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| Product NDC Code | 24979-041 | ||||
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| Drug Name | Megestrol acetate |
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| Type | Generic | ||||
| Pharm Class | Progesterone Congeners [CS], Progestin [EPC] |
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| Active Ingredients |
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| Route | ORAL | ||||
| Dosage Form | SUSPENSION | ||||
| RxCUI drug identifier | 577154 | ||||
| Application Number | ANDA203139 | ||||
| Labeler Name | TWi Pharmaceuticals, Inc. | ||||
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Overdosage of Megestrol Acetate
Information about signs, symptoms, and laboratory findings of acute ovedosage and the general principles of overdose treatment.10 OVERDOSAGE No serious unexpected side effects have resulted from studies involving megestrol acetate oral suspension administered in dosages as high as 1200 mg/day. In post-marketing experience, limited reports of overdose have been received. Signs and symptoms reported in the context of overdose included diarrhea, nausea, abdominal pain, shortness of breath, cough, unsteady gait, listlessness, and chest pain. There is no specific antidote for overdose with megestrol acetate oral suspension. In case of overdose, appropriate supportive measures should be taken. 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.
Adverse reactions
Information about undesirable effects, reasonably associated with use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. Adverse reactions include those that occur with the drug, and if applicable, with drugs in the same pharmacologically active and chemically related class. There is considerable variation in the listing of adverse reactions. They may be categorized by organ system, by severity of reaction, by frequency, by toxicological mechanism, or by a combination of these.6 ADVERSE 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.
Megestrol Acetate Drug Interactions
Information about and practical guidance on preventing clinically significant drug/drug and drug/food interactions that may occur in people taking the drug.7 DRUG INTERACTIONS Due to a significant decrease in indinavir exposure, administration of a higher dose of indinavir should be considered when coadministering with megestrol acetate ( 7.1 , 12.3 ). 7.1 Indinavir Due to the significant decrease in the exposure of indinavir by megestrol acetate, administration of a higher dose of indinavir should be considered when coadministering with megestrol acetate [See Clinical Pharmacology ( 12.3 )] . 7.2 Zidovudine and Rifabutin No dosage adjustment for zidovudine and rifabutin is needed when megestrol acetate is coadministered with these drugs [See Clinical Pharmacology ( 12.3 )] .
Clinical pharmacology
Information about the clinical pharmacology and actions of the drug in humans.12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 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. 12.3 Pharmacokinetics Absorption and Distribution Mean plasma concentrations of megestrol acetate after administration of 625 mg (125 mg/mL) of megestrol acetate oral suspension are equivalent under fed conditions to 800 mg (40 mg/mL) of megestrol acetate oral suspension in healthy volunteers. In order to characterize the dose proportionality of megestrol acetate oral suspension, pharmacokinetic studies across a range of doses were conducted when administered under fasting and fed conditions. Pharmacokinetics of megestrol acetate was linear in the dosing range between 150 mg and 675 mg after megestrol acetate oral suspension administration regardless of meal condition. The mean peak plasma concentration (C max ) and the mean area under the concentration time-curve (AUC) after a high fat meal were increased by 48% and 36%, respectively, compared to those under the fasting condition after 625 mg megestrol acetate oral suspension administration. This food effect is less than that seen for the original formulation, megestrol acetate 800 mg/20 mL, where a high fat meal significantly increased AUC and C max of megestrol acetate to 2-fold and 7-fold, respectively, compared to those under the fasting condition. There was no difference in safety following administration in the fed state, therefore megestrol acetate oral suspension could be taken without regard to meals. Plasma steady state pharmacokinetics of megestrol acetate was evaluated in 10 adult, cachectic male adult patients with acquired immunodeficiency syndrome (AIDS) and an involuntary weight loss greater than 10% of baseline who received single oral doses of 800 mg/day of megestrol acetate oral suspension for 21 days. The Mean (±1SD) C max of megestrol acetate was 753 (±539) ng/mL. The mean AUC was 10476 (±7788) ng x hr/mL. Median T max value was five hours. In another study, 24 asymptomatic HIV seropositive male adult subjects were dosed once daily with 750 mg of megestrol acetate oral suspension for 14 days. Mean C max and AUC values were 490 (±238) ng/mL and 6779 (±3048) hr x ng/mL, respectively. The median T max value was three hours. The mean C min value was 202 (±101) ng/mL. The mean % of fluctuation value was 107 (±40). Metabolism and Excretion The major route of drug elimination in humans is urine. When radio-labeled 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. The mean elimination half-life of megestrol ranged from 20 to 50 hours in healthy subjects. Specific Populations The pharmacokinetics of megestrol acetate has not been studied in specific population, for example, pediatric, renal impairment, and hepatic impairment. Drug Interactions The effects of indinavir, zidovudine or rifabutin on the pharmacokinetics of megestrol acetate were not studied. Zidovudine Pharmacokinetic studies show that there are no significant alterations in exposure of zidovudine when megestrol acetate is administered with this drug. Rifabutin Pharmacokinetic studies show that there are no significant alterations in exposure of rifabutin when megestrol acetate is administered with this drug. Indinavir A pharmacokinetic study in healthy male subjects demonstrated that coadministration of megestrol acetate (675 mg for 14 days) and indinavir (single dose 800 mg) results in a significant decrease in the pharmacokinetic parameters (~32% for C max and ~21% for AUC) of indinavir.
