MEGESTROL: 731 Adverse Event Reports & Safety Profile

DESCRIPTION Megestrol acetate oral suspension, USP contains megestrol acetate, a synthetic derivative of the steroid hormone, progesterone. Megestrol acetate is a white, crystalline solid chemically designated as 17-Hydroxy-6-methylpregna-4,6-diene-3,20-dione acetate. Solubility at 37°C in water is 2 mcg per mL, solubility in plasma is 24 mcg per mL. Its molecular weight is 384.52. The chemical formula is C 24 H 32 O 4 and the structural formula is represented as follows: megestrol acetate, USP Megestrol acetate oral suspension is supplied as an oral suspension containing 40 mg of micronized megestrol acetate per mL. Megestrol acetate oral suspension contains the following inactive ingredients: alcohol (max 0.06% v/v from flavor), artificial lime flavor, citric acid monohydrate, docusate sodium, glycerin, natural and artificial lemon flavor, purified water, sodium benzoate, sodium citrate dihydrate, sucrose and xanthan gum. Megestrol acetate oral suspension, 40 mg/mL complies with USP Dissolution Test 2. this is the structure

AND USAGE Megestrol acetate oral suspension is indicated for the treatment of anorexia, cachexia, or an unexplained significant weight loss in patients with a diagnosis of acquired immunodeficiency syndrome (AIDS). Limitations of Use Therapy with megestrol acetate oral suspension for weight loss should only be insti­tuted after treatable causes of weight loss are sought and addressed. These treatable causes include possible malignancies, systemic infections, gastrointestinal disorders affecting absorption, endocrine disease, renal disease or psychiatric diseases. Megestrol acetate oral suspension is not intended for prophylactic use to avoid weight loss. Megestrol acetate oral suspension is a progestin indicated for the treatment of anorexia, cachexia, or an unexplained significant weight loss in patients with a diagnosis of acquired immunodeficiency syndrome (AIDS) (1) .

AND ADMINISTRATION

• Obtain a negative pregnancy test in females of reproductive potential prior to initiating treatment ( 2.1 )
• The recommended adult initial dosage of megestrol acetate oral suspension is 625 mg/day (5 mL/day or one teaspoon daily) ( 2.2 ).
• Shake container well before using ( 2.2 ).

2.1 Testing Prior to Megestrol Acetate Oral Suspension Administration

• Obtain a negative pregnancy test in females of reproductive potential prior to initiating treatment with megestrol acetate oral suspension [see Contraindications ( 4 ), Warnings and Precautions ( 5.2 ), Use in Specific Populations ( 8.1 , 8.3 )].

2.2 Dosing and Administration

• The recommended adult initial dosage of megestrol acetate oral suspension is 625 mg/day (5 mL/day or one teaspoon daily).
• Shake the container well before using.
• This strength (125 mg/mL) is not substitutable with other strengths (e.g., 40 mg/mL). Refer to the prescribing information of the 40 mg/mL product for dosage recommendations for the 40 mg/mL strength.

4 CONTRAINDICATIONS

• History of hypersensitivity to megestrol acetate or any component of the formulation.
• Pregnancy [see Warnings and Precautions ( 5.2 ), Use in Specific Populations ( 8.1 , 8.3 )].
• History of hypersensitivity to megestrol acetate or any component of the formulation ( 4 ).
• Pregnancy ( 4 )( 8.1 ).

REACTIONS The most common adverse events occurring in > 5% of all patients receiving 800mg/20mL of megestrol acetate oral suspension in the two clinical efficacy trials were nausea, diarrhea, impotence, rash, flatulence, hypertension, and asthenia (6.2) . To report SUSPECTED ADVERSE REACTIONS, contact TWi Pharmaceuticals, Inc. at 1-844-518-2989 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Serious and Otherwise Important Adverse Reactions The following serious reactions and otherwise important adverse drug reactions are discussed in greater detail in other sections of the labeling:

• Hypersensitivity [see Contraindications ( 4 )]
• Thromboembolic Disease [see Warnings and Precautions ( 5.1 )]
• Adrenal Insufficiency [see Warnings and Precautions ( 5.3 )]
• Diabetes [see Warnings and Precautions ( 5.4 )]

6.2 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reactions observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of megestrol acetate oral suspension, 125 mg/mL was based on three studies of megestrol acetate oral suspension (40 mg/mL). The adverse reaction profile of these 3 studies are presented below. Adverse events which occurred in at least 5% of patients in any arm of the two clinical efficacy trials and the open trial for megestrol acetate oral suspension are listed below by treatment group. All patients listed had at least one post baseline visit during the 12 study weeks.

