Letrozole

L02B - Hormone antagonists and related agents ATC L02BG04 Small molecule approved 1997 Oral Natural product

JFDA label: Femara Tab

Mechanism of Action

Inhibitor of Aromatase — Cytochrome P450 19A1 inhibitor

Target	Action	Gene / class
Aromatase efficacy	INHIBITOR	CYP19A1

Indications

Approved

Breast cancer in postmenopausal women

Off-label

Infertility/ovulation stimulation in anovulatory women with polycystic ovarian syndrome (PCOS)
Ovarian (epithelial) cancer, recurrent

Contraindications

Source: Lexicomp

Additional contraindications (not in the US labeling): Hypersensitivity to other aromatase inhibitors Absolute
Hypersensitivity to letrozole or any component of the formulation Absolute
use in patients Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (10)

Very Common Edema

Common angina pectoris · cerebrovascular accident · Chest pain · chest wall pain · hypertension · myocardial infarction · peripheral edema · thromboembolism · transient ischemic attacks

Nervous system disorders (6)

Very Common dizziness · fatigue · Headache

Common anxiety, alopecia, pruritus · Insomnia · pain

Renal and urinary disorders (6)

Common Mastalgia · Renal disease · urinary tract infection · vaginal dryness · vaginal hemorrhage · vaginal irritation

Blood and lymphatic system disorders (1)

Common Metastases

Metabolism and nutrition disorders (5)

Very Common hot flash · Hypercholesterolemia · weight gain

Common hypercalcemia, vomiting, abdominal pain, anorexia, dyspepsia · Weight loss

Gastrointestinal disorders (2)

Very Common constipation · Nausea

Skin and subcutaneous tissue disorders (2)

Very Common Diaphoresis · night sweats

Musculoskeletal and connective tissue disorders (10)

Very Common arthralgia · arthritis · back pain · bone fracture · decreased bone mineral density · ostealgia · osteoporosis · Weakness

Common Limb pain · myalgia

Eye disorders (1)

Common Cataract

Infections and infestations (3)

Common Infection · influenza · viral infection

Respiratory, thoracic and mediastinal disorders (3)

Very Common cough · Dyspnea

Common Pleural effusion (

Dosing

Source: Lexicomp

Breast cancer, advanced (first- or second-line treatment): Females: Postmenopausal: Oral: 2.5 mg once daily; continue until tumor progression Breast cancer, early (adjuvant treatment): Females: Postmenopausal: Oral: 2.5 mg once daily 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 (Burstein 2014). 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 and 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 (Goss 2016). Breast cancer, early (extended adjuvant treatment): Females: Postmenopausal: Oral: 2.5 mg once daily 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 (Goss 2003; Jin 2012). 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 10 years of endocrine therapy. Refer to the guidelines for specific recommendations based on menopausal status and tolerability (Burstein 2014). 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 and 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 (Goss 2016). Off-label combinations: Breast cancer, advanced, estrogen receptor-positive, HER2-negative: Females: Oral: 2.5 mg once daily (in combination with palbociclib) until disease progression or unacceptable toxicity (Finn 2015) or 2.5 mg once daily (in combination with ribociclib) until disease progression or unacceptable toxicity (Hortobagyi 2016) Breast cancer, metastatic, hormone receptor-positive, HER2-positive: Females: Oral: 2.5 mg once daily (in combination with lapatinib) until disease progression or unacceptable toxicity (Johnston 2009) Infertility/

Refer to adult dosing.

CrCl ≥10 mL/minute: No dosage adjustment necessary. CrCl

Mild to moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary. Severe impairment (Child-Pugh class C) and cirrhosis: 2.5 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).

Warnings & Precautions

Source: Lexicomp

CNS depression

May cause dizziness, fatigue, and somnolence; patients should be cautioned before performing tasks which require mental alertness (eg, operating machinery or driving).

Decreased bone mineral density

May cause decreases in bone mineral density (BMD). In one study, a decrease in hip BMD by 3.8% from baseline in letrozole-treated patients vs 2% in placebo at 2 years was demonstrated, however, while lumbar spine BMD was decreased, the difference was not statistically significant. Results of a safety study did demonstrate a decrease in lumbar spine BMD with letrozole (compared to tamoxifen). Osteoporosis and bone fractures have occurred at higher rates when compared to tamoxifen or to placebo. Monitor BMD.

