药品名称
通用名称：醋酸甲地孕酮口服混悬液/片
英文名称：Megestrol　Acetate　Tablets
规 格
160mg/20mg/40mg
药理毒理
本品为孕激素对垂体促性腺激素的释放有一定的抑制作用，但比左炔诺孕酮和炔诺酮为弱。不具有雌激素和雄激素样活性，但有明显抗雌激素作用。与雌激素合用，抑制排卵。动物致畸试验表明对家兔具有死胎率增加和致畸作用。
药代动力学
口服后生物半衰期明显比左炔诺孕酮为短，大部分代谢产物以葡萄糖醛酸酯形式排出.
适应症

治疗月经不调、功能性子宫出血、子宫内膜异位症；晚期乳腺癌和子宫内膜腺癌；亦可用于短效复方口服避孕片的孕激素成分.
用法用量

口服：
1）治疗闭经（雌激素水平足够时），一次4mg，一日2-3次，连服2-3日，停药2周内即有撤退性出血；
2）治疗功能性子宫出血，一日4mg-8mg，共20天，开始自月经第5天服或同于1）；
3）治疗子宫内膜异位症，一次4mg-8mg，一日1-2次，自月经第5天服，连服3-6个月；
4）乳腺癌，一次40mg，一日4次，一日量160mg，连续2个月；
5）子宫内膜癌，一次10-80mg，一日4次，一日量40-320mg,或一次160mg，每日一次.
任何疑问，请遵医嘱！
不良反应

①主要为恶心，头晕，倦怠；
②突破性出血；
③孕期服用有比较明确的增加女性后代男性化的作用.
禁 忌

严重肝，肾功能不全者，乳房肿块者，孕妇禁用.
注意事项

1）有子宫肌瘤，血栓病史及高血压、糖尿病、哮喘病、癫痫、偏头痛、精神抑郁患者慎用。
2）长期用药注意检查肝功能、乳房检查.
孕妇及哺乳期妇女用药

孕妇及哺乳期妇女用药禁用.
贮 藏

遮光，密封保存

药品中文名称  醋酸甲地孕酮口服混悬液 
药品名称说明  醋酸甲地孕酮口服混悬液 
药品英文名称  Megestrol Acetate Oral Suspension 
药品中文商品名  梅格施 
药品英文商品名  Megace 
中文剂型  口服混悬剂 
英文剂型  Oral Suspension 
药品规格  1ml：40mg 
包装规格  240ml/瓶 
注册证号  H20040187 
原注册证号  
注册证号说明  
分包装文号  
公司中文名称  
公司英文名称  Bristol-Myers Squibb Company 
公司中文地址  
公司英文地址  P.O.Box 4000,Princeton,NJ08540 
公司中文国别  美国 
公司英文国别  U.S.A. 
生产厂商中文名  
生产厂商英文名  Bristol-Myers Squibb Manufacturing Company 
生产厂国内地址  
生产厂国内地址  Road No.3 Km77.5 Humacao,Puerto Rico 00791 
生产厂中文国别  波多黎各 
生产厂英文国别  Puerto Rico 
批准日期  2004-03-17 
注册证效期  2009-03-16 

DESCRIPTION

MEGACE® (megestrol acetate, USP) Oral Suspension contains megestrol acetate, a synthetic derivative of the naturally occurring steroid hormone, progesterone. Megestrol acetate is a white, crystalline solid chemically designated as 17α-(acetyloxy)-6-methylpregna-4,6-diene-3,20-dione. Solubility at 37° C in water is 2 µg per mL, solubility in plasma is 24 µg per mL. Its molecular weight is 384.51.

The empirical formula is C24H32O4 and the structural formula is represented as follows:

MEGACE Oral Suspension is supplied as an oral suspension containing 40 mg of micronized megestrol acetate per mL.

MEGACE Oral Suspension contains the following inactive ingredients: alcohol (max. 0.06% v/v from flavor), citric acid, lemon-lime flavor, polyethylene glycol, polysorbate 80, purified water, sodium benzoate, sodium citrate, sucrose and xanthan gum.

