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Letrozole

Pronunciation

Pronunciation

(LET roe zole)

Index Terms

  • CGS-20267

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Femara: 2.5 mg

Generic: 2.5 mg

Brand Names: U.S.

  • Femara

Pharmacologic Category

  • Antineoplastic Agent, Aromatase Inhibitor

Pharmacology

Nonsteroidal competitive inhibitor of the aromatase enzyme system which 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 (estrone, estradiol and estrone sulfate) levels. Does not affect synthesis of adrenal or thyroid hormones, aldosterone, or androgens.

Absorption

Rapid and well absorbed; not affected by food

Distribution

Vd: ~1.9 L/kg

Metabolism

Hepatic via CYP3A4 and 2A6 to an inactive carbinol metabolite

Excretion

Urine (90%; 6% as unchanged drug, 75% as glucuronide carbinol metabolite, 9% as unidentified metabolites)

Time to Peak

Steady state, plasma: 2 to 6 weeks; steady state serum concentrations are 1.5 to 2 times higher than single-dose values. In girls 3 to 9 years, steady state concentrations were 25% to 67% that of the mean adult values (Feuillan 2007)

Half-Life Elimination

Terminal: ~2 days

Protein Binding

Plasma: Weak

Special Populations: Hepatic Function Impairment

AUC was 37% higher in patients with mild to moderate hepatic impairment (Child-Pugh class A and B). AUC increased 2-fold and systemic Cl reduced 47% in patients with severe hepatic impairment (Child-Pugh class C).

Use: Labeled Indications

Breast cancer in postmenopausal women: Adjuvant treatment of hormone receptor-positive early breast cancer, extended adjuvant treatment of early breast cancer after 5 years of tamoxifen; treatment of advanced breast cancer with disease progression following antiestrogen therapy; first-line treatment of hormone receptor–positive or hormone receptor-unknown, locally-advanced, or metastatic breast cancer

Use: Unlabeled

Infertility/ovulation stimulation in anovulatory women with polycystic ovarian syndrome (PCOS); treatment of ovarian (epithelial) cancer.

Contraindications

Use in women who are or may become pregnant

Canadian labeling: Additional contraindications (not in U.S. labeling): Hypersensitivity to letrozole, other aromatase inhibitors, or any component of the formulation; use in patients <18 years of age; breast-feeding

Dosing: Adult

Breast cancer, advanced (first- or second-line treatment): Females: Postmenopausal: Oral: 2.5 mg once daily; continue until tumor progression

Breast cancer, early (adjuvant treatment): Females: Postmenopausal: Oral: 2.5 mg once daily for a planned duration of 5 years; discontinue at relapse. Note: American Society of Clinical Oncology (ASCO) guidelines for Adjuvant Endocrine Therapy of Hormone Receptor–Positive Breast Cancer (Focused Update) recommend a maximum duration of 5 years of aromatase inhibitor therapy for postmenopausal women; aromatase inhibitors may be combined with tamoxifen for a total duration of up to 10 years of endocrine therapy. Refer to the guidelines for specific recommendations based on menopausal status and tolerability (Burstein 2014).

Breast cancer, early (extended adjuvant treatment): Females: Postmenopausal: Oral: 2.5 mg once daily for a planned duration of 5 years (after 5 years of tamoxifen); discontinue at relapse. In clinical trials, letrozole was initiated within 3 months of discontinuing tamoxifen (Goss 2003; Jin 2012). Note: ASCO guidelines for Adjuvant Endocrine Therapy of Hormone Receptor–Positive Breast Cancer (Focused Update) recommend a maximum duration of 5 years of aromatase inhibitor therapy for postmenopausal women; aromatase inhibitors may be combined with tamoxifen for a total duration of up to 10 years of endocrine therapy. Refer to the guidelines for specific recommendations based on menopausal status and tolerability (Burstein 2014).

Off-label combinations:

Breast cancer, advanced, estrogen receptor–positive, HER2-negative: Females: Oral: 2.5 mg once daily (in combination with palbociclib) until disease progression or unacceptable toxicity (Finn 2015)

Breast cancer, metastatic, hormone receptor–positive, HER2-positive: Females: Oral: 2.5 mg once daily (in combination with lapatinib) until disease progression or unacceptable toxicity (Johnston 2009)

Infertility/ovulation stimulation in anovulatory women with polycystic ovarian syndrome (PCOS; off-label use): Oral: 2.5 to 7.5 mg daily on cycle days 3 to 7 (Franik 2014; Legro 2013; Legro 2014; Misso 2012). Up to 5 treatment cycles may be administered with the dose increased in subsequent cycles for nonresponse or poor ovulatory response as determined by progesterone levels; maximum dose 7.5 mg daily (Legro 2014). Additional trials may be necessary to further define the routine use of letrozole in infertile women with PCOS.

Ovarian (epithelial) cancer (off-label use): Oral: 2.5 mg once daily; continue until disease progression (Ramirez 2008)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl ≥10 mL/minute: No dosage adjustment necessary.

CrCl <10 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Hepatic Impairment

U.S. labeling:

Mild to moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary.

Severe impairment (Child-Pugh class C) and cirrhosis: 2.5 mg every other day

Noncirrhotic patients with elevated bilirubin: There are no dosage adjustments provided in the manufacturer’s labeling (effect has not been determined).

Canadian labeling:

Mild to moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary.

Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer’s labeling (insufficient data). Monitor closely.

Administration

Administer orally with or without food. Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Dietary Considerations

Calcium and vitamin D supplementation are recommended.

Storage

Store at room temperature of 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Artesunate: CYP2A6 Inhibitors may decrease serum concentrations of the active metabolite(s) of Artesunate. CYP2A6 Inhibitors may increase the serum concentration of Artesunate. Avoid combination

CYP2A6 Substrates: CYP2A6 Inhibitors (Strong) may decrease the metabolism of CYP2A6 Substrates. Consider therapy modification

Methadone: Aromatase Inhibitors may increase the serum concentration of Methadone. Monitor therapy

Tamoxifen: May decrease the serum concentration of Letrozole. Monitor therapy

Tegafur: CYP2A6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Tegafur. Specifically, CYP2A6 inhibitors may inhibit the conversion of tegafur into its active metabolite, 5-fluorouracil. Avoid combination

Adverse Reactions

>10%:

Cardiovascular: Edema (7% to 18%)

Central nervous system: Headache (4% to 20%), dizziness (3% to 14%), fatigue (8% to 13%)

Endocrine & metabolic: Hypercholesterolemia (3% to 52%), hot flashes (6% to 50%)

Gastrointestinal: Nausea (9% to 17%), weight gain (2% to 13%), constipation (2% to 11%)

Neuromuscular & skeletal: Weakness (4% to 34%), arthralgia (8% to 25%), arthritis (7% to 25%), bone pain (5% to 22%), back pain (5% to 18%), bone mineral density decreased/osteoporosis (5% to 15%), bone fracture (10% to 14%)

Respiratory: Dyspnea (6% to 18%), cough (6% to 13%)

Miscellaneous: Diaphoresis (≤24%), night sweats (15%)

1% to 10%:

Cardiovascular: Chest pain (6% to 8%), hypertension (5% to 8%), chest wall pain (6%), peripheral edema (5%); cerebrovascular accident including hemorrhagic stroke, thrombotic stroke (2% to 3%); thromboembolic event including venous thrombosis, thrombophlebitis, portal vein thrombosis, pulmonary embolism (2% to 3%); MI (1% to 2%), angina (1% to 2%), transient ischemic attack

Central nervous system: Insomnia (6% to 7%), pain (5%), anxiety (<5%), depression (<5%), vertigo (<5%), somnolence (3%)

Dermatologic: Rash (5%), alopecia (3% to 5%), pruritus (1%)

