10 mg (3)

CONTRAINDICATIONS

•
Pregnancy, except in women with mechanical heart valves (4)
•
Hemorrhagic tendencies or blood dyscrasias (4)
•
Recent or contemplated surgery of the central nervous system (CNS) or eye, or traumatic surgery resulting in large open surfaces (4, 5.7)
•
Bleeding tendencies associated with certain conditions (4)
•
Threatened abortion, eclampsia, and preeclampsia (4)
•
Unsupervised patients with potential high levels of non-compliance (4)
•
Spinal puncture and other diagnostic or therapeutic procedures with potential for uncontrollable bleeding (4)
•
Hypersensitivity to warfarin or any component of the product (4)
•
Major regional or lumbar block anesthesia (4)
•
Malignant hypertension (4)

WARNINGS AND PRECAUTIONS

•
Tissue necrosis: Necrosis or gangrene of skin or other tissues can occur, with severe cases requiring debridement or amputation. Discontinue warfarin sodium and consider alternative anticoagulants if necessary. (5.2)
•
Systemic atheroemboli and cholesterol microemboli: Some cases have progressed to necrosis or death. Discontinue warfarin sodium if such emboli occur. (5.3)
•
Heparin-induced thrombocytopenia (HIT): Initial therapy with warfarin sodium in HIT has resulted in cases of amputation and death. Warfarin sodium may be considered after platelet count has normalized. (5.4)
•
Pregnant women with mechanical heart valves: Warfarin sodium may cause fetal harm; however, the benefits may outweigh the risks. (5.5)

ADVERSE REACTIONS

Most common adverse reactions to warfarin sodium are fatal and nonfatal hemorrhage from any tissue or organ. (6)

To report SUSPECTED ADVERSE REACTIONS, contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

•
Consult labeling of all concurrently used drugs for complete information about interactions with warfarin sodium or increased risks for bleeding. (7)
•
Inhibitors and inducers of CYP2C9, 1A2, or 3A4: May alter warfarin exposure. Monitor INR closely when any such drug is used with warfarin sodium. (7.1)
•
Drugs that increase bleeding risk: Closely monitor patients receiving any such drug (e.g., other anticoagulants, antiplatelet agents, nonsteroidal anti-inflammatory drugs, serotonin reuptake inhibitors). (7.2)
•
Antibiotics and antifungals: Closely monitor INR when initiating or stopping an antibiotic or antifungal course of therapy. (7.3)
•
Botanical (herbal) products: Some may influence patient response to warfarin sodium necessitating close INR monitoring. (7.4)

USE IN SPECIFIC POPULATIONS

•
Nursing mothers: Use with caution in a nursing woman. Monitor breast-feeding infants for bruising or bleeding. (8.3)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 07/2012

Back to Highlights and Tabs

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: BLEEDING RISK

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Individualized Dosing

2.2 Recommended Target INR Ranges and Durations for Individual Indications

2.3 Initial and Maintenance Dosing

2.4 Monitoring to Achieve Optimal Anticoagulation

2.5 Missed Dose

2.7 Treatment During Dentistry and Surgery

2.8 Conversion From Other Anticoagulants

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Hemorrhage

5.2 Tissue Necrosis

5.3 Systemic Atheroemboli and Cholesterol Microemboli

5.4 Heparin-Induced Thrombocytopenia

5.5 Use in Pregnant Women with Mechanical Heart Valves

5.6 Females of Reproductive Potential

5.7 Other Clinical Settings with Increased Risks

5.8 Endogenous Factors Affecting INR

6 ADVERSE REACTIONS

7 DRUG INTERACTIONS

7.1 CYP450 Interactions

7.2 Drugs that Increase Bleeding Risk

7.3 Antibiotics and Antifungals

7.4 Botanical (Herbal) Products and Foods

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

8.8 Females of Reproductive Potential

10 OVERDOSAGE

10.1 Signs and Symptoms

10.2 Treatment

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

12.5 Pharmacogenomics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Atrial Fibrillation

14.2 Mechanical and Bioprosthetic Heart Valves

14.3 Myocardial Infarction

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

*
Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

WARNING: BLEEDING RISK

•
Warfarin sodium can cause major or fatal bleeding [see Warnings and Precautions (5.1)].
•
Perform regular monitoring of INR in all treated patients [see Dosage and Administration (2.1)].
•
Drugs, dietary changes, and other factors affect INR levels achieved with warfarin sodium therapy [see Drug Interactions (7)].
•
Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding [see Patient Counseling Information (17)].

1 INDICATIONS AND USAGE

Warfarin sodium tablets, USP are indicated for:

•
Prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism (PE).
•
Prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation (AF) and/or cardiac valve replacement.
•
Reduction in the risk of death, recurrent myocardial infarction (MI), and thromboembolic events such as stroke or systemic embolization after myocardial infarction.

Limitations of Use

Warfarin sodium has no direct effect on an established thrombus, nor does it reverse ischemic tissue damage. Once a thrombus has occurred, however, the goals of anticoagulant treatment are to prevent further extension of the formed clot and to prevent secondary thromboembolic complications that may result in serious and possibly fatal sequelae.

2 DOSAGE AND ADMINISTRATION

2.1 Individualized Dosing

The dosage and administration of warfarin sodium must be individualized for each patient according to the patient's INR response to the drug. Adjust the dose based on the patient's INR and the condition being treated. Consult the latest evidence-based clinical practice guidelines from the American College of Chest Physicians (ACCP) to assist in the determination of the duration and intensity of anticoagulation with warfarin sodium [see References (15)].

2.2 Recommended Target INR Ranges and Durations for Individual Indications

An INR of greater than 4.0 appears to provide no additional therapeutic benefit in most patients and is associated with a higher risk of bleeding.

Venous Thromboembolism (including deep venous thrombosis [DVT] and PE)

Adjust the warfarin dose to maintain a target INR of 2.5 (INR range, 2.0-3.0) for all treatment durations. The duration of treatment is based on the indication as follows:

•
For patients with a DVT or PE secondary to a transient (reversible) risk factor, treatment with warfarin for 3 months is recommended.
•
For patients with an unprovoked DVT or PE, treatment with warfarin is recommended for at least 3 months. After 3 months of therapy, evaluate the risk-benefit ratio of long-term treatment for the individual patient.
•
For patients with two episodes of unprovoked DVT or PE, long-term treatment with warfarin is recommended. For a patient receiving long-term anticoagulant treatment, periodically reassess the risk-benefit ratio of continuing such treatment in the individual patient.

Atrial Fibrillation

In patients with non-valvular AF, anticoagulate with warfarin to target INR of 2.5 (range, 2.0-3.0).

•
In patients with non-valvular AF that is persistent or paroxysmal and at high risk of stroke (i.e., having any of the following features: prior ischemic stroke, transient ischemic attack, or systemic embolism, or 2 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended.
•
In patients with non-valvular AF that is persistent or paroxysmal and at an intermediate risk of ischemic stroke (i.e., having 1 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended.
•
For patients with AF and mitral stenosis, long-term anticoagulation with warfarin is recommended.
•
For patients with AF and prosthetic heart valves, long-term anticoagulation with warfarin is recommended; the target INR may be increased and aspirin added depending on valve type and position, and on patient factors.

Mechanical and Bioprosthetic Heart Valves

•
For patients with a bileaflet mechanical valve or a Medtronic Hall (Minneapolis, MN) tilting disk valve in the aortic position who are in sinus rhythm and without left atrial enlargement, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) is recommended.
•
For patients with tilting disk valves and bileaflet mechanical valves in the mitral position, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended.
•
For patients with caged ball or caged disk valves, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended.
•
For patients with a bioprosthetic valve in the mitral position, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) for the first 3 months after valve insertion is recommended. If additional risk factors for thromboembolism are present (AF, previous thromboembolism, left ventricular dysfunction), a target INR of 2.5 (range, 2.0-3.0) is recommended.

Post-Myocardial Infarction

•
For high-risk patients with MI (e.g., those with a large anterior MI, those with significant heart failure, those with intracardiac thrombus visible on transthoracic echocardiography, those with AF, and those with a history of a thromboembolic event), therapy with combined moderate-intensity (INR, 2.0-3.0) warfarin plus low-dose aspirin (≤100 mg/day) for at least 3 months after the MI is recommended.

Recurrent Systemic Embolism and Other Indications

Oral anticoagulation therapy with warfarin has not been fully evaluated by clinical trials in patients with valvular disease associated with AF, patients with mitral stenosis, and patients with recurrent systemic embolism of unknown etiology. However, a moderate dose regimen (INR 2.0-3.0) may be used for these patients.

2.3 Initial and Maintenance Dosing

The appropriate initial dosing of warfarin sodium varies widely for different patients. Not all factors responsible for warfarin dose variability are known, and the initial dose is influenced by:

•
Clinical factors including age, race, body weight, sex, concomitant medications, and comorbidities
•
Genetic factors (CYP2C9 and VKORC1 genotypes) [see Clinical Pharmacology (12.5)]

Select the initial dose based on the expected maintenance dose, taking into account the above factors. Modify this dose based on consideration of patient-specific clinical factors. Consider lower initial and maintenance doses for elderly and/or debilitated patients and in Asian patients [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)]. Routine use of loading doses is not recommended as this practice may increase hemorrhagic and other complications and does not offer more rapid protection against clot formation.

Individualize the duration of therapy for each patient. In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed [see Dosage and Administration (2.2)].

Dosing Recommendations without Consideration of Genotype

If the patient's CYP2C9 and VKORC1 genotypes are not known, the initial dose of warfarin sodium is usually 2 to 5 mg once daily. Determine each patient's dosing needs by close monitoring of the INR response and consideration of the indication being treated. Typical maintenance doses are 2 to 10 mg once daily.

Dosing Recommendations with Consideration of Genotype

Table 1 displays three ranges of expected maintenance warfarin sodium doses observed in subgroups of patients having different combinations of CYP2C9 and VKORC1 gene variants [see Clinical Pharmacology (12.5)]. If the patient's CYP2C9 and/or VKORC1 genotype are known, consider these ranges in choosing the initial dose. Patients with CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3 may require more prolonged time (>2 to 4 weeks) to achieve maximum INR effect for a given dosage regimen than patients without these CYP variants.

