MOBILE VIEW  | 

ANASTROZOLE AND RELATED AGENTS

Classification   |    Detailed evidence-based information

Therapeutic Toxic Class

    A) Anastrozole is a nonsteroidal aromatase inhibitor. Inhibits the conversion of adrenally-generated androstenedione to estrone.
    B) Vorozole is a selective nonsteroidal aromatase inhibitor.

Specific Substances

    A) ANASTROZOLE
    1) Anastrozole
    2) Arimidex (Zeneca Pharmaceuticals)
    VOROZOLE
    1) R#83842
    2) JK#201
    3) (+)-Vorozole

Available Forms Sources

    A) FORMS
    1) Anastrozole is available as 1 mg film coated tablet in bottles of 30 (Prod Info ARIMIDEX(R) oral tablet, 2011).
    B) USES
    1) Anastrozole is used for adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer. It is also used for the first-line treatment of postmenopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer. In addition, anastrozole is used for the treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy (Prod Info ARIMIDEX(R) oral tablet, 2011).
    2) Vorozole is indicated in postmenopausal patients with advanced breast cancer progressing; used as a second-line therapy after tamoxifen.

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Anastrozole is used to treat postmenopausal women with breast cancer (hormone receptor-positive or unknown).
    B) PHARMACOLOGY: Growth of many breast cancer tumors is stimulated or maintained by estrogen. Anastrozole is a nonsteroidal aromatase inhibitor that interferes with estradiol production in peripheral tissues by inhibiting conversion of adrenally-generated androstenedione to estrone by aromatase. Adrenally generated androstenedione is the chief source of circulating estrogen in postmenopausal women.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON (GREATER THAN 10%): Nausea, vomiting, rash, hot flashes, headache, hypertension, vasodilation, peripheral edema, lymphedema, arthritis, arthralgia, back pain, asthenia, fatigue, depression, mood disturbances, cough, pharyngitis, and pain. OTHER EFFECTS: Chest pain, thromboembolic events (eg, pulmonary embolus, thrombophlebitis, and retinal vein thrombosis), pruritus, paresthesia, sweating, abdominal pain, diarrhea, dyspepsia, constipation, anorexia, dry mouth, urinary tract infection, vaginal bleeding, leukopenia, anemia, elevated liver enzymes, acute hepatitis, bone pain, myalgia, arthrosis, confusion, anxiety, nervousness, dizziness, dyspnea, sinusitis, bronchitis, and infection.
    E) WITH POISONING/EXPOSURE
    1) Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses. Severe overdose has not been reported.
    0.2.20) REPRODUCTIVE
    A) Anastrozole is classified as FDA Pregnancy Category X. Although teratogenicity has not been observed in some drugs in this category, some reportedly cross the placenta and may increase pregnancy losses. Anastrozole use in animal studies led to increased incidences of pregnancy failure, pregnancy loss, and delayed fetal development. Female rats given anastrozole had a significant incidence of infertility and reduced numbers of viable pregnancies.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs, CBC, and liver enzymes.
    C) Monitor serum electrolytes 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. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. For severe hypertension, nitroprusside is preferred. 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: Consider activated charcoal for recent, substantial ingestion in a patient who is alert and can protect the airway.
    D) AIRWAY MANAGEMENT
    1) Airway management is very unlikely to be necessary unless other toxic agents have been administered concurrently.
    E) ANTIDOTE
    1) None
    F) ENHANCED ELIMINATION
    1) Dialysis may be helpful in a severe overdose because anastrozole is not highly protein bound.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolyte and fluid balance. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities.
    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.
    H) PITFALLS
    1) When managing a suspected anastrozole overdose, the possibility of multidrug involvement should be considered. Symptoms of overdose are similar to reported side effects of the medication.
    I) PHARMACOKINETICS
    1) Tmax: Oral: 2 hours. Bioavailability: Oral, tablet: 80%. Protein binding: 40%. Metabolism: Hepatic metabolism via N-dealkylation, hydroxylation, and glucuronidation, accounts for approximately 85% of the elimination of anastrozole. Excretion: feces: about 75%; renal: about 10%. Elimination half-life: 50 hours.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause elevated liver enzymes or hypertension.

Range Of Toxicity

    A) TOXICITY: In clinical trials, healthy, male volunteers tolerated a 60 mg single dose. The administration of 10 mg/day doses to postmenopausal women was also well tolerated. THERAPEUTIC DOSE: ADULTS: ANASTROZOLE: one 1-mg tablet orally once daily. CHILDREN: Efficacy has not been demonstrated in girls with McCune-Albright Syndrome and progressive precocious puberty or in pubertal, adolescent-age boys with gynecomastia.

