Abiraterone

Abiraterone acetate is a prodrug. After it is swallowed it is rapidly hydrolysed to abiraterone, which selectively blocks CYP17, an enzyme the body needs to make androgens. Lowering testosterone and the other androgens that fuel prostate cancer cells is the basis of its use in metastatic disease.

Mechanism of Action

• Prodrug conversion: abiraterone acetate is converted in the body to abiraterone, the active androgen biosynthesis inhibitor.
• CYP17 inhibition: abiraterone selectively inhibits 17α-hydroxylase/C17,20-lyase (CYP17), an enzyme expressed in testicular, adrenal and prostatic tumour tissue. CYP17 turns pregnenolone and progesterone into the testosterone precursors dehydroepiandrosterone (DHEA) and androstenedione, by 17α-hydroxylation and cleavage of the C17,20 bond.
• More complete androgen suppression: androgen deprivation with LHRH analogues or orchiectomy lowers androgen production in the testes but not in the adrenal glands or the tumour. Abiraterone also blocks those sources. Given with an LHRH analogue (or after orchiectomy), it lowers serum testosterone to undetectable levels with commercial assays, below the levels that LHRH analogues alone or orchiectomy achieve.
• Mineralocorticoid excess: CYP17 inhibition also increases adrenal mineralocorticoid production, which causes hypertension, low potassium and fluid retention. A corticosteroid taken at the same time suppresses the ACTH drive behind this and reduces these effects, which is why prednisone or prednisolone always accompanies abiraterone.
• PSA: prostate-specific antigen (PSA) serves as a biomarker. In a phase 3 study in men whose disease had progressed after taxane chemotherapy, 38% of those given abiraterone acetate had a fall in PSA of at least 50%, against 10% with placebo.

Pharmacokinetics

• Absorption: after a dose in the fasting state, plasma abiraterone peaks in about 2 hours. Food increases exposure sharply and unpredictably, up to 10-fold for AUC and up to 17-fold for Cmax depending on the fat content of the meal, which is why the tablets must be taken on an empty stomach.
• Distribution: about 99.8% bound to plasma proteins; apparent volume of distribution about 5,630 L, indicating extensive distribution into peripheral tissues.
• Metabolism: abiraterone is metabolised mainly in the liver by sulphation, hydroxylation and oxidation. About 92% of the circulating radioactivity is metabolites; the two main ones, abiraterone sulphate and N-oxide abiraterone sulphate, each account for about 43% of total radioactivity and are pharmacologically inactive. CYP3A4 and SULT2A1 take part in forming them.
• Elimination: mean plasma half-life about 15 hours. After a radiolabelled 1,000 mg dose, about 88% of the radioactivity was recovered in faeces (mainly unchanged abiraterone acetate, about 55% of the dose, and abiraterone, about 22%) and about 5% in urine.
• Special populations: in moderate hepatic impairment (Child-Pugh class B), exposure to abiraterone after a single 1,000 mg dose was about four times higher. Renal impairment requires no dose adjustment.

Abiraterone is always taken together with prednisone or prednisolone.

• Newly diagnosed high-risk metastatic hormone-sensitive prostate cancer (mHSPC): adult men, in combination with androgen deprivation therapy (ADT).
• Metastatic castration-resistant prostate cancer (mCRPC), before chemotherapy: adult men who are asymptomatic or mildly symptomatic after failure of ADT and in whom chemotherapy is not yet clinically indicated.
• mCRPC, after chemotherapy: adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen.

• Hypersensitivity to abiraterone acetate or to any of the excipients.
• Women who are or may potentially be pregnant.
• Severe hepatic impairment (Child-Pugh class C).
• Use of abiraterone with prednisone or prednisolone in combination with radium-223 (Ra-223).

In the composite phase 3 studies, the reactions seen in at least 10% of patients were peripheral oedema, hypokalaemia, hypertension, urinary tract infection, and raised alanine and/or aspartate aminotransferase. Other important reactions are cardiac disorders, hepatotoxicity, fractures and allergic alveolitis. Hypertension, hypokalaemia and fluid retention follow from the mechanism of action: with abiraterone acetate versus placebo, hypokalaemia occurred in 18% versus 8%, hypertension in 22% versus 16% and fluid retention (peripheral oedema) in 23% versus 17% of patients. A corticosteroid taken at the same time reduces their frequency and severity, and they can generally be managed medically.

