Each uncoated tablets contains:
Abiraterone Acetate IP……. 250 mg
Abiraterone acetate, the active ingredient of ZABITERON is the acetyl ester of abiraterone. Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17, 20-lyase). Each ZABITERON tablet contains 250 mg of abiraterone acetate. Abiraterone acetate is designated chemically as (3β)-17-(3-pyridinyl) androsta-5,16-dien-3-yl acetate and its structure is:
Abiraterone acetate is a white to off-white, non-hygroscopic, crystalline powder. Its molecular formula is C26H33NO2 and it has a molecular weight of 391.55.
Abiraterone Acetate is an anti-androgen given orally with prednisone or prednisolone. It is metabolized to abiraterone which has been shown to suppress testosterone production by inhibiting the enzyme CYP17 – which plays a key role in sex hormone synthesis.
Abiraterone in combination with prednisone was introduced as anti-androgen therapy for the treatment of castration-resistant metastatic prostate cancer (mCRPC) in asymptomatic or mildly symptomatic patients after failure of androgen deprivation therapy or in patients having received docetaxel containing combination chemotherapy after failure of androgen deprivation therapy or in the treatment of Castration-Sensitive Prostate Cancer (CSPC). It has also been indicated in combination with prednisone and androgen deprivation therapy (ADT) for the treatment of patients with newly diagnosed hormone-sensitive high-risk metastatic prostate cancer who may have received up to 3 months of prior ADT.
Abiraterone acetate is converted in vivo to abiraterone, an androgen biosynthesis inhibitor, that inhibits 17 a-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis.
- Absorption: Good oral bioavaliability with peak plasma levels seen within 2 hours of administration. Systemic exposure of Abiraterone is increased when administered with food.
- Distribution: Highly plasma protein bound (>90%).
- Metabolism: Following oral administration, Abiraterone Acetate is hydrolyzed to its active metabolite Abiraterone by as yet an unidentified esterase. Abiraterone is further metabolized to inactive metabolites like Abiraterone Sulphate and N-oxide Abiraterone Sulphate via the action of CYP3A4 and SULT2A1 enzymes.
- Half-life: The mean terminal half-life of Abiraterone reported in healthy subjects is 15 hours and about 12 hours in patients with CRPC.
- Elimination: Mainly excreted in the feces (88%) and approximately 5% in urine.
A CYP17 inhibitor, Abiraterone in combination with prednisone is indicated for the treatment of patients with
- Metastatic castration-resistant prostate cancer (CRPC).
- Metastatic high-risk castration-sensitive prostate cancer (CSPC).
Recommended Dosage: The recommended dose of Abiraterone Acetate is 1,000 mg (four 250 mg tablets) administered orally once daily in combination with prednisone 5 mg administered orally twice daily (see: administration below).
- Abiraterone Acetate must be taken on an empty stomach.
- No food should be consumed for at least two hours before the dose of Abiraterone Acetate is taken and for at least one hour after the dose of Abiraterone Acetate is taken.
- The tablets should be swallowed whole with water. Do not crush or chew tablets.
- In patients with mild hepatic impairment (Child-Pugh Class A): No dose modification
- In patients with moderate hepatic impairment (Child-Pugh Class B): Use with caution in patients with hepatic impairment. Dose should be reduced to 250 mg PO once daily.
- In patients with severe hepatic impairment (Child-Pugh Class C): Should be avoided.
- For patients who develop increases in liver enzymes above 5 times the upper limit of normal (ULN) or total bilirubin >3times ULN during treatment, abiraterone therapy should be interrupted, and only restarted at a dose of 500 mg once these values have fallen to acceptable levels (baselines or no more than half the increased values above).
- If hepatotoxicity recurs at the reduced dose of 500 mg daily, treatment with Abiraterone should be discontinued.
- If patients develop increases in enzymes 20 times the ULN at any time while on therapy, abiraterone should be stopped permanently.
- In patients who develop severe hepatotoxicity: Abiraterone should be discontinued.
- No dosage modifications are necessary.
Abiraterone has been adequately studied for its efficacy in different settings such as patients with metastatic castration-resistant prostate cancer (CRPC) that has progressed on androgen deprivation therapy, patients with metastatic CRPC who had not received prior chemotherapy as well as patients with metastatic high-risk Castration Sensitive Prostate cancer (CSPC). The results of several phase III clinical trials demonstrated Abiraterone to significantly prolong the overall survival and progression free survival along with a high PSA response rate as compared to placebo.
- Monitor patients for hypertension, hypokalemia and fluid relation at least once a month.
- Monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions or experience unusual stress.
- Monitor LFTs – serum transminases (ALT and AST) and serum bilirubin levels prior to starting treatment with Abiraterone every two weeks for the first three months of treatment and monthly thereafter monitor Prostate-specific antigen (PSA).
Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: Abiraterone acetate may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition.
Adrenocortical Insufficiency: Adrenocortical insufficiency was reported in patients
receiving Abiraterone acetate in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress.
Hepatotoxicity: In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5× ULN) were reported in 4% of patients who received Abiraterone acetate, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking Abiraterone acetate. No deaths clearly related to Abiraterone acetate were reported due to hepatotoxicity events.
- Abiraterone acetate inhibits the enzyme CYP17, which can result in mineralocorticoid excess, very often leading to hypertension, hypokalemia, and fluid retention or oedema; patients should be monitored at least monthly for these effects and treated appropriately.
- Use with a glucocorticoid can reduce the incidence and severity of these adverse effects. However, adrenocortical insufficiency has been reported in those treated with abiraterone acetate plus prednisone or prednisolone and patients should be monitored for manifestations of this, particularly after withdrawal from the corticosteroid.
- Caution is needed when treating patients with heart failure, recent myocardial infarction, ventricular arrhythmia, or with any underlying medical conditions which are likely to be adversely affected by mineralocorticoid effects.
- Cardiac disorders are common with abiraterone acetate and include cardiac failure, chest pain, angina pectoris, arrhythmias, atrial fibrillation and tachycardia.
- Hepatotoxicity can occur, and treatment may need to be stopped or the dose adjusted (see Dose modifications).
- Serum transaminases and bilirubin levels should be measured before starting treatment, then every two weeks for the first three months and monthly thereafter.
- Abiraterone Acetate should not be taken with food and that no food should be consumed for at least two hours before the dose of Abiraterone Acetate is taken and for at least one hour after the dose of Abiraterone Acetate is taken. Taking Abiraterone Acetate with food causes increased exposure and this may result in adverse reactions.
Pregnancy Category X
Abiraterone Acetate can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with Abiraterone Acetate in pregnant women and Abiraterone Acetate is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose.
Abiraterone Acetate is not indicated for use in women. It is not known if abiraterone acetate is secreted in human milk. Because many drugs are secreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Abiraterone Acetate, caution is necessary for use of this drug in nursing mothers.
Safety and effectiveness of Abiraterone Acetate in pediatric patients have not been established.
Of the total number of patients receiving Abiraterone Acetate in Phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Serious adverse reactions reported with Abiraterone treatment are described below:
|Side effects||Common (>30%)||Less common (10-29%)|
|Musculoskeletal and connective tissue disorder.||Joint swelling or discomfort, muscle aches and discomfort|
|General disorder||Fluid retention||Hypokalemia, peripheral edema, hypophosphatemia, nocturia|
|Vascular disorders||Hot flashes|
|Gastrointestinal disorder||Diarrhoea, dyspepsia|
|Infections and Infestations||Urinary tract infections|
|Respiratory, thoracic and mediastinal disorder||Cough|
|Hepatic and urinary||Increased triglycerides, increased liver enzymes (AST)||Increased liver enzymes, increased urine frequency|
|Injury, poisoning and procedural complications||Fractures (all types except pathological fractures)|
Abiraterone inhibits the cytochrome P450 isoenzyme CYP2D6; caution is advised when abiraterone acetate is used with drugs activated or metabolized by CYP2D6, especially those with a narrow therapeutic index. In vitro studies have shown that abiraterone is also an inhibitor of CYP2C8.
Abiraterone is metabolized by the cytochrome P450 isoenzyme CYP3A4. Strong inhibitors or inducers of CYP3A4 should be avoided, or used with caution, during treatment with abiraterone acetate.
Human experience of overdose with Abiraterone Acetate is limited. There is no specific antidote. In the event of an overdose, stop Abiraterone Acetate, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function.
Abiraterone acetate is not indicated for use in women.
Store at a temperature not exceeding 30º C. Protect from light. Keep out of reach of children.
HDPE Bottle of 120 tablets.
- Patients should be informed that Abiraterone Acetate and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician.
- Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with Abiraterone Acetate and prednisone.
- Patients should be informed that Abiraterone Acetate should not be taken with food and that no food should be consumed for at least two hours before the dose of Abiraterone Acetate is taken and for at least one hour after the dose of Abiraterone Acetate is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking Abiraterone Acetate with food causes increased exposure and this may result in adverse reactions.
- Patients should be informed that Abiraterone Acetate is taken once daily and prednisone is taken twice daily according to their physician’s instructions.
- Patients should be informed that in the event of a missed daily dose of Abiraterone Acetate or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician.
- Patients should be apprised of the common side effects associated with Abiraterone Acetate including peripheral oedema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection.
- Patients should be advised that their liver function will be monitored using blood tests.
- Patients should be informed that Abiraterone Acetate may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle Abiraterone Acetate without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with Abiraterone Acetate.
- The Complete Drug Reference. 39th edition.