Megestrol Acetate

Class: Antineoplastic Agents
VA Class: AN500
Chemical Name: 17-Hydroxy-6-methylpregna-4,6-diene-3,20-dione acetate
Molecular Formula: C₂₄H₃₂O₄
CAS Number: 595-33-5
Brands: Megace

Introduction

Synthetic progestin; antineoplastic agent and appetite stimulant.

Uses for Megestrol Acetate

Breast Cancer

Palliative management of recurrent, inoperable, or metastatic breast cancer.^{b c}

Estrogen and/or progesterone receptor-positive breast cancer is more likely to respond to megestrol therapy.^b

Does not replace appropriate methods of treatment of advanced breast cancer (e.g., surgery, radiation, chemotherapy).^{b c}

Not recommended for treatment of other types of neoplastic disease; use only for treatment of breast cancer or endometrial cancer.^b

Endometrial Cancer

Palliative management of recurrent, inoperable, or metastatic endometrial carcinoma.^{b c}

Does not replace appropriate methods of treatment of advanced endometrial carcinoma (e.g., surgery, radiation, chemotherapy).^{b c}

Not recommended for treatment of other types of neoplastic disease; use only for treatment of endometrial cancer or breast cancer.^b

Cachexia

Management of anorexia, cachexia, or an unexplained, substantial weight loss in HIV-infected individuals (designated an orphan drug by FDA for this use).^{102 104 106 107 108 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 138 a}

Also has been used to stimulate appetite and promote weight gain in a limited number of patients with cachexia associated with neoplastic disease†.^{100 101 103 108 116 117 118 119 134 135}

Therapy should be initiated only after treatable causes (e.g., possible malignancies; systemic infections; GI disorders affecting absorption; endocrine, renal, or psychiatric diseases) of the condition have been evaluated.¹²¹

Manufacturer states that megestrol should not be used prophylactically to avoid weight loss.

Megestrol Acetate Dosage and Administration

Administration

Oral Administration

Administer orally.^{138 a b}

Manufacturer makes no specific recommendations regarding administration with meals.^a

Oral suspensions containing 200 mg/5 mL are not bioequivalent or interchangeable on a mg-per-mg basis with the oral suspension containing 625 mg/5 mL (Megace ES).¹³⁸ (See Plasma Concentrations under Pharmacokinetics.)

Dosage

Available as megestrol acetate; dosage expressed in terms of the salt.^{138 a b}

Adults

Breast Cancer

Oral (Tablets)

160 mg daily in 4 equally divided doses (40 mg 4 times daily); continue therapy for at least 2 months to determine antineoplastic effectiveness.^b

Dosages of 480-1600 mg daily in divided doses have been used in clinical trials.^{100 108 110 114}

Endometrial Carcinoma

Oral (Tablets)

40–320 mg daily in divided doses; continue therapy for at least 2 months to determine antineoplastic effectiveness.^b

Cachexia

Treatment in HIV-infected Individuals

Oral (Oral Suspension)

Initially, 800 mg daily (20 mL per day).^{121 122 126 127 128 130 a}

In clinical trials, 400 mg daily also has been used effectively.^a

Oral (Concentrated Oral Suspension [Megace ES])

Initially, 625 mg daily.¹³⁸

Clinically effective dosages are expected to range from 312.5–625 mg daily.¹³⁸

Treatment in Individuals with Neoplastic Disease†

Oral

480–600 mg daily generally have been used.^c However, some patients may exhibit weight gain with dosages as low as 160 mg daily.^c

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.^{138 a b}

Renal Impairment

No specific dosage recommendations at this time.^{138 a b} (See Renal Impairment under Cautions.)

Geriatric Patients

Treatment of cachexia in HIV-infected individuals: Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.¹³⁸

Treatment of breast cancer or endometrial cancer: No specific dosage recommendations at this time.^b

Cautions for Megestrol Acetate

Contraindications

• 
  

  Known hypersensitivity to megestrol or any ingredient in the formulation.^{138 a c}

  
  

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity

May cause fetal harm; animal studies indicate dose-related feminization of male fetuses.^{138 a c} If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.^{138 a c}

Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression

Asymptomatic pituitary-adrenal suppression occurs frequently in patients receiving chronic therapy; suppression of HPA function may be fatal if not recognized.^{138 a b} Adrenal insufficiency reported in patients receiving or being withdrawn from chronic therapy.^{138 a b}

Laboratory evaluation recommended if signs/symptoms of adrenal insufficiency (e.g., hypotension, nausea, vomiting, dizziness, weakness) occur in patients receiving or being withdrawn from chronic therapy; administration of replacement or stress dosages of a rapidly acting glucocorticoid may be required, especially in patients subjected to stress (e.g., surgery, infection).^{138 a b}

Glucocorticoid activity of megestrol not fully evaluated.^{138 a b}

Endocrine Effects

May increase insulin requirements and aggravate or precipitate diabetes mellitus.^{138 a b}

Administration over a prolonged period may produce hypercorticism (Cushing's syndrome).^{138 a b}

General Precautions

Cardiovascular Effects

Thromboembolic events (e.g., deep-vein thrombophlebitis, pulmonary embolism), sometimes fatal, reported.^b Use with caution in patients with a history of thromboembolic disease.^{138 a b}

HIV Viral Replication

Effect of megestrol therapy on HIV viral replication not evaluated.^{138 a}

Respiratory Effects

Possible increased risk of respiratory infections associated with chronic therapy.^{138 a}

Specific Populations

Pregnancy

Category X (Oral Suspensions);^{138 a} Category D (Tablets).^b (See Fetal/Neonatal Morbidity under Cautions.)

Lactation

Discontinue nursing because of potential risk to nursing infants.^{138 a b}

Pediatric Use

Safety and efficacy not established.^{138 a b}

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients with cachexia respond differently than younger adults; select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.¹³⁸ (See Geriatric Patients under Dosage and Administration.)

Substantially eliminated by kidneys; assess renal function periodically since geriatric patients are more likely to have decreased renal function.¹³⁸

Renal Impairment

Substantially eliminated by kidneys; possible increased risk of toxicity.¹³⁸

Common Adverse Effects

In patients with breast cancer or endometrial cancer: Weight gain,^b nausea,^b vomiting,^b hypertension,^b vaginal bleeding and discharge (including breakthrough bleeding),^{108 b} hyperglycemia,^b asthenia,^b rash.^b

In patients with cachexia: Diarrhea, flatulence, nausea, vomiting, hypertension, impotence, decreased libido, asthenia, rash, insomnia, anemia, fever, hyperglycemia, pain.^{138 a}

Interactions for Megestrol Acetate

Specific Drugs

Drug	Interaction	Comments
Indinavir	Decreased plasma concentrations and AUC of indinavir138 Effect of indinavir on megestrol pharmacokinetics not evaluated138	If used with megestrol, consider increasing indinavir dosage138
Rifabutin	Pharmacokinetics of rifabutin not significantly altered138 Effect of rifabutin on megestrol pharmacokinetics not evaluated138	Dosage adjustments not required138
Zidovudine	Pharmacokinetics of zidovudine not significantly altered138 Effect of zidovudine on megestrol pharmacokinetics not evaluated138	Dosage adjustments not required138

Megestrol Acetate Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration, with peak plasma concentration usually attained within 1–5 hours.^c

Plasma Concentrations

Plasma concentrations achieved with a 625-mg dose of the concentrated oral suspension (Megace ES 625 mg/5 mL) are equivalent to those achieved with an 800-mg dose of the original formulation (200 mg/5 mL) under fed conditions.¹³⁸

Elimination

Metabolism

Completely metabolized in the liver to free steroids and glucuronide conjugates.

