Letrozole (Femara) is an anti-estrogen and aromatase inhibitor that is primarily used to treat breast cancer.

Letrozole Uses:

• Breast cancer in postmenopausal women:

  • Prolonged adjuvant treatment for early breast cancer after taking tamoxifen for five years, adjuvant treatment of hormone receptor-positive early breast cancer
  • Aggressive breast cancer therapy with disease progression after oestrogen therapy
  • First-line therapy for breast cancer with hormone receptors that are positive or negative, locally progressed, or metastatic

• Off-Label Use of Letrozole in Adults:

  • Polycystic ovarian syndrome in anovulatory females: infertility/stimulating ovulation
  • Recurrent Ovarian (epithelial) cancer

Letrozole (Femara) Dose in Adults:

Letrozole (Femara) Dose in the treatment of advanced Breast cancer (first- or second-line treatment):

• Females:

  • Postmenopausal:
    • Oral: Continue taking 2.5 mg once daily until tumour development.

Letrozole (Femara) Dose in the treatment of Breast cancer, early (adjuvant treatment):

• Females:

  • Postmenopausal:
    • Oral:2.5 mg once daily for five years with the intention of stopping at relapse.

• Duration of therapy:

  • A maximum of five years of aromatase inhibitor medication is advised for postmenopausal women in the Adjuvant Endocrine
  • Therapy of Hormone Receptor-Positive Breast Cancer (Focused Update) guidelines from the American Society of Clinical Oncology (ASCO).
  • Tamoxifen and aromatase inhibitors can be used together for a maximum of 10 years of endocrine therapy.
  • For specific suggestions based on menopausal status and tolerability, consult the guidelines.
  • For a total of 10 years of aromatase inhibitor medication, treatment with an additional 5 years of therapy has shown a considerably better rate of disease-free survival and a lowered risk of disease recurrence and contralateral breast cancer (when used in conjunction with other treatments).

Letrozole (Femara) Dose in the treatment of Breast cancer, early (extended adjuvant treatment):

• Females:

  • Postmenopausal:
    • Oral: After five years of tamoxifen use, 2.5 mg once daily for five years; stop at relapse.
    • Letrozole was started in clinical trials three months after stopping tamoxifen.

• Duration of therapy:

  • For postmenopausal women, the ASCO guidelines for adjuvant endocrine therapy of hormone receptor-positive breast cancer (Focused Update) prescribe an aromatase inhibitor therapy regimen that lasts no longer than five years.
  • Tamoxifen and aromatase inhibitors can be used together for a maximum of ten years of endocrine therapy.
  • For specific suggestions based on menopausal status and tolerability, consult the guidelines.
  • Although overall survival was not significantly different between groups and bone-related adverse events were more frequent with letrozole than placebo, treatment with an additional 5 years of therapy (for a total of 10 years of aromatase inhibitor therapy) has shown a significantly improved rate of disease-free survival & a decreased risk of disease recurrence & contralateral breast cancer (when compared to placebo).
  • An evaluation of the risk of recurrence and the initial adjuvant medication (tamoxifen vs. an aromatase inhibitor) should be done before deciding whether to continue aromatase inhibitor therapy for an additional 5 years.

Letrozole (Femara) Dose in the treatment of Breast cancer off-label combinations:

• Breast cancer, advanced, estrogen receptor-positive, HER2-negative:

  • Females:
    • In postmenopausal patients, oral dosages of 2.5 mg once a day (in combination with palbociclib) or 2.5 mg OD (in combination with ribociclib) until disease progression or intolerable toxicity or 2.5 mg OD are recommended.

• Breast cancer, metastatic, hormone receptor-positive, HER2-positive:

  • Females:
    • After menopause, use 2.5 mg orally every day (in conjunction with lapatinib) until the condition worsens or the side effects become intolerable.

Letrozole (Femara) Dose for Anovulatory Females with Polycystic Ovary Syndrome (PCOS) in the Treatment of Infertility/Ovulation Stimulation: Oral:

• Initial dosage: 2.5 mg OD for 5 days beginning on days 3, 4, or 5 after menstruation or a progestin-induced bleed; in subsequent cycles, if ovulation is unsuccessful, the dose may be increased to 5 mg/day for 5 days.
• Maximum daily dose: 7.5 mg. In one trial, dosing for up to 5 cycles was employed.

Letrozole (Femara) Dose for treating Ovarian (epithelial) cancer, recurrent (off-label):

• 2.5 mg orally every day until the condition progresses or the toxicity becomes intolerable.