CLINICAL PHARMACOLOGY

Several investigators have reported on the appetite enhancing property of megestrol acetate and its possible use in cachexia. The precise mechanism by which megestrol acetate produces effects in anorexia and cachexia is unknown at the present time.

There are several analytical methods used to estimate megestrol acetate plasma concentrations, including gas chromatography-mass fragmentography (GC-MF), high pressure liquid chromatography (HPLC) and radioimmunoassay (RIA). The GC-MF and HPLC methods are specific for megestrol acetate and yield equivalent concentrations. The RIA method reacts to megestrol acetate metabolites and is, therefore, non-specific and indicates higher concentrations than the GC-MF and HPLC methods. Plasma concentrations are dependent, not only on the method used, but also on intestinal and hepatic inactivation of the drug, which may be affected by factors such as intestinal tract motility, intestinal bacteria, antibiotics administered, body weight, diet and liver function.

The major route of drug elimination in humans is urine. When radiolabeled megestrol acetate was administered to humans in doses of 4 to 90 mg, the urinary excretion within 10 days ranged from 56.5% to 78.4% (mean 66.4%) and fecal excretion ranged from 7.7% to 30.3% (mean 19.8%). The total recovered radioactivity varied between 83.1% and 94.7% (mean 86.2%). Megestrol acetate metabolites which were identified in urine constituted 5% to 8% of the dose administered. Respiratory excretion as labeled carbon dioxide and fat storage may have accounted for at least part of the radioactivity not found in urine and feces.

Plasma steady state pharmacokinetics of megestrol acetate were evaluated in 10 adult, cachectic male patients with acquired immunodeficiency syndrome (AIDS) and an involuntary weight loss greater than 10% of baseline. Patients received single oral doses of 800 mg/day of MEGACE (megestrol acetate, USP) Oral Suspension for 21 days. Plasma concentration data obtained on day 21 were evaluated for up to 48 hours past the last dose.

Mean (±1SD) peak plasma concentration (Cmax) of megestrol acetate was 753 (±539) ng/mL. Mean area under the concentration time-curve (AUC) was 10476 (±7788) ng × hr/mL. Median Tmax value was five hours. Seven of 10 patients gained weight in three weeks.

Additionally, 24 adult, asymptomatic HIV seropositive male subjects were dosed once daily with 750 mg of MEGACE Oral Suspension. The treatment was administered for 14 days. Mean Cmax and AUC values were 490 (±238) ng/mL and 6779 (±3048) hr × ng/mL, respectively. The median Tmax value was three hours. The mean Cmin value was 202 (±101) ng/mL. The mean percent of fluctuation value was 107 (±40).

The effect of food on the bioavailability of MEGACE Oral Suspension has not been evaluated.

DESCRIPTION OF CLINICAL STUDIES

The clinical efficacy of MEGACE Oral Suspension was assessed in two clinical trials. One was a multicenter, randomized, double-blind, placebo-controlled study comparing megestrol acetate (MA) at doses of 100 mg, 400 mg, and 800 mg per day versus placebo in AIDS patients with anorexia/cachexia and significant weight loss. Of the 270 patients entered on study, 195 met all inclusion/exclusion criteria, had at least two additional post baseline weight measurements over a 12-week period or had one post baseline weight measurement but dropped out for therapeutic failure. The percent of patients gaining five or more pounds at maximum weight gain in 12 study weeks was statistically significantly greater for the 800 mg (64%) and 400 mg (57%) MA-treated groups than for the placebo group (24%). Mean weight increased from baseline to last evaluation in 12 study weeks in the 800 mg MA-treated group by 7.8 pounds, the 400 mg MA group by 4.2 pounds, the 100 mg MA group by 1.9 pounds and decreased in the placebo group by 1.6 pounds. Mean weight changes at 4, 8 and 12 weeks for patients evaluable for efficacy in the two clinical trials are shown graphically. Changes in body composition during the 12 study weeks as measured by bioelectrical impedance analysis showed increases in non-water body weight in the MA-treated groups (see clinical studies table). In addition, edema developed or worsened in only 3 patients.

