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EXEMESTANE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Exemestane is an irreversible, steroidal aromatase inactivator.

Specific Substances

    1) Nikidess
    2) PNU-155971
    3) FCE-24304
    4) 6-methylenandrosta-1,4-diene-3,17-dione
    5) CAS 107868-30-4
    1.2.1) MOLECULAR FORMULA
    1) C20-H24-O2

Available Forms Sources

    A) FORMS
    1) Exemestane is available as 25 mg tablets (Prod Info AROMASIN(R) oral tablets, 2014).
    B) USES
    1) Exemestane is used to treat advanced breast cancer in postmenopausal women who have not responded to tamoxifen therapy(Prod Info AROMASIN(R) oral tablets, 2014).

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: Exemestane is used in postmenopausal women with advanced breast cancer not responsive to tamoxifen or as an adjunctive therapy for women with estrogen-receptor positive early breast cancer after tamoxifen therapy.
    B) PHARMACOLOGY: Exemestane is an irreversible steroidal aromatase inactivator, structurally related to the natural substrate androstenedione. In the aromatase enzyme, exemestane causes inactivation by suicide inhibition when it is processed as an intermediate and binds to the active site of the enzyme. This effect significantly lowers circulating estrogen levels. Exemestane has no other effect on enzymes other than aromatase.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: COMMON: dizziness, headache, fatigue, insomnia, hot flashes, nausea, and vomiting. LESS COMMON: Depression, insomnia, anxiety, elevations in alkaline phosphatase, and dyspnea.
    E) WITH POISONING/EXPOSURE
    1) TOXICITY: Toxicity is expected to be an extension of adverse effects. A child (age unknown) developed leukocytosis 1 hour after accidentally ingesting a 25 mg tablet of exemestane. His blood tests obtained 4 days after the incident were normal.
    0.2.5) CARDIOVASCULAR
    A) WITH THERAPEUTIC USE
    1) Dysrhythmias, myocardial infarction, chest pain, hypertension, and edema have been reported following exemestane therapy.
    0.2.6) RESPIRATORY
    A) WITH THERAPEUTIC USE
    1) Dyspnea, bronchitis, cough, pharyngitis, rhinitis, sinusitis, and upper respiratory tract infection have been reported following exemestane therapy.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Headache, dizziness, depression, insomnia, anxiety, confusion, and fatigue have been reported following exemestane therapy.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) Nausea, vomiting, abdominal pain, anorexia, diarrhea, and dyspepsia have been reported following exemestane therapy.
    0.2.13) HEMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Grade 3 or 4 lymphocytopenia was reported in approximately 20% of patients in exemestane clinical trials.
    B) WITH POISONING/EXPOSURE
    1) A child (age unknown) developed leukocytosis 1 hour after accidentally ingesting a 25 mg tablet of exemestane.
    0.2.14) DERMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Increased sweating, paresthesia, alopecia, and pruritus have been reported following exemestane therapy.
    0.2.15) MUSCULOSKELETAL
    A) WITH THERAPEUTIC USE
    1) Myalgia, arthralgia, and back pain have been reported following exemestane therapy.
    0.2.20) REPRODUCTIVE
    A) Do not administer exemestane to pregnant women. Advise pregnant women of the potential for fetal harm. Verify a negative pregnancy status 7 days prior to drug initiation. Advise female patients of reproductive potential to use adequate contraception during treatment and for at least 1 month after discontinuation. In animal studies, exemestane crossed the placenta and was embryotoxic, fetotoxic, and an abortifacient. Advise women to not breastfeed while taking exemestane and for at least 1 month after discontinuation.

Laboratory Monitoring

    A) Monitor vital signs in all patients.
    B) Monitor CBC and liver function in symptomatic patients.
    C) Monitor fluid and electrolyte status in patients with significant vomiting and/or diarrhea.

