Pharmacy & Therapeutics - October 2008 - (Page PP14)

PRODUCT PROFILER: Granisetron Transdermal Delivery System Study 392MD/26/C: A Phase 1 Skin Irritation And Sensitization Study15 A double-blind, randomized placebo-controlled, single-center phase 1 study was conducted to assess the cumulative skin irritation and sensitization potential of GTDS. The primary objectives were to assess the incidence and prevalence of irritation at the site of application after repeated applications and to evaluate the incidence of sensitization at an alternative skin site after another application of the study patches. The secondary objective was to assess the delivery of granisetron from the patch by determining plasma granisetron levels.15 Granisetron was supplied in a 52-cm2 patch containing 34.3 mg of granisetron free base. The placebo patch was identical in appearance and composition to the granisetron patch, but it did not contain any active medication.15 The study consisted of a 28-day screening period, a three-week induction phase, followed by a rest phase of two weeks and a subsequent challenge phase of six days. If required, an additional one-week rechallenge phase was to be completed. All participants completed a 7- to 10-day follow-up phase. During the induction phase, a total of three applications of the two test products—active and placebo patches—were performed on opposite upper outer arms. The patches remained in place for one week during each application, and each new patch was applied to the same area of previously treated skin. Skin reactions were assessed before the patches were applied on Day 1 and at 30 minutes after each patch removal on Days 8, 15, and 22. It is worth noting that in clinical practice, this procedure would be not followed, because one of the most effective ways to reduce local irritation is to allow skin to recover by rotating the patch site. All subjects completed a rest period of at least two weeks between the induction phase and the challenge phase. During the challenge phase, the two test products were applied for 48 hours on the back, and skin sensitization was scored at 30 minutes, 24 hours, 48 hours, and 72 hours after patch removal. Subjects who experienced any skin reactions during the challenge phase returned to the clinic within 14 days for a rechallenge phase. During the rechallenge phase, the patches were applied to new skin sites on the back for 48 hours. Assessments were performed at 30 minutes, 24 hours, 48 hours, and 72 hours after patch removal. Patch adhesion and subjective responses were also evaluated three times per week during the induction phase and after 48 hours during the challenge phase. During a 7- to 10-day follow-up period after patch removal, subjects attended the clinic for a physical examination, routine laboratory tests, and observation of any AEs.15 Using a grading scale (Table 5), the investigators assessed dermal responses. Subjective comments reported by the participants (pruritus, stinging, burning sensation) were scored as follows: 0 = weak, 1 = moderate, and 2 = severe. Sensitization reactions were assessed as follows: 0 = negative, 1 = equivocal, and 2 = positive. Any subjects with a sensitization score of 1 or 2 (equivocal or positive) were to be rechallenged after a two-week period.15 Patch adhesion was also evaluated at each visit.15 Two hundred twelve subjects (158 women and 54 men) between 19 and 63 years of age (mean age, 37) were enrolled; 201 subjects were analyzed for irritation, and 200 were analyzed for sensitization. Blood collection was performed in a subset of 24 subjects to assess granisetron’s pharmacokinetic parameters.15 Of the 201 subjects evaluated for irritation, 91 (45.3%) and 66 (32.9%) subjects, respectively, displayed no erythema on the active granisetron or placebo test sites on Day 8. Skin reactions with the placebo patch on Day 8 were slightly higher for those with moderate or severe erythema (45 subjects [22.4%]), compared with 27 subjects (13.5%) wearing the active granisetron patch. At Day 8, severe erythema was reported in one subject who was wearing the active granisetron patch (Figure 5).15 The investigator also calculated the incidence and prevalence of skin irritation. Table 6 presents the incidence of positive irritant reactions, defined as the percentage of subjects whose skin reaction score was greater than 1. Mean cumulative irritation (MCI) and total cumulative irritation (TCI) scores were also calculated, as in Table 7 (see page 16). Based on these results, the Table 5 Dermal Response Grading Scale After the Induction Phase Score 0 1 2 3 4 Definition No reaction Slight erythema (faint pink to definite pink) Moderate erythema (definite redness) Severe erythema (very intense redness) or erythema with edema Erythema with vesicles or erosion or bullae From Study 392MD/26/C, p 27.15 14

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Pharmacy & Therapeutics - October 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/ New Medical Devices Drug Forecast Medical Management of Parkinson’s Disease Why Is Health Care Regulation So Complex? The Next President’s Prescription for Action on Drugs Trends in Managing Multiple Sclerosis Product Profiler: Sancuso®

Pharmacy & Therapeutics - October 2008

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