Letrozole (Femara) is an aromatase inhibitor (anti-estrogen drug) that is primarily used in the treatment of breast cancer.

Letrozole Uses:

• 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

• Off Label Use of Letrozole in Adults:

  • Infertility/Ovulation stimulation in anovulatory females with polycystic ovary syndrome
  • 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: 2.5 mg once a day; continue until tumor progression

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

• Females:

  • Postmenopausal:
    • Oral: 2.5 mg once a day for a planned duration of 5 years; discontinue at relapse.

• Duration of therapy:

  • 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.
  • 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), although overall survival was not significantly different between groups & bone-related adverse events occurred more frequently with letrozole versus placebo.

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

• Females:

  • Postmenopausal:
    • Oral: 2.5 mg once a day 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.

• Duration of therapy:

  • 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 Ten years of endocrine therapy.
  • Refer to the guidelines for specific recommendations based on menopausal status and tolerability.
  • Treatment with an additional 5 years of therapy (for a total of 10 years of aromatase inhibitor therapy) has demonstrated a significantly improved rate of disease-free survival & a decreased risk of disease recurrence and contralateral breast cancer (when compared to placebo), although overall survival was not significantly different between groups and bone-related adverse events occurred more frequently with letrozole versus placebo.
  • The decision to extend aromatase inhibitor therapy for an additional 5 years should include initial adjuvant therapy (tamoxifen versus an aromatase inhibitor) & an assessment of the risk of recurrence.

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

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

  • Females:
    • Postmenopausal: Oral: 2.5 mg once a day (in combination with palbociclib) until disease progression or unacceptable toxicity or 2.5 mg OD (in combination with ribociclib) until disease progression or unacceptable toxicity or 2.5 mg OD (in combination with abemaciclib) until disease progression or unacceptable toxicity.

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

  • Females:
    • Postmenopausal: Oral: 2.5 mg OD (in combination with lapatinib) until disease progression or unacceptable toxicity.

Letrozole (Femara) Dose in the treatment of Infertility/Ovulation stimulation in anovulatory females with polycystic ovary syndrome (PCOS) (off-label): Oral:

• Initial dose: 2.5 mg OD for 5 days, starting on day 3, 4, or 5 following menses or progestin induced bleed; may increase to 5 mg/day for 5 days in subsequent cycles if ovulation does not occur.
• Maximum dose: 7.5 mg/day. Dosing for up to 5 cycles was used in 1 study.

Letrozole (Femara) Dose in the treatment of Ovarian (epithelial) cancer, recurrent (off-label):

• Oral: 2.5 mg OD; continue until disease progression or unacceptable toxicity.

Letrozole (Femara) Dose in Childrens:

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 a day in combination with testosterone therapy;

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 /day divided every 12 hours for days 1-7, then 1 mg/m²/day divided every 12 hours on days 8-14, then 1.5 mg/m² /day divided every 12 hours beginning on day 15
    • If needed, it may further increase to 2 mg/m² /day if markers of precocious puberty including serum estradiol levels progress.

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. 
  • Letrozole can cause harm to fetuses based on its mechanism of action and data derived from animal reproduction studies.
  • It is recommended that women with reproductive potential undergo a pregnancy test before starting letrozole therapy.
  • Effective contraception should also be used during the therapy, and at least for 3 weeks after the last dose.
• Polycystic Ovarian Syndrome (PCOS), causes infertility
  • When there are no other causes of infertility, it is used off-label to induce ovulation in females who have PCOS or anovulatory problems.
• 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:

• It is unknown if the drug is found in breast milk.
• 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
  • Before performing tasks that require mental alertness (e.g. driving or operating machinery), patients should be supervised.

• Reduced bone mineral density

  • Could lead to a decrease in bone mineral density (BMD).
  • Osteoporosis and bone fractures have occurred at higher rates when compared to tamoxifen or to placebo.
  • Monitor BMD.

• Increasing cholesterol

  • May raise the 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 (non-fasting) 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
  • 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 (prior to treatment in females of reproductive potential). Monitor adherence.
• 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; the poor ovulatory response was defined as progesterone concentrations indicating ovulation but just above the cutoff point).

How to administer Letrozole (Femara)?

•  Oral: Administer without regard to meals.

Mechanism of action of Letrozole (Femara):

• It is a nonsteroidal competitive inhibitor of the aromatase enzyme system which binds to the heme group of aromatase, a cytochrome P-450 enzyme that catalyzes the 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.
• Letrozole appears not to have any effect on the synthesis or production of adrenal hormones or thyroid hormones, aldosterone or androgens.

Absorption:

• Rapid and well absorbed; not affected by food.

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; 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.

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: