Abiraterone Sandoz

Abiraterone acetate.

Abiraterone Sandoz (250 mg): White to off-white, oval-shaped film-coated tablets, debossed with "250" on one side.
Each tablet contains 250 mg of abiraterone acetate.
Abiraterone Sandoz (500 mg): Purple, oval-shaped film-coated tablets, debossed with "500" on one side.
Each tablet contains 500 mg of abiraterone acetate.

Pharmacotherapeutic group: Endocrine therapy, 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 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 (see Precautions).
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 when given with LHRH analogues (or orchiectomy).
Pharmacodynamic effects: 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. PSA serves as a biomarker in patients with prostate cancer. In a Phase 3 clinical study of patients who failed prior chemotherapy with taxanes, 38% of patients treated with abiraterone acetate, versus 10% of patients treated with placebo, had at least a 50% decline from baseline in PSA levels.
Clinical efficacy and safety: Efficacy was established in three randomised placebo-controlled multicentre Phase 3 clinical studies (studies 3011, 302 and 301) of patients with mHSPC and mCRPC. Study 3011 enrolled patients who were newly diagnosed (within 3 months of randomization) mHSPC who had high-risk prognostic factors. High-risk prognosis was defined as having at least 2 of the following 3 risk factors: (1) Gleason score of ≥8; (2) presence of 3 or more lesions on bone scan; (3) presence of measurable visceral (excluding lymph node disease) metastasis. In the active arm, abiraterone was administered at a dose of 1000 mg daily in combination with low dose prednisone 5 mg once daily in addition to ADT (LHRH agonist or orchiectomy), which was the standard of care treatment. Patients in the control arm received ADT and placebos for both abiraterone and prednisone. Study 302 enrolled docetaxel naïve patients; whereas, study 301 enrolled patients who had received prior docetaxel. Patients were using an LHRH analogue or were previously treated with orchiectomy. In the active treatment arm, abiraterone was administered at a dose of 1,000 mg daily in combination with low dose prednisone or prednisolone 5 mg twice daily. Control patients received placebo and low dose prednisone or prednisolone 5 mg twice daily.
Changes in PSA serum concentration independently do not always predict clinical benefit. Therefore, in all studies it was recommended that patients be maintained on their study treatments until discontinuation criteria were met as specified as follows for each study.
In all studies spironolactone use was not allowed as spironolactone binds to the androgen receptor and may increase PSA levels.
Pharmacokinetics: Following administration of abiraterone acetate, the pharmacokinetics of abiraterone and abiraterone acetate have been studied in healthy subjects, patients with metastatic advanced prostate cancer and subjects without cancer with hepatic or renal impairment. Abiraterone acetate is rapidly converted in vivo to abiraterone, an androgen biosynthesis inhibitor (see Pharmacology: Pharmacodynamics under Actions).
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 (see Dosage & Administration).
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 based on data from healthy subjects. 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).
Toxicology: Preclinical safety data: In all animal toxicity studies, circulating testosterone levels were significantly reduced. As a result, reduction in organ weights and morphological and/or histopathological changes in the reproductive organs, and the adrenal, pituitary and mammary glands were observed. All changes showed complete or partial reversibility. The changes in the reproductive organs and androgen-sensitive organs are consistent with the pharmacology of abiraterone. All treatment-related hormonal changes reversed or were shown to be resolving after a 4-week recovery period.
In fertility studies in both male and female rats, abiraterone acetate reduced fertility, which was completely reversible in 4 to 16 weeks after abiraterone acetate was stopped.
In a developmental toxicity study in the rat, abiraterone acetate affected pregnancy including reduced foetal weight and survival. Effects on the external genitalia were observed though abiraterone acetate was not teratogenic.
In these fertility and developmental toxicity studies performed in the rat, all effects were related to the pharmacological activity of abiraterone.
Aside from reproductive organ changes seen in all animal toxicology studies, non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. Abiraterone acetate was not carcinogenic in a 6-month study in the transgenic (Tg.rasH2) mouse. In a 24-month carcinogenicity study in the rat, abiraterone acetate increased the incidence of interstitial cell neoplasms in the testes. This finding is considered related to the pharmacological action of abiraterone and rat specific. Abiraterone acetate was not carcinogenic in female rats.
The active substance, abiraterone, shows an environmental risk for the aquatic environment, especially to fish.

