MOBILE VIEW  | 

ABIRATERONE ACETATE

Classification   |    Detailed evidence-based information

Therapeutic Toxic Class

    A) Abiraterone acetate is an inhibitor of 17 alpha-hydroxylase/C 17, 20-lyase (CYP 17), an enzymes required for androgen biosynthesis. It is used to treat patients with metastatic castration-resistant prostate cancer.

Specific Substances

    1) Abirateron-azetat
    2) Abirateroni acetas
    3) Acetato de abiraterona
    4) CB-7630
    5) CAS 154229-19-3 (abiraterone)
    6) CAS 154229-18-2 (abiraterone acetate)
    1.2.1) MOLECULAR FORMULA
    1) C26-H33-N-O2 (Prod Info ZYTIGA(TM) oral tablets, 2011)

Available Forms Sources

    A) FORMS
    1) Abiraterone acetate is available in the United States as 250 mg tablets (Prod Info ZYTIGA(TM) oral tablets, 2011).
    B) USES
    1) Abiraterone acetate is used in combination with prednisone to treat patients with metastatic castration-resistant prostate cancer who have received prior chemotherapy containing docetaxel (Prod Info ZYTIGA(TM) oral tablets, 2011).

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Abiraterone acetate is used in combination with prednisone to treat patients with metastatic castration-resistant prostate cancer who have received prior chemotherapy containing docetaxel.
    B) PHARMACOLOGY: Abiraterone acetate is metabolized to abiraterone, an androgen biosynthesis inhibitor of 17 alpha-hydroxylase/C 17, 20-lyase (CYP 17) which decreases androgen levels and deprives androgen-sensitive prostatic carcinomas. It accomplishes this by interfering with the CYP17-catalyzed reactions involved in the production of dehydroepiandrosterone (DHEA) and androstenedione. Inhibition of CYP17 can result in increased mineralocorticoid production by the adrenals.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) The following adverse effects have been reported: Joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, dysrhythmias, urinary frequency, nocturia, dyspepsia, and upper respiratory tract infection, heart failure, chest pain, hypophosphatemia, hypertriglyceridemia, and elevated bilirubin and liver enzymes.
    E) WITH POISONING/EXPOSURE
    1) At the time of this review, there is no acute overdose data available. Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses.
    0.2.20) REPRODUCTIVE
    A) Abiraterone acetate is classified as FDA pregnancy category X.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no human data were available to assess the potential carcinogenic activity of abiraterone acetate.

Laboratory Monitoring

    A) Monitor vital signs, serum electrolytes, liver enzymes, and renal function following significant overdose.
    B) Obtain an ECG and institute continuous cardiac monitoring in symptomatic patients.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. For severe hypertension with end organ effects, nitroprusside or phentolamine are preferred. Labetalol or nitroglycerin are alternatives.
    C) DECONTAMINATION
    1) PREHOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is alert and able to maintain airway.
    2) HOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with life-threatening cardiac dysrhythmias or hemodynamic instability.
    E) ANTIDOTE
    1) None.
    F) HYPERTENSIVE EPISODE
    1) Mild/moderate asymptomatic hypertension does not usually require treatment. For severe hypertension with end organ effects, nitroprusside or phentolamine are preferred, with nitroglycerin or labetalol as alternatives.
    G) VENTRICULAR DYSRHYTHMIAS
    1) Institute continuous cardiac monitoring, obtain an ECG, and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders. Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.
    H) ENHANCED ELIMINATION
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding and large volume of distribution.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: An adult with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions should be observed in a healthcare facility, as should women who may be pregnant.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite adequate treatment should be admitted.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear. Consult an expert in teratogenesis for exposures in pregnant women.
    J) PITFALLS
    1) When managing a suspected abiraterone acetate overdose, the possibility of multidrug involvement should be considered. Symptoms of overdose are similar to reported side effects of the medication. Exposure in pregnant women may affect the sexual development of the fetus, particularly if the fetus is male.
    K) PHARMACOKINETICS
    1) Tmax: Oral: 2 hours; protein binding: greater than 99%; Vd: 19,669 +/- 13,358 L. Following oral administration of abiraterone acetate, it is hydrolyzed to abiraterone, the active metabolite. Abiraterone is metabolized by both CYP3A4 and SULT2A1 enzymes to N-oxide abiraterone sulphate (inactive), and by SULT2A1 to abiraterone sulphate (inactive), which account for approximately 43% of exposure each. Excretion: renal: approximately 5% of the radioactive dose is recovered in the urine. Feces: approximately 88% of the radioactive dose is recovered in the feces, of which approximately 55% is unchanged abiraterone acetate and 22% is unchanged abiraterone. Elimination half-life: 12 +/- 5 hours.
    L) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause hypertension, hepatotoxicity, hypokalemia, or dysrhythmias.

