Exemestane

Exemestane is an antineoplastic agent belonging to the pharmacological class of aromatase inhibitors.

The FDA has approved exemestane for the treatment of breast cancer in postmenopausal women after treatment with tamoxifen.

Once administered, exemestane is rapidly and completely absorbed from the gastrointestinal, swiftly initiating therapeutic effects. It extensively distributes throughout various tissues, crossing the placental barrier. It undergoes extensive liver metabolism involving oxidation and reduction and produces inactive metabolites. Exemestane is mainly eliminated through occurs through urine (≤1% unchanged, 39-45% as metabolites) and faeces (36-48%).

The most common side effects of exemestane are hot flashes, nausea, rashes, joint pain, osteoporosis, and weakness.

Exemestane is available in the form of oral tablets.

Exemestane is an antineoplastic agent belonging to the pharmacological class of aromatase inhibitors.

Growth of breast cancer cells may be influenced by estrogen. Aromatase, also known as exemestane, is the main enzyme that changes androgens into estrogens in premenopausal and postmenopausal women. In premenopausal women, the ovary is the primary source of estrogen (primarily estradiol); however, in postmenopausal women, the aromatase enzyme in the peripheral tissues converts adrenal and ovarian androgens (androstenedione and testosterone) to estrogens (estrone and estradiol). For specific postmenopausal individuals with hormone-dependent breast cancer, aromatase inhibition provides an efficient and targeted approach to estrogen deprivation. With a structural resemblance to the natural substrate androstenedione, exemestane is an irreversible steroidal aromatase inactivator. It irreversibly attaches itself to the active site, resulting in persistent inhibition that calls for de novo synthesis to restore enzymatic function. Exemestane significantly decreases the levels of circulating estrogen in postmenopausal women, but it has no apparent effect on the ability of adrenal gland to produce corticosteroids or aldosterone. A decrease in blood and tumour concentrations of estrogen causes this delay in tumour development and disease progression. At least 600 times higher than the concentration that inhibits the aromatase enzyme, exemestane does not affect other enzymes that are involved in the steroidogenic pathway.

In women with breast cancer, the peak time for exemestane is approximately 1.2 hours after administration.

Exemestane is available in the form of an oral tablet.

Tablet: To be swallowed whole with water/liquid. Do not chew, crush or break it.

As the physician recommends, take the medication orally once daily, preferably after meals as directed.

• Treatment of Breast cancer.
• Breast Cancer Prevention (Off-label).

Limitation Use: Exemestane is not indicated for the treatment of breast cancer in premenopausal women.

In Breast Cancer: Exemestane significantly lowers estrogen production, a major factor in hormone receptor-positive breast cancer, by inhibiting the synthesis of estrogen, hence halting the growth of tumors. Postmenopausal women's survival rates are increased and cancer recurrence is decreased with this focused treatment. It is an essential part of adjuvant therapy, particularly in cases where tumors express hormone receptors. It reduces the likelihood that the disease will progress, improves the effectiveness of treatment overall, and makes a substantial contribution to the management of hormone-sensitive breast cancer in postmenopausal women.

• Indicated for postmenopausal women whose disease has advanced after tamoxifen therapy to treat advanced breast cancer.
• Exemestane is indicated as an adjuvant treatment for postmenopausal women with estrogen-receptor-positive early-stage breast cancer who have been treated with tamoxifen for two to three years before switching to the medication.
• Exemestane has been suggested by ASCO and NCCN guidelines as an alternative to tamoxifen or raloxifene in the prevention of invasive breast cancer in high-risk women.

Considerations for Dosing

A high risk of breast cancer is defined as having one or more first-degree relatives who have breast cancer, at least one breast biopsy showing lobular carcinoma in situ (LCIS) or atypical hyperplasia, or a 5-year estimated risk of breast cancer greater than 1.66% (derived using the modified Gail model).

