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ENZALUTAMIDE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Enzalutamide is an androgen receptor inhibitor that competitively inhibits androgen binding to androgen receptors and inhibits androgen receptor nuclear translocation and interaction with DNA. It is used to treat metastatic castration-resistant prostate cancer in men who have previously received docetaxel.

Specific Substances

    1) MDV3100
    2) Androgen receptor inhibitor
    3) CAS 915087-33-1
    1.2.1) MOLECULAR FORMULA
    1) C21H16F4N4O2S (Prod Info XTANDI(R) oral capsules, 2012)

Available Forms Sources

    A) FORMS
    1) Enzalutamide is available as 40 mg capsules (Prod Info XTANDI(R) oral capsules, 2012).
    B) USES
    1) Enzalutamide is indicated for the treatment of metastatic castration-resistant prostate cancer in men who have previously received docetaxel (Prod Info XTANDI(R) oral capsules, 2012).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Enzalutamide is indicated for the treatment of metastatic castration-resistant prostate cancer in men who have previously received docetaxel.
    B) PHARMACOLOGY: Enzalutamide is an androgen receptor inhibitor that competitively inhibits androgen binding to androgen receptors and inhibits androgen receptor nuclear translocation and interaction with DNA.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON (5% or greater): Asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, neutropenia, and hypertension. OTHER EFFECTS: Pruritus and dry skin, pollakiuria, elevations in bilirubin, nonpathologic fractures, hypoesthesia, seizures, mental impairment disorders, including amnesia, memory impairment, cognitive disorder, and attention disturbances. Enzalutamide is classified as FDA pregnancy category X.
    E) WITH POISONING/EXPOSURE
    1) Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses. Seizures have been reported following enzalutamide doses of 360 mg to 600 mg.
    0.2.20) REPRODUCTIVE
    A) Enzalutamide is classified as FDA pregnancy category X. The drug is not indicated for use by women. Despite the lack of data, known substance properties suggest that maternal exposure to enzalutamide may pose significant danger to the developing embryo/fetus.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no human data were available to assess the potential carcinogenic activity of enzalutamide.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Monitor CBC with differential with platelet count, renal function, and liver enzymes after significant overdose.

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. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Neutropenia has been reported. Monitor serial CBC with differential. For severe neutropenia, administer colony stimulating factor (eg; filgrastim, sargramostim). For severe hypertension, nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is not recommended because of the risk of persistent seizures and subsequent aspiration.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is alert and able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with persistent seizures.
    E) ANTIDOTE
    1) None.
    F) NEUTROPENIA
    1) Administer colony stimulating factors in patients who develop severe neutropenia or neutropenic sepsis. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours. Monitor CBC with differential daily for evidence of bone marrow suppression until recovery has occurred. Patients with severe neutropenia should be in protective isolation.
    G) ENHANCED ELIMINATION
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding and large volume of distribution.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic adults with an inadvertent ingestion of an extra dose, or a child that remains asymptomatic after 1 or 2 pills can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, ingestions of more than an extra dose in an adult or 2 pills in child, and those who are symptomatic should be referred to a healthcare facility for observation with frequent monitoring of vital signs and mental status. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients with severe neutropenia or persistent seizures should be admitted to the hospital.
    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.
    I) PITFALLS
    1) When managing a suspected enzalutamide overdose, the possibility of multidrug involvement should be considered. Symptoms of overdose are similar to reported side effects of the medication. Early symptoms of overdose may be delayed or not evident (ie, particularly neutropenia), so reliable follow-up is imperative.
    J) PHARMACOKINETICS
    1) Tmax: Oral, multiple dose, 160 mg: 1 hour (range, 0.5 to 3 hours); Protein binding; 97% to 98% (enzalutamide); 95% (N-desmethyl enzalutamide); Vd: 110 L. Metabolism: Liver; metabolized by CYP2C8 and CYP3A4; metabolite: N-desmethyl enzalutamide, active; excretion: renal: 71% of the radioactivity was recovered in urine by 77 days after use. Fecal: 14% of the radioactivity was recovered in feces by 77 days after use. Total body clearance: 0.56 L/hr. Elimination half-life: 5.8 days (range, 2.8 to 10.2 days). N-desmethyl enzalutamide, 7.8 to 8.6 days.
    K) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause neutropenia, seizures, or hypertension.