Table 1: Three Ranges of Expected Maintenance Warfarin Sodium Daily Doses Based on CYP2C9 and VKORC1 Genotypes*
VKORC1CYP2C9
*1/*1*1/*2*1/*3*2/*2*2/*3*3/*3
*
Includes death, nonfatal reinfarction, and thromboembolic cerebral stroke.

GG

5-7 mg

5-7 mg

3-4 mg

3-4 mg

3-4 mg

0.5-2 mg

AG

5-7 mg

3-4 mg

3-4 mg

3-4 mg

0.5-2 mg

0.5-2 mg

AA

3-4 mg

3-4 mg

0.5-2 mg

0.5-2 mg

0.5-2 mg

0.5-2 mg

2.4 Monitoring to Achieve Optimal Anticoagulation

Warfarin sodium is a narrow therapeutic range (index) drug, and its action may be affected by factors such as other drugs and dietary vitamin K. Therefore, anticoagulation must be carefully monitored during warfarin sodium therapy. Determine the INR daily after the administration of the initial dose until INR results stabilize in the therapeutic range. After stabilization, maintain dosing within the therapeutic range by performing periodic INRs. The frequency of performing INR should be based on the clinical situation but generally acceptable intervals for INR determinations are 1 to 4 weeks. Perform additional INR tests when other warfarin products are interchanged with warfarin sodium, as well as whenever other medications are initiated, discontinued, or taken irregularly. Heparin, a common concomitant drug, increases the INR [see Dosage and Administration (2.8) and Drug Interactions (7)].

Determinations of whole blood clotting and bleeding times are not effective measures for monitoring of warfarin sodium therapy.

2.5 Missed Dose

The anticoagulant effect of warfarin sodium persists beyond 24 hours. If a patient misses a dose of warfarin sodium at the intended time of day, the patient should take the dose as soon as possible on the same day. The patient should not double the dose the next day to make up for a missed dose.

2.7 Treatment During Dentistry and Surgery

Some dental or surgical procedures may necessitate the interruption or change in the dose of warfarin sodium therapy. Consider the benefits and risks when discontinuing warfarin sodium even for a short period of time. Determine the INR immediately prior to any dental or surgical procedure. In patients undergoing minimally invasive procedures who must be anticoagulated prior to, during, or immediately following these procedures, adjusting the dosage of warfarin sodium to maintain the INR at the low end of the therapeutic range may safely allow for continued anticoagulation.

2.8 Conversion From Other Anticoagulants

Heparin

Since the full anticoagulant effect of warfarin sodium is not achieved for several days, heparin is preferred for initial rapid anticoagulation. During initial therapy with warfarin sodium, the interference with heparin anticoagulation is of minimal clinical significance. Conversion to warfarin sodium may begin concomitantly with heparin therapy or may be delayed 3 to 6 days. To ensure therapeutic anticoagulation, continue full dose heparin therapy and overlap warfarin sodium therapy with heparin for 4 to 5 days and until warfarin sodium has produced the desired therapeutic response as determined by INR, at which point heparin may be discontinued.

As heparin may affect the INR, patients receiving both heparin and warfarin sodium should have INR monitoring at least:

•
5 hours after the last intravenous bolus dose of heparin, or
•
4 hours after cessation of a continuous intravenous infusion of heparin, or
•
24 hours after the last subcutaneous heparin injection.

Warfarin sodium may increase the activated partial thromboplastin time (aPTT) test, even in the absence of heparin. A severe elevation (>50 seconds) in aPTT with an INR in the desired range has been identified as an indication of increased risk of postoperative hemorrhage.

Other Anticoagulants

Consult the labeling of other anticoagulants for instructions on conversion to warfarin sodium.

3 DOSAGE FORMS AND STRENGTHS

Warfarin Sodium Tablets, USP are single scored, engraved numerically with 1, 2, 2½, 3, 4, 5, 6, 7½, or 10 on one side, and engraved with "WARFARIN" on top of "TARO" on the other side.

Warfarin Sodium Tablets, USP are supplied in the following strengths:

Warfarin Sodium Tablets, USP
StrengthColor

1 mg

pink

2 mg

lavender

2.5 mg

green

3 mg

tan

4 mg

blue

5 mg

peach

6 mg

teal

7.5 mg

yellow

10 mg

white (dye-free)

4 CONTRAINDICATIONS

•
Pregnancy

Warfarin sodium tablets, USP are contraindicated in women who are pregnant except in pregnant women with mechanical heart valves, who are at high risk of thromboembolism [see Warnings and Precautions (5.5) and Use in Specific Populations (8.1)]. Warfarin sodium can cause fetal harm when administered to a pregnant woman. Warfarin sodium exposure during pregnancy causes a recognized pattern of major congenital malformations (warfarin embryopathy and fetotoxicity), fatal fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality. If warfarin sodium is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)].

•
Hemorrhagic tendencies or blood dyscrasias
•
Recent or contemplated surgery of the central nervous system or eye, or traumatic surgery resulting in large open surfaces [see Warnings and Precautions (5.7)]
•
Bleeding tendencies associated with:
?
Active ulceration or overt bleeding of the gastrointestinal, genitourinary, or respiratory tract
?
Central nervous system hemorrhage
?
Cerebral aneurysms, dissecting aorta
?
Pericarditis and pericardial effusions
?
Bacterial endocarditis
•
Threatened abortion, eclampsia, and preeclampsia
•
Unsupervised patients with conditions associated with potential high level of non-compliance
•
Spinal puncture and other diagnostic or therapeutic procedures with potential for uncontrollable bleeding
•
Hypersensitivity to warfarin or to any other components of this product (e.g., anaphylaxis) [see Adverse Reactions (6)]
•
Major regional or lumbar block anesthesia
•
Malignant hypertension

5 WARNINGS AND PRECAUTIONS

5.1 Hemorrhage

Warfarin sodium can cause major or fatal bleeding. Bleeding is more likely to occur within the first month. Risk factors for bleeding include high intensity of anticoagulation (INR >4.0), age greater than or equal to 65, history of highly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, anemia, malignancy, trauma, renal impairment, certain genetic factors [see Clinical Pharmacology (12.5)], certain concomitant drugs [see Drug Interactions (7)], and long duration of warfarin therapy.

Perform regular monitoring of INR in all treated patients. Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shortest duration of therapy appropriate for the clinical condition. However, maintenance of INR in the therapeutic range does not eliminate the risk of bleeding.

Drugs, dietary changes, and other factors affect INR levels achieved with warfarin sodium therapy. Perform more frequent INR monitoring when starting or stopping other drugs, including botanicals, or when changing dosages of other drugs [see Drug Interactions (7)]. Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding [see Patient Counseling Information (17)].

5.2 Tissue Necrosis

Necrosis and/or gangrene of skin and other tissues is an uncommon but serious risk (<0.1%). Necrosis may be associated with local thrombosis and usually appears within a few days of the start of warfarin sodium therapy. In severe cases of necrosis, treatment through debridement or amputation of the affected tissue, limb, breast, or penis has been reported.

Careful clinical evaluation is required to determine whether necrosis is caused by an underlying disease. Although various treatments have been attempted, no treatment for necrosis has been considered uniformly effective. Discontinue warfarin sodium therapy if necrosis occurs. Consider alternative drugs if continued anticoagulation therapy is necessary.

5.3 Systemic Atheroemboli and Cholesterol Microemboli

Anticoagulation therapy with warfarin sodium may enhance the release of atheromatous plaque emboli. Systemic atheroemboli and cholesterol microemboli can present with a variety of signs and symptoms depending on the site of embolization. The most commonly involved visceral organs are the kidneys followed by the pancreas, spleen, and liver. Some cases have progressed to necrosis or death. A distinct syndrome resulting from microemboli to the feet is known as "purple toes syndrome." Discontinue warfarin sodium therapy if such phenomena are observed. Consider alternative drugs if continued anticoagulation therapy is necessary.

5.4 Heparin-Induced Thrombocytopenia

Do not use warfarin sodium as initial therapy in patients with heparin-induced thrombocytopenia (HIT) and with heparin-induced thrombocytopenia with thrombosis syndrome (HITTS). Cases of limb ischemia, necrosis, and gangrene have occurred in patients with HIT and HITTS when heparin treatment was discontinued and warfarin therapy was started or continued. In some patients, sequelae have included amputation of the involved area and/or death. Treatment with warfarin sodium may be considered after the platelet count has normalized.

5.5 Use in Pregnant Women with Mechanical Heart Valves

Warfarin sodium can cause fetal harm when administered to a pregnant woman. While warfarin sodium is contraindicated during pregnancy, the potential benefits of using warfarin sodium may outweigh the risks for pregnant women with mechanical heart valves at high risk of thromboembolism. In those individual situations, the decision to initiate or continue warfarin sodium should be reviewed with the patient, taking into consideration the specific risks and benefits pertaining to the individual patient's medical situation, as well as the most current medical guidelines. Warfarin sodium exposure during pregnancy causes a recognized pattern of major congenital malformations (warfarin embryopathy and fetotoxicity), fatal fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

5.6 Females of Reproductive Potential

Warfarin sodium exposure during pregnancy can cause pregnancy loss, birth defects, or fetal death. Discuss pregnancy planning with females of reproductive potential who are on warfarin sodium therapy [see Contraindications (4) and Use in Specific Populations (8.8)].

