Anastrozole

L02B - Hormone antagonists and related agents ATC L02BG03 Small molecule approved 1995 Oral Natural product

JFDA label: Arimidex Tablet

Mechanism of Action

Inhibitor of Aromatase — Cytochrome P450 19A1 inhibitor

Target	Action	Gene / class
Aromatase efficacy	INHIBITOR	CYP19A1

Indications

Approved

Breast cancer

Off-label

Endometrial or uterine cancers (recurrent or metastatic)
Ovarian cancer (recurrent)
Risk reduction for breast cancer in postmenopausal women

Contraindications

Source: Lexicomp

Additional contraindications (not in US labeling): Lactating women Absolute
Hypersensitivity to anastrozole or any component of the formulation Absolute
use in women who are or may become pregnant 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 (9)

Very Common angina pectoris · edema · hypertension · ischemic heart disease · Vasodilatation

Common chest pain · myocardial infarction · Peripheral edema · venous thrombosis

Nervous system disorders (17)

Very Common depression · Fatigue · headache · mood disorder · pain

Common anxiety · carpal tunnel syndrome · cerebrovascular insufficiency · confusion · dizziness · drowsiness · hypertonia · Insomnia · lethargy · malaise · nervousness · paresthesia

Hepatobiliary disorders (3)

Common Increased serum alkaline phosphatase · increased serum ALT · increased serum AST

Renal and urinary disorders (9)

Common leukorrhea · Mastalgia · pelvic pain · urinary tract infection · vaginal discharge · vaginal dryness · vaginal hemorrhage · vaginitis · vulvovaginitis

Blood and lymphatic system disorders (6)

Common anemia · breast neoplasm · leukopenia · Lymphedema · neoplasm · tumor flare

Metabolism and nutrition disorders (6)

Very Common Hot flash

Common Hypercholesterolemia · increased gamma-glutamyl transferase · increased serum cholesterol · weight gain · weight loss

Gastrointestinal disorders (10)

Very Common Gastrointestinal distress · nausea · vomiting

Common abdominal pain · anorexia · Constipation · diarrhea · dyspepsia · gastrointestinal disease · xerostomia

Skin and subcutaneous tissue disorders (4)

Very Common Skin rash

Common Alopecia · diaphoresis · pruritus

Musculoskeletal and connective tissue disorders (11)

Very Common arthralgia · arthritis · back pain · ostealgia · osteoporosis · Weakness

Common arthrosis · Bone fracture · myalgia · neck pain · pathological fracture

Eye disorders (1)

Common Cataract

Infections and infestations (1)

Common Infection

General disorders and administration site conditions (3)

Common Accidental injury · cyst · fever

Respiratory, thoracic and mediastinal disorders (7)

Very Common dyspnea · increased cough · Pharyngitis

Common bronchitis · Flu-like symptoms · rhinitis · sinusitis

Dosing

Source: Lexicomp

Breast cancer, advanced: Postmenopausal females: Oral: 1 mg once daily; continue until tumor progression Breast cancer, early (adjuvant treatment): Postmenopausal females: Oral: 1 mg once daily. Duration of therapy: The 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 AI 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 ≥40 years: Oral: 1 mg once daily for 5 years (Cuzick 2014) Endometrial or uterine cancer, recurrent or metastatic (off-label use): Oral: 1 mg once daily (Rose 2000) Ovarian cancer, recurrent (off-label use): Oral: 1 mg once daily until disease progression or unacceptable toxicity (del Carmen 2003)

Refer to adult dosing.

No dosage adjustment necessary.

Mild to moderate impairment or stable hepatic cirrhosis: No dosage adjustment necessary. Severe hepatic impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Warnings & Precautions

Source: Lexicomp

Decreased bone mineral density

Due to decreased circulating estrogen levels, anastrozole is associated with a reduction in bone mineral density (BMD); decreases (from baseline) in total hip and lumbar spine BMD have been reported. Patients with preexisting osteopenia are at higher risk for developing osteoporosis (Eastell 2008). When initiating anastrozole treatment, follow available guidelines for bone mineral density management in postmenopausal women with similar fracture risk; concurrent use of bisphosphonates may be useful in patients at risk for fractures.