Range Of Toxicity

    A) TOXICITY: A toxic dose has not been established.
    B) THERAPEUTIC DOSE: ADULTS: 1000 mg orally once daily with prednisone 5 mg orally twice daily. CHILDREN: Abiraterone acetate is not indicated in children.

Summary Of Exposure

    A) USES: Abiraterone acetate is used in combination with prednisone to treat patients with metastatic castration-resistant prostate cancer who have received prior chemotherapy containing docetaxel.
    B) PHARMACOLOGY: Abiraterone acetate is metabolized to abiraterone, an androgen biosynthesis inhibitor of 17 alpha-hydroxylase/C 17, 20-lyase (CYP 17) which decreases androgen levels and deprives androgen-sensitive prostatic carcinomas. It accomplishes this by interfering with the CYP17-catalyzed reactions involved in the production of dehydroepiandrosterone (DHEA) and androstenedione. Inhibition of CYP17 can result in increased mineralocorticoid production by the adrenals.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) The following adverse effects have been reported: Joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, dysrhythmias, urinary frequency, nocturia, dyspepsia, and upper respiratory tract infection, heart failure, chest pain, hypophosphatemia, hypertriglyceridemia, and elevated bilirubin and liver enzymes.
    E) WITH POISONING/EXPOSURE
    1) At the time of this review, there is no acute overdose data available. Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HEART FAILURE
    1) WITH THERAPEUTIC USE
    a) In a phase 3, placebo-controlled clinical study of patients with metastatic castration-resistant prostate cancer, cardiac failure (includes congestive heart failure, left ventricular dysfunction, cardiogenic shock, cardiomegaly, cardiomyopathy, and decreased ejection fraction) was reported in 2.3% of patients who received abiraterone 1000 mg daily in combination with prednisone 5 mg twice daily for a median duration of 8 months (n=791), compared with 1% of patients who received placebo with prednisone 5 mg twice daily (n=394). In the abiraterone/prednisone-treated group, grades 3 to 4 cardiac failure occurred in 1.9% of patients, compared with 0.3% of patients in the placebo/prednisone-treated group. Cardiac failure was one of the most commonly reported adverse event resulting in drug discontinuation (Prod Info ZYTIGA(TM) oral tablets, 2011).
    B) CHEST PAIN
    1) WITH THERAPEUTIC USE
    a) In a phase 3, placebo-controlled clinical study of patients with metastatic castration-resistant prostate cancer, chest pain or chest discomfort (includes angina pectoris and unstable angina) was reported in 3.8% of patients who received abiraterone 1000 mg daily in combination with prednisone 5 mg twice daily for a median duration of 8 months (n=791), compared with 2.8% of patients who received placebo with prednisone 5 mg twice daily (n=394). In the abiraterone/prednisone-treated group, grades 3 to 4 chest pain or chest discomfort occurred in 0.5% of patients, compared with 0% of patients in the placebo/prednisone-treated group. However, myocardial infarction or ischemia occurred more frequently in the placebo arm than in the abiraterone arm at 1.3% and 1.1%, respectively (Prod Info ZYTIGA(TM) oral tablets, 2011).
    C) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) In a phase 3, placebo-controlled clinical study of patients with metastatic castration-resistant prostate cancer, hypertension relating to mineralocorticoid effects were reported in 8.5% of patients who received abiraterone 1000 mg daily in combination with prednisone 5 mg twice daily for a median duration of 8 months (n=791), compared with 6.9% of patients who received placebo with prednisone 5 mg twice daily (n=394). In the abiraterone/prednisone-treated group, grades 3 to 4 hypertension occurred in 1.3% of patients, compared with 0.3% of patients in the placebo/prednisone-treated group (Prod Info ZYTIGA(TM) oral tablets, 2011).
    D) EDEMA
    1) WITH THERAPEUTIC USE
    a) In a phase 3, placebo-controlled clinical study of patients with metastatic castration-resistant prostate cancer, edema (includes peripheral, pitting, or generalized edema) was reported in 26.7% of patients who received abiraterone 1000 mg daily in combination with prednisone 5 mg twice daily for a median duration of 8 months (n=791), compared with 18.3% of patients who received placebo with prednisone 5 mg twice daily (n=394). In the abiraterone/prednisone-treated group, grades 3 to 4 edema occurred in 1.9% of patients, compared with 0.8% of patients in the placebo/prednisone-treated group (Prod Info ZYTIGA(TM) oral tablets, 2011).
