8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies with ELIDEL Cream, 1% in pregnant women. Therefore, ELIDEL Cream, 1% should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In dermal embryofetal developmental studies, no maternal or fetal toxicity was observed up to the highest practicable doses tested, 10 mg/kg/day (1% pimecrolimus cream) in rats (0.14X MRHD based on body surface area) and 10 mg/kg/day (1% pimecrolimus cream) in rabbits (0.65X MRHD based on AUC comparisons). The 1% pimecrolimus cream was administered topically for 6 hours/day during the period of organogenesis in rats and rabbits (gestational days 6-21 in rats and gestational days 6-20 in rabbits).

A second dermal embryofetal development study was conducted in rats using pimecrolimus cream applied dermally to pregnant rats (1 g cream/kg body weight of 0.2%, 0.6% and 1.0% pimecrolimus cream) from gestation day 6 to 17 at doses of 2, 6, and 10 mg/kg/day with daily exposure of approximately 22 hours.

No maternal, reproductive, or embryofetal toxicity attributable to pimecrolimus was noted at 10 mg/kg/day (0.66X MRHD based on AUC comparisons), the highest dose evaluated in this study. No teratogenicity was noted in this study at any dose.

A combined oral fertility and embryofetal developmental study was conducted in rats and an oral embryofetal developmental study was conducted in rabbits. Pimecrolimus was administered during the period of organogenesis (2 weeks prior to mating until gestational day 16 in rats, gestational days 6-18 in rabbits) up to dose levels of 45 mg/kg/day in rats and 20 mg/kg/day in rabbits. In the absence of maternal toxicity, indicators of embryofetal toxicity (post-implantation loss and reduction in litter size) were noted at 45 mg/kg/day (38X MRHD based on AUC comparisons) in the oral fertility and embryofetal developmental study conducted in rats. No malformations in the fetuses were noted at 45 mg/kg/day (38X MRHD based on AUC comparisons) in this study. No maternal toxicity, embryotoxicity or teratogenicity were noted in the oral rabbit embryofetal developmental toxicity study at 20 mg/kg/day (3.9X MRHD based on AUC comparisons), which was the highest dose tested in this study.

A second oral embryofetal development study was conducted in rats. Pimecrolimus was administered during the period of organogenesis (gestational days 6 – 17) at doses of 2, 10 and 45 mg/kg/day. Maternal toxicity, embryolethality and fetotoxicity were noted at 45 mg/kg/day (271X MRHD based on AUC comparisons). A slight increase in skeletal variations that were indicative of delayed skeletal ossification was also noted at this dose. No maternal toxicity, embryolethality or fetotoxicity were noted at 10 mg/kg/day (16X MRHD based on AUC comparisons). No teratogenicity was noted in this study at any dose.

A second oral embryofetal development study was conducted in rabbits. Pimecrolimus was administered during the period of organogenesis (gestational days 7 – 20) at doses of 2, 6 and 20 mg/kg/day. Maternal toxicity, embryotoxicity and fetotoxicity were noted at 20 mg/kg/day (12X MRHD based on AUC comparisons). A slight increase in skeletal variations that were indicative of delayed skeletal ossification was also noted at this dose. No maternal toxicity, embryotoxicity or fetotoxicity were noted at 6 mg/kg/day (5X MRHD based on AUC comparisons). No teratogenicity was noted in this study at any dose.

An oral peri- and postnatal developmental study was conducted in rats. Pimecrolimus was administered from gestational day 6 through lactational day 21 up to a dose level of 40 mg/kg/day. Only 2 of 22 females delivered live pups at the highest dose of 40 mg/kg/day. Postnatal survival, development of the F1 generation, their subsequent maturation and fertility were not affected at 10 mg/kg/day (12X MRHD based on AUC comparisons), the highest dose evaluated in this study.

Pimecrolimus was transferred across the placenta in oral rat and rabbit embryofetal developmental studies.

8.3 Nursing Mothers

It is not known whether this drug is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from pimecrolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

ELIDEL Cream, 1% is not indicated for use in children less than 2 years of age.

The long-term safety and effects of ELIDEL Cream, 1% on the developing immune system are unknown.

Three Phase 3 pediatric trials were conducted involving 1114 subjects 2-17 years of age. Two trials were 6-week randomized vehicle-controlled trials with a 20-week open-label phase and one was a vehicle-controlled (up to 1 year) safety trial with the option for sequential topical corticosteroid use. Of these subjects, 542 (49%) were 2-6 years of age. In the short-term trials, 11% of ELIDEL subjects did not complete these trials and 1.5% of ELIDEL subjects discontinued due to adverse events. In the 1-year trial, 32% of ELIDEL subjects did not complete this trial and 3% of ELIDEL subjects discontinued due to adverse events. Most discontinuations were due to unsatisfactory therapeutic effect.