Greater percentages of MA-treated patients in the 800 mg group (89%), the 400 mg group (68%) and the 100 mg group (72%), than in the placebo group (50%), showed an improvement in appetite at last evaluation during the 12 study weeks. A statistically significant difference was observed between the 800 mg MA-treated group and the placebo group in the change in caloric intake from baseline to time of maximum weight change. Patients were asked to assess weight change, appetite, appearance, and overall perception of well-being in a 9 question survey. At maximum weight change only the 800 mg MA-treated group gave responses that were statistically significantly more favorable to all questions when compared to the placebo-treated group. A dose response was noted in the survey with positive responses correlating with higher dose for all questions.

The second trial was a multicenter, randomized, double-blind, placebo-controlled study comparing megestrol acetate 800 mg/day versus placebo in AIDS patients with anorexia/cachexia and significant weight loss. Of the 100 patients entered on study, 65 met all inclusion/exclusion criteria, had at least two additional post baseline weight measurements over a 12-week period or had one post baseline weight measurement but dropped out for therapeutic failure. Patients in the 800 mg MA-treated group had a statistically significantly larger increase in mean maximum weight change than patients in the placebo group. From baseline to study week 12, mean weight increased by 11.2 pounds in the MA-treated group and decreased 2.1 pounds in the placebo group. Changes in body composition as measured by bioelectrical impedance analysis showed increases in non-water weight in the MA-treated group (see clinical studies table). No edema was reported in the MA-treated group. A greater percentage of MA-treated patients (67%) than placebo-treated patients (38%) showed an improvement in appetite at last evaluation during the 12 study weeks; this difference was statistically significant. There were no statistically significant differences between treatment groups in mean caloric change or in daily caloric intake at time to maximum weight change. In the same 9 question survey referenced in the first trial, patients' assessments of weight change, appetite, appearance, and overall perception of well-being showed increases in mean scores in MA-treated patients as compared to the placebo group.

In both trials, patients tolerated the drug well and no statistically significant differences were seen between the treatment groups with regard to laboratory abnormalities, new opportunistic infections, lymphocyte counts, T4 counts, T8 counts, or skin reactivity tests (see ADVERSE REACTIONS).

MEGACE (megestrol acetate, USP) Oral Suspension Clinical Efficacy Trials

	Trial 1 Study Accrual Dates 11/88 to 12/90				Trial 2 Study Accrual Dates 5/89 to 4/91
*Based on bioelectrical impedance analysis determinations at last evaluation in 12 weeks
Megestrol Acetate, mg/day	0	100	400	800	0	800
Entered Patients	38	82	75	75	48	52
Evaluable Patients	28	61	53	53	29	36
Mean Change in Weight (lb.)     Baseline to 12 Weeks	0.0	2.9	9.3	10.7	-2.1	11.2
% Patients ≥ 5 Pound Gain     at Last Evaluation in 12 Weeks	21	44	57	64	28	47
Mean Changes in Body Composition*     Fat Body Mass (lb.)     Lean Body Mass (lb.)     Water (liters)	0.0 -1.7 -1.3	2.2 -0.3 -0.3	2.9 1.5 0.0	5.5 2.5 0.0	1.5 -1.6 -0.1	5.7 -0.6 -0.1
% Patients With Improved Appetite     At Time of Maximum Wt. Change     At Last Evaluation in 12 Weeks	50 50	72 72	72 68	93 89	48 38	69 67
Mean Change in Daily Caloric Intake:     Baseline to Time of Maximum     Weight Change	-107	326	308	646	30	464

Presented below are the results of mean weight changes for patients evaluable for efficacy in Trials 1 and 2.

INDICATIONS AND USAGE

MEGACE 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).

CONTRAINDICATIONS

History of hypersensitivity to megestrol acetate or any component of the formulation. Known or suspected pregnancy.

WARNINGS

Megestrol acetate may cause fetal harm when administered to a pregnant woman. For animal data on fetal effects, see PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility: Impairment of Fertility. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking (receiving) this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

Megestrol acetate is not intended for prophylactic use to avoid weight loss.

(See also PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility.)