Table

1: Adverse Events Percentage of Patients Reporting Adverse Events Trial 1 (N=236)

Trial

2 (N=87)

Open Label Trial Placebo Placebo

Megestrol Acetate mg/day 0 100 400 800 0 800 1200 No. of Patients N=34 N=68 N=69 N=65 N=38 N=49 N=176 Diarrhea 15 13 8 15 8 6 10 Impotence 3 4 6 14 0 4 7 Rash 9 9 4 12 3 2 6 Flatulence 9 0 1 9 3 10 6 Hypertension 0 0 0 8 0 0 4 Asthenia 3 2 3 6 8 4 5 Insomnia 0 3 4 6 0 0 1 Nausea 9 4 0 5 3 4 5 Anemia 6 3 3 5 0 0 0 Fever 3 6 4 5 3 2 1 Libido Decreased 3 4 0 5 0 2 1 Dyspepsia 0 0 3 3 5 4 2 Hyperglycemia 3 0 6 3 0 0 3 Headache 6 10 1 3 3 0 3 Pain 6 0 0 2 5 6 4 Vomiting 9 3 0 2 3 6 4 Pneumonia 6 2 0 2 3 0 1 Urinary Frequency 0 0 1 2 5 2 1 Adverse events which occurred in 1% to 3% of all patients enrolled in the two clinical efficacy trials with at least one follow-up visit during the first 12 weeks of the study are listed below by body system. Adverse events occurring less than 1% are not included. There were no significant differences between incidence of these events in patients treated with megestrol acetate and patients treated with placebo. Body as a Whole - abdominal pain, chest pain, infection, moniliasis and sarcoma Cardiovascular System - cardiomyopathy and palpitation Digestive System - constipation, dry mouth, hepatomegaly, increased salivation and oral moniliasis Hemic and Lymphatic System - leukopenia Metabolic and Nutritional - LDH increased, edema and peripheral edema Nervous System - paresthesia, confusion, convulsion, depression, neuropathy, hypesthesia and abnormal thinking Respiratory System - dyspnea, cough, pharyngitis and lung disorder Skin and Appendages - alopecia, herpes, pruritus, vesiculobullous rash, sweating and skin disorder Special Senses - amblyopia Urogenital System - albuminuria, urinary incontinence, urinary tract infection and gynecomastia.

6.3 Postmarketing Experience Postmarketing reports associated with megestrol acetate oral suspension include thromboembolic phenomena including thrombophlebitis, deep vein thrombosis, and pulmonary embolism; and glucose intolerance.

AND PRECAUTIONS

• Use with caution in patients with a history of thromboembolic disease (5.1) .
• Fetal Effects: May cause fetal harm. Females of reproductive potential should be advised to avoid becoming pregnant ( 5.2 ).
• Clinical cases of overt Cushing's Syndrome have been reported in association with the chronic use of megestrol acetate. In addition, clinical cases of adrenal insufficiency have been observed in patients receiving or being withdrawn from chronic megestrol acetate in the stressed and non-stressed state (5.3) .
• New onset and exacerbation of pre-existing diabetes have been reported (5.4) .

5.1 General

• Effects on HIV viral replication have not been determined.
• Use with caution in patients with a history of thromboembolic disease.

5.2 Fetal Toxicity Based on animal studies, megestrol acetate may cause fetal harm when administered to a pregnant woman. Pregnant rats treated with low doses of megestrol acetate resulted in a reduction in fetal weight and number of live births, and feminization of male fetuses. There are no available human data to assess for any drug associated risks of miscarriage, birth defects, or adverse maternal or fetal outcomes. If this drug is used during pregnancy, or if the patient becomes pregnant while taking (receiving) this drug, advise the patient of the poten ‑ tial hazard to the fetus <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 ), Nonclinical Toxicology ( 13.1 )]</span>. Obtain a pregnancy test in females of reproductive potential prior to initiating treatment with megestrol acetate oral suspension <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 )]</span>. Advise females of reproductive potential to use effective contraception while taking megestrol acetate oral suspension <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.3 )]</span>.

5.3 Adrenal Insufficiency The glucocorticoid activity of megestrol acetate oral suspension has not been fully evaluated. Clinical cases of overt Cushing&apos;s Syndrome have been reported in association with the chronic use of megestrol acetate. In addition, clinical cases of adrenal insufficiency have been observed in patients receiving or being withdrawn from chronic megestrol acetate therapy in the stressed and non-stressed state. Furthermore, adrenocorticotropin (ACTH) stimulation testing has revealed the frequent occurrence of asymptomatic pituitary-adrenal suppression in patients treated with chronic megestrol acetate therapy. Therefore, the possibility of adrenal insufficiency should be considered in any patient receiving or being withdrawn from chronic megestrol acetate oral suspension therapy who presents with symptoms and/or signs suggestive of hypoadrenalism (e.g., hypotension, nausea, vomiting, dizziness, or weakness) in either the stressed or non-stressed state. Laboratory evaluation for adrenal insufficiency and consideration of replacement or stress doses of a rapidly acting glucocorticoid are strongly recommended in such patients. Failure to recognize inhibition of the hypothalamic-pituitary adrenal axis may result in death. Finally, in patients who are receiving or being withdrawn from chronic megestrol acetate oral suspension therapy, consideration should be given to the use of empiric therapy with stress doses of a rapidly acting glucocorticoid during stress or serious intercurrent illness (e.g., surgery, infection).

