Megestrol

Mechanism of Action

Megestrol is a synthetic form of progesterone. The mechanism of action has not been fully elucidated in terms of distinguishing its various functions, such as appetite stimulant and antineoplastic agent. It functions as an agonist with a higher affinity to the progesterone receptor than progesterone. There is also a suggestion that megestrol is a glucocorticoid agonist.[10] One study revealed that megestrol binds more strongly than cortisol, the primary naturally occurring ligand, to glucocorticoid receptors with a 46% affinity compared to cortisol’s 25% affinity. This mechanism has correlated with long-term-use adverse effects such as steroid diabetes and Cushing-like symptoms.

Megestrol also possesses anti-gonadotropic activity as a downstream effect activating the progesterone receptor by reducing overall natural steroid synthesis. This action includes inducing suppression of luteinizing hormone and estrogen release from the anterior pituitary gland and has thus linked to megestrol’s application against breast and endometrial cancer. A proposed theory about the management of prostate cancer suggests megestrol blocks gonadotropins by inhibiting 5-alpha reductase and thus reducing dihydrotestosterone levels. Overall, megestrol likely suppresses the hypothalamic-pituitary-adrenal axis and the hypothalamic-pituitary-gonadal axis.[11]

Another hypothesis about appetite stimulation and increased body mass is an increase in Neuropeptide Y levels and inhibition of tumor necrosis factor- α, interleukin-1, and interleukin-6. Preclinical studies have shown that the food and water intake significantly improved in megestrol-treated rats compared to the untreated group. In addition, the synthesis, transport, and release of Neuropeptide Y in the lateral hypothalamus increased, indicating that Neuropeptide Y may be responsible for the appetite-stimulating effect. These studies suggest that megestrol acetate can be orexigenic in cancer/AIDS-induced cachectic patients. In addition, it causes down-regulation of pro-inflammatory molecules such as  IL-6, TNF alpha, interleukin-1, and interleukin-6, and up-regulation of the Neuropeptide Y level. Consequently, there is an increased appetite and body mass and decreased muscle protein degradation.[12][13]

Pharmacokinetics

Absorption: Megestrol is well absorbed. Time to peak concentrations is from 1 to 3 hours for megestrol acetate tablets. The onset of the action takes 3 to 4 weeks for weight gain.

Metabolism: Megestrol is metabolized by  UDP-glucuronosyltransferases (UGTs) and CYP3A4.[14]

Excretion: Urinary excretion is the major route; urinary excretion varies between 56.5% to 78.4%(mean 66.4%). Fecal excretion varies from 7.7% to 30.3% (mean 19.8%).

Administration

Two approved forms of administration exist for megestrol: tablet form and concentrated oral suspension form. In addition, a newly synthesized nanocrystal oral suspension form is currently under investigation for improving bioavailability in the fasting state and optimizing bioavailability and delivery. The tablet form is available as a 20 mg or 40 mg tablet, while the concentrated oral suspension form is available at 40 mg/1mL or a more concentrated form of 125 mg/1mL. The 40 mg oral tablet is usually prescribed four times a day as a starting dosage until a maximum dosage of 800 mg. In contrast, the liquid form is prescribed for once-daily administration.

Literature has indicated that dosages can vary from 100 mg to 1600 mg/day for appetite stimulation. Megestrol demonstrates a positive dose-response effect for improving appetite. Megestrol is typically recommended for a minimum of six weeks. The dosage ranges from 480 to 600 mg/day for the treatment of neoplastic disease. The most common dosages for endometrial cancer or atypical hyperplasia are 160 to 400 mg daily. The initial adult dosage of the oral suspension form for HIV patients is 800 mg/day.

Specific Patient Population

Patients with Hepatic Impairment: No information regarding the use of megestrol in patients with hepatic impairment is provided in the product labeling. However, the metabolism of megestrol is primarily hepatic by cytochrome P450 and UDP-glucuronosyltransferases (UGTs). Therefore, clinicians should exercise caution when prescribing megestrol to patients with hepatic impairment. CYP3A4 may also metabolize megestrol; drug interaction can occur with other CYP3A4 substrates.[14]

Patient with Renal Impairment: Megestrol is significantly excreted by the kidney, so dosage adjustments are necessary for patients with impaired renal function. Additionally, geriatric patients are more likely to have impaired renal function. Consequently, clinicians should closely monitor renal function and adjust the dose accordingly.[15]

Pregnancy Considerations: Megestrol is categorized as a Category-X drug (FDA category), making it an absolute contraindication during pregnancy. Women of childbearing age should use effective birth control and notify the prescribing physician immediately if they become pregnant during treatment. If the patient becomes pregnant while receiving megestrol, the clinician should inform the patient of the potential hazard to the fetus.

Breastfeeding Considerations: According to the product labeling, there are potential adverse effects on the newborn when megestrol is used during breastfeeding; consequently, breastfeeding should be stopped if megestrol is required.