Endocrine & metabolic: Breast pain (2% to 7%), hypercalcemia (<5%)

Gastrointestinal: Diarrhea (5% to 8%), vomiting (3% to 7%), weight loss (6% to 7%), abdominal pain (6%), anorexia (1% to 5%), dyspepsia (3%)

Genitourinary: Urinary tract infection (6%), vaginal bleeding (5%), vaginal dryness (5%), vaginal hemorrhage (5%), vaginal irritation (5%)

Neuromuscular & skeletal: Limb pain (4% to 10%), myalgia (7% to 9%)

Ocular: Cataract (2%)

Renal: Renal disorder (5%)

Respiratory: Pleural effusion (<5%)

Miscellaneous: Infection (7%), influenza (6%), viral infection (6%), secondary malignancy (2% to 4%)

<1%, postmarketing, and/or case reports (Limited to important or life-threatening): Anaphylactic reaction, angioedema, arterial thrombosis, cardiac failure, carpal tunnel syndrome, endometrial cancer, endometrial hyperplasia, endometrial proliferation, erythema multiforme, hepatitis, leukopenia, memory impairment, stomatitis, tachycardia, thrombocytopenia, toxic epidermal necrolysis, trigger finger

Warnings/Precautions

Concerns related to adverse effects:

• CNS depression: May cause dizziness, fatigue, and somnolence; patients should be cautioned before performing tasks which require mental alertness (eg, operating machinery or driving).

• Decreased bone mineral density: May cause decreases in bone mineral density (BMD). A decrease in hip BMD by 3.8% from baseline in letrozole-treated patients vs 2% in placebo at 2 years has been demonstrated; however, there was no statistical difference in changes to the lumbar spine BMD scores. Monitor BMD.

• Increased cholesterol: May increase total serum cholesterol. In patients treated with adjuvant therapy and cholesterol levels within normal limits, an increase of ≥1.5 x ULN in total cholesterol has been demonstrated in 8.2% of letrozole-treated patients (25% requiring lipid-lowering medications) vs 3.2% of tamoxifen-treated patients (16% requiring medications). Monitor cholesterol panel; may require antihyperlipidemics.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment; dose adjustment recommended in patients with cirrhosis or severe hepatic dysfunction.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Other warnings/precautions:

• Appropriate use: Not generally indicated for known hormone-receptor negative disease.

Monitoring Parameters

Monitor periodically during therapy: Complete blood counts, thyroid function tests; serum electrolytes, cholesterol, transaminases, and creatinine; blood pressure; bone density

Canadian labeling recommends monitoring LH, FSH, and/or estradiol prior to initiating therapy and regularly for the first 6 months in women whose menopausal status is unclear or who become amenorrheic following chemotherapy. For infertility/ovarian stimulation (off-label use), a pregnancy test is recommended prior to initiation. Midluteal progestin concentrations (in a clinical study, nonresponse to treatment was defined as a progesterone concentration <3 ng/mL during the midluteal phase; poor ovulatory response was defined as progesterone concentrations indicating ovulation but just above the cutoff point) (Legro 2014).

Pregnancy Risk Factor

X

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Letrozole is FDA approved for postmenopausal women only (no clinical benefit for breast cancer has been demonstrated in premenopausal women). Use in women who are or who may become pregnant is contraindicated. Women who are perimenopausal or recently postmenopausal should use adequate contraception until postmenopausal status is fully established.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience asthenia, hot flashes, nausea, back pain, myalgia, arthralgia, constipation, night sweats, hyperhidrosis, insomnia, or weight gain. Have patient report immediately to prescriber angina, tachycardia, severe dizziness, syncope, dyspnea, strength differences from one side to another, difficulty speaking or thinking, change in balance, blurred vision, paresthesia of extremities, extremity discoloration, painful extremities, considerable headache, intolerable osteodynia, vaginal hemorrhaging, depression, chills, pharyngitis, polyuria, dysuria, or severe dyspepsia (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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