CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 205641Orig1s000 PHARMACOLOGY REVIEW(S) 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: 205,641 Supporting document/s: #01 Applicant’s letter date: June 27, 2013 CDER stamp date: June 27, 2013 Product: ASMANEX HFA (Mometasone Furoate) Indication: Asthma Applicant: Merck Review Division: Pulmonary, Allergy, and Rheumatology Products Reviewer/Team Leader: Timothy W. Robison, Ph.D., D.A.B.T. Division Director: Badrul Chowdhury, M.D., Ph.D. Project Manager: Jessica Lee Template Version: September 1, 2010 Disclaimer Except as specifically identified, all data and information discussed below and necessary for approval of NDA 205641 are owned by Merck or are data for which Merck has obtained a written right of reference. Any information or data necessary for approval of NDA 205641 that Merck 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 205641. 1 Reference ID: 3467446 NDA #205641 Reviewer: Timothy W. Robison, Ph.D., D.A.B.T TABLE OF CONTENTS 1 EXECUTIVE SUMMARY ......................................................................................... 4 1.1 1.2 1.3 2 INTRODUCTION .................................................................................................... 4 BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 4 RECOMMENDATIONS ............................................................................................ 4 DRUG INFORMATION ............................................................................................ 7 2.1 2.2 2.3 2.4 2.5 2.6 2.7 3 DRUG ................................................................................................................. 7 RELEVANT IND/S, NDA/S, AND DMF/S ................................................................. 8 DRUG FORMULATION ........................................................................................... 8 COMMENTS ON NOVEL EXCIPIENTS ....................................................................... 9 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ......................................... 9 PROPOSED CLINICAL POPULATION AND DOSING REGIMEN ...................................... 9 REGULATORY BACKGROUND ................................................................................ 9 STUDIES SUBMITTED .......................................................................................... 10 3.1 3.3 11 STUDIES REVIEWED ........................................................................................... 10 PREVIOUS REVIEWS REFERENCED...................................................................... 10 INTEGRATED SUMMARY AND SAFETY EVALUATION ................................. 10 2 Reference ID: 3467446 NDA #205641 Reviewer: Timothy W. Robison, Ph.D., D.A.B.T Table of Tables Table 1 Mometasone Furoate: 100 µg per actuation ....................................................... 8  Table 2 Mometasone Furoate: 200 µg per actuation ....................................................... 8  Table 3 Target organs of toxicity observed in rats and dogs treated with SCH418131 . 11  3 Reference ID: 3467446 NDA #205641 1 Reviewer: Timothy W. Robison, Ph.D., D.A.B.T Executive Summary 1.1 Introduction ASMANEX® HFA (Mometasone Furoate [MF]) is indicated for the maintenance treatment of asthma as prophylactic therapy in patients 12 years of age and older. The MF MDI is essentially the same product as the approved DULERA® (MF + Formoterol Fumarate [FF]) without the formoterol fumarate component. Two dosing regimens of MF MDI (200 mcg BID and 400 mcg BID) are proposed to offer treatment options for a spectrum of patients to step-down from MF/FF to MF alone. This is to support the goal of an optimal step-down approach that decreases treatment to the least medication necessary to maintain control of asthma. 1.2 Brief Discussion of Nonclinical Findings There is a complete nonclinical program for mometasone furoate. No new nonclinical pharmacology or toxicology studies were submitted with this application. 1.3 Recommendations 1.3.1 Approvability From a nonclinical perspective, the application is recommended for approval. 1.3.2 Additional Nonclinical Recommendations There are no outstanding issues from a nonclinical perspective. 