Elimination Route

Excreted principally in urine (about 66%) and in feces (about 20%).^{138 a b}

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15-30°C); protect from heat.^b

Suspension

Tight containers at 15–25°C; protect from heat.^{138 a}

ActionsActions

• 
  

  Induces secretory changes in the endometrium, increases basal body temperature, inhibits pituitary function, and produces withdrawal bleeding in the presence of estrogen.^c

  
  


• 
  

  In animals, suppresses ovulation and produces antigonadotropic, antiuterotropic, and antiandrogenic/antimyotropic effects; has slight glucocorticoid activity and a very slight degree of mineralocorticoid activity; and has no estrogenic, androgenic, or anabolic activity.^c

  
  


• 
  

  Antineoplastic effect may result from inhibition of pituitary gonadotropin production which results in decreased estrogen secretion.^b

  
  


• 
  

  Decreases the number of hormone-dependent breast cancer cells and eliminates the stimulatory effect that estrogen has on these cells.^b

  
  


• 
  

  May produce a local effect on cancerous cells by converting the actively growing stroma into decidua.^c

  
  


• 
  

  May directly or indirectly stimulate appetite or may alter metabolic pathways via interference with the production or action of mediators such as cachectin (a hormone that inhibits adipocyte lipogenic enzymes);^{100 101 103 109 110 111} however precise mechanism for weight gain not clearly established.^{100 101 103 108 109 116 121}

  
  

Advice to Patients

• 
  

  Importance of taking megestrol exactly as prescribed.

  
  


• 
  

  Importance of informing patients that the more concentrated oral suspension containing 625 mg/5 mL (Megace ES) does not contain the same amount of megestrol as oral suspensions containing 200 mg/5 mL and therefore are not interchangeable.¹³⁸

  
  


• 
  

  Importance of patients informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs.^{128 135 c}

  
  


• 
  

  Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy and advise pregnant women of risk to the fetus.^{138 a b}

  
  


• 
  

  Importance of informing patients of other important precautionary information.^{138 a b} (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Megestrol Acetate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Suspension	200 mg/5 mL*	Megace (with alcohol 0.06% v/v, polyethylene glycol, polysorbate [Tween] 80, and xanthan gum)	Bristol-Myers Squibb
			Megestrol Acetate Suspension	Barr, Morton Grove, Par, Roxane, Teva
		625 mg/5 mL	Megace ES (with alcohol 0.06% v/v, docusate sodium, and hydroxypropyl methylcellulose)	Par
	Tablets	20 mg*	Megestrol Acetate Tablets	Barr, Par, Roxane, Teva
		40 mg*	Megestrol Acetate Tablets	Barr, Par, Roxane, Teva

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Megace ES 625MG/5ML Suspension (PAR): 150/$639.99 or 450/$1813.9

Megace Oral 40MG/ML Suspension (B-M SQUIBB ONCOLOGY/IMMUNOLOGY): 240/$167.99 or 480/$313.97

Megestrol Acetate 20MG Tablets (PAR): 100/$37.99 or 300/$104.96

Megestrol Acetate 40MG/ML Suspension (MORTON GROVE PHARMACEUTICALS): 240/$131.99 or 480/$257.99

Megestrol Acetate 40MG Tablets (TEVA PHARMACEUTICALS USA): 100/$52.99 or 300/$152.98

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions June 2006. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

1. Ref 1 is cited but not in AHFS mono or Word copy of essential.

2. Mead Johnson. Megace (megestrol acetate) prescribing information. Evansville, IN; 1971 Dec.

24. Cooper JM, Kellie AE. The metabolism of megestrol acetate (17α-acetoxy-6-methylpregna-4,6-diene-3,20-dione) in women. Steroids. 1968; 11:133-49. [PubMed 5636707]

100. Tchekmedyian NS, Tait N, Moody M et al. Appetite stimulation with megestrol acetate in cachectic cancer patients. Semin Oncol. 1986; 13(4 Suppl 4):37-43. [PubMed 3798127]

