Pimecrolimus

1 INDICATIONS AND USAGE 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 c ream, 1% is not indicated for use in children less than 2 years of age [see Warnings and Precautions (5.1) , Use in Specific Populations (8.4) ]. Pimecrolimus cream, 1% is a calcineurin inhibitor immunosuppressant indicated as s e c o n d -l i n e th e r a p y 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. ( 1 )

2 DOSAGE AND ADMINISTRATION 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 [see Warnings and Precautions (5.1) ] . 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. ( 2 ) • If signs and symptoms persist beyond 6 weeks, patients should be re-examined. ( 2 ) • Continuous long-term use of Pimecrolimus Cream, 1% should be avoided. ( 2 ) • Avoid use with occlusive dressings. ( 2 )

3 DOSAGE FORMS AND STRENGTHS Cream, 1%. Each gram of Pimecrolimus Cream, 1% contains 10 mg of pimecrolimus in a white to off-white cream base. Cream, 1%. ( 3 )

4 CONTRAINDICATIONS Pimecrolimus Cream, 1% is contraindicated in individuals with a history of hypersensitivity to pimecrolimus or any of the components of the cream. Pimecrolimus Cream, 1% is contraindicated in individuals with a history of hypersensitivity to pimecrolimus or any of the components of the cream. ( 4 , 6.2 )

6 ADVERSE REACTIONS The most commonly reported adverse reactions (greater than or equal to 1%) were application site burning, headache, nasopharyngitis, cough, influenza, pyrexia and viral infection. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals USA, Inc. at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6. 1 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. In a one-year safety trial in pediatric subjects age 2 to 17 years old involving sequential use of pimecrolimus cream, 1% and a topical corticosteroid, 43% of pimecrolimus cream, 1% treated subjects and 68% of vehicle-treated subjects used corticosteroids during the trial. Corticosteroids were used for more than 7 days by 34% of pimecrolimus cream, 1% treated subjects and 54% of vehicle-treated subjects. 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 3 randomized, double-blind vehicle-controlled pediatric trials and one active-controlled adult trial, 843 and 328 subjects respectively, were treated with pimecrolimus cream, 1%. In these clinical trials, 48 (4%) of the 1,171 pimecrolimus treated subjects and 13 (3%) of 408 vehicle-treated subjects discontinued therapy due to adverse events. 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% to 26% of subjects treated with pimecrolimus cream, 1%. Table 1 depicts the incidence of adverse events pooled across the 2 identically designed 6-week trials with their open label extensions and the 1-year safety trial for pediatric subjects ages 2 to 17. Data from the adult active-controlled trial is also included in Table 1. Adverse events are listed regardless of relationship to trial drug. Table 1. Treatment Emergent Adverse Events (≥1%) in Pimecrolimus Cream Treatment Groups P e di a t r i c Subj e c t s* P e di a t r i c Subj e c t s* P e di a t r i c Subj e c t s* Adu l t A c t i v e V e h i c le -C o nt r o lle d O p e n- La b e l V e h i c le -C o nt r o lle d C o m p ara to r ( 6 wee k s) ( 2 0 w ee k s) ( 1 y e ar ) ( 1 y e ar) Pimecrolimus Cream Vehicle Pimecrolimus Cream Pimecrolimus Cream Vehicle Pimecrolimus Cream (N=267) (N=136) (N=335) (N=272) (N=75) (N=328) N (%) N (%) N (%) N (%) N (%) N (%) At least 1 AE 182 (68.2%) 97 (71.3%) 240 (72.0%) 230 (84.6%) 56 (74.7%) 256 (78.0%) I n f e c ti o n s a n d I nf e s t a t io n s Upper Respiratory Tract Infection NOS 38 (14.2%) 18 (13.2%) 65 (19.4%) 13 (4.8%) 6 (8.0%) 14 (4.3%) Nasopharyngitis 27 (10.1%) 10 (7.4%) 32 (19.6%) 72 (26.5%) 16 (21.3%) 25 (7.6%) Skin Infection NOS 8 (3.0%) 9 (5.1%) 18 (5.4%) 6 (2.2%) 3 (4.0%) 21 (6.4%) Influenza 8 (3.0%) 1 (0.7%) 22 (6.6%) 36 (13.2%) 3 (4.0%) 32 (9.8%) Ear Infection NOS 6 (2.2%) 2 (1.5%) 19 (5.7%) 9 (3.3%) 1 (1.3%) 2 (0.6%) Otitis Media 6 (2.2%) 1 (0.7%) 10 (3.0%) 8 (2.9%) 4 (5.3%) 2 (0.6%) Impetigo 5 (1.9%) 3 (2.2%) 12 (3.6%) 11 (4.0%) 4 (5.3%) 8 (2.4%) Bacterial Infection 4 (1.5%) 3 (2.2%) 4 (1.2%) 3 (1.1%) 0 6 (1.8%) Folliculitis 3 (1.1%) 1 (0.7%) 3 (0.9%) 6 (2.2%) 3 (4.0%) 20 (6.1%) Sinusitis 3 (1.1%) 1 (0.7%) 11 (3.3%) 6 (2.2%) 1 (1.3%) 2 (0.6%) Pneumonia NOS 3 (1.1%) 1 (0.7%) 5 (1.5%) 0 1 (1.3%) 1 (0.3%) Pharyngitis NOS 2 (0.7%) 2 (1.5%) 3 (0.9%) 2 …

