Each film coated tablet contains: Abiraterone Acetate 250 mg.
Excipients/Inactive Ingredients: Lactose Monohydrate, Microcrystalline Cellulose, Croscarmellose sodium, Povidone, Sodium Lauryl Sulfate, Colloidal Silicon Dioxide, Magnesium Stearate, Opadry White OY-58900 and Purified Water.
Colour: Titanium Dioxide.
Pharmacology: Pharmacodynamics: Mechanism of action: Abiraterone acetate is converted in vivo to abiraterone, an androgen biosynthesis inhibitor. Specifically, abiraterone selectively inhibits the enzyme 17α-hydroxylase/C17, 20-lyase (CYP17). This enzyme is expressed in and is required for androgen biosynthesis in testicular, adrenal and prostatic tumour tissues. CYP17 catalyses the conversion of pregnenolone and progesterone into testosterone precursors, DHEA and androstenedione, respectively, by 17α-hydroxylation and cleavage of the C17, 20 bond. CYP17 inhibition also results in increased mineralocorticoid production by the adrenals.
Androgen-sensitive prostatic carcinoma responds to treatment that decreases androgen levels. Androgen deprivation therapies, such as treatment with LHRH analogues or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumour. Treatment with abiraterone decreases serum testosterone to undetectable levels (using commercial assays) when given with LHRH analogues (or orchiectomy).
Abiraterone decreases serum testosterone and other androgens to levels lower than those achieved by the use of LHRH analogues alone or by orchiectomy. This results from the selective inhibition of the CYP17 enzyme required for androgen biosynthesis. Prostate specific antigen (PSA) serves as a biomarker in patients with prostate cancer.
Pharmacokinetics: Following administration abiraterone acetate is rapidly converted in vivo to abiraterone, an androgen biosynthesis inhibitor.
Absorption: Following oral administration of abiraterone acetate in the fasting state, the time to reach maximum plasma abiraterone concentration is approximately 2 hours.
Administration of abiraterone acetate with food, compared with administration in a fasted state, results in up to a 10-fold (AUC) and up to a 17-fold (Cmax) increase in mean systemic exposure of abiraterone, depending on the fat content of the meal. Given the normal variation in the content and composition of meals, taking abiraterone with meals has the potential to result in highly variable exposures. Therefore, abiraterone must not be taken with food. It should be taken at least two hours after eating and no food should be eaten for at least one hour after taking abiraterone. The tablets should be swallowed whole with water.
Distribution: The plasma protein binding of 14C-abiraterone in human plasma is 99.8%. The apparent volume of distribution is approximately 5,630 l, suggesting that abiraterone extensively distributes to peripheral tissues.
Biotransformation: Following oral administration of 14C-abiraterone acetate as capsules, abiraterone acetate is hydrolysed to abiraterone, which then undergoes metabolism including sulphation, hydroxylation and oxidation primarily in the liver. The majority of circulating radioactivity (approximately 92%) is found in the form of metabolites of abiraterone. Of 15 detectable metabolites, 2 main metabolites, abiraterone sulphate and N-oxide abiraterone sulphate, each represents approximately 43% of total radioactivity.
Elimination: The mean half-life of abiraterone in plasma is approximately 15 hours. Following oral administration of 14C-abiraterone acetate 1,000 mg, approximately 88% of the radioactive dose is recovered in faeces and approximately 5% in urine. The major compounds present in faeces are unchanged abiraterone acetate and abiraterone (approximately 55% and 22% of the administered dose, respectively).
Patients with hepatic impairment: No dose adjustment is necessary for patients with pre-existing mild hepatic impairment.
The use of abiraterone acetate should be cautiously assessed in patients with moderate hepatic impairment in whom the benefit clearly should outweigh the possible risk. Abiraterone acetate should not be used in patients with severe hepatic impairment.
For patients who develop hepatotoxicity during treatment, suspension of treatment and dose adjustment may be required.
Patients with renal impairment: Systemic exposure to abiraterone after a single oral 1,000 mg dose did not increase in subjects with end-stage renal disease on dialysis. Administration in patients with renal impairment, including severe renal impairment, does not require dose reduction. However, there is no information in patients with prostate cancer and severe renal impairment. Caution is advised in these patients.
Abiraterone is indicated with prednisone or prednisolone for: The treatment of metastatic castration resistant prostate cancer in adult men whose disease has progressed after a docetaxel-based chemotherapy regimen; The treatment of metastatic castration resistant prostate cancer in adult men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated.
Posology: The recommended dose is 1,000 mg (four 250 mg tablets) as a single daily dose that must not be taken with food (see information on the Method of administration as follows). Taking the tablets with food increases systemic exposure to abiraterone. (See Interactions and Pharmacology: Pharmacokinetics under Actions.)
Abiraterone is to be taken with low dose prednisone or prednisolone. The recommended dose of prednisone or prednisolone is 10 mg daily.
Medical castration with LHRH analogue should be continued during treatment in patients not surgically castrated.
Serum transaminases should be measured prior to starting treatment, every two weeks for the first three months of treatment and monthly thereafter. Blood pressure, serum potassium and fluid retention should be monitored monthly (see Precautions). 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 (see Precautions).
In patients with pre-existing hypokalaemia or those that develop hypokalaemia whilst being treated with abiraterone, consider maintaining the patient's potassium level at ≥ 4.0 mM.
For patients who develop Grade ≥ 3 toxicities including hypertension, hypo-kalaemia, oedema and other non-mineralocorticoid toxicities, treatment should be withheld and appropriate medical management should be instituted. Treatment with abiraterone 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 abiraterone, prednisone or prednisolone, treatment should be resumed the following day with the usual daily dose.
Hepatotoxicity: For patients who develop hepatotoxicity during treatment (alanine aminotransferase [ALT] increases or aspartate aminotransferase [AST] increases above 5 times the upper limit of normal [ULN]), treatment should be withheld immediately (see Precautions). Re-treatment following return of liver function tests to the patient's baseline may be given at a reduced dose of 500 mg (two tablets) once daily. For patients being re-treated, serum transaminases should be monitored at a minimum of every two weeks for three months and monthly thereafter. If hepatotoxicity recurs at the reduced dose of 500 mg daily, treatment should be discontinued.
If patients develop severe hepatotoxicity (ALT or AST 20 times the upper limit of normal) anytime while on therapy, treatment should be discontinued and patients should not be re-treated.
Hepatic impairment: No dose adjustment is necessary for patients with pre-existing mild hepatic impairment, Child-Pugh Class A.
Moderate hepatic impairment (Child-Pugh Class B) has been shown to increase the systemic exposure to abiraterone by approximately four-fold following single oral doses of abiraterone acetate 1,000 mg. 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). No dose adjustment can be predicted. The use of abiraterone should be cautiously assessed in patients with moderate hepatic impairment, in whom the benefit clearly should outweigh the possible risk. Abiraterone should not be used in patients with severe hepatic impairment. (See Contraindications, Precautions.)
Renal impairment: No dose adjustment is necessary for patients with renal impairment. However, there is no clinical experience in patients with prostate cancer and severe renal impairment. Caution is advised in these patients.
Paediatric population: There is no relevant use of abiraterone in the paediatric population, as prostate cancer is not present in children and adolescent.
Method of administration: Abiraterone should be taken at least two hours after eating and no food should be eaten for at least one hour after taking the tablets. Abiraterone is to be administered orally. These should be swallowed whole with water.
Human experience of overdose with abiraterone 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.
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].
Hypertension, hypokalaemia, fluid retention and cardiac failure due to mineralocorticoid excess: Abiraterone 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.
Abiraterone 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 abiraterone, 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 in association with abiraterone 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.
Hepatotoxicity and hepatic impairment: Marked increases in liver enzymes leading to treatment discontinuation or dose modification. 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 upper limit of normal, 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 upper limit of normal) anytime while on therapy, treatment should be discontinued and patients should not be re-treated.
Patients with active or symptomatic viral hepatitis were excluded, there are no data to support the use of abiraterone in this population.
The use of abiraterone should be cautiously assessed in patients with moderate hepatic impairment, in whom the benefit clearly should outweigh the possible risk. Abiraterone should not be used in patients with severe hepatic impairment.
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 is continued after corticosteroids are withdrawn, patients should be monitored for symptoms of mineralocorticoid excess.
In patients on prednisone or prednisolone 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 (castration resistant prostate cancer). The use of abiraterone 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 of abiraterone with cytotoxic chemotherapy has not been established.
Potential risks: Anemia and sexual dysfunction may occur in men with metastatic castration resistant prostate cancer including those undergoing treatment with abiraterone.
Skeletal muscle effects: Cases of myopathy have been reported in patients treated with abiraterone. Some patients had rhabdomyolysis with renal failure. Most cases developed within the first month of treatment and recovered after abiraterone withdrawal. Caution is recommended in patients concomitantly treated with drugs 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.
Effects on ability to drive and use machines: Abiraterone has no or negligible influence on the ability to drive or use machines.
Women of childbearing potential: There are no human data on the use of abiraterone in pregnancy and this medicinal product is not for use in women of childbearing potential.
Contraception in males and females: It is not known whether abiraterone 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. Studies in animals have shown reproductive toxicity.
Pregnancy: Abiraterone is not for use in women and is contraindicated in women who are or may potentially be pregnant.
Breast-feeding: Abiraterone is not for use in women.
Fertility: Abiraterone affected fertility in male and female rats, but these effects were fully reversible.
Summary of the safety profile:
Adverse reactions that were observed were peripheral oedema, hypokalaemia, hypertension urinary tract infection, and alanine aminotransferase increased and/or aspartate aminotransferase increased. Other important adverse reactions include, cardiac disorders, hepatotoxicity, fractures, and allergic alveolitis.
Abiraterone may cause hypertension, hypokalaemia and fluid retention as a pharmacodynamic consequence of its mechanism of action. Adverse reactions were seen more commonly in patients treated with abiraterone acetate: hypokalaemia, hypertension and fluid retention (peripheral oedema).
Frequency categories are defined as follows: very common, common, uncommon, rare, very rare and not known. (See table.)
Click on icon to see table/diagram/image
Effect of food on abiraterone acetate: Administration with food significantly increases the absorption of abiraterone acetate. The efficacy and safety when given with food have not been established therefore this medicinal product must not be taken with food.
Interactions with other medicinal products: Potential for other medicinal products to affect abiraterone exposures: 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.
Potential to affect exposures to other medicinal products: Abiraterone is an inhibitor of the hepatic drug-metabolising enzymes CYP2D6 and CYP2C8.
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 products requiring CYP2D6 to form their active analgesic metabolites).
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 drugs 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 abiraterone with medicinal products known to prolong the QT interval or medicinal products able to induce Torsade 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 abiraterone is not recommended.
Store below 30°C.
Precautions for Storage: Protect from light and moisture.
Shelf Life: 36 months.
L02BX03 - abiraterone ; Belongs to the class of other hormone antagonists and related agents. Used in the treatment of metastatic castration-resistant prostate cancer.
FC tab 250 mg (white to off white, oval shaped, debossed with 'Click on icon to see table/diagram/image
' (logo) on one side and "358" on other side) x 120's.