Range Of Toxicity

    A) TOXICITY: Seizures have been reported following enzalutamide doses of 360 mg to 600 mg. However, no seizures were observed following doses of 240 mg or lower. THERAPEUTIC DOSE: ADULTS: 160 mg (four 40 mg capsules) orally once daily. CHILDREN: Safety and effectiveness have not been established in children.

Clinical Effects

Summary Of Exposure

    A) USES: Enzalutamide is indicated for the treatment of metastatic castration-resistant prostate cancer in men who have previously received docetaxel.
    B) PHARMACOLOGY: Enzalutamide is an androgen receptor inhibitor that competitively inhibits androgen binding to androgen receptors and inhibits androgen receptor nuclear translocation and interaction with DNA.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON (5% or greater): Asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, neutropenia, and hypertension. OTHER EFFECTS: Pruritus and dry skin, pollakiuria, elevations in bilirubin, nonpathologic fractures, hypoesthesia, seizures, mental impairment disorders, including amnesia, memory impairment, cognitive disorder, and attention disturbances. Enzalutamide is classified as FDA pregnancy category X.
    E) WITH POISONING/EXPOSURE
    1) Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses. Seizures have been reported following enzalutamide doses of 360 mg to 600 mg.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) In a randomized clinical trial, hypertension (all grades) occurred in 6.4% of patients with metastatic castration-resistant prostate cancer who received oral enzalutamide 160 mg/day (n=800) for a median of 8.3 months compared with 2.8% of patients who received placebo (n=399) for a median of 3 months (Prod Info XTANDI(R) oral capsules, 2012).
    B) PERIPHERAL EDEMA
    1) WITH THERAPEUTIC USE
    a) In a randomized clinical trial, peripheral edema (all grades) occurred in 15.4% of patients with metastatic castration-resistant prostate cancer who received oral enzalutamide 160 mg/day (n=800) for a median of 8.3 months compared with 13.3% of patients who received placebo (n=399) for a median of 3 months (Prod Info XTANDI(R) oral capsules, 2012).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) UPPER RESPIRATORY INFECTION
    1) WITH THERAPEUTIC USE
    a) In a randomized clinical trial, upper respiratory tract infections (all grades), including nasopharyngitis, sinusitis, rhinitis, pharyngitis, and laryngitis, occurred in 10.9% of patients with metastatic castration-resistant prostate cancer who received oral enzalutamide 160 mg/day (n=800) for a median of 8.3 months compared with 6.5% of patients who received placebo (n=399) for a median of 3 months (Prod Info XTANDI(R) oral capsules, 2012).
    B) LOWER RESPIRATORY TRACT INFECTION
    1) WITH THERAPEUTIC USE
    a) In a randomized clinical trial, lower respiratory tract infections (all grades), including pneumonia, bronchitis, and lung infections, occurred in 8.5% of patients with metastatic castration-resistant prostate cancer who received oral enzalutamide 160 mg/day (n=800) for a median of 8.3 months compared with 4.8% of patients who received placebo (n=399) for a median of 3 months (Prod Info XTANDI(R) oral capsules, 2012).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) In a randomized clinical trial, asthenic conditions (all grades), including asthenia and fatigue, occurred in 50.6% of patients with metastatic castration-resistant prostate cancer who received oral enzalutamide 160 mg/day (n=800) for a median of 8.3 months compared with 44.4% of patients who received placebo (n=399) for a median of 3 months (Prod Info XTANDI(R) oral capsules, 2012).
    B) HEADACHE
    1) WITH THERAPEUTIC USE
    a) In a randomized clinical trial, headache (all grades) occurred in 12.1% of patients with metastatic castration-resistant prostate cancer who received oral enzalutamide 160 mg/day (n=800) for a median of 8.3 months compared with 5.5% of patients who received placebo (n=399) for a median of 3 months (Prod Info XTANDI(R) oral capsules, 2012).
    C) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) In a randomized clinical trial, dizziness (all grades), including vertigo, occurred in 9.5% of patients with metastatic castration-resistant prostate cancer who received oral enzalutamide 160 mg/day (n=800) for a median of 8.3 months compared with 7.5% of patients who received placebo (n=399) for a median of 3 months (Prod Info XTANDI(R) oral capsules, 2012).