5.7 Other Clinical Settings with Increased Risks

In the following clinical settings, the risks of warfarin sodium therapy may be increased:

•
Moderate to severe hepatic impairment
•
Infectious diseases or disturbances of intestinal flora (e.g., sprue, antibiotic therapy)
•
Use of an indwelling catheter
•
Severe to moderate hypertension
•
Deficiency in protein C-mediated anticoagulant response: warfarin sodium reduces the synthesis of the naturally occurring anticoagulants, protein C and protein S. Hereditary or acquired deficiencies of protein C or its cofactor, protein S, have been associated with tissue necrosis following warfarin administration. Concomitant anticoagulation therapy with heparin for 5 to 7 days during initiation of therapy with warfarin sodium may minimize the incidence of tissue necrosis in these patients.
•
Eye surgery: In cataract surgery, warfarin sodium use was associated with a significant increase in minor complications of sharp needle and local anesthesia block but not associated with potentially sight-threatening operative hemorrhagic complications. As warfarin sodium cessation or reduction may lead to serious thromboembolic complications, the decision to discontinue warfarin sodium before a relatively less invasive and complex eye surgery, such as lens surgery, should be based upon the risks of anticoagulant therapy weighed against the benefits.
•
Polycythemia vera
•
Vasculitis
•
Diabetes mellitus

5.8 Endogenous Factors Affecting INR

The following factors may be responsible for increased INR response: diarrhea, hepatic disorders, poor nutritional state, steatorrhea, or vitamin K deficiency.

The following factors may be responsible for decreased INR response: increased vitamin K intake or hereditary warfarin resistance.

6 ADVERSE REACTIONS

The following serious adverse reactions to warfarin sodium are discussed in greater detail in other sections of the labeling:

•
Hemorrhage [see Boxed Warning, Warnings and Precautions (5.1), and Overdosage (10)]
•
Necrosis of skin and other tissues [see Warnings and Precautions (5.2)]
•
Systemic atheroemboli and cholesterol microemboli [see Warnings and Precautions (5.3)]

Other adverse reactions to warfarin sodium include:

•
Immune system disorders: hypersensitivity/allergic reactions (including urticaria and anaphylactic reactions)
•
Vascular disorders: vasculitis
•
Hepatobiliary disorders: hepatitis, elevated liver enzymes. Cholestatic hepatitis has been associated with concomitant administration of warfarin sodium and ticlopidine.
•
Gastrointestinal disorders: nausea, vomiting, diarrhea, taste perversion, abdominal pain, flatulence, bloating
•
Skin disorders: rash, dermatitis (including bullous eruptions), pruritus, alopecia
•
Respiratory disorders: tracheal or tracheobronchial calcification
•
General disorders: chills

7 DRUG INTERACTIONS

Drugs may interact with warfarin sodium through pharmacodynamic or pharmacokinetic mechanisms. Pharmacodynamic mechanisms for drug interactions with warfarin sodium are synergism (impaired hemostasis, reduced clotting factor synthesis), competitive antagonism (vitamin K), and alteration of the physiologic control loop for vitamin K metabolism (hereditary resistance). Pharmacokinetic mechanisms for drug interactions with warfarin sodium are mainly enzyme induction, enzyme inhibition, and reduced plasma protein binding. It is important to note that some drugs may interact by more than one mechanism.

More frequent INR monitoring should be performed when starting or stopping other drugs, including botanicals, or when changing dosages of other drugs, including drugs intended for short-term use (e.g., antibiotics, antifungals, corticosteroids) [see Boxed Warning]. Consult the labeling of all concurrently used drugs to obtain further information about interactions with warfarin sodium or adverse reactions pertaining to bleeding.

7.1 CYP450 Interactions

CYP450 isozymes involved in the metabolism of warfarin include CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. The more potent warfarin S-enantiomer is metabolized by CYP2C9 while the R-enantiomer is metabolized by CYP1A2 and 3A4.

•
Inhibitors of CYP2C9, 1A2, and/or 3A4 have the potential to increase the effect (increase INR) of warfarin by increasing the exposure of warfarin.
•
Inducers of CYP2C9, 1A2, and/or 3A4 have the potential to decrease the effect (decrease INR) of warfarin by decreasing the exposure of warfarin.

Examples of inhibitors and inducers of CYP2C9, 1A2, and 3A4 are below in Table 2; however, this list should not be considered all-inclusive. Consult the labeling of all concurrently used drugs to obtain further information about CYP450 interaction potential. The CYP450 inhibition and induction potential should be considered when starting, stopping, or changing dose of concomitant mediations. Closely monitor INR if a concomitant drug is a CYP2C9, 1A2, and/or 3A4 inhibitor or inducer.

Table 2: Examples of CYP450 Interactions with Warfarin
EnzymeInhibitorsInducers

CYP2C9

amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast

aprepitant, bosentan, carbamazepine, phenobarbital, rifampin

CYP1A2

acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton

montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking

CYP3A4

alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton

armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

7.2 Drugs that Increase Bleeding Risk

Examples of drugs known to increase the risk of bleeding are presented in Table 3. Because bleeding risk is increased when these drugs are used concomitantly with warfarin, closely monitor patients receiving any such drug with warfarin.

Table 3: Drugs that Can Increase the Risk of Bleeding
Drug ClassSpecific Drugs

Anticoagulants

argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin

Antiplatelet Agents

aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine

Nonsteroidal Anti-Inflammatory Agents

celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac

Serotonin Reuptake Inhibitors

citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

7.3 Antibiotics and Antifungals

There have been reports of changes in INR in patients taking warfarin and antibiotics or antifungals, but clinical pharmacokinetic studies have not shown consistent effects of these agents on plasma concentrations of warfarin.

Closely monitor INR when starting or stopping any antibiotic or antifungal in patients taking warfarin.

7.4 Botanical (Herbal) Products and Foods

Exercise caution when botanical (herbal) products are taken concomitantly with warfarin sodium. Few adequate, well-controlled studies evaluating the potential for metabolic and/or pharmacologic interactions between botanicals and warfarin sodium exist. Due to a lack of manufacturing standardization with botanical medicinal preparations, the amount of active ingredients may vary. This could further confound the ability to assess potential interactions and effects on anticoagulation.

Some botanicals may cause bleeding events when taken alone (e.g., garlic and Ginkgo biloba) and may have anticoagulant, antiplatelet, and/or fibrinolytic properties. These effects would be expected to be additive to the anticoagulant effects of warfarin sodium. Conversely, some botanicals may decrease the effects of warfarin sodium (e.g., co-enzyme Q10, St. John's wort ginseng). Some botanicals and foods can interact with warfarin sodium through CYP450 interactions (e.g., echinacea, grapefruit juice, ginkgo, goldenseal, St. John's wort).

Monitor the patient's response with additional INR determinations when initiating or discontinuing any botanicals.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category D for women with mechanical heart valves [see Warnings and Precautions (5.5)] and Pregnancy Category X for other pregnant populations [see Contraindications (4)].

Warfarin Sodium Tablets, USP are contraindicated in women who are pregnant except in pregnant women with mechanical heart valves, who are at high risk of thromboembolism, and for whom the benefits of warfarin sodium may outweigh the risks. Warfarin sodium can cause fetal harm when administered to a pregnant woman. Warfarin sodium exposure during pregnancy causes a recognized pattern of major congenital malformations (warfarin embryopathy), fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality. The reproductive and developmental effects of warfarin sodium have not been evaluated in animals. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

In humans, warfarin crosses the placenta, and concentrations in fetal plasma approach the maternal values. Exposure to warfarin during the first trimester of pregnancy caused a pattern of congenital malformations in about 5% of exposed offspring. Warfarin embryopathy is characterized by nasal hypoplasia with or without stippled epiphyses (chondrodysplasia punctata) and growth retardation (including low birth weight). Central nervous system and eye abnormalities have also been reported, including dorsal midline dysplasia characterized by agenesis of the corpus callosum, Dandy-Walker malformation, midline cerebellar atrophy, and ventral midline dysplasia characterized by optic atrophy. Mental retardation, blindness, schizencephaly, microcephaly, hydrocephalus, and other adverse pregnancy outcomes have been reported following warfarin exposure during the second and third trimesters of pregnancy [see Contraindications (4) and Warnings and Precautions (5.6)].

8.3 Nursing Mothers

Based on published data in 15 nursing mothers, warfarin was not detected in human milk. Among the 15 full-term newborns, 6 nursing infants had documented prothrombin times within the expected range. Prothrombin times were not obtained for the other 9 nursing infants. Monitor breast-feeding infants for bruising or bleeding. Effects in premature infants have not been evaluated. Caution should be exercised when warfarin sodium is administered to a nursing woman.

8.4 Pediatric Use

Adequate and well-controlled studies with warfarin sodium have not been conducted in any pediatric population, and the optimum dosing, safety, and efficacy in pediatric patients is unknown. Pediatric use of warfarin sodium is based on adult data and recommendations, and available limited pediatric data from observational studies and patient registries. Pediatric patients administered warfarin sodium should avoid any activity or sport that may result in traumatic injury.

The developing hemostatic system in infants and children results in a changing physiology of thrombosis and response to anticoagulants. Dosing of warfarin in the pediatric population varies by patient age, with infants generally having the highest, and adolescents having the lowest milligram per kilogram dose requirements to maintain target INRs. Because of changing warfarin requirements due to age, concomitant medications, diet, and existing medical condition, target INR ranges may be difficult to achieve and maintain in pediatric patients, and more frequent INR determinations are recommended. Bleeding rates varied by patient population and clinical care center in pediatric observational studies and patient registries.

Infants and children receiving vitamin K-supplemented nutrition, including infant formulas, may be resistant to warfarin therapy, while human milk-fed infants may be sensitive to warfarin therapy.

8.5 Geriatric Use

Of the total number of patients receiving warfarin sodium in controlled clinical trials for which data were available for analysis, 1885 patients (24.4%) were 65 years and older, while 185 patients (2.4%) were 75 years and older. No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients 60 years or older appear to exhibit greater than expected INR response to the anticoagulant effects of warfarin [see Clinical Pharmacology (12.3)]. Warfarin sodium is contraindicated in any unsupervised patient with senility. Observe caution with administration of warfarin sodium to elderly patients in any situation or with any physical condition where added risk of hemorrhage is present. Consider lower initiation and maintenance doses of warfarin sodium in elderly patients [see Dosage and Administration (2.2, 2.3)].

8.6 Renal Impairment

Renal clearance is considered to be a minor determinant of anticoagulant response to warfarin. No dosage adjustment is necessary for patients with renal impairment.

