Letrozole

The recommended dose is 2.5 mg once daily with or without food. Patients with severe liver impairment should receive 2.5 mg every other day.

Before receiving letrozole, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to any ingredient in letrozole
• have high cholesterol
• have osteoporosis
• have liver disease
• have not gone through menopause
• are pregnant or breastfeeding

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Take letrozole exactly as prescribed. 

Letrozole comes in tablet form and is taken once daily, with or without food.

If this medication upsets your stomach, try taking it with food and try to take letrozole at the same time each day.

If you miss a dose, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of letrozole at the same time.

This medication may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

This medicine can pass into body fluids (urine, feces, vomit). Caregivers should wear rubber gloves while cleaning up a patient's body fluids, handling contaminated trash or laundry or changing diapers. Wash hands before and after removing gloves. Wash soiled clothing and linens separately from other laundry.

Storage

Oral

25°C (may be exposed to 15–30°C).1

In the U.S.

• Femara

Available Dosage Forms:

• Tablet

Therapeutic Class: Antineoplastic Agent

Pharmacologic Class: Aromatase Inhibitor

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For letrozole, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to letrozole or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of letrozole in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of letrozole in the elderly. However, elderly patients are more likely to have age-related liver disease, which may require an adjustment in the dose for patients receiving letrozole.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking letrozole, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using letrozole with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Ceritinib
• Cilostazol
• Clarithromycin
• Idelalisib
• Tegafur

Using letrozole with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Tamoxifen

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of letrozole. Make sure you tell your doctor if you have any other medical problems, especially:

• Bone problems (e.g., osteoporosis) or
• Hypercholesterolemia (high cholesterol or fat in the blood)—Use with caution. May make these conditions worse.

• Cirrhosis or
• Liver disease, severe—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

• Premenopausal women (have menstrual cycles)—Should not be used in these patients.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Bone fracture
• breast pain
• chest pain
• chills, fever, or flu-like symptoms
• mental depression
• shortness of breath
• swelling of the feet or lower legs

• Continuing or severe nervousness
• cough
• dizziness or lightheadedness
• fainting
• fast heartbeat
• heart attack
• increased sweating
• nausea
• pain in the chest, groin, or legs, especially the calves
• severe and sudden, unexplained shortness of breath
• severe, sudden headache
• slurred speech
• sudden loss of coordination
• sudden, severe weakness or numbness in the arm or leg
• vaginal bleeding
• vision changes

• Black, tarry stools
• blindness
• blurred vision
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• chest discomfort
• decreased vision
• dilated neck veins
• extreme fatigue
• increased need to urinate
• irregular breathing
• irregular heartbeat
• painful or difficult urination
• passing urine more often
• sore throat
• sores, ulcers, or white spots on the lips or in the mouth
• swollen glands
• unusual bleeding or bruising
• unusual tiredness or weakness
• weight gain
• wheezing
• white or brownish vaginal discharge

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Back pain
• bone pain
• hot flashes (sudden sweating and feeling of warmth)
• joint pain
• muscle pain

• Anxiety
• confusion
• constipation
• diarrhea
• dry mouth
• headache
• increased thirst
• loss of appetite or weight loss
• metallic taste
• skin rash or itching
• sleepiness
• spinning or whirling sensation causing loss of balance
• stomach pain or upset
• trouble sleeping
• vomiting
• weakness

• Bad, unusual, or unpleasant (after) taste and thirst
• being forgetful
• change in taste
• dryness of the skin
• hair loss
• hives or welts
• increased appetite
• irritability
• nervousness
• red, sore eyes
• redness of the skin
• swelling or inflammation of the mouth

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• It is used to treat breast cancer in women after change of life.
• It may be given to you for other reasons. Talk with the doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Feeling tired or weak.
• Hot flashes.
• Headache.
• Dizziness.
• Upset stomach or throwing up.
• Cough.
• Back pain.
• Muscle or joint pain.
• Hard stools (constipation).
• Loose stools (diarrhea).
• Night sweats.
• Sweating a lot.
• Not able to sleep.
• Weight gain or loss.
• Belly pain.
• Hair loss.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Pregnancy

Risk Summary

Based on post-marketing reports, findings from animal studies and the mechanism of action, Letrozole can cause fetal harm and is contraindicated for use in pregnant women. In post-marketing reports, use of Letrozole during pregnancy resulted in cases of spontaneous abortions and congenital birth defects; however, the data are insufficient to inform a drug-associated risk. [see Contraindications (4), Warnings and Precautions (5.6), Postmarketing Experience (6.2), and Clinical Pharmacology (12.1)].

In animal reproduction studies, administration of Letrozole to pregnant animals during organogenesis resulted in increased post-implantation pregnancy loss and resorption, fewer live fetuses, and fetal malformation affecting the renal and skeletal systems in rats and rabbits at doses approximately 0.1 times the daily maximum recommended human dose (MRHD) on a mg/m2basis (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

Data

Animal Data

In a fertility and early embryonic development toxicity study in female rats, oral administration of Letrozole starting 2 weeks before mating until pregnancy day 6 resulted in an increase in pre-implantation loss at doses ≥ 0.003 mg/kg/day (approximately 0.01 times the maximum recommended human dose on a mg/m2basis).