Orally: Exemestane, administered orally, is typically prescribed as a once-daily tablet. Patients are advised to take the medication simultaneously daily, usually after meals. The tablets should be swallowed whole with a glass of water, avoiding crushing or breaking them. Individuals must adhere strictly to the prescribed dosage and administration schedule. Patients are also advised to consult their healthcare provider about the medication's benefits and potential side effects.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Tablet: 25mg

Exemestane is available in the form of oral tablets.

Dose Adjustment in Adult Patients:

Breast Cancer

Advanced disease

25 mg orally qDay; continue until tumour progression

Adjuvant treatment

25 mg orally qDay; continue until tumour progression

Breast Cancer Prevention (Off-label)

25 mg orally qDay for five years

When taking exemestane, adhere to dietary recommendations and safety guidelines for optimal well-being. It is crucial to maintain a healthy diet rich in essential nutrients and incorporating leafy vegetables, fruits, fatty fish, and dairy is necessary. Limit intake of processed foods, refined carbs, and added sugars. Encourage regular exercise to support overall health and weight management. Refrain from smoking and excessive alcohol consumption.

The dietary restriction should be individualized as per patient requirements.

Hypersensitivity: Anyone previously experienced hypersensitivity to any of the product's constituents.

• Avoid concurrent use with estrogen-containing agents, as they might interfere with the intended pharmacological action of exemestane.
• Assess Vitamin D Levels: Prior to initiating aromatase inhibitor treatment, routinely assess 25-hydroxy vitamin D levels. Due to the increase prevalence of vitamin D deficiency in women with early breast cancer, those identified with deficiency should receive vitamin D supplementation.

• Monitor Bone Mineral Density (BMD): Exemestane may lead to reductions in bone mineral density over time. Women with osteoporosis or at risk should undergo formal bone densitometry assessment at the start of adjuvant treatment. Regular monitoring for BMD loss is advised, and appropriate treatment should be initiated.

• Not for Premenopausal Women: Exemestane is not indicated for breast cancer treatment in premenopausal women.

• Contraception Advisory: Women of reproductive potential should use effective contraception during exemestane treatment and for one month after the final dose.

• Fertility Impairment: Based on animal findings, both male and female fertility may be impaired by exemestane treatment. Caution is advised regarding potential fertility implications.

It is unsafe to consume exemestane with alcohol.

It is not recommended for use during breastfeeding.

It is not recommended for use during pregnancy.

Limit intake of saturated fats for safety and consume nutrient-rich foods.

The adverse reactions related to exemestane can be categorized as

•Common Adverse Effects: Hot flashes, fatigue, nausea, depression, pain, and insomnia.

•Less Common Adverse Effects: Anxiety, dyspnea, dizziness, headache, oedema, vomiting, flu-like symptoms, abdominal pain, anorexia, cough, hypertension, constipation, and diarrhoea.

•Rare Adverse Effects: Cardiac failure, uterine polyps, endometrial hyperplasia, and gastric ulcer.

Reports on Postmarketing

Immunological conditions: Hypersensitivity

Disorders of the hepatobiliary system: Hepatitis, particularly cholestatic hepatitis

Paresthesia: A nervous system condition

Acute generalized exanthematous pustulosis, urticaria, and pruritus are skin and subcutaneous tissue issues.

Senosynovitis stenosis: A condition of the musculoskeletal and connective tissue.

The clinically relevant drug interactions of exemestane are briefly summarized here.

• Drugs that Induce CYP 3A4: Co-medications that induce CYP 3A4, such as St. John's wort, phenytoin, carbamazepine, rifampicin, or phenobarbital, may considerably reduce the amount of time that exemestane is exposed to. Dose adjustment is advised for patients also taking a potent CYP 3A4 inducer.
• Food Interaction: Enhanced bioavailability with food. Reduced therapeutic benefit when using St. John's wort.

The common side effects of exemestane include:

• Hot flashes
• Nausea
• Osteoporosis
• Insomnia, or trouble falling asleep
• Headache
• Musculoskeletal (bone, muscle or joint) pain
• Increased sweating
• Fatigue
• Rash on the skin
• Weakness

Pregnancy

Pregnancy Category X (FDA): The risks outweigh the potential benefits. Safer alternatives exist.

