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MEGESTROL

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Megestrol is a synthetic derivative of progesterone.

Specific Substances

    1) Megestrol acetate
    2) Megestrol
    3) 6-Methyl-3,20-dioxopregna-4,6-dien-17alpha-yl acetate
    4) BDH-1298
    5) Compound 5071
    6) NSC-71423
    7) SC-10363
    8) CAS 3562-63-8 (megestrol)
    9) CAS 595-33-5 (megestrol acetate)
    1.2.1) MOLECULAR FORMULA
    1) C24-H32-O4 (Prod Info megestrol acetate oral tablets, 2007)

Available Forms Sources

    A) FORMS
    1) Megestrol acetate is available as 20 mg and 40 mg tablets, and as 40 mg/mL oral suspension (Prod Info Megace(R) oral suspension, 2012; Prod Info megestrol acetate oral suspension, 2007; Prod Info megestrol acetate oral tablets, 2007).
    2) Megestrol acetate is also available as an oral suspension in a concentrated formula of 625 mg/5 mL (Prod Info MEGACE(R) ES oral suspension, 2006).
    B) USES
    1) Megestrol acetate is indicated, in patients with acquired immunodeficiency syndrome (AIDS), for the treatment of anorexia, cachexia, or significant weight loss that is unexplained (Prod Info Megace(R) oral suspension, 2012; Prod Info MEGACE(R)ES oral suspension, 2008).
    2) Megestrol acetate is also indicated, as palliative therapy, for the treatment of advanced carcinoma of the breast or endometrium (Prod Info MEGACE(R)ES oral suspension, 2008).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Megestrol acetate is indicated, in patients with acquired immunodeficiency syndrome (AIDS), for the treatment of anorexia, cachexia, or significant weight loss that is unexplained. It is also indicated, as palliative therapy, for the treatment of advanced carcinoma of the breast or endometrium.
    B) PHARMACOLOGY: Megestrol acetate, a synthetic derivative of progesterone, is suggested to reduce estrogen secretion by inhibiting the production of pituitary gonadotropin in endometrial carcinoma. As an antineoplastic, it is suggested that megestrol acetate exerts direct cytotoxic effects on breast cancer cells by either interfering with availability, stability and turnover of estrogen and the interaction with genes at the estrogen receptor complex or at the progestin receptor complex by interacting directly to turn of the specific estrogen-responsive genes. The exact mechanism of action for its clinical use in endometrial cancer and as appetite-enhancing agent in cachexia remains unknown.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Most adverse effects are related to chronic or high-dose therapy. CHRONIC: Hyperglycemia, impotence, decreased libido, deep venous thrombosis, and tachypnea may occur with chronic therapy. Other adverse effects that have been reported include: hypertension, nausea and vomiting, diarrhea, insomnia, asthenia, hot flashes, thrombophlebitis, and pulmonary embolism. HIGH-DOSE THERAPY: Cushing syndrome and cholestatic hepatitis were reported following high-dose megestrol therapy (800 to 1200 mg/day). Mild blood pressure elevation, weight gain, increased appetite, hyperglycemia, edema, dyspnea, and congestive heart failure have been reported in patients receiving high-dose regimens (480 to 1600 mg/day) for the treatment of advanced breast cancer. RARE: Alopecia and skin rashes have been rarely reported.
    E) WITH POISONING/EXPOSURE
    1) In several overdose cases during postmarketing period, diarrhea, nausea, abdominal pain, shortness of breath, cough, unsteady gait, listlessness, and chest pain were reported.
    0.2.20) REPRODUCTIVE
    A) Megestrol acetate oral suspension is classified as pregnancy category X and megestrol acetate tablets are classified as pregnancy category D.

