Zytiga

/ Janssen

Recommended dose for metastatic CRPC
The recommended dose is 1,000 mg (four 250mg tablets) administered orally once daily in combination with prednisone 5 mg administered orally twice daily.
Recommended dose for metastatic High-risk mHSPC
The recommended dose is 1,000 mg (four 250mg tablets) administered orally once daily in combination with prednisone 5mg administered orally once daily.
Important administration instructions
Patients receiving this drug should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy.
This medicinal product 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.
Serum transaminases should be measured prior to starting treatment with this drug, every two weeks for the first three months of treatment and monthly thereafter. Blood pressure, serum potassium and fluid retention should be monitored monthly. However, patients with a significant risk for congestive heart failure should be monitored every 2 weeks for the first three months of treatment and monthly thereafter.
In patients with pre-existing hypokalemia or those that develop hypokalemia whilst being treated with this drug, consider maintaining the patient’s potassium level at ≥ 4.0 mM.
For patients who develop Grade ≥ 3 toxicities including hypertension, hypokalemia, oedema and other non-mineralocorticoid toxicities, treatment should be withheld and appropriate medical management should be instituted. Treatment should not be reinitiated until symptoms of the toxicity have resolved to Grade 1 or baseline.
In the event of a missed daily dose of either this drug or prednisone, treatment should be resumed the following day with the usual daily dose.
See prescribing information for dose modifications and further details.

This is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer.
The treatment of newly diagnosed high risk metastatic hormone sensitive prostate cancer (mHSPC) in adult men in combination with androgen deprivation therapy (ADT).

– Hypersensitivity to the active substance or to any of the excipients.
– Women who are or may potentially be pregnant.
– Severe hepatic impairment (Child-Pugh Class C).
– ZYTIGA 250 MG with prednisone is contraindicated in combination with Ra-223.

Hypertension, hypokalaemia, fluid retention and cardiac failure 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).
This drug should be used with caution in patients with a history of cardiovascular disease. 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 this drug, 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. QT prolongation has been observed in patients experiencing hypokalaemia. 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.
Hepatotoxicity and hepatic impairment:
Marked increases in liver enzymes leading to treatment discontinuation or dose modification occurred in controlled clinical studies. 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 take place only after return of liver function tests to the patient’s baseline and at a reduced dose level.
If patients develop severe hepatotoxicity (ALT or AST 20 times the ULN) anytime while on therapy, treatment 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 this drug 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 this drug should be cautiously assessed in patients with moderate hepatic impairment, in whom the benefit clearly should outweigh the possible risk. This drug should not be used in patients with severe hepatic impairment.
There have been rare post-marketing reports of acute liver failure and hepatitis fulminant, some with fatal outcome.
Corticosteroid withdrawal and coverage of stress situations:
Caution is advised and monitoring for adrenocortical insufficiency should occur if patients are withdrawn from prednisone If this drug is continued after corticosteroids are withdrawn, patients should be monitored for symptoms of mineralocorticoid excess.
In patients on prednisone who are subjected to unusual stress, an 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 ZYTIGA 250 MG 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.
Hypoglycaemia:
Cases of hypoglycaemia have been reported when this drug plus prednisone was administered to patients with pre-existing diabetes receiving pioglitazone or repaglinide; therefore, blood sugar should be monitored 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, total lactase deficiency or glucose-galactose malabsorption should not take this medicine. This medicinal product contains 27.2 mg (1.18 mmol) sodium per dose of four tablets, equivalent to 1.36% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Potential risks:
Anaemia and sexual dysfunction may occur in men with metastatic prostate cancer including those undergoing treatment with this drug.
Skeletal muscle effects:
Cases of myopathy and rhabdomyolysis have been reported in patients treated with this drug. Most cases developed within the first 6 months of treatment and recovered after the drug 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.
Combination of abiraterone and prednisone with Ra-223:
Treatment with abiraterone and prednisone in combination with Ra-223 is contraindicated 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 this drug in combination with prednisone.
See prescribing information for full details.

Very common: Urinary tract infection, hypokalaemia, diarrhea, alanine aminotransferase increased and/or aspartate aminotransferase increased, oedema peripheral.
Common: Sepsis, hypertriglyceridaemia, cardiac failure, angina pectoris, atrial fibrillation, tachycardia, dyspepsia, rash, haematuria, fractures.
See prescribing information for full details.

Effect of food on abiraterone:
Administration with food significantly increases the absorption of abiraterone. The efficacy and safety when given with food have not been established therefore this medicinal product must not be taken with food.
Potential for other medicinal products to affect abiraterone exposures:
In a clinical pharmacokinetic interaction study of healthy subjects pretreated with a strong CYP3A4 inducer rifampicin, 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%.
Strong inducers of CYP3A4 (e.g., phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital, St John’s wort [Hypericum perforatum]) during treatment are to be avoided, unless there is no therapeutic alternative.
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.
Potential to affect exposures to other medicinal products:
Abiraterone is an inhibitor of the hepatic drug-metabolising enzymes CYP2D6 and CYP2C8.
In a study to determine the effects of abiraterone acetate (plus prednisone) on a single dose of the CYP2D6 substrate dextromethorphan, the systemic exposure (AUC) of dextromethorphan was increased approximately 2.9 fold. The AUC24 for dextrorphan, the active metabolite of dextromethorphan, increased approximately 33%.
Caution is advised when administering with medicinal products activated by or metabolised by CYP2D6, particularly with medicinal products that have a narrow therapeutic index. Dose reduction of medicinal products with a narrow therapeutic index that are metabolised by CYP2D6 should be considered. Examples of medicinal products metabolised by CYP2D6 include metoprolol, propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, flecainide, codeine, oxycodone and tramadol (the latter three medicinal products requiring CYP2D6 to form their active analgesic metabolites).
In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone was increased by 46% and the AUCs for M-III and M-IV, the active metabolites of pioglitazone, each decreased by 10% when pioglitazone was given together with a single dose of 1 000 mg abiraterone acetate. ZYTIGA 250 MG. Patients should be monitored for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly. Examples of medicinal products metabolised by CYP2C8 include pioglitazone and repaglinide.
In vitro, the major metabolites abiraterone sulphate and N-oxide abiraterone sulphate were shown to inhibit the hepatic uptake transporter OATP1B1 and as a consequence it may increase the concentrations of medicinal products eliminated by OATP1B1. There are no clinical data available to confirm transporter based interaction.
Use with products known to prolong QT interval:
Since androgen deprivation treatment may prolong the QT interval, caution is advised when administering this drug with medicinal products known to prolong the QT interval or medicinal products able to induce torsades de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc.
Use with Spironolactone:
Spironolactone binds to the androgen receptor and may increase prostate specific antigen (PSA) levels. Use with this drug is not recommended.

Pregnancy
This medicinal product is not for use in women and is contraindicated in women who are or may potentially be pregnant.
Breast-feeding
This medicinal product is not for use in women.
Fertility
Abiraterone acetate affected fertility in male and female rats, but these effects were fully reversible.
See prescribing information for full details.

Human experience of overdose is limited.
There is no specific antidote. In the event of an overdose, administration should be withheld and general supportive measures undertaken, including monitoring for arrhythmias, hypokalaemia and for signs and symptoms of fluid retention. Liver function also should be assessed.

Shelf life after first opening: 30 days.