According to research on animals and the drug mechanism of action, exemestane can harm a developing fetus if it is given to a pregnant woman. There is insufficient human data from case reports to determine a drug's potential harm. Exemestane given to pregnant rats and rabbits resulted in longer gestations with abnormal or difficult labour, a higher frequency of abortions, and embryo-fetal damage in animal reproduction experiments. Inform expectant mothers about the possible danger to the fetus.

For this population, the estimated background risk of severe birth abnormalities and miscarriages is not known.

Animal Data

In animal reproduction studies on rats and rabbits, exemestane induced embryo-fetal toxicity and acted as an abortifacient. Following oral administration of 1 mg per kg exemestane, 14C-exemestane's radioactivity crossed the placenta in rats, with concentrations in maternal and fetal blood being approximately equivalent. When rats received exemestane from 14 days before mating until either day 15 or 20 of gestation and resumed for the 21 days of lactation, an increase in placental weight occurred at 4 mg/kg/day (about 1.5 times the recommended human daily dose on a mg/m2 basis). Doses equal to or greater than 20 mg/kg/day resulted in adverse outcomes, including increased resorptions, reduced live fetuses, decreased fetal weight, delayed ossification, prolonged gestation, and abnormal labour. In rabbits, daily doses during organogenesis led to decreased placental weight at 90 mg/kg/day (approximately 70 times the daily recommended human dose on a mg/m2 basis), and in the presence of maternal toxicity, increased resorptions, abortions, and reduced fetal body weight were observed at 270 mg/kg/day. No malformations occurred when administering exemestane during the organogenesis period at doses up to 810 mg/kg/day in rats and 270 mg/kg/day in rabbits (about 320 and 210 times the daily recommended human dose on a mg/m2 basis, respectively).

• Nursing Mothers

No information is available on the presence of exemestane in human milk, its effects on nursing infants, or how much milk is produced. Rat milk has exemestane levels comparable to those in mother plasma. It is recommended that a woman refrain from breastfeeding while using exemestane pills and for one month following the last dose due to the possibility of severe adverse reactions in breastfed newborns.

• Pediatric Use

As per the FDA, Safety and effectiveness in pediatric patients have not been established.

• Geriatric Use

The pharmacokinetic trials included healthy postmenopausal women between the ages of 43 and 68. Over this age range, no changes in exemestane pharmacokinetics related to age were seen.

Dose Adjustment in Patients on strong CYP3A4 enzyme inducers: 50 mg once daily.

Dose Adjustment in Kidney Impairment Patients:

Individuals with moderate to severe renal impairment (creatinine clearance <35 mL/min/1.73 m2) had higher AUCs for Exemestane. It does not appear that exemestane dosage needs to be changed, though, given that experience with the drug at repeated doses of up to 200 mg daily showed a moderate rise in non-life-threatening adverse events.

Dose Adjustment in Hepatic Impairment Patients:

Individuals with moderate or severe hepatic impairment (Childs-Pugh B or C), the AUC of Exemestane was higher. It does not appear that exemestane dosage needed to be changed, given that experience with the drug at repeated doses of up to 200 mg daily showed a moderate rise in non-life-threatening adverse events.

The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of exemestane.

Exemestane has been administered in single dosages up to 800 mg to healthy female volunteers in clinical trials and at doses up to 600 mg daily for 12 weeks to postmenopausal women with metastatic breast cancer. The dosages were highly well tolerated.

Overdosing has no known cure; hence, the only option for therapy is symptomatic. It is essential to keep in mind that more than one agent may have been ingested when managing an overdose. If the patient is awake, it is possible to induce vomiting. It is recommended to provide general supportive care, which includes regular vital sign monitoring and careful patient observation.

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• US Food and Drug Administration (FDA) [Internet]. Maryland. USA; Package leaflet information for the user; Aromasin® (exemestane)