In an embryo-fetal developmental toxicity study in rats, daily administration of oral Letrozole during the period of organogenesis at doses ≥ 0.003 mg/kg (approximately 0.01 time the maximum recommended human dose on a mg/m2 basis) resulted in embryo-fetal toxicity including intrauterine mortality, increased resorptions and postimplantation loss, decreased numbers of live fetuses and fetal anomalies including absence and shortening of renal papilla, dilation of ureter, edema and incomplete ossification of frontal skull and metatarsals. Letrozole was teratogenic to rats at a dose of 0.03 mg/kg (approximately 0.01 times the maximum recommended human dose on a mg/m2 basis) and caused fetal domed head and cervical/centrum vertebral fusion.

In the embryo-fetal development toxicity study in rabbits, daily administration of oral Letrozole during the period of organogenesis at doses ≥ 0.002 mg/kg (approximately 0.01 times the maximum recommended human dose on a mg/m2 basis) resulted in embryo-fetal toxicity including intrauterine mortality, increased resorption, increased postimplantation loss and decreased numbers of live fetuses. Fetal anomalies included incomplete ossification of the skull, sternebrae, and fore- and hind legs.

Lactation

Risk Summary

It is not known if Letrozole is present in human milk. There are no data on the effects of Letrozole on the breastfed infant or milk production. Exposure of lactating rats to Letrozole was associated with impaired reproductive performance of the male offspring (see Data). Because of the potential for serious adverse reactions in breastfed infants from Letrozole, advise lactating women not to breastfeed while taking Letrozole and for at least 3 weeks after the last dose.

Data

Animal Data

In a postnatal developmental toxicity study in lactating rats, Letrozole was administered orally at doses of 1, 0.003, 0.03 or 0.3 mg/kg/day on day 0 through day 20 of lactation. The reproductive performance of the male offspring was impaired at Letrozole dose as low as 0.003 mg/kg/day (approximately 0.01 times the maximum recommended human dose on a mg/m2 basis), as reflected by decreased mating and pregnancy ratios. There were no effects on the reproductive performance of female offspring.

Females and Males of Reproductive Potential

Pregnancy Testing

Based on animal studies, Letrozole can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Females of reproductive potential should have a pregnancy test prior to starting treatment with Letrozole.

Contraception

Females

Based on animal studies, Letrozole can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with Letrozole and for at least 3 weeks after the last dose.

Infertility

Females

Based on studies in female animals, Letrozole may impair fertility in females of reproductive potential [see Nonclinical Toxicology (13.1)].

Males

Based on studies in male animals, Letrozole may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].

Pediatric Use

The safety and effectiveness in pediatric patients have not been established.

Letrozole administration to young (postnatal day 7) rats for 12 weeks duration at 0.003, 0.03, 0.3 mg/kg/day by oral gavage resulted in adverse skeletal/growth effects (bone maturation, bone mineral density) and neuroendocrine and reproductive developmental perturbations of the hypothalamic-pituitary axis. Administration of 0.3 mg/kg/day resulted in AUC values that were similar to the AUC in adult patients receiving the recommended dose of 2.5 mg/day. Decreased fertility was accompanied by hypertrophy of the hypophysis and testicular changes that included degeneration of the seminiferous tubular epithelium and atrophy of the female reproductive tract. Young rats in this study were allowed to recover following discontinuation of Letrozole treatment for 42 days. Histopathological changes were not reversible at clinically relevant exposures.

Geriatric Use

The median age of patients in all studies of first-line and second-line treatment of metastatic breast cancer was 64 to 65 years. About 1/3 of the patients were greater than or equal to 70 years old. In the first-line study, patients greater than or equal to 70 years of age experienced longer time to tumor progression and higher response rates than patients less than 70.

For the extended adjuvant setting (MA-17), more than 5,100 postmenopausal women were enrolled in the clinical study. In total, 41% of patients were aged 65 years or older at enrollment, while 12% were 75 or older. In the extended adjuvant setting, no overall differences in safety or efficacy were observed between these older patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

In the adjuvant setting (BIG 1-98), more than 8,000 postmenopausal women were enrolled in the clinical study. In total, 36% of patients were aged 65 years or older at enrollment, while 12% were 75 or older. More adverse reactions were generally reported in elderly patients irrespective of study treatment allocation. However, in comparison to tamoxifen, no overall differences with regards to the safety and efficacy profiles were observed between elderly patients and younger patients. 

2.5 mg tablets - dark yellow, round, biconvex, film-coated tablets debossed with “511” on one side and plain on other side.
 
Bottles of 30’s with Child Resistant Closure………………...NDC 62756-511-83
Bottles of 100’s with Child Resistant Closure…………….....NDC 62756-511-88
Bottles of 100’s with Non Child Resistant Closure ………....NDC 62756-511-08
Bottles of 1000’s with Non Child Resistant Closure……… . NDC 62756-511-18
 

Store at 20° to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Dispense in tight container (USP).

• Femara

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

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

Administer orally without regard to meals.

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