Adverse Effects

The most common side effects of megestrol are weight gain and an increase in appetite. Adverse effects include nausea, vomiting, rash, diarrhea, vaginal bleeding, edema, dyspnea, hypogonadism, hyperglycemia, fluid retention, loss of libido, and hypertension. A severe adverse effect is an increased risk for venous thromboembolic events such as thrombophlebitis and deep venous thrombosis due to increased coagulopathy.[16]

Another severe adverse effect is glucocorticoid side effects such as new-onset diabetes mellitus, worsening of pre-existing diabetes, Cushing-like symptoms, and symptoms of secondary adrenal insufficiency like hypotension, fatigue, and muscle weakness.[17] It is necessary to evaluate the side effects of long-term use, which have links to the glucocorticoid side effects and sudden discontinuation of megestrol, which has demonstrated symptoms of adrenal gland suppression. If the patient or prescribing physician decides to discontinue the drug, the drug should be tapered off and not suddenly discontinued to minimize the risk of adverse side effects.[18][19] In patients withdrawn from chronic megestrol therapy, empiric therapy is indicated with stress doses of a rapidly acting glucocorticoid in conditions of surgery or infection.

Contraindications

 A history of hypersensitivity to any drug components is also a contraindication. A history of thromboembolism, an active thromboembolic event, and a high risk for thromboembolism are relative contraindications. Megestrol is contraindicated in a known or suspected pregnancy according to product labeling. Women of childbearing age should use effective birth control and notify the prescribing physician immediately if they become pregnant during treatment. American Geriatrics Society 2019 Updated AGS Beers Criteria 2019, clinicians should avoid megestrol use due to the increased risk of thrombotic events and possibly death in older adults.[16][20]

Monitoring

An interprofessional healthcare team, including the prescribing clinician, nurses, pharmacists, and registered dieticians, should carefully monitor the signs and symptoms of megestrol use and, in particular, for the off-label uses of megestrol. In an article, the CARE model has been described for patients with cancer and cachexia. In the CARE (Cancer Appetite and Rehabilitation clinic) model, the patients would be evaluated and managed by the entire healthcare team, rather than having numerous appointments and being evaluated by multiple providers at further visits. The clinic's interdisciplinary model includes a clinician, a nurse practitioner, a nutritionist, and a physical therapist, which can help patients suffering from cachexia, eventually enhancing patient outcomes.[21]

Patients require specific monitoring for serious adverse effects such as venous thromboembolism and adrenal insufficiency. Stringent criteria are necessary to determine the use of megestrol in patients with clinically significant weight loss due to the risk of severe side effects. Clinicians should properly inform patients about the possible adverse drug reactions associated with megestrol for their safety. They should also be encouraged to consult the prescribing clinician and pharmacist for additional information. By providing evidence-based, patient-centered care, patient outcomes will ultimately improve. [Level 5]

Toxicity

Generally, toxicity to megestrol is very mild, rated on a scale of Grade 0 or 1. No serious adverse drug reactions have resulted from megestrol acetate administered in dosages as high as 1200 mg/day. Clinicians should properly adjust the dosage of megestrol to prevent toxicity for patients with comorbidities involving hepatic and cardiovascular disease. Secondary adrenal insufficiency also serves as an indicator of toxicity after the withdrawal of long-term treatment. No antidote currently exists for an overdose of megestrol. Supportive treatment should be provided to patients experiencing overdose symptoms such as diarrhea, nausea, and shortness of breath. According to product labeling, it is unknown whether megestrol can be removed by dialysis or not, but due to low solubility, it is hypothesized that it is potentially dialyzable.

Enhancing Healthcare Team Outcomes

An interprofessional healthcare team, including the prescribing clinician, nurses, pharmacists, and registered dieticians, should carefully monitor the signs and symptoms of megestrol use, particularly for the off-label uses of megestrol. In an article, the CARE model has been described for patients with cancer and cachexia. In the CARE (Cancer Appetite and Rehabilitation clinic) model, the entire healthcare team would evaluate and manage the patients, rather than having numerous appointments and being assessed by multiple providers at further visits. The clinic's interprofessional model includes a clinician, a nurse practitioner, a nutritionist, and a physical therapist, which can help patients suffering from cachexia, eventually enhancing patient outcomes.[21]

Patients require specific monitoring for serious adverse effects such as venous thromboembolism and adrenal insufficiency. Stringent criteria are necessary to determine the use of megestrol in patients with clinically significant weight loss due to the risk of severe side effects. Clinicians should properly inform patients about the possible adverse drug reactions associated with megestrol for their safety. They should also be encouraged to consult the prescribing clinician and pharmacist for additional information. All interprofessional team members are responsible for recording their observations in the patient's medical record, so everyone on the team can access the same accurate, up-to-date patient data. They must also communicate any status changes promptly to the appropriate team members so that corrective actions can be implemented if necessary. By providing evidence-based, patient-centered care, patient outcomes will ultimately improve. [Level 5]