Exemestane

L02B - Hormone antagonists and related agents ATC L02BG06 Small molecule approved 1999 Oral Natural product

JFDA label: Aromasin Tab

Mechanism of Action

Inhibitor of Aromatase — Cytochrome P450 19A1 inhibitor

Target	Action	Gene / class
Aromatase efficacy	INHIBITOR	CYP19A1

Indications

Approved

Breast cancer

Off-label

First-line adjuvant treatment of estrogen receptor-positive early breast cancer in postmenopausal women
Risk reduction for invasive breast cancer in postmenopausal women

Contraindications

Source: Lexicomp

Known hypersensitivity to exemestane or any component of the formulation 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 (4)

Not Known chest pain* · edema · Hypertension · ischemic heart disease

Nervous system disorders (11)

Not Known * hypoesthesia* · anxiety · carpal tunnel syndrome · confusion · depression · dizziness · Fatigue · headache · insomnia · pain · paresthesia

Hepatobiliary disorders (2)

Not Known Increased serum alkaline phosphatase · increased serum bilirubin

Renal and urinary disorders (2)

Not Known Increased serum creatinine · Urinary tract infection

Blood and lymphatic system disorders (1)

Not Known Lymphedema*

Metabolism and nutrition disorders (5)

Not Known Hot flash · increased follicle-stimulating hormone · increased luteinizing hormone · increased sex hormone binding globulin (with daily doses of ≥2.5 mg; dose-dependent) · weight gain

Gastrointestinal disorders (8)

Not Known abdominal pain · anorexia · constipation · diarrhea · dyspepsia* · increased appetite · Nausea · vomiting

Skin and subcutaneous tissue disorders (5)

Not Known * skin rash* · alopecia · dermatitis · Hyperhidrosis · pruritus

Musculoskeletal and connective tissue disorders (9)

Not Known Arthralgia · back pain · limb pain · muscle cramps · myalgia · osteoarthritis · osteoporosis · pathological fracture · weakness

Eye disorders (1)

Not Known Visual disturbance

Infections and infestations (1)

Not Known Infection*

General disorders and administration site conditions (1)

Not Known Fever

Respiratory, thoracic and mediastinal disorders (8)

Not Known * pharyngitis · * rhinitis · * sinusitis · * upper respiratory tract infection* · bronchitis · cough · Dyspnea · flu-like symptoms

Dosing

Source: Lexicomp

Breast cancer, advanced: Postmenopausal females: Oral: 25 mg once daily; continue until tumor progression Breast cancer, early (adjuvant treatment): Postmenopausal females: Oral: 25 mg once daily (following 2 to 3 years of tamoxifen therapy) for a total duration of 5 years of endocrine therapy (in the absence of recurrence or contralateral breast cancer). 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 (AI) therapy for postmenopausal women; AIs 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). In a phase III study with another AI (letrozole), treatment with an additional 5 years of AI therapy (for a total of 10 years of aromatase inhibitor therapy) 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 (first-line adjuvant treatment; off-label use): Postmenopausal females: Oral: 25 mg once daily for 5 years (Burstein 2010; van de Velde 2011). 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 (AI) therapy for postmenopausal women; AIs 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). In a phase III study with another AI (letrozole), treatment with an additional 5 years of AI therapy (for a total of 10 years of aromatase inhibitor therapy) 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, risk reduction (off-label use): Postmenopausal females ≥35 years: Oral: 25 mg once daily for 5 years (Goss 2011; Visvanathan 2013) Dosage adjustment with strong CYP3A4 inducers: 50 mg once daily when used with potent inducers (eg, rifampin, phenytoin)

Refer to adult dosing.

No adjustment necessary (although the safety of chronic doses in patients with moderate-to-severe renal impairment has not been studied, dosage adjustment does not appear necessary).

No adjustment necessary (although the safety of chronic doses in patients with moderate-to-severe hepatic impairment has not been studied, dosage adjustment does not appear necessary).

Warnings & Precautions

Source: Lexicomp

Decreased bone mineral density

Due to decreased circulating estrogen levels, exemestane is associated with a reduction in bone mineral density over time. Decreases (from baseline) in lumbar spine and femoral neck density have been observed (when compared to tamoxifen or placebo in studies where concomitant use of bisphosphonates, calcium and vitamin D were not allowed). Assess bone mineral density at baseline in patients with, or at risk for osteoporosis; monitor during exemestane therapy and initiate osteoporosis treatment if indicated.