Abiraterone is indicated with prednisone or prednisolone for: the treatment of newly diagnosed high risk metastatic hormone sensitive prostate cancer (mHSPC) in adult men in combination with androgen deprivation therapy (ADT) (see Pharmacology: Pharmacodynamics under Actions); 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 (see Pharmacology: Pharmacodynamics under Actions).

This medicinal product should be prescribed by an appropriate healthcare professional.
Posology: The recommended dose is 1,000 mg (four 250 mg tablets or two 500 mg tablets) as a single daily dose that must not be taken with food (see "Method of administration" as follows). Taking the tablets with food increases systemic exposure to abiraterone (see Interactions and Pharmacology: Pharmacokinetics under Actions).
Dosage of prednisone or prednisolone: For mHSPC, abiraterone is used with 5 mg prednisone or prednisolone daily.
For mCRPC, abiraterone is used with 10 mg prednisone or prednisolone daily.
Medical castration with luteinising hormone releasing hormone (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 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, hypokalaemia, 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] or total bilirubin increases above 3 times the 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 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 ULN) 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 (see Pharmacology: Pharmacokinetics under Actions). 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 (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions). Abiraterone should not be used in patients with severe hepatic impairment (see Contraindications, Precautions and Pharmacology: Pharmacokinetics under Actions).
Renal impairment: No dose adjustment is necessary for patients with renal impairment (see Pharmacology: Pharmacokinetics under Actions). However, there is no clinical experience in patients with prostate cancer and severe renal impairment. Caution is advised in these patients (see Precautions).
Paediatric population: There is no relevant use of abiraterone in the paediatric population.
Method of administration: Abiraterone 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.

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 (see Use in Pregnancy & Lactation).
Severe hepatic impairment [Child-Pugh Class C (see Dosage & Administration, Precautions and Pharmacology: Pharmacokinetics under Actions)].
Abiraterone with prednisone or prednisolone is contraindicated in combination with Ra-223.

Hypertension, hypokalaemia, fluid retention and cardiac failure due to mineralocorticoid excess: Abiraterone may cause hypertension, hypokalaemia and fluid retention (see Adverse Reactions) as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition (see Pharmacology: Pharmacodynamics under Actions). 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 (see Dosage & Administration).
Hepatotoxicity and hepatic impairment: Marked increases in liver enzymes leading to treatment discontinuation or dose modification occurred in controlled clinical studies (see Adverse Reactions). 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 (see Dosage & Administration).
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 abiraterone 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 abiraterone should be cautiously assessed in patients with moderate hepatic impairment, in whom the benefit clearly should outweigh the possible risk (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions). Abiraterone should not be used in patients with severe hepatic impairment (see Dosage & Administration, Contraindications and Pharmacology: Pharmacokinetics under Actions).
There have been rare post-marketing reports of acute liver failure and hepatitis fulminant, some with fatal outcome (see Adverse Reactions).
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 (see information as previously mentioned).
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. 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.
Hypoglycaemia: Cases of hypoglycaemia have been reported when abiraterone plus prednisone/prednisolone was administered to patients with pre-existing diabetes receiving pioglitazone or repaglinide (see Interactions); therefore, blood sugar should be measured in patients with diabetes.
Use with chemotherapy: The safety and efficacy of concomitant use of abiraterone with cytotoxic chemotherapy has not been established (see Pharmacology: Pharmacodynamics under Actions).
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 less than 1 mmol (or 27.2 mg) sodium per dose of 1000 mg. To be taken into consideration by patients on a controlled sodium diet.
Potential risks: Anaemia and sexual dysfunction may occur in men with metastatic prostate cancer including those undergoing treatment with abiraterone.
Skeletal muscle effects: Cases of myopathy and rhabdomyolysis have been reported in patients treated with abiraterone. Most cases developed within the first 6 months of treatment and recovered after abiraterone 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 (see Interactions).
Combination of abiraterone and prednisone/prednisolone with Ra-223: Treatment with abiraterone and prednisone/prednisolone in combination with Ra-223 is contraindicated (see Contraindications) 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.
Effects on ability to drive and use machines: Abiraterone has no or negligible influence on the ability to drive and use machines.
Use in Pregnancy: Embryo-Fetal Toxicity: There are no human data on the use of abiraterone in pregnant women. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17).

