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  • Zytiga
    / Janssen


    Active Ingredient

    Status in Israel
    RX

    Presentation and Status in Health Basket

    Presentation Basket Yarpa Pharmasoft

    Tablets

    120 X 250 mg

    partial basket chart 34314 26181

    Related information


    Dosage

    Recommended Dosage: The recommended dose  is 1,000 mg (four 250mg tablets) administered orally once daily in combination with prednisone 5 mg administered orally twice daily. This drug must be taken on an empty stomach. No food should be consumed for at least two hours before the dose  is taken and for at least one hour after the dose  is taken. The tablets should be swallowed whole with water. Do not crush or chew tablets.Dose Modification Guidelines
    Hepatic Impairment: In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose 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 5X upper limit of normal (ULN) or total bilirubin greater than 3X ULN occur in patients with baseline moderate hepatic impairment, discontinue  and do not re-treat patients with this drug. It should not be used in patients with severe hepatic impairment (Child-Pugh Class C).
    Hepatotoxicity: For patients who develop hepatotoxicity during treatment (ALT and/or AST greater than 5X ULN or total bilirubin greater than 3X ULN), interrupt treatment. 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 2.5X ULN and total bilirubin less than or equal to 1.5X 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 2.5X ULN and total bilirubin less than or equal to 1.5X ULN. If hepatotoxicity recurs at the reduced dose of 500 mg once daily, discontinue treatment. The safety in re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.
    For full details see prescribing information.


    Indications

    In combination with prednisone, for the the treatment of patients with metastatic castration-resistant prostate cancer (CRPC), who have received prior chemotherapy containing docetaxel.


    Contra-Indications

    Pregnancy: This drug may cause fetal harm when administered to a pregnant woman. It is not indicated for use in women. It 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.
    Hypersensitivity to the active substance or to any of the excipients listed.
    Severe hepatic impairment Child-Pugh Class C.
    For full details see prescribing information.


    Special Precautions

    Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess This drug may cause hypertension, hypokalaemia and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition .Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in incidence and severity of these adverse reactions. Caution is required in treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalaemia (e.g., those on cardiac glycosides), or fluid retention (e.g., those with heart failure), severe or unstable angina pectoris, recent myocardial infarction or ventricular arrhythmia and those with severe renal impairment.
    It should be used with caution in patients with a history of cardiovascular disease. The phase 3 studies conducted excluded patients with uncontrolled hypertension, clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association Class (NYHA) III or IV heart failure (study 301) or Class II to IV heart failure (study 302) or cardiac ejection fraction measurement of < 50%. In study 302 patients with atrial fibrillation, or other cardiac arrhythmia requiring medical therapy were excluded. Safety in patients with left ventricular ejection fraction (LVEF) < 50% or NYHA Class III or IV heart failure (in study 301) or NYHA Class II to IV heart failure (in study 302) was not established .
    Before treating patients with a significant risk for congestive heart failure (e.g.a history of cardiac failure, uncontrolled hypertension, or cardiac events such as ischaemic heart disease), consider obtaining an assessment of cardiac function (e.g. echocardiogram). Before treatment with ZYTIGA, cardiac failure should be treated and cardiac function optimised. Hypertension, hypokalaemia and fluid retention should be corrected and controlled. During treatment, blood pressure, serum potassium, fluid retention (weight gain, peripheral oedema), and other signs and symptoms of congestive heart failure should be monitored every 2 weeks for 3 months, then monthly thereafter and abnormalities corrected. Assess cardiac function as clinically indicated, institute appropriate management and consider discontinuation of treatment if there is a clinically significant decrease in cardiac function .
    Adrenocortical Insufficiency Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking this drug and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving it 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 it. 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.
    Hepatotoxicity In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X 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 it. No deaths clearly related to it were reported due to hepatotoxicity events.
    Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced 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 treatment and closely monitor liver function. Re-treatment 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 2.5X ULN and total bilirubin less than or equal to 1.5X ULN.
    The safety of re-treatment with patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.
    Increased Zytiga Exposures with Food It must be taken on an empty stomach. No food should be consumed for at least two hours before the dose is taken and for at least one hour after the dose is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed.
    Bone density Decreased bone density may occur in men with metastatic advanced prostate cancer (castration resistant prostate cancer). The use in combination with a glucocorticoid could increase this effect.
    Prior use of ketoconazole Lower rates of response might be expected in patients previously treated with ketoconazole for prostate cancer.
    Hyperglycaemia The use of glucocorticoids could increase hyperglycaemia, therefore blood sugar should be measured frequently in patients with diabetes.
    Use with chemotherapy The safety and efficacy of concomitant use with cytotoxic chemotherapy has not been established .
    Intolerance to excipients This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. This medicinal product also contains more than 1 mmol (or 27.2 mg) sodium per dose of four tablets. To be taken into consideration by patients on a controlled sodium diet.
    Potential risks Anaemia and sexual dysfunction may occur in men with metastatic castration resistant prostate cancer including those undergoing treatment.
    For full details see prescribing information.


    Side Effects

    The following are discussed in more detail in other sections of the labeling:
    – Hypertension, hypokalemia, and fluid retention due to mineralocorticoid excess.
    – Adrenocortical insufficiency.
    – Hepatotoxicity.
    – Increased Exposures with Food.
    For full details see prescribing information.


    Drug interactions

    Effects of Abiraterone on Drug Metabolizing Enzymes ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. 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 ClinicalPharmacology (12.3)]. In vitro, ZYTIGA inhibits CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8. However, patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.
    Drugs that Inhibit or Induce CYP3A4 Enzymes Based on in vitro data, ZYTIGA is a substrate of CYP3A4. The effects of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) on the pharmacokinetics of abiraterone have not been evaluated, in vivo. Avoid or use with caution, strong inhibitors and inducers of CYP3A4 during ZYTIGA treatment.
    For full details see prescribing information.


    Pregnancy and Lactation

    Pregnancy: Pregnancy Category X:  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  in pregnant women and it 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. It 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. 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.
    Nursing Mothers: It 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, a decision should be made to either discontinue nursing, or discontinue the drug
    taking into account the importance of the drug to the mother.
    Pediatric Use: Safety and effectiveness in pediatric patients have not been established.


    Overdose

    There have been no reports of overdose of ZYTIGA during clinical studies. 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.


    Manufacturer
    Janssen Pharmaceuticals
    Licence holder
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