Drug Formulary information is intended for use by healthcare professionals. It is not intended to be medical advice. Some of the information, including information about funding for cancer drugs, does not apply to all patients. Cancer treatment plans are unique to each patient. If you are a patient, please speak with your healthcare team to understand how this information applies to you.
letrozole
Letrozole is a selective non-steroidal aromatase inhibitor and inhibits the conversion of adrenally generated androstenedione to estrone or estradiol by aromatase in peripheral tissues (e.g., adipose tissue), as well as in tumours. It significantly lowers serum estradiol concentration in postmenopausal women and has no detectable effect on thyroid function, formation of adrenal corticosteroids or aldosterone and plasma androgen levels.
| Bioavailability |
99.9% |
| Effects with food |
Not significantly affected by food |
| Time to reach steady state |
2 to 6 weeks |
Rapidly and extensively distributed into tissues.
| PPB |
60% (albumin) |
The major route of elimination is via metabolism (CYP 2A6 and 3A4) to a pharmacologically inactive carbinol metabolite (CGP44645), followed by glucuronidation. Doses above 2.5 mg daily produce over-proportional increases in exposure, possibly due to a saturation of metabolic elimination processes.
| Active metabolites |
No |
| Inactive metabolites |
Yes |
Letrozole and metabolites are excreted mainly via the kidneys.
| Urine |
88% of dose within 2 weeks (mostly as metabolites) |
| Feces | 4% of dose within 2 weeks |
| Half-life |
2 to 5 days (terminal) |
- For first-line treatment of advanced hormone-receptor positive breast cancer in postmenopausal women
- For hormonal treatment of advanced/metastatic hormone-receptor positive breast cancer after relapse or disease progression, in women with natural or artificially-induced postmenopausal endocrine status, who have previously been treated with anti-estrogens
- For adjuvant treatment of postmenopausal women with hormone-receptor positive invasive early breast cancer*
- For the extended adjuvant treatment of hormone-receptor positive invasive early breast cancer in postmenopausal women who have received approximately 5 years of prior standard adjuvant tamoxifen therapy*
Notes:
*Marketing approvals are based on disease-free survival as no improvement in overall survival was shown. The risk of death in node-negative patients was increased compared to placebo in the extended adjuvant setting.
Other Uses:
- Ovarian cancer
Emetogenic Potential:
The following table contains adverse events reported in > 2% of patients in an extended adjuvant treatment study of early breast cancer in postmenopausal women. It also includes severe, life-threatening, or post-marketing adverse events from other sources.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Arrhythmia (4%) | E | |||
| Arterial thromboembolism (3%) | D | ||||
| Cardiotoxicity (rare) | D | ||||
| Hypertension (8%) | E | ||||
| Venous thromboembolism (1%) | D | ||||
| Dermatological | Alopecia (6%) | D | |||
| Rash (2%) (may be severe) | E | ||||
| Gastrointestinal | Abdominal pain (5%) | E | |||
| Anorexia (8%) | E | ||||
| Constipation (18%) | I E | ||||
| Diarrhea (8%) | I E | ||||
| Dyspepsia (5%) | I | ||||
| Nausea, vomiting (18%) | I E | ||||
| Weight changes (3%) | E | ||||
| General | Edema (28%) | E | |||
| Fatigue (47%) | E | ||||
| Hematological | Leukopenia (rare) | E | |||
| Hepatobiliary | ↑ LFTs (rare) | E | |||
| Hypersensitivity | Hypersensitivity (rare) | I | |||
| Metabolic / Endocrine | ↑ Cholesterol (23%) | D | |||
| Hyperglycemia (3%) | E | ||||
| Musculoskeletal | Fracture (13%) | D | |||
| Musculoskeletal pain (42%) | E | ||||
| Osteoporosis (15%) | D | ||||
| Nervous System | Anxiety (4%) | E | |||
| Depression (7%) | E | ||||
| Dizziness (22%) | E | ||||
| Headache (32%) | E | ||||
| Insomnia (9%) | E | ||||
| Memory impairment (2%) | E | ||||
| Ophthalmic | Cataract (<1%) | D | |||
| Eye disorders (Blurred vision, eye irritation; rare) | D | ||||
| Reproductive and breast disorders | Estrogen deprivation symptoms (up to 61%) | E | |||
| Vaginal dryness (8%) | E | ||||
| Respiratory | Cough, dyspnea (9%) | E | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for letrozole include estrogen deprivation symptoms, fatigue, musculoskeletal pain, headache, edema, ↑ cholesterol, dizziness, constipation, nausea, vomiting, and osteoporosis.
Letrozole, when used in the metastatic setting, is associated with a lower overall incidence of thromboembolic events as compared to tamoxifen. When compared to megestrol, lower weight gain and vaginal bleeding have been observed with letrozole, but higher incidences of hot flashes, headache, rash, nausea, musculoskeletal pain, other gastrointestinal effects and peripheral edema were reported with letrozole.
In the adjuvant early breast cancer trial, there were higher rates of osteoporosis, fractures, hypercholesterolemia, arthralgia, myalgia, MI and CHF when compared to tamoxifen, but reduced incidences of thromboembolic events, uterine polyps, vaginal hemorrhage and endometrial hyperplasia.
