Precautions for ABIRATAJ

Prostate and other male cancers

Hypertension, Hypokalemia And Fluid Retention Due To Mineralocorticoid Excess

ABIRATAJ may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see CLINICAL PHARMACOLOGY]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ABIRATAJ.

In the combined data from 4 placebo-controlled trials using prednisone 5 mg twice daily in combination with 1000 mg abiraterone acetate daily, grades 3-4 hypokalemia were detected in 4% of patients on the ABIRATAJ arm and 2% of patients on the placebo arm. Grades 3-4 hypertension were observed in 2% of patients each arm and grades 3-4 fluid retention in 1% of patients each arm.

In LATITUDE (a randomized placebo-controlled, multicenter clinical trial), which used prednisone 5 mg daily in combination with 1000 mg abiraterone acetate daily, grades 3-4 hypokalemia were detected in 10% of patients on the ABIRATAJ arm and 1% of patients on the placebo arm, grades 3-4 hypertension were observed in 20% of patients on the ABIRATAJ arm and 10% of patients on the placebo arm. Grades 3-4 fluid retention occurred in 1% of patients each arm [see ADVERSE REACTIONS].

Closely monitor patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, such as those with heart failure, recent myocardial infarction, cardiovascular disease, or ventricular arrhythmia. The safety of ABIRATAJ in patients with left ventricular ejection fraction 50% or New York Heart Association (NYHA) Class III or IV heart failure (in COU-AA-301) or NYHA Class II to IV heart failure (in COU-AA-302 and LATITUDE) has not been established because these patients were excluded from these randomized clinical trials [see Clinical Studies].

Adrenocortical Insufficiency

Adrenal insufficiency occurred in 0.3% of 2230 patients taking ABIRATAJ and in 0.1% of 1763 patients taking placebo in the combined data of the 5 randomized, placebo-controlled clinical studies. Adrenocortical insufficiency was reported in patients receiving ABIRATAJ in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress.

Monitor patients for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ABIRATAJ. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Hypertension, Hypokalemia And Fluid Retention Due To Mineralocorticoid Excess].

Hepatotoxicity

In postmarketing experience, there have been ABIRATAJ-associated severe hepatic toxicity, including fulminant hepatitis, acute liver failure and deaths [see ADVERSE REACTIONS].

In the combined data of 5 randomized clinical trials, grade 3-4 ALT or AST increases (at least 5X ULN) were reported in 6% of 2230 patients who received ABIRATAJ, 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 ALT and AST increases or abnormal hepatic function occurred in 1.1% of 2230 patients taking ABIRATAJ. In these clinical trials, no deaths clearly related to ABIRATAJ were reported due to hepatotoxicity events.

Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ABIRATAJ, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ABIRATAJ dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ABIRATAJ treatment and closely monitor liver function.

Re-treatment with ABIRATAJ at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see DOSAGE AND ADMINISTRATION].

Permanently discontinue ABIRATAJ for patients who develop a concurrent elevation of ALT greater than 3 x ULN and total bilirubin greater than 2 x ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation [see DOSAGE AND ADMINISTRATION].

The safety of ABIRATAJ re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION)

Hypertension, Hypokalemia, And Fluid Retention

• Inform patients that ABIRATAJ is associated with hypertension, hypokalemia, and peripheral edema. Advise patients to report symptoms of hypertension, hypokalemia, or edema to their healthcare provider [see WARNINGS AND PRECAUTIONS].

Adrenocortical Insufficiency

• Inform patients that ABIRATAJ with prednisone is associated with adrenal insufficiency. Advise patients to report symptoms of adrenocortical insufficiency to their healthcare provider [see WARNINGS AND PRECAUTIONS].

Hepatotoxicity

• Inform patients that ABIRATAJ is associated with severe hepatotoxicity. Inform patients that their liver function will be monitored using blood tests. Advise patients to immediately report symptoms of hepatotoxicity to their healthcare provider [see WARNINGS AND PRECAUTIONS].

Dosing And Administration

• Inform patients that ABIRATAJ is taken once daily with prednisone (once or twice daily according to their healthcare provider’s instructions) and to not interrupt or stop either of these medications without consulting their healthcare provider.

• Inform patients receiving GnRH therapy that they need to maintain this treatment during the course of treatment with ABIRATAJ.

• Instruct patients to take ABIRATAJ on an empty stomach, either one hour before or two hours after a meal. ABIRATAJ taken with food causes increased exposure and may result in adverse reactions. Instruct patients to swallow tablets whole with water and not to crush or chew the tablets [see DOSAGE AND ADMINISTRATION].

• Inform patients that if they miss a dose of ABIRATAJ or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, inform patients to contact their healthcare provider [see DOSAGE AND ADMINISTRATION].

Fetal Toxicity

• Inform patients that ABIRATAJ may harm a developing fetus. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 weeks after the final dose of ABIRATAJ [see Use In Specific Populations].

• Women who are pregnant or women who may be pregnant should not handle ABIRATAJ 250 mg uncoated tablets or other ABIRATAJ tablets if broken, crushed, or damaged without protection, e.g., gloves [see Use In Specific Populations and HOW SUPPLIED].