Very common (≥1/10): urinary tract infection, hypokalaemia, hypertension, diarrhoea, raised alanine aminotransferase and/or aspartate aminotransferase, peripheral oedema.

Common (≥1/100 to <1/10): sepsis, hypertriglyceridaemia, cardiac failure (including congestive heart failure, left ventricular dysfunction and reduced ejection fraction), angina pectoris, atrial fibrillation, tachycardia, dyspepsia, rash, haematuria, fractures (including osteoporosis and all fractures other than pathological ones).

Uncommon (≥1/1,000 to <1/100): adrenal insufficiency, other arrhythmias, myopathy, rhabdomyolysis.

Rare (≥1/10,000 to <1/1,000): allergic alveolitis, fulminant hepatitis, acute hepatic failure.

Not known: anaphylactic reactions, myocardial infarction, QT prolongation.

Hypertension and hypokalaemia were more frequent in men with hormone-sensitive disease (hypertension 36.7% and hypokalaemia 20.4%) than in the castration-resistant studies. The frequency and severity of adverse reactions were higher in patients with a baseline ECOG performance status of 2 and in older patients (75 years and above).

Important serious reactions are rare reports of acute liver failure and fulminant hepatitis, some fatal; cardiac failure and arrhythmias; adrenal insufficiency; myopathy and rhabdomyolysis, mostly within the first 6 months and recovering after withdrawal; and fractures.

Abiraterone is taken on an empty stomach, it inhibits CYP2D6 and CYP2C8, and its own exposure falls with strong CYP3A4 inducers.

• Food: food greatly increases absorption of abiraterone, and efficacy and safety with food have not been established, so the tablets must not be taken with food.
• Strong CYP3A4 inducers (phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital, St John’s wort): avoid unless there is no therapeutic alternative. Rifampicin 600 mg daily for 6 days lowered the AUC of a single abiraterone acetate dose by 55%.
• CYP3A4 inhibitors: ketoconazole, a strong CYP3A4 inhibitor, had no clinically meaningful effect on the pharmacokinetics of abiraterone.
• CYP2D6 substrates: abiraterone inhibits CYP2D6, and exposure to dextromethorphan rose about 2.9-fold. Use caution, particularly with medicines with a narrow therapeutic index, and consider reducing their dose. Examples are metoprolol, propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, flecainide, codeine, oxycodone and tramadol (the last three need CYP2D6 to form their active analgesic metabolites).
• CYP2C8 substrates: the AUC of pioglitazone rose by 46%. Patients should be monitored for signs of toxicity of CYP2C8 substrates with a narrow therapeutic index; pioglitazone and repaglinide are examples. Hypoglycaemia has been reported when abiraterone with prednisone or prednisolone was given to patients with diabetes taking pioglitazone or repaglinide, so blood sugar should be monitored.
• OATP1B1 substrates: in vitro, the main metabolites (abiraterone sulphate and N-oxide abiraterone sulphate) inhibit the hepatic uptake transporter OATP1B1 and could raise concentrations of medicines eliminated by it; no clinical data confirm this.
• QT-prolonging medicines: androgen deprivation may itself prolong the QT interval, so use caution with medicines known to prolong the QT interval or to cause torsades de pointes, such as class IA (quinidine, disopyramide) and class III (amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmics, methadone, moxifloxacin and antipsychotics.
• Spironolactone: it binds to the androgen receptor and may raise PSA; use with abiraterone is not recommended.
• Radium-223: contraindicated together with abiraterone and prednisone or prednisolone, because of more fractures and a trend towards higher mortality in trials. Radium-223 should not be started until at least 5 days after the last dose of abiraterone with prednisone or prednisolone.
• Medicines that can cause myopathy: caution is advised with medicines known to be associated with myopathy or rhabdomyolysis.

Zytiga should be prescribed by an appropriate healthcare professional. The tablets are taken once daily as a single dose on an empty stomach: at least 2 hours after eating, with no food for at least 1 hour after the dose. They are swallowed whole with water. Medical castration with a luteinising hormone-releasing hormone (LHRH) analogue continues in patients who have not had surgical castration.