In the extended adjuvant study (median treatment duration of 60 months), significantly higher rates of cardiovascular events (including arterial or venous thromboembolism) were observed in the letrozole group (9.8%), as compared to placebo (7%; median treatment duration 60 months). A significantly higher incidence of osteoporosis was observed in the patients who received letrozole (14.5%) than those who received placebo (7.8%).
Refer to protocol by which patient is being treated.
Assess patient’s risk factors for osteoporosis and consider calcium and vitamin D supplements and bisphosphonates where appropriate. Refer patients to the Bone Health During Cancer Treatment pamphlet for more information.
Dosage in myelosuppression: No dosage adjustment required.
| Hepatic Impairment | Letrozole Dose |
|
Mild to Moderate (Child-Pugh Class A or Class B) |
No dose adjustment needed, although exposure may ↑ by 37%. |
|
Severe (Child-Pugh Class C) |
No data. Monitor patients closely and consider dose modification. |
| Creatinine Clearance (mL/min) | Letrozole Dose |
| ≥ 10 | No dose adjustment needed. |
| < 10 | No data. Consider potential benefit-risk carefully. |
No dosage adjustment required. Older patients have an increased risk of osteoporosis and fracture.
CONTRAINDICATED in patients under 18 years of age. Safety and efficacy not established.
- Tablets should be taken with a glass of water, with or without food, at around the same time every day.
- Tablets should not be crushed or chewed.
- Missed doses should be taken as soon as possible, but should be skipped if within a few hours (e.g. within 2 or 3 hours) of the next planned dose. Do not double the dose due to over-proportionality of exposure at doses above 2.5 mg daily.
- Store tablets at room temperature (15-30°C).
- Patients with known hypersensitivity to letrozole, or any of its components, or other aromatase inhibitors.
- Premenopausal women*
- Pregnant and/or breastfeeding women
- Patients under 18 years of age
*not receiving ovarian suppression
Other Warnings/Precautions:
- Letrozole is not indicated in hormone-receptor negative disease.
- Use of letrozole in the adjuvant setting should be carefully considered for patients with osteoporosis or risk factors for cardiovascular events or osteoporosis.
- Carefully assess benefit-risk before using letrozole as extended adjuvant treatment for early breast cancer patients with low recurrence risk, as an increase in deaths was observed in node-negative patients in the letrozole arm as compared to patients on placebo.
- Some brands contain lactose; carefully consider use in patients with hereditary galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption.
Other Drug Properties:
-
Carcinogenicity:
Unknown
An increased incidence of benign ovarian stromal tumours was observed in animal studies.
-
Mutagenicity:
No
-
Clastogenicity:
No
-
Embryotoxicity:
Yes
-
Fetotoxicity:
Yes
Spontaneous abortions and congenital anomalies have been reported.
-
Teratogenicity:
Yes
Letrozole is contraindicated in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least:
- 20 days after the last dose for females (product monograph recommendation) or
- 6 months after the last dose for males (general recommendation).
-
Breastfeeding:
Contraindicated
-
Fertility effects:
Probable
Administration of letrozole to female rats resulted in decreased mating/pregnancy ratios and increased pre-implantation loss. Administration of letrozole to male rats resulted in decreased sperm count and motility and testicular changes; severe reductions in the number of sperm-positive and pregnant females were evident.
Administration with cimetidine had no significant effect on letrozole’s pharmacokinetics, and letrozole had no significant effect on warfarin’s pharmacokinetic parameters.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Tamoxifen, other anti-estrogens, estrogen-containing or estrogenic agents | May ↓ letrozole efficacy; tamoxifen ↓ letrozole levels by 38% on average | Unknown | Avoid concomitant use |
| CYP3A4 inhibitors (i.e. ketoconazole, clarithromycin, ritonavir, fruit or juice from grapefruit, Seville oranges or starfruit) | ↑ letrozole concentration or adverse effects (theoretical) | ↓ letrozole metabolism | Caution with strong CYP3A4 inhibitors (theoretical) |
| CYP2A6 inhibitors (e.g. methoxsalen, tranylcypromine) | ↑ letrozole concentration or adverse effects (theoretical) | ↓ letrozole metabolism | Caution with strong CYP2A6 inhibitors (theoretical) |
| CYP3A4 inducers (i.e. phenytoin, rifampin, dexamethasone, carbamazepine, phenobarbital, St. John’s Wort, etc) | ↓ letrozole concentration or efficacy (theoretical) | ↑ letrozole metabolism | Caution with strong CYP3A4 inducers (theoretical) |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
Serum cholesterol and lipids evaluation |
Baseline and as clinically indicated |
Bone mineral density |
Baseline and as clinically indicated |
LH, FSH and/or estradiol levels (in patients whose menopausal status is unclear or who become amenorrheic after chemotherapy) |
Baseline and regularly during the first 6 months of treatment |
Clinical toxicity assessment of fatigue, estrogen deprivation symptoms, musculoskeletal, cardiovascular, thromboembolism, GI and GU effects, ophthalmic, dermatologic effects |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
McEvoy GK, editor. AHFS Drug Information 2013. Bethesda: American Society of Health-System Pharmacists, p. 1104-9.
November 2020 Updated dosing section
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.
Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.
While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.
CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.