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209089Orig1s000 209090Orig1s000 CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 209089Orig1s000 209090Orig1s000 CROSS DISCIPLINE TEAM LEADER REVIEW Cross Discipline Team Leader Review Dimension Evidence and Uncertainties Conclusions and Reasons • Allergic Rhinitis (AR) affects up to 30% of the adult population in the There is a significant negative impact of United States (Wallace DV et al, J Allergy Clin Immunol 2008; Allergic Rhinitis (AR) on quality of life. 112:S1-84) • AR is associated with sleep disturbance, impaired performance and productivity loss (Blaiss MS et al, Allergy Asthma Proc. 2007a; 28 (Supp 1): S4-10, and Meltzer EO, Clinical Therapeutics. 2007; 29 (7): 1428-1440) Analysis of • Approximately 30% of patients with AR report that AR symptoms Condition have caused them to miss work. Half (51%) reported that AR Significant economic loss is associated with adversely affects their daily lives to a moderate extent (Blaiss MS, AR due to missed work, decreased Allergy Asthma Proc. 2007b; 28 (2):145-52). productivity, and frequent doctor visits. • Two studies suggested that allergies are among the major contributors to the total cost of health-related absenteeism and contribute to decreased productivity (Lamb CE et al, Curr Med Res Opin, 2006; 22:1203-1210, and Burton WM et al, Occu Environ Med, 2001; 43:64-71). • A key aspect of the management of AR is avoidance; however, total Pharmacotherapy has been the mainstay of avoidance is not practical. treatment for SAR and PAR. The high Current • OTC pharmacological treatments for AR include oral antihistamines, prevalence and chronic nature of this condition, Treatment antihistamine/decongestant combination products, oral and nasal and the fact that most sufferers self-treat Options decongestants, cromolyn nasal spray, antihistamine eye drops, and (Malone 1997, Conner 2002) highlight the intranasal corticosteroids. importance of OTC allergy treatments with established efficacy and safety. • The efficacy and safety of levocetirizine for the treatment of nasal and Overall, the effectiveness of levocetirizine for ocular symptoms associated with AR has been established in the treatment of AR was well established for the original NDA. The clinical studies supporting the efficacy and safety approval of the Rx product, Xyzal. The were reviewed for approval of prescription Xyzal. No new clinical data consumer is well-versed in the use of oral were submitted with this application. antihistamines in the OTC setting. Consumers Benefit • There is over 8 years of experience with use of levocetirizine in the can appropriately self-diagnose AR and use the United States with an estimated 10.6 million patient-years exposure. product safely and effectively. In addition, For a benefit assessment in this application, the sponsor submitted a levocetirizine provides an additional choice for draft DFL a Label Comprehension Study, and an Integrated Summary consumers. of Effectiveness. CDER Cross Discipline Team Leader Review Template 2015 Edition 4 Version date: June 9, 2015. For initial rollout (NME/original BLA reviews) Reference ID: 4039504 Cross Discipline Team Leader Review 126507 Xyzal solution) for a single preIND meeting to discuss a Rx to OTC switch for both Xyzal Rx NDAs. The meeting package was submitted on August 20, 2015 to both preINDs, the meeting was held on October 1, 2015 and the FDA meeting minutes were finalized on November 9, 2015. Some issues resolved during this meeting and listed in the FDA meeting minutes included: • Sanofi US Services Inc. (Sanofi US) could provide one comprehensive Summary of Clinical Efficacy (SCE) in the tablet NDA to support the switch of both the levocetirizine tablet and the oral solution formulation. • Sanofi US could provide one comprehensive Summary of Clinical Safety (SCS) and one Integrated Summary of Safety (ISS) located in the tablet NDA to support the switch of both levocetirizine tablets and oral solution to OTC status. • Sanofi US would analyze postmarketing safety data and note adverse events most likely to occur with accidental or intentional overdose in the OTC population and adverse events most likely to occur with the labeled dose and duration in the OTC population. • The cut-off date for data included in the sponsor’s clinical study summary would be October 31, 2015. In writing this review, I have used the following primary FDA reviews in Table 1 below: Table 1: Primary Reviews Materials Reviewed Name of Discipline Primary Reviewer DMEPA Human Factors Study Review Grace P. Jones, PharmD, BCPS DNDP Labeling Review Karen Livornese, MSN DNDP Medical Officer Review Brenda Gierhart, M.D. DNDP Pharmacology/Toxicology Review Donald C. Thompson, Ph.D. DNDP Social Science Review Amanda Pike-McCrudden, MAA DPARP Medical Officer