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 (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Pregnancy: Abiraterone is not for use in women and is contraindicated in women who are or may potentially be pregnant (see Contraindications and Pharmacology: Toxicology: Preclinical safety data under Actions).
Breast-feeding: Abiraterone is not for use in women.
Fertility: Abiraterone acetate affected fertility in male and female rats, but these effects were fully reversible (see Pharmacology: Toxicology: Preclinical safety data under Actions).

Summary of the safety profile: In an analysis of adverse reactions of composite Phase 3 studies with abiraterone, adverse reactions that were observed in ≥10% of patients 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. In Phase 3 studies, anticipated mineralocorticoid adverse reactions were seen more commonly in patients treated with abiraterone acetate than in patients treated with placebo: hypokalaemia 18% vs. 8%, hypertension 22% vs. 16% and fluid retention (peripheral oedema) 23% vs. 17%, respectively.
In patients treated with abiraterone acetate versus patients treated with placebo: CTCAE (version 4.0) Grades 3 and 4 hypokalaemia were observed in 6% versus 1%, CTCAE (version 4.0) Grades 3 and 4 hypertension were observed in 7% versus 5%, and fluid retention (peripheral oedema) Grades 3 and 4 were observed in 1% versus 1% of patients, respectively. Mineralocorticoid reactions generally were able to be successfully managed medically. Concomitant use of a corticosteroid reduces the incidence and severity of these adverse reactions (see Precautions).
Tabulated list of adverse reactions: In studies of patients with metastatic advanced prostate cancer who were using an LHRH analogue, or were previously treated with orchiectomy, abiraterone was administered at a dose of 1,000 mg daily in combination with low dose prednisone or prednisolone (either 5 or 10 mg daily depending on the indication).
Adverse reactions observed during clinical studies and post-marketing experience are listed as follows by frequency category. Frequency categories are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000) and not known (frequency cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. (See table.)

