Megace ES

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Megace ES

Classes

Appetite Stimulants, Other
Cytostatic Progestogens

Administration

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 Classification
NIOSH 2016 List: Group 1
NIOSH (Draft) 2020 List: Table 2
Observe 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.

Oral Administration Oral Solid Formulations

Megestrol acetate oral tablets:
It is unknown whether the tablets are affected by food.

Oral Liquid Formulations

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.

Adverse Reactions
Severe

cardiomyopathy / Delayed / 1.0-3.0
seizures / Delayed / 1.0-3.0
heart failure / Delayed / Incidence not known
thrombosis / Delayed / Incidence not known
thromboembolism / Delayed / Incidence not known

Moderate

impotence (erectile dysfunction) / Delayed / 4.0-14.0
hypertension / Early / 0-8.0
hyperglycemia / Delayed / 0-6.0
anemia / Delayed / 3.0-5.0
candidiasis / Delayed / 1.0-3.0
hepatomegaly / Delayed / 1.0-3.0
constipation / Delayed / 1.0-3.0
chest pain (unspecified) / Early / 1.0-3.0
peripheral edema / Delayed / 1.0-3.0
palpitations / Early / 1.0-3.0
edema / Delayed / 1.0-3.0
dyspnea / Early / 1.0-3.0
confusion / Early / 1.0-3.0
depression / Delayed / 1.0-3.0
impaired cognition / Early / 1.0-3.0
peripheral neuropathy / Delayed / 1.0-3.0
leukopenia / Delayed / 1.0-3.0
urinary incontinence / Early / 1.0-3.0
amblyopia / Delayed / 1.0-3.0
hot flashes / Early / Incidence not known
phlebitis / Rapid / Incidence not known
diabetes mellitus / Delayed / Incidence not known
adrenocortical insufficiency / Delayed / Incidence not known
Cushing's syndrome / Delayed / Incidence not known
hypotension / Rapid / Incidence not known
hypothalamic-pituitary-adrenal (HPA) suppression / Delayed / Incidence not known
hypercalcemia / Delayed / Incidence not known

Mild

diarrhea / Early / 6.0-15.0
rash / Early / 2.0-12.0
flatulence / Early / 1.0-10.0
vomiting / Early / 0-6.0
insomnia / Early / 0-6.0
asthenia / Delayed / 3.0-6.0
nausea / Early / 0-5.0
libido decrease / Delayed / 0-5.0
fever / Early / 2.0-5.0
dyspepsia / Early / 3.0-4.0
infection / Delayed / 1.0-3.0
hypersalivation / Early / 1.0-3.0
abdominal pain / Early / 1.0-3.0
xerostomia / Early / 1.0-3.0
diaphoresis / Early / 1.0-3.0
alopecia / Delayed / 1.0-3.0
vesicular rash / Delayed / 1.0-3.0
pruritus / Rapid / 1.0-3.0
pharyngitis / Delayed / 1.0-3.0
cough / Delayed / 1.0-3.0
headache / Early / 1.0-3.0
paresthesias / Delayed / 1.0-3.0
hypoesthesia / Delayed / 1.0-3.0
gynecomastia / Delayed / 1.0-3.0
increased urinary frequency / Early / 1.0-2.0
weight gain / Delayed / 10.0
appetite stimulation / Delayed / Incidence not known
menstrual irregularity / Delayed / Incidence not known
breakthrough bleeding / Delayed / Incidence not known
weakness / Early / Incidence not known
insulin resistance / Delayed / Incidence not known
dizziness / Early / Incidence not known
carpal tunnel syndrome / Delayed / Incidence not known
malaise / Early / Incidence not known
lethargy / Early / Incidence not known

Common Brand Names

Megace, Megace ES

Dea Class

Rx

Description

Synthetic oral progestin with slight glucocorticoid and mineralocorticoid activity; lacks estrogenic, androgenic, or anabolic effects
Used for appetite stimulation and the palliative treatment of advanced breast or endometrial cancer
Used off-label for endometriosis, hormone-refractory prostate cancer, metastatic renal cell cancer, hot flashes

Dosage And Indications
For the treatment of anorexia, cachexia, or unexplained weight loss. In adult patients with acquired immunodeficiency syndrome (AIDS). Oral dosage (125 mg/mL suspension, e.g., Megace ES) Adults

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.

Oral dosage (40 mg/mL suspension) Adults

800 mg PO once daily. Doses of 400 to 800 mg/day were effective in clinical trials.

In pediatric patients with chronic conditions (e.g., cancer, cystic fibrosis, chronic kidney disease, human immunodeficiency virus [HIV])†. Oral dosage (40 mg/mL suspension or tablets) Infants, Children, and Adolescents 6 months to 17 years

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.

For the palliative treatment of advanced, inoperable, recurrent metastatic breast cancer. Oral dosage (tablets) Adults

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.

For the palliative treatment of advanced, inoperable, recurrent metastatic endometrial cancer. Oral dosage (tablets) Adults

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.

For the treatment of advanced hormone-refractory prostate cancer†. Oral dosage (tablets) Adult males

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.

For the for the treatment of metastatic renal cell cancer†. Oral dosage (tablets) Adults

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.

For the treatment of endometriosis†-associated pain†. Oral dosage (tablets) Adult females

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.

For the treatment of hot flashes† in women with a history of breast cancer or in men with prostate cancer who have undergone androgen-deprivation therapy. Oral dosage (tablets) Adults

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

Dosing Considerations
Hepatic Impairment

Hepatic impairment can affect megestrol plasma concentrations; however, specific guidelines for dosage adjustments in hepatic impairment are not available.

Renal Impairment

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 hemodialysis
Megestrol 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.

Drug Interactions

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.

How Supplied

Megace/Megace ES/Megestrol Acetate Oral Susp: 1mL, 5mL, 40mg, 625mg
Megace/Megestrol Acetate Oral Tab: 20mg, 40mg

Maximum Dosage
Adults

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.

Geriatric

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.

Adolescents

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.

Children

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.

Infants

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.

Mechanism Of Action

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.

Pharmacokinetics

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.

Oral Route

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.[63971]
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.[30301]
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.[31330] 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.[31330]

Pregnancy And Lactation
Pregnancy

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.[31330]

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.[31330]