White to off-white, oval shaped tablets debossed with "NA250" on one side and plain on other side.
Composition: Each tablet contains 250 mg of abiraterone acetate.
Pharmacotherapeutic group: endocrine therapy, other hormone antagonists and related agents. ATC code: L02BX03.
Pharmacology: Pharmacodynamics: Mechanism of action: Abiraterone acetate 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 acetate tablets decreases serum testosterone to undetectable levels (using commercial assays) when given with LHRH analogues (or orchiectomy).
Pharmacodynamic effects: Abiraterone acetate tablets decrease 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.
Pharmacokinetics: Abiraterone acetate is rapidly converted in vivo to abiraterone, an androgen biosynthesis inhibitor (see Pharmacodynamics as previously mentioned).
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 acetate tablets with meals has the potential to result in highly variable exposures. Therefore, abiraterone acetate tablets must not be taken with food. It should be taken at least one hour before or at least two hours after eating.
The tablets should be swallowed whole with water (see Recommended Dosage under 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 in 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).
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 (see Recommended Dosage under Dosage & Administration and Precautions). Abiraterone acetate should not be used in patients with severe hepatic impairment (see Recommended Dosage under Dosage & Administration, Contraindications and Precautions).
For patients who develop hepatotoxicity during treatment, suspension of treatment and dose adjustment may be required (see Recommended Dosage under Dosage & Administration and Precautions).
Renal impairment: Administration in patients with renal impairment, including severe renal impairment, does not require dose reduction (see Recommended Dosage under Dosage & Administration). However, there is no clinical experience in patients with prostate cancer and severe renal impairment. Caution is advised in these patients.
ARTESTO 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.
ARTESTO 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.
Recommended Dosage: This medicinal product should be prescribed by an appropriate healthcare professional.
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 "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 acetate tablets are used with 5 mg prednisone or prednisolone daily.
For mCRPC, abiraterone acetate tablets are 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 acetate tablets, 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 acetate tablets 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 acetate tablets, 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 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 acetate tablets should be cautiously assessed in patients with moderate hepatic impairment, in whom the benefit clearly should outweigh the possible risk (see Recommended Dosage as previously mentioned and Pharmacology: Pharmacokinetics under Actions). Abiraterone acetate tablets 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 acetate tablets in the paediatric population.
Method of administration: Abiraterone acetate tablets are for oral use.
The tablets should be taken at least one hour before or at least two hours after eating. These should be swallowed whole with water.
Route of Administration: Oral.
Symptoms and Treatment of Overdose: Human experience of overdose with abiraterone acetate tablets 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 of this product.
Women who are or may potentially be pregnant (see Use in Pregnancy & Lactation).
Severe hepatic impairment [Child-Pugh Class C (see Recommended Dosage under Dosage & Administration, Precautions and Pharmacology: Pharmacokinetics under Actions)].
Abiraterone acetate tablets with prednisone or prednisolone is contraindicated in combination with Ra-223.
Hypertension, hypokalaemia, fluid retention and cardiac failure due to mineralocorticoid excess: Abiraterone acetate tablets may cause hypertension, hypokalaemia and fluid retention (see Side Effects) 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 acetate tablets 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 acetate tablets, 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 acetate tablets 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 Recommended Dosage under Dosage & Administration).
Hepatotoxicity and hepatic impairment: Marked increases in liver enzymes leading to treatment discontinuation or dose modification occurred. 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 Recommended Dosage under 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. There are no data to support the use of abiraterone acetate tablets in patients with active or symptomatic viral hepatitis.
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 acetate tablets should be cautiously assessed in patients with moderate hepatic impairment, in whom the benefit clearly should outweigh the possible risk (see Recommended Dosage under Dosage & Administration and Pharmacology: Pharmacokinetics under Actions). Abiraterone acetate tablets should not be used in patients with severe hepatic impairment (see Recommended Dosage under Dosage & Administration, Contraindications and Pharmacology: Pharmacokinetics under Actions).
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 acetate tablet is continued after corticosteroids are withdrawn, patients should be monitored for symptoms of mineralocorticoid excess (see previously mentioned information).
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 acetate tablets 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 acetate tablets 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 more than 1 mmol (or 27.2 mg) sodium per dose of four tablets of 250 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 acetate tablets.
Skeletal muscle effects: Cases of myopathy and rhabdomyolysis have been reported in patients treated with abiraterone acetate tablets. Most cases developed within the first 6 months of treatment and recovered after abiraterone acetate tablets 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: It is recommended that subsequent treatment with Ra-223 is not initiated for at least 5 days after the last administration of abiraterone acetate tablets in combination with prednisone/prednisolone.
Hypoglycaemia: Cases of hypoglycaemia have been reported when ARTESTO was administered to patients with pre-existing diabetes receiving pioglitazone or repaglinide; therefore, blood sugar should be measured frequently in patients with diabetes.
Effects on ability to drive and use machines: Abiraterone acetate tablets have no or negligible influence on the ability to drive and use machines.
Women of childbearing potential: There are no human data on the use of abiraterone acetate tablets 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 acetate tablets are not for use in women and is contraindicated in women who are or may potentially be pregnant (see Contraindications). To avoid inadvertent exposure, women who are pregnant or women who may be pregnant should not handle ARTESTO without protection, e.g., gloves.
Fertility: Abiraterone affected fertility in male and female rats, but these effects were fully reversible.
Breast-feeding: Abiraterone acetate tablets are not for use in women.
Tabulated list of adverse reactions: Frequency categories are defined as follows: very common, common, uncommon, rare, very rare and not known.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. (See table.)
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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 (see Recommended Dosage under Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
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 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 1000 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 metabolized by CYP2C8 include pioglitazone and repaglinide.
Use with products known to prolong QT interval: Since androgen deprivation treatment may prolong the QT interval, caution is advised when administering abiraterone acetate tablets 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 acetate tablets is not recommended (see Pharmacology: Pharmacodynamics under Actions).
Incompatibilities: Not Applicable.
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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