Contact Us    Contact Us     |     Feedback
MOBILE VIEW  | 

LETROZOLE

Export To Excel

Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Letrozole is a nonsteroidal aromatase inhibitor of estrogen synthesis.

Specific Substances

    1) CGS-2067
    2) CGS-20267
    3) 4,4'-(1H-1,2,4-Triazol-1-ylmethylene)dibenzonitrile
    4) CAS 112809-51-5
    1.2.1) MOLECULAR FORMULA
    1) C17H11N5

Available Forms Sources

    A) FORMS
    1) Letrozole is available as a 2.5 mg film-coated tablet in bottles of 30 (Prod Info letrozole oral tablets, 2011).
    B) USES
    1) Letrozole is used for the extended adjuvant treatment of early breast cancer in postmenopausal women who have received 5 years of adjuvant tamoxifen therapy. 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, letrozole is used for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy (Prod Info letrozole oral tablets, 2011).

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: Letrozole is used to treat postmenopausal women with breast cancers.
    B) PHARMACOLOGY: Letrozole is a nonsteroidal competitive inhibitor of aromatase and thus, in postmenopausal women, inhibits conversion of adrenal androgens (primarily androstenedione and testosterone) to estrogens (estrone and estradiol) in peripheral tissues and cancer tissue. As a result, letrozole interferes with estrogen-induced stimulation or maintenance of growth of hormonally responsive (estrogen and/or progesterone receptor positive or receptor unknown) breast cancers.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON (more than 20%): Hot flashes, arthralgia, flushing, asthenia, edema, bone pain, headache, dizziness, hypercholesterolemia, and increased sweating. OTHER EFFECTS: Nausea, vomiting, diarrhea, anorexia, dyspepsia, abdominal pain, constipation, hypertension, chest pain, rash, alopecia, vaginal discharge, bleeding, and irritation, urinary tract infection, elevated liver enzymes, muscle pain, joint pain, back pain, limb pain, fatigue, insomnia, dyspnea, and cough. Pancytopenia, leukopenia, and peripheral thromboembolic events, such as venous thrombosis, thrombophlebitis, portal vein thrombosis, and pulmonary embolism have rarely been reported in clinical trials and postmarketing reports, however, cause and effect relationships have not been established. Letrozole is classified as pregnancy category X.
    E) WITH POISONING/EXPOSURE
    1) TOXICITY: Overdose data are limited. Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses. In isolated cases of letrozole overdose, the highest single dose of 62.5 mg or 25 tablets did not result in serious adverse effects.
    0.2.20) REPRODUCTIVE
    A) Letrozole is classified as FDA pregnancy category X and is CONTRAINDICATED in women who are or who may become pregnant. In rats and rabbits, there was evidence of embryotoxicity, fetotoxicity, and teratogenicity that were exposed to small doses of letrozole.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturer does not report any carcinogenic potential with letrozole use in humans.

Laboratory Monitoring

    A) Monitor vital signs and liver enzymes.
    B) Monitor CBC with differential after a substantial overdose.
    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.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. For severe hypertension, nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives. Evidence of an acute thrombotic/thromboembolic event (eg, sudden onset of swelling/tenderness in a limb and/or shortness of breath) requires prompt diagnostic evaluation (eg, ultrasound, CT scan) and anticoagulation as indicated.
    C) DECONTAMINATION
    1) PREHOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    2) HOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) ANTIDOTE
    1) None.
    E) ENHANCED ELIMINATION
    1) Dialysis is unlikely to be helpful since letrozole has a large volume of distribution (1.9 L/kg)
    F) 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 and gastrointestinal function. 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.
    G) PITFALLS
    1) When managing a suspected letrozole overdose, the possibility of multidrug involvement should be considered. Symptoms of overdose are similar to reported side effects of the medication.
    H) PHARMACOKINETICS
    1) Letrozole is rapidly and completely absorbed from the gastrointestinal tract. It is weakly protein-bound and has a large Vd (approximately 1.9 L/kg). Letrozole is metabolized by CYP3A4 to the pharmacologically-inactive carbinol metabolite (4,4'-methanolbisbenzonitrile) while CYP2A6 catalyzes the formation of the carbinol metabolite and its ketone analog. Letrozole has been shown to strongly inhibit the human liver microsome CYP2A6 and to moderately inhibit CYP2C19 in vitro. Excretion: Approximately 90% is excreted in the urine. Terminal elimination half-life: About 2 days and steady-state plasma concentrations (a 2.5 mg dose daily) occur in 2 to 6 weeks.
    I) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause elevated liver enzymes or hypertension.

Range Of Toxicity

    A) TOXICITY: In isolated cases of letrozole overdose, the highest single dose of 62.5 mg or 25 tablets did not result in serious adverse effects. In single dose studies, 30 mg was the highest dose used; in multiple dose trials, a 10-mg dose was given. Both were well tolerated.
    B) THERAPEUTIC DOSE: ADULTS: 2.5 mg orally once daily. CHILDREN: Safety and efficacy have not been established in pediatric patients.

