Elidel

[pimecrolimus Cream 1%]

However, oral studies may not reflect continuous exposure or the same metabolic profile as by the dermal route. In a mouse dermal carcinogenicity study using pimecrolimus in an ethanolic solution, no increase in incidence of neoplasms was observed in the skin or other organs up to the highest dose of 4 mg/kg/day (0.32% pimecrolimus in ethanol) 27X MR HD based on AUC comparisons. However, lymphoproliferative changes (including lymphoma) were noted in a 13 week repeat dose dermal toxicity study conducted in mice using pimecrolimus in an ethanolic solution at a dose of 25 mg/kg/day (47X MRHD based on AUC comparisons). No lymphoproliferative changes were noted in this study at a dose of 10 mg /kg/day (17X MRHD based on AUC comparison).

However, the latency time to lymphoma formation was shortened to 8 weeks after dermal administration of pimecrolimus dissolved in ethanol at a dose of 100 mg/kg/day (179-217X MRHD based on AUC comparisons).

In a mouse oral (gavage) carcinogenicity study, a statistically significant increase in the incidence of lymphoma was noted in high dose male and female animals compared to vehicle control male and female animals. Lymphomas we re noted in the oral mouse carcinogenicity study at a dose of 45 mg/kg/day ( 258-340X MRHD based on AUC comparisons). No drug- related tumors were noted in the mouse oral carcinogenicity study at a dose of 15 mg/kg/day (60-133X MRHD based on AUC comparisons).

In an oral (gavage) rat carcinogenicity study, a statistically significant increase in the incidence of benign thymoma was noted in 10 mg/kg/day pimecrolimus treated male and female animals compared to vehicle control treated male and female animals. In addition, a significant increase in the incidence of benign thymoma was noted in another oral (gavage) rat carcinogenicity study in 5 mg/kg/day pimecrolimus treated male animals compared to vehicle control treated male animals. No drug-related tumors were noted in the rat oral carcinogenicity study at a dose of 1 mg/kg/day male animals (1.1X MRHD based on AUC comparisons) and at a dose of 5 mg/kg/day for female animals (21X MRHD based on AUC comparisons).

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In a 52-week dermal photo-carcinogenicity study, the median time to onset of skin tumor formation was decreased in hairless mice following chronic topical dosing with concurrent exposure to UV radiation (40 weeks of treatment followed by 12 weeks of observation) with the Elidel Cream vehicle al one. No additional effect on tumor development beyond the vehicle effect was noted with the addition of the active ingredient, pimecrolimus, to the vehicle cream.

A battery of in vitro genotoxicity tests, including Ames assay, mouse lymphoma L5178Y assay, and chromosome aberration test in V79 Chinese hamster cells and an in vivo mouse micronucleus test revealed no evidence for a mutagenic or clastogenic potential for the drug.

An oral fertility and embryo fetal developmental study in rats revealed estrus cycle disturbances, post-implantation loss and reduction in litter size at the 45 mg/kg/day dose (38X MRHD based on AUC comparisons). No effect on fertility in female rats was noted at 10 mg/kg/day (12X MRHD based on AUC comparisons ). No effect on fertility in male rats was noted at 45 mg/kg/day (23X MRHD based on AUC comparisons), which was the highest dose tested in this study.

Pregnancy

Teratogenic Effects:

Pregnancy Category C

There are no adequate and well-controlled studies of topically administered pimecrolimus in pregnant women. The experience with Elidel Cream when used by pregnant women is too limited to permit assessment of the safety of its use during pregnancy.

In dermal embryo fetal 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 combined oral fertility and embryo fetal developmental study was conducted in rats and an oral embryo fetal 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 embryo fetal 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 embryo fetal 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, embryo toxicity or teratogenicity were noted in the oral rabbit embryo fetal developmental toxicity study at 20 mg/kg/day (3.9X MRHD based on AUC comparisons ), which was the highest dose tested in this study.

An oral peri- and post-natal 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 embryo fetal
developmental studies.

There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used only if clearly needed during pregnancy.

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.

Pediatric Use

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

The most common local adverse event in the short-term studies of Elidel Cream in pediatric patients ages 2-17 was application site burning (10% vs. 13% vehicle); the incidence in the long-term study was 9% Elidel vs. 7% vehicle (see ADVERSE REACTIONS ).

Adverse events that were more frequent (> 5%) in patients treated with Elidel Cream 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 study (see ADVERSE REACTIONS). In 843 patients ages 2-17 years treated with Elidel Cream, 9 (0.8%) developed eczema herpeticum (5 on Elidel Cream alone and 4 on Elidel Cream used in sequence with corticosteroids). In 211 patients on vehicle alone, there were no cases of eczema herpeticum. The majority of adverse events were mild to moderate in severity.

Elidel Cream is not recommended for use in pediatric patients below the age of 2 years. Two Phase 3 studies were conducted involving 436 infants age 3 months - 23 months. One 6-week randomized vehicle-controlled study with a 20-week open-label phase and one long term safety study were conducted. In the 6-week study, 11% of Elidel and 48% of vehicle patients did not complete this study; no patient in either group discontinued due to adverse events. Infants on Elidel Cream had an increased incidence of some adverse events compared to vehicle. In the 6-week vehicle-controlled study 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 study, for infants who switched to Elidel Cream from vehicle, the incidence of the above-cited adverse events approached or equaled the incidence of those patients who remained on Elidel Cream. In the 6 month safety data, 16% of Elidel and 35% of vehicle patients discontinued early and 1.5% of Elidel and 0% of vehicle patients discontinued due to adverse events. Infants on Elidel Cream 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 effects of Elidel Cream on the developing immune system in infants are unknown.

Geriatric Use

Nine (9) patients 65 years old received Elidel Cream in Phase 3 studies. Clinical studies of Elidel did not include sufficient numbers of patients aged 65 and over to assess efficacy and safety.

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