Increased cholesterol

May increase 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; may require antihyperlipidemics. Disease-related concerns:

Hepatic impairment

Use with caution in patients with hepatic impairment; dose adjustment recommended in patients with cirrhosis or severe hepatic dysfunction. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Pregnancy & Lactation

Pregnancy

FDA category X Teratogenic Contraindicated

Contraindicated

Contraindicated in pregnancy. Paradoxically used for ovulation induction before conception (off-label)

Lactation

Avoid

It is not known if letrozole is present in breast milk. Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy and for at least 3 weeks after the last dose.

Monitoring

Clinical pearl	Cholesterol, hepatic function tests; bone density; pregnancy test (prior to treatment in females of reproductive potential). 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

Chemistry & Properties

Formula	C17H11N5
Molecular weight	285.31 g/mol
IUPAC name	4-[(4-cyanophenyl)-(1,2,4-triazol-1-yl)methyl]benzonitrile
CAS	112809-51-5
PubChem CID	3902
InChIKey	`HPJKCIUCZWXJDR-UHFFFAOYSA-N`
logP	2.66 (XLogP 2.7)
Polar surface area	78.29 Å²
H-bond acceptors / donors	5 / 0
Drug-likeness (QED)	0.74
Lipinski violations	0

SMILES

N#Cc1ccc(C(c2ccc(C#N)cc2)n2cncn2)cc1

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Substrate	—
CYP2C9	Inhibitor	—
CYP3A4	Inhibitor	—
CYP3A4	Substrate	—

Receptor binding (top 2)

Target	Action	Affinity
CYP19A1 (CYP19A1)	Inhibitor	pKi 10.7
CYP19A1 (CYP19A1)	Inhibitor	pIC50 7.9

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)MDR1 (Substrate)P-gp (Substrate)

Drug–drug interactions (87, DDInter)

Interacting drug	Severity	Management
Citalopram	major
Thalidomide	major
Abametapir (topical)	moderate
Apalutamide	moderate
Aprepitant	moderate
Berotralstat	moderate
Bexarotene	moderate
Boceprevir	moderate
Bosentan	moderate
Brigatinib	moderate
Cenobamate	moderate
Ceritinib	moderate
Cilostazol	moderate
Clobazam	moderate
Clopidogrel	moderate
Conivaptan	moderate
Conjugated estrogens	moderate
Conjugated estrogens (topical)	moderate
Dabrafenib	moderate
Darunavir	moderate
Dasatinib	moderate
Deferasirox	moderate
Dienestrol (topical)	moderate
Diethylstilbestrol	moderate
Dronedarone	moderate
Duvelisib	moderate
Echinacea	moderate
Efavirenz	moderate
Enzalutamide	moderate
Escitalopram	moderate
Esterified estrogens	moderate
Estradiol	moderate
Estradiol (topical)	moderate
Estramustine	moderate
Estrone	moderate
Estrone sulfate	moderate
Estrone sulfate (topical)	moderate
Ethinylestradiol	moderate
Etravirine	moderate
Fedratinib	moderate

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Registered Products (11)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Letrasan	Tablet 2.5 mg	30 tab	Reda Jardaneh Drug Store	9.510
Letroz	Tablet 2.5 mg	25 tab pack varies	Reda Jardaneh Drug Store	11.920
Letroz	Tablet 2.5 mg	28 tab pack varies	Reda Jardaneh Drug Store	13.350
LEZROL	Tablet 2.5 mg	3 X 10 S BLISTERS	Omicron Pharma	13.610
Estrodex	Tablet 2.5 mg	30 tab	Al-Taqqadom Pharmaceutical Industries	17.320
Femaplex	Tablet 2.5 mg	30 tab	Orient Montreal Drug Store	17.320
Letrozole Pharmacare	Tablet 2.5 mg	30 tab	Sabbagh Drug Store	23.660
Femara Tab	Tablet 2.5 mg	30 tab	The Jordan Drugstore Co	27.390
Flobex	Tablet 2.5 mg	30 tab	Dar Al Dawa Development and Investment Co Ltd/Jordan	27.990
Etofem 2.5mg f.C Tab	Film-Coated Tablet 2.5 mg	30 tab	MS PHARMA/JORDAN	37.350
Lefftara 2.5mg F.C Tab	Film-Coated Tablet 2.5 mg	30 F.C Tab	Hikma Pharmaceuticals Co.Ltd/Jordan	44.380