5.4 Diabetes Clinical cases of new onset diabetes mellitus and exacerbation of pre-existing diabetes mellitus have been reported in association with the chronic use of megestrol acetate.

PRECAUTIONS General Therapy with megestrol acetate oral suspension for weight loss should only be instituted after treatable causes of weight loss are sought and addressed. These treatable causes include possible malignancies, systemic infections, gastrointestinal disorders affecting absorption, endocrine disease and renal or psychiatric diseases. Effects on HIV viral replication have not been determined. Use with caution in patients with a history of thromboembolic disease. Use in Diabetics Exacerbation of pre-existing diabetes with increased insulin requirements has been reported in association with the use of megestrol acetate. Information for Patients Patients using megestrol acetate should receive the following instructions: This medication is to be used as directed by the physician. Report any adverse reaction experiences while taking this medication. Use contraception while taking this medication if you are a woman capable of becoming pregnant. Notify your physician if you become pregnant while taking this medication.

Drug Interactions

Pharmacokinetic studies show that there are no significant alterations in pharmacokinetic parameters of zidovudine or rifabutin to warrant dosage adjustment when megestrol acetate is administered with these drugs. The effects of zidovudine or rifabutin on the pharmacokinetics of megestrol acetate were not studied. Megestrol acetate may interact with warfarin and increase International Normalized Ratio (INR). Closely monitor INR in patients taking megestrol acetate and warfarin.

Animal Toxicology

Long-term treatment with megestrol acetate may increase the risk of respiratory infections. A trend toward increased frequency of respiratory infections, decreased lymphocyte counts and increased neutrophil counts was observed in a two-year chronic toxicity/carcinogenicity study of megestrol acetate conducted in rats. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Data on carcinogenesis were obtained from studies conducted in dogs, monkeys and rats treated with megestrol acetate at doses 53.2, 26.6 and 1.3 times lower than the proposed dose (13.3 mg/kg/day) for humans. No males were used in the dog and monkey studies. In female beagles, megestrol acetate (0.01, 0.1 or 0.25 mg/kg/day) administered for up to 7 years induced both benign and malignant tumors of the breast. In female monkeys, no tumors were found following 10 years of treatment with 0.01, 0.1 or 0.5 mg/kg/day megestrol acetate. Pituitary tumors were observed in female rats treated with 3.9 or 10 mg/kg/day of megestrol acetate for 2 years. The relationship of these tumors in rats and dogs to humans is unknown but should be considered in assessing the risk-to-benefit ratio when prescribing megestrol acetate oral suspension and in surveillance of patients on therapy. (See WARNINGS section) Mutagenesis No mutagenesis data are currently available. Impairment of Fertility Perinatal/postnatal (segment III) toxicity studies were performed in rats at doses (0.05 to 12.5 mg/kg) less than that indicated for humans (13.3 mg/kg); in these low dose studies, the reproductive capability of male offspring of megestrol acetate-treated females was impaired. Similar results were obtained in dogs. Pregnant rats treated with megestrol acetate showed a reduction in fetal weight and number of live births, and feminization of male fetuses. No toxicity data are currently available on male reproduction (spermatogenesis). Pregnancy No adequate animal teratology information is available at clinically relevant doses. (See WARNINGS and PRECAUTIONS: Carcinogenesis, Mutagenesis, impairment of Fertility: Impairment of Fertility .)

Nursing Mothers

Because of the potential for adverse effects on the newborn, nursing should be discontinued if megestrol acetate oral suspension is required. Use in Women Breakthrough bleeding was observed in all 10 female patients participating in the clinical trials. Megestrol acetate oral suspension is a progesterone derivative, which may induce vaginal bleeding in women.

All

10 women in the clinical trials reported breakthrough bleeding.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of megestrol acetate oral suspension in the treatment of anorexia, cachexia, or an unexplained, significant weight loss in patients with AIDS did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease of other drug therapy. Megestrol acetate is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

DRUG INTERACTIONS Pharmacokinetic studies show that there are no significant alterations in pharmacokinetic parameters of zidovudine or rifabutin to warrant dosage adjustment when megestrol acetate is administered with these drugs. The effects of zidovudine or rifabutin on the pharmacokinetics of megestrol acetate were not studied. Megestrol acetate may interact with warfarin and increase International Normalized Ratio (INR). Closely monitor INR in patients taking megestrol acetate and warfarin.

Animal Toxicology

Long-term treatment with megestrol acetate may increase the risk of respiratory infections. A trend toward increased frequency of respiratory infections, decreased lymphocyte counts, and increased neutrophil counts was observed in a two-year chronic toxicity/carcinogenicity study of megestrol acetate conducted in rats.