    E) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) In a phase 3, placebo-controlled clinical study of patients with metastatic castration-resistant prostate cancer, dysrhythmias (includes tachycardia, atrial fibrillation, supraventricular tachycardia, atrial tachycardia, ventricular tachycardia, atrial flutter, bradycardia, complete atrioventricular block, conduction disorder, and bradyarrhythmia) were reported in 7.2% of patients who received abiraterone 1000 mg daily in combination with prednisone 5 mg twice daily for a median duration of 8 months (n=791), compared with 4.6% of patients who received placebo with prednisone 5 mg twice daily (n=394). In the abiraterone/prednisone-treated group, grades 3 to 4 arrhythmia occurred in 1.1% of patients, compared with 1% of patients in the placebo/prednisone-treated group. There was one death in the abiraterone/prednisone-treated group associated with dysrhythmia and no deaths in the placebo/prednisone group (Prod Info ZYTIGA(TM) oral tablets, 2011).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) COUGH
    1) WITH THERAPEUTIC USE
    a) In a phase 3, placebo-controlled clinical study of patients with metastatic castration-resistant prostate cancer, cough was reported in 10.6% of patients who received abiraterone 1000 mg daily in combination with prednisone 5 mg twice daily for a median duration of 8 months (n=791), compared with 7.6% of patients who received placebo with prednisone 5 mg twice daily (n=394) (Prod Info ZYTIGA(TM) oral tablets, 2011).
    B) UPPER RESPIRATORY INFECTION
    1) WITH THERAPEUTIC USE
    a) In a phase 3, placebo-controlled clinical study of patients with metastatic castration-resistant prostate cancer, upper respiratory tract infection was reported in 5.4% of patients who received abiraterone 1000 mg daily in combination with prednisone 5 mg twice daily for a median duration of 8 months (n=791), compared with 2.5% of patients who received placebo with prednisone 5 mg twice daily (n=394) (Prod Info ZYTIGA(TM) oral tablets, 2011).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In a phase 3, placebo-controlled clinical study of patients with metastatic castration-resistant prostate cancer, diarrhea was reported in 17.6% of patients who received abiraterone 1000 mg daily in combination with prednisone 5 mg twice daily for a median duration of 8 months (n=791), compared with 13.5% of patients who received placebo with prednisone 5 mg twice daily (n=394). In the abiraterone/prednisone-treated group, grades 3 to 4 diarrhea occurred in 0.6% of patients, compared with 1.3% of patients in the placebo/prednisone-treated group (Prod Info ZYTIGA(TM) oral tablets, 2011).
    B) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) In a phase 3, placebo-controlled clinical study of patients with metastatic castration-resistant prostate cancer, dyspepsia was reported in 6.1% of patients who received abiraterone 1000 mg daily in combination with prednisone 5 mg twice daily for a median duration of 8 months (n=791), compared with 3.3% of patients who received placebo with prednisone 5 mg twice daily (n=394) (Prod Info ZYTIGA(TM) oral tablets, 2011).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) SERUM BILIRUBIN RAISED
    1) WITH THERAPEUTIC USE
    a) In a phase 3, placebo-controlled clinical study of patients with metastatic castration-resistant prostate cancer, high total bilirubin was reported in 6.6% of patients who received abiraterone 1000 mg daily in combination with prednisone 5 mg twice daily for a median duration of 8 months (n=791), compared with 4.6% of patients who received placebo with prednisone 5 mg twice daily (n=394). In the abiraterone/prednisone-treated group, grades 3 to 4 high total bilirubin occurred in 0.1% of patients, compared with 0% of patients in the placebo/prednisone-treated group (Prod Info ZYTIGA(TM) oral tablets, 2011).
    b) During clinical trials, 2 patients with normal baseline hepatic function experienced ALT or AST elevations 15 to 40 times upper limit of normal (ULN) and bilirubin elevations 2 to 6 times ULN. Patients experiencing elevations of ALT or AST greater than 20 times the ULN were not retreated (Prod Info ZYTIGA(TM) oral tablets, 2011).
    B) INCREASED LIVER ENZYMES
    1) WITH THERAPEUTIC USE
    a) In clinical trials, elevated liver enzymes (ALT and AST increases greater than 5 times the upper limit of normal (ULN)) was reported in 2.3% of patients receiving abiraterone in combination with prednisone (Prod Info ZYTIGA(TM) oral tablets, 2011).
    b) In a phase 3, placebo-controlled clinical study of patients with metastatic castration-resistant prostate cancer, high ALT was reported in 11.1% of patients who received abiraterone 1000 mg daily in combination with prednisone 5 mg twice daily for a median duration of 8 months (n=791), compared with 10.4% of patients who received placebo with prednisone 5 mg twice daily (n=394). In the abiraterone/prednisone-treated group, grades 3 to 4 high ALT occurred in 1.4% of patients, compared with 0.8% of patients in the placebo/prednisone-treated group. Increased ALT was one of the most commonly reported adverse event resulting in drug discontinuation (Prod Info ZYTIGA(TM) oral tablets, 2011).