Mechanism of action
Information about the established mechanism(s) of the drugÕs action in humans at various levels (for example receptor, membrane, tissue, organ, whole body). If the mechanism of action is not known, this field contains a statement about the lack of information.12.1 Mechanism of Action 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.
Pharmacokinetics
Information about the clinically significant pharmacokinetics of a drug or active metabolites, for instance pertinent absorption, distribution, metabolism, and excretion parameters.12.3 Pharmacokinetics Absorption and Distribution Mean plasma concentrations of megestrol acetate after administration of 625 mg (125 mg/mL) of megestrol acetate oral suspension are equivalent under fed conditions to 800 mg (40 mg/mL) of megestrol acetate oral suspension in healthy volunteers. In order to characterize the dose proportionality of megestrol acetate oral suspension, pharmacokinetic studies across a range of doses were conducted when administered under fasting and fed conditions. Pharmacokinetics of megestrol acetate was linear in the dosing range between 150 mg and 675 mg after megestrol acetate oral suspension administration regardless of meal condition. The mean peak plasma concentration (C max ) and the mean area under the concentration time-curve (AUC) after a high fat meal were increased by 48% and 36%, respectively, compared to those under the fasting condition after 625 mg megestrol acetate oral suspension administration. This food effect is less than that seen for the original formulation, megestrol acetate 800 mg/20 mL, where a high fat meal significantly increased AUC and C max of megestrol acetate to 2-fold and 7-fold, respectively, compared to those under the fasting condition. There was no difference in safety following administration in the fed state, therefore megestrol acetate oral suspension could be taken without regard to meals. Plasma steady state pharmacokinetics of megestrol acetate was evaluated in 10 adult, cachectic male adult patients with acquired immunodeficiency syndrome (AIDS) and an involuntary weight loss greater than 10% of baseline who received single oral doses of 800 mg/day of megestrol acetate oral suspension for 21 days. The Mean (±1SD) C max of megestrol acetate was 753 (±539) ng/mL. The mean AUC was 10476 (±7788) ng x hr/mL. Median T max value was five hours. In another study, 24 asymptomatic HIV seropositive male adult subjects were dosed once daily with 750 mg of megestrol acetate oral suspension for 14 days. Mean C max and AUC values were 490 (±238) ng/mL and 6779 (±3048) hr x ng/mL, respectively. The median T max value was three hours. The mean C min value was 202 (±101) ng/mL. The mean % of fluctuation value was 107 (±40). Metabolism and Excretion The major route of drug elimination in humans is urine. When radio-labeled 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. The mean elimination half-life of megestrol ranged from 20 to 50 hours in healthy subjects. Specific Populations The pharmacokinetics of megestrol acetate has not been studied in specific population, for example, pediatric, renal impairment, and hepatic impairment. Drug Interactions The effects of indinavir, zidovudine or rifabutin on the pharmacokinetics of megestrol acetate were not studied. Zidovudine Pharmacokinetic studies show that there are no significant alterations in exposure of zidovudine when megestrol acetate is administered with this drug. Rifabutin Pharmacokinetic studies show that there are no significant alterations in exposure of rifabutin when megestrol acetate is administered with this drug. Indinavir A pharmacokinetic study in healthy male subjects demonstrated that coadministration of megestrol acetate (675 mg for 14 days) and indinavir (single dose 800 mg) results in a significant decrease in the pharmacokinetic parameters (~32% for C max and ~21% for AUC) of indinavir.
