Cipla Abiraterone aceteta Xbira 250mg

[Drug Name] Zytiga (Abiraterone Acetate Tablets)

[Indications] Zytiga, in combination with prednisone, is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) who have previously received docetaxel-containing chemotherapy.

[Dosage and Administration] Dosage

Recommended Dosage

Recommended dosage: Zytiga is administered orally at a dose of 1,000 mg once daily in combination with prednisone 5 mg administered orally twice daily. Zytiga must be taken on an empty stomach. No food should be consumed for at least 2 hours before and at least 1 hour after taking Zytiga [see Clinical Pharmacology]. Tablets should be swallowed whole with water.

Dosage Adjustment Guidelines for Hepatic Impairment

Reduce the recommended dosage for patients with baseline moderate hepatic impairment (Child-Pugh Class B): reduce Zytiga to 250 mg once daily. A once-daily dose of 250 mg in patients with moderate hepatic impairment is predicted to result in an area under the curve (AUC) similar to that observed with 1,000 mg once daily in patients with normal hepatic function. However, there are no clinical data regarding the 250 mg once-daily dose in patients with moderate hepatic impairment, and caution is advised. Monitor ALT, AST, and bilirubin in patients with moderate hepatic impairment before starting treatment, weekly for the first month, every two weeks for the following two months, and monthly thereafter. If elevations in ALT and/or AST greater than 5 × the upper limit of normal (ULN) or total bilirubin greater than 3 × ULN occur in patients with baseline moderate hepatic impairment, discontinue Zytiga and do not re-treat the patient with Zytiga [see Use in Specific Populations and Clinical Pharmacology]. Avoid using Zytiga in patients with baseline severe hepatic impairment (Child-Pugh Class C), as Zytiga has not been studied in this population and dose adjustments cannot be predicted.

Hepatotoxicity

For patients who develop hepatotoxicity during treatment with Zytiga (ALT and/or AST greater than 5 × ULN or total bilirubin greater than 3 × ULN), interrupt Zytiga treatment [see Warnings and Precautions]. Treatment may be resumed at a reduced dose of 750 mg once daily once liver function tests return to the patient's baseline or to AST and ALT ≤ 2.5 × ULN and total bilirubin ≤ 1.5 × ULN. For patients resuming treatment, monitor serum transaminases and bilirubin at least every 2 weeks for the first three months and monthly thereafter.

If hepatotoxicity recurs at the 750 mg once-daily dose, treatment may be restarted at a reduced dose of 500 mg once daily once liver function tests return to the patient's baseline or to AST and ALT ≤ 2.5 × ULN and total bilirubin ≤ 1.5 × ULN.

If hepatotoxicity recurs at the lower dose of 500 mg once daily, discontinue ZYTIGA treatment. The safety of resuming ZYTIGA treatment in patients who experience AST or ALT ≥ 20 × ULN and/or bilirubin ≥ 10 × ULN is unknown.

[Adverse Reactions] The following are discussed in greater detail in other sections of the prescribing information:

(1) Hypertension, hypokalemia, and fluid retention due to mineralocorticoid excess [see Warnings and Precautions].

(2) Adrenocortical insufficiency [see Warnings and Precautions].

(3) Hepatotoxicity [see Warnings and Precautions].

(4) Food effect [see Warnings and Precautions].

[Contraindications] Pregnancy

ZYTIGA may cause fetal harm when administered to a pregnant woman. ZYTIGA is contraindicated in women who are or may become pregnant. If the drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus.

[Precautions] History of cardiovascular disease

Hypertension, hypokalemia, and fluid retention due to mineralocorticoid excess

Use ZYTIGA with caution in patients with a history of cardiovascular disease. ZYTIGA may cause hypertension, hypokalemia, and fluid retention due to increased mineralocorticoid levels as a result of CYP17 inhibition [see Adverse Reactions and Clinical Pharmacology]. Co-administration of corticosteroids suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Caution must be exercised when treating patients whose medical conditions might be compromised by increases in blood pressure, hypokalemia, or fluid retention, such as those with heart failure, recent myocardial infarction, or ventricular arrhythmias. The safety of ZYTIGA in patients with a left ventricular ejection fraction <50% or NYHA Class III or IV heart failure has not been established, as these patients were excluded from randomized clinical trials. Monitor patients for hypertension, hypokalemia, and fluid retention at least monthly. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA.

Adrenocortical Insufficiency

Adrenocortical insufficiency has been reported in clinical trials in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or in the presence of concurrent infection or stress. Exercise caution and monitor for signs and symptoms of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have a reduction in prednisone dose, or experience unusual stress. Adverse reactions associated with mineralocorticoid excess observed in patients treated with ZYTIGA may mask the signs and symptoms of adrenocortical insufficiency. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. An increase in corticosteroid dosage may be indicated before, during, and after stressful situations [see Warnings and Precautions].