Laboratory Monitoring

    A) Routine lab studies are generally not necessary unless otherwise clinically indicated. Obtain a pregnancy test in women of reproductive age. In self-harm ingestions, monitor serum electrolytes. Monitor vital signs, particularly blood pressure.
    B) Obtain an ECG, and institute continuous cardiac monitoring in patients with cardiac symptoms or severe hypertension.
    C) CHRONIC TOXICITY: Discontinue medication and monitor for signs of toxicity and treat symptomatically. Obtain a baseline CBC, hepatic enzymes, and renal function tests in symptomatic patients. Obtain a pregnancy test in women of reproductive age.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) ACUTE OVERDOSE: Single acute overdoses will seldom result in toxicity. Supportive treatment is adequate in most situations. CHRONIC POISONING: Discontinue medication and monitor for signs of severe toxicity and treat symptomatically. Obtain a baseline CBC, hepatic enzymes, and renal function tests. Obtain a pregnancy test in women of reproductive age because of possible fetotoxic effects.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Severe toxicity is not expected after megestrol overdose.
    C) DECONTAMINATION
    1) PREHOSPITAL: Toxicity after acute ingestion is unlikely, and is generally only expected with chronic use. Gastrointestinal decontamination is generally unnecessary.
    2) HOSPITAL: Toxicity after acute ingestion is unlikely, and is generally only expected with chronic use. Gastrointestinal decontamination is generally unnecessary. Consider activated charcoal only after very large ingestions or if coingestants with significant toxicity are involved.
    D) AIRWAY MANAGEMENT
    1) Should not be required in these cases.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION
    1) Due to the low solubility of megestrol, hemodialysis may not be an effective method of elimination.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients with unintentional exposures can be watched at home with follow up with their regular physician as needed.
    2) OBSERVATION CRITERIA: Patients with significant adverse effects or deliberate overdose should be sent to a healthcare facility.
    3) ADMISSION CRITERIA: Admission is rarely necessary after acute overdose. Patients with severe adverse reactions (eg, pulmonary embolism) should be admitted, and depending on the severity of their symptoms, may merit an ICU admission. Criteria for discharge include resolution or treatment of their symptoms.
    4) CONSULT CRITERIA: Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear. Pregnant women who ingest megestrol should be referred for evaluation of fetotoxic effects.
    H) PITFALLS
    1) When managing a suspected overdose with megestrol, the possibility of coingestants should be considered. If severe toxicity develops, other causes should be sought.
    I) PHARMACOKINETICS
    1) Tmax: 1 to 5 hours. Oral absorption: variable. Urinary excretion: 56.5% to 78.4% (mean 66.4%) within 10 days after megestrol doses of 4 to 90 mg. Elimination half-life: 13 to 104.9 hours (mean, 34.2 hours).
    J) DIFFERENTIAL DIAGNOSIS
    1) The differential diagnosis for some of the adverse reactions from the use of megestrol can be quite large.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. Mild blood pressure elevation, weight gain, increased appetite, hyperglycemia, edema, dyspnea, cholestatic hepatitis, and congestive heart failure were reported with high-dose megestrol therapy of approximately 400 to 1600 mg/day. In other studies, megestrol doses up to 1200 mg/day did not result in serious unexpected side effects. In several overdose cases during postmarketing period, diarrhea, nausea, abdominal pain, shortness of breath, cough, unsteady gait, listlessness, and chest pain were reported. Cushing syndrome and cholestatic hepatitis were reported following high-dose megestrol therapy (800 to 1200 mg/day).
    B) THERAPEUTIC DOSE: ADULTS: Varies by indication: Tablets: 40 to 320 mg orally daily in divided doses; oral suspension: 800 mg (20 mL) daily; 625 mg (5 mL) orally daily of a concentrated formula. CHILDREN: Safety and efficacy have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Megestrol acetate is indicated, in patients with acquired immunodeficiency syndrome (AIDS), for the treatment of anorexia, cachexia, or significant weight loss that is unexplained. It is also indicated, as palliative therapy, for the treatment of advanced carcinoma of the breast or endometrium.