Contraindications
Information about situations in which the drug product is contraindicated or should not be used because the risk of use clearly outweighs any possible benefit, including the type and nature of reactions that have been reported.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 ).
Description
General information about the drug product, including the proprietary and established name of the drug, the type of dosage form and route of administration to which the label applies, qualitative and quantitative ingredient information, the pharmacologic or therapeutic class of the drug, and the chemical name and structural formula of the drug.11 DESCRIPTION Megestrol acetate 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 17-Hydroxy-6-methyl pregna-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: Figure 1: Megestrol Acetate Chemical Structure Megestrol acetate oral suspension is an oral suspension containing 125 mg of megestrol acetate per mL. Megestrol acetate oral suspension contains the following inactive ingredients: alcohol (max 0.07% v/v from flavor), citric acid monohydrate, hypromellose, lemon flavor, sodium benzoate, sodium citrate dihydrate, sodium lauryl sulfate, and sucrose. The USP dissolution test is pending. b5862d67-figure-01
Dosage and administration
Information about the drug product’s dosage and administration recommendations, including starting dose, dose range, titration regimens, and any other clinically sigificant information that affects dosing recommendations.2 DOSAGE 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.
Dosage forms and strengths
Information about all available dosage forms and strengths for the drug product to which the labeling applies. This field may contain descriptions of product appearance.3 DOSAGE FORMS AND STRENGTHS Megestrol acetate oral suspension is milky white, lemon flavored, and contains 125 mg per mL. Oral suspension containing 125 mg of megestrol acetate per mL (3) .
Indications and usage
A statement of each of the drug products indications for use, such as for the treatment, prevention, mitigation, cure, or diagnosis of a disease or condition, or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition. This field may also describe any relevant limitations of use.1 INDICATIONS 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) .
Spl product data elements
Usually a list of ingredients in a drug product.Megestrol Acetate Megestrol Acetate HYPROMELLOSE 2910 (3 MPA.S) SODIUM LAURYL SULFATE SODIUM BENZOATE TRISODIUM CITRATE DIHYDRATE SUCROSE ALCOHOL Megestrol Acetate MEGESTROL
Animal pharmacology and or toxicology
Information from studies of the drug in animals, if the data were not relevant to nor included in other parts of the labeling. Most labels do not contain this field.13.2 Animal Pharmacology and/or Toxicology Long-term treatment with megestrol acetate oral suspension 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 and mutagenesis and impairment of fertility
Information about carcinogenic, mutagenic, or fertility impairment potential revealed by studies in animals. Information from human data about such potential is part of the warnings field.13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Data on carcinogenesis were obtained from studies conducted in dogs, monkeys and rats treated with megestrol acetate at doses below the recommended clinical dose based on body surface area. 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 at doses greater than or equal to 0.01 mg/kg/day, approximately 75 to 187 times below the maximum clinical dose. 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, up to 65 times below the maximum clinical dose. Pituitary tumors were observed in female rats treated for 2 years with 3.9 or 10 mg/kg/day of megestrol acetate, approximately 6 to 17 times below the maximum clinical dose. 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. Megestrol acetate induced unscheduled DNA synthesis in primary cultures of human hepatocytes, but not in rat hepatocytes. Megestrol administered to mice increased the frequency of sister chromatid exchange and chromosomal aberrations in bone marrow cells after single intraperitonial doses of 16.25 and 32.50 mg/kg. Impaired reproductive capability was observed in male offspring born to female rats treated during gestation days 13 through 20 with oral doses greater than or equal to 3 mg/kg/day megestrol, approximately 22 times below the maximum clinical dose. Female dogs treated daily with megestrol oral capsules for 7 years experienced a complete cessation of estrus activity and ovulation at doses of 0.1, or 0.25 mg/kg/day, approximately 187 and 75 times below the maximum clinical dose, respectively.