Recommended Dose

• 1,000 mg once daily (four 250 mg tablets, or two 500 mg tablets), always with prednisone or prednisolone.
• Metastatic hormone-sensitive prostate cancer (mHSPC): with prednisone or prednisolone 5 mg daily.
• Metastatic castration-resistant prostate cancer (mCRPC): with prednisone or prednisolone 10 mg daily.

Recommended Monitoring

• Liver: serum transaminases before starting, every 2 weeks for the first 3 months, then monthly.
• Blood pressure, potassium and fluid retention: monthly. Patients at significant risk of congestive heart failure are monitored every 2 weeks for the first 3 months, then monthly.
• Potassium target: in patients with pre-existing or treatment-related hypokalaemia, consider keeping serum potassium at 4.0 mM or above.

Dose Adjustments for Side Effects

• Grade 3 or higher toxicity (including hypertension, hypokalaemia, oedema and other non-mineralocorticoid toxicities): withhold treatment and start appropriate medical management. Do not restart until the toxicity has resolved to grade 1 or baseline.
• Hepatotoxicity (ALT or AST above 5 times the upper limit of normal): withhold treatment immediately. Once liver tests are back to baseline, treatment may be resumed at a reduced dose of 500 mg once daily (two 250 mg tablets or one 500 mg tablet), with transaminases checked at least every 2 weeks for 3 months and monthly after that. If hepatotoxicity recurs at 500 mg daily, stop treatment.
• Severe hepatotoxicity (ALT or AST 20 times the upper limit of normal) at any time: stop treatment and do not re-treat.

Special Populations

• Hepatic impairment: no dose adjustment in mild impairment (Child-Pugh class A). In moderate impairment (class B), exposure to abiraterone rises about four-fold after single doses and there are no clinical data on repeated doses, so no dose adjustment can be predicted; use should be assessed cautiously and only when the benefit clearly outweighs the possible risk. Not to be used in severe impairment (class C).
• Renal impairment: no dose adjustment. There is no clinical experience in prostate cancer with severe renal impairment, so caution is advised.
• Children and adolescents: there is no relevant use of Zytiga in the paediatric population.

Missed Dose

If a daily dose of Zytiga, prednisone or prednisolone is missed, treatment is resumed the next day with the usual daily dose.

Handling by Women Who Are or May Be Pregnant

Abiraterone is not for use in women and is contraindicated in women who are or may be pregnant. Women who are or may be pregnant must not handle the tablets without gloves.

Blood Pressure, Potassium, Fluid Retention and Heart Failure

• Mineralocorticoid excess: abiraterone can cause hypertension, hypokalaemia and fluid retention. Caution is needed in patients whose condition could be made worse by higher blood pressure, low potassium (for example those taking cardiac glycosides) or fluid retention (for example heart failure, severe or unstable angina, recent myocardial infarction, ventricular arrhythmia or severe renal impairment).
• Cardiovascular disease: use with caution in patients with a history of cardiovascular disease. The phase 3 studies excluded patients with uncontrolled hypertension, a recent myocardial infarction or arterial thrombotic event (within 6 months), severe or unstable angina, significant heart failure or an ejection fraction below 50%. Safety in patients with a left ventricular ejection fraction below 50% or NYHA class III–IV heart failure (study 301), or class II–IV (studies 3011 and 302), has not been established.
• Before treatment: in patients at significant risk of congestive heart failure (for example a history of cardiac failure, uncontrolled hypertension or ischaemic heart disease), consider assessing cardiac function, such as by echocardiogram. Heart failure should be treated and cardiac function optimised, and hypertension, hypokalaemia and fluid retention corrected and controlled, before starting.
• During treatment: blood pressure, potassium, fluid retention (weight gain, peripheral oedema) and signs of heart failure are monitored every 2 weeks for 3 months, then monthly, and abnormalities are corrected. QT prolongation has been seen in patients with hypokalaemia on abiraterone. Cardiac function is reassessed as clinically indicated, and discontinuation is considered if it falls significantly.