    c) During clinical trials, 2 patients with normal baseline hepatic function experienced ALT or AST elevations 15 to 40 times ULN and bilirubin elevations 2 to 6 times ULN. Patients experiencing elevations of ALT or AST greater than 20 times the ULN were not retreated (Prod Info ZYTIGA(TM) oral tablets, 2011).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) URINARY TRACT INFECTIOUS DISEASE
    1) WITH THERAPEUTIC USE
    a) In a phase 3, placebo-controlled clinical study of patients with metastatic castration-resistant prostate cancer, urinary tract infection was reported in 11.5% of patients who received abiraterone 1000 mg daily in combination with prednisone 5 mg twice daily for a median duration of 8 months (n=791), compared with 7.1% of patients who received placebo with prednisone 5 mg twice daily (n=394). In the abiraterone/prednisone-treated group, grades 3 to 4 urinary tract infection occurred in 2.1% of patients, compared with 0.5% of patients in the placebo/prednisone-treated group. Urosepsis was one of the most commonly reported adverse events resulting in drug discontinuation (Prod Info ZYTIGA(TM) oral tablets, 2011).
    B) INCREASED FREQUENCY OF URINATION
    1) WITH THERAPEUTIC USE
    a) In a phase 3, placebo-controlled clinical study of patients with metastatic castration-resistant prostate cancer, urinary frequency was reported in 7.2% of patients who received abiraterone 1000 mg daily in combination with prednisone 5 mg twice daily for a median duration of 8 months (n=791), compared with 5.1% of patients who received placebo with prednisone 5 mg twice daily (n=394). Grades 3 to 4 urinary frequency were reported in 0.3% of patients in both the abiraterone/prednisone-treated and placebo/prednisone-treated groups (Prod Info ZYTIGA(TM) oral tablets, 2011).
    C) NOCTURIA
    1) WITH THERAPEUTIC USE
    a) In a phase 3, placebo-controlled clinical study of patients with metastatic castration-resistant prostate cancer, nocturia was reported in 6.2% of patients who received abiraterone 1000 mg daily in combination with prednisone 5 mg twice daily for a median duration of 8 months (n=791), compared with 4.1% of patients who received placebo with prednisone 5 mg twice daily (n=394) (Prod Info ZYTIGA(TM) oral tablets, 2011).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) FLUSHING
    1) WITH THERAPEUTIC USE
    a) In a phase 3, placebo-controlled clinical study of patients with metastatic castration-resistant prostate cancer, hot flush was reported in 19% of patients who received abiraterone 1000 mg daily in combination with prednisone 5 mg twice daily for a median duration of 8 months (n=791), compared with 16.8% of patients who received placebo with prednisone 5 mg twice daily (n=394). In the abiraterone/prednisone-treated group, grades 3 to 4 hot flush occurred in 0.3% of patients, compared with 0.3% of patients in the placebo/prednisone-treated group (Prod Info ZYTIGA(TM) oral tablets, 2011).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) JOINT SWELLING
    1) WITH THERAPEUTIC USE
    a) In a phase 3, placebo-controlled clinical study of patients with metastatic castration-resistant prostate cancer, joint swelling/discomfort (includes arthritis, arthralgia, and joint stiffness) was reported in 29.5% of patients who received abiraterone 1000 mg daily in combination with prednisone 5 mg twice daily for a median duration of 8 months (n=791), compared with 23.4% of patients who received placebo with prednisone 5 mg twice daily (n=394). In the abiraterone/prednisone-treated group, grades 3 to 4 joint swelling/discomfort occurred in 4.2% of patients, compared with 4.1% of patients in the placebo/prednisone-treated group (Prod Info ZYTIGA(TM) oral tablets, 2011).
    B) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) In a phase 3, placebo-controlled clinical study of patients with metastatic castration-resistant prostate cancer, muscle discomfort (includes muscle spasms, musculoskeletal pain, myalgia, musculoskeletal discomfort, and musculoskeletal stiffness) was reported in 26.2% of patients who received abiraterone 1000 mg daily in combination with prednisone 5 mg twice daily for a median duration of 8 months (n=791), compared with 23.1% of patients who received placebo with prednisone 5 mg twice daily (n=394). In the abiraterone/prednisone-treated group, grades 3 to 4 muscle discomfort occurred in 3% of patients, compared with 2.3% of patients in the placebo/prednisone-treated group (Prod Info ZYTIGA(TM) oral tablets, 2011).