1.3.3 Labeling No changes are recommended for product labeling with respect to Indications and Usage and Sections 8.1, 8.2, 8.3, 12.1, 13.1, and 13.2 at this time. INDICATIONS AND USAGE ASMANEX HFA is a corticosteroid indicated for: 8.1 Pregnancy Teratogenic Effects: Pregnancy Category C There are no adequate and well-controlled studies of ASMANEX HFA in pregnant women. Animal reproduction studies of mometasone furoate in mice, rats, and rabbits revealed evidence of teratogenicity. Because animal reproduction studies are not always predictive of human response, ASMANEX HFA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Teratogenic Effects When administered to pregnant mice, rats, and rabbits, mometasone furoate increased fetal malformations and decreased fetal growth (measured by lower fetal weights and/or delayed ossification). Dystocia and related complications were also observed when 4 Reference ID: 3467446 NDA #205641 Reviewer: Timothy W. Robison, Ph.D., D.A.B.T mometasone furoate was administered to rats late in gestation. However, experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroid exposure than humans. In a mouse reproduction study, subcutaneous mometasone furoate produced cleft palate at approximately one-third of the maximum recommended daily human dose (MRHD) on a mcg/m2 basis and decreased fetal survival at approximately 1 times the MRHD. No toxicity was observed at approximately one-tenth of the MRHD on a mcg/m2 basis. In a rat reproduction study, mometasone furoate produced umbilical hernia at topical dermal doses approximately 6 times the MRHD on a mcg/m2 basis and delays in ossification at approximately 3 times the MRHD on a mcg/m2 basis. In another study, rats received subcutaneous doses of mometasone furoate throughout pregnancy or late in gestation. Treated animals had prolonged and difficult labor, fewer live births, lower birth weight, and reduced early pup survival at a dose that was approximately 8 times the MRHD on an area under the curve (AUC) basis. Similar effects were not observed at approximately 4 times MRHD on an AUC basis. In rabbits, mometasone furoate caused multiple malformations (e.g., flexed front paws, gallbladder agenesis, umbilical hernia, hydrocephaly) at topical dermal doses approximately 3 times the MRHD on a mcg/m2 basis. In an oral study, mometasone furoate increased resorptions and caused cleft palate and/or head malformations (hydrocephaly and domed head) at a dose less than the MRHD based on AUC. At a dose approximately 2 times the MRHD based on AUC, most litters were aborted or resorbed [see Nonclinical Toxicology (13.2)]. Nonteratogenic Effects Hypoadrenalism may occur in infants born to women receiving corticosteroids during pregnancy. Infants born to mothers taking substantial corticosteroid doses during pregnancy should be monitored for signs of hypoadrenalism. 8.2 Labor and Delivery There are no adequate and well-controlled human studies that have studied the effects of ASMANEX HFA during labor and delivery. 8.3 Nursing Mothers It is not known whether ASMANEX HFA is excreted in human milk. Because other corticosteroids are excreted in human milk, caution should be exercised when ASMANEX HFA is administered to a nursing woman. Since there are no data from well-controlled human studies on the use of ASMANEX HFA on nursing mothers, a decision should be made whether to discontinue nursing or 5 Reference ID: 3467446 NDA #205641 Reviewer: Timothy W. Robison, Ph.D., D.A.B.T to discontinue ASMANEX HFA, taking into account the importance of ASMANEX HFA to the mother. 12.1 Mechanism of Action Mometasone furoate is a corticosteroid demonstrating potent anti-inflammatory activity. The precise mechanism of corticosteroid action on asthma is not known. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of inhibitory effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation and in the asthmatic response. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma. Mometasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor, which is approximately 12 times that of dexamethasone, 7 times that of triamcinolone acetonide, 5 times that of budesonide, and 1.5 times that of fluticasone. The clinical significance of these findings is unknown. 13 Nonclinical Toxicology 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year carcinogenicity study in Sprague Dawley rats, mometasone furoate demonstrated no statistically significant increase in the incidence of tumors at inhalation doses up to 67 mcg/kg (approximately 14 times the MRHD on an AUC basis). In a 19month carcinogenicity study in Swiss CD-1 mice, mometasone furoate demonstrated no statistically significant increase in the incidence of tumors at inhalation doses up to 160 mcg/kg (approximately 9 times the MRHD on an AUC basis). Mometasone furoate increased chromosomal aberrations in an in vitro Chinese hamster ovary cell assay, but did not have this effect in an in vitro Chinese hamster lung cell assay. Mometasone furoate was not mutagenic in the Ames test or mouse lymphoma assay, and was not clastogenic in an in vivo mouse micronucleus assay, a rat bone marrow chromosomal aberration assay, or a mouse male germ-cell chromosomal aberration assay. Mometasone furoate also did not induce unscheduled DNA synthesis in vivo in rat hepatocytes. In reproductive studies in rats, impairment of fertility was not produced by subcutaneous doses up to 15 mcg/kg (approximately 8 times the MRHD on an AUC basis). 13.2 Animal Toxicology and/or Pharmacology Reproductive Toxicology Studies In mice, mometasone furoate caused cleft palate at subcutaneous doses of 60 mcg/kg and above (approximately one-third of the maximum recommended human dose MRHD on a mcg/m2 basis). Fetal survival was reduced at 180 mcg/kg (approximately equal to 6 Reference ID: 3467446 NDA #205641 Reviewer: Timothy W. Robison, Ph.D., D.A.B.T the MRHD on a mcg/m2 basis). No toxicity was observed at 20 mcg/kg (approximately one-tenth of the MRHD on a mcg/m2 basis). In rats, mometasone furoate produced umbilical hernia at topical dermal doses of 600 mcg/kg and above (approximately 6 times the MRHD on a mcg/m2 basis). A dose of 300 mcg/kg (approximately 3 times the MRHD on a mcg/m2 basis) produced delays in ossification, but no malformations. When rats received subcutaneous doses of mometasone furoate throughout pregnancy or during the later stages of pregnancy, 15 mcg/kg (approximately 8 times the MRHD on an AUC basis) caused prolonged and difficult labor and reduced the number of live births, birth weight, and early pup survival. Similar effects were not observed at 7.5 mcg/kg (approximately 4 times the MRHD on an AUC basis). In rabbits, mometasone furoate caused multiple malformations (e.g., flexed front paws, gallbladder agenesis, umbilical hernia, hydrocephaly) at topical dermal doses of 150 mcg/kg and above (approximately 3 times the MRHD on a mcg/m2 basis). In an oral study, mometasone furoate increased resorptions and caused cleft palate and/or head malformations (hydrocephaly and domed head) at 700 mcg/kg (less than the MRHD on an AUC basis). At 2800 mcg/kg (approximately 2 times the MRHD on an AUC basis) most litters were aborted or resorbed. No toxicity was observed at 140 mcg/kg (less than the MRHD on an AUC basis). 2 Drug Information 2.1 Drug Tradename: Asmanex HFA Generic Name: Mometasone Furoate Chemical Name: 9α,21-dichloro-11,17α-dihydroxy-16α-methyl-pregna-1,4-diene-3,20dione17-(2')-furoate Molecular Formula/Molecular Weight: C27H30O6Cl2 / 521.4 g/mole Structure: Pharmacologic Class: Corticosteroid 7 Reference ID: 3467446 NDA #205641 Reviewer: Timothy W. Robison, D.A.B.T 2.2 Relevant and DMFIs NDA 22-518 (Merck, and IND 70,283 (Merck, Mometasone Furoate Formoterol Fumarate) Mometasone from Merck: IND 24,088, IND 46,216 IND 52 214, IND 55,108, NDA 19-543, NDA 19-625, NDA 19-796, NDA 20-762, - NDA 21 -067 (Merck, Asmanex? Twisthaler?), and 2.3 Drug Formulation The Mometasone Furoate pressurized metered dose inhalers are formulated with two of mometasone furoate 100 and 200 er actuation ex-actuator. The drug roducts also contains (USP-NF), oleic acid HFA 227 - epa uoropropane) One herapeutic dose is obtained from two single actuations oft rug pro uc s. Table 1 Mometasone Furoate: 100 pg per actuation Inpa- Mona, P-ai- hos-u Ina-f In m- an luk- sum up:- Inc-Hr TOE 09.3?! 1m.? Th 8 a ?Cw?ktdahum??ln7 Table 2 Mometasone Furoate: 200 pg per actuation 1&3 Reference ID: 3467446 NDA #205641 Reviewer: Timothy W. Robison, D.A.B.T The container closure system for the drug products consists of a 16 mL aluminum canister closed with a valve. A press and breathe actuator with the mouthpiece cap is provided with the pressurized canister to deliver a dose to the patient. The actuator incorporates an integrated displacement driven dose counter. (4) (4) 2.4 Comments on Novel Excipients None 2.5 Comments on lmpurities/Degradants of Concern None 2.6 Proposed Clinical Population and Dosing Regimen ASMANEX HFA is a corticosteroid indicated for maintenance treatment of asthma as prophylactic therapy in patients 12 years of age and older. The dosing regimen is 2 inhalations twice daily of ASMANEX HFA 100 or 200 pg. The starting dosage is based on prior asthma therapy. 