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 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%) 4 (5.3%) 4 (1.2%) Application Site Reaction NOS 8 (3.0%) 7 (5.1%) 7 (2.1%) 9 (3.3%) 2 (2.7%) 48 (14.6%) Application Site Irritation 8 (3.0%) 8 (5.9%) 3 (0.9%) 1 (0.4%) 3 (4.0%) 21 (6.4%) Influenza-Like Illness 1 (0.4%) 0 2 (0.6%) 5 (1.8%) 2 (2.7%) 6 (1.8%) Application Site Erythema 1 (0.4%) 0 0 6 (2.2%) 0 7 (2.1%) Application Site Pruritus 3 (1.1%) 2 (1.5%) 2 (0.6%) 5 (1.8%) 0 18 (5.5%) Respiratory, Thoracic and Mediastinal Disorders Cough 31 (11.6%) 11 (8.1%) 31 (9.3%) 43 (15.8%) 8 (10.7%) 8 (2.4%) Nasal Congestion 7 (2.6%) 2 (1.5%) 6 (1.8%) 4 (1.5%) 1 (1.3%) 2 (0.6%) Rhinorrhea 5 (1.9%) 1 (0.7%) 3 (0.9%) 1 (0.4%) 1 (1.3%) 0 Asthma Aggravated 4 (1.5%) 3 (2.2%) 13 (3.9%) 3 (1.1%) 1 (1.3%) 0 Sinus Congestion 3 (1.1%) 1 (0.7%) 2 (0.6%) <1% <1% 3 (0.9%) Rhinitis 1 (0.4%) 0 5 (1.5%) 12 (4.4%) 5 (6.7%) 7 (2.1%) Wheezing 1 (0.4%) 1 (0.7%) 4 (1.2%) 2 (0.7%) <1% 0 Asthma NOS 2 (0.7%) 1 (0.7%) 11 (3.3%) 10 (3.7%) 2 (2.7%) 8 (2.4%) Epistaxis 0 1 (0.7%) 0 9 (3.3%) 1 (1.3%) 1 (0.3%) Dyspnea NOS 0 0 0 5 (1.8%) 1 (1.3%) 2 (0.6%) Gastrointestinal Disorders Abdominal Pain Upper 11 (4.1%) 6 (4.4%) 10 (3.0%) 15 (5.5%) 5 (6.7%) 1 (0.3%) Sore Throat 9 (3.4%) 5 (3.7%) 15 (5.4%) 22 (8.1%) 4 (5.3%) 12 (3.7%) Vomiting NOS 8 (3.0%) 6 (4.4%) 14 (4.2%) 18 (6.6%) 6 (8.0%) 2 (0.6%) Diarrhea NOS 3 (1.1%) 1 (0.7%) 2 (0.6%) 21 (7.7%) 4 (5.3%) 7 (2.1%) Nausea 1 (0.4%) 3 (2.2%) 4 (1.2%) 11 (4.0%) 5 (6.7%) 6 (1.8%) Abdominal Pain NOS 1 (0.4%) 1 (0.7%) 5 (1.5%) 12 (4.4%) 3 (4.0%) 1 (0.3%) Toothache 1 (0.4%) 1 (0.7%) 2 (0.6%) 7 (2.6%) 1 (1.3%) 2 (0.6%) Constipation 1 (0.4%) 0 2 (0.6%) 10 (3.7%) <1% 0 Loose Stools 0 1 (0.7%) 4 (1.2%) <1% <1% 0 Reproductive System and Breast Disorders Dysmenorrhea 3 (1.1%) 0 5 (1.5%) 3 (1.1%) 1 (1.3%) 4 (1.2%) Eye Disorders Conjunctivitis NEC 2 (0.7%) 1 (0.7%) 7 (2.1%) 6 (2.2%) 3 (4.0%) 10 (3.0%) Skin and Subcutaneous Tissue Disorders Urticaria 3 (1.1%) 0 1 (0.3%) 1 (0.4%) <1% 3 (0.9%) Acne NOS 0 1 (0.7%) 1 (0.3%) 4 (1.5%) <1% 6 (1.8%) Immune System Disorders Hypersensitivity NOS 11 (4.1%) 6 (4.4%) 16 (4.8%) 14 (5.1%) 1 (1.3%) 11 (3.4%) Injury and Poisoning Accident NOS 3 (1.1%) 1 (0.7%) 1 (0.3%) <1% 1 (1.3%) 0 Laceration 2 (0.7%) 1 (0.7%) 5 (1.5%) <1% <1% 0 Musculoskeletal, Connective Tissue and Bone Disorders Back Pain 1 (0.4%) 2 (1.5%) 1 (0.3%) <1% 0 6 (1.8%) Arthralgias 0 0 1 (0.3%) 3 (1.1%) 1 (1.3%) 5 (1.5%) Ear and Labyrinth Disorders Earache 2 (0.7%) 1 (0.7%) 0 8 (2.9%) 2 (2.7%) 0 Nervous System Disorders Headache 37 (13.9%) 12 (8.8%) 38 (11.3%) 69 (25.4%) 12 (16.0%) 23 (7.0%) 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. 6.2 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.

12.3 Pharmacokinetics Absorption In adult subjects (n=52) being treated for atopic dermatitis [13%-62% Body Surface Area (BSA) involvement] for periods up to a year, a maximum pimecrolimus concentration of 1.4 ng/mL was observed among those subjects with detectable blood levels. In the majority of samples in adult (91%; 1244/1362) subjects, blood concentrations of pimecrolimus were below 0.5 ng/mL. Data on blood levels of pimecrolimus measured in pediatric subjects are described in Use in Specific Populations (8.4). Distribution Laboratory in vitro plasma protein binding studies using equilibrium gel filtration have shown that 99.5% of pimecrolimus in plasma is bound to proteins over the pimecrolimus concentration range of 2-100 ng/mL tested. The major fraction of pimecrolimus in plasma appears to be bound to various lipoproteins. As with other topical calcineurin inhibitors, it is not known whether pimecrolimus is absorbed into cutaneous lymphatic vessels or in regional lymph nodes. Metabolism Following the administration of a single oral radiolabeled dose of pimecrolimus, numerous circulating O-demethylation metabolites were seen. Studies with human liver microsomes indicate that pimecrolimus is metabolized in vitro by the CYP3A subfamily of metabolizing enzymes. No evidence of skin mediated drug metabolism was identified in vivo using the minipig or in vitro using stripped human skin. Elimination Based on the results of the aforementioned radiolabeled study, following a single oral dose of pimecrolimus, ~81% of the administered radioactivity was recovered, primarily in the feces (78.4%) as metabolites. Less than 1% of the radioactivity found in the feces was due to unchanged pimecrolimus.