Summary Of Exposure

    A) USES: Anastrozole is used to treat postmenopausal women with breast cancer (hormone receptor-positive or unknown).
    B) PHARMACOLOGY: Growth of many breast cancer tumors is stimulated or maintained by estrogen. Anastrozole is a nonsteroidal aromatase inhibitor that interferes with estradiol production in peripheral tissues by inhibiting conversion of adrenally-generated androstenedione to estrone by aromatase. Adrenally generated androstenedione is the chief source of circulating estrogen in postmenopausal women.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON (GREATER THAN 10%): Nausea, vomiting, rash, hot flashes, headache, hypertension, vasodilation, peripheral edema, lymphedema, arthritis, arthralgia, back pain, asthenia, fatigue, depression, mood disturbances, cough, pharyngitis, and pain. OTHER EFFECTS: Chest pain, thromboembolic events (eg, pulmonary embolus, thrombophlebitis, and retinal vein thrombosis), pruritus, paresthesia, sweating, abdominal pain, diarrhea, dyspepsia, constipation, anorexia, dry mouth, urinary tract infection, vaginal bleeding, leukopenia, anemia, elevated liver enzymes, acute hepatitis, bone pain, myalgia, arthrosis, confusion, anxiety, nervousness, dizziness, dyspnea, sinusitis, bronchitis, and infection.
    E) WITH POISONING/EXPOSURE
    1) Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses. Severe overdose has not been reported.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypertension developed in 13% (402 of 3092) of patients treated with anastrozole in clinical trials (Prod Info ARIMIDEX(R) oral tablet, 2011).
    B) VASODILATATION
    1) WITH THERAPEUTIC USE
    a) Vasodilation developed in 36% (1104 of 3092) of patients treated with anastrozole in clinical trials (Prod Info ARIMIDEX(R) oral tablet, 2011).
    C) PERIPHERAL EDEMA
    1) WITH THERAPEUTIC USE
    a) Peripheral edema was reported in 10% (311 of 3092) of patients treated with anastrozole in clinical trials (Prod Info ARIMIDEX(R) oral tablet, 2011).
    D) CHEST PAIN
    1) WITH THERAPEUTIC USE
    a) Chest pain developed in 7% (200 of 3092) of patients who received anastrozole in clinical trials (Prod Info ARIMIDEX(R) oral tablet, 2011).
    E) THROMBOEMBOLIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thromboembolic disease (eg, pulmonary embolus, thrombophlebitis, and retinal vein thrombosis) was reported in 4% (18 of 506) of patients treated with anastrozole in clinical trials (Prod Info ARIMIDEX(R) oral tablet, 2011).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) Dyspnea developed in 6% of patients (n=3092) in one clinical trial and in 10% of patients (n=506) in another trial (Prod Info ARIMIDEX(R) oral tablet, 2011).
    b) CASE REPORT: A 58-year-old woman with breast cancer, developed jaundice, dyspnea, and severe asthenia approximately 3 weeks after beginning anastrozole therapy. Laboratory data revealed thrombocytopenia, an increase in prothrombin time, and elevated liver enzyme levels, and a liver biopsy showed diffuse liver cell necrosis and mild steatosis and cholestasis. Following discontinuation of anastrozole therapy, the patient's liver enzyme levels decreased and prothrombin time normalized; however, following a repair of a perforated duodenal ulcer, she developed septic shock and subsequently died post-operatively (delaCruz et al, 2007).
    B) SINUSITIS
    1) WITH THERAPEUTIC USE
    a) Sinusitis developed in 6% (184 of 3092) of patients treated with anastrozole in clinical trials (Prod Info ARIMIDEX(R) oral tablet, 2011).
    C) BRONCHITIS
    1) WITH THERAPEUTIC USE
    a) Bronchitis developed in 5% (167 of 3092) of patients treated with anastrozole in clinical trials (Prod Info ARIMIDEX(R) oral tablet, 2011).
    D) PHARYNGITIS
    1) WITH THERAPEUTIC USE
    a) Pharyngitis developed in 14% (443 of 3092) of patients treated with anastrozole in clinical trials (Prod Info ARIMIDEX(R) oral tablet, 2011).
    E) COUGH
    1) WITH THERAPEUTIC USE
    a) Cough developed in 11% (55 of 506) of patients treated with anastrozole in clinical trials (Prod Info ARIMIDEX(R) oral tablet, 2011).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache was reported in 9% to 18% of subjects in clinical trials (Prod Info ARIMIDEX(R) oral tablet, 2011; Buzdar et al, 1996). Prevalence may be dependent on dose.
    B) CLOUDED CONSCIOUSNESS
    1) WITH THERAPEUTIC USE
    a) Confusion developed in up to 5% of patients treated with anastrozole in clinical trials (Prod Info ARIMIDEX(R) oral tablet, 2011).
    C) ANXIETY
    1) WITH THERAPEUTIC USE
    a) Anxiety and nervousness developed in up to 6% of patients treated with anastrozole in clinical trials (Prod Info ARIMIDEX(R) oral tablet, 2011).
    D) FATIGUE
    1) WITH THERAPEUTIC USE
    a) Fatigue developed in 13% of patients in clinical trials (Prod Info ARIMIDEX(R) oral tablet, 2011; Buzdar et al, 1996).
    E) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness developed in 8% (236 of 3092) of patients treated with anastrozole in clinical trials (Prod Info ARIMIDEX(R) oral tablet, 2011).
    F) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) Asthenia developed in 19% (575 of 3092) of patients treated with anastrozole in clinical trials (Prod Info ARIMIDEX(R) oral tablet, 2011).
    b) CASE REPORT: A 58-year-old woman, with breast cancer, developed jaundice, dyspnea, and severe asthenia approximately 3 weeks after beginning anastrozole therapy. Laboratory data revealed thrombocytopenia, an increase in prothrombin time, and elevated liver enzyme levels, and a liver biopsy showed diffuse liver cell necrosis and mild steatosis and cholestasis. Following discontinuation of anastrozole therapy, the patient's liver enzyme levels decreased and prothrombin time normalized; however, following a repair of a perforated duodenal ulcer, she developed septic shock and subsequently died post-operatively (delaCruz et al, 2007).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea (10% to 20%) and vomiting (up to 10%) were noted during clinical trials (Prod Info ARIMIDEX(R) oral tablet, 2011; Buzdar et al, 1996).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea developed in 9% of patients treated with anastrozole during clinical trials (Prod Info ARIMIDEX(R) oral tablet, 2011; Buzdar et al, 1996).