Nonclinical toxicology
Information about toxicology in non-human subjects.13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Data on carcinogenesis were obtained from studies conducted in dogs, monkeys and rats treated with megestrol acetate at doses below the recommended clinical dose based on body surface area. 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 at doses greater than or equal to 0.01 mg/kg/day, approximately 75 to 187 times below the maximum clinical dose. 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, up to 65 times below the maximum clinical dose. Pituitary tumors were observed in female rats treated for 2 years with 3.9 or 10 mg/kg/day of megestrol acetate, approximately 6 to 17 times below the maximum clinical dose. 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. Megestrol acetate induced unscheduled DNA synthesis in primary cultures of human hepatocytes, but not in rat hepatocytes. Megestrol administered to mice increased the frequency of sister chromatid exchange and chromosomal aberrations in bone marrow cells after single intraperitonial doses of 16.25 and 32.50 mg/kg. Impaired reproductive capability was observed in male offspring born to female rats treated during gestation days 13 through 20 with oral doses greater than or equal to 3 mg/kg/day megestrol, approximately 22 times below the maximum clinical dose. Female dogs treated daily with megestrol oral capsules for 7 years experienced a complete cessation of estrus activity and ovulation at doses of 0.1, or 0.25 mg/kg/day, approximately 187 and 75 times below the maximum clinical dose, respectively. 13.2 Animal Pharmacology and/or Toxicology Long-term treatment with megestrol acetate oral suspension 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.
Package label principal display panel
The content of the principal display panel of the product package, usually including the product’s name, dosage forms, and other key information about the drug product.PRINCIPAL DISPLAY PANEL - 150 mL Bottle Label 05
Recent major changes
A list of the section(s) that contain substantive changes that have been approved by FDA in the product labeling. The headings and subheadings, if appropriate, affected by the change are listed together with each section’s identifying number and the month and year on which the change was incorporated in the labeling.Dosage and Administration (2.1) 12/2018 Warnings and Precautions (5.2) 12/2018 Dosage and Administration ( 2.1 ) 12/2018 Warnings and Precautions ( 5.2 ) 12/2018
Megestrol Acetate: Information for patients
Information necessary for patients to use the drug safely and effectively, such as precautions concerning driving or the concomitant use of other substances that may have harmful additive effects.17 PATIENT COUNSELING INFORMATION 023The prescriber should inform the patient about the product differences to avoid overdosing or underdosing of megestrol acetate. The recommended adult dosage of megestrol acetate oral suspension is one teaspoon (5 mL) once a day [see Dosage and Administration ( 2 )]. Patients using megestrol acetate oral suspension should receive the following instructions: This medication is to be used as directed by the physician. Megestrol acetate oral suspension (625 mg/5 mL) does not contain the same amount of megestrol acetate as Megace oral suspension or any of the other megestrol acetate oral suspensions. Megestrol acetate oral suspension contains 625 mg of megestrol acetate per 5 mL (125mg/mL) whereas Megace oral suspension and other megestrol acetate oral suspensions contain 800 mg per 20 mL (40 mg/mL). Report any adverse reaction experiences while taking this medication. Fetal Toxicity [see Warnings and Precautions ( 5.2 ), Use in Specific Populations ( 8.1 , 8.3 )] Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy. Advise female patients of reproductive potential to use effective contraception during treatment with megestrol acetate oral suspension. Lactation [see Use in Specific Populations ( 8.2 )] Advise mothers not to breastfeed because of the risk of passing the HIV-1 virus to the baby in breast milk. Manufactured for: TWi Pharmaceuticals USA, Inc. Paramus, NJ 07652 Manufactured by: TWi Pharmaceuticals, Inc. Taoyuan City, 320023, Taiwan LA-3136-01 Revised: 03/23 Megace® is a registered trademark of Bristol-Myers Squibb Company licensed to Endo Pharmaceuticals Inc. b5862d67-figure-04