Letrozole (Femara) Dose in Children:

Letrozole (Femara) dose in delayed puberty and growth in males:

[CDGP (constitutional delay of growth and puberty)]:

• Adolescents ≥14 years:

  • Oral:
    • 2.5 mg once daily along with testosterone treatment;

Letrozole (Femara) Dose in the treatment of McCune-Albright syndrome and precocious puberty in females:

• Children >2-10 years at the time of treatment initiation:

  • Oral:
    • Initial: 0.5 mg/m2 per day split into 12 equal portions for days 1 through 7, then 1 mg/m2/day divided into 12 equal portions for days 8 through 14, and finally 1.5 mg/m2 per day divided into 12 equal portions starting on day 15
    • If necessary, it may be raised to 2 mg/m2/day when serum oestrogen levels and other premature puberty indicators develop.

Letrozole (Femara) Dose in the treatment of idiopathic short-stature in males:

• Children and Adolescents 9-16 years:

  • Oral:
    • 2.5 mg once a day.

Letrozole (Femara) Pregnancy Risk Category: X

• Women with an existing pregnancy are not advised to use contraindicated.
• Breast cancer
  • It has been approved for postmenopausal women to treat breast cancer. 
  • Based on its mode of action and information obtained from studies on animal reproduction, letrozole may be harmful to foetuses.
  • It is recommended that women with reproductive potential undergo a pregnancy test before starting letrozole therapy.
  • Additionally, while receiving treatment and for at least three weeks after the final dose, effective contraception should be taken.
• Polycystic Ovarian Syndrome (PCOS), causes infertility
  • It is used off-label to induce ovulation in females with PCOS or anovulatory issues when there are no other causes of infertility.
• To rule out unplanned ovulation, baseline testing is performed before beginning therapy. This prevents early exposure.
• Because of limited information regarding the effects on newborns following maternal use, guidelines recommend that females be counseled about their off-label status before they use.

Letrozole use during breastfeeding:

• If the medication is detected in breast milk is unknown.
• Breastfeeding is not recommended for therapy or for more than 3 weeks following the last dose.

Letrozole (Femara) Dose in Kidney Disease:

• CrCl ≥10 mL/minute:

  • Dosage adjustment not necessary.

• CrCl <10 mL/minute:

  • Dosage adjustment not necessary.

Letrozole (Femara) Dose in Liver disease:

• Mild to moderate impairment (Child-Pugh class A or B):

  • Dosage adjustment not necessary.

• Severe impairment (Child-Pugh class C) and cirrhosis:

  • 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).

Common Side Effects of Letrozole (Femara):

• Cardiovascular:

  • Flushing
  • Edema

• Central Nervous System:

  • Headache
  • Dizziness
  • Fatigue

• Dermatologic:

  • Diaphoresis
  • Night Sweats

• Endocrine & Metabolic:

  • Hypercholesterolemia
  • Hot Flash
  • Weight Gain

• Gastrointestinal:

  • Nausea
  • Constipation

• Neuromuscular & Skeletal:

  • Weakness
  • Arthralgia
  • Arthritis
  • Ostealgia
  • Musculoskeletal Pain
  • Back Pain
  • Bone Fracture
  • Osteoporosis

• Respiratory:

  • Dyspnea
  • Cough

Less Common Side Effects Of Letrozole (Femara):

• Cardiovascular:

  • Chest Pain
  • Hypertension
  • Chest Wall Pain
  • Peripheral Edema
  • Cerebrovascular Accident
  • Thromboembolism
  • Transient Ischemic Attacks
  • Angina Pectoris
  • Hemorrhagic Stroke
  • Ischemic Heart Disease
  • Thrombotic Stroke
  • Cardiac Failure
  • Myocardial Infarction

• Central Nervous System:

  • Insomnia
  • Pain
  • Anxiety
  • Depression
  • Vertigo
  • Drowsiness
  • Hemiparesis

• Dermatologic:

  • Skin Rash
  • Alopecia
  • Pruritus

• Endocrine & Metabolic:

  • Weight Loss
  • Hypercalcemia

• Gastrointestinal:

  • Diarrhea
  • Vomiting
  • Abdominal Pain
  • Anorexia
  • Dyspepsia

• Genitourinary:

  • Mastalgia
  • Urinary Tract Infection
  • Vaginal Dryness
  • Vaginal Hemorrhage
  • Vaginal Irritation