Liver Function

• Hepatotoxicity: marked rises in liver enzymes leading to dose modification or discontinuation occurred in controlled studies. Transaminases are measured before starting, every 2 weeks for the first 3 months and monthly after that, and immediately if symptoms or signs of liver toxicity develop.
• Thresholds: if ALT or AST rises above 5 times the upper limit of normal, treatment is interrupted immediately and liver function closely monitored; re-treatment is possible only after liver tests return to baseline, at a reduced dose. If ALT or AST reaches 20 times the upper limit of normal, treatment is stopped and not restarted.
• Viral hepatitis: patients with active or symptomatic viral hepatitis were excluded from the clinical trials, so there are no data in this group.
• Hepatic impairment: there are no data on repeated doses in moderate or severe hepatic impairment (Child-Pugh class B or C). Rare post-marketing reports describe acute liver failure and fulminant hepatitis, some with fatal outcome.

Corticosteroid Withdrawal and Stress

Caution and monitoring for adrenocortical insufficiency are advised if prednisone or prednisolone is withdrawn. If abiraterone is continued after the corticosteroid is stopped, patients should be monitored for symptoms of mineralocorticoid excess. In patients on prednisone or prednisolone who face unusual stress, a higher corticosteroid dose may be indicated before, during and after the stressful situation.

Bone Density and Muscle Effects

• Bone density: bone density may fall in men with metastatic advanced prostate cancer, and a glucocorticoid taken with abiraterone could add to this effect.
• Myopathy and rhabdomyolysis: cases have been reported, most within the first 6 months of treatment and recovering after abiraterone was withdrawn.

Blood Sugar

Glucocorticoids can increase hyperglycaemia, so blood sugar should be measured frequently in patients with diabetes. Hypoglycaemia has been reported in patients with diabetes taking pioglitazone or repaglinide, so blood sugar should be monitored in them too.

Other Precautions

• Radium-223: combination with radium-223 and prednisone or prednisolone is contraindicated; subsequent radium-223 treatment should not start for at least 5 days after the last dose of abiraterone.
• Chemotherapy: the safety and efficacy of using abiraterone together with cytotoxic chemotherapy have not been established.
• Prior ketoconazole: lower response rates might be expected in patients previously treated with ketoconazole for prostate cancer.
• Anaemia and sexual dysfunction: both may occur in men with metastatic prostate cancer, including those taking abiraterone.

Pregnancy, Breastfeeding, Contraception and Fertility

• Pregnancy: abiraterone is not for use in women and is contraindicated in women who are or may be pregnant. There are no human data on its use in pregnancy, and animal studies have shown reproductive toxicity.
• Contraception in men: it is not known whether abiraterone or its metabolites are present in semen. A condom is required if the patient has sexual activity with a pregnant woman. With a woman of childbearing potential, a condom is required together with another effective contraceptive method.
• Breastfeeding: abiraterone is not for use in women.
• Fertility: abiraterone acetate affected fertility in male and female rats; these effects were fully reversible.

Lactose and Sodium

Each 250 mg tablet contains 198.65 mg of lactose monohydrate (each 500 mg tablet contains 253.2 mg). Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take it. A dose of four 250 mg tablets contains 27.2 mg (1.18 mmol) of sodium, equal to 1.36% of the WHO recommended maximum daily intake of 2 g sodium for an adult. Each 500 mg tablet contains 13.5 mg of sodium.

Effect on Driving

Abiraterone has no or negligible influence on the ability to drive and use machines.

Zytiga tablets do not require any special storage conditions. The 250 mg tablets are supplied in white HDPE bottles with a child-resistant closure, 120 tablets per bottle. The 500 mg film-coated tablets are supplied in blisters in cardboard wallets, in cartons of 56 tablets (4 wallets of 14) or 60 tablets (5 wallets of 12); not all pack sizes may be marketed. Keep them out of the sight and reach of children. Women who are or may be pregnant should not handle the tablets without gloves.

250 mg tablets: 2 years. 500 mg film-coated tablets: 3 years. Do not use after the expiry date on the pack.

Prescription only (Rx), on the prescription of an appropriate healthcare professional (medicinal product subject to medical prescription). Abiraterone is taken at home as tablets, so it is supplied to the patient or to the treating clinic on prescription. Women who are or may be pregnant should not handle the tablets without gloves.