2.7 Regulatory Background a combination product containing the corticosteroid, mometasone furoate (MF), and the long-acting betaz-adrenergic agonist (LABA), formoterol fumarate dihydrate (FF), was approved on June 22, 2010 for treatment of asthma in patients 212 years old. The approved dose of is two inhalation twice daily of 100 pg/5 pg or 200 pg/5 pg. In discussion during the review of the FDA noted that commercial availabilitg of the MF monotherapy metered dose inhaler (MDI) comparator used in the DULERA program would facilitate step-down to inhaled corticosteroids alone for patients no longer in need of continuous LABA treatment, and suggested that Schering Corporation, a subsidiary of Merck Co, Inc., consider its development. Oral MF monotherapy is commercially available as a dry powder inhaler but not as the Agency- suggested MDI. The proposed NDA is in response to that request. The MF MDI is essentially the same product as the approved without the formoterol fumarate component. The clinical bene?t of the MF MDI was demonstrated in the adult asthma program, in which three dose regimens of MF MDI (100 twice daily 200 BID, and 400 BID) were included in the trials as active comparators to better de?ne the efficacy and safety of Two dosing regimens of MF MDI (200 BID and 400 BID) are proposed to offer treatment options for a spectrum of patients to step-down from to MF alone. This is to support the goal of an optimal step-down approach that decreases treatment to the least medication necessary to maintain control of asthma. Reference ID: 3467446 NDA #205641 3 Reviewer: Timothy W. Robison, Ph.D., D.A.B.T Studies Submitted 3.1 Studies Reviewed No new nonclinical pharmacology or toxicology studies were submitted with this application. 3.3 Previous Reviews Referenced Pharmacology and Toxicology Reviews of NDA 22-518 dated January 19, 2010, May 12, 2010, June 7, 2010, and June 10, 2010 11 Integrated Summary and Safety Evaluation ASMANEX® HFA (Mometasone Furoate [MF]) is indicated for the maintenance treatment of asthma as prophylactic therapy in patients 12 years of age and older. The MF MDI is essentially the same product as the approved DULERA® (MF + Formoterol Fumarate [FF]) without the formoterol fumarate component. Two dosing regimens of MF MDI (200 mcg BID and 400 mcg BID) are proposed to offer treatment options for a spectrum of patients to step-down from MF/FF to MF alone. This is to support the goal of an optimal step-down approach that decreases treatment to the least medication necessary to maintain control of asthma. Mometasone furoate, a synthetic 17-heterocyclin glucocorticosteroid, has been approved by the FDA as a multiple dose DPI formulation (NDA 21,067, ASMANEX®) for maintenance treatment of asthma as prophylactic therapy in patients 4 years of age and older. Mometasone furoate (ASMANEX®) has been marketed in the US for the treatment of asthma since 2005. Pharmacology: Mometasone furoate is a corticosteroid demonstrating potent anti-inflammatory activity. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of inhibitory effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation and in the asthmatic response. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma. General Toxicology: See NDAs 20-762 and 21-067 for reviews of general toxicology studies conducted with mometasone furoate. Multiple target organs were observed in rats and dogs treated with mometasone by the inhalation route (see table below). These findings were attributed to the pharmacological action of mometasone (lymphoid depletion in BALT and GALT, thymus, spleen, and lymph nodes; atrophy of the adrenal cortex). 10 Reference ID: 3467446 NDA #205641 Reviewer: Timothy W. Robison, Ph.D., D.A.B.T Table 3 Target organs of toxicity observed in rats and dogs treated with mometasone by the inhalation route Organ/Tissue Lungs Thymus Nose/Turbinates Spleen Mesenteric LN Bronchial LN Mandibular LN Mediastinal LN Mammary gland Bone marrow Ovaries Vagina Adrenal gland Rat BALT (bronchial-associated lymphoid tissue) depletion, accumulation of alveolar macrophages, and pigmented macrophages. Involution/atrophy Lymphoid depletion Lymphoid depletion Lymphoid depletion and infiltration of mast cells Lymphoid depletion Lymphoid depletion Lymphoid depletion Abnormal lobule development Increased marrow fat Decrease corpora lutea Abnormal mucification Dog Hyperplasia of bronchioloalveolar cells and bronchial inflammation Lymphoid depletion Lymphoid depletion Lymphoid depletion Lymphoid depletion and erythrophagocytosis Lymphoid depletion Lymphoid depletion Lymphoid