Letrozole Indications is a nonsteroidal inhibitor of estrogen synthesis with antineoplastic activity. As a third-generation aromatase inhibitor, letrozole selectively and reversibly inhibits aromatase, which may result in growth inhibition of estrogen-dependent breast cancer cells. Aromatase, a cytochrome P-450 enzyme localized to the endoplasmic reticulum of the cell and found in many tissues including those of the premenopausal ovary, liver, and breast, catalyzes the aromatization of androstenedione and testosterone into estrone and estradiol, the final step in estrogen biosynthesis.
Mechanism of Action of Letrozole
Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system; it inhibits the conversion of androgens to estrogens. In adult nontumor- and tumor-bearing female animals, letrozole is as effective as ovariectomy in reducing uterine weight, elevating serum Leuteinizing hormone (LH), and causing the regression of estrogen-dependent tumors. In contrast to ovariectomy, treatment with letrozole does not lead to an increase in serum (follicle stimulating hormone (FSH). Letrozole selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis.
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Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system; it inhibits the conversion of androgens to estrogens. In adult nontumor- and tumor-bearing female animals, letrozole is as effective as ovariectomy in reducing uterine weight, elevating serum LH, and causing the regression of estrogen-dependent tumors. In contrast to ovariectomy, treatment with letrozole does not lead to an increase in serum FSH. Letrozole selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis. Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues. Treatment of women with letrozole significantly lowers serum estrone, estradiol and estrone sulfate and has not been shown to significantly affect adrenal corticosteroid synthesis, aldosterone synthesis, or synthesis of thyroid hormones.
Letrozole Indications
- For the extended adjuvant treatment of early breast cancer in postmenopausal women who have received 5 years of adjuvant tamoxifen therapy. Also for first-line treatment of postmenopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer. Also indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy.
- Letrozole is a nonsteroidal inhibitor of aromatase which effectively blocks estrogen synthesis in postmenopausal women and is used as a therapy of estrogen receptor-positive breast cancer, usually after resection and after the failure of tamoxifen. Letrozole has been associated with a low rate of serum enzyme elevations during therapy and rare instances of clinically apparent liver injury.
- Letrozole is indicated for first-line treatment of postmenopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer. Letrozole is also indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy.
- Female Infertility
- Breast Cancer
- Breast Cancer, Adjuvant
- Breast Cancer, Metastatic
- Advanced Breast Cancer
- Anovulatory cycle
- Ovarian Epithelial Cancer
- Stage I Breast Carcinoma
- Advanced HR + HER2 – breast cancer
- Metastatic HR + HER2 – breast cancer
FDA Level
- Letrozole is approved to be used alone or with another drug to treat: Breast cancer in postmenopausal women who have any of the following types of breast cancer Early stage, hormone receptorâ positive(HR+) breast cancer in women who have already received other treatment.
- Early-stage breast cancer that has been treated with tamoxifen citrate for at least five years.
- Breast cancer that is locally advanced or has metastasized(spread to other parts of the body), is HER2 positive(HER2+) and HR+.
- Breast cancer that is locally advanced or has metastasized and it is not known whether the cancer is HR+ or hormone receptor negative(HR-).
Advanced breast cancer that has gotten worse after antiestrogen therapy.
Letrozole is also being studied in the treatment of other types of cancer. - Letrozole is indicated for first-line treatment of postmenopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer. Letrozole is also indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy.
Contraindications of Letrozole
- Letrozole is contraindicated in women having a pre-menopausal hormonal status, during pregnancy and lactation.[rx]
- High cholesterol
- Disorder of the Blood Vessels of the Brain
- Obstruction of a Blood Vessel by a Blood Clot
- Hardening of the Liver
- Severe liver disease
- Osteoporosis
- Decreased Calcification or Density of Bone
- High Amount of Bilirubin in the Blood
- Abnormal liver function tests
- Pregnancy
- A mother who is producing milk and breastfeeding
- Increased Cardiovascular Event Risk
- Allergies to Letrozole Analogues
Dosage of Letrozole
- Strengths: 2.5 mg
Breast Cancer
- 2.5 mg orally once a day
Duration of Therapy
- Adjuvant and Extended Adjuvant Settings: Optimal duration is unknown; discontinue treatment at relapse.
