Abiraterone acetate 250 mg.
Excipients/Inactive Ingredients: Lactose monohydrate, Microcrystalline cellulose, Croscarmelose sodium, Colloidal silicon dioxide, Magnesium sterate, Povidone K-30, and Sodium lauryl sulfate.
Pharmacotherapeutic group: Other hormone antagonists and related agents. ATC code: L02BX03.
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 tumor tissues. It catalyzes 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 agonists or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumor. Treatment with abiraterone acetate decreases serum testosterone to undetectable levels (using commercial assays) when given with LHRH agonists (or orchiectomy).
Pharmacodynamic effects: Abiraterone acetate decreases serum testosterone and other androgens to levels lower than those achieved by the use of LHRH agonists 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.
Use of Spironolactone: Spironolactone binds to the androgen receptor and may increase PSA levels.
Pharmacokinetics: General introduction: 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 17-fold 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 Arabitro with meals has the potential to result in highly variable exposures. Therefore, Arabitro must not be taken with food. Arabitro should be taken at least two hours after eating and no food should be eaten for at least one hour after taking Arabitro.
The tablets should be swallowed whole with water.
Distribution and protein binding: The plasma protein binding of 14C-abiraterone in human plasma is 99.8%. The apparent volume of distribution is approximately 5630 L, suggesting that abiraterone extensively distributes to peripheral tissues.
Biotransformation: Following oral administration of 14C-abiraterone acetate as capsules, abiraterone acetate is hydrolyzed 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.
Excretion: The mean half-life of abiraterone in plasma is approximately 15 hours in healthy subjects. Following oral administration of 14C-abiraterone acetate, approximately 88% of the radioactive dose is recovered in feces and approximately 5% in urine. The major compounds present in feces are unchanged abiraterone acetate and abiraterone (approximately 55% and 22% of the administered dose, respectively).
Special Populations: Renal impairment: Systemic exposure to abiraterone after a single oral 1000 mg dose did not increase in patients with end-stage renal disease on dialysis.
Administration of abiraterone acetate in patients with renal impairment including severe renal impairment does not require dose reduction.
Hepatic impairment: Systemic exposure to abiraterone after a single oral 1,000 mg dose increases by approximately 11% and 260% in subjects with mild and moderate pre-existing hepatic impairment, respectively. The mean half-life of abiraterone is prolonged to approximately 18 hours in subjects with mild hepatic impairment and to approximately 19 hours in subjects with moderate hepatic impairment. No dose adjustment is necessary for patients with pre-existing mild hepatic impairment. 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 dosage adjustment can be predicted. Arabitro should be used with caution in patients with moderate hepatic impairment, only if the benefit clearly outweighs the possible risk. Arabitro should not be used in patients with severe hepatic impairment. For patients who develop hepatotoxicity during treatment with Arabitro, suspension of treatment and dosage adjustment may be required.
Effects on the QT interval: In patients with metastatic advanced prostate cancer there were no significant effects of abiraterone acetate on the cardiac QT/QTc interval.
Arabitro is indicated with prednisone or prednisolone for: the treatment of metastatic castration resistant prostate cancer (mCRPC) in adult men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated;
the treatment of mCRPC in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen.
Arabitro is also indicated in combination with prednisone or prednisolone and androgen deprivation therapy (ADT) for the treatment of patients with newly diagnosed high risk metastatic hormone sensitive prostate cancer (mHSPC) who may have received up to 3 months of prior ADT.
Posology: The recommended dose is 1000 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.
Dosage of prednisone or prednisolone: For mCRPC, Arabitro is used with 10 mg prednisone or prednisolone daily.
For mHSPC, Arabitro is used with 5 mg prednisone or prednisolone daily.
Medical castration with LHRH analogue should be continued during treatment in patients not surgically castrated.
Recommended monitoring: 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. However, patients with a significant risk or congestive heart failure should be monitored every 2 weeks for the first three months of treatment and monthly thereafter.
In patients with pre-existing hypokalaemia or those that develop hypokalaemia whilst being treated with Arabitro, consider maintaining the patient's potassium level at ≥ 4.0mM.