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) Supportive care is the mainstay of therapy. Nitroprusside is the preferred agent for severe hypertension. Labetalol, nitroglycerin, and phentolamine are alternatives.
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal for recent, substantial ingestion in a patient who is alert and can protect the airway.
    2) HOSPITAL: Activated charcoal may be considered for patients who present early after overdose and are alert and able to maintain their airway.
    D) ANTIDOTE
    1) None.
    E) ENHANCED ELIMINATION
    1) Hemodialysis is unlikely to be beneficial in the management of overdose since exemestane is highly protein bound and has a large volume of distribution.
    F) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic children and adults with an inadvertent minor ingestion (or 1 or 2 doses) of a exemestane can be observed at home.
    2) OBSERVATION CRITERIA: All patients with a deliberate self-harm ingestion should be evaluated in a healthcare facility and monitored until symptoms resolve. Patients who remain asymptomatic may be discharged.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite adequate treatment should be admitted.
    4) CONSULT CRITERIA: Consult a medical toxicologist or poison center for patients with severe toxicity or in whom the diagnosis is unclear.
    G) PITFALLS
    1) When managing a suspected exemestane overdose, the possibility of multidrug involvement should be considered. Symptoms of overdose are similar to reported side effects of the medication.
    H) PHARMACOKINETICS
    1) Bioavailability is approximately 42%. Higher systemic exposure and lower average oral clearance (45% lower) occurs in postmenopausal women with breast cancer compared to healthy postmenopausal women. Mean AUC values after multiple doses in diseased subjects were twice as high as those in healthy subjects. Total protein binding is 90% with alpha-1-acid glycoprotein and albumin contribute to binding. Metabolism is via CYP450 and aldoketoreductase; however, exemestane does not inhibit major pathways (1A2, 2C9, 2D6, 2E1, and 3A4). Elimination half-life is approximately 24 hours and is primarily excreted in the urine and feces.
    I) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause elevated liver enzymes or hypertension.

Range Of Toxicity

    A) In clinical trials, single doses as high as 800 mg daily for 12 weeks in healthy female volunteers were well tolerated. In postmenopausal women with advanced breast cancer, doses as high as 600 mg were well tolerated.
    B) A child (age unknown) developed leukocytosis (WBC 25000/(mm)3 with 90% neutrophils) 1 hour after ingesting a 25 mg tablet of exemestane. His blood tests obtained 4 days after the incident were normal.
    C) THERAPEUTIC DOSE: The recommended dose is exemestane 25 mg once daily after a meal, and should be continued until tumor progression is evident.

Clinical Effects

Summary Of Exposure

    A) USES: Exemestane is used in postmenopausal women with advanced breast cancer not responsive to tamoxifen or as an adjunctive therapy for women with estrogen-receptor positive early breast cancer after tamoxifen therapy.
    B) PHARMACOLOGY: Exemestane is an irreversible steroidal aromatase inactivator, structurally related to the natural substrate androstenedione. In the aromatase enzyme, exemestane causes inactivation by suicide inhibition when it is processed as an intermediate and binds to the active site of the enzyme. This effect significantly lowers circulating estrogen levels. Exemestane has no other effect on enzymes other than aromatase.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: COMMON: dizziness, headache, fatigue, insomnia, hot flashes, nausea, and vomiting. LESS COMMON: Depression, insomnia, anxiety, elevations in alkaline phosphatase, and dyspnea.
    E) WITH POISONING/EXPOSURE
    1) TOXICITY: Toxicity is expected to be an extension of adverse effects. A child (age unknown) developed leukocytosis 1 hour after accidentally ingesting a 25 mg tablet of exemestane. His blood tests obtained 4 days after the incident were normal.

Cardiovascular

    3.5.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Dysrhythmias, myocardial infarction, chest pain, hypertension, and edema have been reported following exemestane therapy.
    3.5.2) CLINICAL EFFECTS
    A) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) Atrial dysrhythmias (rare; causal relationship uncertain) have been reported (Zilembo et al, 1995).
    B) MYOCARDIAL INFARCTION
    1) WITH THERAPEUTIC USE
    a) Myocardial infarction and multisystem organ failure resulted in the death of an 80-year-old woman with preexisting coronary artery disease. This event was assessed as possibly related to exemestane as a study medication (dose unspecified) (Prod Info AROMASIN(R) oral tablets, 2011).
    C) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypertension has been reported following exemestane therapy (Prod Info AROMASIN(R) oral tablets, 2011).
    D) EDEMA
    1) WITH THERAPEUTIC USE
    a) Edema has been reported following exemestane therapy (Prod Info AROMASIN(R) oral tablets, 2011) .
    E) CHEST PAIN
    1) WITH THERAPEUTIC USE
    a) Chest pain has been reported following exemestane therapy (Prod Info AROMASIN(R) oral tablets, 2011).