Reproductive

    3.20.1) SUMMARY
    A) Abiraterone acetate is classified as FDA pregnancy category X.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) In animal studies, fetal developmental toxicity was observed when animals were administered oral abiraterone acetate doses of approximately 0.03, 0.1 and 0.3 times the AUC in patients throughout the period of organogenesis (gestational days 6 to 17). Following doses of 0.03 times the AUC in patients and greater, embryofetal lethality (increased postimplantation loss and resorptions and reduced number of live fetuses), fetal developmental delay (skeletal effects), urogenital effects (bilateral ureter dilation), as well as maternal toxicity were observed. Reduced fetal ano-genital distance and fetal body weight were observed with doses of 0.1 and 0.3 times or more the AUC in humans, respectively (Prod Info ZYTIGA(R) oral tablets, 2015).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) Adequate and well-controlled studies with abiraterone acetate in pregnant women are not available (Prod Info ZYTIGA(R) oral tablets, 2015).
    B) PREGNANCY CATEGORY
    1) Abiraterone acetate is classified by the manufacturer as FDA pregnancy category X (Prod Info ZYTIGA(R) oral tablets, 2015).
    2) Abiraterone acetate is not indicated for use in women. Abiraterone acetate is contraindicated in women who are or who may become pregnant. Therefore, women of childbearing potential should be advised to avoid becoming pregnant during treatment. If the drug is used during pregnancy or if a patient becomes pregnant during therapy, advise the patient of the potential hazard to the fetus and the risk for loss of pregnancy (Prod Info ZYTIGA(R) oral tablets, 2015).
    C) ANIMAL STUDIES
    1) In animal studies, fetal developmental toxicity was observed when animals were administered oral abiraterone acetate doses of up to approximately 0.3 times the AUC in patients throughout the period of organogenesis (gestational days 6 to 17). Following doses of 0.03 times the AUC in patients, embryofetal lethality (increased postimplantation loss and resorptions and reduced number of live fetuses), fetal developmental delay (skeletal effects), urogenital effects (bilateral ureter dilation), as well as maternal toxicity were observed. Reduced fetal ano-genital distance and fetal body weight were observed with doses of 0.1 and 0.3 times and greater the AUC in humans, respectively (Prod Info ZYTIGA(R) oral tablets, 2015).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is unknown whether abiraterone is excreted in human milk (Prod Info ZYTIGA(R) oral tablets, 2015).
    B) BREAST MILK
    1) Abiraterone acetate is not indicated for use in women. There are no reports describing the use of abiraterone acetate during human lactation and the effects on the nursing infant from exposure to the drug in milk are unknown. Until more data are available, a decision should be made whether to discontinue abiraterone acetate or discontinue nursing after considering the importance of the drug to the nursing mother (Prod Info ZYTIGA(R) oral tablets, 2015).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Atrophy, aspermia/hypospermia, and hyperplasia in the reproductive system were noted after animals (13, 26, and 39 weeks) were administered abiraterone up to approximately 0.6 times the human clinical exposure based on the AUC. These effects were consistent with the antiandrogenic pharmacological activity of abiraterone (Prod Info ZYTIGA(R) oral tablets, 2015).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no human data were available to assess the potential carcinogenic activity of abiraterone acetate.
    3.21.4) ANIMAL STUDIES
    A) TESTICULAR ADENOMAS AND CARCINOMAS
    1) In a 2-year carcinogenicity study, male rats given oral abiraterone acetate doses of 5, 15, and 50 mg/kg/day had an increased combined incidence of interstitial cell adenomas and carcinomas in the testes at all dose levels tested. However, rats are more likely than humans to develop interstitial cell tumors in the testes (Prod Info ZYTIGA(R) oral tablets, 2014).
    B) LACK OF EFFECT
    1) Female rats exposed to oral abiraterone acetate doses up to 150 mg/kg/day (up to 0.8 times the human clinical exposure based on AUC) in a 2-year study did not exhibit carcinogenic effects. A 6-month study in the transgenic mouse did not find abiraterone acetate to be carcinogenic (Prod Info ZYTIGA(R) oral tablets, 2014).

