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Hypertension, hypokalemia, fluid retention and cardiac failure due to mineralocorticoid excess: Abiraterone acetate (Zytiga) may cause hypertension, hypokalemia and fluid retention (see Adverse Reactions) as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition (see Pharmacology: Pharmacodynamics under Actions).
Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the 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, hypokalemia (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).
Abiraterone acetate (Zytiga) should be used with caution in patients with a history of cardiovascular disease. The Phase 3 studies conducted with abiraterone acetate (Zytiga) 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 (studies 3011 and 302) or cardiac ejection fraction measurement of < 50%. In studies 3011 and 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 studies 3011 and 302) was not established (see Adverse Reactions and Pharmacology: Pharmacodynamics under Actions).
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 ischemic heart disease), consider obtaining an assessment of cardiac function (e.g. echocardiogram). Before treatment with abiraterone acetate (Zytiga), cardiac failure should be treated and cardiac function optimized. Hypertension, hypokalemia and fluid retention should be corrected and controlled. During treatment, blood pressure, serum potassium, fluid retention (weight gain, peripheral edema) and other signs and symptoms of congestive heart failure should be monitored every 2 weeks for 3 months, then monthly thereafter and abnormalities corrected. QT prolongation has been observed in patients experiencing hypokalemia in association with abiraterone acetate (Zytiga) treatment. Assess cardiac function as clinically indicated, institute appropriate management and consider discontinuation of this treatment if there is a clinically significant decrease in cardiac function (see Dosage & Administration).
Hepatotoxicity and Hepatic Impairment: Marked increases in liver enzymes leading to treatment discontinuation or dose modification occurred in controlled clinical studies (see Adverse Reactions). Serum transaminase levels should be measured prior to starting treatment, every two weeks for the first three months of treatment, and monthly thereafter. If clinical symptoms or signs suggestive of hepatotoxicity develop, serum transaminases should be measured immediately. If at any time the ALT or AST rises above 5 times the ULN, treatment should be interrupted immediately and liver function closely monitored.
Re-treatment may only take place after the return of liver function tests to the patient's baseline and at a reduced dose level (see Dosage & Administration).
If patients develop severe hepatotoxicity (ALT or AST 20 times the ULN) anytime while on therapy, abiraterone acetate (Zytiga) should be discontinued and patients should not be re-treated.
Patients with active or symptomatic viral hepatitis were excluded from clinical trials; thus, there are no data to support the use of abiraterone acetate (Zytiga) in this population.
There are no data on the clinical safety and efficacy of multiple doses of abiraterone acetate when administered to patients with moderate or severe hepatic impairment (Child-Pugh Class B or C). The use of abiraterone acetate (Zytiga) should be cautiously assessed in patients with moderate hepatic impairment, in whom the benefit clearly should outweigh the possible risk (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions). Abiraterone acetate (Zytiga) should not be used in patients with severe hepatic impairment (see Dosage & Administration, Contraindications and Pharmacology: Pharmacokinetics under Actions).
There have been rare post-marketing reports of acute liver failure and hepatitis fulminant, some with fatal outcome (see Adverse Reactions).
Corticosteroid withdrawal and coverage of stress situations: Caution is advised and monitoring for adrenocortical insufficiency should occur if patients are withdrawn from prednisone or prednisolone. If abiraterone acetate (Zytiga) is continued after corticosteroids are withdrawn, patients should be monitored for symptoms of mineralocorticoid excess (see information as previously mentioned).
In patients on prednisone or prednisolone who are subjected to unusual stress, increased dose of corticosteroids may be indicated before, during and after the stressful situation.
Bone density: Decreased bone density may occur in men with metastatic advanced prostate cancer. The use of abiraterone acetate (Zytiga) 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.
Hyperglycemia: The use of glucocorticoids could increase hyperglycemia, therefore blood sugar should be measured frequently in patients with diabetes.
Hypoglycemia: Cases of hypoglycemia have been reported when abiraterone acetate (Zytiga) plus prednisone/prednisolone was administered to patients with pre-existing diabetes receiving pioglitazone or repaglinide (see Interactions); therefore, blood sugar should be monitored in patients with diabetes.
Use with chemotherapy: The safety and efficacy of concomitant use of abiraterone acetate (Zytiga) with cytotoxic chemotherapy has not been established (see Pharmacology under Actions).
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 250 mg tablets or 1.18 mmol (or 27 mg) sodium per dose of two 500 mg tablets. To be taken into consideration by patients on a controlled sodium diet.
Potential risks: Anemia and sexual dysfunction may occur in men with metastatic prostate cancer including those undergoing treatment with abiraterone acetate (Zytiga).
Skeletal muscle effects: Cases of myopathy and rhabdomyolysis have been reported in patients treated with abiraterone acetate (Zytiga). Most cases developed within the first 6 months of treatment and recovered after abiraterone acetate (Zytiga) withdrawal. Caution is recommended in patients concomitantly treated with medicinal products known to be associated with myopathy/rhabdomyolysis.
Interactions with other medicinal products: Strong inducers of CYP3A4 during treatment are to be avoided unless there is no therapeutic alternative, due to risk of decreased exposure to abiraterone (see Interactions).
Combination of abiraterone and prednisone/prednisolone with Ra-223: Treatment with abiraterone and prednisone/prednisolone in combination with Ra-223 is contraindicated (see Contraindications) due to an increased risk of fractures and a trend for increased mortality among asymptomatic or mildly symptomatic prostate cancer patients as observed in clinical trials.
It is recommended that subsequent treatment with Ra-223 is not initiated for at least 5 days after the last administration of abiraterone acetate (Zytiga) in combination with prednisone/prednisolone.
Effects on Ability to Drive and Use Machines: Abiraterone acetate (Zytiga) has no or negligible influence on the ability to drive and use machines.