Respiratory

    3.6.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Dyspnea, bronchitis, cough, pharyngitis, rhinitis, sinusitis, and upper respiratory tract infection have been reported following exemestane therapy.
    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY FINDING
    1) WITH THERAPEUTIC USE
    a) Dyspnea, bronchitis, cough, pharyngitis, rhinitis, sinusitis, and upper respiratory tract infection have been reported following exemestane therapy (Prod Info AROMASIN(R) oral tablets, 2011).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Headache, dizziness, depression, insomnia, anxiety, confusion, and fatigue have been reported following exemestane therapy.
    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Headache, dizziness, depression, insomnia, anxiety, confusion, and fatigue have been reported following exemestane therapy (Prod Info AROMASIN(R) oral tablets, 2011; Evans et al, 1992; Zilembo et al, 1995; Bajetta et al, 1997).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Nausea, vomiting, abdominal pain, anorexia, diarrhea, and dyspepsia have been reported following exemestane therapy.
    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL COMPLICATION
    1) WITH THERAPEUTIC USE
    a) Nausea, vomiting, abdominal pain, anorexia, diarrhea and dyspepsia have been reported following exemestane therapy (Prod Info AROMASIN(R) oral tablets, 2011; Zilembo et al, 1995; Bajetta et al, 1997; Johannessen et al, 1997; Evans et al, 1992). Some symptoms may respond to dose reduction (Johannessen et al, 1997).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) ALKALINE PHOSPHATASE RAISED
    1) WITH THERAPEUTIC USE
    a) Elevations in alkaline phosphatase (any grade) occurred in 13.7% of patients who received exemestane (n=73) for the adjuvant treatment of early breast cancer versus 6.9% of patients who received placebo (n=73) in a 2-year, randomized, placebo-controlled, double-blind, parallel group study (Prod Info AROMASIN(R) oral tablets, 2011).
    b) In the randomized, double-blind, multicenter Intergroup Exemestane Study (IES), elevations in alkaline phosphatase (any grade) occurred in 15% of patients who received 2 to 3 years of exemestane after 2 to 3 years of tamoxifen (n=2252) compared with 2.6% of patients who received 5 years of tamoxifen (n=2280) for the adjuvant treatment of early breast cancer (Prod Info AROMASIN(R) oral tablets, 2011).
    c) Elevations in AST, ALT, alkaline phosphatase, and gamma glutamyl transferase greater than 5 times ULN has been reported rarely in patients receiving exemestane for the treatment of advanced breast cancer (Prod Info AROMASIN(R) oral tablets, 2011).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) SERUM CREATININE RAISED
    1) WITH THERAPEUTIC USE
    a) Slight rises in serum creatinine have occurred (Johannessen et al, 1997); clinical significance is questionable.

Hematologic

    3.13.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Grade 3 or 4 lymphocytopenia was reported in approximately 20% of patients in exemestane clinical trials.
    B) WITH POISONING/EXPOSURE
    1) A child (age unknown) developed leukocytosis 1 hour after accidentally ingesting a 25 mg tablet of exemestane.
    3.13.2) CLINICAL EFFECTS
    A) HEMATOLOGY FINDING
    1) WITH THERAPEUTIC USE
    a) Grade 3 or 4 lymphocytopenia was reported in approximately 20% of patients in exemestane clinical trials, 89% of whom had preexisting low-grade lymphopenia (Prod Info AROMASIN(R) oral tablets, 2011).
    b) Hematologic effects were not reported in most studies with oral doses up to 800 mg daily (Bajetta et al, 1997; Johannessen et al, 1997; Di Salle et al, 1992). Transient leukopenia/eosinophilia after single oral doses in one report; half of patients with eosinophilia had history of allergies (Evans et al, 1992).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A child (age unknown) developed leukocytosis (WBC 25000/(mm)3 with 90% neutrophils) 1 hour after accidentally ingesting a 25 mg tablet of exemestane. His blood tests obtained 4 days after the incident were normal (Prod Info AROMASIN(R) oral tablets, 2011).

Dermatologic

    3.14.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Increased sweating, paresthesia, alopecia, and pruritus have been reported following exemestane therapy.
    3.14.2) CLINICAL EFFECTS
    A) EXCESSIVE SWEATING
    1) WITH THERAPEUTIC USE
    a) Increased sweating has been reported following exemestane therapy (Prod Info AROMASIN(R) oral tablets, 2011).
    B) PARESTHESIA
    1) WITH THERAPEUTIC USE
    a) Paresthesia has been reported following exemestane therapy (Prod Info AROMASIN(R) oral tablets, 2011).
    C) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) Alopecia has been reported following exemestane therapy (Prod Info AROMASIN(R) oral tablets, 2011).
    D) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) Pruritus has been reported following exemestane therapy (Prod Info AROMASIN(R) oral tablets, 2011).