    D) SPINAL CORD COMPRESSION
    1) WITH THERAPEUTIC USE
    a) In a randomized clinical trial, spinal cord compression and cauda equina syndrome (all grades) occurred in 7.4% of patients with metastatic castration-resistant prostate cancer who received oral enzalutamide 160 mg/day (n=800) for a median of 8.3 months compared with 4.5% of patients who received placebo (n=399) for a median of 3 months. Grade 3 and 4 spinal cord compression and cauda equina syndrome occurred in 6.6% and 3.8% of patients who received enzalutamide or placebo, respectively (Prod Info XTANDI(R) oral capsules, 2012).
    E) PARESTHESIA
    1) WITH THERAPEUTIC USE
    a) In a randomized clinical trial, paresthesia (all grades) occurred in 6.6% of patients with metastatic castration-resistant prostate cancer who received oral enzalutamide 160 mg/day (n=800) for a median of 8.3 months compared with 4.5% of patients who received placebo (n=399) for a median of 3 months (Prod Info XTANDI(R) oral capsules, 2012).
    F) COGNITIVE DISORDER
    1) WITH THERAPEUTIC USE
    a) In a randomized clinical trial, mental impairment disorders (all grades), including amnesia, memory impairment, cognitive disorder, and attention disturbances, occurred in 4.3% of patients with metastatic castration-resistant prostate cancer who received oral enzalutamide 160 mg/day (n=800) for a median of 8.3 months compared with 1.8% of patients who received placebo (n=399) for a median of 3 months (Prod Info XTANDI(R) oral capsules, 2012).
    G) HYPESTHESIA
    1) WITH THERAPEUTIC USE
    a) In a randomized clinical trial, hypoesthesia (all grades) occurred in 4% of patients with metastatic castration-resistant prostate cancer who received oral enzalutamide 160 mg/day (n=800) for a median of 8.3 months compared with 1.8% of patients who received placebo (n=399) for a median of 3 months (Prod Info XTANDI(R) oral capsules, 2012).
    H) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) In a randomized clinical trial, insomnia (all grades) occurred in 8.8% of patients with metastatic castration-resistant prostate cancer who received oral enzalutamide 160 mg/day (n=800) for a median of 8.3 months compared with 6% of patients who received placebo (n=399) for a median of 3 months (Prod Info XTANDI(R) oral capsules, 2012).
    I) SEIZURE
    1) WITH THERAPEUTIC USE
    a) In a randomized clinical trial, seizures occurred in 0.9% (7/800) of patients with metastatic castration-resistant prostate cancer who received oral enzalutamide 160 mg/day for a median of 8.3 months compared with 0% of patients who received placebo (n=399) for a median of 3 months, and was the most common adverse effect leading to discontinuation of therapy. Seizures occurred from 31 to 603 days after enzalutamide initiation and resolved after therapy was discontinued. Patients who experienced seizures were not rechallenged with enzalutamide, and patients with predisposing factors for seizures were excluded from the study (Prod Info XTANDI(R) oral capsules, 2012).
    2) WITH POISONING/EXPOSURE
    a) Seizures have been reported following enzalutamide doses of 360 mg to 600 mg. However, no seizures were observed following doses of 240 mg or lower (Prod Info XTANDI(R) oral capsules, 2012).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In a randomized clinical trial, diarrhea (all grades) occurred in 21.8% of patients with metastatic castration-resistant prostate cancer who received oral enzalutamide 160 mg/day (n=800) for a median of 8.3 months compared with 17.5% of patients who received placebo (n=399) for a median of 3 months (Prod Info XTANDI(R) oral capsules, 2012).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) SERUM BILIRUBIN RAISED
    1) WITH THERAPEUTIC USE
    a) In a randomized clinical trial, elevations in bilirubin (all grades) occurred in 3% of patients with metastatic castration-resistant prostate cancer who received oral enzalutamide 160 mg/day (n=800) for a median of 8.3 months compared with 2% of patients who received placebo (n=399) for a median of 3 months (Prod Info XTANDI(R) oral capsules, 2012).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) BLOOD IN URINE