Hypercholesterolemia

Elevated total cholesterol levels (contributed to by LDL cholesterol increases) have been reported in patients receiving anastrozole; use with caution in patients with hyperlipidemias. Cholesterol levels should be monitored/managed in accordance with current guidelines for patients with LDL elevations. Disease-related concerns:

Hepatic impairment

Plasma concentrations in patients with stable hepatic cirrhosis were within the range of concentrations seen in normal subjects across all clinical trials. Has not been studied in patients with severe hepatic impairment.

Ischemic disease

Patients with preexisting ischemic cardiac disease have an increased risk for ischemic cardiovascular events. Special populations:

Pregnancy

Use is contraindicated in women who are or may become pregnant.

Premenopausal women

Anastrozole offers no clinical benefit in premenopausal women with breast cancer.

Pregnancy & Lactation

Pregnancy

FDA category X Teratogenic Contraindicated

Contraindicated

Contraindicated in pregnancy

Lactation

It is not known if anastrozole is excreted in breast milk. Due to the potential for serious adverse reactions in the nursing infant, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of treatment to the mother.

Monitoring

Clinical pearl	Bone mineral density; total cholesterol and LDL Breast cancer risk reduction (off-label use): Bone mineral density at baseline, mammograms, and clinical breast exam at baseline and at least every 2 years (Cuzick, 2014)

Chemistry & Properties

Formula	C17H19N5
Molecular weight	293.37 g/mol
IUPAC name	2-[3-(2-cyanopropan-2-yl)-5-(1,2,4-triazol-1-ylmethyl)phenyl]-2-methylpropanenitrile
CAS	120511-73-1
PubChem CID	2187
InChIKey	`YBBLVLTVTVSKRW-UHFFFAOYSA-N`
logP	2.93 (XLogP 2.1)
Polar surface area	78.29 Å²
H-bond acceptors / donors	5 / 0
Drug-likeness (QED)	0.87
Lipinski violations	0

SMILES

CC(C)(C#N)c1cc(Cn2cncn2)cc(C(C)(C)C#N)c1

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	No

Enzyme interactions

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

Receptor binding (top 1)

Target	Action	Affinity
CYP19A1 (CYP19A1)	Inhibitor	pIC50 7.8

Transporters

ASBT (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OCT2 (Inhibitor)P-gp (Inhibitor)MDR1 (Substrate)P-gp (Substrate)

Drug–drug interactions (18, DDInter)

Interacting drug	Severity	Management
Thalidomide	major
Conjugated estrogens	moderate
Conjugated estrogens (topical)	moderate
Dienestrol (topical)	moderate
Diethylstilbestrol	moderate
Esterified estrogens	moderate
Estradiol	moderate
Estradiol (topical)	moderate
Estramustine	moderate
Estrone	moderate
Estrone sulfate	moderate
Estrone sulfate (topical)	moderate
Ethinylestradiol	moderate
Fostamatinib	moderate
Mestranol	moderate
Quinestrol	moderate
Tamoxifen	moderate
Tucatinib	moderate

Registered Products (9)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Armotraz Tablet	Tablet 1 mg	10 tab	ORIENT DRUG STORE CO	8.590
Avomin 1 mg F.C tab	Film-Coated Tablet 1 mg	28 tab	Orient Montreal Drug Store	16.240
Aremed	Tablet 1 mg	28 tab	JAWEDA INT. DRUD STORE	23.900
Stardex	Tablet 1 mg	30 tab	THE JORDANIAN PHARMACEUTICAL MANUFACTURING COMPANY/JORDAN	32.230
Rozalip	Tablet 1 mg	28 tab	Dar Al Dawa Development and Investment Co Ltd/Jordan	35.840
Arimidex Tablet	Tablet 1 mg	28 tab	Shawi & Rushedat Drug Store	42.970
Anarix	Tablet 1 mg	28 tab pack varies	Al-Taqqadom Pharmaceutical Industries	79.740
Anazol	Tablet 1 mg	28 tab	MS PHARMA/JORDAN	83.240
Anarix	Tablet 1 mg	30 tab pack varies	Al-Taqqadom Pharmaceutical Industries	85.440