Clinical Effects

Summary Of Exposure

    A) USES: Letrozole is used to treat postmenopausal women with breast cancers.
    B) PHARMACOLOGY: Letrozole is a nonsteroidal competitive inhibitor of aromatase and thus, in postmenopausal women, inhibits conversion of adrenal androgens (primarily androstenedione and testosterone) to estrogens (estrone and estradiol) in peripheral tissues and cancer tissue. As a result, letrozole interferes with estrogen-induced stimulation or maintenance of growth of hormonally responsive (estrogen and/or progesterone receptor positive or receptor unknown) breast cancers.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON (more than 20%): Hot flashes, arthralgia, flushing, asthenia, edema, bone pain, headache, dizziness, hypercholesterolemia, and increased sweating. OTHER EFFECTS: Nausea, vomiting, diarrhea, anorexia, dyspepsia, abdominal pain, constipation, hypertension, chest pain, rash, alopecia, vaginal discharge, bleeding, and irritation, urinary tract infection, elevated liver enzymes, muscle pain, joint pain, back pain, limb pain, fatigue, insomnia, dyspnea, and cough. Pancytopenia, leukopenia, and peripheral thromboembolic events, such as venous thrombosis, thrombophlebitis, portal vein thrombosis, and pulmonary embolism have rarely been reported in clinical trials and postmarketing reports, however, cause and effect relationships have not been established. Letrozole is classified as pregnancy category X.
    E) WITH POISONING/EXPOSURE
    1) TOXICITY: Overdose data are limited. Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses. In isolated cases of letrozole overdose, the highest single dose of 62.5 mg or 25 tablets did not result in serious adverse effects.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypertension was reported in 8% of patients who received letrozole 2.5 mg (n=455) for the first-line treatment of advanced breast cancer for a median duration of 11 months (Prod Info FEMARA(R) oral tablets, 2010a).
    B) PERIPHERAL EDEMA
    1) WITH THERAPEUTIC USE
    a) Peripheral edema was reported in 5% of patients who received letrozole 2.5 mg (n=455) for the first-line treatment of advanced breast cancer for a median duration of 11 months (Prod Info FEMARA(R) oral tablets, 2010a).
    C) CHEST PAIN
    1) WITH THERAPEUTIC USE
    a) Chest pain was reported in 8% of patients who received letrozole 2.5 mg (n=455) for the first-line treatment of advanced breast cancer for a median duration of 11 months (Prod Info FEMARA(R) oral tablets, 2010a).
    D) CARDIOVASCULAR FINDING
    1) WITH THERAPEUTIC USE
    a) Non-specified cardiovascular events occurred in 261 (6.6%, n=3975) compared with 248 patients (6.2%, n=3988) for letrozole and tamoxifen, respectively, in a comparative trial (Prod Info letrozole oral tablets, 2011). In previous clinical trials described by the manufacturer, such events were defined as angina, myocardial infarction, myocardial ischemia, and coronary heart disease (Prod Info FEMARA(R) oral tablets, 2010a).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY FINDING
    1) WITH THERAPEUTIC USE
    a) Dyspnea (7% to 18%), cough (5% to 13%), and chest wall pain (6%) have been reported in patients taking letrozole in clinical trials (Prod Info letrozole oral tablets, 2011).
    b) In other clinical studies, dyspnea was reported in 2% to 11% of patients receiving letrozole 0.5 mg and in 1.5% to 14% of those receiving 2.5 mg daily (Buzdar et al, 2001; Dombernowsky et al, 1998; Mouridsen et al, 2001).
    B) PULMONARY EMBOLISM
    1) WITH THERAPEUTIC USE
    a) Pulmonary embolism was reported in 2% or less of patients who received letrozole 2.5 mg for the first-line treatment of advanced breast cancer (n=455) for a median duration of 11 months (Prod Info FEMARA(R) oral tablets, 2010a).
    C) PLEURAL EFFUSION
    1) WITH THERAPEUTIC USE
    a) Pleural effusion was reported in less than 5% of patients who received either letrozole 0.5 mg (n=380) or 2.5 mg (n=359) for the second-line treatment of advanced breast cancer in 2 clinical trials (Prod Info FEMARA(R) oral tablets, 2010a).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) In clinical trials, headache was reported in up to 30% of breast cancer patients receiving letrozole (Prod Info FEMARA(R) oral tablets, 2010a; Buzdar et al, 2001; Dombernowsky et al, 1998; Iveson et al, 1993).
    B) FATIGUE
    1) WITH THERAPEUTIC USE
    a) Fatigue has been reported in 6% to 13% of patients in clinical trials of letrozole (Prod Info letrozole oral tablets, 2011).
    b) In other clinical studies, fatigue was reported in 3.5% to 5.9% of patients receiving 0.5 mg of letrozole and in 5.5% to 11% of those receiving 2.5 mg daily (Buzdar et al, 2001; Dombernowsky et al, 1998; Mouridsen et al, 2001).
    C) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) Asthenia was reported in 5% and 4% of patients treated with letrozole 0.5 mg (n=380) and 2.5 mg (n=359), respectively, in 2 clinical trials of patients receiving letrozole for the second-line treatment of advanced breast cancer (Prod Info FEMARA(R) oral tablets, 2010a).
    D) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) Insomnia was reported in 7% of patients who received letrozole 2.5 mg for the first-line treatment of advanced breast cancer (n=455) for a median duration of 11 months (Prod Info FEMARA(R) oral tablets, 2010a).
    E) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness was reported in 14.2% of letrozole-treated patients (n=2563) and 13.3% placebo-treated patients (n=2573) in a clinical trial of postmenopausal women who have received 5 years of adjuvant tamoxifen therapy and received extended adjuvant treatment of early breast cancer for 24 months (Prod Info FEMARA(R) oral tablets, 2010a).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL TRACT FINDING
    1) WITH THERAPEUTIC USE
    a) Nausea (3.5% to 19%), vomiting (7% to 8%), diarrhea (2.5% to 8%), anorexia (3% to 5%), dyspepsia (3% to 4%), abdominal pain (5% to 6%), and constipation (6% to 10%) were noted in clinical trials (Prod Info letrozole oral tablets, 2011; Buzdar et al, 2001; Mouridsen et al, 2001; Dombernowsky et al, 1998).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) In clinical trials, approximately 3% of patients taking letrozole had elevated liver enzymes not associated with documented metastases (Prod Info letrozole oral tablets, 2011).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) URINARY TRACT INFECTIOUS DISEASE