8.7 Hepatic Impairment

Hepatic impairment can potentiate the response to warfarin through impaired synthesis of clotting factors and decreased metabolism of warfarin. Use caution when using warfarin sodium in these patients.

8.8 Females of Reproductive Potential

Warfarin sodium exposure during pregnancy can cause spontaneous abortion, birth defects, or fetal death. Females of reproductive potential who are candidates for warfarin sodium therapy should be counseled regarding the benefits of therapy and potential reproductive risks. Discuss pregnancy planning with females of reproductive potential who are on warfarin sodium therapy. If the patient becomes pregnant while taking warfarin sodium, she should be apprised of the potential risks to the fetus.

10 OVERDOSAGE

10.1 Signs and Symptoms

Bleeding (e.g., appearance of blood in stools or urine, hematuria, excessive menstrual bleeding, melena, petechiae, excessive bruising or persistent oozing from superficial injuries, unexplained fall in hemoglobin) is a manifestation of excessive anticoagulation.

10.2 Treatment

The treatment of excessive anticoagulation is based on the level of the INR, the presence or absence of bleeding, and clinical circumstances. Reversal of warfarin sodium anticoagulation may be obtained by discontinuing warfarin sodium therapy and, if necessary, by administration of oral or parenteral vitamin K1.

The use of vitamin K1 reduces response to subsequent warfarin sodium therapy and patients may return to a pretreatment thrombotic status following the rapid reversal of a prolonged INR. Resumption of warfarin sodium administration reverses the effect of vitamin K, and a therapeutic INR can again be obtained by careful dosage adjustment. If rapid re-anticoagulation is indicated, heparin may be preferable for initial therapy.

Prothrombin complex concentrate (PCC), fresh frozen plasma, or activated Factor VII treatment may be considered if the requirement to reverse the effects of warfarin sodium is urgent. A risk of hepatitis and other viral diseases is associated with the use of blood products; PCC and activated Factor VII are also associated with an increased risk of thrombosis. Therefore, these preparations should be used only in exceptional or life-threatening bleeding episodes secondary to warfarin sodium overdosage.

11 DESCRIPTION

Warfarin sodium is an anticoagulant that acts by inhibiting vitamin K-dependent coagulation factors. Chemically, it is 3-(?-acetonylbenzyl)-4-hydroxycoumarin and is a racemic mixture of the R- and S-enantiomers. Crystalline warfarin sodium is an isopropanol clathrate. Its empirical formula is C19H15NaO4, and its structural formula is represented by the following:

Warfarin Structure

Crystalline warfarin sodium occurs as a white, odorless, crystalline powder that is discolored by light. It is very soluble in water, freely soluble in alcohol, and very slightly soluble in chloroform and ether.

Warfarin Sodium Tablets, USP for oral use also contain:

All strengths: Anhydrous lactose, corn starch, and magnesium stearate

1 mg:

D&C Red No. 6 Barium Lake.

2 mg:

FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake.

2.5 mg:

D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake.

3 mg:

D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake.

4 mg:

FD&C Blue No. 1 Aluminum Lake.

5 mg:

D&C Red No. 6 Barium Lake, D&C Yellow No. 10 Aluminum Lake.

6 mg:

D&C Yellow No.10 Aluminum Lake, FD&C Blue No.2 Aluminum Lake.

7.5 mg:

D&C Yellow No. 10 Aluminum Lake.

10 mg:

Dye Free

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Warfarin acts by inhibiting the synthesis of vitamin K-dependent clotting factors, which include Factors II, VII, IX, and X, and the anticoagulant proteins C and S. Vitamin K is an essential cofactor for the post ribosomal synthesis of the vitamin K-dependent clotting factors. Vitamin K promotes the biosynthesis of ?-carboxyglutamic acid residues in the proteins that are essential for biological activity. Warfarin is thought to interfere with clotting factor synthesis by inhibition of the C1 subunit of vitamin K epoxide reductase (VKORC1) enzyme complex, thereby reducing the regeneration of vitamin K1 epoxide [see Clinical Pharmacology (12.5)].

12.2 Pharmacodynamics

An anticoagulation effect generally occurs within 24 hours after warfarin administration. However, peak anticoagulant effect may be delayed 72 to 96 hours. The duration of action of a single dose of racemic warfarin is 2 to 5 days. The effects of warfarin sodium may become more pronounced as effects of daily maintenance doses overlap. This is consistent with the half-lives of the affected vitamin K-dependent clotting factors and anticoagulation proteins: Factor II - 60 hours, VII - 4 to 6 hours, IX - 24 hours, X - 48 to 72 hours, and proteins C and S are approximately 8 hours and 30 hours, respectively.

12.3 Pharmacokinetics

Warfarin sodium is a racemic mixture of the R- and S-enantiomers of warfarin. The S-enantiomer exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer in humans, but generally has a more rapid clearance.

Absorption

Warfarin is essentially completely absorbed after oral administration, with peak concentration generally attained within the first 4 hours.

Distribution

Warfarin distributes into a relatively small apparent volume of distribution of about 0.14 L/kg. A distribution phase lasting 6 to 12 hours is distinguishable after rapid intravenous or oral administration of an aqueous solution. Approximately 99% of the drug is bound to plasma proteins.

Metabolism

The elimination of warfarin is almost entirely by metabolism. Warfarin is stereoselectively metabolized by hepatic cytochrome P-450 (CYP450) microsomal enzymes to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites (warfarin alcohols) with minimal anticoagulant activity. Identified metabolites of warfarin include dehydrowarfarin, two diastereoisomer alcohols, and 4' -, 6-, 7-, 8-, and 10-hydroxywarfarin. The CYP450 isozymes involved in the metabolism of warfarin include CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. CYP2C9, a polymorphic enzyme, is likely to be the principal form of human liver CYP450 that modulates the in vivo anticoagulant activity of warfarin. Patients with one or more variant CYP2C9 alleles have decreased S-warfarin clearance [see Clinical Pharmacology (12.5)].

Excretion

The terminal half-life of warfarin after a single dose is approximately 1 week; however, the effective half-life ranges from 20 to 60 hours, with a mean of about 40 hours. The clearance of R-warfarin is generally half that of S-warfarin, thus as the volumes of distribution are similar, the half-life of R-warfarin is longer than that of S-warfarin. The half-life of R-warfarin ranges from 37 to 89 hours, while that of S-warfarin ranges from 21 to 43 hours. Studies with radiolabeled drug have demonstrated that up to 92% of the orally administered dose is recovered in urine. Very little warfarin is excreted unchanged in urine. Urinary excretion is in the form of metabolites.

Geriatric Patients

Patients 60 years or older appear to exhibit greater than expected INR response to the anticoagulant effects of warfarin. The cause of the increased sensitivity to the anticoagulant effects of warfarin in this age group is unknown but may be due to a combination of pharmacokinetic and pharmacodynamic factors. Limited information suggests there is no difference in the clearance of S-warfarin; however, there may be a slight decrease in the clearance of R-warfarin in the elderly as compared to the young. Therefore, as patient age increases, a lower dose of warfarin is usually required to produce a therapeutic level of anticoagulation [see Dosage and Administration (2.3, 2.4)].

Asian Patients

Asian patients may require lower initiation and maintenance doses of warfarin. A non-controlled study of 151 Chinese outpatients stabilized on warfarin for various indications reported a mean daily warfarin requirement of 3.3 ± 1.4 mg to achieve an INR of 2 to 2.5. Patient age was the most important determinant of warfarin requirement in these patients, with a progressively lower warfarin requirement with increasing age.

12.5 Pharmacogenomics

CYP2C9 and VKORC1 Polymorphisms

The S-enantiomer of warfarin is mainly metabolized to 7-hydroxywarfarin by CYP2C9, a polymorphic enzyme. The variant alleles, CYP2C9*2 and CYP2C9*3, result in decreased in vitro CYP2C9 enzymatic 7-hydroxylation of S-warfarin. The frequencies of these alleles in Caucasians are approximately 11% and 7% for CYP2C9*2 and CYP2C9*3, respectively. Other CYP2C9 alleles associated with reduced enzymatic activity occur at lower frequencies, including *5, *6, and *11 alleles in populations of African ancestry and *5, *9, and *11 alleles in Caucasians.

Warfarin reduces the regeneration of vitamin K from vitamin K epoxide in the vitamin K cycle through inhibition of VKOR, a multiprotein enzyme complex. Certain single nucleotide polymorphisms in the VKORC1 gene (e.g., –1639G>A) have been associated with variable warfarin dose requirements. VKORC1 and CYP2C9 gene variants generally explain the largest proportion of known variability in warfarin dose requirements.

CYP2C9 and VKORC1 genotype information, when available, can assist in selection of the initial dose of warfarin [see Dosage and Administration (2.3)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, mutagenicity, or fertility studies have not been performed with warfarin.

14 CLINICAL STUDIES

14.1 Atrial Fibrillation

In five prospective, randomized, controlled clinical trials involving 3711 patients with nonrheumatic AF, warfarin significantly reduced the risk of systemic thromboembolism including stroke (see Table 4). The risk reduction ranged from 60% to 86% in all except one trial (CAFA: 45%), which was stopped early due to published positive results from two of these trials. The incidence of major bleeding in these trials ranged from 0.6% to 2.7% (see Table 4).

Table 4: Clinical Studies of Warfarin in Non-Rheumatic AF PatientsError! Bookmark not defined.Error! Bookmark not defined.
NThromboembolism% Major Bleeding
StudyWarfarin-Treated PatientsControl PatientsPT RatioINR% Risk Reductionp-valueWarfarin-Treated PatientsControl Patients

AFASAK

335

336

1.5-2.0

2.8-4.2

60

0.027

0.6

0.0

SPAF

210

211

1.3-1.8

2.0-4.5

67

0.01

1.9

1.9

BAATAF

212

208

1.2-1.5

1.5-2.7

86

<0.05

0.9

0.5

CAFA

187

191

1.3-1.6

2.0-3.0

45

0.25

2.7

0.5

SPINAF

260

265

1.2-1.5

1.4-2.8

79

0.001

2.3

1.5

Trials in patients with both AF and mitral stenosis suggest a benefit from anticoagulation with warfarin sodium [see Dosage and Administration (2.2)].

