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Appetite Stimulants, OtherCytostatic Progestogens
Synthetic oral progestin with slight glucocorticoid and mineralocorticoid activity; lacks estrogenic, androgenic, or anabolic effectsUsed for appetite stimulation and the palliative treatment of advanced breast or endometrial cancerUsed off-label for endometriosis, hormone-refractory prostate cancer, metastatic renal cell cancer, hot flashes
Megace, Megace ES
Megace/Megace ES/Megestrol Acetate Oral Susp: 1mL, 5mL, 40mg, 625mgMegace/Megestrol Acetate Oral Tab: 20mg, 40mg
625 mg PO once daily. This oral suspension strength (125 mg/mL) is not substitutable with other strengths (e.g., 40 mg/mL), due to dosage differences for this indication.
800 mg PO once daily. Doses of 400 to 800 mg/day were effective in clinical trials.
7.5 to 10 mg/kg/day PO in 1 to 2 divided doses; adjust to individual response. Max: 15 mg/kg/day or 800 mg/day. Reported treatment duration: 1 to 11 months. A higher initial dose of 14 mg/kg/day was used and tapered to 10 mg/kg/day over 5 to 6 months in a retrospective review of pediatric patients (n = 25; age range: 1.7 to 19.7 years) with chronic kidney disease.
40 mg PO given 4 times per day. At least 2 months of therapy is considered an adequate period for determining the antineoplastic effectiveness of megestrol.
40 to 320 mg/day PO, given in divided doses. At least 2 months of therapy is adequate for determining the antineoplastic effectiveness of megestrol.
Dosage has not been established. In a randomized study that compared low-doses of 160 mg PO once daily to high-doses of 640 mg PO once daily in 149 patients with progressive prostate cancer following androgen ablation and 1 prior hormone therapy, there was no significant difference in response rate (2 partial responses (PR) vs. 1 PR), median overall survival time (11.2 vs. 12.1 months), or progression-free survival time (3.8 vs. 4.3 months) between the 2 treatment arms. Toxicity was similar in both study arms and 7% of patients experienced a pain flare. In another randomized phase II trial of 58 patients, 40 mg PO 4 times daily resulted in an objective response rate of 10% compared with 7% in patients who received dexamethasone 0.75 mg PO twice daily. A separate randomized trial was closed early after enrolling 22% of the planned patient accrual; no complete or PR were observed in 86 patients with HRPC who received 1 of 4 treatments: megestrol 40 mg PO 3 times per day as monotherapy, megestrol 40 mg PO given 3 times per day plus diethylstilbestrol 0.1 mg PO once daily, stilphostrol, or streptozotocin.
Dosage has not been established. In a randomized, 4-arm phase II study in 144 evaluable patients, 1 partial response (PR) was reported in 37 patients who received initial treatment with megestrol acetate 150 mg/m2/day PO in 3 divided doses; additionally, 2 PR were reported in 48 patients who crossed over to the megestrol arm after failing initial therapy with one of the other 3 study treatments (etoposide, cyclophosphamide, or dianhydrogalactitol). In another phase II trial, no complete response or PR was observed in 15 patients who received megestrol 80 mg PO twice daily plus interferon alpha-2b (10 million international units/m2 subcutaneously 5 days/week). Stable disease was achieved in 5 patients; 12 patients discontinued therapy due to fatigue.
40 mg PO once daily for 3 to 6 months has been described in a restrospective case study of patients (n = 29) treated for up to 2 years. Disease-related symptoms (dysmenorrhea, noncyclic pelvic pain, and dyspareunia) were relieved in 86% of the subjects treated with an adequate course of therapy. Eight women discontinued treatment within 2 months and 2 others stopped the drug by 4 months, but side effects were typically well tolerated. Treatment guidelines recommend an oral progestogen as a treatment option for reducing endometriosis-associated pain; however, other progestins have more data supporting their use.
Dosage not established. A double-blind, cross over study of 4 weeks of megestrol 20 mg PO twice daily compared to placebo was studied in 97 females with breast cancer and 66 males with prostate cancer who had hot flashes. During the first 4 weeks, 74% of the megestrol group vs. 20% of the placebo group had a 50% decrease in hot flashes compared to baseline. In general, 2 to 3 weeks of therapy was needed to achieve optimal effect. Cross over data demonstrated a carry-over effect of the megestrol and therefore this data was not included in the data analysis.
