Abiraterone Acetate

General

• Increasing the corticosteroid dosage before, during, and after stressful situations may be indicated to prevent adrenocortical insufficiency.1 (See Adrenocortical Insufficiency under Cautions.)

• Women who are or may be pregnant should not handle abiraterone acetate tablets without protection (e.g., gloves).1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Administration

Oral Administration

Administer orally once daily on an empty stomach; consume no food for at least 2 hours before or 1 hour after a dose.1 18 (See Effect of Food on Abiraterone Absorption under Cautions.)

Administer tablets whole with water.1

Dosage

Available as abiraterone acetate; dosage expressed in terms of the salt.1

Adults

1 g once daily in combination with prednisone 5 mg orally twice daily.1 4

Continue therapy for as long as the patient derives clinical benefit from the drug or until unacceptable toxicity occurs.1 3

For ALT and/or AST elevations >5 times ULN or total bilirubin elevations >3 times ULN, interrupt dosing until liver function test results return to baseline or until ALT and AST return to ≤2.5 times ULN and total bilirubin returns to ≤1.5 times ULN, and then resume at a reduced dosage of 750 mg once daily.1

If hepatic toxicity recurs on dosage of 750 mg daily, interrupt dosing until liver function test results return to baseline or until ALT and AST return to ≤2.5 times ULN and total bilirubin returns to ≤1.5 times ULN, and then resume at a reduced dosage of 500 mg once daily.1

If hepatic toxicity recurs on dosage of 500 mg daily, discontinue abiraterone.1

In patients reinitiating therapy, measure serum transaminases and bilirubin at least every 2 weeks for 3 months and then monthly thereafter.1 (See Hepatic Toxicity under Cautions.)

Safety of reinitiating abiraterone in patients who exhibited ALT or AST elevations ≥20 times ULN and/or bilirubin elevations ≥10 times ULN is unknown.1

Special Populations

Hepatic Impairment

Mild preexisting hepatic impairment (Child-Pugh class A): No dosage adjustment required.1

Moderate preexisting hepatic impairment (Child-Pugh class B): 250 mg once daily.1 Monitor serum transaminases and bilirubin at baseline, every week for the first month of therapy, every 2 weeks during the second and third months, and then monthly thereafter.1 If elevations in ALT and/or AST to >5 times ULN or in total bilirubin to >3 times ULN occur, permanently discontinue abiraterone.1 (See Pharmacokinetics and also see Hepatic Toxicity under Cautions.)

Severe preexisting hepatic impairment (Child-Pugh class C): Use not recommended.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

No dosage adjustment required.1

Geriatric Patients

No dosage adjustment required.1

Contraindications

• Women who are or may become pregnant.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Warnings/Precautions

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 Contraindicated in women who are or may become pregnant.1 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1

Women who are or may be pregnant should not handle abiraterone acetate tablets without protection (e.g., gloves).1

Not known whether abiraterone or its metabolites distribute into semen.1 During and for 1 week following discontinuance of abiraterone therapy, men receiving the drug should use a condom during sexual encounters with pregnant women and should use a condom in conjunction with another effective contraceptive method during sexual encounters with women of childbearing potential.1

Excessive Mineralocorticoid Activity

Mineralocorticoid excess occurs secondary to CYP17 blockade by abiraterone; commonly manifested as hypertension, hypokalemia, and fluid retention.1 9 10 12 14 Concomitant glucocorticoid administration may reduce severity and incidence of these adverse effects.1 5 7 8 9 10 12 14

Monitor at least monthly for hypertension, hypokalemia, and fluid retention.1 Control BP and correct hypokalemia before and during treatment.1

Use with caution in patients with a history of cardiovascular disease or underlying medical condition that might be compromised by increased BP, hypokalemia, or fluid retention (e.g., heart failure, recent MI, ventricular arrhythmia).1

Safety not established in patients with left ventricular ejection fraction <50% or NYHA class III or IV heart failure.1

Adrenocortical Insufficiency

Adrenocortical insufficiency reported following interruption of daily corticosteroid regimen and/or during periods of infection or stress.1

Use with caution and monitor for manifestations of adrenocortical insufficiency, especially following prednisone dosage reduction or discontinuance or when patient is subjected to unusual stress.1 Consider possible need for increased corticosteroid dosage before, during, and after stressful situations.1

