Pimecrolimus Cream 1% PI
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Mat# 238328-01 Filename: 238328-01_PimecroCrm30gPi_5_18.indd Proof# 1 Artist Name/Date: Mike Aspinall 9/10/18 AMT Version: 10 Sep 2018 Vault# VV-141752 Approvals:* NDA/ANDA# 209345 Black Approval: Date: Approval: Date: ” n/a Rev: * Applicable when approver is not able to apply electronic signature to PDF in Veeva Vault or Acrobat® Electronic and scanned proxy approval signatures appear on separate pages following the proof pages within this PDF Iss. 5/2018 n/a Created by: Outsert Configuration: Regulatory Affairs US Artwork Management Team Flat: 10” x 27” 1070 Horsham Road, North Wales, PA, 19454 Phone 215-591-3000 Fold: 5” x 2.25” Die Line - No Print 10” 10.00 1/8” 5” 5” 2.25” .25” 238328-01 238328-01 Pimecrolimus Cream Pimecrolimus Cream Rx only Rx only 238328-01 238328-01 Iss. 5/2018 Iss. 5/2018 HIGHLIGHTS OF PRESCRIBING INFORMATION • If signs and symptoms persist beyond 6 weeks, patients should be 8 USE IN SPECIFIC POPULATIONS These highlights do not include all the information needed to use re-examined. (2) 8.1 Pregnancy PIMECROLIMUS CREAM safely and effectively. See full prescribing • Continuous long-term use of pimecrolimus cream, 1% should be Pregnancy Category C information for PIMECROLIMUS CREAM. avoided. (2) 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. PIMECROLIMUS cream, 1% for topical use • Avoid use with occlusive dressings. (2) Initial U.S. Approval: 2001 In dermal embryofetal developmental studies, no maternal or fetal toxicity was observed up to the highest practicable doses tested, 10 mg/kg/day DOSAGE FORMS AND STRENGTHS ”2 (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 WARNING: LONG-TERM SAFETY OF TOPICAL CALCINEURIN Cream, 1%. (3) INHIBITORS HAS NOT BEEN ESTABLISHED based on AUC comparisons). The 1% pimecrolimus cream was administered topically for 6 hours/day during the period of organogenesis in rats See full prescribing information for complete boxed warning. CONTRAINDICATIONS and rabbits (gestational days 6 to 21 in rats and gestational days 6 to 20 in rabbits). Although a causal relationship has not been established, rare Pimecrolimus cream 1% is contraindicated in individuals with a history A second dermal embryofetal development study was conducted in rats using pimecrolimus cream applied dermally to pregnant rats (1 g cream/kg cases of malignancy (e.g., skin and lymphoma) have been reported of hypersensitivity to pimecrolimus or any of the components of the 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 in patients treated with topical calcineurin inhibitors, including cream. (4, 6.2) approximately 22 hours. No maternal, reproductive, or embryo-fetal toxicity attributable to pimecrolimus was noted at 10 mg/kg/day (0.66X MRHD pimecrolimus cream, 1%. (5.1) WARNINGS AND PRECAUTIONS based on AUC comparisons), the highest dose evaluated in this study. No teratogenicity was noted in this study at any dose. Therefore: • Should not be used in immunocompromised adults and children, A combined oral fertility and embryofetal developmental study was conducted in rats and an oral embryofetal developmental study was conducted including patients on systemic immunosuppressive medications. (5.1) 2.25 • Continuous long-term use of topical calcineurin inhibitors, in rabbits. Pimecrolimus was administered during the period of organogenesis (2 weeks prior to mating until gestational day 16 in rats, gestational including pimecrolimus cream, 1%, in any age group should be • Avoid treatment on malignant or pre-malignant skin conditions, as 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 avoided, and application limited to areas of involvement with these can present as dermatitis. (5.2) 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 atopic dermatitis. (2, 5.1) • Should not be used in patients with Netherton’s Syndrome or skin oral fertility and embryofetal developmental study conducted in rats. No malformations in the fetuses were noted at 45 mg/kg/day (38X MRHD based • Pimecrolimus