Team2_PharmD7

Megestrol acetate

Megestrol acetate

Team2 Members1. Rehab Aly Rayan2. Doaa Aly Hegy3. Ereeni Alfons4. Eman Ali5. Amaal Shetewy6. Dina Mohamed Magdy7. Gehan Basiony8. Rania Sakr9. Dina Esmat10.Riham Abdelrahman11.Sabrin Abdel SalamHegazy12.Sherin Taha04/12/2023 Team2_PharmD7 1

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Megestrol acetate

To be Discussed…1. Introduction, Brand Names, Forms, Prices.

2. Mechanism of Action.

3. Dosing, Administration, Uses.

4. Pharmacodynamics/Kinetics

5. Safety, Adverse Reactions, Contra Indications.

6. Warnings, Drug Interactions.

7. Pregnancy, Lactation.

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Megestrol acetate

Introduction

• Megestrol acetate is a synthetic derivative of naturally occurring progesterone.

• A white, crystalline solid, delivered in both tablet and suspension form.

• The suspension is generally preferred over the tablet because it has significantly greater bioavailability as well as a lower cost, which tends to improve adherence.

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Megestrol acetate

Megace ES; Megace Oral

U.S. Apo-Megestrol®;Megace®;Megace® OS;Nu-Megestrol

Canada

Brand Names

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Megestrol acetate

Forms: US

• Suspension, Oral, as acetate:– Megace ES: 625 mg/5 mL (150 mL) – Megace Oral: 40 mg/mL (240 mL)– Generic: 40 mg/mL (10 mL, 240 mL,

480 mL); 400 mg/10 mL (10 mL)

• Tablet, Oral, as acetate:– Generic: 20 mg, 40 mg

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Megestrol acetate

Forms: US

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Megestrol acetate

Mechanism of Action• Synthetic progestin with ant estrogenic properties which disrupt the estrogen receptor cycle, interfering with the normal estrogen cycle and resulting in a lower LH titer.

•Antineoplastic progestin acting through an antileutenizing effect mediated via the pituitary.

•May stimulate appetite by antagonizing the metabolic effects of catabolic cytokines.

•May also have a direct effect on the endometrium.

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Megestrol acetate

Dosing

• Oral: Suspension:• Megace®: Initial

dose: 800 mg/day; daily doses of 400 and 800 mg/day were found to be clinically effective

• Megace® ES: 625 mg/day

• the urinary excretion of doses of 4-90 mg ranged from 57% to 78% within 10 days

• Oral: Tablet: 40-320 mg/day in divided doses; use for 2 months to determine efficacy; maximum doses used have been up to 800 mg/day

• Oral: Tablet: 40 mg 4 times/day

Breast carcinoma (females):

Endometrial

carcinoma

HIV-related cachexia

(males/females)

Renal Impairmen

t

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Megestrol acetate

Adminestration

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Megestrol acetate

Adminestration

• The benefits of megestrol acetate are dose related.

• Megestrol acetate (Megace®) oral suspension is compatible with water, orange juice, apple juice, or Sustacal H.C. for immediate consumption. Shake suspension well before use.

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Megestrol acetate

Use

• Tablet: Palliative treatment of advanced breast and endometrial carcinoma

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

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Megestrol acetate

Pharmacodynamics/kinetics

• Absorption: Well absorbed orally

• Metabolism: Hepatic (to free steroids and glucuronide conjugates)

• Half-life elimination: 13-105 hours

• Time to peak, serum: 1-3 hours

• Excretion: Urine (57% to 78%; 5% to 8% as metabolites); feces (8% to 30%)

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Megestrol acetate

Safety• Sound-alike/look-alike issues:

– Megace® may be confused with Reglan®

– Megestrol may be confused with mesalamine

• BEERS Criteria – may be potentially inappropriate for use

in geriatric patients (Quality of evidence - moderate; Strength of recommendation - strong)

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Megestrol acetate

Adverse Reactions

• Cardiovascular: Hypertension (≤8%), cardiomyopathy (1% to 3%), chest pain (1% to 3%), edema (1% to 3%), palpitation (1% to 3%), peripheral edema (1% to 3%), heart failure

• Central nervous system: Headache (≤10%), insomnia (≤6%), fever (1% to 6%), pain (≤6%, similar to placebo), abnormal thinking (1% to 3%), confusion (1% to 3%), depression (1% to 3%), hypoesthesia (1% to 3%), seizure (1% to 3%), mood changes, malaise, lethargy

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Megestrol acetate

• Dermatologic: Rash (2% to 12%), alopecia (1% to 3%), pruritus (1% to 3%), vesiculobullous rash (1% to 3%)

• Endocrine & metabolic: Hyperglycemia (≤6%), gynecomastia (1% to 3%), adrenal insufficiency, amenorrhea, breakthrough bleeding, cervical erosion and secretions (changes), breast tenderness increased, Cushing's syndrome, diabetes, glucose intolerance, HPA axis suppression, hot flashes, hypercalcemia, menstrual flow changes, spotting, vaginal bleeding pattern changes

Adverse Reactions

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Megestrol acetate

• Gastrointestinal: Diarrhea (6% to 15%, similar to placebo), flatulence (≤10%), vomiting (≤6%), nausea (≤5%), dyspepsia (≤4%), abdominal pain (1% to 3%), constipation (1% to 3%), salivation increased (1% to 3%), xerostomia (1% to 3%), weight gain (not attributed to edema or fluid retention)

• Genitourinary: Impotence (4% to 14%), decreased libido (≤5%), urinary incontinence (1% to 3%), urinary tract infection (1% to 3%), urinary frequency (≤2%)