Click on icon to see table/diagram/image

The following CTCAE (version 4.0) Grade 3 adverse reactions occurred in patients treated with abiraterone acetate: hypokalaemia 5%; urinary tract infection 2%; alanine aminotransferase increased and/or aspartate aminotransferase increased 4%; hypertension 6%; fractures 2%; peripheral oedema, cardiac failure, and atrial fibrillation 1% each. CTCAE (version 4.0) Grade 3 hypertriglyceridaemia and angina pectoris occurred in < 1% of patients. CTCAE (version 4.0) Grade 4 urinary tract infection, alanine aminotransferase increased and/or aspartate aminotransferase increased, hypokalemia, cardiac failure, atrial fibrillation, and fractures occurred in < 1% of patients.
A higher incidence of hypertension and hypokalemia was observed in the hormone sensitive population (study 3011). Hypertension was reported in 36.7% of patients in the hormone sensitive population (study 3011) compared to 11.8% and 20.2% in studies 301 and 302, respectively. Hypokalemia was observed in 20.4% of patients in the hormone sensitive population (study 3011) compared to 19.2% and 14.9% in 301 and 302, respectively).
The incidence and severity of adverse events was higher in the subgroup of patients with baseline ECOG2 performance status grade and also in elderly patients (≥75 years).
Description of selected adverse reactions: Cardiovascular reactions: The three Phase 3 studies 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 NYHA Class III or IV heart failure (study 301) or Class II to IV heart failure (studies 3011 and 302) or cardiac ejection fraction measurement of < 50%. All patients enrolled (both active and placebo-treated patients) were concomitantly treated with androgen deprivation therapy, predominantly with the use of LHRH analogues, which has been associated with diabetes, myocardial infarction, cerebrovascular accident and sudden cardiac death. The incidence of cardiovascular adverse reactions in the Phase 3 studies in patients taking abiraterone acetate versus patients taking placebo were as follows: atrial fibrillation 2.6% vs. 2.0%, tachycardia 1.9% vs. 1.0%, angina pectoris 1.7% vs. 0.8%, cardiac failure 0.7% vs. 0.2%, and arrhythmia 0.7% vs. 0.5%.
Hepatotoxicity: Hepatotoxicity with elevated ALT, AST and total bilirubin has been reported in patients treated with abiraterone acetate. Across Phase 3 clinical studies, hepatotoxicity grades 3 and 4 (e.g., ALT or AST increases of >5 x ULN or bilirubin increases >1.5 x ULN) were reported in approximately 6% of patients who received abiraterone acetate, typically during the first 3 months after starting treatment. In Study 3011, grade 3 or 4 hepatotoxicity was observed in 8.4% of patients treated with abiraterone. Ten patients who received abiraterone were discontinued because of hepatotoxicity; two had Grade 2 hepatotoxicity, six had Grade 3 hepatotoxicity, and two had Grade 4 hepatotoxicity. No patient died of hepatotoxicity in Study 3011. In the Phase 3 clinical studies, patients whose baseline ALT or AST were elevated were more likely to experience liver function test elevations than those beginning with normal values. When elevations of either ALT or AST > 5 x ULN, or elevations in bilirubin > 3 x ULN were observed, abiraterone acetate was withheld or discontinued. In two instances marked increases in liver function tests occurred (see Precautions). These two patients with normal baseline hepatic function, experienced ALT or AST elevations 15 to 40 x ULN and bilirubin elevations 2 to 6 x ULN. Upon discontinuation of treatment, both patients had normalisation of their liver function tests and one patient was re-treated without recurrence of the elevations. In study 302, Grade 3 or 4 ALT or AST elevations were observed in 35 (6.5%) patients treated with abiraterone acetate. Aminotransferase elevations resolved in all but 3 patients (2 with new multiple liver metastases and 1 with AST elevation approximately 3 weeks after the last dose of abiraterone acetate). In Phase 3 clinical studies, treatment discontinuations due to ALT and AST increases or abnormal hepatic function were reported in 1.1% of patients treated with abiraterone acetate and 0.6% of patients treated with placebo; no deaths were reported due to hepatotoxicity events.
In clinical trials, the risk for hepatotoxicity was mitigated by exclusion of patients with baseline hepatitis or significant abnormalities of liver function tests. In the 3011 trial, patients with baseline ALT and AST >2.5 X ULN, bilirubin >1.5 X ULN or those with active or symptomatic viral hepatitis or chronic liver disease; ascites or bleeding disorders secondary to hepatic dysfunction were excluded. In the 301 trial, patients with baseline ALT and AST ≥2.5 x ULN in the absence of liver metastases and >5 x ULN in the presence of liver metastases were excluded. In the 302 trial, patients with liver metastases were not eligible and patients with baseline ALT and AST ≥2.5 x ULN were excluded. Abnormal liver function tests developing in patients participating in clinical trials were vigorously managed by requiring treatment interruption and permitting re-treatment only after return of liver function tests to the patient's baseline (see Dosage & Administration). Patients with elevations of ALT or AST >20 x ULN were not re-treated. The safety of re-treatment in such patients is unknown. The mechanism for hepatotoxicity is not understood.

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 (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Interactions with other medicinal products: 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. 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 (see Precautions).
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 abiraterone 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 abiraterone is not recommended (see Pharmacology: Pharmacodynamics under Actions).

Incompatibilities: Not applicable.
Special precautions for disposal and other handling: Disposal of unused/expired medicines: The release of pharmaceuticals in the environment should be minimized. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Use established "collection systems", if available in the patient's location.

Do not store above 30°C.

Cancer Hormone Therapy

L02BX03 - abiraterone ; Belongs to the class of other hormone antagonists and related agents. Used in the treatment of metastatic castration-resistant prostate cancer.

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