For patients who develop Grade ≥ 3 toxicities including hypertension, hypokalaemia, oedema and other non-mineralocorticoid toxicities, treatment should be withheld and appropriate medical management should be instituted. Treatment with Arabitro 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 Arabitro, 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. 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 1000 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 Arabitro should be cautiously assessed in patients with moderate hepatic impairment, in whom the benefit clearly should outweigh the possible risk. Arabitro should not be used in patients with severe hepatic impairment.
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 this medicinal product in the paediatric population, as prostate cancer is not present in children and adolescents.
Method of administration: Arabitro is for oral use.
The tablets should be taken at least two hours after eating and no food should be eaten for at least one hour after taking the tablets. These should be swallowed whole with water.
Should be swallowed whole with water and cannot be subdivided.
Human experience of overdose with Arabitro is limited.
There is no specific antidote. In the event of an overdose, administration of Arabitro should be stopped and general supportive measures undertaken, including monitoring for arrhythmias. Liver function also should be assessed.
Hypersensitivity to the active substance or to any of the excipients listed in Description.
Women who are or may potentially be pregnant.
Severe hepatic impairment [(Child-Pugh Class C)].
Abiraterone acetate with prednisone or prednisolone is contraindicated in combination with Ra-223.
Hypertension, hypokalaemia and fluid retention due to mineralocorticoid excess: Arabitro 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 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, hypokalaemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. In postmarketing experience, QT prolongation and Torsades de Pointes have been observed in patients who develop hypokalemia or have underlying cardiovascular conditions while taking abiraterone acetate.
Arabitro should be used with caution in patients with a history of cardiovascular disease. The safety of Arabitro in patients with left ventricular ejection fraction (LVEF) <50% or New York Heart Association (NYHA) Class III or IV heart failure or NYHA Class II to IV heart failure was not established. Before treatment with Arabitro, hypertension must be controlled and hypokalemia must be corrected. Blood pressure, serum potassium and fluid retention should be monitored at least monthly.
Hepatotoxicity and hepatic impairment: Marked increases in liver enzymes leading to drug discontinuation or dosage modification is seen. Serum transaminase and bilirubin levels should be measured prior to starting treatment with Arabitro, 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 or the bilirubin rises above 3 times the upper limit of normal, treatment with Arabitro should be interrupted immediately and liver function closely monitored.
Re-treatment with Arabitro may only take place after the 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, Arabitro should be discontinued and patients should not be re-treated with Arabitro.
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. Arabitro should be used with caution in patients with moderate hepatic impairment only if the benefit clearly outweighs the possible risk. Arabitro 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 need to be withdrawn from prednisone or prednisolone. If Arabitro is continued after corticosteroids are withdrawn, patients should be monitored for symptoms of mineralocorticoid excess (see previous information).
In patients on prednisone or prednisolone who are subjected to unusual stress, increased dosage of a corticosteroid may be indicated before, during and after the stressful situation.
Use with chemotherapy: The safety and efficacy of concomitant use of Arabitro with cytotoxic chemotherapy has not been established.
Combination of abiraterone and prednisone/prednisolone with Ra-223: Treatment with abiraterone and prednisone/prednisolone 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.
It is recommended that subsequent treatment with Ra-223 is not initiated for at least 5 days after the last administration of Arabitro in combination with prednisone/prednisolone.
Bone density: Decreased bone density may occur in men with metastatic advanced prostate cancer (castration resistant prostate cancer). The use of Arabitro 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.
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 25.04 mg) sodium per dose of four tablets. To be taken into consideration by patients on a controlled sodium diet.
Effects on ability to drive and use machines: No studies on the effects of Arabitro on the ability to drive or use machines have been performed. It is not anticipated that Arabitro will affect the ability to drive and use machines.
Pregnancy: Arabitro are contraindicated in women who are or may potentially be pregnant.
There are no human data on the use of Arabitro in pregnancy and Arabitro is not for use in women of child-bearing potential. Maternal use of a CYP17 inhibitor is expected to produce changes in hormone levels that could affect development of the fetus.
It is not known if 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 child-bearing potential, a condom is required along with another effective contraceptive method.
To avoid inadvertent exposure, women who are pregnant or women who may be pregnant should not handle Arabitro without protection, e.g., gloves.
Lactation: Arabitro are not for use in women.
It is not known if either abiraterone acetate or its metabolites are excreted in human breast milk.