    C) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain developed in 9% (271 of 3092) of patients treated with anastrozole in clinical trials (Prod Info ARIMIDEX(R) oral tablet, 2011).
    D) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) Dyspepsia developed in 7% (206 of 3092) of patients treated with anastrozole in clinical trials (Prod Info ARIMIDEX(R) oral tablet, 2011).
    E) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation developed in 9% (47 of 506) of patients treated with anastrozole in clinical trials (Prod Info ARIMIDEX(R) oral tablet, 2011).
    F) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) Anorexia developed in 8% (19 of 246) of patients treated with anastrozole 10 mg daily in clinical trials (Prod Info ARIMIDEX(R) oral tablet, 2011).
    G) APTYALISM
    1) WITH THERAPEUTIC USE
    a) Dry mouth developed in 6% (15 of 262) of patients treated with anastrozole in clinical trials (Prod Info ARIMIDEX(R) oral tablet, 2011).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Liver enzymes (gamma GT, SGOT and SGPT) increased in 2% to 5% of patients evaluated (n=262)(Prod Info ARIMIDEX(R) oral tablet, 2011).
    B) ACUTE HEPATITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 58-year-old woman, with breast cancer, developed jaundice, dyspnea, and severe asthenia approximately 3 weeks after beginning anastrozole therapy. Laboratory data revealed thrombocytopenia, an increase in prothrombin time, and elevated liver enzyme levels, and a liver biopsy showed diffuse liver cell necrosis and mild steatosis and cholestasis. Following discontinuation of anastrozole therapy, the patient's liver enzyme levels decreased and prothrombin time normalized (delaCruz et al, 2007).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) URINARY TRACT INFECTIOUS DISEASE
    1) WITH THERAPEUTIC USE
    a) Urinary tract infection was reported in 8% (244 of 3092) of patients treated with anastrozole 1 mg daily and 10% (313 of 3094) of those treated with tamoxifen 20 mg daily in the ATAC trial, a multicenter, double-blind trial of adjuvant treatment of breast cancer in postmenopausal women treated for 5 years or until recurrence of the disease (Prod Info ARIMIDEX(R) oral tablet, 2008).
    B) ABNORMAL VAGINAL BLEEDING
    1) WITH THERAPEUTIC USE
    a) Vaginal bleeding was reported in 5% (167 of 3092) of patients treated with anastrozole 1 mg daily and 10% (317 of 3094) of those treated with tamoxifen 20 mg daily (odds ratio, 0.5; 95% CI, 0.41 to 0.61) in the ATAC trial, a multicenter, double-blind trial of adjuvant treatment of breast cancer in postmenopausal women treated for 5 years or until recurrence of the disease (Prod Info ARIMIDEX(R) oral tablet, 2011).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia was reported in 2% to 5% of patients treated with anastrozole 1 mg daily in 2 controlled, clinical trials (0004, a North American study and 0005, a predominately European study) of postmenopausal women with advanced breast cancer who had disease progression following tamoxifen therapy for either advanced or early breast cancer (Prod Info ARIMIDEX(R) oral tablet, 2008).
    B) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Anemia was reported in 2% to 5% of patients treated with anastrozole 1 mg daily in two controlled, clinical trials (0004, a North American study and 0005, a predominately European study) of postmenopausal women with advanced breast cancer who had disease progression following tamoxifen therapy for either advanced or early breast cancer (Prod Info ARIMIDEX(R) oral tablet, 2008).
    C) LYMPHEDEMA
    1) WITH THERAPEUTIC USE
    a) Lymphedema was reported in 10% (304 of 3092) of patients treated with anastrozole 1 mg daily and 11% (341 of 3094) of those treated with tamoxifen 20 mg daily in the ATAC trial, a multicenter, double-blind trial of adjuvant treatment of breast cancer in postmenopausal women treated for 5 years or until recurrence of the disease (Prod Info ARIMIDEX(R) oral tablet, 2008).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) Pruritus developed in up to 5% of patients (n=262) treated with anastrozole in clinical trials (Prod Info ARIMIDEX(R) oral tablet, 2011).
    B) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Rash developed in 11% (333 of 3092) of patients who received anastrozole in clinical trials (Prod Info ARIMIDEX(R) oral tablet, 2011).
    C) FLUSHING
    1) WITH THERAPEUTIC USE
    a) Hot flashes developed in 36% of patients (1104 of 3092) who received anastrozole in clinical trials (Prod Info ARIMIDEX(R) oral tablet, 2011).
    D) PARESTHESIA
    1) WITH THERAPEUTIC USE
    a) Paresthesia developed in 7% (215 of 3092) of patients who received anastrozole in clinical trials (Prod Info ARIMIDEX(R) oral tablet, 2011).
    E) SWEATING
    1) WITH THERAPEUTIC USE
    a) Sweating developed in 5% (145 of 3092) of patients who received anastrozole in clinical trials (Prod Info ARIMIDEX(R) oral tablet, 2011).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCULOSKELETAL FINDING
    1) WITH THERAPEUTIC USE
    a) In clinical trials, the following musculoskeletal effects were reported: arthritis 17% (512 of 3092); bone pain 7% (201 of 3092); arthralgia 15% (467 of 3092); myalgia 6% (179 of 3092); back pain 12% (60 of 506); arthrosis 7% (207 of 3092) (Prod Info ARIMIDEX(R) oral tablet, 2011).