depletion Hypoplasia Vacuolization and/or atrophy of the adrenal cortex Lymphoid depletion Lymphoid depletion Lymphoid depletion Lymphoid depletion Lymphoid depletion Lymphoid depletion Lymphoid depletion Lymphoid depletion Lymphoid depletion Lymphoid depletion Infiltration of adipocytes Hypoplasia Cytoplasmic vacuolation Increased fat deposition Increased fat deposition Increased fat deposition Decreased globule leukocytes Cecum Colon Duodenum Ileum Jejunum Larynx Axillary LN Pharynx Rectum Stomach Salivary gland Uterus Liver Femur Rib Sternum Trachea Genetic Toxicology: Mometasone furoate increased chromosomal aberrations in an in vitro Chinese hamster ovary cell assay, but did not have this effect in an in vitro Chinese hamster lung cell assay. Mometasone furoate was not mutagenic in the Ames test or mouse lymphoma assay, and was not clastogenic in an in vivo mouse micronucleus assay, a rat bone marrow chromosomal aberration assay, or a mouse male germ-cell chromosomal aberration assay. Mometasone furoate also did not induce unscheduled DNA synthesis in vivo in rat hepatocytes. 11 Reference ID: 3467446 NDA #205641 Reviewer: Timothy W. Robison, D.A.B.T Carcinogenicig: In a 2-year carcinogenicity study in Sprague Dawley? rats, mometasone furoate demonstrated no statistically signi?cant increase in the incidence of tumors at inhalation doses up to 67 ug/kg. In a 19-month carcinogenicity study in Swiss CD-1 mice, mometasone furoate demonstrated no statistically signi?cant increase in the incidence of tumors at inhalation doses up to 160 ug/kg. Reproductive Toxicology: In reproductive studies in rats, impairment of fertility was not produced by subcutaneous doses up to 15 ug/kg. In mice, mometasone furoate caused cleft palate at subcutaneous doses of 60 ug/kg and above. Fetal survival was reduced at 180 ug/kg. No toxicity was observed at 20 ug/kg- In rats, mometasone furoate produced umbilical hernia at topical dermal doses of 600 ug/kg and above. A dose of 300 ug/kg produced delays in ossi?cation, but no malformations. When rats received subcutaneous doses of mometasone furoate throughout pregnancy or during the later stages of pregnancy, 15 ug/kg caused prolonged and difficult labor and reduced the number of live births, birth weight, and early pup survival. Similar effects were not observed at 7.5 ug/kg. In rabbits, mometasone furoate caused multiple malformations ?exed front paws, gallbladder agenesis, umbilical hernia, hydrocephaly) at topical dermal doses of 150 ug/kg and above. In an oral study, mometasone furoate increased resorptions and caused cleft palate and/or head malformations (hydrocephaly and domed head) at 700 ug/kg. At 2800 ug/kg most litters were aborted or resorbed. No toxicity was observed at 140 ug/kg. Excipients/Propellant: The excipients, (?""ethanol (USP-NF) and oleic acid (USP-NF) and the propellant, HFA 227 are the same as those found in the approved product, DULERAW (Merck, NDA 22?518). Recommendations: There is a complete nonclinical program for mometasone furoate. The application is recommended for approval from the nonclinical perspective. Both the and ASMANEX labels should be revised at the same time to comply with the Maternal and Lactation Labeling Rule that is expected in 2014. 1 2 Reference ID: 3467446 NDA #205641 Reviewer: Timothy W. Robison, Ph.D., D.A.B.T Labeling Review: The Sponsor submitted proposed labeling in general conformance with 21 CFR Parts 201, 314, and 601 Requirements on Content and Format of Labeling for Human Prescription Drug and Biological Products and Draft Guidances and Two Guidances for Industry on the Content and Format of Labeling for Human Prescription Drug and Biological Products; Final Rule and Notices (January 24, 2006). ASMANEX HFA is essentially the same product as the approved DULERA® (MF + Formoterol Fumarate [FF]) without the formoterol fumarate component. Doses of mometasone furoate in the ASMANEX HFA and DULERA® products are identical. Thus, there are no changes of exposure ratio calculations in the Sponsor’s proposed labeling for ASMANEX HFA. The Reviewer recommends no changes for Indications and Usage and Sections 8.1, 8.2, 8.3, 12.1, 13.1, and 13.2 at this time. It is standard labeling practice at this time to delete Section 13.2 and incorporate the information into Section 8.1. However, Section 13.2 is still present in the current DULERA® label. Deletion of Section 13.2 and revision of Section 8.1 in the ASMANEX HFA label would cause the same information in the two product labels for mometasone to appear different. No changes are recommended at this time. Both the DULERA® and ASMANEX HFA® labels should be revised at the same time to comply with the Maternal and Lactation Labeling Rule that is expected in 2014. INDICATIONS AND USAGE Sponsor’s Labeling: ASMANEX HFA is a corticosteroid indicated for: Evaluation: The established pharmacological classification is listed. No changes are recommended. 