Pimecrolimus

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.

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 Cream, 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 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. ( 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 )

6 ADVERSE REACTIONS The most commonly reported adverse reactions (≥1%) were application site burning, headache, nasopharyngitis, cough, influenza, pyrexia and viral infection. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Oceanside Pharmaceuticals at 1-800-321-4576 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 1-year safety trial in pediatric subjects age 2-17 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 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%. In these clinical trials, 48 (4%) of the 1171 Pimecrolimus Cream, 1% 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%-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 Pimecrolimus Cream, 1% Treatment Groups Pediatric Subjects Ages 2-17 years Vehicle-Controlled (6 weeks) Pediatric Subjects Open-Label Pediatric Subjects Vehicle-Controlled (1 year) Adult Active Comparator (1 year) (20 weeks) Pimecrolimus Cream, 1% Vehicle Pimecrolimus Cream, 1% Pimecrolimus Cream, 1% Vehicle Pimecrolimus Cream, 1% (N=267) N (%) (N=136) N (%) (N=335) N (%) (N=272) N (%) (N=75) N (%) (N=328) N (%) At least 1 AE 182 (68.2%) 97 (71.3%) 240 (72.0%) 230 (84.6%) 56 (74.7%) 256 (78.0%) Infections and Infestations 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%) 22 (8.1%) 2 (2.7%) 3 (0.9%) Pharyngitis Streptococcal 2 (0.7%) 2 (1.5%) 10 (3.0%) 0 <1% 0 Molluscum Contagiosum 2 (0.7%) 0 4 (1.2%) 5 (1.8%) 0 0 Staphylococcal Infection 1 (0.4%) 5 (3.7%) 7 (2.1%) 0 <1% 3 (0.9%) Bronchitis NOS 1 (0.4%) 3 (2.2%) 4 (1.2%) 29 (10.7%) 6 (8.0%) 8 (2.4%) Herpes Simplex 1 (0.4%) 0 4 (1.2%) 9 (3.3%) 2 (2.7%) 13 (4.0%) Tonsillitis NOS 1 (0.4%) 0 3 (0.9%) 17 (6.3%) 0 2 (0.6%) Viral Infection NOS 2 (0.7%) 1 (0.7%) 1 (0.3%) 18 (6.6%) 1 (1.3%) 0 Gastroenteritis NOS 0 3 (2.2%) 2 (0.6%) 20 (7.4%) 2 (2.7%) 6 (1.8%) Chickenpox 2 (0.7%) 0 3 (0.9%) 8 (2.9%) 3 (4.0%) 1 (0.3%) Skin Papilloma 1 (0.4%) 0 2 (0.6%) 9 (3.3%) <1% 0 Tonsillitis Acute NOS 0 0 0 7 (2.6%) 0 0 Upper Respiratory Tract Infection Viral NOS 1 (0.4%) 0 3 (0.9%) 4 (1.5%) 0 1 (0.3%) Herpes Simplex Dermatitis 0 0 1 (0.3%) 4 (1.5%) 0 2 (0.6%) Bronchitis Acute NOS 0 0 0 4 (1.5%) 0 0 Eye Infection NOS 0 0 0 3 (1.1%) <1% 1 (0.3%) General Disorders and Administration Site Conditions Application Site Burning 28 (10.4%) 17 (12.5%) 5 (1.5%) 23 (8.5%) 5 (6.7%) 85 (25.9%) Pyrexia 20 (7.5%) 12 (8.8%) 41 (12.2%) 34 (12.5%

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.