Symptoms of mineralocorticoid excess may mask manifestations of adrenocortical insufficiency; perform appropriate tests to confirm diagnosis of adrenocortical insufficiency if clinically indicated.1

Hepatic Toxicity

ALT or AST elevations of >5 times ULN reported in 2.3% of patients, generally during the initial 3 months of therapy.1

Elevations in liver function test results reported more frequently in patients with preexisting ALT or AST elevations than in patients with normal baseline values.1

Monitor serum transaminase and bilirubin concentrations at baseline, every 2 weeks for the first 3 months of therapy, and then monthly thereafter.1 In patients with moderate preexisting hepatic impairment, monitor serum transaminase and bilirubin concentrations at baseline, every week for the first month of therapy, every 2 weeks during the second and third months, and then monthly thereafter.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

More frequent monitoring is indicated if transaminase or bilirubin concentrations rise above pretreatment levels.1 Evaluate liver function tests promptly if manifestations suggestive of hepatotoxicity develop.1

Effect of Food on Abiraterone Absorption

Systemic exposure and peak plasma concentration of abiraterone are increased up to tenfold and 17-fold, respectively, when administered with a meal instead of in fasted state.1 8 13 (See Food under Pharmacokinetics.)

Because of normal variations in content and composition of meals, administration with food is likely to result in highly variable exposure to the drug.1 Safety of administering multiple doses with food not established.1

Abiraterone acetate must be taken on an empty stomach; consume no food for at least 2 hours before or 1 hour after a dose.1

Specific Populations

Category X.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Not known whether distributed into milk; discontinue nursing or drug.1

Not indicated in children; safety and efficacy not established.1

No substantial differences in safety and efficacy relative to younger adults.1

Systemic exposure may be increased.1 (See Absorption: Special Populations, under Pharmacokinetics.)

Dosage adjustment and careful monitoring of hepatic function required in patients with moderate hepatic impairment (Child-Pugh class B).1 (See Hepatic Impairment under Dosage and Administration.)

Not studied and not recommended in patients with severe hepatic impairment (Child-Pugh class C).1 Patients with active hepatitis or with baseline ALT and/or AST concentrations ≥2.5 times ULN in the absence of liver metastases or >5 times ULN in the presence of liver metastases were excluded from clinical trials.1 4

Common Adverse Effects

Joint swelling or discomfort,1 hypokalemia,1 4 edema,1 4 muscle discomfort,1 hot flush,1 diarrhea,1 4 urinary tract infection,1 4 cough,1 hypertension,1 4 arrhythmia,1 4 urinary frequency,1 nocturia,1 dyspepsia,1 upper respiratory tract infection,1 hypertriglyceridemia,1 hypophosphatemia,1 elevated transaminase and total bilirubin concentrations.1 4

• Abiraterone acetate is a prodrug of abiraterone, a potent, selective, and irreversible inhibitor of 17α-hydroxylase/C17,20-lyase (CYP17), an enzyme expressed in adrenal glands, testes, and prostate tumor.1 5 6 10 12 13 CYP17 inhibition results in suppression of androgen production.10 12

• 17α-Hydroxylase catalyzes conversion of pregnenolone and progesterone to their 17α-hydroxy derivatives; C17,20-lyase catalyzes conversion of these 17α-hydroxy derivatives to DHEA and androstenedione, respectively.1 6 10 12 DHEA and androstenedione are androgenic precursors of testosterone.1 6 10 12

• Abiraterone is tenfold to 30-fold more potent than ketoconazole (a nonspecific CYP inhibitor and weak inhibitor of CYP17) in its inhibition of CYP17.5 9