Reproductive

    3.20.1) SUMMARY
    A) Anastrozole is classified as FDA Pregnancy Category X. Although teratogenicity has not been observed in some drugs in this category, some reportedly cross the placenta and may increase pregnancy losses. Anastrozole use in animal studies led to increased incidences of pregnancy failure, pregnancy loss, and delayed fetal development. Female rats given anastrozole had a significant incidence of infertility and reduced numbers of viable pregnancies.
    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 anastrozole (Prod Info ARIMIDEX(R) oral tablets, 2014).
    B) ANIMAL STUDIES
    1) ANASTROZOLE
    a) Fetal incomplete ossification occurredat doses that produced plasma anastrozole Cmax and AUC that were 19 times and 9 times higher, respectively, than those found in postmenopausal volunteers at the recommended dose (Prod Info ARIMIDEX(R) oral tablets, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to anastrozole during pregnancy in humans (Prod Info ARIMIDEX(R) oral tablets, 2014).
    B) PREGNANCY CATEGORY
    1) Anastrozole is classified as FDA Pregnancy Category X (Prod Info ARIMIDEX(R) oral tablets, 2014).
    C) ANIMAL STUDIES
    1) ANASTROZOLE
    a) Anastrozole has been shown to cross the placenta. Anastrozole was shown to cause pregnancy failure at doses equal to or greater than 16 times the recommended human dose on a mg/m(2) basis. Increased pre- and postimplantation losses, resorption, and decreased numbers of live fetuses were observed following anastrozole use at doses equal to or greater than one-third the recommended human dose on a mg/m(2) basis given during organogenesis. Similar dose-related effects were seen and placental weights were significantly increased at the recommended human dose on a mg/m(2) basis during organogenesis. Delayed fetal development and fetotoxicity also occurred in rats given doses of anastrozole that produced peak plasma levels 19 times higher than serum levels in humans at the therapeutic dose (Prod Info ARIMIDEX(R) oral tablets, 2014).
    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 anastrozole exposure during human lactation (Prod Info ARIMIDEX(R) oral tablets, 2014).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of anastrozole exposure on fertility (Prod Info ARIMIDEX(R) oral tablets, 2014).
    B) ANIMAL STUDIES
    1) A significant incidence of infertility and reduced numbers of viable pregnancies were noted at doses 10 times the recommended human dose on a mg/m(2) basis, which produced a plasma anastrozole AUC that was 9 times higher than those of postmenopausal volunteers at the recommended dose. There were higher rates of preimplantation ova loss and fetal loss at doses one-fifth the recommended human dose on a mg/m(2) basis administered for 3 weeks, although fertility was recovered after a 5-week non-dosing period.. Doses producing plasma Cmax and AUC values that were 9 to 19 times higher than those in healthy postmenopausal women at the recommended dose resulted in ovarian hypertrophy and follicular cysts (Prod Info ARIMIDEX(R) oral tablets, 2014).
    2) Hyperplastic uteri were observed after the 6-month administration of anastrozole doses producing plasma anastrozole Cmax and AUC values that were 22 times and 16 times higher than those in postmenopausal women at the recommended dose (Prod Info ARIMIDEX(R) oral tablets, 2014).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) RATS
    1) A study in rats using oral doses of 1.0 to 25 mg/kg/day (approximately 10 to 243 times the daily maximum recommended human dose on a mg/m(2) basis) revealed an increase in the incidence of hepatocellular adenoma and carcinoma and uterine stromal polyps in females and thyroid adenoma in males at the high dose. A dose related increase in the incidence of uterine and ovarian hyperplasia was observed in females (Prod Info Arimidex, 2004).

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, CBC, and liver enzymes.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

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 should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient 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.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolyte and fluid balance. 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, CBC, and liver enzymes.