7 DRUG INTERACTIONS 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.

8 USE IN SPECIFIC POPULATIONS 8. 1 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). The 1% pimecrolimus cream was administered topically for 6 hours/day during the period of organogenesis in rats and rabbits (gestational days 6 to 21 in rats and gestational days 6 to 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 embryo-fetal 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 to 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 to 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 to 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 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 …

12.1 Mechanism of Action The mechanism of action of pimecrolimus in atopic dermatitis is not known. While the following have been observed, the clinical significance of these observations in atopic dermatitis is not known. It has been demonstrated that pimecrolimus binds with high affinity to macrophilin-12 (FKBP-12) and inhibits the calcium-dependent phosphatase, calcineurin. As a consequence, it inhibits T-cell activation by blocking the transcription of early cytokines. In particular, pimecrolimus inhibits at nanomolar concentrations Interleukin-2 and interferon gamma (Th1-type) and Interleukin-4 and Interleukin-10 (Th2-type) cytokine synthesis in human T-cells. In addition, pimecrolimus prevents the release of inflammatory cytokines and mediators from mast cells in vitro after stimulation by antigen/IgE.

11 DESCRIPTION Pimecrolimus cream, 1%, for topical use, contains the compound pimecrolimus, the immunosuppressant 33-epi-chloro-derivative of the macrolactam ascomycin. Chemically, pimecrolimus is (1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-12-[(1E)-2-{(1R,3R,4S)-4-chloro-3-methoxycyclohexyl}-1-methylvinyl]-17-ethyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone. The compound has the molecular formula C 43 H 68 CINO 11 and the molecular weight of 810.47. The structural formula is: Pimecrolimus is a white to off-white fine crystalline powder. It is soluble in methanol and ethanol and insoluble in water. Each gram of pimecrolimus cream, 1% contains 10 mg of pimecrolimus in a whitish cream base of benzyl alcohol, cetyl alcohol, cetostearyl alcohol (type A), citric acid anhydrous, medium-chain triglycerides, mono- and di-glycerides, oleyl alcohol, propylene glycol, sodium hydroxide, stearyl alcohol, and water. The Structural formula of pimecrolimus is (1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-12-[(1E)-2-{(1R,3R,4S)-4-chloro-3-methoxycyclohexyl}-1-methylvinyl]-17-ethyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone. The compound has the molecular formula C43H68CINO11 and the molecular weight of 810.47.

16 HOW SUPPLIED/STORAGE AND HANDLING Pimecrolimus cream, 1% is a whitish cream available in tubes of 30 grams, 60 grams, and 100 grams. 30 gram tube........................................................................NDC 0591-2944-30 60 gram tube........................................................................NDC 0591-2944-60 100 gram tube.......................................................................NDC 0591-2944-87 Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Do not freeze.