    B) PHARMACOLOGY: Megestrol acetate, a synthetic derivative of progesterone, is suggested to reduce estrogen secretion by inhibiting the production of pituitary gonadotropin in endometrial carcinoma. As an antineoplastic, it is suggested that megestrol acetate exerts direct cytotoxic effects on breast cancer cells by either interfering with availability, stability and turnover of estrogen and the interaction with genes at the estrogen receptor complex or at the progestin receptor complex by interacting directly to turn of the specific estrogen-responsive genes. The exact mechanism of action for its clinical use in endometrial cancer and as appetite-enhancing agent in cachexia remains unknown.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Most adverse effects are related to chronic or high-dose therapy. CHRONIC: Hyperglycemia, impotence, decreased libido, deep venous thrombosis, and tachypnea may occur with chronic therapy. Other adverse effects that have been reported include: hypertension, nausea and vomiting, diarrhea, insomnia, asthenia, hot flashes, thrombophlebitis, and pulmonary embolism. HIGH-DOSE THERAPY: Cushing syndrome and cholestatic hepatitis were reported following high-dose megestrol therapy (800 to 1200 mg/day). Mild blood pressure elevation, weight gain, increased appetite, hyperglycemia, edema, dyspnea, and congestive heart failure have been reported in patients receiving high-dose regimens (480 to 1600 mg/day) for the treatment of advanced breast cancer. RARE: Alopecia and skin rashes have been rarely reported.
    E) WITH POISONING/EXPOSURE
    1) In several overdose cases during postmarketing period, diarrhea, nausea, abdominal pain, shortness of breath, cough, unsteady gait, listlessness, and chest pain were reported.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypertension was reported in 8 of 65 patients (12%) who received 800 mg/day of megestrol acetate oral suspension during a clinical efficacy trial (Prod Info Megace(R) oral suspension, 2012).
    b) High-dose regimens (480 to 1600 mg/day) used for the treatment of advanced breast cancer were associated with mild blood pressure elevation, weight gain, increased appetite, hyperglycemia, edema, dyspnea, and congestive heart failure (Aisner et al, 1987).
    B) HEART FAILURE
    1) WITH THERAPEUTIC USE
    a) Heart failure was reported with megestrol acetate therapy during clinical trials (Prod Info megestrol acetate oral tablets, 2007).
    b) High-dose regimen (480 to 1600 mg/day) used for the treatment of advanced breast cancer was associated with mild blood pressure elevation, weight gain, increased appetite, hyperglycemia, edema, dyspnea, and congestive heart failure (Aisner et al, 1987).
    C) CHEST PAIN
    1) WITH THERAPEUTIC USE
    a) Chest pain has been reported with overdose (Prod Info Megace(R) oral suspension, 2012).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) PULMONARY EMBOLISM
    1) WITH THERAPEUTIC USE
    a) Cases of pulmonary embolism (sometimes fatal) were reported with megestrol therapy during clinical trials (Prod Info megestrol acetate oral tablets, 2007).
    b) Pulmonary embolism has also been reported following post-marketing use of megestrol acetate oral suspension (Prod Info Megace(R) oral suspension, 2012).
    B) TACHYPNEA
    1) WITH THERAPEUTIC USE
    a) Tachypnea and hyperventilation have been reported to occur in association with the use of megestrol acetate at a dose of 80 mg three times daily (Fessel, 1989).
    C) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) High-dose regimen (480 to 1600 mg/day) used for the treatment of advanced breast cancer was associated with mild blood pressure elevation, weight gain, increased appetite, hyperglycemia, edema, dyspnea, and congestive heart failure (Aisner et al, 1987).
    2) WITH POISONING/EXPOSURE
    a) Shortness of breath has been reported with overdose (Prod Info Megace(R) oral suspension, 2012).
    D) COUGH
    1) WITH POISONING/EXPOSURE
    a) Cough has been reported with overdose (Prod Info Megace(R) oral suspension, 2012).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) Asthenia has been reported with megestrol acetate therapy during clinical trials (Prod Info Megace(R) oral suspension, 2012; Prod Info megestrol acetate oral tablets, 2007).
    B) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) Insomnia has been reported with megestrol acetate therapy during clinical trials, and appears to be dose-dependent (Prod Info Megace(R) oral suspension, 2012).
    C) UNSTEADY GAIT
    1) WITH THERAPEUTIC USE
    a) Unsteady gait and listlessness have been reported with overdose (Prod Info Megace(R) oral suspension, 2012).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting have occurred with megestrol therapy (Prod Info Megace(R) oral suspension, 2012; Prod Info megestrol acetate oral tablets, 2007; Gal et al, 1983).
    b) INCIDENCE: One study reported a 7% incidence of nausea and vomiting during megestrol therapy of advanced breast cancer (Ingle et al, 1982).
    2) WITH POISONING/EXPOSURE
    a) Nausea has been reported with overdose (Prod Info Megace(R) oral suspension, 2012).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea has been reported following administration of megestrol acetate oral suspension during clinical trials (Prod Info Megace(R) oral suspension, 2012).
    2) WITH POISONING/EXPOSURE
    a) Diarrhea has been reported with overdose (Prod Info Megace(R) oral suspension, 2012).
    C) ABDOMINAL PAIN
    1) WITH POISONING/EXPOSURE
    a) Abdominal pain has been reported with overdose (Prod Info Megace(R) oral suspension, 2012).
    D) HICCOUGHS
    1) WITH THERAPEUTIC USE