    1) WITH THERAPEUTIC USE
    a) Urinary tract infection was reported in 6% of patients who received letrozole 2.5 mg (n=455) for a median duration of 11 months for the first-line treatment of advanced breast cancer (Prod Info letrozole oral tablets, 2011).
    B) VAGINAL DISCHARGE
    1) WITH THERAPEUTIC USE
    a) Vaginal discharge has also been reported in the combined analysis of the first- and second-line treatment of metastatic cancer and postmarketing use of letrozole (Prod Info FEMARA(R) oral tablets, 2010a).
    C) BLEEDING
    1) WITH THERAPEUTIC USE
    a) Vaginal bleeding occurred in 177 (4.5%, n=3975) compared with 411 patients (10.3%, n=3988) for letrozole and tamoxifen, respectively, in a comparative trial for the adjuvant treatment of early breast cancer in postmenopausal women (Prod Info letrozole oral tablets, 2011).
    D) VAGINAL IRRITATION
    1) WITH THERAPEUTIC USE
    a) Vaginal irritation occurred in 139 (3.5%, n=3975) compared with 122 patients (3.1%, n=3988) for letrozole and tamoxifen, respectively, in a comparative trial for the adjuvant treatment of early breast cancer in postmenopausal women (Prod Info letrozole oral tablets, 2011).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) PANCYTOPENIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Severe pancytopenia was reported in a 64-year-old woman four months after initiating letrozole 2.5 mg daily therapy. She had a hemoglobin level of 6.3 g/dL, a leukocyte count of 2000/microliter, and platelet count of 47,000/microliter. The patient recovered after hospitalization, transfusion of 3 units of packed red blood cells, and discontinuation of letrozole. Platelet and leukocyte counts returned to normal within 2 weeks of discontinuation of letrozole. Subsequent blood cell counts performed monthly for 3 months were in normal range (Sperone et al, 2002).
    b) LACK OF EFFECTS: No significant changes in hematologic parameters were reported during oral letrozole therapy in a phase I study involving advanced breast cancer patients (Iveson et al, 1993a).
    B) THROMBOEMBOLIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Peripheral thromboembolic events such as venous thrombosis, thrombophlebitis, portal vein thrombosis, and pulmonary embolism have rarely been reported in patients receiving letrozole (Prod Info FEMARA(R) oral tablets, 2010a).
    C) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia has been reported with letrozole therapy in clinical trials and postmarketing experience (Prod Info FEMARA(R) oral tablets, 2010a).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) FLUSHING
    1) WITH THERAPEUTIC USE
    a) Hot flushes were noted in 19% of patients taking letrozole (n=455), compared with 16% of patients taking tamoxifen (n=455). In another study, hot flushes were reported in 49.7% of patients (n=2563) taking letrozole, compared with 43.3% of patients (n=2573) taking placebo in clinical trials (Prod Info FEMARA(R) oral tablets, 2010a).
    B) ERUPTION
    1) WITH THERAPEUTIC USE
    a) In clinical trials, rash has been reported in 5% of patients (n=359) administered letrozole 2.5 mg and 4% of patients (n=380) administered letrozole 0.5 mg. Types of rashes associated with letrozole include erythematous rash, maculopapular rash, psoriasiform rash, and vesicular rash (Prod Info letrozole oral tablets, 2011).
    C) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) Alopecia was reported in 3.5% (n=202) of patients taking letrozole 0.5 mg and in 6% (n=199) of those taking letrozole 2.5 mg in a phase III clinical study (Buzdar et al, 2001).
    b) CASE REPORT: Alopecia was reported in a 37-year-old premenopausal woman being treated with letrozole and triptorelin for recurrent breast cancer. The patient was started on letrozole 2.5 mg daily plus triptorelin 3.75 mg every 28 days after failed treatment with triptorelin plus tamoxifen. After 6 months of letrozole and triptorelin therapy, the patient complained of daily scalp hair loss and progressively developed alopecia. There was no sign of virilization, her previous medical history was unremarkable, and she was receiving no other drugs. Approximately 6 to 8 weeks after initiating topical minoxidil treatment, hair loss stopped and hair regrowth became apparent (Carlini et al, 2003).
    D) EXCESSIVE SWEATING
    1) WITH THERAPEUTIC USE
    a) For postmenopausal women who have received 5 years of adjuvant tamoxifen therapy and received extended adjuvant treatment of early breast cancer, the frequencies of increased sweating were 24.2% in letrozole-treated patients (n=2563) and 22.4% in placebo-treated patients (n=2573) (Prod Info FEMARA(R) oral tablets, 2010a).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) In clinical trials, arthralgia was noted in 22% of patients (n=2563) taking letrozole, compared with 18.1% of patients (n=2573) taking placebo. In another study, arthralgia was reported in 16% of patients (n=455) taking letrozole, compared with 15% of patients (n=455) taking tamoxifen (Prod Info letrozole oral tablets, 2011).
    B) PAIN
    1) WITH THERAPEUTIC USE
    a) Musculoskeletal effects (22%) are the most frequently reported adverse effects associated with letrozole use. Bone pain (22%), back pain (18%), and limb pain (10%) are common complaints (Prod Info letrozole oral tablets, 2011).
    b) In 2 clinical studies, musculoskeletal pain was reported in 2.5% to 25.5% of patients taking letrozole 0.5 mg and in 4.5% to 27% of patients taking letrozole 2.5 mg (Buzdar et al, 2001; Dombernowsky et al, 1998).
    C) ARTHRITIS
    1) WITH THERAPEUTIC USE
    a) In clinical trials, arthritis was reported in 6.7% of patients (n=2563) taking letrozole, compared with 4.8% of patients (n=2573) taking placebo (Prod Info letrozole oral tablets, 2011).
    D) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) Myalgia was reported in 6.7% of patients (n=2563) taking letrozole, compared with 4.7% of patients (n=2573) taking placebo in clinical trials (Prod Info letrozole oral tablets, 2011).