†Indicates off-label use
Specific maximum dose information is not available for oncologic treatments; see indications. 800 mg/day PO (40 mg/mL suspension) or 625 mg/day PO (125 mg/mL suspension) for anorexia/cachexia.
Safety and efficacy have not been established; however, doses up to 15 mg/kg/day PO or 800 mg/day PO have been used off-label for anorexia/cachexia.
6 to 11 months: Safety and efficacy have not been established; however, doses up to 15 mg/kg/day PO or 800 mg/day PO have been used off-label for anorexia/cachexia.1 to 5 months: Safety and efficacy have not been established.
Hepatic impairment can affect megestrol plasma concentrations; however, specific guidelines for dosage adjustments in hepatic impairment are not available.
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. However, megestrol is substantially excreted by the kidney and the risk of toxic reactions may be greater in patients with impaired renal function. Intermittent hemodialysisMegestrol acetate has not been tested for dialyzability; however, due to its low solubility it is postulated that hemodialysis is not an effective means of drug removal. No supplemental dosages are needed.
NOTE: The correct dose of megestrol for the treatment of neoplastic disease will vary from protocol to protocol. Clinicians should consult the appropriate references to verify the dose.For storage information see specific product information, within the How Supplied section.Hazardous Drugs ClassificationNIOSH 2016 List: Group 1 NIOSH (Draft) 2020 List: Table 2Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
Megestrol acetate oral tablets:It is unknown whether the tablets are affected by food.
Megestrol Acetate Oral Suspension:Shake well prior to administration. Measure dosage with calibrated cup, spoon, or oral syringe.Megestrol suspension (40 mg/mL) and megestrol ES suspension (125 mg/mL) are available in different strengths and the dosage for the treatment of cachexia and anorexia in AIDS patients is different for these 2 formulations. It is imperative that health care providers inform patients of these differences to prevent errors in dosage. This Megace ES suspension (125 mg/mL) is not substitutable with other strengths (e.g., 40 mg/mL).Recommendations on the administration of the original 40 mg/mL suspension with food have NOT been made.The concentrated 125 mg/mL ES suspension can be taken without regard to meals.
Megace:- Protect from heat- Store between 68 to 77 degrees FMegace ES:- Avoid exposure to heat- Store at controlled room temperature (between 68 and 77 degrees F)
Megestrol is contraindicated in those patients with a history of hypersensitivity to megestrol acetate or any component of the formulation. Megestrol acetate is not intended for prophylactic use to avoid weight loss. Therapy with megestrol acetate oral suspension for weight loss should only be instituted after treatable causes of weight loss are sought and addressed. These treatable causes include possible malignancies, systemic infections, gastrointestinal disorders affecting absorption, endocrine disease, renal disease, or psychiatric disease.
Megestrol acetate has been used extensively in women for the treatment of breast and endometrial cancer; its use in HIV-infected females has been limited. Megestrol is a progesterone derivative, which may induce vaginal bleeding in women. In establishing the indication for the treatment of anorexia and cachexia secondary to human immunodeficiency virus (HIV), all ten females in the clinical trial reported the side effect of menstrual irregularity (breakthrough bleeding). However, vaginal bleeding can also be a sign of a serious gynecological problem. Prior to starting megestrol, females with undiagnosed abnormal vaginal bleeding or dysfunctional uterine bleeding should be evaluated.
Breast cancer in which estrogen and/or progesterone receptors are positive are more likely to respond to megestrol. The use of megestrol in other types of neoplastic disease is not recommended. Close surveillance is indicated for any patient treated for recurrent or metastatic cancer. Administration of megestrol acetate to female dogs for up to 7 years is associated with an increased incidence of both benign and malignant tumors of the breast. Comparable studies in rats and studies in monkeys are not associated with an increased incidence of tumors. Pituitary tumors were observed in female rats treated with 3.9 or 10 mg/kg/day of megestrol acetate for 2 years. The relationship of the dog tumors to humans is unknown but should be considered in assessing the benefit-to-risk ratio when prescribing megestrol and in surveillance of patients on therapy.