The most common local adverse event in the short-term trials of ELIDEL Cream, 1% in pediatric subjects ages 2-17 was application site burning (10% vs. 13% vehicle); the incidence in the long-term trial was 9% ELIDEL vs. 7% vehicle [see Adverse Reactions (6.1)]. Adverse events that were more frequent (>5%) in subjects treated with ELIDEL Cream, 1% compared to vehicle were headache (14% vs. 9%) in the short-term trial. Nasopharyngitis (26% vs. 21%), influenza (13% vs. 4%), pharyngitis (8% vs. 3%), viral infection (7% vs. 1%), pyrexia (13% vs. 5%), cough (16% vs. 11%), and headache (25% vs. 16%) were increased over vehicle in the 1-year safety trial [see Adverse Reactions (6.1)]. In 843 subjects ages 2-17 years treated with ELIDEL Cream, 1%, 9 (0.8%) developed eczema herpeticum (5 on ELIDEL Cream, 1% alone and 4 on ELIDEL Cream, 1% used in sequence with corticosteroids). In 211 subjects on vehicle alone, there were no cases of eczema herpeticum. The majority of adverse events were mild to moderate in severity.

Two Phase 3 trials were conducted involving 436 infants age 3 months-23 months. One 6-week randomized vehicle-controlled trial with a 20-week open- label phase and one safety trial, up to one year, were conducted. In the 6-week trial, 11% of ELIDEL and 48% of vehicle subjects did not complete this trial; no subject in either group discontinued due to adverse events. Infants on ELIDEL Cream, 1% had an increased incidence of some adverse events compared to vehicle. In the 6-week vehicle-controlled trial, these adverse events included pyrexia (32% vs. 13% vehicle), URI (24% vs. 14%), nasopharyngitis (15% vs. 8%), gastroenteritis (7% vs. 3%), otitis media (4% vs. 0%), and diarrhea (8% vs. 0%). In the open-label phase of the trial, for infants who switched to ELIDEL Cream, 1% from vehicle, the incidence of the above-cited adverse events approached or equaled the incidence of those subjects who remained on ELIDEL Cream, 1%. In the 6-month safety data, 16% of ELIDEL and 35% of vehicle subjects discontinued early and 1.5% of ELIDEL and 0% of vehicle subjects discontinued due to adverse events. Infants on ELIDEL Cream, 1% had a greater incidence of some adverse events as compared to vehicle. These included pyrexia (30% vs. 20%), URI (21% vs. 17%), cough (15% vs. 9%), hypersensitivity (8% vs. 2%), teething (27% vs. 22%), vomiting (9% vs. 4%), rhinitis (13% vs. 9%), viral rash (4% vs. 0%), rhinorrhea (4% vs. 0%), and wheezing (4% vs. 0%).

The systemic exposure to pimecrolimus from ELIDEL Cream, 1% was investigated in 28 pediatric subjects with atopic dermatitis (20%-80% BSA involvement) between the ages of 8 months-14 years. Following twice daily application for 3 weeks, blood concentrations of pimecrolimus were <2 ng/mL with 60% (96/161) of the blood samples having blood concentration below the limit of quantification (0.5 ng/mL). However, more children (23 children out of the total 28 children investigated) had at least one detectable blood level as compared to the adults (12 adults out of the total 52 adults investigated) over a 3-week treatment period. Due to the erratic nature of the blood levels observed, no correlation could be made between amount of cream, degree of BSA involvement, and blood concentrations. In general, the blood concentrations measured in adult atopic dermatitis subjects were comparable to those seen in the pediatric population.

In a second group of 30 pediatric subjects aged 3-23 months with 10%-92% BSA involvement, following twice daily application for 3 weeks, blood concentrations of pimecrolimus were <2.6 ng/mL with 65% (75/116) of the blood samples having blood concentration below 0.5 ng/mL, and 27% (31/116) below the limit of quantification (0.1 ng/mL) for these trials.

Overall, a higher proportion of detectable blood levels was seen in the pediatric subject population as compared to adult population. This increase in the absolute number of positive blood levels may be due to the larger surface area to body mass ratio seen in these younger subjects. In addition, a higher incidence of upper respiratory symptoms/infections was also seen relative to the older age group in the PK trials. At this time, a causal relationship between these findings and ELIDEL use cannot be ruled out.

8.5 Geriatric Use

Nine (9) subjects ≥65 years old received ELIDEL Cream, 1% in Phase 3 trials. Clinical trials of ELIDEL Cream, 1% did not include sufficient numbers of subjects aged 65 and over to assess efficacy and safety.