Reproductive

    3.20.1) SUMMARY
    A) Letrozole is classified as FDA pregnancy category X and is CONTRAINDICATED in women who are or who may become pregnant. In rats and rabbits, there was evidence of embryotoxicity, fetotoxicity, and teratogenicity that were exposed to small doses of letrozole.
    3.20.2) TERATOGENICITY
    A) CONGENITAL MALFORMATION
    1) Use of either clomiPHENE or letrozole for induction of ovulation did not increase the risk of congenital malformations compared with natural conception. The mean birthweight of babies in the clomiPHENE group was significantly lower than those in the letrozole and natural conception groups. Structural malformations and chromosomal abnormalities were observed in 2.9% of infants in the natural conception group compared with 2.5% in the letrozole group and 3.9% in the clomiPHENE group. Ventricular septal defect was reported in 1 patient in the natural conception group. Malformations in the letrozole group included paraumbilical hernia, congenital deafness, club foot, and albinism. In the clomiPHENE group, there were reports of congenital heart disease, duplication of urethra, cleft lip and palate, inguinal hernia, and neural tube defect. There were 2 reports of Down's syndrome in the clomiPHENE group (Sharma et al, 2014).
    B) ANIMAL STUDIES
    1) RATS: When letrozole doses greater than or equal to 0.003 mg/kg (approximately 1/100 the daily maximum recommended human dose (MRHD) on a mg/m(2) basis) were administered to rats during the period of organogenesis, anomalies, including absence and shortening of renal papilla, dilation of ureter, edema, and incomplete ossification of frontal skull and metatarsals, were observed. Additional effects seen were intrauterine mortality, increased resorption, increased implantation loss, and decreased numbers of live fetuses. A 0.03 mg/kg dose (approximately 1/10 the MRHD on a mg/m(2) basis) caused cervical/centrum vertebral fusion and fetal domed head (Prod Info letrozole oral tablets, 2011).
    2) RABBITS: Letrozole administered to rabbits at 0.02 mg/kg (approximately 1/10,000 the daily maximum recommended human dose on a mg/m(2) basis) caused incomplete ossification of the skull, sternebrae, and fore- and hind legs (Prod Info letrozole oral tablets, 2011).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified letrozole as FDA pregnancy category X. Letrozole is CONTRAINDICATED in women who are pregnant or who may become pregnant (Prod Info letrozole oral tablets, 2011).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is not known if letrozole is excreted in human breast milk (Prod Info letrozole oral tablets, 2011).
    B) BREAST MILK
    1) No reports describing the use of letrozole during human lactation or measuring the amount, if any, of the drug excreted into human milk have been located. The effects on the nursing infant from exposure to letrozole in milk are unknown. Because data are limited, a decision should be made to discontinue nursing or discontinue the drug, taking into account the potential fetal risks and maternal benefits (Prod Info letrozole oral tablets, 2011; Prod Info FEMARA(R) oral tablets, 2010a).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) MALE RATS: On days 21 and 22 of pregnancy, rats received 1 mg/kg/day of letrozole by gavage. Fertility of adult male offspring was assessed. Sexual maturation, body weight, and wet weights of levatori ani muscle, testis, pituitary, seminal vesicle, and ventral prostate were unchanged at adult life. Fifty percent of the adult males were able to mate with normal females which became pregnant, but there was an increased number of preimplantation loss. There was also a decrease in daily sperm production and the number of spermatozoa found in the testes (Gerardin & Pereira, 2002).
    2) MICE, RATS, DOGS: In male and female mice, rats, and dogs receiving repeated dosing with 0.6, 0.1, and 0.03 mg/kg, respectively (approximately 1, 0.4, and 0.4 times the maximum recommended human dose on a mg/m(2) basis, respectively), letrozole caused sexual inactivity in females and atrophy of the reproductive tract in males and females (Prod Info Femara oral tablets, 2014).
    3) RATS: Administration of letrozole greater than or equal to 0.03 mg/kg/day (approximately 0.1 times the recommended human dose (RHD) on a mg/m(2) basis) to female rats beginning 2 weeks before mating and continuing until pregnancy day 6 resulted in decreases in successful mating and pregnancy. Increases in pre-implantation loss were also reported at doses greater than or equal to 0.003 mg/kg/day (approximately 0.01 time the RHD) (Prod Info Femara oral tablets, 2014).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS112809-51-5 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturer does not report any carcinogenic potential with letrozole use in humans.
    3.21.4) ANIMAL STUDIES
    A) MICE
    1) Dose-related increases in benign ovarian stromal tumors were reported in mice administered oral letrozole doses of 0.6 to 60 mg/kg/day (approximately 1 to 100 times the daily maximum recommended human dose on a mg/m(2) basis) for up to 2 years. These tumors, likely related to pharmacological estrogen synthesis inhibition, may be a result of increased luteinizing hormone due to a decrease in circulating estrogen. When the high-dose group was excluded from analysis due to low survival, the incidence of hepatocellular carcinoma and adenoma showed a significant trend in females (Prod Info Femara oral tablets, 2014).
    B) RATS
    1) An increased incidence in benign ovarian stromal tumors was reported with oral letrozole doses of 10 mg/kg/day in a study of rats administered oral doses of 0.1 to 10 mg/kg/day (approximately 0.4 to 40 times the maximum daily recommended human dose on a mg/m(2) basis) for up to 2 years. These tumors, likely related to pharmacological estrogen synthesis inhibition, may be a result of increased luteinizing hormone due to a decrease in circulating estrogen. Ovarian hyperplasia was reported in the female rats administered oral letrozole doses of 0.1 mg/kg/day or greater (Prod Info Femara oral tablets, 2014).

Genotoxicity

    A) No mutagenicity was noted with letrozole in the in vitro Ames and E. coli bacterial tests; however, potential clastogenicity was observed in the in vitro Chinese hamster ovary cell assays. No clastogenicity was observed with letrozole in vivo in the micronucleus test in rats (Prod Info Femara oral tablets, 2014).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and liver enzymes.
    B) Monitor CBC with differential after a substantial overdose.
    C) Monitor serum electrolytes 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 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 and gastrointestinal function. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Monitor vital signs and liver enzymes.
    B) Monitor CBC with differential after a substantial overdose.
    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) Monitor vital signs and liver enzymes.
    2) Monitor CBC with differential after a substantial overdose.
    3) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    B) MYELOSUPPRESSION
    1) Pancytopenia and leukopenia have been reported in clinical trials and postmarketing reports (Prod Info FEMARA(R) oral tablets, 2010a); however, cause and effect relationships have not been established.
    2) LACK OF EFFECTS: No significant changes in hematologic parameters were reported during oral letrozole therapy in a phase I study involving advanced breast cancer patients (Iveson et al, 1993a).
    3) CASE REPORT: Severe pancytopenia was reported in a 64-year-old woman four months after initiating letrozole 2.5 mg daily therapy. She had a hemoglobin level of 6.3 g/dL, a leukocyte count of 2000/microliter, and platelet count of 47,000/microliter. The patient recovered after hospitalization, transfusion of 3 units of packed red blood cells, and discontinuation of letrozole. Platelet and leukocyte counts returned to normal within 2 weeks of discontinuation of letrozole. Subsequent blood cell counts performed monthly for 3 months were in normal range (Sperone et al, 2002).
    4) There is little data on the use of hematopoietic colony stimulating factors to treat neutropenia after drug overdose or idiosyncratic reactions. These agents have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Hartman et al, 1997; Stull et al, 2005). They have also been used to treat agranulocytosis induced by nonchemotherapy drugs (Beauchesne & Shalansky, 1999). They may be considered in patients with severe neutropenia who have or are at significant risk for developing febrile neutropenia.
    a) Filgrastim: The usual starting dose in adults is 5 micrograms/kilogram/day by intravenous infusion or subcutaneous injection (Prod Info NEUPOGEN(R) injection, 2006).
    b) Sargramostim: Usual dose is 250 micrograms/square meter/day infused IV over 4 hours (Prod Info LEUKINE(R) injection, 2006).
    c) Monitor CBC with differential.
    5) Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage.
    C) 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).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Dialysis is unlikely to be helpful since letrozole has a large volume of distribution (1.9 L/kg) (Prod Info letrozole oral tablets, 2011).