    C) Monitor serum electrolytes 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) MONITORING OF PATIENT
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor vital signs, CBC, and liver enzymes.
    3) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    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) 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).
    9) 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).
    10) 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).
    11) 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).
    12) 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).
    13) 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).
    14) 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).
    15) 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).
    16) LABETALOL
    a) INTRAVENOUS INDICATIONS
    1) Consider if severe hypertension is unresponsive to short acting titratable agents such as sodium nitroprusside. Although labetalol has mixed alpha and beta adrenergic effects (Pearce & Wallin, 1994), it should be used cautiously if sympathomimetic agents are involved in the poisoning, as worsening hypertension may develop from alpha adrenergic effects.
    b) ADULT DOSE
    1) INTRAVENOUS BOLUS: Initial dose of 20 mg by slow IV injection over 2 minutes. Repeat with 40 to 80 mg at 10 minute intervals. Maximum total dose: 300 mg. Maximum effects on blood pressure usually occur within 5 minutes (Prod Info Trandate(R) IV injection, 2010).
    2) INTRAVENOUS INFUSION: Administer infusion after initial bolus, until desired blood pressure is reached. Administer IV at 2 mg/min of diluted labetalol solution (1 mg/mL or 2 mg/3 mL concentrations); adjust as indicated and continue until adequate response is achieved; usual effective IV dose range is 50 to 200 mg total dose; maximum dose: 300 mg. Prepare 1 mg/mL concentration by adding 200 mg labetalol (40 mL) to 160 mL of a compatible solution and administered at a rate of 2 mL/min (2 mg/min); also can be mixed as an approximate 2 mg/3 mL concentration by adding 200 mg labetalol (40 mL) to 250 mL of solution and administered at a rate of 3 mL/min (2 mg/min) (Prod Info Trandate(R) IV injection, 2010). Use of an infusion pump is recommended (Prod Info Trandate(R) IV injection, 2010).
    c) PEDIATRIC DOSE
    1) INTRAVENOUS: LOADING DOSE: 0.2 to 1 mg/kg, may repeat every 5 to 10 minutes (Hari & Sinha, 2011; Flynn & Tullus, 2009; Temple & Nahata, 2000; Fivush et al, 1997; Fivush et al, 1997; Bunchman et al, 1992). Maximum dose: 40 mg/dose (Hari & Sinha, 2011; Flynn & Tullus, 2009). CONTINUOUS INFUSION: 0.25 to 3 mg/kg/hour IV (Hari & Sinha, 2011; Flynn & Tullus, 2009; Temple & Nahata, 2000; Fivush et al, 1997; Miller, 1994; Deal et al, 1992; Bunchman et al, 1992).
    d) ADVERSE REACTIONS
    1) Common adverse events include postural hypotension, dizziness; fatigue; nausea; vomiting, sweating, and flushing (Pearce & Wallin, 1994).
    e) PRECAUTIONS
    1) Contraindicated in patients with bronchial asthma, congestive heart failure, greater than first degree heart block, cardiogenic shock, or severe bradycardia or other conditions associated with prolonged or severe hypotension. In patients with pheochromocytoma, labetalol should be used with caution because it has produced a paradoxical hypertensive response in some patients with this tumor (Prod Info Trandate(R) IV injection, 2010).
    2) Use caution in hepatic disease or intermittent claudication; effects of halothane may be enhanced by labetalol (Prod Info Trandate(R) IV injection, 2010). Labetalol should be stopped if there is laboratory evidence of liver injury or jaundice (Prod Info Trandate(R) IV injection, 2010).
    f) MONITORING PARAMETER
    1) Monitor blood pressure frequently during initial dosing and infusion (Prod Info Trandate(R) IV injection, 2010).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Dialysis may be helpful in a severe overdose since anastrozole is not highly protein bound (Prod Info Arimidex, 2004).

