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Megestrol


General


Pronunciation

(me JES trole)


Brand Names: U.S.

  • Megace ES
  • Megace Oral

Indications


Use: Labeled Indications

Anorexia or cachexia:Suspension: Treatment of anorexia, cachexia, or unexplained significant weight loss in patients with AIDS

Limitations of use: Treatment of AIDS-related weight loss should only be initiated after addressing the treatable causes (eg, malignancy, infection, malabsorption, endocrine disease, renal disease, psychiatric disorder) for weight loss. Megestrol is not intended to prevent weight loss.

Breast cancer:Tablet: Treatment (palliative) of advanced breast cancer

Endometrial cancer:Tablet: Treatment (palliative) of advanced endometrial carcinoma

Additional Canadian use (not an approved use in the U.S.):Tablet: Treatment of anorexia, cachexia, or weight loss secondary to metastatic cancer


Contraindications


Hypersensitivity to megestrol or any component of the formulation; known or suspected pregnancy (suspension).

Documentation of allergenic cross-reactivity for progestins is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.


Dosing and Administration


Dosing: Adult

Note: Megace ES suspension is not equivalent to other formulations on a mg-per-mg basis.

Anorexia or cachexia associated with AIDS: Oral: Suspension:

U.S. labeling: Initial: 625 mg daily (of the 125 mg/mL suspension) or 800 mg daily (of the 40 mg/mL suspension); daily doses of 400 mg to 800 mg have been found to be effective

Canadian labeling: Usual dose: 400 to 800 mg once daily for at least 2 months

Breast cancer, advanced: Oral: Tablet:

U.S. labeling: 160 mg per day in divided doses of 40 mg 4 times daily for at least 2 months

Canadian labeling: 160 mg or 125 mg/m2 daily (40 mg 4 times daily or 160 mg once daily) for at least 2 months

Endometrial cancer, advanced: Oral: Tablet:

U.S. labeling: 40 to 320 mg daily in divided doses for at least 2 months

Canadian labeling: 80 to 320 mg or 62.5 to 250 mg/m2 daily in divided doses (40 to 80 mg 1 to 4 times daily or 160 to 320mg daily) for at least 2 months

Cancer-related cachexia:Canadian labeling: Oral: Tablet: 400 to 800 mg once daily for at least 2 months

Cancer-related cachexia (off-label use/dosing in U.S.): Oral: Doses ranging from 160 to 800 mg per day were effective in achieving weight gain, higher doses (>160 mg) were associated with more weight gain (Beller, 1997; Loprinzi, 1990; Loprinzi, 1993; Vadell, 1998); based on a meta-analysis, an optimal dose has not been determined (Ruiz Garcia, 2013)


Dosing: Geriatric

Use with caution; refer to adult dosing.


Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturers labeling; however, the urinary excretion of megestrol acetate is substantial, use caution.


Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturers labeling.


Administration

Oral: Shake suspension well before use. Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).


Storage

Suspension: Store at 15 � �C to 25 � �C (59 � �F to 77 � �F); protect from heat. Store/dispense in a tight container.

Tablet: Store at 15 � �C to 30 � �C (59 � �F to 86 � �F); protect from light. Protect from temperatures above 40 � �C (104 � �F).


Dosage Forms/Strengths


Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Suspension, Oral, as acetate:

Megace ES: 625 mg/5 mL (150 mL) [contains alcohol, usp, sodium benzoate; lemon-lime flavor]

Megace Oral: 40 mg/mL (240 mL) [lemon-lime flavor]

Generic: 40 mg/mL (10 mL, 240 mL, 480 mL); 400 mg/10 mL (10 mL); 625 mg/5 mL (150 mL)

Tablet, Oral, as acetate:

Generic: 20 mg, 40 mg


Drug Interactions

Anticoagulants: Progestins may diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of progestins against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Consider therapy modification

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

C1 inhibitors: Progestins may enhance the thrombogenic effect of C1 inhibitors. Monitor therapy

Choline C 11: Antiandrogens may diminish the therapeutic effect of Choline C 11. Monitor therapy

Dofetilide: Megestrol may increase the serum concentration of Dofetilide. Avoid combination

Herbs (Progestogenic Properties) (eg, Bloodroot, Yucca): May enhance the adverse/toxic effect of Progestins. Monitor therapy

Indium 111 Capromab Pendetide: Antiandrogens may diminish the diagnostic effect of Indium 111 Capromab Pendetide. Avoid combination

Pomalidomide: Progestins may enhance the thrombogenic effect of Pomalidomide. Management: Canadian pomalidomide labeling recommends caution with use of hormone replacement therapy and states that hormonal contraceptives are not recommended. US pomalidomide labeling does not contain these specific recommendations. Consider therapy modification

Ulipristal: May diminish the therapeutic effect of Progestins. Progestins may diminish the therapeutic effect of Ulipristal. Management: Ulipristal for uterine fibroids (Canadian indication): avoid progestins within 12 days of stopping ulipristal; as emergency contraceptive (U.S. indication): avoid progestins within 5 days of stopping ulipristal. Avoid combination


Monitoring Parameters

Observe for signs of thromboembolic events; blood pressure, weight; serum glucose


Adverse Reactions


Frequency not always defined.