    a) Four cases of hiccups have been reported in patients with acquired immunodeficiency syndrome receiving megestrol suspension 800 milligrams daily. Hiccups in all cases resolved when megestrol was discontinued. In one patient, megestrol was restarted and hiccups returned (Pertel & Till, 1998).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) CHOLESTATIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) Jaundice and intrahepatic cholestasis have been described following high-dose megestrol acetate therapy for breast cancer. In this case report, a 66-year-old woman received high-dose megestrol therapy (800 to 1200 mg/day) in conjunction with fluoroxymesterone and prednisone for management of breast cancer metastases for several days; therapy was discontinued because of nausea. One year later the patient again required high-dose megestrol and received the drug for 13 days. On day 14 the patient was observed to be jaundiced and laboratory parameters were consistent with cholestasis. No other cause of cholestasis was identified and it was felt that this hepatotoxic reaction was due to megestrol (Foitl et al, 1989).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) KIDNEY DISEASE
    1) WITH THERAPEUTIC USE
    a) Megestrol-induced Cushing syndrome and worsening renal function developed in a 17-year-old boy with unilateral renal agenesis. The boy had been treated for 2 months with high-dose (900 milligrams/day) megestrol acetate for an eating disorder. The authors suggest megestrol acetate can worsen its own clearance via the kidneys in patients with preexisting renal insufficiency and thus precipitate the development of Cushing syndrome (Capparros et al, 2001).
    B) ABNORMAL SEXUAL FUNCTION
    1) WITH THERAPEUTIC USE
    a) Testicular failure secondary to megestrol acetate (MA) occurred in a 47-year-old man with cystic fibrosis. MA was initiated at a dose of 800 milligrams (mg) daily for anorexia. The dose was tapered over 8 weeks to 200 mg daily at which time the patient had complaints of impotence and low libido. The patient's cortisol and free testosterone levels were low (1.1 microgram/deciliter and 8.7 picograms/milliliter, respectively). In addition, the patient demonstrated a blunted response to adrenocorticotropic hormone (ACTH) challenge. MA therapy was discontinued and within 3 months, symptoms resolved and cortisol response to ACTH was normal, as was his free testosterone level (McKone et al, 2002).
    b) There have been reports of impotence and decreased libido in patients receiving megestrol acetate oral suspension (Prod Info Megace(R) oral suspension, 2012).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) DEEP VENOUS THROMBOSIS
    1) WITH THERAPEUTIC USE
    a) Two cases of deep vein thrombosis (DVT) have been reported in elderly patients being treated with megestrol acetate for unplanned weight loss. The first patient (aged 86 years) developed a DVT 10 days after initiating megestrol acetate oral suspension 400 milligrams (mg) twice daily while the second patient (aged 85 years) developed a DVT four months after initiating megestrol acetate oral tablets 40 mg twice daily. After discontinuation of megestrol acetate and hospitalization, both patients completely recovered (Marshall, 2003).
    B) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Cases of anemia have been reported with the use of megestrol acetate suspension during clinical trials (Prod Info Megace(R) oral suspension, 2012).
    C) THROMBOPHLEBITIS
    1) WITH THERAPEUTIC USE
    a) Thrombophlebitis has been reported following post-marketing use of megestrol acetate oral suspension (Prod Info Megace(R) oral suspension, 2012).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Skin rashes have occurred during treatment, requiring withdrawal of therapy (Prod Info Megace(R) oral suspension, 2012; Ingle et al, 1982). However, this complication appears to be rare.
    B) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) Alopecia has occurred rarely during megestrol acetate therapy (Prod Info Megace(R) oral suspension, 2012; Prod Info megestrol acetate oral tablets, 2007).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) BONE PAIN
    1) WITH THERAPEUTIC USE
    a) Four women treated with 40 mg orally twice daily of megestrol for 2 weeks for adenocarcinoma of the ovary developed severe pain in their hands. There were no sensory or motor losses and symptoms followed a median nerve distribution. Discontinuation of the megestrol resulted in remission of the symptoms with no occurrence (DiSaia & Morrow, 1977).
    b) A flare in bone pain secondary to megestrol acetate was suspected in 11 patients who reported increased pain within 7 days of initiating treatment for advanced prostate carcinoma. Bone pain did improve in 5 patients, who continued on megestrol acetate, however, none of them demonstrated evidence of tumor regression (Dawson et al, 2000).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) Hyperglycemia was reported when megestrol was given orally in doses of 40 mg twice daily for 6 weeks (Bottino & Tashima, 1976); however, other data failed to demonstrate impairment of glucose control in a series of 300 patients treated with megestrol 40 mg four times daily for durations of therapy between 6 weeks to 18 months (Ansfield, 1977).