Clinical studies
This field may contain references to clinical studies in place of detailed discussion in other sections of the labeling.14 CLINICAL STUDIES The efficacy of megestrol acetate oral suspension, 125 mg/mL, was based on two trials of megestrol acetate oral suspension (40 mg/mL). These two trials are described below. Trial 1 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 2.3 kg or more 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 3.5 kg, the 400 mg MA group by 1.9 kg, the 100 mg MA group by 0.9 kg and decreased in the placebo group by 0.7 kg. Mean weight changes at 4, 8 and 12 weeks for patients evaluable for efficacy in the two clinical trials is 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. 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. Trial 2 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 5.1 kg in the MA-treated group and decreased 1.0 kg 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 ( 6 )]. Table 2: Megestrol Acetate 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 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 (kg) • Baseline to 12 Weeks 0.0 1.3 4.2 4..9 -1.0 5.1 % Patients ≥2.3 kg Gain • at Last Evaluation in 12 Weeks 21 44 57 64 28 47 •Mean Changes in Body Composition*: • Fat Body Mass (kg) 0.0 1.0 1.3 2.5 0.7 2.6 • Lean Body Mass (kg) -0.8 -0.1 0.7 1.1 -0.7 -0.3 • Water (liters) -1.3 -0.3 0.0 0.0 -0.1 -0.1 % Patients With Improved Appetite: • At Time of Maximum • Weight Change 50 72 72 93 48 69 • At Last Evaluation in 12 Weeks 50 72 68 89 38 67 Mean Change in Daily Caloric Intake: • Baseline to Time of Maximum • Weight Change -107 326 308 646 30 464 *Based on bioelectrical impedance analysis determinations at last evaluation in 12 weeks. b5862d67-figure-02 b5862d67-figure-03
| Trial 1 Study Accrual Dates 11/88 to 12/90 | Trial 2 Study Accrual Dates 5/89 to 4/91 | |||||
| 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 (kg) | ||||||
| • Baseline to 12 Weeks | 0.0 | 1.3 | 4.2 | 4..9 | -1.0 | 5.1 |
| % Patients ≥2.3 kg Gain | ||||||
| • at Last Evaluation in 12 Weeks | 21 | 44 | 57 | 64 | 28 | 47 |
| •Mean Changes in Body Composition*: | ||||||
| • Fat Body Mass (kg) | 0.0 | 1.0 | 1.3 | 2.5 | 0.7 | 2.6 |
| • Lean Body Mass (kg) | -0.8 | -0.1 | 0.7 | 1.1 | -0.7 | -0.3 |
| • Water (liters) | -1.3 | -0.3 | 0.0 | 0.0 | -0.1 | -0.1 |
| % Patients With Improved Appetite: | ||||||
| • At Time of Maximum | ||||||
| • Weight Change | 50 | 72 | 72 | 93 | 48 | 69 |
| • At Last Evaluation in 12 Weeks | 50 | 72 | 68 | 89 | 38 | 67 |
| Mean Change in Daily Caloric Intake: | ||||||
| • Baseline to Time of Maximum | ||||||
| • Weight Change | -107 | 326 | 308 | 646 | 30 | 464 |
| *Based on bioelectrical impedance analysis determinations at last evaluation in 12 weeks. | ||||||
Geriatric use
Information about any limitations on any geriatric indications, needs for specific monitoring, hazards associated with use of the drug in the geriatric population.8.5 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 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.
Nursing mothers
Information about excretion of the drug in human milk and effects on the nursing infant, including pertinent adverse effects observed in animal offspring.8.3 Females and Males of Reproductive Potential Pregnancy testing Pregnancy testing is recommended prior to treatment with megestrol acetate oral suspension [see Dosage and Administration ( 2.1 ), Use in Specific Populations ( 8.1 )]. Contraception Megestrol acetate oral suspension may cause fetal harm when administered during pregnancy [see Use in Specific Populations ( 8.1 )]. Advise females of reproductive potential to use effective contraception during treatment with megestrol acetate oral suspension.
Pediatric use
Information about any limitations on any pediatric indications, needs for specific monitoring, hazards associated with use of the drug in any subsets of the pediatric population (such as neonates, infants, children, or adolescents), differences between pediatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug.8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.