Hepatotoxicity

Marked increases in liver enzymes leading to drug discontinuation or dose adjustment have occurred [see Adverse Reactions]. Measure serum transaminases (ALT and AST) and bilirubin levels before starting ZYTIGA treatment, every 2 weeks for the first three months of treatment, and monthly thereafter. For patients with baseline severe hepatic impairment receiving a reduced dose of ZYTIGA (250 mg), measure ALT, AST, and bilirubin before starting treatment, weekly for the first month, every 2 weeks for the next 2 months, and monthly thereafter. Measure serum total bilirubin, AST, and ALT promptly if clinical symptoms or signs suggestive of hepatotoxicity develop. If AST, ALT, or bilirubin levels rise above the patient's baseline, monitor AST and ALT more frequently. If at any time AST or ALT rises to more than 5 times the upper limit of normal (ULN), or bilirubin rises to more than 3 times the ULN, discontinue ZYTIGA treatment and closely monitor liver function.

Retreatment with ZYTIGA at a reduced dose level may be considered only after liver function tests return to the patient's baseline or to AST and ALT levels ≤ 2.5 × ULN and total bilirubin ≤ 1.5 × ULN [see Dosage and Administration].

The safety of retreatment with ZYTIGA in patients who experience AST or ALT ≥ 20 × ULN and/or bilirubin ≥ 10 × ULN is unknown.

[Drug Interactions] In vitro studies using human liver microsomes indicate that abiraterone is a strong inhibitor of CYP1A2 and CYP2D6, and a moderate inhibitor of CYP2C9, CYP2C19, and CYP3A4/5.

In an in vivo drug-drug interaction trial, the Cmax and AUC of dextromethorphan (a CYP2D6 substrate) increased 2.8-fold and 2.9-fold, respectively, when dextromethorphan 30 mg was administered with abiraterone acetate 1,000 mg (plus prednisone 5 mg twice daily). The AUC of dextrorphan, the active metabolite of dextromethorphan, increased approximately 1.3-fold [see Drug Interactions].

In a clinical study evaluating the effect of abiraterone acetate 1,000 mg daily (plus prednisone 5 mg twice daily) on a single 100 mg dose of theophylline (a CYP1A2 substrate), no increase in systemic exposure to theophylline was observed.

Abiraterone is a substrate of CYP3A4 in vitro. The effect of strong CYP3A4 inhibitors or inducers on the pharmacokinetics of abiraterone has not been evaluated in vivo. Avoid strong CYP3A4 inhibitors and inducers, or use with caution [see Drug Interactions].

QT Prolongation

In a multicenter, open-label, single-arm trial, 33 patients with metastatic CRPC received oral ZYTIGA 1,000 mg once daily in combination with prednisone 5 mg twice daily, administered at least 1 hour before or 2 hours after a meal. Assessments up to Day 2 of Cycle 2 showed no significant changes (i.e., >20 ms) in the QTc interval from baseline. However, due to study design limitations, small increases in the QTc interval (i.e., <10 ms) attributable to abiraterone acetate cannot be ruled out.

Toxicology

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of abiraterone acetate have not been conducted.

Abiraterone acetate and abiraterone were not mutagenic in the microbial mutagenesis (Ames) assay and were not clastogenic in the *in vitro* cytogenetic assay using primary human lymphocytes or the *in vivo* rat micronucleus assay.

Developmental or reproductive toxicology studies have not been conducted with abiraterone acetate. In 13- and 26-week rat studies and a 39-week monkey study, atrophy, aspermia/hypospermia, and hyperplasia of the reproductive system were observed at doses ≥50 mg/kg/day in rats and ≥250 mg/kg/day in monkeys; these findings are consistent with the anti-androgenic pharmacological activity of abiraterone [see Nonclinical Toxicology]. These effects were observed at exposures (based on AUC) approximately 1.14 times and 0.6 times the human clinical exposure in rats and monkeys, respectively.

Animal Toxicology and/or Pharmacology

In 13- and 26-week rat studies and 13- and 39-week monkey studies, decreases in circulating testosterone levels occurred with abiraterone acetate at exposures (based on AUC) approximately half of the human clinical exposure. As a result, decreased organ weights and toxicity were observed in the male and female reproductive systems, adrenal glands, liver, pituitary gland (in rats), and male mammary glands. Changes in the reproductive organs were consistent with the anti-androgenic pharmacological activity of abiraterone acetate. In rats, a dose-dependent increase in cataracts was observed starting at 26 weeks at doses >50 mg/kg/day (1.14 times the human clinical exposure based on AUC). No cataracts were observed in a 39-week monkey study at higher doses (2 times the clinical exposure based on AUC). All other toxicities associated with abiraterone acetate were reversible or partially resolved after a 4-week recovery period.