8.1 Pregnancy Sponsor’s Labeling: Teratogenic Effects: Pregnancy Category C There are no adequate and well-controlled studies of ASMANEX HFA in pregnant women. Animal reproduction studies of mometasone furoate in mice, rats, and rabbits revealed evidence of teratogenicity. Because animal reproduction studies are not always predictive of human response, ASMANEX HFA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Teratogenic Effects When administered to pregnant mice, rats, and rabbits, mometasone furoate increased fetal malformations and decreased fetal growth (measured by lower fetal weights and/or 13 Reference ID: 3467446 NDA #205641 Reviewer: Timothy W. Robison, Ph.D., D.A.B.T delayed ossification). Dystocia and related complications were also observed when mometasone furoate was administered to rats late in gestation. However, experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroid exposure than humans. In a mouse reproduction study, subcutaneous mometasone furoate produced cleft palate at approximately one-third of the maximum recommended daily human dose (MRHD) on a mcg/m2 basis and decreased fetal survival at approximately 1 times the MRHD. No toxicity was observed at approximately one-tenth of the MRHD on a mcg/m2 basis. In a rat reproduction study, mometasone furoate produced umbilical hernia at topical dermal doses approximately 6 times the MRHD on a mcg/m2 basis and delays in ossification at approximately 3 times the MRHD on a mcg/m2 basis. In another study, rats received subcutaneous doses of mometasone furoate throughout pregnancy or late in gestation. Treated animals had prolonged and difficult labor, fewer live births, lower birth weight, and reduced early pup survival at a dose that was approximately 8 times the MRHD on an area under the curve (AUC) basis. Similar effects were not observed at approximately 4 times MRHD on an AUC basis. In rabbits, mometasone furoate caused multiple malformations (e.g., flexed front paws, gallbladder agenesis, umbilical hernia, hydrocephaly) at topical dermal doses approximately 3 times the MRHD on a mcg/m2 basis. In an oral study, mometasone furoate increased resorptions and caused cleft palate and/or head malformations (hydrocephaly and domed head) at a dose less than the MRHD based on AUC. At a dose approximately 2 times the MRHD based on AUC, most litters were aborted or resorbed [see Nonclinical Toxicology (13.2)]. Nonteratogenic Effects Hypoadrenalism may occur in infants born to women receiving corticosteroids during pregnancy. Infants born to mothers taking substantial corticosteroid doses during pregnancy should be monitored for signs of hypoadrenalism. Evaluation: The labeling is identical to the mometasone section of the DULERA® labeling. No changes are recommended at this time. Both the DULERA® and ASMANEX HFA® labels should be revised at the same time to comply with the Maternal and Lactation Labeling Rule that is expected in 2014. 8.2 Labor and Delivery Sponsor’s Labeling: There are no adequate and well-controlled human studies that have studied the effects of ASMANEX HFA during labor and delivery. 14 Reference ID: 3467446 NDA #205641 Reviewer: Timothy W. Robison, Ph.D., D.A.B.T Evaluation: No changes are recommended. 8.3 Nursing Mothers Sponsor’s Labeling: It is not known whether ASMANEX HFA is excreted in human milk. Because other corticosteroids are excreted in human milk, caution should be exercised when ASMANEX HFA is administered to a nursing woman. Since there are no data from well-controlled human studies on the use of ASMANEX HFA on nursing mothers, a decision should be made whether to discontinue nursing or to discontinue ASMANEX HFA, taking into account the importance of ASMANEX HFA to the mother. Evaluation: No changes are recommended at this time. Both the DULERA® and ASMANEX HFA® labels should be revised at the same time to comply with the Maternal and Lactation Labeling Rule that is expected in 2014. 12.1 Mechanism of Action Sponsor’s Labeling: Mometasone furoate is a corticosteroid demonstrating potent anti-inflammatory activity. The precise mechanism of corticosteroid action on asthma is not known. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of inhibitory effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation and in the asthmatic response. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma. Mometasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor, which is approximately 12 times that of dexamethasone, 7 times that of triamcinolone acetonide, 5 times that of budesonide, and 1.5 times that of fluticasone. The clinical significance of these findings is unknown. Evaluation: The labeling is identical to the mechanism of action description for mometasone in the DULERA® labeling. No changes are recommended. 13 Nonclinical Toxicology Sponsor’s Labeling: 15 Reference ID: 3467446 NDA #205641 Reviewer: Timothy W. Robison, Ph.D., D.A.B.T 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year carcinogenicity study in Sprague Dawley rats, mometasone furoate demonstrated no statistically significant increase in the incidence of tumors at inhalation doses up to 67 mcg/kg (approximately 14 times the MRHD on an AUC basis). In a 19month carcinogenicity study in Swiss CD-1 mice, mometasone furoate demonstrated no statistically significant increase in the incidence of tumors at inhalation doses up to 160 mcg/kg (approximately 9 times the MRHD on an AUC basis). Mometasone furoate increased chromosomal aberrations in an in vitro Chinese hamster ovary cell assay, but did not have this effect in an in vitro Chinese hamster lung cell assay. Mometasone furoate was not mutagenic in the Ames test or mouse lymphoma assay, and was not clastogenic in an in vivo mouse micronucleus assay, a rat bone marrow chromosomal aberration assay, or a mouse male germ-cell chromosomal aberration assay. Mometasone furoate also did not induce unscheduled DNA synthesis in vivo in rat hepatocytes. In reproductive studies in rats, impairment of fertility was not produced by subcutaneous doses up to 15 mcg/kg (approximately 8 times the MRHD on an AUC basis). Evaluation: The labeling is identical to the description of studies with mometasone in Section 13.1 of the DULERA® label. No changes are recommended. 13.2 Animal Toxicology and/or Pharmacology Sponsor’s Labeling: Reproductive Toxicology Studies In mice, mometasone furoate caused cleft palate at subcutaneous doses of 60 mcg/kg and above (approximately one-third of the maximum recommended human dose MRHD on a mcg/m2 basis). Fetal survival was reduced at 180 mcg/kg (approximately equal to the MRHD on a mcg/m2 basis). No toxicity was observed at 20 mcg/kg (approximately one-tenth of the MRHD on a mcg/m2 basis). In rats, mometasone furoate produced umbilical hernia at topical dermal doses of 600 mcg/kg and above (approximately 6 times the MRHD on a mcg/m2 basis). A dose of 300 mcg/kg (approximately 3 times the MRHD on a mcg/m2 basis) produced delays in ossification, but no malformations. When rats received subcutaneous doses of mometasone furoate throughout pregnancy or during the later stages of pregnancy, 15 mcg/kg (approximately 8 times the MRHD on an AUC basis) caused prolonged and difficult labor and reduced the number of live births, birth weight, and early pup survival. Similar effects were not observed at 7.5 mcg/kg (approximately 4 times the MRHD on an AUC basis). In rabbits, mometasone furoate caused multiple malformations (e.g., flexed front paws, gallbladder agenesis, umbilical hernia, hydrocephaly) at topical dermal doses of 150 16 Reference ID: 3467446 NDA #205641 Reviewer: Timothy W. Robison, Ph.D., D.A.B.T mcg/kg and above (approximately 3 times the MRHD on a mcg/m2 basis). In an oral study, mometasone furoate increased resorptions and caused cleft palate and/or head malformations (hydrocephaly and domed head) at 700 mcg/kg (less than the MRHD on an AUC basis). At 2800 mcg/kg (approximately 2 times the MRHD on an AUC basis) most litters were aborted or resorbed. No toxicity was observed at 140 mcg/kg (less than the MRHD on an AUC basis). Evaluation: The labeling is identical to the description of studies with mometasone in Section 13.2 of the DULERA® label. It is standard labeling practice at this time to delete Section 13.2 and incorporate the information into Section 8.1. However, Section 13.2 is still present in the current DULERA® label. Deletion of Section 13.2 and revision of Section 8.1 in the ASMANEX HFA label would cause the same information in the two product labels for mometasone to appear different. No changes are recommended at this time. Both the DULERA® and ASMANEX HFA® labels should be revised at the same time to comply with the Maternal and Lactation Labeling Rule that is expected in 2014. 