cream, 1% is not indicated for use in children less diseases with a potential for increased systemic absorption. (5.2) 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. than 2 years of age. (1, 5.1, 8.4) ADVERSE REACTIONS The most commonly reported adverse reactions (greater than or equal A second oral embryofetal development study was conducted in rats. Pimecrolimus was administered during the period of organogenesis (gestational days INDICATIONS AND USAGE 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 Pimecrolimus cream, 1% is a calcineurin inhibitor immunosuppressant to 1%) were application site burning, headache, nasopharyngitis, cough, influenza, pyrexia and viral infection. (6.1) comparisons). A slight increase in skeletal variations that were indicative of delayed skeletal ossification was also noted at this dose. No maternal toxicity, indicated as second-line therapy for the short-term and non-continuous 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. chronic treatment of mild to moderate atopic dermatitis in non- To report SUSPECTED ADVERSE REACTIONS, contact immunocompromised adults and children 2 years of age and older, Teva Pharmaceuticals USA, Inc. at 1-888-838-2872 or FDA at A second oral embryofetal development study was conducted in rabbits. Pimecrolimus was administered during the period of organogenesis who have failed to respond adequately to other topical prescription 1-800-FDA-1088 or www.fda.gov/medwatch. (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 treatments, or when those treatments are not advisable. (1) MRHD based on AUC comparisons). A slight increase in skeletal variations that were indicative of delayed skeletal ossification was also noted at See 17 for PATIENT COUNSELING INFORMATION and Medication Guide this dose. No maternal toxicity, embryotoxicity or fetotoxicity were noted at 6 mg/kg/day (5X MRHD based on AUC comparisons). No teratogenicity DOSAGE AND ADMINISTRATION Revised: 5/2018 was noted in this study at any dose. • Apply a thin layer of pimecrolimus cream, 1% to the affected skin twice daily. (2) 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 FULL PRESCRIBING INFORMATION: CONTENTS* 7 DRUG INTERACTIONS comparisons), the highest dose evaluated in this study. WARNING: LONG-TERM SAFETY OF TOPICAL CALCINEURIN INHIBITORS 8 USE IN SPECIFIC POPULATIONS 27” Pimecrolimus was transferred across the placenta in oral rat and rabbit embryofetal developmental studies. HAS NOT BEEN ESTABLISHED 8.1 Pregnancy 1 INDICATION AND USAGE 8.3 Nursing Mothers 8.3 Nursing Mothers .25” 2 DOSAGE AND ADMINISTRATION 8.4 Pediatric Use It is not known whether this drug is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from 3 DOSAGE FORMS AND STRENGTHS 8.5 Geriatric Use pimecrolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the 4 CONTRAINDICATIONS 11 DESCRIPTION drug to the mother. 5 WARNINGS AND PRECAUTIONS 12 CLINICAL PHARMACOLOGY 8.4 Pediatric Use 5.1 Risk of Immunosuppression 12.1 Mechanism of Action Pimecrolimus cream, 1% is not indicated for use in children less than 2 years of age. 5.2 Application to Malignant or Pre-malignant Skin Conditions 12.3 Pharmacokinetics The long-term safety and effects of pimecrolimus cream, 1% on the developing immune system are unknown. 5.3 Bacterial and Viral Skin Infections 13 NONCLINICAL TOXICOLOGY 5.4 Patients with Lymphadenopathy 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Three Phase 3 pediatric trials were conducted involving 1,114 subjects 2 to 17 years of age. Two trials were 6-week randomized vehicle-controlled 5.5 Sun Exposure 14 CLINICAL STUDIES 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 5.6 Immunocompromised Patients 16 HOW SUPPLIED/STORAGE AND HANDLING use. Of these subjects 542 (49%) were 2 to 6 years of age. In the short-term trials, 11% of pimecrolimus subjects did not complete these trials 6 ADVERSE REACTIONS 17 PATIENT COUNSELING INFORMATION and 1.5% of pimecrolimus subjects discontinued due to adverse events. In the one-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.