    1) WITH THERAPEUTIC USE
    a) In a randomized clinical trial, hematuria (all grades) occurred in 6.9% of patients with metastatic castration-resistant prostate cancer who received oral enzalutamide 160 mg/day (n=800) for a median of 8.3 months compared with 4.5% of patients who received placebo (n=399) for a median of 3 months (Prod Info XTANDI(R) oral capsules, 2012).
    B) INCREASED FREQUENCY OF URINATION
    1) WITH THERAPEUTIC USE
    a) In a randomized clinical trial, pollakiuria (all grades) occurred in 4.8% of patients with metastatic castration-resistant prostate cancer who received oral enzalutamide 160 mg/day (n=800) for a median of 8.3 months compared with 2.5% of patients who received placebo (n=399) for a median of 3 months (Prod Info XTANDI(R) oral capsules, 2012).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) In a randomized clinical trial, neutropenia (all grades) occurred in 15% of patients with metastatic castration-resistant prostate cancer who received oral enzalutamide 160 mg/day (n=800) for a median of 8.3 months compared with 6% of patients who received placebo (n=399) for a median of 3 months (Prod Info XTANDI(R) oral capsules, 2012).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) FLUSHING
    1) WITH THERAPEUTIC USE
    a) In a randomized clinical trial, hot flushes (all grades) occurred in 20.3% of patients with metastatic castration-resistant prostate cancer who received oral enzalutamide 160 mg/day (n=800) for a median of 8.3 months compared with 10.3% of patients who received placebo (n=399) for a median of 3 months (Prod Info XTANDI(R) oral capsules, 2012).
    B) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) In a randomized clinical trial, pruritus and dry skin (all grades) occurred in 3.8% of patients with metastatic castration-resistant prostate cancer who received oral enzalutamide 160 mg/day (n=800) for a median of 8.3 months compared with 1.3% of patients who received placebo (n=399) for a median of 3 months (Prod Info XTANDI(R) oral capsules, 2012).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) BACKACHE
    1) WITH THERAPEUTIC USE
    a) In a randomized clinical trial, back pain (all grades) occurred in 26.4% of patients with metastatic castration-resistant prostate cancer who received oral enzalutamide 160 mg/day (n=800) for a median of 8.3 months compared with 24.3% of patients who received placebo (n=399) for a median of 3 months. Grade 3 and 4 back pain occurred in 5.3% and 4% of patients who received enzalutamide or placebo, respectively (Prod Info XTANDI(R) oral capsules, 2012).
    B) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) In a randomized clinical trial, arthralgia (all grades) occurred in 20.5% of patients with metastatic castration-resistant prostate cancer who received oral enzalutamide 160 mg/day (n=800) for a median of 8.3 months compared with 17.3% of patients who received placebo (n=399) for a median of 3 months (Prod Info XTANDI(R) oral capsules, 2012).
    C) MUSCULOSKELETAL PAIN
    1) WITH THERAPEUTIC USE
    a) In a randomized clinical trial, musculoskeletal pain (all grades) occurred in 15% of patients with metastatic castration-resistant prostate cancer who received oral enzalutamide 160 mg/day (n=800) for a median of 8.3 months compared with 11.5% of patients who received placebo (n=399) for a median of 3 months (Prod Info XTANDI(R) oral capsules, 2012).
    D) MUSCLE WEAKNESS
    1) WITH THERAPEUTIC USE
    a) In a randomized clinical trial, muscle weakness (all grades) occurred in 9.8% of patients with metastatic castration-resistant prostate cancer who received oral enzalutamide 160 mg/day (n=800) for a median of 8.3 months compared with 6.8% of patients who received placebo (n=399) for a median of 3 months (Prod Info XTANDI(R) oral capsules, 2012).
    E) FRACTURE OF BONE
    1) WITH THERAPEUTIC USE
    a) In a randomized clinical trial, nonpathologic fractures (all grades) occurred in 4% of patients with metastatic castration-resistant prostate cancer who received oral enzalutamide 160 mg/day (n=800) for a median of 8.3 months compared with 0.8% of patients who received placebo (n=399) for a median of 3 months (Prod Info XTANDI(R) oral capsules, 2012).