Cardiovascular: Hypertension (4% to 8%), cardiomyopathy (1% to 3%), chest pain (1% to 3%), edema (1% to 3%), palpitations (1% to 3%), peripheral edema (1% to 3%), cardiac failure

Central nervous system: Headache (3% to 10%), pain (4% to 6%, similar to placebo), insomnia (1% to 6%), abnormality in thinking (1% to 3%), confusion (1% to 3%), convulsions (1% to 3%), depression (1% to 3%), hypoesthesia (1% to 3%), neuropathy (1% to 3%), paresthesia (1% to 3%), carpal tunnel syndrome, lethargy, malaise, mood changes

Dermatologic: Skin rash (6% to 12%), alopecia (1% to 3%), dermatological disease (1% to 3%), diaphoresis (1% to 3%), pruritus (1% to 3%), vesicobullous dermatitis (1% to 3%)

Endocrine & metabolic: Hyperglycemia (6%), decreased libido (1% to 5%), albuminuria (1% to 3%), gynecomastia (1% to 3%), increased lactate dehydrogenase (1% to 3%), adrenocortical insufficiency, amenorrhea, Cushings syndrome, diabetes mellitus, hot flash, HPA-axis suppression, hypercalcemia, weight gain (not attributed to edema or fluid retention)

Gastrointestinal: Diarrhea (10%, similar to placebo), flatulence (6% to 10%), vomiting (4% to 6%), nausea (4% to 5%), dyspepsia (2% to 3%), abdominal pain (1% to 3%), constipation (1% to 3%), oral moniliasis (1% to 3%), sialorrhea (1% to 3%), xerostomia (1% to 3%)

Genitourinary: Impotence (4% to 14%), urinary incontinence (1% to 3%), urinary tract infection (1% to 3%), urinary frequency (1% to 2%), breakthrough bleeding

Hematologic & oncologic: Leukopenia (1% to 3%), sarcoma (1% to 3%), tumor flare

Hepatic: Hepatomegaly (1% to 3%)

Infection: Candidiasis (1% to 3%), herpes virus infection (1% to 3%), infection (1% to 3%)

Neuromuscular & skeletal: Weakness (5% to 6%)

Ophthalmic: Amblyopia (1% to 3%)

Respiratory: Cough (1% to 3%), dyspnea (1% to 3%), pharyngitis (1% to 3%), pulmonary disorder (1% to 3%), pneumonia (1%), hyperventilation

Miscellaneous: Fever (1% to 6%)

Postmarketing and/or case reports (Limited to important or life-threatening): Decreased glucose tolerance, thromboembolic phenomena (including deep vein thrombosis, pulmonary embolism, thrombophlebitis)


Warnings/Precautions


Concerns related to adverse effects:

- Adrenal suppression: May suppress hypothalamic-pituitary-adrenal (HPA) axis during chronic administration; consider the possibility of adrenal suppression in any patient receiving or being withdrawn from chronic therapy when signs/symptoms suggestive of hypoadrenalism are noted (during stress or in unstressed state). Laboratory evaluation and replacement/stress doses of rapid-acting glucocorticoid should be considered.

- Cushing syndrome: Has been reported with long-term use.

Disease-related concerns:

- AIDS-related cachexia: The effects on HIV viral replications are unknown.

- Diabetes: New-onset diabetes mellitus and exacerbation of pre-existing diabetes have been reported with long-term use.

- Thromboembolism: Use with caution in patients with a history of thromboembolic disease.

Special populations:

- Females: Vaginal bleeding or discharge may occur.

Concurrent drug therapy issues:

- Drug-drug interactions: Potentially significant drug interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

- Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol ( ≥99 mg/kg/day) have been associated with a potentially fatal toxicity ( "gasping syndrome " �) in neonates; the "gasping syndrome " � consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP [Inactive" 1997]; CDC, 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors, 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer 's labeling.

- Concentrated suspension: Megace ES suspension in not equivalent to other formulations on a mg-per-mg basis; Megace ES suspension 625 mg/5 mL is equivalent to megestrol acetate suspension 800 mg/20 mL.

Special handling:

- Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).


Pregnancy Risk Factor

D (tablet) / X (suspension)


Pregnancy Considerations

Adverse events were demonstrated in animal reproduction studies. May cause fetal harm if administered to a pregnant woman. Use during pregnancy is contraindicated (suspension) and appropriate contraception is recommended in women who may become pregnant. In clinical studies, megestrol was shown to cause breakthrough vaginal bleeding in women.


Actions


Pharmacology

A synthetic progestin with antiestrogenic properties which disrupt the estrogen receptor cycle. Megestrol interferes with the normal estrogen cycle and results in a lower LH titer. May also have a direct effect on the endometrium. Megestrol is an antineoplastic progestin thought to act through an antileutenizing effect mediated via the pituitary. May stimulate appetite by antagonizing the metabolic effects of catabolic cytokines.


Absorption

Well absorbed


Metabolism

Hepatic (to free steroids and glucuronide conjugates)


Excretion

Urine (57% to 78%; 5% to 8% as metabolites); feces (8% to 30%) within 10 days


Onset of Action

Antineoplastic: 2 months of continuous therapy; Weight gain: 2 to 4 weeks


Time to Peak

Serum: Tablet: 2 to 3 hours; Suspension: 3 to 5 hours


Half-Life Elimination

Suspension: 20 to 50 hours; Tablet: 13 to 105 hours


Patient and Family Education


Patient Education

- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

- Patient may experience nausea, polyphagia, insomnia, or flatulence. Have patient report immediately to prescriber signs of hyperglycemia, signs of depression (ie, suicidal ideation, anxiety, emotional instability, illogical thinking), signs of infection, dyspnea, excessive weight gain, edema of extremities, vaginal hemorrhaging, paresthesia, sexual dysfunction, decreased libido, difficult urination, male macromastia, hot flashes, urinary incontinence, arrhythmia, severe dizziness, considerable headache, significant asthenia, vision changes, or signs of thrombosis (HCAHPS).

- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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