Genotoxicity

    A) In studies, no mutagenicity was observed in microbial mutagenesis (Ames) assay and no clastogenicity was observed in both in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay (Prod Info ZYTIGA(R) oral tablets, 2014).

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs, serum electrolytes, liver enzymes, and renal function following significant overdose.
    B) Obtain an ECG and institute continuous cardiac monitoring in symptomatic patients.

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who remain symptomatic despite adequate treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) An adult with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear. Consult an expert in teratogenesis for exposures in pregnant women.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions should be observed in a healthcare facility.

Monitoring

    A) Monitor vital signs, serum electrolytes, liver enzymes, and renal function following significant overdose.
    B) Obtain an ECG and institute continuous cardiac monitoring in symptomatic patients.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor vital signs, serum electrolytes, liver enzymes, and renal function following significant overdose.
    2) Obtain an ECG and institute continuous cardiac monitoring in symptomatic patients.
    B) HYPERTENSIVE EPISODE
    1) Monitor vital signs regularly. For mild/moderate hypertension without evidence of end organ damage, pharmacologic intervention is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients, especially if a sympathomimetic agent is involved in the poisoning.
    2) For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20% to 25% within one hour), sodium nitroprusside is preferred. Nitroglycerin and phentolamine are possible alternatives.
    3) SODIUM NITROPRUSSIDE/INDICATIONS
    a) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.
    4) SODIUM NITROPRUSSIDE/DOSE
    a) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).
    5) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION
    a) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    6) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS
    a) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    7) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS
    a) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    8) PHENTOLAMINE/INDICATIONS
    a) Useful for severe hypertension, particularly if caused by agents with alpha adrenergic agonist effects usually induced by catecholamine excess (Rhoney & Peacock, 2009).
    9) PHENTOLAMINE/ADULT DOSE
    a) BOLUS DOSE: 5 to 15 mg IV bolus repeated as needed (U.S. Departement of Health and Human Services, National Institutes of Health, and National Heart, Lung, and Blood Institute, 2004). Onset of action is 1 to 2 minutes with a duration of 10 to 30 minutes (Rhoney & Peacock, 2009).
    b) CONTINUOUS INFUSION: 1 mg/hr, adjusted hourly to stabilize blood pressure. Prepared by adding 60 mg of phentolamine mesylate to 100 mL of 0.9% sodium chloride injection; continuous infusion ranging from 12 to 52 mg/hr over 4 days has been used in case reports (McMillian et al, 2011).
    10) PHENTOLAMINE/PEDIATRIC DOSE
    a) 0.05 to 0.1 mg/kg/dose (maximum of 5 mg per dose) intravenously every 5 minutes until hypertension is controlled, then every 2 to 4 hours as needed (Singh et al, 2012; Koch-Weser, 1974).
    11) PHENTOLAMINE/ADVERSE EFFECTS
    a) Adverse events can include orthostatic or prolonged hypotension, tachycardia, dysrhythmias, angina, flushing, headache, nasal congestion, nausea, vomiting, abdominal pain and diarrhea (Rhoney & Peacock, 2009; Prod Info Phentolamine Mesylate IM, IV injection Sandoz Standard, 2005).
    12) CAUTION
    a) Phentolamine should be used with caution in patients with coronary artery disease because it may induce angina or myocardial infarction (Rhoney & Peacock, 2009).
    13) NITROGLYCERIN/INDICATIONS
    a) May be used to control hypertension, and is particularly useful in patients with acute coronary syndromes or acute pulmonary edema (Rhoney & Peacock, 2009).
