Abiratred

Abiraterone acetate.

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).
Pharmacodynamics 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. Prostate specific antigen (PSA) serves as a biomarker in patients with prostate cancer.
Use of Spironolactone: Patients in pivotal clinical trials with abiraterone were not allowed to use spironolactone as spironolactone binds to the androgen receptor and may increase PSA levels.
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 (C_max) 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.

ABIRATRED 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 (see Pharmacology: Pharmacodynamics under Actions); the treatment of mCRPC in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen.
ABIRATRED 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 (two 500 mg tablets or 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, ABIRATRED is used with 10 mg prednisone or prednisolone daily.
For mHSPC, ABIRATRED 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 ABIRATRED, 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 ABIRATRED 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 ABIRATRED, 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 (one 500 mg tablet or two 250 mg 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 ABIRATRED should be cautiously assessed in patients with moderate hepatic impairment, in whom the benefit clearly should outweigh the possible risk. ABIRATRED 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: ABIRATRED is for oral use.
The tablets must be taken as a single dose once daily on an empty stomach. ABIRATRED must be taken at least two hours after eating and food must not be eaten for at least one hour after taking ABIRATRED. ABIRATRED tablets must 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].
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 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. 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.
Abiraterone should be used with caution in patients with a history of cardiovascular disease. The safety of abiraterone in patients with left ventricular ejection fraction (LVEF) < 50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 301) or NYHA Class II to IV heart failure was not established. Before treatment with abiraterone, 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 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 with abiraterone.
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. Abiraterone should be used with caution in patients with moderate hepatic impairment only if the benefit clearly outweighs the possible risk. Abiraterone 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 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.
Hypoglycemia: Cases of hypoglycemia have been reported when abiraterone was administered to patients with pre-existing diabetes receiving pioglitazone or repaglinide; 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.
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 as observed in clinical trials.
It is recommended that subsequent treatment with Ra-223 is not initiated for at least 5 days after the last administration of abiraterone 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 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.
Intolerance to excipients: This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
This medicinal product contains 27.2 mg (1.18 mmol) sodium per dose of four tablets, equivalent to 1.36% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
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.

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.
In an analysis of adverse reaction of composite Phase 3 studies with ABIRATERONE, adverse reactions that were observed in ≥ 10% of patients were hypertension, peripheral edema, hypokalemia, urinary tract infection, and aspartate aminotransferase increased and/or alanine aminotransferase increased.
ABIRATERONE may cause hypertension, hypokalemia and fluid retention as a pharmacodynamic consequence of its mechanism of action. In Phase 3 studies anticipated mineralocorticoid effects were seen more commonly in patients treated with ABIRATERONE versus patients treated with placebo: hypokalemia 18% versus 8%, hypertension 22% versus 16% and fluid retention (peripheral edema) 23% versus 17%, respectively. In patients treated with ABIRATERONE, grades 3 and 4 hypokalemia were observed in 6% and 2% of patients, grades 3 and 4 hypertension were observed in 8% and 5% of patients, and grades 3 and 4 fluid retention edema were observed in 1% and 1% of patients, respectively. Mineralocorticoid effects generally were able to be successfully managed medically. Concomitant use of a corticosteroid reduces the incidence and severity of these adverse reactions (see Hypertension, hypokalaemia, fluid retention and cardiac failure due to mineralocorticoid excess under Precautions).
In studies of patients with metastatic advanced prostate cancer who were using a LHRH agonist, or were previously treated with orchiectomy, ABIRATERONE was administered at a dose of 1000 mg daily in combination with low dose prednisone or prednisolone (5 or 10 mg daily).
Adverse reactions that occurred at a rate of ≥ 1% (all grades) are shown in table as follows: (See table.)

Click on icon to see table/diagram/image

The adverse reaction, adrenal insufficiency, occurred in the Phase 3 clinical studies at a rate of 0.3% in patients taking ABIRATERONE and at a rate of 0.1% in patients taking placebo.
Cardiovascular effects: The three Phase 3 studies excluded patients with uncontrolled hypertension, clinically significant heart disease as evidenced by myocardial infarction, arterial thrombotic events in the past 6 months, severe or unstable angina, 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 agonists, 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 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: Drug associated hepatotoxicity with elevated ALT, aspartate transaminase (AST) and total bilirubin has been reported in patients treated with ABIRATERONE. Across Phase 3 clinical studies, 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, 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 was elevated were more likely to experience liver function test elevations than those beginning with normal values. When elevations of either ALT or AST > 5X ULN, or elevations in bilirubin > 3X ULN were observed, ABIRATERONE was withheld or discontinued. In two instances marked increases in liver function tests occurred (see Hepatotoxicity and Hepatic impairment under Precautions). These two patients with normal baseline hepatic function, experienced ALT or AST elevations 15 to 40X ULN and bilirubin elevations 2 to 6X ULN. Upon discontinuation of ABIRATERONE, both patients had normalisation of their liver function tests and one patient was re-treated with ABIRATERONE 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. 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). 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 and 0.6% of patients treated with placebo; no deaths were reported due to hepatotoxicity event.
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 > 2.5X ULN, bilirubin > 1.5X 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 ≥ 2.5X ULN in the absence of liver metastases and > 5X 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 ≥ 2.5X 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 > 20X ULN were not re-treated. The safety of re-treatment in such patients is unknown. The mechanism for hepatotoxicity associated with ABIRATERONE is not understood.
Post-marketing experience: Adverse reactions identified during the post-marketing experience based on spontaneous reports with ABIRATERONE are described as follows. The frequencies are provided according to the following convention: Uncommon ≥ 1/1000 and < 1/100, Rare ≥ 1/10000 and < 1/1000, Very Rare < 1/10000.
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).
System Organ Class: Immune System Disorders - Hypersensitivity.
Very rare: Anaphylactic reaction (severe allergic reactions that include, but are not limited to difficulty swallowing or breathing, swollen face, lips, tongue or throat, or an itchy rash (urticaria)).

Effect of food on abiraterone: Administration of Abiraterone with food significantly increases the absorption of abiraterone. The efficacy and safety of Abiraterone given with food has not been established. Abiraterone 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.
In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone was increased by 46% and the AUCs for M-111 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.

Store below 30°C.
Precautions for Storage: Protect from light and moisture.
Shelf Life: 36 months.

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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