Review Xu Wang, M.D. Office of Biostatistics Review Rongmei Zhang, Ph.D. Office of Clinical Pharmacology Review Bhawana Saluja, Ph.D. OPQ CMC Review Swapan De, Ph.D. OPQ Division of Microbiology Review Not needed for this application CMC = Chemistry, Manufacturing and Controls DMEPA = Division of Medication Error Prevention and Analysis DNDP = Division of Nonprescription Drug Product DPARP = Division of Pulmonary, Allergy, and Rheumatology Products OPQ = Office of Pharmaceutical Quality 3. Product Quality The Product Quality (Chemistry, Manufacturing, and Controls; CMC) Review was conducted by Dr. Swapan De, who recommended approval. Dr. De notes that per the Original NDA 209089 (tablet 5 mg) cover letter, there were no changes, except as noted below, to the previously approved Chemistry, Manufacturing, and Controls (CMC)/Quality information, including tablet size and shape, drug substance and drug CDER Cross Discipline Team Leader Review Template 2015 Edition 8 Version date: June 9, 2015. For initial rollout (NME/original BLA reviews) Reference ID: 4039504 Cross Discipline Team Leader Review product specifications, drug substance and drug product manufacturers, container closure systems, and expiration dates associated with this Rx-to-OTC switch. NDA 209089 does include the following CMC changes: • inclusion of a debossed tablet (with updated appearance specification) • new packaging configurations for HDPE bottles • addition of a peel-push aluminum lidding (b) (4) (b) (4) to the blister packages • addition of new packaging sites Per the Original NDA 209090 (oral solution 2.5 mg/5ml) cover letter, there were no changes to previously approved CMC/Quality information, including drug substance and drug product specifications, drug substance and drug product manufacturers and packagers, container closure systems, and expiration dates associated with this Rx-to-OTC switch. However, NDA 209090 includes a dosing cup administration device. See the Chemistry review for additional details. 4. Nonclinical Pharmacology/Toxicology The Pharmacology / Toxicology review was conducted by Dr. Donald C. Thompson who recommended approval. Dr. Thompson determined that no new nonclinical pharmacology or toxicology data were submitted for this application. Rather, the Sponsor cross referenced nonclinical data submitted under its own NDA 022064 for the prescription oral tablet levocetirizine dihydrochloride 5 mg drug product. These same data had previously been referenced by the Sponsor in support of NDA 022157 (levocetirizine oral solution). Dr. Thompson noted that Dr. Lawrence Sancilio from DPARP-PharmTox conducted the original PharmTox review for NDA 022064 and determined that: • “Levocetirizine is the R-enantiomer of cetirizine, a marketed H1 receptor antagonist. In view of this, the long term toxicity, fertility and early developmental and prenatal postnatal developmental toxicity studies with cetirizine represent the toxicity profile of levocetirizine with supplemental bridging toxicity, and embryofetal developmental studies of levocetirizine. • In chronic oral toxicity studies in mice and rats with cetirizine, the liver was the target organ. The liver changes were enzyme induction and fat deposition. In Beagle dogs, the targeted organ was the gastrointestinal system. The major clinical sign was emesis. In a dietary carcinogenicity study in rats, cetirizine was not tumorigenic, but the livers showed hypertrophy, vacuolation and fat deposition. In a dietary carcinogenicity study, male mice showed hepatic hypertrophy and benign liver tumors, the latter was due to enzyme induction. In embryofetal development studies in mice, rats and rabbits, cetirizine was not teratogenic although increased skeletal anomalies/variants were observed in rabbits. CDER Cross Discipline Team Leader Review Template 2015 Edition 9 Version date: June 9, 2015. For initial rollout (NME/original BLA reviews) Reference ID: 4039504 Cross Discipline Team Leader Review • Levocetirizine was not mutagenic in the Reverse Bacterial Mutation Assay and not genotoxic in the Mouse Lymphoma, Human Lymphocyte Chromosomal Aberration and Micronucleus Assays. In a bridging Embryofetal Developmental study in rats and rabbits with levocetirizine and cetirizine, both compounds were not teratogenic although cetirizine did increase skeletal anomalies/variants in rabbits. Dr. Thompson concluded that Dr. Sancilio’s review “…confirms that all required toxicological endpoints have been sufficiently and adequately addressed for levocetirizine and that the data do not identify adverse effects that would raise safety concerns in the OTC environment. Thus, it is concluded that the current applications proposing a switch from prescription to nonprescription status for levocetirizine dihydrochloride oral
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