14.2 Mechanical and Bioprosthetic Heart Valves

In a prospective, randomized, open-label, positive-controlled study in 254 patients with mechanical prosthetic heart valves, the thromboembolic-free interval was found to be significantly greater in patients treated with warfarin alone compared with dipyridamole/aspirin-treated patients (p<0.005) and pentoxifylline/aspirin-treated patients (p<0.05). The results of this study are presented in Table 5.

Table 5: Prospective, Randomized, Open-Label, Positive-Controlled Clinical Study of Warfarin in Patients with Mechanical Prosthetic Heart Valves
Patients Treated With
EventWarfarinDipyridamole/
Aspirin		Pentoxifylline/
Aspirin
py= patient years

Thromboembolism

2.2/100 py

8.6/100 py

7.9/100 py

Major Bleeding

2.5/100 py

0.0/100 py

0.9/100 py

In a prospective, open-label, clinical study comparing moderate (INR 2.65) vs. high intensity (INR 9.0) warfarin therapies in 258 patients with mechanical prosthetic heart valves, thromboembolism occurred with similar frequency in the two groups (4.0 and 3.7 events per 100 patient years, respectively). Major bleeding was more common in the high intensity group. The results of this study are presented in Table 6.

Table 6: Prospective, Open-Label Clinical Study of Warfarin in Patients with Mechanical Prosthetic Heart Valves
EventModerate Warfarin Therapy INR 2.65High Intensity Warfarin Therapy INR 9.0
py= patient years

Thromboembolism

4.0/100 py

3.7/100 py

Major Bleeding

0.95/100 py

2.1/100 py

In a randomized trial in 210 patients comparing two intensities of warfarin therapy (INR 2.0-2.25 vs. INR 2.5-4.0) for a three-month period following tissue heart valve replacement, thromboembolism occurred with similar frequency in the two groups (major embolic events 2.0% vs. 1.9%, respectively, and minor embolic events 10.8% vs. 10.2%, respectively). Major hemorrhages occurred in 4.6% of patients in the higher intensity INR group compared to zero in the lower intensity INR group.

14.3 Myocardial Infarction

WARIS (The Warfarin Re-Infarction Study) was a double-blind, randomized study of 1214 patients 2 to 4 weeks post-infarction treated with warfarin to a target INR of 2.8 to 4.8. The primary endpoint was a composite of total mortality and recurrent infarction. A secondary endpoint of cerebrovascular events was assessed. Mean follow-up of the patients was 37 months. The results for each endpoint separately, including an analysis of vascular death, are provided in Table 7:

Table 7: WARIS – Endpoint Analysis of Separate Events
EventWarfarin
(N=607)		Placebo
(N=607)		RR (95% CI)% Risk Reduction
(p-value)
RR=Relative risk; Risk reduction=(1-RR); CI=Confidence interval; MI=Myocardial infarction; py=patient years

Total Patient Years of Follow-up

2018

1944

Total Mortality

94 (4.7/100 py)

123 (6.3/100 py)

0.76 (0.60, 0.97)

24 (p=0.030)

  Vascular Death

82 (4.1/100 py)

105 (5.4/100 py)

0.78 (0.60, 1.02)

22 (p=0.068)

Recurrent MI

82 (4.1/100 py)

124 (6.4/100 py)

0.66 (0.51, 0.85)

34 (p=0.001)

Cerebrovascular Event

20 (1.0/100 py)

44 (2.3/100 py)

0.46 (0.28, 0.75)

54 (p=0.002)

WARIS II (The Warfarin, Aspirin, Re-Infarction Study) was an open-label, randomized study of 3630 patients hospitalized for acute myocardial infarction treated with warfarin to a target INR 2.8 to 4.2, aspirin 160 mg per day, or warfarin to a target INR 2.0 to 2.5 plus aspirin 75 mg per day prior to hospital discharge. The primary endpoint was a composite of death, nonfatal reinfarction, or thromboembolic stroke. The mean duration of observation was approximately 4 years. The results for WARIS II are provided in the Table 8.

Table 8: WARIS II – Distribution of Events According to Treatment Group
EventAspirin
(N=1206)		Warfarin
(N=1216)		Aspirin plus Warfarin
(N=1208)		Rate Ratio
(95% CI)		p-value
CI=confidence interval
ND=not determined
*
The rate ratio is for aspirin plus warfarin as compared with aspirin.
†
The rate ratio is for warfarin as compared with aspirin.

No. of Events

Major BleedingError! Bookmark not defined.

8

33

28

3.35* (ND)
4.00† (ND)

ND
ND

Minor BleedingError! Bookmark not defined.

39

103

133

3.21* (ND)
2.55† (ND)

ND
ND

Composite
EndpointsError! Bookmark not defined.

241

203

181

0.81 (0.69-0.95)*
0.71 (0.60-0.83)†

0.03
0.001

  Reinfarction

117

90

69

0.56 (0.41-0.78)*
0.74 (0.55-0.98)†

<0.001
0.03

  Thromboembolic
  Stroke

32

17

17

0.52 (0.28-0.98)*
0.52 (0.28-0.97)†

0.03
0.03

  Death

92

96

95

0.82

There were approximately four times as many major bleeding episodes in the two groups receiving warfarin than in the group receiving aspirin alone. Major bleeding episodes were not more frequent among patients receiving aspirin plus warfarin than among those receiving warfarin alone, but the incidence of minor bleeding episodes was higher in the combined therapy group.

15 REFERENCES

•
Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 8th Ed. Chest. 2008;133:160S-198S.
•
Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ. Antithrombotic therapy for venous thromboembolic disease. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 8th Ed. Chest. 2008;133:454S-545S.
•
Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial fibrillation. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 8th Ed. Chest. 2008;133:546S-592S.
•
Becker RC, Meade TW, Berger PB, et al. The primary and secondary prevention of coronary artery disease. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 8th Ed. Chest. 2008;133:776S-814S.
•
Salem DN, O'Gara PT, Madias C, Pauker SG. Valvular and structural heart disease. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 8th Ed. Chest. 2008;133:593S-629S.
•
Monagle P, Chalmers E, Chan A, et al. Antithrombotic therapy in neonates and children. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 8th Ed. Chest. 2008;133:887S-968S.

16 HOW SUPPLIED/STORAGE AND HANDLING

Tablets

Warfarin Sodium Tablets, USP are single scored, flat beveled capsule shaped tablets, engraved numerically with 2, 2½, or 5on one side and engraved with "WARFARIN" on top of "TARO" on the other side. They are packaged with potencies and colors as follows:

Color________________Engraving_______________Unit dose packages of 100

2 mg Lavender 2 NDC 62584-984-01

5 mg Peach 5 NDC 62584-994-01

Protect from light and moisture. Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature].

Store the unit-dose blister packages in the carton until contents have been used.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Medication Guide).

Advise patients to:

•
Tell their physician if they fall often as this may increase their risk for complications.
•
Strictly adhere to the prescribed dosage schedule. Do not take or discontinue any other drug, including salicylates (e.g., aspirin and topical analgesics), other over-the-counter drugs, and botanical (herbal) products except on advice of your physician.
•
Notify their physician immediately if any unusual bleeding or symptoms occur. Signs and symptoms of bleeding include: pain, swelling or discomfort, prolonged bleeding from cuts, increased menstrual flow or vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or dark brown urine, red or tar black stools, headache, dizziness, or weakness.
•
Contact their doctor
?
immediately if they think they are pregnant
?
to discuss pregnancy planning
?
if they are considering breast-feeding
•
Avoid any activity or sport that may result in traumatic injury.
•
Obtain prothrombin time tests and make regular visits to their physician or clinic to monitor therapy.
•
Carry identification stating that they are taking warfarin sodium.
•
If the prescribed dose of warfarin sodium is missed, take the dose as soon as possible on the same day but do not take a double dose of warfarin sodium the next day to make up for missed doses.
•
Eat a normal, balanced diet to maintain a consistent intake of vitamin K. Avoid drastic changes in dietary habits, such as eating large amounts of leafy, green vegetables.
•
Contact their physician to report any serious illness, such as severe diarrhea, infection, or fever.
•
Be aware that if therapy with warfarin sodium is discontinued, the anticoagulant effects of warfarin sodium may persist for about 2 to 5 days.

PACKAGING INFORMATION

American Health Packaging unit dose blisters (see How Supplied section) contain drug product from Taro Pharmaceuticals U.S.A., Inc. as follows:

(2 mg / 100 UD) NDC 62584-984-01 packaged from NDC 51672-4028

(5 mg / 100 UD) NDC 62584-994-01 packaged from NDC 51672-4032

Packaged and Distributed by:

American Health Packaging

Columbus, OH 43217

MEDICATION GUIDE

Warfarin Sodium Tablets, USP

Read this Medication Guide before you start taking warfarin sodium and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. You and your healthcare provider should talk about warfarin sodium when you start taking it and at regular checkups.

What is the most important information I should know about warfarin sodium?

Warfarin sodium can cause bleeding which can be serious and sometimes lead to death. This is because warfarin sodium is a blood thinner medicine that lowers the chance of blood clots forming in your body.

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You may have a higher risk of bleeding if you take warfarin sodium and:
?
are 65 years of age or older
?
have a history of stomach or intestinal bleeding
?
have high blood pressure (hypertension)
?
have a history of stroke, or "mini-stroke" (transient ischemic attack or TIA)
?
have serious heart disease
?
have a low blood count or cancer
?
have had trauma, such as an accident or surgery
?
have kidney problems
?
take other medicines that increase your risk of bleeding, including:
?
a medicine that contains heparin
?
other medicines to prevent or treat blood clots
?
nonsteroidal anti-inflammatory drugs (NSAIDs)
?
take warfarin sodium for a long time. Warfarin sodium is the active ingredient in Warfarin Sodium Tablets, USP.

Tell your healthcare provider if you take any of these medicines. Ask your healthcare provider if you are not sure if your medicine is one listed above.

