Letrozole (letrozole)

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Letrozole is administered orally. Food does not affect the absorption of letrozole, and the drug may be administered without regard to meals.

Commercially available letrozole tablets should be stored at a controlled room temperature of 20-25degreesC (excursions permitted between 15-30degreesC).

Letrozole is a substrate of cytochrome P-450 (CYP) 3A4 and CYP2A6. Letrozole has been shown to inhibit CYP2A6 and CYP2C19 in human liver microsomes, but the clinical significance of this is not known.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Anastrozole; Letrozole/Tamoxifen

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Tamoxifen may induce the metabolism of anastrozole(1) and letrozole(2) by induction of CYP3A4.

CLINICAL EFFECTS: Concurrent use of tamoxifen may result in decreased plasma levels and effectiveness of anastrozole(1,3) and letrozole.(2,3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturers of anastrozole(1) and tamoxifen(3) state that these agents should not be coadministered. The manufacturer of letrozole does not recommend concurrent therapy with tamoxifen(4) and the manufacturer of tamoxifen states they should not be used concurrently.(3) Patients may benefit more from sequential therapy, rather than concurrent therapy.(2,5)

DISCUSSION: Based on clinical and pharmacokinetic data from the ATAC trial, tamoxifen should not be administered with anastrozole. Concurrent use decreased anastrozole plasma levels by 27%. The combination had no efficacy benefit when compared to tamoxifen administration alone. Tamoxifen pharmacokinetics were not affected.(1,3) A study in 12 subjects examined the concurrent administration of tamoxifen and letrozole for six weeks. Concurrent use decreased the mean concentration of letrozole by 37.6%.(3,4) Although suppression of estradiol, estrone, and estrone sulfate were not effected, the authors speculated that patients may not receive the full benefit of combination therapy.(4) A study in 23 patients found that letrozole had no effect on tamoxifen levels. However, the antitumor effects of combination therapy were less than expected.(6) The therapeutic effect of letrozole is not affected if letrozole is administered immediately after tamoxifen.(5)

Selected Anti-Aromatase Agents/Estrogens

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Aromatase inhibitors(1-6) and inactivators(7-10) treat breast cancer by inhibiting estrogen synthesis therefore lowering serum estrone and estradiol levels. In postmenopausal women, androgens are metabolized to estrogens via the primary pathway of the aromatase enzyme.

CLINICAL EFFECTS: Concurrent administration of estrogen may decrease the effectiveness of aromatase inhibitors.(1-6)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Canadian,(1) UK,(2) and US(3) manufacturers of anastrozole state that estrogen containing therapies should not be used during anastrozole therapy. The Australian,(7) Canadian,(8) UK,(9) and US(10) manufacturers of exemestane state that exemestane should not be administered with estrogen containing therapies. The Canadian(4) and UK(5) manufacturer of letrozole state that estrogen containing therapies should be avoided during letrozole therapy.

DISCUSSION: Many breast cancers have estrogen receptors and their growth can be stimulated by estrogen. Anastrozole is a potent and selective non-steroidal aromatase inhibitor that lowers serum estradiol levels. Concurrent use of estrogen may diminish the effects of anastrozole.(1-3) Exemestane is a steroidal aromatase inactivator that lowers serum estradiol levels. Concurrent use of estrogen may diminish the effects of exemestane.(7-10)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Selected Anti-Aromatase Agents/Selected Vaginal Estrogens

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Aromatase inhibitors(1-6) and inactivators(7-10) treat breast cancer by inhibiting estrogen synthesis therefore lowering serum estrone and estradiol levels. In postmenopausal women, androgens are metabolized to estrogens via the primary pathway of the aromatase enzyme.

CLINICAL EFFECTS: Concurrent administration of estrogen may decrease the effectiveness of aromatase inhibitors.(1-6)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Canadian,(1) UK,(2) and US(3) manufacturers of anastrozole state that estrogen containing therapies should not be used during anastrozole therapy. The Australian,(7) Canadian,(8) UK,(9) and US(10) manufacturers of exemestane state that exemestane should not be administered with estrogen containing therapies. The Canadian(4) and UK(5) manufacturer of letrozole state that estrogen containing therapies should be avoided during letrozole therapy. A clinical consensus from the American College of Obstetricians and Gynecologists states that low-dose vaginal estrogen may be used in patients on aromatase inhibitors who have failed non-hormonal treatment after shared decision making.(11) The Fifth International Consultation on Sexual Medicine also made recommendations on treatment of genitourinary syndrome of menopause (GSM). They state that local estrogen therapy cannot be a first line treatment for GSM in women on adjuvant hormone therapy but low- and ultra-low dose local estrogens can be used after trying non-hormonal approaches, and after a discussion of risks and benefits with the patient.(12)

DISCUSSION: Many breast cancers have estrogen receptors and their growth can be stimulated by estrogen. Anastrozole is a potent and selective non-steroidal aromatase inhibitor that lowers serum estradiol levels. Concurrent use of estrogen may diminish the effects of anastrozole.(1-3) Exemestane is a steroidal aromatase inactivator that lowers serum estradiol levels. Concurrent use of estrogen may diminish the effects of exemestane.(7-10) Several meta-analyses and systematic reviews have concluded that vaginal estrogens are likely to be safe in women on aromatase inhibitors. Nevertheless, they recommend using vaginal estrogens after a trial with nonhormonal therapies has failed and following shared decision making including a discussion with the patient of the risks and benefits of treatment.(13-16)

There are no moderate interactions for this drug.