• Hematologic: Anemia (≤5%), leukopenia (1% to 3%)

Adverse Reactions

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Megestrol acetate

• Hepatic: Hepatomegaly (1% to 3%), LDH increased (1% to 3%), cholestatic jaundice, hepatotoxicity

• Neuromuscular & skeletal: Weakness (2% to 6%), neuropathy (1% to 3%), paresthesia (1% to 3%), carpal tunnel syndrome

• Ocular: Amblyopia (1% to 3%)

Adverse Reactions

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Megestrol acetate

• Renal: Albuminuria (1% to 3%)• Respiratory: Dyspnea (1% to 3%), cough (1% to

3%), pharyngitis (1% to 3%), pneumonia (≤2%), hyperpnea

• Miscellaneous: Diaphoresis (1% to 3%), herpes infection (1% to 3%), infection (1% to 3%), moniliasis (1% to 3%), tumor flare

• Post marketing and/or case reports: Thromboembolic phenomena (including deep vein thrombosis, pulmonary embolism, thrombophlebitis)

Adverse Reactions

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Megestrol acetate

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

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

Adverse Reactions

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Megestrol acetate

Warnings• Adrenal suppression: May suppress

hypothalamic-pituitary-adrenal (HPA) axis during chronic administration; considered 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.

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Megestrol acetate

• Disease-related concerns:– 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:– Elderly: Avoid use in older adults due to minimal effect

on weight, and an increased risk of thrombosis and possibly death (Beers Criteria).

– Females: Vaginal bleeding or discharge may occur.

Warnings

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Megestrol acetate

Drug Interactions• Aminoglutethimide: May increase the metabolism of

Progestins. – Management: Progestin-containing contraceptives are not

recommended; consider the use of alternative, nonhormonal contraceptives. Risk D: Consider therapy modification

• Anticoagulants: Progestins may diminish the therapeutic effect of Anticoagulants. specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects. – Management: Carefully weigh the benefits of progestins against the

increased risk of procoagulant effects and thromboembolism. Risk D: Consider therapy modification

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

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Megestrol acetate

• Herbs (Progestogenic Properties) (e.g., Bloodroot, Yucca): May enhance the adverse/toxic effect of Progestins. Risk C: Monitor therapy

• Indium 111 Capromab Pendetide: Ant androgens may diminish the diagnostic effect of Indium 111 Capromab Pendetide. Risk X: Avoid combination

• Ulipristal: May diminish the therapeutic effect of Progestins. – Management: Patients using ulipristal for uterine fibroids

(Canadian indication) should avoid any progestin within 12 days of stopping ulipristal; patients using hormonal contraceptives should use a barrier contraceptive. Risk X: Avoid combination

Drug Interactions

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Megestrol acetate

Pregnancy

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Megestrol acetate

Pregnancy • D (tablet) / X (suspension)• Adverse events were demonstrated in

animal reproduction studies. • 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

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Megestrol acetate

Lactation • Excreted into breast milk.

– Information is available from five nursing women, ~8 weeks postpartum, who were administered megestrol 4 mg in combination with ethinyl estradiol 50 mcg daily for contraception. (Nilsson, 1977).

– Due to the potential for adverse reaction in the newborn, the manufacturer recommends discontinuing breast-feeding while receiving megestrol. In addition, in the United States, where formula is accessible, affordable, safe, and sustainable, and the risk of infant mortality due to diarrhea and respiratory infections is low, complete avoidance of breast-feeding by HIV-infected women is recommended to decrease potential transmission of HIV

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Megestrol acetate

Refrences• American Geriatrics Society 2012 Beers Criteria Update Expert Panel,

"American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults," J Am Geriatr Soc, 2012, 60(4):616-31. [PubMed 22376048]

• Canetta R, Florentine S, Hunter H, et al, “Megestrol Acetate,” Cancer Treat Rev, 1983, 10(3);141-57.

• Chang AY, "Megestrol Acetate as a Biomodulator," Semin Oncol, 1998, 25(2 Suppl 6):58-61.

• DHHS Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States. July 31, 2012. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/perinatalgl.pdf

• Farrar DJ, "Megestrol Acetate: Promises and Pitfalls," AIDS Patient Care STDS, 1999, 13(3):149-52. [PubMed 10375262]

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• Fietkau R, Riepl M, Kettner H, et al, “Supportive Use of Megestrol Acetate in Patients With Head and Neck Cancer During Radio(Chemo)Therapy,” Eur J Cancer, 1997, 33(1):75-9. [PubMed 9071903]

• Lentz SS, Brady MF, Major FJ, et al, “High-Dose Megestrol Acetate in Advanced or Recurrent Endometrial Carcinoma: A Gynecologic Oncology Group Study,” J Clin Oncol, 1996, 14(2):357-61. [PubMed 8636744]

• National Institute for Occupational Safety and Health (NIOSH), "NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings 2012." Available at http://www.cdc.gov/niosh/docs/2012-150/pdfs/2012-150.pdf. Accessed January 21, 2013.

• Nilsson S, Nygren KG, Johansson ED. Megestrol acetate concentrations in plasma and milk during administration of an oral contraceptive containing 4 mg megestrol acetate to nursing women. Contraception. 1977;16(6):615-24. [PubMed 606501]

• Schacter L, Rozencweig M, Canett R, et al, “Megestrol Acetate: Clinical Experience,” Cancer Treat Rev, 1989, 16(1):49-63.

• Strang P, “The Effect of Megestrol Acetate on Anorexia, Weight Loss and Cachexia in Cancer and AIDS Patients,” Anticancer Res, 1997, 17(1B):657-62. [PubMed 9066597]

Refrences

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