Many other medicines can interact with warfarin sodium and affect the dose you need or increase warfarin sodium side effects. Do not change or stop any of your medicines or start any new medicines before you talk to your healthcare provider.

Do not take other medicines that contain warfarin sodium while taking Warfarin Sodium Tablets, USP.

•
Get your regular blood test to check for your response to warfarin sodium. This blood test is called an INR test. The INR test checks to see how fast your blood clots. Your healthcare provider will decide what INR numbers are best for you. Your dose of warfarin sodium will be adjusted to keep your INR in a target range for you.
•
Call your healthcare provider right away if you get any of the following signs or symptoms of bleeding problems:
?
pain, swelling, or discomfort
?
headaches, dizziness, or weakness
?
unusual bruising (bruises that develop without known cause or grow in size)
?
nosebleeds
?
bleeding gums
?
bleeding from cuts takes a long time to stop
?
menstrual bleeding or vaginal bleeding that is heavier than normal
?
pink or brown urine
?
red or black stools
?
coughing up blood
?
vomiting blood or material that looks like coffee grounds
•
Some foods and beverages can interact with warfarin sodium and affect your treatment and dose.
?
Eat a normal, balanced diet. Talk to your healthcare provider before you make any diet changes. Do not eat large amounts of leafy, green vegetables. Leafy, green vegetables contain vitamin K. Certain vegetable oils also contain large amounts of vitamin K. Too much vitamin K can lower the effect of warfarin sodium.
•
Always tell all of your healthcare providers that you take warfarin sodium.
•
Wear or carry information that you take warfarin sodium.

See "What are the possible side effects of warfarin sodium?" for more information about side effects.

What is warfarin sodium?

Warfarin sodium is prescription medicine used to treat blood clots and to lower the chance of blood clots forming in your body. Blood clots can cause a stroke, heart attack, or other serious conditions if they form in the legs or lungs.

It is not known if warfarin sodium is safe and effective in children.

Who should not take warfarin sodium?

Do not take warfarin sodium if:

•
your chance of having bleeding problems is higher than the possible benefit of treatment. Your healthcare provider will decide if warfarin sodium is right for you. Talk to your healthcare provider about all of your health conditions.
•
you are pregnant unless you have a mechanical heart valve. Warfarin sodium may cause birth defects, miscarriage, or death of your unborn baby.
•
you are allergic to warfarin or any of the other ingredients in Warfarin Sodium Tablets, USP. See the end of this leaflet for a complete list of ingredients in Warfarin Sodium Tablets, USP.

What should I tell my healthcare provider before taking warfarin sodium?

Before you take warfarin sodium, tell your healthcare provider if you:

•
have bleeding problems
•
fall often
•
have liver or kidney problems
•
have high blood pressure
•
have a heart problem called congestive heart failure
•
have diabetes
•
plan to have any surgery or a dental procedure
•
have any other medical conditions
•
are pregnant or plan to become pregnant. See "Who should not take warfarin sodium?"
•
are breast-feeding. You and your healthcare provider should decide if you will take warfarin sodium and breast-feed.

Tell all of your healthcare providers and dentists that you are taking warfarin sodium. They should talk to the healthcare provider who prescribed warfarin sodium for you before you have any surgery or dental procedure. Your warfarin sodium may need to be stopped for a short time or your may need your dose adjusted.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Some of your other medicines may affect the way warfarin sodium works. Certain medicines may increase your risk of bleeding. See "What is the most important information I should know about warfarin sodium?"

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

How should I take warfarin sodium?

•
Take warfarin sodium exactly as prescribed. Your healthcare provider will adjust your dose from time to time depending on your response to warfarin sodium.
•
You must have regular blood tests and visits with your healthcare provider to monitor your condition.
•
If you miss a dose of warfarin sodium, call your healthcare provider.Take the dose as soon as possible on the same day. Do not take a double dose of warfarin sodium the next day to make up for a missed dose.
•
Call your healthcare provider right away if you:
?
take too much warfarin sodium
?
are sick with diarrhea, an infection, or have a fever
?
fall or injure yourself, especially if you hit your head. Your healthcare provider may need to check you

What should I avoid while taking warfarin sodium?

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Do not do any activity or sport that may cause a serious injury.

What are the possible side effects of warfarin sodium?

Warfarin sodium may cause serious side effects including:

•
See "What is the most important information I should know about warfarin sodium?"
?
Death of skin tissue (skin necrosis or gangrene). This can happen soon after starting warfarin sodium. It happens because blood clots form and block blood flow to an area of your body. Call your healthcare provider right away if you have pain, color, or temperature change to any area of your body. You may need medical care right away to prevent death or loss (amputation) of your affected body part.
?
"Purple toes syndrome." Call your healthcare provider right away if you have pain in your toes and they look purple in color or dark in color.

Tell your healthcare provider if you have any side effect that bothers you or does not go away.

These are not all of the side effects of warfarin sodium. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Warfarin Sodium Tablets, USP?

•
Store warfarin sodium at 68°F to 77°F (20°C to 25°C).
•
Keep warfarin sodium in a tightly closed container, and keep warfarin sodium out of the light.

Keep Warfarin Sodium Tablets, USP and all medicines out of the reach of children.

General information about warfarin sodium.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use warfarin sodium for a condition for which it was not prescribed. Do not give warfarin sodium to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about warfarin sodium. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about warfarin sodium that is written for healthcare professionals.

What are the ingredients in Warfarin Sodium Tablets, USP?

Active ingredient: Warfarin Sodium

Inactive ingredients: Anhydrous lactose, corn starch, and magnesium stearate

1 mg:

D&C Red No. 6 Barium Lake

2 mg:

FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake

2.5 mg:

D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake

3 mg:

D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake

4 mg:

FD&C Blue No. 1 Aluminum Lake

5 mg:

D&C Red No. 6 Barium Lake, D&C Yellow No. 10 Aluminum Lake

6 mg:

D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake

7.5 mg:

D&C Yellow No. 10 Aluminum Lake

This Medication Guide has been approved by the U.S. Food and Drug Administration.

**The brands listed are registered trademarks of their respective owners and are not trademarks of Taro Pharmaceuticals U.S.A., Inc. or its affiliates.

Packaged and Distributed by:

American Health Packaging

Columbus, OH 43217

8000813-0412

PRINCIPAL DISPLAY PANEL - 2 mg

Warfarin 2mg label

PRINCIPAL DISPLAY PANEL - 5 mg Tablet

Warfarin 5 mg label
WARFARIN SODIUM 
warfarin sodium tablet
Product Information
Product TypeHUMAN PRESCRIPTION DRUG LABELItem Code (Source)NDC:62584-984(NDC:51672-4028)
Route of AdministrationORALDEA Schedule    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
Warfarin Sodium (Warfarin) Warfarin Sodium2 mg
Inactive Ingredients
Ingredient NameStrength
anhydrous lactose 
starch, corn 
magnesium stearate 
FD&C Blue No. 2 
FD&C Red No. 40 
Aluminum Oxide 
Product Characteristics
ColorPURPLE (Lavender) Score2 pieces
ShapeOVAL (Flat beveled capsule shaped) Size11mm
FlavorImprint Code 2;WARFARIN;TARO
Contains    
Packaging
#Item CodePackage Description
1NDC:62584-984-0110 in 1 CARTON
1NDC:62584-984-1110 in 1 BLISTER PACK
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA04030104/02/2012
WARFARIN SODIUM 
warfarin sodium tablet
Product Information
Product TypeHUMAN PRESCRIPTION DRUG LABELItem Code (Source)NDC:62584-994(NDC:51672-4032)
Route of AdministrationORALDEA Schedule    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
Warfarin Sodium (Warfarin) Warfarin Sodium5 mg
Inactive Ingredients
Ingredient NameStrength
anhydrous lactose 
starch, corn 
magnesium stearate 
D&C Yellow No. 10 
Aluminum Oxide 
D&C Red No. 6 
Barium Oxide 
Product Characteristics
ColorORANGE (Peach) Score2 pieces
ShapeOVAL (Flat beveled capsule shaped) Size11mm
FlavorImprint Code 5;WARFARIN;TARO
Contains    
Packaging
#Item CodePackage Description
1NDC:62584-994-0110 in 1 CARTON
1NDC:62584-994-1110 in 1 BLISTER PACK
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA04030104/02/2012
Labeler - American Health Packaging (007914906)
Establishment
NameAddressID/FEIBusiness Operations
American Health Packagin929561009REPACK(62584-984, 62584-994)

Revised: 07/2012
Document Id: d63d7b8d-69e1-4887-a138-37144eab7b55
Set id: ab047628-67d0-4a64-8d77-36b054969b44
Version: 2
Effective Time: 20120712
 