-Advanced Disease: Until tumor progression is evident.
Breast Cancer – Adjuvant
- 2.5 mg orally once a day
Duration of Therapy
- Adjuvant and Extended Adjuvant Settings: Optimal duration is unknown; discontinue treatment at relapse.
-Advanced Disease: Until tumor progression is evident.
Side Effects of Letrozole
The Most Common
- abdominal pain
- bone fractures
- increased blood pressure
- increased cholesterol levels
- signs of infection (e.g., severe fever, chills, mouth ulcers, shortness of breath, sudden lack of energy)
- signs of depression (such as feeling sad, losing interest in things you used to enjoy, weight changes, changes in sleep habits, feelings of guilt or worthlessness, thoughts of suicide)
- signs of high blood sugar (e.g., frequent urination, increased thirst, excessive eating, unexplained weight loss, poor wound healing, infections, fruity breath odor)
- signs of liver problems (e.g., yellow skin and eyes, nausea, loss of appetite, dark-colored urine)
- unusual vaginal bleeding
Less Common
- Bone fracture
- breast pain
- chest pain
- constipation
- diarrhea
- dizziness
- dry skin
- fatigue
- headache
- hot flushes
- increase or loss of appetite
- increased sweating
- joint stiffness
- chills, fever, or flu-like symptoms
- mental depression
- swelling of the feet or lower legs
Rare
- 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 troubled breathing
- severe, sudden headache
- slurred speech
- sudden loss of coordination
- sudden, severe weakness or numbness in the arm or leg
Drug Interactions of Letrozole
Letrozole may interact with following drugs, supplements & may change the efficacy of drugs
- “azole” antifungals (e.g., itraconazole, ketoconazole, voriconazole)
- BCG vaccine
- calcium channel blockers (e.g., diltiazem, nicardipine, verapamil)
- carbamazepine
- carvedilol
- cimetidine
- clozapine
- cyclosporine
- desipramine
- dexamethasone
- diabetes medications (e.g., chlorpropamide, glipizide, glyburide, insulin, metformin, rosiglitazone)
- hepatitis protease inhibitors (e.g., boceprevir, simeprevir)
- fosphenytoin
- grapefruit juice
- haloperidol
- HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs; e.g., delavirdine, efavirenz, etravirine, nevirapine)
- HIV protease inhibitors (atazanavir, darunavir, lopinavir, ritonavir)
- macrolide antibiotics (e.g., azithromycin, clarithromycin, erythromycin)
- metronidazole
- mifepristone
- mirabegron
- modafinil
- norfloxacin
- oxcarbazepine
- pentobarbital
- phenobarbital
- phenytoin
- prazosin
- progesterone
- propranolol
- protein kinase inhibitors (e.g., crizotinib, dabrafenib, imatinib, lapatinib, nilotinib)
- St. John’s Wort
- tacrolimus
- tamoxifen
- tocilizumab
- trastuzumab
Pregnancy Category
AU TGA pregnancy category: D
US FDA pregnancy category: X
Pregnancy
It is suspected that the use of letrozole during pregnancy could cause miscarriages and other serious problems. It is not intended to be taken by women who have not reached menopause. This medication should not be taken during pregnancy unless the benefits outweigh the risks. Any woman taking this medication who may become pregnant should practice effective birth control and contact her doctor immediately if pregnancy is suspected while taking this medication.
Lactation
It is not known if letrozole passes into breast milk. If you breastfeeding feeding mother and are taking this medication, it may affect your baby. Talk to your doctor about whether you should continue breast-feeding. The safety and effectiveness of this medication have not been established for children. Children under 18 years of age should not use this medication.
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