101. Tchekmedyian NS, Tait N, Moody M et al. High-dose megestrol acetate: a possible treatment for cachexia. JAMA. 1987; 257:1195-8. [IDIS 225863] [PubMed 3806918]

102. Von Roenn JH, Murphy RL, Weber KM et al. Megestrol acetate for treatment of cachexia associated with human immunodeficiency virus (HIV) infections. Ann Intern Med. 1988; 109:840-1. [IDIS 248037] [PubMed 3190032]

103. Aisner J, Tchekmedyian NS, Tait N et al. Studies of high-dose megestrol acetate: potential applications in cachexia. Semin Oncol. 1988; 15(2 Suppl 1):68-75. [PubMed 3285486]

104. Furth PA. Megestrol acetate and cachexia associated with human immunodeficiency virus (HIV) infection. Ann Intern Med. 1989; 110:667. [IDIS 253261] [PubMed 2535614]

105. Von Roenn JH, Murphy RL, Weber KM et al. Megestrol acetate and cachexia associated with human immunodeficiency virus (HIV) infection. Ann Intern Med. 1989; 110:667-8. [IDIS 253261] [PubMed 2535614]

106. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414), to June 30, 1993. Rockville, MD; 1993 Aug.

107. Fessel WJ. Megestrol acetate and hyperpnea. Ann Intern Med. 1989; 110:1034-5. [IDIS 255911] [PubMed 2729805]

108. Schacter L, Rozencweig M, Canetta R et al. Megestrol acetate: clinical experience. Cancer Treat Rev. 1989; 16:49-63. [PubMed 2471590]

109. Hamburger AW, Parnes H, Gordon GB et al. Megestrol acetate-induced differentiation of 3T3-L1 adipocytes in vitro. Semin Oncol. 1988; 15(2 Suppl 1):76-8. [PubMed 2453082]

110. Aisner J, Tchekmedyian NS, Moody M et al. High-dose megestrol acetate for the treatment of advanced breast cancer: dose and toxicities. Semin Hematol. 1987; 24(2 Suppl 1):48-55. [PubMed 3589708]

111. Torti FM, Dieckmann B, Beutler B et al. A macrophage factor inhibits adipocyte gene expression: an in vitro model of cachexia. Science. 1985; 229:867-9. [PubMed 3839597]

112. Miksicek R, Heber A, Schmid W et al. Glucocorticoid responsiveness of the transcriptional enhancer of Moloney murine sarcoma virus. Cell. 1989; 46:283-90.

113. Muss HB, Wells HB, Paschold EH et al. Megestrol acetate versus tamoxifen in advanced breast cancer: 5-year analysis—a phase III trial of the Piedmont Oncology Association. J Clin Oncol. 1988; 6:1098-106. [PubMed 3292710]

114. Tchekmedyian NS, Tait N, Abrams J et al. High-dose megestrol acetate in the treatment of advanced breast cancer. Semin Oncol. 1988; 15(2 Suppl 1):44-9. [PubMed 3368800]

115. Reviewer’s comments (personal observations). 1989 Dec 28.

116. Loprinzi CL, Ellison NM, Schaid DS et al. Controlled trial of megestrol acetate for the treatment of cancer anorexia and cachexia. J Natl Cancer Inst. 1990; 82:1127-32. [PubMed 2193166]

117. Heckmayr M, Gatzemeier U. Megestrol acetate in cachectic patients with advanced bronchogenic cancer. Onkologie. 1990; 13:285-7. [PubMed 2172885]

118. Bruera E, Macmillan K, Kuehn N et al. A controlled trial of megestrol acetate on appetite, caloric intake, nutritional status, and other symptoms in patients with advanced cancer. Cancer. 1990; 66:1279-82. [IDIS 273026] [PubMed 2205358]

119. Raub W. Possible antianorexia/cachexia therapy for cancer patients. JAMA. 1990; 264:1086. [PubMed 2117074]

120. Megace prescribing information. In: Barnhart ER, publisher. Physicians’ desk reference. 44th ed. Oradell, NJ: Medical Economics Company Inc; 1990:749.