Range Of Toxicity

Summary

    A) TOXICITY: In isolated cases of letrozole overdose, the highest single dose of 62.5 mg or 25 tablets did not result in serious adverse effects. In single dose studies, 30 mg was the highest dose used; in multiple dose trials, a 10-mg dose was given. Both were well tolerated.
    B) THERAPEUTIC DOSE: ADULTS: 2.5 mg orally once daily. CHILDREN: Safety and efficacy have not been established in pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    A) The recommended dose is one 2.5-mg tablet daily (Prod Info letrozole oral tablets, 2011).
    7.2.2) PEDIATRIC
    A) Safety and efficacy have not been established in pediatric patients (Prod Info letrozole oral tablets, 2011).

Minimum Lethal Exposure

    A) GENERAL SUMMARY
    1) A single dose that results in death is unknown.
    B) ANIMAL DATA
    1) MICE AND RATS: Lethality was observed in both animals following single oral doses that were equal to or greater than 2000 mg/kg (about 4000 to 8000 times the daily maximum recommended human dose on a mg/m2 basis). Symptoms observed prior to death were reduced motor activity, ataxia, and dyspnea (Prod Info letrozole oral tablets, 2011).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) In isolated cases of letrozole overdose, the highest single dose of 62.5 mg or 25 tablets did not result in serious adverse effects (Prod Info letrozole oral tablets, 2011).
    2) In clinical studies, single dose trials up to 30 mg and multiple dose trials of 10 mg have been well tolerated (Prod Info letrozole oral tablets, 2011).

Workplace Standards

    A) ACGIH TLV Values for CAS112809-51-5 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS112809-51-5 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS112809-51-5 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS112809-51-5 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Letrozole binds to the heme group of aromatase, a cytochrome P450 enzyme which catalyzes conversion of androgens to estrogens (specifically, androstenedione to estrone and testosterone to estradiol). This leads to inhibition of the enzyme and a significant reduction in plasma estrogen levels; approximately 30% of human breast cancers are sensitive to this estrogen deprivation (Iveson et al, 1993a; Bhatnagar et al, 1990).
    B) Aromatase inhibition by letrozole appears to be relatively specific, with sparing of other cytochrome P450 enzymes of the same class involved in glucocorticoid and mineralocorticoid synthesis (Demers et al, 1993; Iveson et al, 1993a).

Physicochemical

Physical Characteristics

    A) A white to yellowish crystalline and practically odorless powder that is freely soluble in dichloromethane, slightly soluble in ethanol, and practically insoluble in water. Melting range is between 184 and 185 degrees C (Prod Info FEMARA(R) oral tablets, 2010).

Molecular Weight

    A) 285.31 (Prod Info FEMARA(R) oral tablets, 2010)

