TEMAZEPAM DOSAGE STRENGTH CHANGES MAY ALTER RATE OF ABSORPTION

TEMAZEPAM DOSAGE STRENGTH CHANGES MAY ALTER RATE OF ABSORPTION and thus alter effectiveness over time, FDA told Wyeth in a Sept. 29 letter denying the firm's ANDA suitability petition for 10 mg and 20 mg temazepam soft gelatin capsules. The reference drug cited by Wyeth is Sandoz' Restoril capsules, 15 mg and 30 mg. "The information you have provided regarding your proposed 10 mg and 20 mg products indicates that they are more rapidly absorbed than the reference listed drug products but that total absorption is proportional to the total amount of the drug present," FDA Office of Drug Standards Director Peter Rheinstein stated. "Although the proposed products might, because of the initial rapid absorption, be expected to be equally effective with respect to sleep latency as the reference products, the smaller total dose and lower blood levels later at night might diminish the effectiveness of your drug products with respect to the duration of sleep or number of wakenings." FDA has approved a number of ANDA suitability petitions for changes in dosage strength from a listed product. Wyeth's temazepam petition is the first ANDA suitability request to be denied when both a higher strength and lower strength (for the proposed 20 mg product) are currently marketed. FDA said it has particular concerns regarding changes in dosage strength for two drug classes, narcotics and hypnotics. Rheinstein explained that the proposed 10 mg product "constitutes a strength that is one-third lower than the lowest approved strength of the listed reference drug product. Therefore, investigations are necessary to establish the effectiveness of the proposed product, including a demonstration of effectiveness with respect to sleep duration and number of wakenings." The 20 mg product "raises questions of both safety and effectiveness," Rheinstein stated. He noted that "based on its Cmax, the 20 mg capsule would be expected to substitute for, and be used in patients for whom the 30 mg dose of the reference product is labeled" even though the total absorption "would raise a question as to the proposed product's effectiveness for duration of sleep." Moreover, Rheinstein said, "if the proposed 20 mg product was used by people who would ordinarily use the referenced 15 mg product, the elderly or debilitated, the 20 mg product would provide a Cmax about twice as high as the 15 mg product." He stated that "this increase in Cmax raises concern regarding safety in people who need only the lower dose."