The glucocorticoid activity of megestrol has not been fully evaluated, clinical cases of new onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, hyperglycemia, and overt Cushing's syndrome have been reported in association with the chronic use of megestrol. In addition, clinical cases of adrenal insufficiency have been observed in patients receiving or being withdrawn from chronic megestrol therapy in the stressed and non-stressed state. Furthermore, adrenocorticotropin (ACTH) stimulation testing has revealed the frequent occurrence of asymptomatic pituitary-adrenal suppression in patients treated with chronic megestrol therapy. The possibility of adrenal suppression should be considered in any patient taking or withdrawing from chronic megestrol therapy who presents with symptoms of adrenal insufficiency (e.g., hypotension, nausea, vomiting, dizziness, or weakness). Laboratory evaluation for adrenal insufficiency and replacement stress doses of a rapidly acting glucocorticoid may be indicated for such patients. Failure to recognize hypothalamic-pituitary-adrenal (HPA) suppression may result in death. Finally, in patients who are receiving or being withdrawn from chronic megestrol therapy, consideration should be given to the use of empiric therapy with stress doses or a rapidly acting glucocorticoid in conditions of stress or serious intercurrent illness (e.g., surgery, infection).
Use megestrol cautiously in patients with a history of thromboembolic disease. Thromboembolism (including deep vein thrombosis and pulmonary embolism) and thrombophlebitis have been associated with megestrol therapy.
Hepatic impairment can affect the inactivation of megestrol and, thus, plasma concentrations, patients with severe hepatic disease should be monitored for adverse effects. Specific guidelines for dosage adjustments in these patients are not available.
Megestrol acetate is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with renal impairment or renal failure. Care should be taken in dose selection, and it may be useful to monitor renal function in patients with impaired renal function, especially in elderly adults.
Clinical studies of megestrol acetate for the treatment of cachexia, anorexia, or an unexplained weight loss in patients with AIDS did not include sufficient numbers of geriatric patients aged 65 years or older. Reported clinical experience has not identified differences in responses between younger adults and geriatric patients. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function. According to the Beers Criteria, megestrol is considered a potentially inappropriate medication (PIM) for use in geriatric patients as a general treatment for cachexia/poor appetite and should be avoided due to a minimal effect on weight and an increased risk of thrombotic events and possibly death in older adults. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of medications in residents of long-term care facilities. According to the OBRA guidelines, use of appetite stimulants should be reserved for situations where assessment and management of underlying correctable causes of anorexia and weight loss are not feasible or successful, and after evaluating the potential benefits versus risks. Appetite and weight should be monitored at least monthly and the appetite stimulant should be discontinued if there is no improvement. Possible adverse effects of megestrol acetate include fluid retention, adrenal suppression, and symptoms of adrenal insufficiency.
Megestrol is contraindicated during pregnancy. Based on animal studies, megestrol may cause fetal harm when administered to pregnant women. There are no available human data to assess for any drug associated risks of miscarriage, birth defects, or adverse maternal or fetal outcomes. Prior to use of megestrol, confirm that a female of childbearing potential is not pregnant. Females of childbearing potential should be advised to avoid becoming pregnant while receiving megestrol treatment. If megestrol is used during pregnancy, or if the patient becomes pregnant while taking megestrol, advise the patient of the potential hazard to the fetus. Reproduction studies were performed in pregnant rats at oral doses ranging from 0.05 to 12.5 mg/kg/day, which are below the maximum recommended human clinical dose (MRHD) based on body surface area. Reduction in fetal weight and number of live births were observed at 12.5 mg/kg/day (5 times lower than the MRHD) when dams were dosed on days 12 through 18 of pregnancy. Feminization of male fetuses also occurred when dams were dosed on days 13 through 20 of pregnancy at 3 mg/kg/day, approximately 22 times below the MRHD.
In female patients of childbearing potential, discuss the reproductive risk of megestrol and the contraception requirements during use including the need for pregnancy testing before therapy. Advise female patients of childbearing potential to contact their physician immediately if they become pregnant or suspect they may be pregnant. If a pregnancy test is positive, counsel the patient on the potential risk to the fetus and discuss options. To prevent pregnancy, females of reproductive potential must use acceptable contraception methods during treatment.
