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FDA Approves Megace ES for Anorexia, Cachexia, or Unexplained, Significant Weight Loss in Patients With AIDS
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Par Pharmaceuticals released this press announcement
Contacts:
Stephen Mock
(201) 802-4000
smock@parpharm.com
WOODCLIFF LAKE, NJ -- July 6, 2005 -- Par Pharmaceutical Companies, Inc. today announced that the U.S. Food and Drug Administration (FDA) has approved Megace ES (megestrol acetate), a concentrated oral suspension for the treatment of anorexia, cachexia, or an unexplained, significant weight loss in patients with a diagnosis of acquired immunodeficiency syndrome (AIDS).
The approval of Megace ES represents the first branded pharmaceutical product developed by Par to be approved for marketing by the FDA. New Megace ES is an advanced formulation of megestrol acetate oral suspension, the appetite stimulant most commonly prescribed by physicians. Megace ES can be taken without regard to meals and is dosed at one-fourth the volume of the original product.
"Unintended weight loss and cachexia, also known as wasting, have been shown to be determining factors in progression of disease in AIDS patients," said Lynn Kramer, MD, senior vice president, clinical development and medical affairs. "For patients who have difficulty swallowing a large dose, or those with a lack of appetite who cannot eat without the help of medication, the approval of Megace ES is a crucial advance."
Megace ES utilizes Elan's NanoCrystal® Technology delivery system* to improve the rate of dissolution and bioavailability of the original megestrol acetate oral suspension. Recent data have shown that the bioavailability of the original formulation is reduced substantially when taken on an empty stomach.
With Megace ES, this reduction in bioavailability is minimized in the fasted state, resulting in improved bioavailability in patients who have not eaten. Megace ES 625 mg/5 mL and megestrol acetate oral suspension 800 mg/20 mL are bioequivalent in a fed state.
Patients taking Megace ES will be able to take a one-teaspoon (625 mg/5 mL) daily dose, or one-fourth of the volume of the original product. Previously, patients had to drink one 20 mL cup (800 mg/20 mL) of megestrol acetate oral suspension daily to receive the drug's full benefit. Megace ES also is 16 times less viscous (10 cP versus 163 cP) than the original formulation.
"Par Pharmaceutical is committed to the science of improving treatment solutions for patients," said Scott Tarriff, president and chief executive officer. "It is gratifying to be able to offer patients this advanced product. Improved bioavailability and reduced volume per dose of Megace ES should allow patients to receive the complete benefit of the therapy."
Efficacy of Megace ES
The FDA approval of Megace ES was based on pharmacokinetic studies demonstrating bioequivalence between 625 mg of Megace ES and 800 mg of megestrol acetate oral suspension when dosed in a fed state.
The clinical benefits of megestrol acetate oral suspension in treating patients with anorexia, cachexia, or an unexplained, significant weight loss have been clearly demonstrated in patients with AIDS. In one of two placebo-controlled, randomized efficacy trials in patients with AIDS, megestrol acetate oral suspension effectively stimulated appetite in nine out of 10 patients, increased mean caloric intake by 646 calories per day, and increased mean weight gain by 10.7 pounds versus placebo in 12 weeks. Patients also reported an improved sense of well being. In a second placebo-controlled study, seven out of 10 patients experienced improved appetite; mean caloric intake was increased by 464 calories a day, and mean weight increased by 13.3 pounds versus placebo.
Moreover, a bioavailability study directly comparing the rate and extent of absorption of Megace ES and megestrol acetate oral suspension revealed that the Cmax** level with the original formulation was 1,364 ng/mL in fed patients and 187 ng/mL in unfed patients. In contrast, the Cmax level with Megace ES was 1,517 ng/mL in fed patients and 1,041 ng/mL in unfed patients. Further, in unfed patients Megace ES achieved 5 times greater peak plasma levels than megestrol acetate oral suspension. Additionally, the study demonstrated that a lower volume of Megace ES achieved maximum blood concentration more rapidly than the currently available oral suspension products.
About Unintended Weight Loss
Anorexia (a persistent lack of appetite), unintended weight loss, and cachexia (significant weight loss that involves depletion of both fat and lean body mass) represent a serious risk in patients with AIDS. Significant weight loss and cachexia are associated with worsening illness, physical impairment, decreased tolerance of some therapeutic agents, and increased susceptibility to infection.
Important Safety Information About Megace ES
Megace ES and megestrol acetate oral suspension are contraindicated in patients with a history of hypersensitivity to megestrol acetate or any component of the formulation, or patients with known or suspected pregnancy.
Evidence of adrenal suppression has been observed in patients receiving megestrol acetate oral suspension. The glucocorticoid activity of megestrol acetate oral suspension has not been fully evaluated.
Clinical cases of new onset diabetes mellitus, exacerbation of pre- existing diabetes mellitus, and overt Cushing's Syndrome have been reported in association with the chronic use of megestrol acetate.
The most common adverse events (less than or equal to 1% and > than placebo) associated with Megace ES 625 mg/5 mL and megestrol acetate oral suspension 800 mg/20 mL are impotence, flatulence, rash, hypertension, insomnia, fever, decreased libido, dyspepsia and hyperglycemia.
Women who participated in studies (n=10) reported breakthrough bleeding; however, it is unknown if these events are drug -- or disease-related. For more information on Megace ES, or for complete prescribing information, visit .
About NanoCrystal Technology
Megace ES was developed with NanoCrystal Technology, a nanoparticulate drug delivery system of Elan Pharma International Limited, a subsidiary of Elan Corporation, plc.
NanoCrystal Technology is applied exclusively to poorly water-soluble drugs, and has been applied successfully to several dosage forms to overcome many of the problems created by low levels of water solubility. An extensive patent estate protects Elan's NanoCrystal Technology.
** Cmax: Maximum drug concentration in blood plasma.
Par Pharma distributed this Fact Sheet
WHAT IS MEGACE ES?
Megace® ES (megestrol acetate), a concentrated suspension, is an advanced formulation of megestrol acetate oral suspension, the appetite stimulant most commonly prescribed by physicians.
Megace ES was approved by the United States Food and Drug Administration based on demonstration of bioequivalence in the fed state to its predecessor product, megestrol acetate oral suspension (Megace® OS). Clinical efficacy studies of Megace ES were not required for approval. Two pivotal trials support the efficacy and safety of megestrol acetate oral suspension.
WHAT IS THE INDICATION FOR MEGACE ES?
Megace ES is indicated for the treatment of anorexia, cachexia, or an unexplained, significant weight loss in patients with a diagnosis of acquired immunodeficiency syndrome (AIDS). This indication is identical to that of the original megestrol acetate oral suspension.
WHY IS TREATMENT FOR THESE CONDITIONS IMPORTANT?
Anorexia (a persistent lack of appetite), unintended weight loss, and cachexia (significant weight loss that involves depletion of both fat and lean body mass) represent a serious risk in patients with AIDS. Significant weight loss and cachexia are associated with worsening illness, physical impairment, decreased tolerance of some therapeutic agents, and increased susceptibility to infection. IV
WHAT IS THE CLINICAL DATA?
Megace ES at a dose of 625 mg/5 mL is bioequivalent to megestrol acetate oral suspension 800 mg/20 mL in the fed state.
Two placebo-controlled, randomized efficacy trials compared megestrol acetate oral suspension 800 mg/20 mL versus placebo in patients with AIDS.
-- In Trial 1 (n=65), megestrol acetate oral suspension:
--Stimulated appetite in nine out of 10 patients
--Increased mean caloric intake by 646 calories per day
--Increased mean weight gain by 10.7 pounds versus placebo in 12 weeks4
--Increased lean body mass by 4.2 pounds and fat body mass by 5.5 pounds
-- In Trial 2 (n=38), seven out 10 patients experienced improved appetite, mean caloric intake was increased by 464 calories per day, and mean weight increased by 13.3 pounds versus placebo. Lean body mass increased by 1 pound and fat body mass increased by 4.2 pounds.
-- In both trials, patients reported an improved sense of well-being.
HOW DOES MEGACE ES DIFFER FROM THE OLDER FORMULATION?
With Megace ES the volume of each dose is significantly reduced. Patients can now take one-fourth the total volume per dose—5 mL—compared with the 20 mL required with megestrol acetate oral suspension. The new formulation is also less viscous. The viscosity of Megace ES is only slightly greater than milk.
In addition, Megace ES can be taken without regard to meals, allowing greater flexibility in the time of dosing, especially important for patients who have minimal food intake.
Taken together, these benefits can be expected to improve adherence to therapy, which in turn will help patients receive the full benefit of the drug.
This advanced formulation is made possible by NanoCrystal® Technology which increases bioavailability under unfed conditions and improves the rate of absorption.*4
WHY IS BIOAVAILABILITY IMPORTANT?
Recent data have shown that the bioavailability of the original megestrol acetate oral suspension is substantially reduced when not administered with food. This characteristic of the drug was not recognized when initially marketed, and the package insert for the drug does not include instructions to take with food. The reduced bioavailability of the original formulation in fasted conditions was discovered when studies were performed to assess the bioequivalence of megestrol acetate oral suspension to the new formulation Megace ES.
The data showed the following:
In fed conditions, Megace ES 625 mg/5 mL is bioequivalent to megestrol acetate oral suspension 800 mg/20 mL.
Bioavailability studies directly comparing the rate and extent of absorption of Megace ES and megestrol acetate oral suspension revealed that the Cmax** level with the original formulation was 1,364 ng/mL in fed patients and 187 ng/mL in unfed patients. In contrast, the Cmax level with Megace ES was 1,517 ng/mL in fed patients and 1,041 ng/mL in unfed patients. Further, in unfed patients Megace ES achieved 5 times greater peak plasma levels than megestrol acetate oral suspension. Additionally, the studies demonstrated that a lower volume of Megace ES achieved maximum blood concentration more rapidly than the currently available oral suspension products.
** Cmax (ng/mL): Maximum drug concentration in blood plasma.
WHAT IS THE SAFETY PROFILE OF MEGACE ES?
Megace ES and megestrol acetate oral suspension are contraindicated in patients with a history of hypersensitivity to megestrol acetate or any component of the formulation, or patients with known or suspected pregnancy.
Evidence of adrenal suppression has been observed in patients receiving megestrol acetate oral suspension. The glucocorticoid activity of megestrol acetate oral suspension has not been fully evaluated.
Clinical cases of new onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and overt Cushing’s Syndrome have been reported in association with the chronic use of megestrol acetate.
The most common adverse events (>6%) associated with Megace ES and megestrol oral suspension are diarrhea, impotence, rash, flatulence, hypertension, asthenia, insomnia, pain, and vomiting. These adverse events should be considered by the physician when prescribing megestrol acetate oral suspension.
Women who participated in studies (n=10) reported breakthrough bleeding; however, it is unknown if these events are drug- or disease-related.
WHERE DO I GO FOR ADDITIONAL INFORMATION ABOUT MEGACE ES?
If you have any questions concerning Megace ES or to see complete prescribing information, please do not hesitate to call Par Pharmaceutical at 1-800-8289393 or visit the Megace ES website at www.MegaceES.com.
Megace ES is not a controlled substance.
REFERENCES
IMS data 2004 for megestrol acetate oral suspension, dronabinol, oxandrolone and somatropin.
Megace ES prescribing information. Par Pharmaceutical, Inc. 2005.
Kotler, DP. Cachexia. Ann Intern Med. 17. Oct. 00. Vol. 133 Number 8.
Oster. Ann Intern Med 1994;121:400 ; Von Roenn Ann Intern Med 1994;121:393; Megace PI.
Data on file. ANA 4-05, Cmax values in fed and unfed conditions respectively are: megestrol acetate oral suspension 800 mg/20 mL (1,364 ng/mL and 187 ng/mL) and Megace ES 625 mg/5 mL (1,501 ng/mL and 1,041 mg/mL). Par Pharmaceutical, Inc. 2005.
Femia, R. Megestrol acetate nanocrystal: Results of dose-escalating studies under fed and fasting conditions. Poster presented at amfAR’s 17th National HIV/AIDS Update Conference.
Megace ES prescribing information. Par Pharmaceutical, Inc. 2005.
Megace ES prescribing information. Par Pharmaceutical, Inc. 2005.
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