    b) Megestrol-induced hyperglycemia was reported in a patient with AIDS (400 mg daily) (Pimentel et al, 1996). The patient was treated with intravenous hydration and insulin for 5 days at which time glucose returned to normal. Hyperglycemia developed in another AIDS patient after receiving megestrol 240 mg/day three months prior to admission for increasing anorexia and weight loss. After discontinuation of megestrol, insulin requirements decreased and insulin was stopped after 1 week (Jain et al, 1996).
    c) CASE REPORT - A 28-year-old man with AIDS developed hyperglycemia requiring insulin therapy after receiving short-term megestrol acetate therapy for weight loss. The patient presented with polydipsia and dry mouth, with blood glucose levels increasing from 216 mg/dL to 546 mg/dL after 5 days and 15 days of therapy, respectively (Gonzalez del Valle et al, 1996).
    d) High-dose regimens (480 to 1600 mg/day) used for the treatment of advanced breast cancer were associated with mild blood pressure elevation, weight gain, increased appetite, hyperglycemia, edema, dyspnea, and congestive heart failure (Aisner et al, 1987).
    e) DIABETES MELLITUS has been reported during therapy with megestrol acetate (Henry et al, 1992). In this case report, rechallenge with megestrol acetate resulted in an exacerbation of the diabetes.
    B) SECONDARY HYPOCORTISOLISM
    1) WITH THERAPEUTIC USE
    a) Adrenal insufficiency secondary to megestrol acetate (MA) occurred in a 47-year-old man with cystic fibrosis. MA was initiated at a dose of 800 milligrams (mg) daily for anorexia. The dose was tapered over 8 weeks to 200 mg daily at which time the patient had complaints of impotence and low libido. The patient's cortisol and free testosterone levels were low (1.1 microgram/deciliter and 8.7 picograms/milliliter, respectively). In addition, the patient demonstrated a blunted response to adrenocorticotropic hormone (ACTH) challenge. MA therapy was discontinued and within 3 months, symptoms resolved and cortisol response to ACTH was normal, as was his free testosterone level (McKone et al, 2002).
    b) Statistically significant decreases occurred in the 8:00 AM and 8:00 PM cortisol serum values (p less than 0.001 and 0.05, respectively) in children using megestrol acetate for treatment of malignant solid tumors. A 6-month study of 35 children receiving megestrol acetate 10 milligram per kilogram daily measured the cortisol circadian rhythm to assess side effects. The dose was progressively reduced throughout the 6 months of therapy. The 8:00 AM serum cortisol values fell below normal limits by the second month and increased progressively to normal 4 months after the minimum serum level was reached. The 8:00 PM serum values fell to almost abnormal values and remained so until the fourth month. No adverse clinical effects were observed during or after megestrol acetate withdrawal. The authors strongly recommend measurements of basal cortisol to assist in screening for adrenal suppression (Azcona & Sierrasesumaga, 2000).
    c) Because they had previously observed adrenal suppression in 2 HIV- (Human Immunodeficiency Virus) infected patients treated with megestrol, investigators questioned whether the adrenal suppression was the result of advanced HIV or reflective of suppression of the hypothalamic- pituitary-adrenal axis by megestrol. In a small study, 7 of 10 pediatric HIV patients treated with megestrol had very low baseline and post- corticotropin cortisol levels compared to 0 of 10 HIV-infected patients not treated with megestrol. Patients should be notified of the risk of, need for monitoring, and possibly treatment for adrenal suppression when receiving megestrol (Stockheim et al, 1999).
    C) HYPERCORTISOLISM
    1) WITH THERAPEUTIC USE
    a) Megestrol-induced Cushing syndrome and worsening renal function developed in a 17-year-old boy with unilateral renal agenesis. The boy had been treated for 2 months with high-dose (900 milligrams/day) megestrol acetate for an eating disorder. The authors suggest megestrol acetate can worsen its own clearance via the kidneys in patients with preexisting renal insufficiency and thus precipitate the development of Cushing syndrome (Capparros et al, 2001).
    b) One patient with AIDS developed Cushing's syndrome 2 years after starting megestrol. The patient had been started on megestrol 600 milligrams (mg) twice daily for 1.5 months, followed by 800 mg daily. Megestrol was tapered over 1.5 months and symptoms resolved (Padmanabhan & Rosenberg, 1998).
    c) A review of the literature from 1984 through 1996 revealed 5 cases of Cushing's syndrome associated with megestrol therapy. All patients received at least 9 months of megestrol therapy. Three of 5 patients were taking 800 mg daily or more. Upon discontinuation or dose reduction of megestrol, 2 patients demonstrated clinical improvement and 1 patient did not improve. Megestrol therapy was continued in 1 patient and no information was available for the 5th patient (Mann et al, 1997).
    D) HOT SWEATS
    1) WITH THERAPEUTIC USE
    a) Limited cases of hot flashes were reported with megestrol acetate therapy (Prod Info megestrol acetate oral tablets, 2007).