    14) NITROGLYCERIN/ADULT DOSE
    a) Begin infusion at 10 to 20 mcg/min and increase by 5 or 10 mcg/min every 5 to 10 minutes until the desired hemodynamic response is achieved (American Heart Association, 2005). Maximum rate 200 mcg/min (Rhoney & Peacock, 2009).
    15) NITROGLYCERIN/PEDIATRIC DOSE
    a) Usual Dose: 29 days or Older: 1 to 5 mcg/kg/min continuous IV infusion. Maximum 60 mcg/kg/min (Laitinen et al, 1997; Nam et al, 1989; Rasch & Lancaster, 1987; Ilbawi et al, 1985; Friedman & George, 1985).
    C) VENTRICULAR ARRHYTHMIA
    1) VENTRICULAR DYSRHYTHMIAS SUMMARY
    a) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.
    2) LIDOCAINE
    a) LIDOCAINE/INDICATIONS
    1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).
    b) LIDOCAINE/DOSE
    1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.
    a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).
    2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    c) LIDOCAINE/MAJOR ADVERSE REACTIONS
    1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).
    d) LIDOCAINE/MONITORING PARAMETERS
    1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    3) AMIODARONE
    a) AMIODARONE/INDICATIONS
    1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).
    b) AMIODARONE/ADULT DOSE
    1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).
    c) AMIODARONE/PEDIATRIC DOSE
    1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).
    d) ADVERSE EFFECTS
    1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).
    4) PROCAINAMIDE
    a) PROCAINAMIDE/INDICATIONS
    1) An alternative drug in the treatment of PVCs or recurrent ventricular tachycardia when lidocaine is contraindicated or not effective. It should be avoided when the ingestion involves agents with quinidine-like effects (e.g. tricyclic antidepressants, phenothiazines, chloroquine, antidysrhythmics) and when the ECG reveals QRS widening or QT prolongation suspected to be secondary to overdose(Neumar et al, 2010; Vanden Hoek,TL,et al).
    b) PROCAINAMIDE/ADULT LOADING DOSE
    1) 20 to 50 milligrams/minute IV until dysrhythmia is suppressed or toxicity develops from procainamide (hypotension develops or the QRS is widened by 50%), or a total dose of 17 milligrams/kilogram is given (1.2 grams for a 70 kilogram person) (Neumar et al, 2010).
    2) ALTERNATIVE DOSING: 100 mg every 5 minutes until dysrhythmia is controlled, or toxicity develops from procainamide (hypotension develops or the QRS is widened by 50%) or 17 mg/kg have been given (Neumar et al, 2010).
    3) MAXIMUM DOSE: 17 milligrams/kilogram (Neumar et al, 2010).
    c) PROCAINAMIDE/CONTROLLED INFUSION
    1) In conscious patients, procainamide should be administered as a controlled infusion (20 milligrams/minute) because of the risk of QT prolongation and its hypotensive effects (Link et al, 2015)
    d) PROCAINAMIDE/ADULT MAINTENANCE DOSE
    1) 1 to 4 milligrams/minute via an intravenous infusion (Neumar et al, 2010).
    e) PROCAINAMIDE/PEDIATRIC LOADING DOSE
    1) 15 milligrams/kilogram IV/Intraosseously over 30 to 60 minutes; discontinue if hypotension develops or the QRS widens by 50% (Kleinman et al, 2010).
    f) PROCAINAMIDE/PEDIATRIC MAINTENANCE DOSE
    1) Initiate at 20 mcg/kg/minute and increase in 10 mcg/kg/minute increments every 15 to 30 minutes until desired effect is achieved; up to 80 mcg/kg/minute (Bouhouch et al, 2008; Ratnasamy et al, 2008; Mandapati et al, 2000; Luedtke et al, 1997; Walsh et al, 1997).
    g) PROCAINAMIDE/PEDIATRIC MAXIMUM DOSE
    1) 2 grams/day (Bouhouch et al, 2008; Ratnasamy et al, 2008; Mandapati et al, 2000; Luedtke et al, 1997; Walsh et al, 1997).
    h) MONITORING PARAMETERS
    1) ECG, blood pressure, and blood concentrations (Prod Info procainamide HCl IV, IM injection solution, 2011). Procainamide can produce hypotension and QT prolongation (Link et al, 2015).
    i) AVOID
    1) Avoid in patients with QT prolongation and CHF (Neumar et al, 2010).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding and large volume of distribution.