References

General Bibliography

    1) 40 CFR 372.28: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Lower thresholds for chemicals of special concern. National Archives and Records Administration (NARA) and the Government Printing Office (GPO). Washington, DC. Final rules current as of Apr 3, 2006.
    2) 40 CFR 372.65: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Chemicals and Chemical Categories to which this part applies. National Archives and Records Association (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Apr 3, 2006.
    3) 49 CFR 172.101 - App. B: Department of Transportation - Table of Hazardous Materials, Appendix B: List of Marine Pollutants. National Archives and Records Administration (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Aug 29, 2005.
    4) 62 FR 58840: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 1997.
    5) 65 FR 14186: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    6) 65 FR 39264: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    7) 65 FR 77866: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    8) 66 FR 21940: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2001.
    9) 67 FR 7164: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2002.
    10) 68 FR 42710: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2003.
    11) 69 FR 54144: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2004.
    12) AIHA: 2006 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook, American Industrial Hygiene Association, Fairfax, VA, 2006.
    13) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    14) American Conference of Governmental Industrial Hygienists : ACGIH 2010 Threshold Limit Values (TLVs(R)) for Chemical Substances and Physical Agents and Biological Exposure Indices (BEIs(R)), American Conference of Governmental Industrial Hygienists, Cincinnati, OH, 2010.
    15) American Heart Association: 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2005; 112(24 Suppl):IV 1-203. Available from URL: http://circ.ahajournals.org/content/vol112/24_suppl/. As accessed 12/14/2005.
    16) Beauchesne MF & Shalansky SJ: Nonchemotherapy drug-induced agranulocytosis: a review of 118 patients treated with colony-stimulating factors. Pharmacotherapy 1999; 19(3):299-305.
    17) Bhatnagar AS, Hausler A, Schieweck K, et al: Highly selective inhibition of estrogen biosynthesis by CGS 20267, a new non-steroidal aromatase inhibitor. J Steroid Biochem Molec Biol 1990; 37:1021-1027.
    18) Buzdar A, Douma J, Davidson N, et al: Phase III, multicenter, double-blind, randomized study of letrozole, an aromatase inhibitor, for advanced breast cancer versus megestrol acetate. J Clin Oncol 2001; 19:3357-3366.
    19) Carlini P, Di Cosimo S, Ferretti G, et al: Alopecia in a premenopausal breast cancer woman treated with letrozole and triptorelin. Ann Oncol 2003; 14:1689-1692.
    20) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    21) DFG: List of MAK and BAT Values 2002, Report No. 38, Deutsche Forschungsgemeinschaft, Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area, Wiley-VCH, Weinheim, Federal Republic of Germany, 2002.
    22) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    23) Demers LM, Lipton A, Harvey HA, et al: The efficacy of CGS29267 in suppressing estrogen biosynthesis in patients with advanced stage breast cancer. J Steroid Biochem Molec Biol 1993; 44:687-691.
    24) Dombernowsky P, Smith L, Falkson G, et al: Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol 1998; 16:453-461.
    25) EPA: Search results for Toxic Substances Control Act (TSCA) Inventory Chemicals. US Environmental Protection Agency, Substance Registry System, U.S. EPA's Office of Pollution Prevention and Toxics. Washington, DC. 2005. Available from URL: http://www.epa.gov/srs/.
    26) Elisaf MS, Bairaktari E, Nicolaides C, et al: Effect of letrozole on the lipid profile in postmenopausal women with breast cancer. Eur J Cancer 2001; 37:1510-1513.
    27) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    28) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    29) Friedman WF & George BL : Treatment of congestive heart failure by altering loading conditions of the heart. J Pediatr 1985; 106(5):697-706.
    30) Gerardin DDC & Pereira CM: Reproductive changes in male rats treated perinatally with an aromatse inhibitor. Pharmacol Biochem Behav 2002; 71:301-305.
    31) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    32) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    33) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    34) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    35) Hartman LC, Tschetter LK, Habermann TM, et al: Granulocyte colony-stimulating factor in severe chemotherapy-induced afebrile neutropenia.. N Engl J Med 1997; 336:1776-1780.
    36) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: 1,3-Butadiene, Ethylene Oxide and Vinyl Halides (Vinyl Fluoride, Vinyl Chloride and Vinyl Bromide), 97, International Agency for Research on Cancer, Lyon, France, 2008.
    37) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Formaldehyde, 2-Butoxyethanol and 1-tert-Butoxypropan-2-ol, 88, International Agency for Research on Cancer, Lyon, France, 2006.
    38) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Household Use of Solid Fuels and High-temperature Frying, 95, International Agency for Research on Cancer, Lyon, France, 2010a.
    39) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Smokeless Tobacco and Some Tobacco-specific N-Nitrosamines, 89, International Agency for Research on Cancer, Lyon, France, 2007.
    40) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Some Non-heterocyclic Polycyclic Aromatic Hydrocarbons and Some Related Exposures, 92, International Agency for Research on Cancer, Lyon, France, 2010.
    41) IARC: List of all agents, mixtures and exposures evaluated to date - IARC Monographs: Overall Evaluations of Carcinogenicity to Humans, Volumes 1-88, 1972-PRESENT. World Health Organization, International Agency for Research on Cancer. Lyon, FranceAvailable from URL: http://monographs.iarc.fr/monoeval/crthall.html. As accessed Oct 07, 2004.
    42) Ilbawi MN, Idriss FS, DeLeon SY, et al: Hemodynamic effects of intravenous nitroglycerin in pediatric patients after heart surgery. Circulation 1985; 72(3 Pt 2):II101-II107.
    43) International Agency for Research on Cancer (IARC): IARC monographs on the evaluation of carcinogenic risks to humans: list of classifications, volumes 1-116. International Agency for Research on Cancer (IARC). Lyon, France. 2016. Available from URL: http://monographs.iarc.fr/ENG/Classification/latest_classif.php. As accessed 2016-08-24.
    44) International Agency for Research on Cancer: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. World Health Organization. Geneva, Switzerland. 2015. Available from URL: http://monographs.iarc.fr/ENG/Classification/. As accessed 2015-08-06.
    45) Iveson TJ, Smith IE, Ahern J, et al: Phase I study of the oral nonsteroidal aromatase inhibitor CGS 20267 in healthy postmenopausal women. J Clin Endocrinol Metabolism 1993; 77:324-331.
    46) Iveson TJ, Smith IE, Ahern J, et al: Phase I study of the oral nonsteroidal aromatase inhibitor CGS 29267 in postmenopausal patients with advanced breast cancer. Cancer Research 1993a; 53:266-270.
    47) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    48) Koch-Weser J: Hypertensive emergencies. N Engl J Med 1974; 290:211.
    49) Laitinen P, Happonen JM, Sairanen H, et al: Amrinone versus dopamine-nitroglycerin after reconstructive surgery for complete atrioventricular septal defect. J Cardiothorac Vasc Anesth 1997; 11(7):870-874.
    50) McMillian WD, Trombley BJ, Charash WE, et al: Phentolamine continuous infusion in a patient with pheochromocytoma. Am J Health Syst Pharm 2011; 68(2):130-134.
    51) Mouridsen H, Gershanovich M, Sun Y, et al: Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 2001; 19:2596-2606.
    52) NFPA: Fire Protection Guide to Hazardous Materials, 13th ed., National Fire Protection Association, Quincy, MA, 2002.
    53) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 1, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2001.
    54) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 2, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2002.
    55) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 3, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2003.
    56) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 4, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2004.
    57) Nam YT, Shin T, & Yoshitake J: Induced hypotension for surgical repair of congenital dislocation of the hip in children. J Anesth 1989; 3(1):58-64.
    58) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2,3-Trimethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d68a&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    59) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2,4-Trimethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006m. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d68a&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    60) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2-Butylene Oxide (Proposed). United States Environmental Protection Agency. Washington, DC. 2008d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648083cdbb&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    61) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2-Dibromoethane (Proposed). United States Environmental Protection Agency. Washington, DC. 2007g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064802796db&disposition=attachment&contentType=pdf. As accessed 2010-08-18.
    62) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,3,5-Trimethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d68a&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    63) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 2-Ethylhexyl Chloroformate (Proposed). United States Environmental Protection Agency. Washington, DC. 2007b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648037904e&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    64) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Acrylonitrile (Proposed). United States Environmental Protection Agency. Washington, DC. 2007c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648028e6a3&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    65) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Adamsite (Proposed). United States Environmental Protection Agency. Washington, DC. 2007h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    66) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Agent BZ (3-quinuclidinyl benzilate) (Proposed). United States Environmental Protection Agency. Washington, DC. 2007f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803ad507&disposition=attachment&contentType=pdf. As accessed 2010-08-18.