Reproductive

    3.20.1) SUMMARY
    A) Megestrol acetate oral suspension is classified as pregnancy category X and megestrol acetate tablets are classified as pregnancy category D.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) There have been no studies on the use of megestrol in pregnant women.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified megestrol acetate oral suspension as FDA pregnancy category X (Prod Info megestrol acetate oral suspension, 2007).
    2) Megestrol acetate tablets have been classified by the manufacturer as FDA pregnancy category D (Prod Info megestrol acetate oral tablets, 2007).
    B) ANIMAL STUDIES
    1) RATS - Administration of megestrol acetate to pregnant rats resulted in a reduction in fetal weights and the number of live births, and feminization of male fetuses (Prod Info megestrol acetate oral suspension, 2007).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) No reports describing the use of megestrol during human lactation are available and the effects on the nursing infant from exposure to the drug in milk are unknown. Due to the potential of adverse effects on newborns, nursing should be stopped if megestrol acetate therapy is required (Prod Info megestrol acetate oral suspension, 2007; Prod Info megestrol acetate oral tablets, 2007).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) In low-dose studies performed in female rats, the reproductive activity of the subjects' male offspring was impaired. Similar results were obtained in dogs (Prod Info megestrol acetate oral suspension, 2007).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS3562-63-8 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.4) ANIMAL STUDIES
    A) BREAST NEOPLASM
    1) DOGS - Benign and malignant tumors of the breast were found in female beagles after administration of megestrol acetate, at doses of 0.01, 0.1, or 0.25 mg/kg/day, for up to 7 years (Prod Info megestrol acetate oral suspension, 2007; Prod Info megestrol acetate oral tablets, 2007).
    B) PITUITARY TUMOR
    1) RATS - In female rats, pituitary tumors were found following administration of megestrol acetate, at doses of 3.9 or 10 mg/kg/day, for 2 years (Prod Info megestrol acetate oral suspension, 2007).
    C) LACK OF EFFECT
    1) MONKEYS - After 10 years of megestrol acetate administration in female monkeys, at doses of 0.01, 0.1, or 0.5 mg/kg/day, no tumors were found (Prod Info megestrol acetate oral suspension, 2007).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Routine lab studies are generally not necessary unless otherwise clinically indicated. Obtain a pregnancy test in women of reproductive age. In self-harm ingestions, monitor serum electrolytes. Monitor vital signs, particularly blood pressure.
    B) Obtain an ECG, and institute continuous cardiac monitoring in patients with cardiac symptoms or severe hypertension.
    C) CHRONIC TOXICITY: Discontinue medication and monitor for signs of toxicity and treat symptomatically. Obtain a baseline CBC, hepatic enzymes, and renal function tests in symptomatic patients. Obtain a pregnancy test in women of reproductive age.