Lymphopenia

Grade 3 or 4 lymphopenia has been observed with exemestane, although most patients had preexisting lower grade lymphopenia; some patients improved or recovered while continuing exemestane. Lymphopenia did not result in a significant increase in viral infections, and no opportunistic infections were observed.

Lab parameters

Elevations of AST, ALT, alkaline phosphatase, and gamma glutamyl transferase >5 times ULN have been observed (rarely) in patients with advanced breast cancer; may be attributable to underlying liver and/or bone metastases. In patients with early breast cancer, elevations of bilirubin, alkaline phosphatase, and serum creatinine were more common with exemestane treatment than with tamoxifen or placebo. 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. Dose adjustment recommended with concomitant strong CYP3A4 inducers.

Estrogen-containing drugs

Exemestane should not be administered concurrently with estrogen-containing drugs. Other warnings/precautions:

Appropriate use

Exemestane is not indicated for use in premenopausal women.

Vitamin D deficiency

Due to high prevalence of vitamin D deficiency in women with breast cancer, assess 25-hydroxy vitamin D levels at baseline and supplement accordingly.

Pregnancy & Lactation

Pregnancy

FDA category X Teratogenic Contraindicated

Contraindicated

Contraindicated in pregnancy

Lactation

Avoid

Exemestane is indicated for use only in postmenopausal women. Due to the potential for serious adverse reactions in the breast-feeding infant, breast-feeding is not recommended by the manufacturer during treatment and for 1 month after the final dose.

Monitoring

Clinical pearl	25-hydroxy vitamin D levels (at baseline); bone mineral density

Chemistry & Properties

Formula	C20H24O2
Molecular weight	296.41 g/mol
IUPAC name	(8R,9S,10R,13S,14S)-10,13-dimethyl-6-methylidene-7,8,9,11,12,14,15,16-octahydrocyclopenta[a]phenanthrene-3,17-dione
CAS	107868-30-4
PubChem CID	60198
InChIKey	`BFYIZQONLCFLEV-DAELLWKTSA-N`
logP	4.03 (XLogP 3.1)
Polar surface area	34.14 Å²
H-bond acceptors / donors	2 / 0
Drug-likeness (QED)	0.68
Lipinski violations	0

SMILES

C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)C=CC(=O)C=C12

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	70.0%
Half-life	0.924 h
Volume of distribution	2.545 L/kg
Protein binding	84.6%
BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP1A	Substrate	—
CYP1A2	Substrate	—
CYP2B6	Substrate	—
CYP2C8	Inhibitor	—
CYP3A4	Substrate	—
CYP4A11	Substrate	—

Receptor binding (top 2)

Target	Action	Affinity
CYP19A1 (CYP19A1)	Inhibitor	pKi 7.6
CYP19A1 (CYP19A1)	Inhibitor	pIC50 7.4

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OCT2 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Drug–drug interactions (74, DDInter)

Interacting drug	Severity	Management
Thalidomide	major
Abametapir (topical)	moderate
Aminoglutethimide	moderate
Amobarbital	moderate
Apalutamide	moderate
Armodafinil	moderate
Bexarotene	moderate
Bosentan	moderate
Brigatinib	moderate
Butabarbital	moderate
Butalbital	moderate
Carbamazepine	moderate
Cenobamate	moderate
Conjugated estrogens	moderate
Conjugated estrogens (topical)	moderate
Dabrafenib	moderate
Deferasirox	moderate
Dexamethasone	moderate
Dienestrol (topical)	moderate
Diethylstilbestrol	moderate
Echinacea	moderate
Efavirenz	moderate
Elagolix	moderate
Enzalutamide	moderate
Eslicarbazepine	moderate
Esterified estrogens	moderate
Estradiol	moderate
Estradiol (topical)	moderate
Estramustine	moderate
Estrone	moderate
Estrone sulfate	moderate
Estrone sulfate (topical)	moderate
Ethinylestradiol	moderate
Etravirine	moderate
Felbamate	moderate
Fosphenytoin	moderate
Fostamatinib	moderate
Griseofulvin	moderate
Ivosidenib	moderate
Lefamulin	moderate

Showing 40 of 74.

Registered Products (5)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Mestane 25	Tablet 25 mg	30 tab	Reda Jardaneh Drug Store	15.020
Aromaplex	Tablet 25 mg	30 tab	Orient Montreal Drug Store	21.620
exedral	Tablet 25 mg	30 tab	JAWEDA INT. DRUD STORE	24.760
Xamaze	Tablet 25 mg	30 tab	JORDAN RIVER PHARMA.IND(JORIVER)/JORDAN	37.420
Aromasin Tab	Tablet 25 mg	30 tab	Petra Drug Store	41.260