Megestrol should not be used during breast-feeding since its effect on the breastfed infant or the effects on milk production are not known. Alternate forms of feeding are recommended if megestrol therapy is essential to the mother. Megestrol is known to be excreted in human breast milk; the amount that an infant absorbs systemically per day is estimated to be 0.1% of the maternal daily ingested dose based on available data. The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed to avoid risking postnatal transmission of HIV-1 to the breastfed child.
cardiomyopathy / Delayed / 1.0-3.0seizures / Delayed / 1.0-3.0heart failure / Delayed / Incidence not knownthrombosis / Delayed / Incidence not knownthromboembolism / Delayed / Incidence not known
impotence (erectile dysfunction) / Delayed / 4.0-14.0hypertension / Early / 0-8.0hyperglycemia / Delayed / 0-6.0anemia / Delayed / 3.0-5.0candidiasis / Delayed / 1.0-3.0hepatomegaly / Delayed / 1.0-3.0constipation / Delayed / 1.0-3.0chest pain (unspecified) / Early / 1.0-3.0peripheral edema / Delayed / 1.0-3.0palpitations / Early / 1.0-3.0edema / Delayed / 1.0-3.0dyspnea / Early / 1.0-3.0confusion / Early / 1.0-3.0depression / Delayed / 1.0-3.0impaired cognition / Early / 1.0-3.0peripheral neuropathy / Delayed / 1.0-3.0leukopenia / Delayed / 1.0-3.0urinary incontinence / Early / 1.0-3.0amblyopia / Delayed / 1.0-3.0hot flashes / Early / Incidence not knownphlebitis / Rapid / Incidence not knowndiabetes mellitus / Delayed / Incidence not knownadrenocortical insufficiency / Delayed / Incidence not knownCushing's syndrome / Delayed / Incidence not knownhypotension / Rapid / Incidence not knownhypothalamic-pituitary-adrenal (HPA) suppression / Delayed / Incidence not knownhypercalcemia / Delayed / Incidence not known
diarrhea / Early / 6.0-15.0rash / Early / 2.0-12.0flatulence / Early / 1.0-10.0vomiting / Early / 0-6.0insomnia / Early / 0-6.0asthenia / Delayed / 3.0-6.0nausea / Early / 0-5.0libido decrease / Delayed / 0-5.0fever / Early / 2.0-5.0dyspepsia / Early / 3.0-4.0infection / Delayed / 1.0-3.0hypersalivation / Early / 1.0-3.0abdominal pain / Early / 1.0-3.0xerostomia / Early / 1.0-3.0diaphoresis / Early / 1.0-3.0alopecia / Delayed / 1.0-3.0vesicular rash / Delayed / 1.0-3.0pruritus / Rapid / 1.0-3.0pharyngitis / Delayed / 1.0-3.0cough / Delayed / 1.0-3.0headache / Early / 1.0-3.0paresthesias / Delayed / 1.0-3.0hypoesthesia / Delayed / 1.0-3.0gynecomastia / Delayed / 1.0-3.0increased urinary frequency / Early / 1.0-2.0weight gain / Delayed / 10.0appetite stimulation / Delayed / Incidence not knownmenstrual irregularity / Delayed / Incidence not knownbreakthrough bleeding / Delayed / Incidence not knownweakness / Early / Incidence not knowninsulin resistance / Delayed / Incidence not knowndizziness / Early / Incidence not knowncarpal tunnel syndrome / Delayed / Incidence not knownmalaise / Early / Incidence not knownlethargy / Early / Incidence not known
Dofetilide: (Contraindicated) All inhibitors of renal cationic secretion, including megestrol, are contraindicated with dofetilide. In a population pharmacokinetic analysis of plasma dofetilide concentrations, the mean clearance of dofetilide was 15% lower in patients receiving inhibitors of tubular organic cation transport. Entecavir: (Minor) Entecavir and megestrol are eliminated by active renal tubular secretion. In theory, coadministration of these drugs may increase the serum concentrations of either drug due to competition for the drug elimination pathway. Coadministration of entecavir with antiviral drugs known to be eliminated by active tubular secretion did not result in significant drug interactions in studies Indinavir: (Major) Due to the significant decrease in the exposure of indinavir by megestrol acetate, administration of a higher dose of indinavir should be considered when coadministering with megestrol acetate. Specific adjustment recommendations are not available, but should be determined by viral response. In one pharmacokinetic study of healthy male subjects, co-administration of megestrol acetate (675 mg/day for 14 days) and indinavir (a single dose 800 mg) resulted in a 32% decrease in the Cmax of indinavir and a 21% decrease in the AUC of indinavir. Trospium: (Minor) Trospium is metabolized by ester hydrolysis and excreted by the kidneys through a combination of tubular secretion and glomerular filtration. Some drugs which are actively secreted by the kidney, including megestrol, may interact with trospium by competing for renal tubular secretion. Be alert for increased effect of either trospium ( anticholinergic effects) or megestrol. Warfarin: (Moderate) At high doses, megestrol may be associated alterations in warfarin pharmacokinetics that may increase warfarin exposure. Carefully monitor the INR when these drugs are used together. Lower doses of warfarin may be necessary when megestrol is given. In one study, a small change in the rate of warfarin clearance was see with concomitant administration of high doses of megestrol; a minor decrease observed in warfarin clearance may be of clinical importance. Additionally, a 71% increase in warfarin's half-life was seen.