Infertility

• Advise male patients that ABIRATAJ may impair fertility [see Use In Specific Populations].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, And Impairment Of Fertility

A two-year carcinogenicity study was conducted in rats at oral abiraterone acetate doses of 5, 15, and 50 mg/kg/day for males and 15, 50, and 150 mg/kg/day for females. Abiraterone acetate increased the combined incidence of interstitial cell adenomas and carcinomas in the testes at all dose levels tested. This finding is considered to be related to the pharmacological activity of abiraterone. Rats are regarded as more sensitive than humans to developing interstitial cell tumors in the testes. Abiraterone acetate was not carcinogenic in female rats at exposure levels up to 0.8 times the human clinical exposure based on AUC. Abiraterone acetate was not carcinogenic in a 6-month study in the transgenic (Tg.rasH2) mouse.

Abiraterone acetate and abiraterone was not mutagenic in an in vitro microbial mutagenesis (Ames) assay or clastogenic in an in vitro cytogenetic assay using primary human lymphocytes or an in vivorat micronucleus assay.

In repeat-dose toxicity studies in male rats (13- and 26-weeks) and monkeys (39-weeks), atrophy, aspermia/hypospermia, and hyperplasia in the reproductive system were observed at ≥50 mg/kg/day in rats and ≥250 mg/kg/day in monkeys and were consistent with the antiandrogenic pharmacological activity of abiraterone. These effects were observed in rats at systemic exposures similar to humans and in monkeys at exposures approximately 0.6 times the AUC in humans.

In a fertility study in male rats, reduced organ weights of the reproductive system, sperm counts, sperm motility, altered sperm morphology and decreased fertility were observed in animals dosed for 4 weeks at ≥30 mg/kg/day orally. Mating of untreated females with males that received 30 mg/kg/day oral abiraterone acetate resulted in a reduced number of corpora lutea, implantations and live embryos and an increased incidence of pre-implantation loss. Effects on male rats were reversible after 16 weeks from the last abiraterone acetate administration.

In a fertility study in female rats, animals dosed orally for 2 weeks until day 7 of pregnancy at ≥30 mg/kg/day had an increased incidence of irregular or extended estrous cycles and preimplantation loss (300 mg/kg/day). There were no differences in mating, fertility, and litter parameters in female rats that received abiraterone acetate. Effects on female rats were reversible after 4 weeks from the last abiraterone acetate administration.

The dose of 30 mg/kg/day in rats is approximately 0.3 times the recommended dose of 1,000 mg/day based on body surface area.

In 13- and 26-week studies in rats and 13- and 39-week studies in monkeys, a reduction in circulating testosterone levels occurred with abiraterone acetate at approximately one half the human clinical exposure based on AUC. As a result, decreases in organ weights and toxicities were observed in the male and female reproductive system, adrenal glands, liver, pituitary (rats only), and male mammary glands. The changes in the reproductive organs are consistent with the antiandrogenic pharmacological activity of abiraterone acetate.

Use In Specific Populations

Pregnancy

Risk Summary

Based on findings from animal studies and the mechanism of action, ABIRATAJ is contraindicated for use in pregnant women because the drug can cause fetal harm and potential loss of pregnancy. ABIRATAJ is not indicated for use in females.

There are no human data on the use of ABIRATAJ in pregnant women. In animal reproduction studies, oral administration of abiraterone acetate to pregnant rats during organogenesis caused adverse developmental effects at maternal exposures approximately ≥ 0.03 times the human exposure (AUC) at the recommended dose (see Data).

Data

Animal Data

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). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients.

Lactation

Risk Summary

ABIRATAJ is not indicated for use in women. There is no information available on the presence of abiraterone acetate in human milk, or on the effects on the breastfed child or milk production.

Females And Males Of Reproductive Potential

Contraception

Males

Based on findings in animal reproduction studies and its mechanism of action, advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 weeks after the final dose of ABIRATAJ [see Use In Specific Populations].

Infertility

Based on animal studies, ABIRATAJ may impair reproductive function and fertility in males of reproductive potential [see Nonclinical Toxicology].

Pediatric Use

Safety and effectiveness of ABIRATAJ in pediatric patients have not been established.

Geriatric Use

Of the total number of patients receiving ABIRATAJ in randomized clinical trials, 70% of patients were 65 years and over and 27% 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.

Patients With Hepatic Impairment

The pharmacokinetics of abiraterone were examined in subjects with baseline mild (N=8) or moderate (N=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ABIRATAJ increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function.

In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (N=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7-fold and the fraction of free drug increased 2-fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function.

No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of ABIRATAJ to 250 mg once daily. Do not use ABIRATAJ in patients with baseline severe hepatic impairment (Child-Pugh Class C). If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ABIRATAJ treatment [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see DOSAGE AND ADMINISTRATION , WARNINGS AND PRECAUTIONSand CLINICAL PHARMACOLOGY].

Patients With Renal Impairment

No dosage adjustment is necessary for patients with renal impairment [see CLINICAL PHARMACOLOGY].