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CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 204275Orig1s000 PHARMACOLOGY REVIEW(S) Tertiary Pharmacology Review By: Paul C. Brown, Ph.D., ODE Associate Director for Pharmacology and Toxicology, OND IO NDA: 204275 Submission date: 7/12/2012 Drug: Fluticasone furoate and vilanterol trifenatate Sponsor: Glaxo Group LTD Indication: Chronic obstructive pulmonary disease Reviewing Division: Division of Pulmonary, Allergy and Rheumatology Products Background Comments: The pharmacology/toxicology reviewer and team leader in the Division of Pulmonary, Allergy, and Rheumatology Products reviewed the nonclinical information for fluticasone and vilanterol and found it adequate to support approval from a pharmacology/toxicology perspective for the indication listed above. This product is a combination of fluticasone furoate and the new molecular entity, vilanterol trifenatate. Vilanterol is a β2-adrenergic receptor agonist. Discussion: Carcinogenicity The carcinogenicity of vilanterol was assessed in 2-year carcinogenicity studies in rats and mice by the inhalation route. The Executive Carcinogenicity Assessment Committee found these studies to be acceptable. The following neoplasms were considered to be clearly drug-related in the rat: adenomas of the pituitary gland in males and females and leiomyomas of mesovarian ligaments in females. Tubulostromal adenomas in the ovaries were considered to be drug- related in mice. These findings are described in proposed labeling. Developmental and Reproductive Toxicity The only apparent effect of vilanterol in development and reproductive toxicity studies was an increase in skeletal variations in rabbits at doses that produced exposures much higher than the maximum human exposures. These findings are described in the proposed labeling. Conclusions: I concur with the Division pharmacology/toxicology recommendation that this NDA can be approved. No additional nonclinical studies are recommended. Use of a pregnancy category of C seems warranted and is consistent with other drugs in these classes. 1 Reference ID: 3305296 --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- PAUL C BROWN 05/08/2013 Reference ID: 3305296 DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION Application number: NDA 204-275 Supporting document/s: Sequences 0000 Applicant’s letter date: July 12, 2012 CDER stamp date: July 12, 2012 Product: Breo Ellipta (Fluticasone furoate /Vilanterol trifenatate) Dry Powder Inhaler Indication: Chronic obstructive pulmonary disease (COPD) Applicant: GSK Review Division: Division of Pulmonary, Allergy, and Rheumatology Products Reviewer: Luqi Pei, Ph.D. Supervisor (acting): Marcie Wood, Ph.D. Division Director: Badrul Chowdhury, M.D., Ph.D. Project Manager: Angela Ramsey Template Version: September 1, 2010 Disclaimer Except as specifically identified, all data and information discussed below and necessary for approval of NDA 204-275 are owned by GSK Inc. or are data for which GSK has obtained a written right of reference. Any information or data necessary for approval of NDA 204-275 that GSK does not own or have a written right to reference constitutes one of the following: (1) published literature, or (2) a prior FDA finding of safety or effectiveness for a listed drug, as reflected in the drug’s approved labeling. Any data or information described or referenced below from reviews or publicly available summaries of a previously approved application is for descriptive purposes only and is not relied upon for approval of NDA 204-275. 1 Reference ID: 3296873 NDA No 204-275 Pharmacology/Toxicology Review Reviewer: Luqi Pei, Ph.D. LABELING REVIEW Edits to nonclinical sections of the proposed labeling of Breo Ellipta are recommended. Edits are made to ensure labeling consistence between products of the same class. The nonclinical sections included Sections 8.1 Pregnancy, 12.1 Mechanism of Action, and 13 Nonclinical Toxicology. Section 13.2 Animal Toxicology and Pharmacology is deleted to comply with the current labeling format. Below is the recommended text for the nonclinical sections of the Breo Ellipta label. See discussions following recommended labeling for rationale and justification for the recommendations. LABELING RECOMMENDATION 8.1 Pregnancy Teratogenic Effects: Pregnancy Category C: There are no adequate and well- controlled trials of BREO ELLIPTA in pregnant women. Corticosteroids and beta2-agonists