    67) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Allyl Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2008. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648039d9ee&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    68) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Aluminum Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    69) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Arsenic Trioxide (Proposed). United States Environmental Protection Agency. Washington, DC. 2007m. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480220305&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    70) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Automotive Gasoline Unleaded (Proposed). United States Environmental Protection Agency. Washington, DC. 2009a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cc17&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    71) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Biphenyl (Proposed). United States Environmental Protection Agency. Washington, DC. 2005j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064801ea1b7&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    72) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Bis-Chloromethyl Ether (BCME) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006n. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648022db11&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    73) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Boron Tribromide (Proposed). United States Environmental Protection Agency. Washington, DC. 2008a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803ae1d3&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    74) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Bromine Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2007d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648039732a&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    75) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Bromoacetone (Proposed). United States Environmental Protection Agency. Washington, DC. 2008e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809187bf&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    76) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Calcium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    77) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Carbonyl Fluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2008b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803ae328&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    78) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Carbonyl Sulfide (Proposed). United States Environmental Protection Agency. Washington, DC. 2007e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648037ff26&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    79) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Chlorobenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2008c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803a52bb&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    80) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Cyanogen (Proposed). United States Environmental Protection Agency. Washington, DC. 2008f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809187fe&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    81) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Dimethyl Phosphite (Proposed). United States Environmental Protection Agency. Washington, DC. 2009. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cbf3&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    82) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Diphenylchloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    83) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethyl Isocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648091884e&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    84) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethyl Phosphorodichloridate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480920347&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    85) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2008g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809203e7&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    86) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethyldichloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    87) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Germane (Proposed). United States Environmental Protection Agency. Washington, DC. 2008j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963906&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    88) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Hexafluoropropylene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064801ea1f5&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    89) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ketene (Proposed). United States Environmental Protection Agency. Washington, DC. 2007. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ee7c&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    90) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Magnesium Aluminum Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    91) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Magnesium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    92) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Malathion (Proposed). United States Environmental Protection Agency. Washington, DC. 2009k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809639df&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    93) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Mercury Vapor (Proposed). United States Environmental Protection Agency. Washington, DC. 2009b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a8a087&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    94) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyl Isothiocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963a03&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    95) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyl Parathion (Proposed). United States Environmental Protection Agency. Washington, DC. 2008l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963a57&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    96) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyl tertiary-butyl ether (Proposed). United States Environmental Protection Agency. Washington, DC. 2007a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064802a4985&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    97) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methylchlorosilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2005. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5f4&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    98) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyldichloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    99) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyldichlorosilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2005a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c646&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    100) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Mustard (HN1 CAS Reg. No. 538-07-8) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6cb&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    101) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Mustard (HN2 CAS Reg. No. 51-75-2) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6cb&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    102) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Mustard (HN3 CAS Reg. No. 555-77-1) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6cb&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    103) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Tetroxide (Proposed). United States Environmental Protection Agency. Washington, DC. 2008n. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648091855b&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    104) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Trifluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2009l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963e0c&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    105) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Parathion (Proposed). United States Environmental Protection Agency. Washington, DC. 2008o. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963e32&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    106) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Perchloryl Fluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2009c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e268&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    107) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Perfluoroisobutylene (Proposed). United States Environmental Protection Agency. Washington, DC. 2009d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e26a&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    108) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phenyl Isocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008p. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096dd58&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    109) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phenyl Mercaptan (Proposed). United States Environmental Protection Agency. Washington, DC. 2006d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020cc0c&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    110) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phenyldichloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    111) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phorate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008q. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096dcc8&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    112) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phosgene (Draft-Revised). United States Environmental Protection Agency. Washington, DC. 2009e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a8a08a&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    113) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phosgene Oxime (Proposed). United States Environmental Protection Agency. Washington, DC. 2009f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e26d&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    114) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Potassium Cyanide (Proposed). United States Environmental Protection Agency. Washington, DC. 2009g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cbb9&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    115) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Potassium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    116) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Propargyl Alcohol (Proposed). United States Environmental Protection Agency. Washington, DC. 2006e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ec91&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    117) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Selenium Hexafluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2006f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ec55&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    118) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Silane (Proposed). United States Environmental Protection Agency. Washington, DC. 2006g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d523&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    119) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Sodium Cyanide (Proposed). United States Environmental Protection Agency. Washington, DC. 2009h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cbb9&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    120) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Sodium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    121) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Strontium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    122) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Sulfuryl Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2006h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ec7a&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    123) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tear Gas (Proposed). United States Environmental Protection Agency. Washington, DC. 2008s. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096e551&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    124) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tellurium Hexafluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2009i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e2a1&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    125) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tert-Octyl Mercaptan (Proposed). United States Environmental Protection Agency. Washington, DC. 2008r. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096e5c7&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    126) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tetramethoxysilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2006j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d632&disposition=attachment&contentType=pdf. As accessed 2010-08-17.
    127) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Trimethoxysilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2006i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d632&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    128) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Trimethyl Phosphite (Proposed). United States Environmental Protection Agency. Washington, DC. 2009j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7d608&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    129) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Trimethylacetyl Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2008t. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096e5cc&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    130) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Zinc Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    131) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for n-Butyl Isocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008m. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064808f9591&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    132) National Institute for Occupational Safety and Health: NIOSH Pocket Guide to Chemical Hazards, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Cincinnati, OH, 2007.
    133) National Research Council : Acute exposure guideline levels for selected airborne chemicals, 5, National Academies Press, Washington, DC, 2007.
    134) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 6, National Academies Press, Washington, DC, 2008.
    135) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 7, National Academies Press, Washington, DC, 2009.
    136) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 8, National Academies Press, Washington, DC, 2010.
    137) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    138) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    139) Product Information: FEMARA(R) oral tablets, letrozole oral tablets. Novartis Pharmaceuticals Corporation, East Hanover, NJ, 2010.
    140) Product Information: FEMARA(R) oral tablets, letrozole oral tablets. Novartis Pharmaceuticals Corporation, East Hanover, NJ, 2010a.
    141) Product Information: Femara oral tablets, letrozole oral tablets. Novartis Pharmaceuticals Corporation (per FDA), East Hanover, NJ, 2014.
    142) Product Information: LEUKINE(R) injection, sargramostim injection. Berlex, Seattle, WA, 2006.
    143) Product Information: NEUPOGEN(R) injection, filgrastim injection. Amgen,Inc, Thousand Oaks, CA, 2006.
    144) Product Information: NITROPRESS(R) injection for IV infusion, Sodium Nitroprusside injection for IV infusion. Hospira, Inc., Lake Forest, IL, 2007.
    145) Product Information: NITROPRESS(R) injection, sodium nitroprusside injection. Hospira,Inc, Lake Forest, IL, 2004.
    146) Product Information: Phentolamine Mesylate IM, IV injection Sandoz Standard, phentolamine mesylate IM, IV injection Sandoz Standard. Sandoz Canada (per manufacturer), Boucherville, QC, 2005.
    147) Product Information: letrozole oral tablets, letrozole oral tablets. Teva Pharmaceuticals USA (per DailyMed), Sellersville, PA, 2011.
    148) Rasch DK & Lancaster L: Successful use of nitroglycerin to treat postoperative pulmonary hypertension. Crit Care Med 1987; 15(6):616-617.
    149) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    150) Rhoney D & Peacock WF: Intravenous therapy for hypertensive emergencies, part 1. Am J Health Syst Pharm 2009; 66(15):1343-1352.
    151) Sharma S, Ghosh S, Singh S, et al: Congenital malformations among babies born following letrozole or clomiphene for infertility treatment. PLoS One 2014; 9(10):e108219.
    152) Singh D, Akingbola O, Yosypiv I, et al: Emergency management of hypertension in children. Int J Nephrol 2012; 2012:420247.
    153) Sperone P, Gorzegano G, Berruti A, et al: Reversible pancytopenia caused by oral letrozole assumption in a patient with recurrent breast cancer. J Clin Oncol 2002; 20(17):3747-3748.
    154) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    155) Stull DM, Bilmes R, Kim H, et al: Comparison of sargramostim and filgrastim in the treatment of chemotherapy-induced neutropenia. Am J Health Syst Pharm 2005; 62(1):83-87.
    156) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.
    157) U.S. Department of Energy, Office of Emergency Management: Protective Action Criteria (PAC) with AEGLs, ERPGs, & TEELs: Rev. 26 for chemicals of concern. U.S. Department of Energy, Office of Emergency Management. Washington, DC. 2010. Available from URL: http://www.hss.doe.gov/HealthSafety/WSHP/Chem_Safety/teel.html. As accessed 2011-06-27.
    158) U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project : 11th Report on Carcinogens. U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program. Washington, DC. 2005. Available from URL: http://ntp.niehs.nih.gov/INDEXA5E1.HTM?objectid=32BA9724-F1F6-975E-7FCE50709CB4C932. As accessed 2011-06-27.
    159) U.S. Department of Health and Human Services; National Institutes of Health; and National Heart, Lung, and Blood Institute: The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. U.S. Department of Health and Human Services. Washington, DC. 2004. Available from URL: http://www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf. As accessed 2012-06-20.
    160) U.S. Environmental Protection Agency: Discarded commercial chemical products, off-specification species, container residues, and spill residues thereof. Environmental Protection Agency's (EPA) Resource Conservation and Recovery Act (RCRA); List of hazardous substances and reportable quantities 2010b; 40CFR(261.33, e-f):77-.
    161) U.S. Environmental Protection Agency: Integrated Risk Information System (IRIS). U.S. Environmental Protection Agency. Washington, DC. 2011. Available from URL: http://cfpub.epa.gov/ncea/iris/index.cfm?fuseaction=iris.showSubstanceList&list_type=date. As accessed 2011-06-21.
    162) U.S. Environmental Protection Agency: List of Radionuclides. U.S. Environmental Protection Agency. Washington, DC. 2010a. Available from URL: http://www.gpo.gov/fdsys/pkg/CFR-2010-title40-vol27/pdf/CFR-2010-title40-vol27-sec302-4.pdf. As accessed 2011-06-17.
    163) U.S. Environmental Protection Agency: List of hazardous substances and reportable quantities. U.S. Environmental Protection Agency. Washington, DC. 2010. Available from URL: http://www.gpo.gov/fdsys/pkg/CFR-2010-title40-vol27/pdf/CFR-2010-title40-vol27-sec302-4.pdf. As accessed 2011-06-17.
    164) U.S. Environmental Protection Agency: The list of extremely hazardous substances and their threshold planning quantities (CAS Number Order). U.S. Environmental Protection Agency. Washington, DC. 2010c. Available from URL: http://www.gpo.gov/fdsys/pkg/CFR-2010-title40-vol27/pdf/CFR-2010-title40-vol27-part355.pdf. As accessed 2011-06-17.
    165) U.S. Occupational Safety and Health Administration: Part 1910 - Occupational safety and health standards (continued) Occupational Safety, and Health Administration's (OSHA) list of highly hazardous chemicals, toxics and reactives. Subpart Z - toxic and hazardous substances. CFR 2010 2010; Vol6(SEC1910):7-.
    166) U.S. Occupational Safety, and Health Administration (OSHA): Process safety management of highly hazardous chemicals. 29 CFR 2010 2010; 29(1910.119):348-.
    167) United States Environmental Protection Agency Office of Pollution Prevention and Toxics: Acute Exposure Guideline Levels (AEGLs) for Vinyl Acetate (Proposed). United States Environmental Protection Agency. Washington, DC. 2006. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6af&disposition=attachment&contentType=pdf. As accessed 2010-08-16.