Abiraterone for Refractory Prostate Cancer

Transcription

1 Abiraterone for Refractory Prostate Cancer Indication (NICE): Abiraterone is indicated with prednisolone for the treatment of metastatic castration resistant prostate cancer in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen. Regimen details: Abiraterone acetate 1000mg PO once daily continuously Prednisolone 5mg PO twice daily continuously Administration: Abiraterone acetate should be taken once a day on an empty stomach, at least one hour before or at least two hours after food. Available as 250mg tablets. Prednisolone should be taken twice a day with food. Available as 5mg tablets. If the patient is no longer receiving Abiraterone acetate, prednisolone should be tapered slowly and monitoring for adrenocortical insufficiency should occur. Conversely, if Abiraterone Acetate is continued after corticosteroids are withdrawn, patients should be monitored for symptoms of mineralocorticoid excess. Frequency: Continuous therapy, until disease progression or unacceptable toxicity Supportive medication: Proton pump inhibitor therapy recommended whilst on prednisolone. Extravasation: N/A Regular investigation: FBC U&Es Baseline, 2 weekly for the first 3 months, then monthly LFT s Baseline, 2 weekly for the first 3 months, then monthly LDH PSA Blood pressure Fluid retention & Potassium (see hypokalemia chart, app.1) ECHO Baseline and periodically if appropriate Triglycerides Baseline and periodically if appropriate Toxicities: hepatotoxicity; hypertension, hypokalemia; fluid retention; urinary tract infection, cardiac disorders; hypertriglyceridemia; fatigue; arthalgia; nausea Symptoms related to prolonged use (Cushing s syndrome) or withdrawal (fever, myalgia, fatigue, arthralgia, malaise) of prednisolone should be monitored Comments: Hepatic toxicity Patient counselling All patients should be counselled at the start of treatment with basic knowledge of the signs and symptoms suggestive of liver toxicity. The patient should be informed to discontinue treatment if they feel unwell or in the event of symptoms such as anorexia, nausea, vomiting, fatigue, jaundice, abdominal pain, dark urine or pale stools. If these occur, serum transaminases, in particular serum ALT, should be measured immediately. If at any time the ALT rises above 5 times the upper limit of normal, treatment should be interrupted immediately and liver function closely monitored. Retreatment may take place only after return of liver function tests to the patient s baseline and at a reduced dose level (see below). Page 1 of 5

2 Monitoring of adrenal function Patients with adrenal insufficiency Adrenal function should be monitored in patients with Addison s Disease, adrenal insufficiency or borderline adrenal function and in patients under prolonged period of stress (major surgery, intensive care etc.), and in patients on prolonged therapy presenting signs and symptoms suggestive of adrenal insufficiency. Cardiac effects - Previous studies have 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 III or IV heart failure or cardiac ejection fraction measurement of < 50%. Abiraterone should be used with caution in patients with a history of cardiovascular disease. Safety in patients with left ventricular ejection fraction < 50% or NYHA Class III or IV heart failure has not been established. Before treatment hypertension must be controlled and hypokalaemia must be corrected. Bone density: Decreased bone density may occur in men with metastatic advanced prostate cancer (castration resistant prostate cancer). The use of abiraterone acetate in combination with a glucocorticoid could increase this effect. Lactose content; Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Abiraterone acetate tablets. Sodium content ; contains more than 1mmol (or 27.2mg) sodium per dose of four tablets (1000mg). To be taken into consideration by patients on a controlled sodium diet. Food and absorption; administration with food significantly increases the absorption of abiraterone acetate. Abiraterone acetate is to be taken on empty stomach. It is not known whether Abiraterone Acetate or its metabolites are present in semen. A condom is required if the patient is engaged in sexual activity with a pregnant woman. If the patient is engaged in sex with a woman of childbearing potential, a condom is required along with another effective contraceptive method. Lower rates of response might be expected in patients previously treated with ketoconazole for prostate cancer To be supplied to the patient for oral self-administration. Ensure that the patient has an information pack and the treatment plan. DOSE MODIFICATIONS Haematological Toxicity: N/A Renal Impairment: No routine dose reduction recommended Page 2 of 5

3 Hepatic Impairment: No dose-adjustment is necessary in mild hepatic impairment (Child Pugh Class A). There are no data on safety and efficacy in moderate or severe hepatic impairment (Child Pugh Class B or C), and Treatment should be avoided in these patients. ALT/AST level Bilirubin level Abiraterone dose x ULN x ULN Increase LFT s monitoring frequency x ULN x ULN Monitor LFT s at least weekly > 5 x ULN or >3 x ULN Withheld until returned to baseline (or ALT/AST 2.5 x ULN and Bilirubin 1.5 x ULN), then reduce dose to 500mg daily. When re-started, monitor LFT s 2 weekly for 3 months, then monthly. If hepatotoxicity re-occurs on 500mg dose, discontinue treatment. > 20 x ULN Discontinue, no re-challenge Managing other toxicities Hypertension, hypokalemia and fluid retention due to mineralocorticoid excess Abiraterone acetate 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. Blood pressure, serum potassium and fluid retention should be monitored before treatment and at least monthly thereafter. Hypertension management Grade 1 or 2 Manage hypertension according local guidelines, no change in abiraterone dosing Grade 3 or 4 Withhold abiraterone until blood pressure is controlled Drug-Drug Interactions (DDIs) : CYP2D6 modified CYP3A4 inducers CYP3A4 inhibitors Abiraterone is a potent inhibitor of CYP2D6. Caution with concomittant administration of medicines that are metabolised or activated by CYP2D6 enzyme (e.g. dextrometorphan, metoprolol, propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, flecanide, codeine, oxycodone and tramadol is advised and dose reductions should be considered partucularly for medicinal products with a narrow therapeutic index. (carbamazepine, phenytoin, rifampicin, rifabutin, rifapentine, phenobarbital) : may reduce the bioavailability of Abiraterone (ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole, grape-fruit juice) : may increase the bioavailability of Abiraterone Page 3 of 5

4 References: accessed Sept-11 Micromedex review: Abiraterone, accessed Sept-11 NICE TA259, June 2012 De Bono J.S. et al. NEJM (2011) 21(364); Page 4 of 5

5 Appendix 1. Page 5 of 5