• CYP17 inhibition can result in increased mineralocorticoid synthesis.3

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of electrolyte problems like mood changes, confusion, muscle pain or weakness, a heartbeat that does not feel normal, seizures, not hungry, or very bad upset stomach or throwing up.
• Signs of high blood pressure like very bad headache or dizziness, passing out, or change in eyesight.
• Signs of a weak adrenal gland like a very bad upset stomach or throwing up, very bad dizziness or passing out, muscle weakness, feeling very tired, mood changes, not hungry, or weight loss.
• Signs of a urinary tract infection (UTI) like blood in the urine, burning or pain when passing urine, feeling the need to pass urine often or right away, fever, lower stomach pain, or pelvic pain.
• Signs of high blood sugar like confusion, feeling sleepy, more thirst, more hungry, passing urine more often, flushing, fast breathing, or breath that smells like fruit.
• Chest pain or pressure.
• Fast or slow heartbeat.
• Shortness of breath, a big weight gain, or swelling in the arms or legs.
• Feeling very tired or weak.
• Any unexplained bruising or bleeding.
• Blood in the urine.
• Bone pain.
• Very bad and sometimes deadly liver problems have happened with this medicine. Call your doctor right away if you have signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

(a bir A ter one AS e tate)

• Abiraterone
• CB7630

Administer abiraterone orally on an empty stomach, at least 1 hour before and 2 hours after food. Note: The prescribing information describes when to give food with respect to abiraterone; no food should be consumed for at least 2 hours before or for at least 1 hour after the abiraterone dose. Swallow tablets whole with water. Do not crush or chew.

Adverse reactions reported for use in combination with prednisone.

>10%:

Cardiovascular: Edema (25% to 27%; includes anasarca, peripheral edema, pitting edema), hypertension (9% to 22%)

Central nervous system: Fatigue (39%), insomnia (14%)

Dermatologic: Bruise (13%)

Endocrine & metabolic: Hypertriglyceridemia (63%), hyperglycemia (57%), hypernatremia (33%), hypokalemia (17% to 28%), hypophosphatemia (24%; grades 3/4: 7%), hot flash (19% to 22%)

Gastrointestinal: Constipation (23%), diarrhea (18% to 22%), dyspepsia (6% to 11%)

Genitourinary: Urinary tract infection (12%)

Hematologic & oncologic: Lymphocytopenia (38%; grades 3/4: 9%)

Hepatic: Increased serum ALT (11% to 42%; grades 3/4: 1% to 6%), increased serum AST (37%; grades 3/4: 3%)

Neuromuscular & skeletal: Joint swelling (30%, includes arthralgia, arthritis, joint discomfort, joint stiffness), myalgia (26%; includes muscle rigidity, muscle spasm, musculoskeletal discomfort, musculoskeletal pain)

Respiratory: Cough (11% to 17%), upper respiratory infection (5% to 13%), dyspnea (12%), nasopharyngitis (11%)

1% to 10%:

Cardiovascular: Cardiac arrhythmia (7%; includes atrial fibrillation, atrial tachycardia, bradycardia, cardiac conduction disturbance, complete atrioventricular block, supraventricular tachycardia, tachycardia), chest pain (4%, includes angina pectoris, chest discomfort, unstable angina pectoris), cardiac failure (2%; includes cardiogenic shock, cardiomegaly, cardiomyopathy, congestive heart failure, left ventricular dysfunction, reduced ejection fraction)

Central nervous system: Falling (6%)

Dermatologic: Skin rash (8%)

Genitourinary: Hematuria (10%), groin pain (7%), urinary frequency (7%), nocturia (6%)

Hepatic: Increased serum bilirubin (7%; grades 3/4: <1%)

Neuromuscular & skeletal: Bone fracture (6%)

Miscellaneous: Fever (9%)

<1% (Limited to important or life-threatening): Acute hepatic failure, adrenocortical insufficiency, fulminant hepatitis, myopathy (includes rhabdomyolysis), pneumonia

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience flushing, muscle pain, joint pain, joint edema, heartburn, cough, diarrhea, common cold symptoms, rhinitis, pharyngitis, or vomiting. Have patient report immediately to prescriber signs of electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of adrenal gland problems (severe nausea, vomiting, severe dizziness, passing out, muscle weakness, severe fatigue, mood changes, lack of appetite, or weight loss), signs of a urinary tract infection (hematuria, burning or painful urination, polyuria, fever, lower abdominal pain, or pelvic pain), signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, polyuria, flushing, fast breathing, or breath that smells like fruit), severe headache, severe dizziness, passing out, vision changes, angina, tachycardia, bradycardia, shortness of breath, excessive weight gain, swelling of arms or legs, severe loss of strength and energy, bruising, bleeding, hematuria, or bone pain (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.