Pregnancy
Information about effects the drug may have on pregnant women or on a fetus. This field may be ommitted if the drug is not absorbed systemically and the drug is not known to have a potential for indirect harm to the fetus. It may contain information about the established pregnancy category classification for the drug. (That information is nominally listed in the teratogenic_effects field, but may be listed here instead.)8.1 Pregnancy Risk Summary Based on animal data, megestrol acetate may cause fetal harm when administered to a pregnant woman and is contraindicated during pregnancy [see Contraindications ( 4 )] . There are no available human data to assess for any drug-associated risks of miscarriage, birth defects, or adverse maternal or fetal outcomes. There are no adequate animal developmental toxicity data at clinically relevant doses. 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 at doses below maximum recommended clinical dosing based on body surface area ( see Data ). Advise a pregnant women of the potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Reproduction studies were performed in pregnant rats at oral doses ranging from 0.05 to 12.5 mg/kg/day, which are below the maximum recommended clinical dose based on body surface area. Reduction in fetal weight and number of live births were observed at 12.5 mg/kg/day (5 times lower than the maximum clinical dose) when dams were dosed on days 12 through 18 of pregnancy. Feminization of male fetuses also occurred when dams were dosed on days 13 through 20 of pregnancy at 3 mg/kg/day, approximately 22 times below the maximum clinical dose.
Use in specific populations
Information about use of the drug by patients in specific populations, including pregnant women and nursing mothers, pediatric patients, and geriatric patients.8 USE IN SPECIFIC POPULATIONS Lactation : Women infected with HIV-1 should be instructed not to breastfeed due to the potential for HIV transmission ( 8.2 ). Geriatrics : 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 therapy ( 8.5 ). 8.1 Pregnancy Risk Summary Based on animal data, megestrol acetate may cause fetal harm when administered to a pregnant woman and is contraindicated during pregnancy [see Contraindications ( 4 )] . There are no available human data to assess for any drug-associated risks of miscarriage, birth defects, or adverse maternal or fetal outcomes. There are no adequate animal developmental toxicity data at clinically relevant doses. 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 at doses below maximum recommended clinical dosing based on body surface area ( see Data ). Advise a pregnant women of the potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Reproduction studies were performed in pregnant rats at oral doses ranging from 0.05 to 12.5 mg/kg/day, which are below the maximum recommended clinical dose based on body surface area. Reduction in fetal weight and number of live births were observed at 12.5 mg/kg/day (5 times lower than the maximum clinical dose) when dams were dosed on days 12 through 18 of pregnancy. Feminization of male fetuses also occurred when dams were dosed on days 13 through 20 of pregnancy at 3 mg/kg/day, approximately 22 times below the maximum clinical dose. 8.2 Lactation Risk Summary The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. Megestrol acetate is present in human milk. There are no data on the effects of megesterol acetate on the breastfed infant or the effects on milk production. Because of the potential for HIV transmission and adverse effects on a breastfed infant, instruct mothers not to breastfeed if they are taking megestrol acetate oral suspension. 8.3 Females and Males of Reproductive Potential Pregnancy testing Pregnancy testing is recommended prior to treatment with megestrol acetate oral suspension [see Dosage and Administration ( 2.1 ), Use in Specific Populations ( 8.1 )]. Contraception Megestrol acetate oral suspension may cause fetal harm when administered during pregnancy [see Use in Specific Populations ( 8.1 )]. Advise females of reproductive potential to use effective contraception during treatment with megestrol acetate oral suspension. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 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 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. 8.6 Use in Women Megestrol acetate has had limited use in HIV infected women. All 10 women in the clinical trials reported breakthrough bleeding. Megestrol acetate oral suspension is a progesterone derivative, which may induce vaginal bleeding in women.
How supplied
Information about the available dosage forms to which the labeling applies, and for which the manufacturer or distributor is responsible. This field ordinarily includes the strength of the dosage form (in metric units), the units in which the dosage form is available for prescribing, appropriate information to facilitate identification of the dosage forms (such as shape, color, coating, scoring, and National Drug Code), and special handling and storage condition information.16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Megestrol acetate oral suspension is a milky white, lemon-lime flavored oral suspension containing 125 mg per mL. Available in bottles of 150 mL (5 fl oz) NDC 24979-041-13. 16.2 Storage Store megestrol acetate oral suspension between 20° to 25° C (68° to 77° F) and dispense in a tight container. Protect from heat. 16.3 Safe 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 Precautions ( 5 ) and Adverse Reactions ( 6 )]. Women at risk of pregnancy should avoid such exposure.
Disclaimer: Do not rely on openFDA or Phanrmacy Near Me to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. Source: OpenFDA, Healthporta Drugs API