121. Mead Johnson. Megace oral suspension (megestrol acetate) prescribing information. Princeton, NJ; 1993 Sep.

122. Oster M, Enders S, Samuels S et al. Randomized, double-blind study comparing high-dose megestrol acetate and placebo in cachectic patients with acquired immunodeficiency syndrome (AIDS). Int Conf AIDS. 1993; 9:528.

123. Berman S, Katz K, Ho M et al. Megestrol acetate produces weight gain in HIV+ patients. Int Conf AIDS. 1993; 9:499.

124. Von Roenn JH, Roth EL, Craig R. HIV-related cachexia: potential mechanisms and treatment. Oncology. 1992; 49(Suppl 2):50-4. [PubMed 1461629]

125. Scevola D, Bottari G, Oberto L et al. Changes in caloric intake, anthropometric parameters and TNF levels induced by megestrol acetate in AIDS patients. Int Conf AIDS. 1992; 8:133.

126. Flynn N, Enders S, Oster M etal. Megestrol acetate 800 mg/day vs placebo for treatment of weight loss and anorexia in AIDS patients. Int Conf Aids. 1992; 8:B205.

127. Mahayni H, Minor JR. Megestrol acetate in AIDS-related cachexia. Am J Hosp Pharm. 1991; 48:2479-80. [PubMed 1746586]

128. Von Roenn J, Roth E, Murphy R et al. Controlled trial of megestrol acetate for the treatment of AIDS-related anorexia and cachexia. Int Conf AIDS. 1991; 7:280.

129. Scevola D, Barbarini G, Bottari G et al. Prevalence, etiology and management of AIDS malnutrition. Int Conf AIDS. 1991; 7:224.

130. Tierney A, Cuff P, Kotler DP. The effect of megestrol acetate (Megace) on appetite, nutritional repletion, and quality of life in AIDS cachexia. Int Conf AIDS. 1991; 7:247.

131. Nathwani D, Green ST, Heslop JM et al. Beneficial response to megoestrol acetate in AIDS-related cachexia and a possible megoestrol withdrawal-associated syndrome? Acta Der Venereol (Stockh). 1990; 70:520-1.

132. Von Roenn JH, Murphy RL, Wegener N. Megestrol acetate for treatment of anorexia and cachexia associated with human immunodeficiency virus infection. Semin Oncol. 1990; 17(Suppl 9):13-6. [PubMed 2259923]

133. Von Roenn JH, Murphy RL, Weitzman S. Megestrol acetate and the treatment of HIV-related cachexia. Proc Ann Meet Am Soc Clin Onco. 1988; 7:A17.

134. Nelson JE. “Pilot” studies. Ann Intern Med. 1989; 111:188-9. [PubMed 2742256]

135. Tchekmedyian NS. Clinical approaches to nutritional support in cancer. Curr Opin Oncol. 1993; 5:633-8. [PubMed 8364079]

136. Henry K, Rathgaber S, Sullivan C et al. Diabetes mellitus induced by megestrol acetate in a patient with AIDS and cachexia. Ann Intern Med. 1992; 116:53-4. [IDIS 289403] [PubMed 1727096]

137. Bristol Myers Squibb, Princeton, NJ: personal communication.

138. Bristol Myers Squibb. Megace ES (megestrol acetate) suspension prescribing information. Spring Valley, NY; 2005 May.

a. Bristol Myers Squibb. Megace oral suspension (megestrol acetate) prescribing information. Princeton, NJ; 2002 Jul.

b. Bristol Myers Squibb. Megace tablets (megestrol acetate) prescribing information. Princeton, NJ; 2002 Jul.

c. AHFS drug information 2006. McEvoy GK, ed. Megestrol Acetate. Bethesda, MD: American Society of Health-System Pharmacists; 2006:1129-31.

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