Pimecrolimus Drug Information

Pimecrolimus Cream, 1% is indicated as second-line therapy for the short-term and non-continuous chronic treatment of mild to moderate atopic dermatitis in non-immunocompromised adults and children 2 years of age and older, who have failed to respond adequately to other topical prescription treatments, or when those treatments are not advisable. Pimecrolimus Cream, 1% is not indicated for use in children less than 2 years of age.

• Apply a thin layer of Pimecrolimus Cream, 1% to the affected skin twice daily. The patient should stop using Pimecrolimus Cream, 1% when signs and symptoms (e.g., itch, rash and redness) resolve and should be instructed on what actions to take if symptoms recur. If signs and symptoms persist beyond 6 weeks, patients should be re-examined by their healthcare provider to confirm the diagnosis of atopic dermatitis. Continuous long-term use of Pimecrolimus Cream, 1% should be avoided, and application should be limited to areas of involvement with atopic dermatitis. The safety of Pimecrolimus Cream, 1% under occlusion, which may promote systemic exposure, has not been evaluated. Avoid use of Pimecrolimus Cream, 1% with occlusive dressings.
• Apply a thin layer of Pimecrolimus Cream, 1% to the affected skin twice daily.
• If signs and symptoms persist beyond 6 weeks, patients should be re-examined.
• Continuous long-term use of Pimecrolimus Cream, 1% should be avoided.
• Avoid use with occlusive dressings.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. No phototoxicity and no photoallergenicity were detected in clinical trials with 24 and 33 normal volunteers, respectively. In human dermal safety trials, Pimecrolimus Cream, 1% did not induce contact sensitization or cumulative irritation.

An increased incidence of impetigo, skin infection, superinfection (infected atopic dermatitis), rhinitis, and urticaria were found in the subjects that had used Pimecrolimus Cream, 1% and topical corticosteroid sequentially as compared to Pimecrolimus Cream, 1% alone. In three randomized, double-blind vehicle-controlled pediatric trials and one active-controlled adult trial, 843 and 328 subjects, respectively, were treated with Pimecrolimus Cream, 1%. Discontinuations for AEs were primarily due to application site reactions and cutaneous infections.

The most common application site reaction was application site burning, which occurred in 8%-26% of subjects treated with Pimecrolimus Cream, 1%. Table 1 depicts the incidence of adverse events pooled across the two identically designed 6-week trials with their open label extensions and the 1-year safety trial for pediatric subjects ages 2-17. Data from the adult active-controlled trial are also included in Table 1.

Adverse events are listed regardless of relationship to trial drug. Table 1. Treatment Emergent Adverse Events (≥1%) in Two cases of septic arthritis have been reported in infants less than one year of age in clinical trials conducted with Pimecrolimus Cream, 1% (n = 2443).

Causality has not been established.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Pimecrolimus Cream, 1%. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. General: Anaphylactic reactions, ocular irritation after application of the cream to the eye lids or near the eyes, angioneurotic edema, facial edema, skin flushing associated with alcohol use, skin discoloration.

Hematology/Oncology: Lymphomas, basal cell carcinoma, malignant melanoma, squamous cell carcinoma.

Potential interactions between Pimecrolimus Cream, 1% and other drugs, including immunizations, have not been systematically evaluated. Due to low blood levels of pimecrolimus detected in some patients after topical application, systemic drug interactions are not expected, but cannot be ruled out. The concomitant administration of known CYP3A family of inhibitors in patients with widespread and/or erythrodermic disease should be done with caution.

Some examples of such drugs are erythromycin, itraconazole, ketoconazole, fluconazole, calcium channel blockers and cimetidine.

Pregnancy Pregnancy Category C There are no adequate and well-controlled studies with Pimecrolimus Cream, 1% in pregnant women. Therefore, Pimecrolimus 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).

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.

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. A second oral embryofetal development study was conducted in rats.

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).

Maternal toxicity, embryotoxicity and fetotoxicity were noted at 20 mg/kg/day (12X MRHD based on AUC comparisons). No maternal toxicity, embryotoxicity or fetotoxicity were noted at 6 mg/kg/day (5X MRHD based on AUC comparisons). 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.

Pediatric Use Pimecrolimus Cream, 1% is not indicated for use in children less than 2 years of age. The long-term safety and effects of Pimecrolimus 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 Pimecrolimus subjects did not complete these trials and 1.5% of Pimecrolimus subjects discontinued due to adverse events.

In the 1-year trial, 32% of Pimecrolimus subjects did not complete this trial and 3% of Pimecrolimus subjects discontinued due to adverse events. Most discontinuations were due to unsatisfactory therapeutic effect. 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. In the 6-week trial, 11% of Pimecrolimus and 48% of vehicle subjects did not complete this trial; no subject in either group discontinued due to adverse events.

Infants on Pimecrolimus Cream, 1% had an increased incidence of some adverse events compared to vehicle. In the open-label phase of the trial, for infants who switched to Pimecrolimus Cream, 1% from vehicle, the incidence of the above-cited adverse events approached or equaled the incidence of those subjects who remained on Pimecrolimus Cream, 1%. Infants on Pimecrolimus Cream, 1% had a greater incidence of some adverse events as compared to vehicle.

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.

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 Pimecrolimus use cannot be ruled out.

Pimecrolimus Cream, 1% is contraindicated in individuals with a history of hypersensitivity to pimecrolimus or any of the components of the cream.