Methods

    A) CHROMATOGRAPHY
    1) Gas chromatography-mass fragmentography (GC-MF) and high pressure liquid chromatography (HPLC) have been used to estimate plasma concentrations of megestrol acetate. GC-MF and HPLC are specific for megestrol acetate and therefore appear to yield equivalent concentrations (Prod Info megestrol acetate oral suspension, 2007).
    B) IMMUNOASSAY
    1) Radioimmunoassay has been used to estimate plasma concentrations of megestrol acetate; however, this method also reacts to megestrol acetate metabolites, and therefore is considered non-specific, yielding higher plasma concentrations than either the GC-MF or HPLC methods (Prod Info megestrol acetate oral suspension, 2007).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Admission is rarely necessary after acute overdose. Patients with severe adverse reactions (eg, pulmonary embolism) should be admitted, and depending on the severity of their symptoms, may merit an ICU admission. Criteria for discharge include resolution or treatment of their symptoms.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients with unintentional exposures can be watched at home with follow up with their regular physician as needed. Pregnant women who ingest megestrol should be referred for evaluation of fetotoxic effects.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear. Pregnant women who ingest megestrol should be referred for evaluation of fetotoxic effects.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with significant adverse effects or deliberate overdose should be sent to a healthcare facility.

Monitoring

    A) Routine lab studies are generally not necessary unless otherwise clinically indicated. Obtain a pregnancy test in women of reproductive age. In self-harm ingestions, monitor serum electrolytes. Monitor vital signs, particularly blood pressure.
    B) Obtain an ECG, and institute continuous cardiac monitoring in patients with cardiac symptoms or severe hypertension.
    C) CHRONIC TOXICITY: Discontinue medication and monitor for signs of toxicity and treat symptomatically. Obtain a baseline CBC, hepatic enzymes, and renal function tests in symptomatic patients. Obtain a pregnancy test in women of reproductive age.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Toxicity after acute ingestion is unlikely, and is generally only expected with chronic use. Gastrointestinal decontamination is generally unnecessary.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Toxicity after acute ingestion is unlikely, and is generally only expected with chronic use. Gastrointestinal decontamination is generally unnecessary. Consider activated charcoal only after very large ingestions or if coingestants with significant toxicity are involved.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Routine lab studies are generally not necessary unless otherwise clinically indicated. Obtain a pregnancy test in women of reproductive age. In self-harm ingestions, monitor serum electrolytes. Monitor vital signs, particularly blood pressure.
    2) Obtain an ECG, and institute continuous cardiac monitoring in patients with cardiac symptoms or severe hypertension.
    3) CHRONIC TOXICITY: Discontinue medication and monitor for signs of toxicity and treat symptomatically. Obtain a baseline CBC, hepatic enzymes, and renal function tests in symptomatic patients. Obtain a pregnancy test in women of reproductive age.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Due to the low solubility of megestrol, hemodialysis may not be an effective method of elimination (Prod Info megestrol acetate oral suspension, 2007; Prod Info megestrol acetate oral tablets, 2007).