Throughout this section, adverse reactions are presented. Adverse reactions are adverse events that were considered to be reasonably associated with the use of abiraterone acetate based on the comprehensive assessment of the available adverse event information. A causal relationship with abiraterone acetate cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Adverse reactions with Arabitro, were observed in ≥10% of patients were hypertension, peripheral edema, hypokalemia, urinary tract infection, and aspartate aminotransferase increased and/or alanine aminotransferase increased.
Arabitro may cause hypertension, hypokalemia and fluid retention as a pharmacodynamic consequence of its mechanism of action. Mineralocorticoid effects were seen more commonly in patients treated with abiraterone acetate: hypokalemia, hypertension and fluid retention (peripheral edema). In patients treated with abiraterone acetate tablets, grades 3 and 4 hypokalemia, grades 3 and 4 hypertension, and grades 3 and 4 fluid retention edema were observed. Mineralocorticoid effects generally were able to be successfully managed medically. Concomitant use of a corticosteroid reduces the incidence and severity of these adverse reactions.
In patients with metastatic advanced prostate cancer who were using a LHRH agonist, or were previously treated with orchiectomy, Arabitro Tablets was administered at a dose of 1000 mg daily in combination with low dose prednisone or prednisolone (5 or 10 mg daily).
The incidence of cardiovascular adverse reactions in patients taking abiraterone acetate tablets were as follows: atrial fibrillation, tachycardia, angina pectoris, cardiac failure and arrhythmia.
Drug associated hepatotoxicity with elevated ALT, aspartate transaminase (AST) and total bilirubin has been reported in patients treated with Abiraterone acetate 250 mg Tablets. Hepatotoxicity grades 3 and 4 (e.g., ALT or AST increases of > 5X ULN or bilirubin increases > 1.5X ULN) were reported in approximately 6% of patients who received Abiraterone acetate 250 mg Tablets, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST was elevated are more likely to experience liver function test elevations than those beginning with normal values. No deaths are reported due to hepatotoxicity event.
The mechanism for hepatotoxicity associated with abiraterone acetate is not understood.
System Organ Class: Respiratory, thoracic and mediastinal disorders
: Rare: Allergic alveolitis.
System Organ Class: Musculoskeletal and connective tissue disorders:
Uncommon: Rhabdomyolysis, Myopathy.
System Organ Class: Hepatobiliary disorders:
Rare: Hepatitis fulminant, Acute hepatic failure.
System Organ Class: Cardiac disorders:
Very rare: QT prolongation and Torsades de Pointes (observed in patients who developed hypokalemia or had underlying cardiovascular conditions).
Reporting of suspected adverse reactions:
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Effect of food on abiraterone acetate: Administration of Arabitro with food significantly increases the absorption of abiraterone acetate. The efficacy and safety of Arabitro given with food has not been established. Arabitro must not be taken with food.
Interactions with other drugs: Potential for other drugs to affect abiraterone exposures: Co-administration of 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 decreases by 55% in healthy subjects.
Strong inducers of CYP3A4 (e.g., phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital) during treatment with Arabitro are to be avoided, or used with careful evaluation of clinical efficacy.
Co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone in healthy subjects.
Potential for Arabitro to affect exposures to other drugs: Abiraterone is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. The effects of abiraterone acetate (plus prednisone) on a single dose of the CYP2D6 substrate dextromethorphan, the systemic exposure (AUC) of dextromethorphan increases by approximately 200%. The AUC24 for dextrorphan, the active metabolite of dextromethorphan, increases approximately 33%.
Caution is advised when Arabitro is administered with drugs activated by or metabolized by abiraterone acetate, particularly with drugs that have a narrow therapeutic index. Dose reduction of narrow therapeutic index drugs metabolized by CYP2D6 should be considered.
The effects of abiraterone acetate (plus prednisone) on a single dose of the CYP1A2 substrate theophylline, no increase in systemic exposure of theophylline is observed.
Special precautions for disposal and other handling: Any unused product or waste material should be disposed off in accordance with local requirements.
Incompatibilities: Not applicable.
Store below 30°C.
Shelf-Life: 24 months.
L02BX03 - abiraterone ; Belongs to the class of other hormone antagonists and related agents. Used in the treatment of metastatic castration-resistant prostate cancer.
Tab 250 mg (white to off white oval shaped uncoated, debossed with "G" on one side and "135" on other side) x 120's.