Mechanism of Action: Megestrol shares the properties of the progestins. The drug induces endometrial secretory changes, increases basal body temperature, inhibits pituitary function, and precipitates bleeding when estrogen is present. The mechanism of its antineoplastic activity is not known, but it has been suggested that megestrol-induced suppression of luteinizing hormone release from the pituitary may have a negative effect on cancerous tissues of the breast and endometrial lining. Megestrol enhances estrogen metabolism, which suppresses estrogen-dependent tumors by lowering plasma estrogen concentrations. Megestrol also may change the actively growing cancer cell stroma into decidua. Because megestrol promotes the differentiation and maintenance of endometrial tissue, it is effective in the therapy of endometriosis and endometrial cancer.The reported weight gain associated with megestrol therapy is believed to be due to the drug's metabolic and appetite-stimulatory effects rather than to its glucocorticoid activity. Megestrol, or its metabolites, may interfere with cachexin, the hormone that inhibits adipocyte lipogenic enzymes and leads to the wasting syndrome of AIDS or cancer. Weight gain occurs within 3 weeks in most patients who receive megestrol for this purpose.
Megestrol is administered orally. The drug is highly bound to plasma proteins, chiefly transcortin. Megestrol tends to concentrate in adipose tissue. Megestrol is inactivated by the liver; however, metabolites account for only 5% to 8% of the administered dose and are considered negligible. The major route of drug elimination in humans is the urine with a minor portion excreted in the feces; the urinary excretion within 10 days after administration ranges from 56.5% to 78.4% and fecal excretion ranges from 7.7% to 30.3%. Respiratory excretion and fat storage of metabolites may account for at least part of the radioactivity not found in urine and feces. During a pharmacokinetic evaluation of megestrol in healthy subjects, the mean elimination half-life ranged from 20 to 50 hours.
Tablets: Megestrol appears to be rapidly absorbed across the GI tract, with a bioavailability of greater than 90%, although this varies significantly among individual patients. Peak concentrations for the tablets occur in 1 to 3 hours. Whether the tablets are affected by food has not been established. The relative bioavailability of the oral tablets to oral suspension has not been determined.Oral suspension (40 mg/mL): The median Tmax for the 40 mg/mL suspension was 5 hours. The effect of food on the absolute bioavailability of megestrol acetate oral suspension has not been evaluated.Oral suspension ES (125 mg/mL; e.g., Megace ES suspension): Mean plasma concentrations of megestrol acetate after administration of 625 mg dose (125 mg/mL) of Megace ES oral suspension are equivalent under fed conditions to a 800 mg dose (40 mg/mL) of the original megestrol acetate oral suspension in healthy volunteers. Per the product label, the 125 mg/mL megestrol ES oral suspension is not substitutable with other suspension strengths (e.g., 40 mg/mL); the dosage recommendations differ by product concentration. The mean Cmax and AUC when administered after a high-fat meal were increased by 48% and 36% respectively, compared to the Cmax and AUC under the fasting conditions. This food effect on Cmax and AUC is significantly less than that seen for the original megestrol 40 mg/mL oral suspension where administration with a high-fat meal significantly increased AUC and Cmax of megestrol acetate to 2-fold and 7-fold, respectively, compared to the fasting condition. There was no difference in safety following administration of the megestrol ES suspension in the fed states; therefore, megestrol ES suspension may be taken without regard to meals.