• Hematologic & Oncologic:

  • Lymphedema
  • Second Primary Malignant Neoplasm

• Infection:

  • Infection
  • Influenza
  • Viral Infection

• Neuromuscular & Skeletal:

  • Limb Pain
  • Myalgia
  • Osteopenia

• Ophthalmic:

  • Cataract

• Renal:

  • Renal Disease

• Respiratory:

  • Pleural Effusion

Contraindication to Letrozole (Femara):

• Pregnancy: Hypersensitivity to letrozole and any component of the formulation

Canadian labeling:Additional contraindications not listed in the US labeling:

• Hypersensitivity to other aromatase inhibitors
• Use for patients under 18 years old
• Premenopausal endocrine status
• Breastfeeding

Warnings and precautions

• CNS depression:

  • Possible dizziness, fatigue, or somnolence
  • Patients should be closely watched before engaging in activities like operating machines or driving that call for mental clarity.

• Reduced bone mineral density

  • Could lead to a decrease in bone mineral density (BMD).
  • When compared to tamoxifen or a placebo, osteoporosis and bone fractures have happened more frequently.
  • Monitor BMD.

• Increasing cholesterol

  • Possibly increasing total serum cholesterol.
  • An increase of >=1.5 x ULN in total cholesterol (non-fasting) has been shown in 8.2% of letrozole-treated patients (25% requiring lipid-lowering medications), compared to 3.2% of tamoxifen-treated patients (16% requiring medications), in patients treated with adjuvant therapy and with cholesterol levels within normal ranges.
  • Monitor cholesterol panel
  • Antihyperlipidemia may be required.

• Hepatic impairment

  • Patients with hepatic impairment should be cautious.
  • Patients with severe hepatic dysfunction or cirrhosis should be adjusted in dosage.

Letrozole: Drug Interaction

Monitoring parameters:

• Cholesterol
• Hepatic function tests
• Bone density
• Pregnancy test 
• Midluteal progestin concentrations 

How to administer Letrozole (Femara)?

•  Oral: Administer without regard to meals.

Mechanism of action of Letrozole (Femara):

• It is a cytochrome P-450 enzyme that binds to the heme group of aromatase, a nonsteroidal competitive inhibitor of the aromatase enzyme system, which catalyses the conversion of androgens to estrogens (particularly, androstenedione to estrone and testosterone to estradiol).
• As a result, the enzyme is inhibited and the levels of plasma oestrogen (estrone, estradiol, and estrone sulphate) are significantly decreased.
• Aldosterone, androgens, thyroid hormones, or the synthesis of these hormones do not appear to be impacted in any way by letrozole.

Absorption:

• Quick and effective absorption; unaffected by meals.

Protein binding, plasma:

• Weak

Metabolism:

• Hepatic via CYP3A4 and 2A6 to an inactive carbinol metabolite

Half-life elimination:

• Terminal: ~2 days

Time to steady-state plasma concentration:

• 2 to 6 weeks; 1.5 to 2 times greater steady-state serum concentrations than single-dose levels.
• Girls aged 3 to 9 had steady-state concentrations that ranged from 25% to 67% higher than the average adult levels.

Excretion:

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

International Brands of Letrozole:

• Femara
• ACH-Letrozole
• APO-Letrozole
• BIO-Letrozole
• CCP-Letrozole
• Femara
• JAMP-Letrozole
• MarLetrozole
• MED-Letrozole
• MYL-Letrozole
• NAT-Letrozole
• PMS-Letrozole
• RAN-Letrozole
• RIVA-Letrozole
• SANDOZ Letrozole
• TEVA-Letrozole
• VAN-Letrozole [DSC]
• Zinda-Letrozole
• Antif
• Avomit
• Bretra
• Eirfem
• Elozora
• Emvia
• Endofree
• Esmara
• Femaplex
• Femar
• Femara
• Femazol
• Femgard
• Femolet
• Fera
• Fezol
• Fu Rui
• Gesamef
• Glotraz
• Hentrozole
• Lenara
• Lenor
• Lentronat
• Lerozol
• Letara
• Letero
• Letoripe
• Letov
• Letov 2.5
• Letrasan
• Letraz
• Letrol
• Letronat
• Letrostad
• Letroz
• Letvex
• Letzo
• Letzol
• Lexel
• Lezol
• Lezra
• Likarda
• Losiral
• Trodis
• Trozet
• Zolet
• Zolstro

Letrozole Brand Names in Pakistan: