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BRISTOL-MYERS SQUIBB’s MEGACE ORAL SOLUTION FOR AIDS-RELATED WEIGHT LOSS AVAILABLE BY END OF MONTH; NEW DOSAGE FORM COVERED UNDER REIMBURSEMENT PROGRAM

Executive Summary

Bristol-Myers Squibb's Megace oral solution for weight loss associated with AIDS will be available in pharmacies by the end of September, the company said. The new formulation of Megace (megestrol acetate) was approved on Sept. 10 for the new indication of "anorexia, cachexia or an unexplained, significant weight-loss in patients with the diagnosis of [AIDS]." FDA designated the approval "3S, V" (designating an orphan-designated new formulation under standard review). Megace was previously available only in tablet form. Bristol-Myers Squibb VP-Medical Affairs Isadore Pike, MD, explained in a Sept. 15 teleconference announcing the approval that while AIDS patients have been taking Megace off-label to enhance weight gain, they have been required to take twenty 40 mg tablets to achieve therapeutic doses. The oral solution of Megace will allow patients to take the equivalent of four teaspoons of liquid to achieve the 800 mg/20 ml per day starting dose. The lemon-lime flavored oral suspension comes with a plastic dosage cup with 10 ml and 20 ml markings. The NDA (20-264) for Megace oral suspension was filed in April 1992. The off-patent drug has been available since the 1970s in the tablet form for the palliative treatment of breast and endometrial cancers. An NDA (20-296) for a 250 mg tablet formulation of Megace is still pending agency approval. It was filed in August 1992. The price to wholesalers for Megace will be $83.04 per 236.6 ml bottle containing 40 mg of micronized mogestrol acetate per ml. The recommended initial dose is 800 mg daily, with a dose adjustment to 400 mg after one month. Labeling does not specify an overall duration of therapy. In the pivotal clinical trials cited in labeling, patients received Megace for four months. During the teleconference, lead clinical investigator Jamie Von Roenn, MD, Northwestern University, said that once a patient has reached his or her desired weight, the dose may be reduced or discontinued until further weight gain is desired. Similar to its handling of Videx and cancer chemotherapy products, BMS has established an assistance program to help secure reimbursement for Megace. The company said that Megace will be made available free of charge to "all patients who do not have adequate insurance coverage and cannot afford the medication." Pike said that physicians with patients in need of free Megace should call 1-800-788-0123 and the company will send a one-page form to fill out and return. Once the form is reviewed and approved, BMS will send a supply of drug to the physician. The efficacy of Megace for the new indication was based on data from two pivotal clinical trials. In the larger trial, patients received either 100 mg, 400 mg, 800 mg Megace or placebo over a period of 12 weeks. Of the 195 evaluable patients, the percentage that had a weight gain of five pounds or more was significantly greater for the 800 mg group (64%) and 400 mg group (57%) compared to placebo (24%). Patients who were treated with 800 mg Megace had a mean weight increase from baseline at 12 weeks of 7.8 lb. compared to 4.2 lb. for the 400 mg group and a loss of 1.6 lb. for the placebo-treated patients. Of the patients treated with 800 mg of Megace, increases in appetite were noted in 89% compared to 68% in the 400 mg group and 50% in the placebo-treated group. Von Roenn said that "although other substances have been approved to stimulate appetite, Megace oral suspension is the first drug shown to enhance lean body weight and muscle mass." Mean changes in body composition assessed in the larger pivotal trial showed gains of 5.5 lb. of fat, 2.5 lb. of lean body mass and no weight gain associated with water retention. Megace will compete with Unimed's Marinol (dronabinol) marketed by Roxane Labs. Approved for AIDS-related anorexia in December ("The Pink Sheet" Jan. 4, p. 14), Marinol is a derivative of marijuana and is a Schedule II controlled substance. The costs of Megace and Marinol therapy are comparable. Although Marinol labeling notes that patients taking the drug had a statistically significant improvement in appetite, labeling states that a trend toward improved body weight was not statistically significant. Roxane recently began to run Marinol ads in major medical journals that depict five friends having dinner with four of them looking with expectant joy as the fifth one, presumably the AIDS patient, eats his meal. The ads contain information about trends in body weight gain and potential side effects. Marinol labeling cautions that the drug may be habit forming and subject to abuse. Patients should not drive or operate machinery until they are able to tolerate Marinol therapy, which normally takes two to three days, labeling states. After initiation of Marinol therapy, some patients have feelings of euphoria, dizziness, confusion or somnolence. Patients taking Marinol may also experience withdrawal symptoms upon discontinuation of the drug. The major side effect associated with Megace therapy was impotence, which occurred in 14% of patients receiving 800 mg in the larger pivotal trial compared to 3% of placebo-treated patients. Von Roenn said that the impotence experienced by patients was reversible, diminishing after patients had discontinued Megace therapy. Other side effects occurring at the highest dose of Megace therapy included diarrhea, rash, edema, flatulence and weakness. Megace carries a warning against use during pregnancy due to potential genital abnormalities in male and female fetuses. Von Roenn emphasized that a follow-up of patients in the trials showed no difference in survival between the Megace- and placebo-treated groups. She explained that there had been a theoretical concern that Megace, a synthetic progesterone, might up-regulate the AIDS virus. The concern that Megace may make AIDS patients more susceptible to opportunistic infections caused FDA's Antiviral Drugs Advisory Committee to split five-to-four in a vote to recommend approval of the drug for the indication early this year ("The Pink Sheet" Feb. 22, p. 13). In clinical trials, there were 20 AIDS-related deaths among the 283 patients treated with Megace compared to two deaths out of the 86 patients receiving placebo. While the differences were not statistically significant, some committee members felt they represented a trend toward increased mortality among the Megace- treated patients. BMS is planning to evaluate whether Megace interacts with any of the current antiviral therapies for AIDS, Pike said, such as AZT (Burroughs Wellcome's Retrovir), the company's own ddl (Videx), and Hoffmann-La Roche's ddC (Hivid). If interactions are discovered, BMS may launch further clinical studies to assess the in vivo effect of the drugs' interactions with Megace, Pike said. Drug interaction studies and a study comparing mortality rates between Megace and Marinol were suggested by advisory committee members. A study comparing the efficacy of Megace and Mazinol is ongoing, Von Roenn said.
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