Reproductive

    3.20.1) SUMMARY
    A) Enzalutamide is classified as FDA pregnancy category X. The drug is not indicated for use by women. Despite the lack of data, known substance properties suggest that maternal exposure to enzalutamide may pose significant danger to the developing embryo/fetus.
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) There are no adequate and well-controlled studies of enzalutamide use in pregnant women and the drug is not indicated for female use. Use of enzalutamide is contraindicated in women who are pregnant or may become pregnant. If pregnancy occurs, or use is required during pregnancy, apprise patient of the potential for fetal harm and the possibility of pregnancy loss (Prod Info XTANDI(R) oral capsules, 2014).
    B) PREGNANCY CATEGORY
    1) Enzalutamide is classified as FDA pregnancy category X (Prod Info XTANDI(R) oral capsules, 2014).
    C) ANIMAL STUDIES
    1) RATS, RABBITS: No human studies of pregnancy outcomes after exposure to enzalutamide have been published, and there are no reports of outcomes after inadvertent exposure during pregnancy. During animal studies, administration of enzalutamide 10 or 30 mg/kg/day during organogenesis resulted in developmental toxicity in the offspring of pregnant rats. Embryofetal lethality and decreased anogenital distance were reported with enzalutamide doses greater than or equal to 10 mg/kg/day as well as cleft palate and absent palatine bone at the 30 mg/kg/day dose. Maternal toxicity occurred with enzalutamide 30 mg/kg/day. Developmental toxicities were not reported in rabbits administered enzalutamide up to 10 mg/kg/day during organogenesis (Prod Info XTANDI(R) oral capsules, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is not known if enzalutamide is excreted in human breast milk; the potential for adverse effects in nursing infants exposed to the drug are unknown. Enzalutamide is not indicated for use by women. Due to a lack of human safety information, it is recommended to discontinue nursing or discontinue enzalutamide in the nursing mother. The importance of therapy to the mother should be taken into consideration (Prod Info XTANDI(R) oral capsules, 2014).
    3.20.5) FERTILITY
    A) IMPAIRED MALE FERTILITY
    1) Enzalutamide may impair male fertility. In a 26-week animal study, atrophy of the prostate and seminal vesicles were noted in rats after receiving enzalutamide 30 mg/kg/day or greater (equal to the human exposure based on AUC). Hypospermatogenesis and atrophy of the prostate and epididymides were noted after dogs received enzalutamide 4 mg/kg/day or greater (0.3 times the human exposure based on AUC) (Prod Info XTANDI(R) oral capsules, 2012).

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 enzalutamide.
    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) No animal carcinogenicity studies have been performed (Prod Info XTANDI(R) oral capsules, 2012).

Genotoxicity

    A) In studies, no mutagenicity (in the bacterial reverse mutation (Ames) assay) and no genotoxicity (in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay) were observed (Prod Info XTANDI(R) oral capsules, 2012).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Monitor CBC with differential with platelet count, renal function, and liver enzymes after significant overdose.

Treatment

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 with severe neutropenia or persistent seizures should be admitted to the hospital.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic adults with an inadvertent ingestion of an extra dose, or a child that remains asymptomatic after 1 or 2 pills 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.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, ingestions of more than an extra dose in an adult or 2 pills in child, and those who are symptomatic should be referred to a healthcare facility for observation with frequent monitoring of vital signs and mental status. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Monitor CBC with differential with platelet count, renal function, and liver enzymes after significant overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is not recommended because of the risk of seizures and subsequent aspiration.
    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) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor vital signs and mental status.
    3) Monitor CBC with differential with platelet count, renal function, and liver enzymes after significant overdose.
    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) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

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.

Range Of Toxicity

Summary

    A) TOXICITY: Seizures have been reported following enzalutamide doses of 360 mg to 600 mg. However, no seizures were observed following doses of 240 mg or lower. THERAPEUTIC DOSE: ADULTS: 160 mg (four 40 mg capsules) orally once daily. CHILDREN: Safety and effectiveness have not been established in children.

Therapeutic Dose

    7.2.1) ADULT
    A) 160 mg (four 40 mg capsules) orally once daily (Prod Info XTANDI(R) oral capsules, 2012).
    7.2.2) PEDIATRIC
    A) Safety and effectiveness have not been established in children (Prod Info XTANDI(R) oral capsules, 2012).

Maximum Tolerated Exposure

    A) Seizures have been reported following enzalutamide doses of 360 mg to 600 mg. No seizures were observed following doses of 240 mg or lower (Prod Info XTANDI(R) oral capsules, 2012).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Enzalutamide, an androgen receptor inhibitor, competitively inhibits androgen binding to androgen receptors and inhibits androgen receptor nuclear translocation and interaction with DNA. The major active metabolite, N-desmethyl enzalutamide, has similar activity. Enzalutamide decreased proliferation and induced cell death of prostate cancer cells in vitro and decreased tumor volume in an animal study (Prod Info XTANDI(R) oral capsules, 2012).

Physicochemical

Physical Characteristics

    A) A white crystalline non-hygroscopic solid, practically insoluble in water (Prod Info XTANDI(R) oral capsules, 2012)

Molecular Weight

    A) 464.44 (Prod Info XTANDI(R) oral capsules, 2012)

References

General Bibliography

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