Musculoskeletal

    3.15.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Myalgia, arthralgia, and back pain have been reported following exemestane therapy.
    3.15.2) CLINICAL EFFECTS
    A) MUSCULOSKELETAL FINDING
    1) WITH THERAPEUTIC USE
    a) Myalgia, arthralgia, and back pain have been reported following exemestane therapy; responded to dose reduction (Prod Info AROMASIN(R) oral tablets, 2011; Johannessen et al, 1997).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) MENOPAUSAL FLUSHING
    1) WITH THERAPEUTIC USE
    a) Hot flashes (occasional) have been reported (Prod Info AROMASIN(R) oral tablets, 2011; Johannessen et al, 1997; Zilembo et al, 1995).

Reproductive

    3.20.1) SUMMARY
    A) Do not administer exemestane to pregnant women. Advise pregnant women of the potential for fetal harm. Verify a negative pregnancy status 7 days prior to drug initiation. Advise female patients of reproductive potential to use adequate contraception during treatment and for at least 1 month after discontinuation. In animal studies, exemestane crossed the placenta and was embryotoxic, fetotoxic, and an abortifacient. Advise women to not breastfeed while taking exemestane and for at least 1 month after discontinuation.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of exemestane (Prod Info AROMASIN(R) oral tablets, 2016).
    B) ANIMAL STUDIES
    1) During animal studies, no fetal malformations occurred with doses up to approximately 320 times the RHD administered to pregnant animals during organogenesis. Exemestane administration during organogenesis at doses approximately 70 times the RHD resulted in decreased placental weight. Doses approximately 210 times the RHD resulted in reduction in fetal body weight, abortions, and an increase in fetal resorptions, but did not cause an increase in malformations (Prod Info AROMASIN(R) oral tablets, 2016).
    3.20.3) EFFECTS IN PREGNANCY
    A) RISK SUMMARY
    1) Do not administer exemestane to pregnant women. Advise pregnant women of the potential for fetal harm (Prod Info AROMASIN(R) oral tablets, 2016).
    B) CONTRACEPTION
    1) Advise female patients of reproductive potential to use adequate contraception during treatment and for at least 1 month after discontinuation (Prod Info AROMASIN(R) oral tablets, 2016).
    C) PREGNANCY TESTING
    1) Verify a negative pregnancy status 7 days prior to drug initiation (Prod Info AROMASIN(R) oral tablets, 2016).
    D) ANIMAL STUDIES
    1) During animal studies, exemestane was embryotoxic, fetotoxic, and an abortifacient. Exemestane crossed the placenta with oral doses of 1 mg/kg, with approximate equal concentrations of drug and metabolites appearing in maternal and fetal blood. Prolonged gestation, abnormal or difficult labor, increased resorptions, reduced number of live fetuses, decreased fetal weight, and retarded ossification were noted in animals administered exemestane at doses approximately 7.5 times the recommended human daily dose (RHD) on a mg/m(2) and increased placental weight was reported after administration of exemestane at doses approximately 1.5 times the RHD from 14 days prior to mating to days 15 or 20 of gestation (Prod Info AROMASIN(R) oral tablets, 2016).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to exemestane during lactation in humans (Prod Info AROMASIN(R) oral tablets, 2016).
    B) BREAST MILK
    1) Advise women to not breastfeed while taking exemestane and for at least 1 month after discontinuation (Prod Info AROMASIN(R) oral tablets, 2016).
    C) ANIMAL STUDIES
    1) Radioactivity related to exemestane appeared in the milk of lactating rats within 15 minutes of oral administration of 1 mg/kg radiolabeled exemestane and milk-to-plasma ratios were approximately equivalent for 24 hours after administration (Prod Info AROMASIN(R) oral tablets, 2016).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Ovarian changes, including hyperplasia and increased cyst ovarian formation, and decreases in the corpus luteum were seen in animals given doses ranging from 3 to 20 times the human dose on a mg/m(2) basis. Reduction in female fertility occurred when untreated female animals were mated with male animals given exemestane doses approximately 200 times or greater the recommended human dose on a mg/m(2) basis for 63 days before and during cohabitation. An increase in placental weight was observed at doses approximately 1.5 times or greater the human dose on a mg/m(2) basis for 14 days prior to mating through day 15 or 20 of gestation. Female fertility parameters, such as ovarian function, mating behavior, and conception rate, were not affected at doses up to approximately 8 times the human dose on a mg/m(2) basis, but mean litter size was reduced (Prod Info AROMASIN(R) oral tablets, 2016).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs in all patients.
    B) Monitor CBC and liver function in symptomatic patients.
    C) Monitor fluid and electrolyte status in patients with significant vomiting and/or diarrhea.

