JANSSEN's RISPERDAL LONG-TERM PHASE IV EFFICACY STUDIES NEEDED, FDA SAYS IN DEC. 29 APPROVAL; AGENCY WARNS AGAINST SUPERIORITY CLAIMS TO OTHER ANTIPSYCHOTICS

Janssen's Risperdal (risperidone) was approved Dec. 29 for the treatment of psychotic disorders with the company's assurance that it will conduct Phase IV long-term efficacy studies.

"Although the evidence submitted unequivocally documents the short-term efficacy of Risperdal in the management of the manifestations of psychosis, there is no evidence bearing directly on the effectiveness of this drug in the maintenance treatment of remitted/partially remitted psychotic patients," FDA's approval letter states.

"Because it is likely that Risperdal will be widely used for these purposes, it is critical that appropriate clinical studies be undertaken to evaluate its safety and effectiveness in long- term use," the letter states. FDA noted that Janssen already has submitted a protocol for a study of relapse prevention.

The NDA for Risperdal (20-272), a benzisoxazole derivative with dopamine (D[2]) and serotonin (5-HT[2]) antagonism, was submitted in April 1992. The approval of the antipsychotic comes eight months after an FDA advisory committee unanimously recommended clearance of the drug for marketing ("The Pink Sheet" May 3, 1993, p. 12). Risperdal received a "1S" rating, designating a new molecular entity given a standard review.

The efficacy of Risperdal was based on one six-week and two eight-week clinical trials totaling 2,029 patients. In the largest eight-week study involving 1,356 patients, Risperdal at doses of 4 mg per day up to 16 mg/day was "generally" superior to a 1 mg dose on the Brief Psychiatric Rating Scale (BPRS) total score, on the BPRS psychosis cluster and the Clinical Global Impression (CGI) severity score, labeling states. No statistical difference was seen on the Positive and Negative Symptoms Scale (PANSS) negative subscale between the higher doses and the 1 mg dose of Risperdal.

Adverse reactions that were reported in the clinical trials with an incidence of 5% or greater in one of the Risperdal groups and at twice the incidence of placebo were: anxiety, somnolence, extrapyramidal symptoms, dizziness, constipation, nausea, dyspepsia, rhinitis, rash and tachycardia.

SmithKline Beecham will copromote Risperdal to psychiatrists in the U.S. under an agreement announced in May that also gave Janssen copromotion rights to SmithKline's serotonin reuptake inhibitor Paxil ("The Pink Sheet" May 17, 1993, T&G-13).

Janssen and SB have a challenge to distinguish Risperdal from older antipsychotic drugs since FDA, in its approval letter, stated that "at the present time, we would consider any advertisement or promotional labeling for Risperdal false, misleading or lacking in fair balance...if there is presentation of data that conveys the impression that risperidone is superior to haloperidol or any other marketed antipsychotic drug product with regard to safety or effectiveness."

At the May advisory committee meeting, Janssen asserted that in clinical trials risperidone was equivalent or superior to haloperidol (marketed as Haldol by McNeil and by several generic companies) and that the 6 mg dose of the drug was significantly better than 20 mg haloperidol as measured by PANSS in one study. However, Neuropharmacologic Drug Products Division Director Paul Leber, MD, said the comparison was a post hoc analysis that proved no difference between risperidone and haloperidol.

FDA also did not allow Janssen to distinguish between risperidone and haloperidol based on reduced side effects. Although Risperdal labeling states that 2.1% of patients discontinued risperidone therapy due to extrapyramidal symptoms (EPS) compared to 3.8% of "active-control" patients, labeling does not state that Risperdal's side effects are significantly less than those of any other antipsychotic.

The "Precautions" section of Risperdal labeling notes that "as with other drugs that antagonize dopamine D[2] receptors, risperidone elevates prolactin levels" and "one-third of human breast cancers are prolactin dependent in vitro." Preclinical toxicity data showing that Risperdal increased prolactin levels led an FDA advisory committee last July to recommend that precautions about elevated prolactin levels be included in all antipsychotic drug labeling ("The Pink Sheet" July 26, 1993, T&G- 8).

Recommended dosing for Risperdal is 1 mg b.i.d. initially, titrating up to 3 mg by the third day, with further dose adjustments at weekly intervals. Labeling notes that the maximal Risperdal effect was seen at doses of 4 mg to 6 mg per day. For elderly patients, it is recommended that the initial dosing start at .5 mg. b.i.d. Risperdal will be available in 1 mg, 2 mg, 3 mg, 4mg and 5 mg tablets.