The glucocorticoid activity of MEGACE Oral Suspension has not been fully evaluated. Clinical cases of new onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and overt Cushing’s syndrome have been reported in association with the chronic use of MEGACE. In addition, clinical cases of adrenal insufficiency have been observed in patients receiving or being withdrawn from chronic MEGACE 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 MEGACE therapy. Therefore, the possibility of adrenal insufficiency should be considered in any patient receiving or being withdrawn from chronic MEGACE 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 MEGACE therapy, consideration should be given to the use of empiric therapy with stress doses of a rapidly acting glucocorticoid in conditions of stress or serious intercurrent illness (e.g., surgery, infection).

PRECAUTIONS

General

Therapy with MEGACE 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 preexisting diabetes with increased insulin requirements has been reported in association with the use of MEGACE.

Information for Patients

Patients using megestrol acetate should receive the following instructions:

1. This medication is to be used as directed by the physician.
2. Report any adverse reaction experiences while taking this medication.
3. Use contraception while taking this medication if you are a woman capable of becoming pregnant.
4. 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.

Animal Toxicology

Long-term treatment with MEGACE 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 MEGACE Oral Suspension and in surveillance of patients on therapy. (See WARNINGS.)

Mutagenesis

No mutagenesis data are currently available.

Impairment of Fertility

Perinatal/postnatal (segment III) toxicity studies were performed in rats at doses (0.05–12.5 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

Pregnancy Category X. (See WARNINGS and PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility: Impairment of Fertility.) No adequate animal teratology information is available at clinically relevant doses.

Nursing Mothers

Because of the potential for adverse effects on the newborn, nursing should be discontinued if MEGACE Oral Suspension is required.

Use in HIV-Infected Women

Although megestrol acetate has been used extensively in women for the treatment of endometrial and breast cancers, its use in HIV-infected women has been limited.

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 MEGACE 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 or 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.

ADVERSE REACTIONS

Clinical Adverse Events

Adverse events which occurred in at least 5% of patients in any arm of the two clinical efficacy trials and the open trial are listed below by treatment group. All patients listed had at least one post baseline visit during the 12 study weeks. These adverse events should be considered by the physician when prescribing MEGACE (megestrol acetate, USP) Oral Suspension.

ADVERSE EVENTS

% of Patients Reporting
	Trial 1 (N=236)				Trial 2 (N=87)		Open Label Trial
Megestrol Acetate, mg/day No. of Patients	Placebo 0 N=34	100 N=68	400 N=69	800 N=65	Placebo 0 N=38	800 N=49	1200 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

Postmarketing

Postmarketing reports associated with MEGACE Oral Suspension include thromboembolic phenomena including thrombophlebitis and pulmonary embolism, and glucose intolerance (see WARNINGS and PRECAUTIONS).

OVERDOSAGE

No serious unexpected side effects have resulted from studies involving MEGACE Oral Suspension administered in dosages as high as 1200 mg/day. Megestrol acetate has not been tested for dialyzability; however, due to its low solubility it is postulated that dialysis would not be an effective means of treating overdose.

DOSAGE AND ADMINISTRATION

The recommended adult initial dosage of MEGACE Oral Suspension is 800 mg/day (20 mL/day). Shake container well before using.

In clinical trials evaluating different dose schedules, daily doses of 400 and 800 mg/day were found to be clinically effective.

A plastic dosage cup with 10 mL and 20 mL markings is provided for convenience.

HOW SUPPLIED

MEGACE® (megestrol acetate, USP) Oral Suspension is available as a lemon-lime flavored oral suspension containing 40 mg of micronized megestrol acetate per mL.

NDC 0015-0508-42 Bottles of 240 mL (8 fl. oz.)

STORAGE

Store MEGACE Oral Suspension between 15° C - 25° C (59° F - 77° F) and dispense in a tight container. Protect from heat.

SPECIAL HANDLING

Health Hazard Data

There is no threshold limit value established by OSHA, NIOSH, or ACGIH.

Exposure or “overdose” at levels approaching recommended dosing levels could result in side effects described above (see WARNINGS and ADVERSE REACTIONS). Women at risk of pregnancy should avoid such exposure.

Distributed by:
Bristol-Myers Squibb Company
Princeton, New Jersey 08543 USA

51-029626-01
Revised March 2007