American Health Packaging

Visit The National Library of Medicine Copyright, Privacy, Accessibility
U.S. National Library of Medicine, 8600 Rockville Pike, Bethesda, MD 20894
National Institutes of Health, Health & Human Services
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background-color:#edf5ff;}/*#rxnormlist a:hover { background-color:#3d80df; color: #fff;}*/.rxnormtable { border-collapse: collapse; margin:0px -10px -10px -10px; border: 0px transparent #8e010a; font: 100%/1.6 "Myriad Pro", Frutiger, "Lucida Grande", "Lucida Sans", "Lucida Sans Unicode", Verdana, sans-serif; width:100%;}.rxnormcol { border-right: 1px solid #ccc;}.rxnormcol1 { border-right: 0px transparent #ccc;}.rxnormthead { background: #ccc; border-top: 1px solid #a5a5a5; border-bottom: 1px solid #a5a5a5;}.rxnormth { font-weight: normal; text-align: left;}#rxnormlistPosHead { text-indent: -1000em;}.rxnormodd { background-color:#edf5ff;}.nlmclose { display: none; } .nlmopen { display: open; }#nlmfirstgroup div{border: 1px solid #bdbdbd;padding:2px;margin-top:5px;background-color:#F6F6F6;/*#dbdadf*/height:85px;}#nlmfirstgroup a{font-weight:bold;text-decoration:underline;color: 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You may obtain a copy of theLicense at http://www.hl7.org/HPL/hpl.txt.Software distributed under the License is distributed on an "AS IS"basis, WITHOUT WARRANTY OF ANY KIND, either express or implied. Seethe License for the specific language governing rights andlimitations under the License.The Original Code is all this file.The Initial Developer of the Original Code is Gunther Schadow.Portions created by Initial Developer are Copyright (C) 2002-2004Health Level Seven, Inc. 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left: 10pt; top: auto;}.spl .titleCase { text-transform: capitalize;}.spl .lowerCase { text-transform: lowercase;}.spl p { text-indent: 0em; margin-top: 1.2ex; margin-bottom: 0ex;}.spl td p { text-indent: 0em; margin-top: 0ex; margin-bottom: 0ex;} .spl th p { text-indent: 0em; margin-top: 0px; margin-bottom: 0px;} .spl p.DocumentTitle { text-indent: 0em; font-size: 100%; font-weight: bold; margin-top: 0ex; margin-bottom: 0ex; text-align: left;}.spl p.DocumentSubTitle { text-indent: 0em; font-size: 100%; font-weight: bold; margin-top: 0ex; margin-bottom: 0ex; text-align: center;}.spl .EffectiveDate { font-size: 80%; margin-top: 1ex; margin-bottom: 1ex; text-align: left; float: left; position: relative;}.spl .DocumentMetadata { display:none; position:absolute; bottom:0px; left:0px; width:30em; background:white;}.spl .EffectiveDate:hover .DocumentMetadata { display:inline;}.spl .DistributorName { font-size: 80%; margin-top: 1ex; margin-bottom: 1ex; float: right;}.spl span.DistributorName { font-size: 80%; margin-top: 1ex; margin-bottom: 1ex; float: right;}.spl span.ParagraphCaption { font-weight: bold; text-indent: 0em;}.spl p.ListCaption { font-weight: bold; font-size: 90%}.spl p.MultiMediaCaption { margin-top: 0; text-align: center; font-weight: bold; font-size: 90%}.spl p.MultiMediaCaptionNotCentered { margin-top: 0; text-align: left; font-weight: bold; font-size: 90%}.spl p.disclaimer { font-style: italic;}.spl .Italics { font-style: italic;}.spl .Bold { font-weight: bold;}.spl .Underline { text-decoration: underline;}.spl .Insert { color: green; border-bottom: 3px double;}.spl .Delete { text-decoration: line-through;}.spl a:link { text-decoration: none; }.spl a:visited { text-decoration: none; }.spl a:active { text-decoration: none; }/* use to avoid ugly uneven line spacing in IE */.spl .Sub { font-size: 80%; position: relative; bottom: -3px;}.spl .Sup { font-size: 80%; position: relative; top: -5px;}.spl table { white-space: wrap; font-size: 80%; /* NLM Change *//* border-top-style: none; border-bottom-style: none; border-right-style: none; border-left-style: none;*/ margin-top: 3ex; margin-bottom: 3ex; border-collapse: collapse; border-color: black; border-width: thin;}/* NLM Change */.spl div.HighlightSection table { font-size:100%}.spl table caption { margin-top: 10px; /* Gecko needs this, IE doesn't add any extra */ text-align: center; font-weight: bold; font-size: 110% /* NLM Change */} .spl th, .spl td { ` border-top-style: none; border-bottom-style: none; border-right-style: none; border-left-style: none; border-collapse: collapse; border-color: black; border-width: thin;/* padding-top: 1px; padding-bottom: 1px;*/}.spl td.twocolumn { width: 50%; text-align: left; vertical-align: top; padding-left: 0.5em; padding-right: 0.5em;}.spl td.Warning { border: 1px solid black; margin-top: 2ex; margin-bottom: 2.2ex; padding-left: 1em; padding-right: 1em; padding-top: 0ex; padding-bottom: 2ex;}/* the preferred way to rules in tables */.spl tr.Botrule td, .spl tr.Botrule th,.spl th.Botrule, .spl td.Botrule { border-bottom-style: solid; border-bottom-width: thin;}.spl thead tr.First td,.spl thead tr.First th { border-top-style: solid; border-top-width: medium;}.spl thead tr.Botrule td,.spl thead tr.Botrule th { border-bottom-style: solid; border-bottom-width: thin;}.spl thead tr.Toprule td,.spl thead tr.Toprule th { border-top-style: solid; border-bottom-width: thin;}.spl thead tr.Last td, .spl thead tr.Last th { border-bottom-style: solid; border-bottom-width: thin; /* rule here might fail with rowspan headers */} .spl tbody tr.First td, .spl tbody tr.First th { border-top-style: solid; border-top-width: thin;} .spl tbody.Headless tr.First td, .spl tbody.Headless tr.First th { border-top-style: solid; border-top-width: medium;} .spl tbody tr.Botrule td, .spl tbody tr.Botrule th { border-bottom-style: solid; border-bottom-width: thin;} .spl tbody tr.Last td,.spl tbody tr.Last th { border-bottom-style: solid; border-bottom-width: medium;} /* begin of combinatorics of individual rules *//* one rule only */.spl th.Lrule,.spl td.Lrule { border-left-style: solid; border-left-width: thin;}.spl .spl th.Rrule, .spl td.Rrule { border-right-style: solid; border-right-width: thin;}.spl .spl th.Toprule, .spl td.Toprule { border-top-style: solid; border-top-width: thin;}.spl th.Botrule, .spl td.Botrule { border-bottom-style: solid; border-bottom-width: thin;}/* end of table rules */.spl ul { margin-top: .2ex; margin-left: 1.5em; padding-left: 0em;} .spl ol { margin-top: .2ex; padding-left: 1.5em;}.spl li { margin-top: .2ex; margin-left: 0em;}.spl li p { margin-top: .2ex;}.spl div.Warning ul { margin-top: .2ex; margin-left: 1.5em; padding-left: 0em; margin-bottom:.2ex;}.spl ul.Disc { list-style-type: disc; }.spl ul.Circle { list-style-type: circle; }.spl ul.Square { list-style-type: square; }.spl ol.LittleRoman { list-style-type: lower-roman; }.spl ol.BigRoman { list-style-type: upper-roman; }.spl ol.LittleAlpha { list-style-type: lower-alpha; }.spl ol.BigAlpha { list-style-type: upper-alpha; }.spl ol.Arabic { list-style-type: arabic; }.spl dl { /* display: compact; compact doesn't seem to work XXX: but display: inline would work */ margin-left:.9em;}.spl dt { padding-top: 0pt; padding-left: 0pt; padding-right: 0pt; padding-bottom: 0pt;}.spl dd { padding-top: 0pt; padding-left: 0pt; padding-right: 0pt; padding-bottom: 0pt; position:relative; margin-top:-2.2ex; margin-left:1.5em;}.spl hr.Footnoterule { margin-top:2ex; width: 30%; text-align: left; /* FIXME: make a normal line, not a grey 3d effect */ }.spl dl.Footnote { margin-left:0em; margin-bottom:0ex; margin-top:0ex;}.spl dl.Footnote dt { font-size:90%;}.spl dl.Footnote dd { margin-left:1em; font-size:90%;}.spl dl.FootnoteContents { text-align: right; margin-left:0em; margin-bottom:0ex; margin-top:0ex;}.spl dl.FootnoteContents dt { font-size:100%;}.spl dl.FootnoteContents dd { margin-left:1em; font-size:90%;}.spl p.Footnote { text-indent:-1em; margin-left:1em; font-size:90%;}.spl p.Footnotesize { margin-bottom:0ex; margin-top:0ex; font-size:90%;}.spl img { display: block; margin-top: 0ex; margin-bottom: 0ex; text-align: center;} .spl p img { display: inline; margin-top: 0ex; margin-bottom: 0ex;} .spl div.Figure { margin-top: 4ex; margin-bottom: 4ex;}.spl div.Warning { border: 4px solid black; margin-top: 2ex; margin-bottom: 2.2ex; padding-left: 1em; padding-right: 1em; padding-top: 0ex; padding-bottom: 1ex;}.spl div.Subject { margin-top: 1ex; margin-bottom: 1ex; padding-top: 1ex; padding-bottom: 1ex; padding-left: .5em; padding-right: .5em; font-size: 80%; background-color: #E0E0E0; cursor: pointer;}.spl .contentTable { border: 1px solid #999999; background-color: #EAEAEA;}.spl .contentTablePetite { border: 1px solid #999999; background-color: #EAEAEA; font-size: 80%;}.spl .contentTableTitle { border-bottom: 1px solid #999999; background-color: #CCCCCC; font-size: 140%; font-weight: bold;}.spl .contentTableReg { border-bottom: none; background-color: #CCCCCC; font-size: 80%; font-weight: lighter;}.spl .formTable { border: 1px solid #FFFFFF; border-collapse: collapse;}.spl .formTablePetite { border: 1px solid #FFFFFF; border-collapse: collapse; font-size: 80%;}.spl .formTableMorePetite { border: 1px solid #FFFFFF; border-collapse: collapse; font-size: 60%;}.spl .formTitle { background-color: #CCCCCC; border: 1px solid #FFFFFF; font-size: 125%; font-weight: bold;}.spl .formHeadingTitle { border: none; background-color: #CCCCCC; font-size: 150%; font-weight: bold;}.spl .formHeadingReg { background-color: #CCCCCC; border: 1px solid #FFFFFF; font-size: 125%;}.spl .formTableRow { background-color: #FFFFFF;}.spl .formTableRowAlt { background-color: #F2F2F2;}.spl .formLabel { border: 1px solid #FFFFFF; background-color: #DDDDDD; font-size: 115%; font-weight: bold;}.spl .formItem { border: 1px solid #CCCCCC; font-size: 110%;}.spl .formTitle a:link { font-weight: bold; color: #006699; text-decoration: underline;}.spl .formTitle a:visited { /*font-family: "Arial Unicode MS"; Arial, Helvetica, sans-serif;*/ font-weight: bold; color: #006699; text-decoration: underline;}.spl .formTitle a:active { /*font-family: "Arial Unicode MS"; Arial, Helvetica, sans-serif;*/ font-weight: bold; /*color: #000000;*/ text-decoration: none;}.spl .formTitle a:hover { /*font-family: "Arial Unicode MS"; Arial, Helvetica, sans-serif;*/ font-weight: bold; /*color: #000000;*/ text-decoration: none;}.spl .normalizer { font-size: 125%; font-weight: lighter;}.spl div.Highlights { font-size: 90%; /* NLM Change */ font-family: "Times New Roman", Times, serif;}.spl div.HighlightsDisclaimer { font-weight: bold;}.spl div.Index { margin-top: 5ex; margin-bottom: 5ex; padding-top: 1ex; padding-bottom: 1ex; border-top-style: solid; border-top-width: thin; border-bottom-style: solid; border-bottom-width: thin;}.spl .Colspan { -moz-column-span: all; -webkit-column-span: all; column-span: all;}.spl div.Index h1,.spl div.Index h2 { margin-top: 0pt;}.spl div.Index h2 { margin-left: 1em; font-weight: normal;}.spl .following_xmChange {/* background: yellow; */}/*.spl span.xmChange { text-indent: 0em; margin-top: 0ex; margin-bottom: 0ex; line-height: 2.7ex; border-left-width: 3px; border-left-style: solid; border-left-color: #000000; position: absolute; left: 2em; padding-left: 2em;}.spl span.xmChange_all_rows { text-indent: 0em; margin-top: 0ex; margin-bottom: 0ex; line-height: 10ex; border-left-width: 3px; border-left-style: solid; border-left-color: #000000; position: absolute; left: 2.5em; padding-left: 2em;}.spl span.xmChange_caption { text-indent: 0em; margin-top: 0ex; margin-bottom: 0ex; line-height: 14ex; border-left-width: 3px; border-left-style: solid; border-left-color: #000000; position: absolute; left: 2.3em; padding-left: 2em;}.spl span.xmChange_footnote { text-indent: 0em; margin-top: -2ex; margin-bottom: 0ex; line-height: 8ex; border-left-width: 3px; border-left-style: solid; border-left-color: #000000; position: absolute; left: 2.5em; padding-left: 2em;}.spl span.xmChange_footnotes { text-indent: 0em; margin-top: -2ex; margin-bottom: 0ex; line-height: 8ex; border-left-width: 3px; border-left-style: solid; border-left-color: #000000; position: absolute; left: 2.8em; padding-left: 2em;}.spl span.xmChange_custom_caption { text-indent: 0em; margin-top: 0ex; margin-bottom: 0ex; line-height: 2.7ex; border-left-width: 3px; border-left-style: solid; border-left-color: #000000; position: absolute; left: -4.4em; padding-left: 0em;}*//* NLM Added */body { background-color: white; color: #000000; font-family: "Arial Unicode MS"; margin-left: 4em; margin-right: 4em;}/** NLM ADDED **/.textHighlights table { border:none;}#nlmftoc table { border:none;}#nlmftoc table *{ border:none;}#nlmftoc table tfoot tr td dl { text-align:left;}#dmsectionsfieldset * table tfoot tr td dl { text-align:left;}#backtodmsections { display:none;}.permalink a:visited { text-decoration: none;}.permalink a:link { text-decoration: none;}#rxnormlist a:visited { text-decoration: none;}#rxnormlist a:link { text-decoration: none;}#nlmdrugstatus table { border: 1px solid #8E010A; padding: 0pt; float: right; margin-bottom: 0.75em; margin-top: 0.75em; position: relative; right: 0pt; font-size: 80%; border-collapse: collapse;; border-width: thin;}#nlmdrugstatus a:visited { text-decoration: none;}#nlmdrugstatus a:link { text-decoration: none;} #disclaimer a { text-decoration: underline !important;}/* end @media screen */ \ No newline at end of file diff --git a/war/tests/SPL-annotation/styles/colorbox.css b/war/tests/SPL-annotation/styles/colorbox.css new file mode 100644 index 0000000..61ef7c2 --- /dev/null +++ b/war/tests/SPL-annotation/styles/colorbox.css @@ -0,0 +1 @@ +/* Colorbox Core Style: The following CSS is consistent between example themes and should not be altered.*/#colorbox, #cboxOverlay, #cboxWrapper{position:absolute; top:0; left:0; z-index:9999; overflow:hidden;}#cboxOverlay{position:fixed; width:100%; height:100%;}#cboxMiddleLeft, #cboxBottomLeft{clear:left;}#cboxContent{position:relative;}#cboxLoadedContent{overflow:auto; -webkit-overflow-scrolling: touch;}#cboxTitle{margin:0;}#cboxLoadingOverlay, #cboxLoadingGraphic{position:absolute; top:0; left:0; width:100%; height:100%;}#cboxPrevious, #cboxNext, #cboxClose, #cboxSlideshow{cursor:pointer;}.cboxPhoto{float:left; margin:auto; border:0; display:block; max-width:none; -ms-interpolation-mode:bicubic;}.cboxIframe{width:100%; height:100%; display:block; border:0;}#colorbox, #cboxContent, #cboxLoadedContent{box-sizing:content-box; -moz-box-sizing:content-box; -webkit-box-sizing:content-box;}/* User Style: Change the following styles to modify the appearance of Colorbox. They are ordered & tabbed in a way that represents the nesting of the generated HTML.*/#cboxOverlay{background:#000;}#colorbox{outline:0;} #cboxTopLeft{width:14px; height:14px; background:url(images/controls.png) no-repeat 0 0;} #cboxTopCenter{height:14px; background:url(images/border.png) repeat-x top left;} #cboxTopRight{width:14px; height:14px; background:url(images/controls.png) no-repeat -36px 0;} #cboxBottomLeft{width:14px; height:43px; background:url(images/controls.png) no-repeat 0 -32px;} #cboxBottomCenter{height:43px; background:url(images/border.png) repeat-x bottom left;} #cboxBottomRight{width:14px; height:43px; background:url(images/controls.png) no-repeat -36px -32px;} #cboxMiddleLeft{width:14px; background:url(images/controls.png) repeat-y -175px 0;} #cboxMiddleRight{width:14px; background:url(images/controls.png) repeat-y -211px 0;} #cboxContent{background:#fff; overflow:visible;} .cboxIframe{background:#fff;} #cboxError{padding:50px; border:1px solid #ccc;} #cboxLoadedContent{margin-bottom:5px;} #cboxLoadingOverlay{background:url(images/loading_background.png) no-repeat center center;} #cboxLoadingGraphic{background:url(images/loading.gif) no-repeat center center;} #cboxTitle{position:absolute; bottom:-25px; left:0; text-align:center; width:100%; font-weight:bold; color:#7C7C7C;} #cboxCurrent{position:absolute; bottom:-25px; left:58px; font-weight:bold; color:#7C7C7C;} /* these elements are buttons, and may need to have additional styles reset to avoid unwanted base styles */ #cboxPrevious, #cboxNext, #cboxSlideshow, #cboxClose {border:0; padding:0; margin:0; overflow:visible; position:absolute; bottom:-29px; background:url(images/controls.png) no-repeat 0px 0px; width:23px; height:23px; text-indent:-9999px;} /* avoid outlines on :active (mouseclick), but preserve outlines on :focus (tabbed navigating) */ #cboxPrevious:active, #cboxNext:active, #cboxSlideshow:active, #cboxClose:active {outline:0;} #cboxPrevious{left:0px; background-position: -51px -25px;} #cboxPrevious:hover{background-position:-51px 0px;} #cboxNext{left:27px; background-position:-75px -25px;} #cboxNext:hover{background-position:-75px 0px;} #cboxClose{right:0; background-position:-100px -25px;} #cboxClose:hover{background-position:-100px 0px;} .cboxSlideshow_on #cboxSlideshow{background-position:-125px 0px; right:27px;} .cboxSlideshow_on #cboxSlideshow:hover{background-position:-150px 0px;} .cboxSlideshow_off #cboxSlideshow{background-position:-150px -25px; right:27px;} .cboxSlideshow_off #cboxSlideshow:hover{background-position:-125px 0px;} \ No newline at end of file diff --git a/war/tests/SPL-annotation/styles/layouts/slidingdoors.css b/war/tests/SPL-annotation/styles/layouts/slidingdoors.css new file mode 100644 index 0000000..d447665 --- /dev/null +++ b/war/tests/SPL-annotation/styles/layouts/slidingdoors.css @@ -0,0 +1 @@ +#dmsectionsfieldset {clear:right;margin-top:0.7em;margin-bottom:0.3em;}#dmsectionsfieldset fieldset{ background:#DAE0D2 url("../../images/layouts/bg.gif") repeat-x bottom; border: 1px solid Firebrick; padding-left:10px; padding-right:10px; padding-bottom:1px; padding-top:0px; border-bottom:none; overflow:hidden;}#dmsectionsfieldset fieldset legend {font-size:1.2em;color:#8e010a;line-height: normal;}#dmsections { font-size:93%; line-height:normal; }#dmsections ul { margin:0; padding:0px; list-style:none; }#dmsections ul li { float:left; background:url("../../images/layouts/left_both.gif") no-repeat left top; margin:0; padding:0 0 0 9px; border-bottom:1px solid #765; }#dmsections ul li a { float:left; display:block; background:url("../../images/layouts/right_both.gif") no-repeat right top; padding:5px 15px 4px 6px; text-decoration:none; font:x-small/1.0em "Times New Roman", Times, serif; voice-family: "\"}\""; voice-family:inherit; font-size:small; font-weight:bold; color:black/*#8e010a*/; }/* Commented Backslash Hack hides rule from IE5-Mac \*/#dmsections ul li a {float:none;}/* End IE5-Mac hack */#dmsections ul li a:hover { color:#8e010a/*#333*/; font-weight:bolder; } #dmsections ul li:hover, #dmsections ul li:hover a.nlmlinktrue { background-position:0% -150px; color:#8e010a; }#dmsections ul li:hover a.nlmlinktrue { background-position:100% -150px; } #dmsections #current { background-image:url("../../images/layouts/left_on.gif"); }#dmsections #current a { background-image:url("../../images/layouts/right_on.gif"); color:#333; padding-bottom:5px; } \ No newline at end of file