Summary

    A) TOXICITY: In clinical trials, healthy, male volunteers tolerated a 60 mg single dose. The administration of 10 mg/day doses to postmenopausal women was also well tolerated. THERAPEUTIC DOSE: ADULTS: ANASTROZOLE: one 1-mg tablet orally once daily. CHILDREN: Efficacy has not been demonstrated in girls with McCune-Albright Syndrome and progressive precocious puberty or in pubertal, adolescent-age boys with gynecomastia.

Therapeutic Dose

    7.2.1) ADULT
    A) ANASTROZOLE: one 1-mg tablet orally once daily (Prod Info ARIMIDEX(R) oral tablet, 2011).
    7.2.2) PEDIATRIC
    A) Efficacy has not been demonstrated in girls with McCune-Albright Syndrome and progressive precocious puberty or in pubertal, adolescent-age boys with gynecomastia (Prod Info ARIMIDEX(R) oral tablet, 2011).

Minimum Lethal Exposure

    A) ANIMAL DATA
    1) RATS: Lethality observed after single oral doses greater than 100 mg/kg (about 800 times the recommended human dose on a milligram/square meter basis) (Prod Info Arimidex, 2004).
    2) Lethality is associated with severe irritation of the stomach (eg, necrosis, gastritis, ulceration and hemorrhage) (Prod Info Arimidex, 2004).
    3) DOGS: The median lethal dose was greater than 45 mg/kg/day in an acute oral toxicity study in dogs (Prod Info Arimidex, 2004).

Maximum Tolerated Exposure

    A) In clinical trials, healthy, male volunteers tolerated a 60 mg single dose (Prod Info ARIMIDEX(R) oral tablet, 2011; Plourde et al, 1994).
    B) The administration of 10 mg/day doses to postmenopausal women was also well tolerated (Prod Info ARIMIDEX(R) oral tablet, 2011; Plourde et al, 1994).

Pharmacologic Mechanism

    A) Growth of many breast cancer tumors is stimulated or maintained by estrogen. Anastrozole is a nonsteroidal aromatase inhibitor that interferes with estradiol production in peripheral tissues by inhibiting conversion of adrenally-generated androstenedione to estrone by aromatase. Adrenally generated androstenedione is the chief source of circulating estrogen in postmenopausal women (Prod Info ARIMIDEX(R) oral tablet, 2011).

Physical Characteristics

    A) Anastrozole is an off-white powder. It is freely soluble in methanol, ethanol, acetone and tetrahydrofuran. It is very soluble in acetonitrile (Prod Info Arimidex, 2004).

Molecular Weight

    A) 293.4

General Bibliography

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