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. Mild blood pressure elevation, weight gain, increased appetite, hyperglycemia, edema, dyspnea, cholestatic hepatitis, and congestive heart failure were reported with high-dose megestrol therapy of approximately 400 to 1600 mg/day. In other studies, megestrol doses up to 1200 mg/day did not result in serious unexpected side effects. In several overdose cases during postmarketing period, diarrhea, nausea, abdominal pain, shortness of breath, cough, unsteady gait, listlessness, and chest pain were reported. Cushing syndrome and cholestatic hepatitis were reported following high-dose megestrol therapy (800 to 1200 mg/day).
    B) THERAPEUTIC DOSE: ADULTS: Varies by indication: Tablets: 40 to 320 mg orally daily in divided doses; oral suspension: 800 mg (20 mL) daily; 625 mg (5 mL) orally daily of a concentrated formula. CHILDREN: Safety and efficacy have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) ANOREXIA/CACHEXIA/UNEXPLAINED WEIGHT LOSS
    1) ORAL SUSPENSION 40 mg/mL: Recommended dose is 800 mg (20 mL) orally daily (Prod Info megestrol acetate oral suspension, 2007)
    2) ORAL SUSPENSION 125 mg/mL: Recommended dose is 625 mg (5 mL) orally daily (Prod Info MEGACE(R) ES oral suspension, 2014)
    B) BREAST CANCER
    1) ORAL TABLET: Recommended dose is 160 mg orally daily in divided doses, for at least 2 months (Prod Info megestrol acetate oral tablets, 2010)
    C) ENDOMETRIAL CANCER
    1) ORAL TABLET: Recommended dose is 40 to 320 mg orally daily in divided doses, for at least 2 months (Prod Info megestrol acetate oral tablets, 2010)
    7.2.2) PEDIATRIC
    A) Safety and efficacy in pediatric patients have not been established (Prod Info MEGACE(R) ES oral suspension, 2014; Prod Info megestrol acetate oral tablets, 2010; Prod Info megestrol acetate oral suspension, 2007).

Maximum Tolerated Exposure

    A) In studies, megestrol doses up to 1200 mg/day did not result in serious unexpected side effects. In several overdose cases during postmarketing period, diarrhea, nausea, abdominal pain, shortness of breath, cough, unsteady gait, listlessness, and chest pain were reported (Prod Info Megace(R) oral suspension, 2012).
    B) High-dose regimens (480 to 1600 mg/day) used for the treatment of advanced breast cancer were associated with mild blood pressure elevation, weight gain, increased appetite, hyperglycemia, edema, dyspnea, and congestive heart failure (Aisner et al, 1987).
    C) Cushing syndrome and cholestatic hepatitis were reported following high-dose megestrol therapy (800 to 1200 mg/day) (Capparros et al, 2001; Foitl et al, 1989).

Workplace Standards

    A) ACGIH TLV Values for CAS3562-63-8 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS3562-63-8 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS3562-63-8 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS3562-63-8 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Megestrol acetate, a synthetic derivative of progesterone, is suggested to reduce estrogen secretion by inhibiting the production of pituitary gonadotropin in endometrial carcinoma. As an antineoplastic, it is suggested that megestrol acetate exerts direct cytotoxic effects on breast cancer cells by either interfering with availability, stability and turnover of estrogen and the interaction with genes at the estrogen receptor complex or at the progestin receptor complex by interacting directly to turn of the specific estrogen-responsive genes. The exact mechanism of action for its clinical use in endometrial cancer and as appetite-enhancing agent in cachexia remains unknown (Prod Info megestrol acetate oral suspension, 2007; Prod Info megestrol acetate oral tablets, 2007).

Physicochemical

Physical Characteristics

    A) Megestrol acetate is a white or almost white crystalline powder, that is practically insoluble in water, sparingly soluble in alcohol, and soluble in acetone (Sweetman, 2007).

Molecular Weight

    A) 384.51

Animal Toxicology

Clinical Effects

    11.1.6) FELINE/CAT
    A) Side effects noted following therapeutic use of megestrol acetate in cats include mammary hyperplasia, pyometra, diabetes mellitus, weight gain, adrenocortical atrophy, CNS depression, or temperament changes (Romatowski, 1989).

Range Of Toxicity

    11.3.1) THERAPEUTIC DOSE
    A) CAT
    1) Although megestrol acetate is not approved for use in cats, it has been used in cats for various dermatologic and behavioral conditions (Romatowski, 1989). Oral induction doses suggested have included 2.5 to 5 mg every third day, every other day, or daily.
    11.3.2) MINIMAL TOXIC DOSE
    A) SUMMARY
    1) A specific minimum toxic dose of megestrol in animals has not been delineated.

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