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 who remain symptomatic despite adequate treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic children and adults with an inadvertent minor ingestion (or 1 or 2 doses) of a exemestane can be observed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or poison center for patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with a deliberate self-harm ingestion should be evaluated in a healthcare facility and monitored until symptoms resolve. Children should be closely monitored for signs of toxicity. Patients who remain asymptomatic may be discharged.

Monitoring

    A) Monitor vital signs in all patients.
    B) Monitor CBC and liver function in symptomatic patients.
    C) Monitor fluid and electrolyte status in patients with significant vomiting and/or diarrhea.

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) SUPPORT
    1) Treatment should be symptomatic and supportive.
    B) MONITORING OF PATIENT
    1) Monitor vital signs in all patients.
    2) Monitor CBC and liver enzymes in symptomatic patients.
    3) Monitor fluid and electrolyte status in patients with significant vomiting and/or diarrhea.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is NOT expected to significantly enhance the clearance of exemestane due to extensive protein binding.

Range Of Toxicity

Summary

    A) In clinical trials, single doses as high as 800 mg daily for 12 weeks in healthy female volunteers were well tolerated. In postmenopausal women with advanced breast cancer, doses as high as 600 mg were well tolerated.
    B) A child (age unknown) developed leukocytosis (WBC 25000/(mm)3 with 90% neutrophils) 1 hour after ingesting a 25 mg tablet of exemestane. His blood tests obtained 4 days after the incident were normal.
    C) THERAPEUTIC DOSE: The recommended dose is exemestane 25 mg once daily after a meal, and should be continued until tumor progression is evident.

Therapeutic Dose

    7.2.1) ADULT
    A) The recommended dose is exemestane 25 mg once daily (Prod Info AROMASIN(R) oral tablets, 2014).
    7.2.2) PEDIATRIC
    A) The safety and efficacy of exemestane use in the pediatric population have not been established (Prod Info AROMASIN(R) oral tablets, 2014).

Maximum Tolerated Exposure

    A) ADULT
    1) In clinical trials, single doses as high as 800 mg daily for 12 weeks in healthy female volunteers were well tolerated. In postmenopausal women with advanced breast cancer, doses as high as 600 mg were well tolerated(Prod Info AROMASIN(R) oral tablets, 2011).
    B) CHILDREN
    1) CASE REPORT - A male child (age unknown) developed leukocytosis (WBC 25000/(mm)3 with 90% neutrophils) 1 hour after ingesting a 25 mg tablet of exemestane. His blood tests obtained 4 days after the incident were normal (Prod Info AROMASIN(R) oral tablets, 2011).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Exemestane is a steroidal irreversible aromatase inhibitor(Di Salle et al, 1994; Zaccheo et al, 1991; Di Salle et al, 1989; Giudici et al, 1988), which is processed to an intermediate that binds to an active site of the aromatase enzyme, inactivating it through an effect known as "suicide inhibition"(Prod Info AROMASIN(R) oral tablets, 2011). Percentage of total body aromatization decreased from 2.059% to 0.042% after 6 to 8 weeks with exemestane 25 milligrams (Geisler et al, 1998). Improved oral activity relative to formestane(Zilembo et al, 1995; Di Salle et al, 1992).
    B) Selective: significant suppression of plasma estrogens/no significant effect on cortisol/aldosterone synthesis (postmenopausal women (healthy/breast cancer)) (Evans et al, 1992; Di Salle et al, 1992; Johannessen et al, 1997).
    C) Estradiol/estrone/estrone sulfate suppression (postmenopausal breast cancer patients): significant throughout range of 2.5 to 200 milligrams (mg) once daily; maximal with 10 mg once daily (25 mg once daily for estrone sulfate) ((Johannessen et al, 1997; Bajetta et al, 1997) . 0.5 to 1 mg daily ineffective for adequate suppression (Bajetta et al, 1997)

Physicochemical

Physical Characteristics

    A) A white to slightly yellow crystalline powder; freely soluble in N, N-dimethylformamide, soluble in methanol, and practically insoluble in water (Prod Info Aromastin(R), 2002).

Molecular Weight

    A) 296.41(Prod Info Aromastin(R), 2002)

References

General Bibliography

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