17 Reference ID: 3467446 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------TIMOTHY W ROBISON 03/07/2014 Reference ID: 3467446 PHARMACOLOGY/TOXICOLOGY FILING CHECKLIST FOR NDA/BLA or Supplement NDA Number: 205641 Applicant: Merck Stamp Date: June 27, 2013 Drug Name: ASMANEX HFA NDA Type: 505b1 On initial overview of the NDA/BLA application for filing: Content Parameter Yes No Not applicable. 1 Is the pharmacology/toxicology section organized in accord with current regulations and guidelines for format and content in a manner to allow substantive review to begin? No new nonclinical pharmacology and toxicology studies were provided in the NDA. The applicant did provide a summary of the nonclinical program. Not applicable. 2 Is the pharmacology/toxicology section indexed and paginated in a manner allowing substantive review to begin? No new nonclinical pharmacology and toxicology studies were provided in the NDA. The applicant did provide a summary of the nonclinical program. Not applicable. 3 Is the pharmacology/toxicology section legible so that substantive review can begin? 4 Are all required (*) and requested IND studies (in accord with 505 b1 and b2 including referenced literature) completed and submitted (carcinogenicity, mutagenicity, teratogenicity, effects on fertility, juvenile studies, acute and repeat dose adult animal studies, animal ADME studies, safety pharmacology, etc)? 5 If the formulation to be marketed is different from the formulation used in the toxicology studies, have studies by the appropriate route been conducted with appropriate formulations? (For other than the oral route, some studies may be by routes different from the clinical route intentionally and by desire of the FDA). 6 Does the route of administration used in the animal studies appear to be the same as the intended human exposure route? If not, has the applicant submitted a rationale to justify the alternative route? Comment X No new nonclinical pharmacology and toxicology studies were provided in the NDA. The applicant did provide a summary of the nonclinical program. Nonclinical pharmacology and toxicology studies with mometasone were reviewed under NDAs 19-543, 19-625, 19-796, 20(b) (4) (b) (4) 762, , 21-067, , and 22-518 Not applicable. Inhalation bridging toxicology studies with the marketed formulation were provided and reviewed under NDA 22-518. X File name: 5_Pharmacology_Toxicology Filing Checklist for NDA_BLA or Supplement 010908 Reference ID: 3355316 PHARMACOLOGY/TOXICOLOGY FILING CHECKLIST FOR NDA/BLA or Supplement Content Parameter 7 Has the applicant submitted a statement(s) that all of the pivotal pharm/tox studies have been performed in accordance with the GLP regulations (21 CFR 58) or an explanation for any significant deviations? Yes No X 8 Has the applicant submitted all special studies/data requested by the Division during pre-submission discussions? 9 Are the proposed labeling sections relative to pharmacology/toxicology appropriate (including human dose multiples expressed in either mg/m2 or comparative serum/plasma levels) and in accordance with 201.57? 10 Have any impurity – etc. issues been addressed? (New toxicity studies may not be needed.) 11 Has the applicant addressed any abuse potential issues in the submission? 12 If this NDA/BLA is to support a Rx to OTC switch, have all relevant studies been submitted? Comment Not applicable. X The Applicant indicated that impurities were identical to those found in the approved product, DULERA. Will consult with the Chemist regarding any impurity issues. Not applicable. Not applicable. IS THE PHARMACOLOGY/TOXICOLOGY SECTION OF THE APPLICATION FILEABLE? YES If the NDA/BLA is not fileable from the pharmacology/toxicology perspective, state the reasons and provide comments to be sent to the Applicant. None Please identify and list any potential review issues to be forwarded to the Applicant for the 74day letter. None File name: 5_Pharmacology_Toxicology Filing Checklist for NDA_BLA or Supplement 010908 Reference ID: 3355316 PHARMACOLOGY/TOXICOLOGY FILING CHECKLIST FOR NDA/BLA or Supplement Reviewing Pharmacologist Date Team Leader/Supervisor Date File name: 5_Pharmacology_Toxicology Filing Checklist for NDA_BLA or Supplement 010908 Reference ID: 3355316 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------TIMOTHY W ROBISON 08/09/2013 Reference ID: 3355316