Clinical Studies

The efficacy and safety of ZYTIGA were evaluated in a randomized, placebo-controlled, multicenter Phase 3 clinical trial involving patients with metastatic castration-resistant prostate cancer (CRPC) who had previously received docetaxel-containing chemotherapy. A total of 1,195 patients were randomized in a 2:1 ratio to receive either ZYTIGA (1,000 mg orally once daily) plus prednisone (5 mg orally twice daily) (N=797) or placebo (once daily) plus prednisone (5 mg orally twice daily) (N=398). Patients randomized to either group continued treatment until disease progression (defined as a PSA increase of >25% above the patient's baseline/nadir, accompanied by protocol-defined radiographic progression and symptomatic or clinical progression), initiation of new therapy, unacceptable toxicity, or withdrawal from the study. Patients with a history of ketoconazole use for prostate cancer treatment or a history of adrenal or pituitary disorders were excluded from the trial.

Patient demographics and baseline disease characteristics were balanced between the treatment groups. The median age was 69 years (range: 39–95), and the racial distribution was 93.3% Caucasian, 3.6% Black, 1.7% Asian, and 1.6% other. Of the enrolled patients, 89% had an ECOG performance status score of 0–1, and 45% had a Brief Pain Inventory score of ≥4 (representing the worst pain reported by patients over the preceding 24 hours). Ninety percent of patients had bone metastases, and 30% had visceral involvement. Seventy percent of patients had radiographic evidence of disease progression, while 30% showed progression based solely on PSA levels. Seventy percent of patients had previously received one cytotoxic chemotherapy regimen, and 30% had received two.

A pre-specified interim analysis conducted after 552 deaths showed a statistically significant improvement in overall survival for patients treated with ZYTIGA compared with the placebo group (Table 3 and Figure 1). An updated survival analysis was performed when 775 deaths had occurred (representing 97% of the deaths planned for the final analysis). The results of this analysis were consistent with those of the interim analysis (Table 3).

Specifications

Product Name: Cipla Abiraterone Tablets (Xbira) 250mg x 120 tablets

Common Name: Xbira

Active Ingredient: Abiraterone acetate

Dosage Form: Tablet

Specification: 250mg x 120 tablets

Manufacturer: Cipla Pharmaceuticals

Indications: ZYTIGA, in combination with prednisone, is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) who have previously received docetaxel-containing chemotherapy.

Dosage and Administration: Recommended dose: ZYTIGA is administered orally at 1,000 mg once daily in combination with prednisone 5 mg administered orally twice daily. ZYTIGA must be taken on an empty stomach. No food should be consumed for at least 2 hours before and at least 1 hour after taking ZYTIGA [see Clinical Pharmacology]. Swallow tablets whole with water.

Dosage Adjustment Guidelines for Hepatic Impairment

Reduce the recommended dose for patients with baseline moderate hepatic impairment (Child-Pugh Class B): Reduce ZYTIGA to 250 mg once daily. A 250 mg once-daily dose in patients with moderate hepatic impairment is predicted to result in an area under the curve (AUC) similar to that observed with 1,000 mg once daily in patients with normal hepatic function. However, there are no clinical data regarding the 250 mg once-daily dose in patients with moderate hepatic impairment, and caution is advised. Monitor ALT, AST, and bilirubin in patients with moderate hepatic impairment before starting treatment, weekly for the first month, every two weeks for the following two months, and monthly thereafter. If ALT and/or AST elevations greater than 5 × the upper limit of normal (ULN) or total bilirubin greater than 3 × ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA and do not re-treat the patient with ZYTIGA [see Use in Specific Populations and Clinical Pharmacology]. Avoid using ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C), as ZYTIGA has not been studied in this population and dose adjustments cannot be predicted. Hepatotoxicity

For patients who develop hepatotoxicity (ALT and/or AST >5 × ULN or total bilirubin >3 × ULN) during treatment with ZYTIGA, interrupt ZYTIGA treatment [see Warnings and Precautions]. Retreatment at a reduced dose of 750 mg once daily may be initiated after liver function tests return to the patient's baseline or to AST and ALT ≤2.5 × ULN and total bilirubin ≤1.5 × ULN. For patients resuming treatment, monitor serum transaminases and bilirubin at least every 2 weeks for three months and monthly thereafter.

If hepatotoxicity recurs at the 750 mg once-daily dose, retreatment at a reduced dose of 500 mg once daily may be initiated after liver function tests return to the patient's baseline or to AST and ALT ≤2.5 × ULN and total bilirubin ≤1.5 × ULN.

If hepatotoxicity recurs at the lower dose of 500 mg once daily, discontinue ZYTIGA treatment. The safety of retreatment with ZYTIGA is unknown for patients who develop AST or ALT ≥20 × ULN and/or bilirubin ≥10 × ULN.