*Pregnancy.

*Known hypersensitivity to letrozole or any ingredient in the formulation.

• Lactation
• Pregnancy

• Disease of liver
• Osteoporosis

• Cerebrovascular disorder
• Hypercholesterolemia
• Osteopenia
• Thromboembolic disorder

The most common adverse effects (occurring in greater than 20% of patients) are hot flashes, arthralgia, flushing, asthenia, edema, headache, dizziness, hypercholesterolemia, increased sweating, bone pain, and musculoskeletal effects.

Less Frequent

• Acute myocardial infarction
• Dyspnea
• Fracture
• Hypertension
• Influenza
• Osteopenia
• Osteoporosis

Rare or Very Rare

• Abnormal hepatic function tests
• Anaphylaxis
• Angioedema
• Cerebrovascular accident
• Endometrial hyperplasia
• Erythema multiforme
• Hepatitis
• Hypersensitivity drug reaction
• Leukopenia
• Ovarian cyst
• Stevens-johnson syndrome
• Tendon rupture
• Tenosynovitis
• Thromboembolic disorder
• Toxic epidermal necrolysis

More Frequent

• Arthralgia
• Dizziness
• Drug-induced hot flash
• Edema
• Flushing
• General weakness
• Headache disorder
• Hypercholesterolemia
• Hyperhidrosis
• Nausea
• Weight gain

Less Frequent

• Abdominal pain with cramps
• Abnormal vaginal bleeding
• Alopecia
• Arthritis
• Back pain
• Bone pain
• Chest pain
• Constipation
• Cough
• Depression
• Diarrhea
• Drowsy
• Fatigue
• Insomnia
• Mastalgia
• Musculoskeletal pain
• Myalgia
• Pain in extremities
• Peripheral edema
• Pruritus of skin
• Skin rash
• Symptoms of anxiety
• Vomiting
• Vulvovaginal dryness
• Weight loss

Rare or Very Rare

• Anorexia
• Blurred vision
• Carpal tunnel syndrome
• Cataracts
• Dry skin
• Dysesthesia
• Dysgeusia
• Increased appetite
• Memory impairment
• Nervousness
• Palpitations
• Tendonitis
• Trigger finger
• Urinary tract infection
• Urticaria
• Vaginal discharge
• Xerostomia

No enhanced messaging available.

The manufacturer states that safety and efficacy of letrozole in pediatric patientshave not been established.

Adverse effects on bone (bone maturation, BMD) and neuroendocrine and reproductive development disorders of the hypothalamic-pituitary axis were reported following administration of letrozole 0.003-0.3 mg/kg daily in young rats (exposures less than that expected at the recommended human adult dosage) for 12 weeks beginning on postnatal day 7.

Letrozole is contraindicated in women who are pregnant since the drug can cause fetal toxicity when administered to pregnant women. The manufacturer states that a pregnancy test should be performed prior to initiation of letrozole therapy in females of reproductive potential and that such women should be advised to use effective contraceptive methods while receiving the drug and for at least 3 weeks after discontinuance of the drug. If letrozole is administered during pregnancy or if the patient becomes pregnant while receiving the drug, inform the patient of the potential hazard to the fetus.

Spontaneous abortion and congenital birth defects have been reported during postmarketing experience when the drug was used in pregnant women; however, postmarketing reports on letrozole use during pregnancy are insufficient to inform a drug-associated risk of adverse pregnancy-related outcomes. In animal reproduction studies, letrozole administered to pregnant rats and rabbits during organogenesis was associated with increased pregnancy loss (increased postimplantation loss, increased resorption, and decreased number of live fetuses) and teratogenicity (skeletal and renal malformations) at dosages approximately 0.1 times the maximum recommended human dosage on a mg/m2 basis.

It is not known whether letrozole is distributed into human milk or if the drug has any effects on nursing infants or on milk production. Because many drugs are distributed into milk and because impaired reproductive performance has been observed in male offspring of lactating rats and letrozole has the potential to cause serious adverse reactions in nursing infants, women should be advised to discontinue breast-feeding during letrozole therapy and for at least 3 weeks after discontinuance of the drug.

The manufacturer makes no specific dosage recommendations for geriatric patients.

In the clinical trial evaluating letrozole as initial adjuvant therapy for early-stage breast cancer, 36% of patients were 65 years of age or older at enrollment, while 12% were 75 years of age or older. Adverse effects generally occurred more frequently in geriatric patients regardless of their assigned study treatment; however, no overall differences in safety and efficacy of letrozole versus tamoxifen were observed between geriatric patients and younger adults.

In the clinical trial evaluating letrozole as extended adjuvant therapy for early-stage breast cancer, 41% of patients were 65 years of age or older at enrollment, while 12% were 75 years of age or older. Although no overall differences in safety or efficacy were observed between geriatric patients and younger adults, and other clinical experience revealed no evidence of age-related differences, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.

In clinical trials evaluating letrozole as first-line or second-line therapy for advanced or metastatic breast cancer, about one-third of patients were 70 years of age or older (median age: 64-65 years). Among patients receiving letrozole as first-line therapy in a clinical trial, higher response rate and longer time to tumor progression were observed in geriatric patients (70 years or older) compared with younger patients.