have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Because animal (b) (4) studies are not always predictive of human response, BREO ELLIPTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women should be advised to contact their physician if they become pregnant while taking BREO ELLIPTA. Fluticasone furoate and Vilanterol: There was no evidence of teratogenic interactions between fluticasone furoate and vilanterol in rats at approximately 9 and 40 times, respectively, the maximum recommended human daily inhalation dose (MRHDID) in adults (on a mcg/m2 basis at maternal inhaled doses of fluticasone and vilanterol, alone or in combination, up to approximately 95-mcg/kg/day each). Fluticasone furoate: There were no teratogenic effects in rats and rabbits at approximately 9 and 2 times, respectively, the MRHDID in adults (on a mcg/m2 basis at maternal inhaled doses up to 91 and 8 mcg/kg/day in rats and rabbits, respectively). There were no effects on perinatal and post-natal development in rats at approximately 3 times the MRHDID in adults (on a mcg/m2 at maternal doses up to 27 mcg/kg/day). Vilanterol: There were no teratogenic effects in rats and rabbits at approximately 13,000 and 160 times, respectively, the MRHDID in adults (on a mcg/m2 basis at maternal inhaled doses up to 33,700 mcg/kg/day in rats and on an AUC basis at maternal inhaled doses up to 591 mcg/kg/day in rabbits). However, fetal skeletal variations were observed in rabbits at approximately 1,000 times the MRHDID in adults (on an AUC basis at maternal inhaled or subcutaneous doses of 5,740 or 300 mcg/kg/day, respectively). The skeletal variations included decreased or absent ossification in cervical vertebral centrum and metacarpals. There were no effects on peri-natal and post-natal developments in rats at approximately 3,900 times the MRHDID in adults (on a mcg/m2 basis at maternal oral doses up to 10,000 mg/kg/day). Non-teratogenic Effects: Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be monitored. 2 Reference ID: 3296873 NDA No 204-275 Pharmacology/Toxicology Review Reviewer: Luqi Pei, Ph.D. Fluticasone furoate did not induce gene mutation in bacteria or chromosomal damage in a mammalian cell mutation test in mouse lymphoma L5178Y cells in vitro. There was also no evidence of genotoxicity in the in vivo micronucleus test in rats. No evidence of impairment of fertility was observed in male and female rats at inhaled doses up to 29 and 91 mcg/kg/day in males and females, respectively (approximately 3 and 9 times, respectively, the MRHDID in adults on a mcg/m2 basis). Vilanterol: In a 2-year carcinogenicity study in mice, vilanterol caused a statistically significant increase in ovarian tubulostromal adenomas in females at an inhalation dose of 29,500 mcg/kg/day (approximately 8,750 times the MRHDID in adults on an AUC basis). No tumors were seen at inhalation doses up to 615 mcg/kg/day (approximately 530 times the MRHDID in adults on an AUC basis). In a 2-year carcinogenicity study in rats, vilanterol caused statistically significant increases in mesovarian leiomyomas in females and shortening of the latency of pituitary tumors at inhalation doses greater than or equal to 84.4 mcg/kg/day (greater than or equal to approximately 45 times the MRHDID in adults on an AUC basis). No tumors were seen at an inhalation dose of 10.5 mcg/kg/day (approximately 2 times the MRHDID in adults on an AUC basis). These tumor findings in rodents are similar to those reported previously for other beta- adrenergic agonist drugs. The relevance of these findings to human use is unknown. Vilanterol tested negative in the following genotoxicity assays: the in vitro Ames assay, in vivo rat bone marrow micronucleus assay, in vivo UDS assay, and in vitro SHE cell assay. Vilanterol tested equivocal in the in vitro mouse lymphoma assay. No evidence of impairment of fertility was observed in rats at inhalation doses from 31,500 to 37,100 mcg/kg/day in males and females, respectively (approximately 12,000 to 14,000 times, respectively, the MRHDID in adults on a mg/m2 basis). INTRODUCTION The review evaluates the nonclinical sections of Breo Ellipta labeling that GSK proposed on October 12, 2012 and April 2, 2013. The review recommends editing both the proposed text and dose ratios between animals and humans. These edits were made to reflect not only the current labeling format but also the Agency’s findings of the animal data. Breo Ellipta is a dry powder inhaler