Summary

    A) TOXICITY: A toxic dose has not been established.
    B) THERAPEUTIC DOSE: ADULTS: 1000 mg orally once daily with prednisone 5 mg orally twice daily. CHILDREN: Abiraterone acetate is not indicated in children.

Therapeutic Dose

    7.2.1) ADULT
    A) METASTATIC PROSTATE CANCER: 1000 mg orally once daily with prednisone 5 mg orally twice daily; no food should be consumed for at least 2 hours before and one hour after dose (Prod Info ZYTIGA(R) oral tablets, 2012)
    7.2.2) PEDIATRIC
    A) Safety and effectiveness in pediatric patients have not been established (Prod Info ZYTIGA(R) oral tablets, 2012).

Maximum Tolerated Exposure

    A) A toxic dose has not been established.

Pharmacologic Mechanism

    A) Abiraterone acetate is metabolized to abiraterone, an androgen biosynthesis inhibitor of CYP17 which decreases androgen levels and deprives androgen-sensitive prostatic carcinomas. It accomplishes this by interfering with the CYP17-catalyzed reactions involved in the production of dehydroepiandrosterone (DHEA) and androstenedione. Inhibition of CYP17 can result in increased mineralocorticoid production by the adrenals (Prod Info ZYTIGA(TM) oral tablets, 2011).

Physical Characteristics

    A) A white to off-white, non-hygroscopic, crystalline powder; lipophilic compound and practically insoluble in water (Prod Info ZYTIGA(TM) oral tablets, 2011).

Molecular Weight

    A) 391.55 (Prod Info ZYTIGA(TM) oral tablets, 2011)

General Bibliography

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    3) Bouhouch R, El Houari T, Fellat I, et al: Pharmacological therapy in children with nodal reentry tachycardia: when, how and how long to treat the affected patients. Curr Pharm Des 2008; 14(8):766-769.
    4) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    5) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
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    7) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
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    25) Product Information: Cordarone(R) oral tablets, amiodarone HCl oral tablets. Wyeth Pharmaceuticals Inc (per FDA), Philadelphia, PA, 2015.
    26) Product Information: Lidocaine HCl intravenous injection solution, lidocaine HCl intravenous injection solution. Hospira (per manufacturer), Lake Forest, IL, 2006.
    27) Product Information: NITROPRESS(R) injection for IV infusion, Sodium Nitroprusside injection for IV infusion. Hospira, Inc., Lake Forest, IL, 2007.
    28) Product Information: NITROPRESS(R) injection, sodium nitroprusside injection. Hospira,Inc, Lake Forest, IL, 2004.
    29) Product Information: Phentolamine Mesylate IM, IV injection Sandoz Standard, phentolamine mesylate IM, IV injection Sandoz Standard. Sandoz Canada (per manufacturer), Boucherville, QC, 2005.
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    45) Walsh EP , Saul JP , Sholler GF , et al: Evaluation of a staged treatment protocol for rapid automatic junctional tachycardia after operation for congenital heart disease. J Am Coll Cardiol 1997; 29(5):1046-1053.
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