CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`209089Orig1s000
` 209090Orig1s000
`
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`

`

`Cross Discipline Team Leader Review
`
`Cross-Discipline Team Leader Review
`
`
`Date
`January 9, 2017
`From
`Steven Osborne, M.D.
`
`
`NDA #, Supplement#
`NDAs 209089 (tablet), 209090 (oral solution)
`Applicant
`IIIIIEB, Inc. (Umon Chnmque Belge, Agent: Sanofi US Serv1ces
`
`
`
`PDUFA Goal Date
`
`Jan .
`
`31, 2017
`
`a) Xyzal® Allergy 24HR (levocetirizine dihydrochloride)
`Proprietary Name (Proposed)/
`
`Non—Proprietary Name
`b) Children’s Xyzal Allergy 24HR
`a Tablet, 5 m
`Dosage form(s) / Strength(s)
`b) Oral solutiogn 25 m
`
`Indication(s)/Population(s)
`
`Applicant Proposed
`
`Recommendation on
`Re ulato
`
`Allergic rhinitis (seasonal and perennial):
`o Tablet, 5 mg (Patients ages 6-64)
`
`0 Oral solution 2.5 mg/5 mL (Patients ages 2—64)
`Approval
`
`Recommended
`
`Allergic rhinitis (seasonal and perennial):
`
`Indication(s)/Population(s) (if
`applicable)
`
`0 Patients ages 6-64: tablet, 5 mg
`0 Patients a - es 2-64: oral solution 2.5 m
`
`1 .
`
`Benefit-Risk Assessment
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9. 2015. For initial rollout (NMEHVoriginal BLA reviews)
`
`1
`
`Reference ID: 4039504
`
`

`

`Cross Discipline Team Leader Review
`
`
`Benefit-Risk Summary and Assessment
`
`I recommend approval of:
`
`levocetirizine tablets 5 mg 0(yzal Allergy 24HR) for over—the—counter (OTC) use for the treatment of seasonal and perennial allergic
`rhinitis in consumers ages 6-64 years
`levocetirizine oral solution 2.5 mg/5 HI] (Children’s Xyzal Allergy 24HR) for the treatment of seasonal and perennial allergic rhinitis in
`consumers ages 2—64 years
`
`0 Both approval recommendations are for the indications and intended populations the sponsor has requested
`0 The proposed Drug Facts Label (DFL) directs children below age 2 to “not use” and adults ages 65 and older to ask a doctor.
`0 Overall, the benefit-risk is favorable for OTC use for these indications.
`
`There are 6 potential safety issues all of which are adequately addressed either by the sponsor, through the discipline reviews, or by a
`warning in the Drug Facts Label. See Section 8 of this review (Safety).
`These products will offer another option to consumers as an oral«gatihistamine.
`the drug should be dosed “in the evening” to match the current
`
`Rx labeling.
`
`Levocetirizine dihydrochloride (also referred to as levocetirizine, LCTZ, Xyzal, or ucb 28556 in this document) is an oral histamine Hl-receptor
`antagonist (antihistamine), the active R-enantiomer of the approved racemate, cetirizine, which itself is the main metabolite of hydroxyzine, a
`first generation antihistamine.
`
`Allergic rhinitis (AR) affects up to 30% of the adult population and has a significant negative impact on quality of life, adversely affecting
`emotional well—being and social behavior, and ofien resulting in sleep disturbance, impaired performance, and loss of productivity. A key
`aspect of the management of AR is avoidance; however, total avoidance is not practical, and pharmacotherapy has been the mainstay of
`treatment. OTC pharmacological treatments include oral antihistamines (first and second generation), antihistamine/decongestant
`combination products, oral and nasal decongestants, cromolyn nasal spray, antihistamine eye drops and intranasal corticosteroids. It is
`unclear whether levocetirizine tablets and oral solution provide any benefit over the racemate, cetirizine, although they provide an
`additional choice for consumers.
`
`The effectiveness of levocetirizine for treatment of AR, including seasonal allergic rhinitis and perennial allergic rhinitis (SAR and PAR), was
`well established in the development program for US approval of the prescription (Rx) products, Xyzal tablets 5 mg NDA 022064 on 5/25/07 and
`Xyzal (levocetirizine) oral solution NDA 022157 on 1/28/08. In addition to submitting final study reports for 33 clinical pharmacology and
`
`

`

`Cross Disci u line Team Leader Review
`
`209089 and 209090, the sponsor submitted final study reports for an additional 21 clinical pharmacology and clinical studies for NDA 209089.
`The sponsor also submitted a draft DFL, a summary of clinical trial experience, and a postmarket safety update. The widespread use of other
`antihistamines in the OTC setting provides assurance that consumers can appropriately self-diagnose the conditions or symptoms for which this
`product will be indicated and use the product safely and effectively.
`
`Levocetirizine has a favorable safety profile based on many years of clinical use and postmarketing experience. There is over 8 years of
`experience with use of this drug product in the United States with an estimated 10.7 million patient-years exposure. LCT2 was first
`approved overseas in 2001 in Germany and Spain. As of 2016, levocetirizine tablets and oral solution have been registered in 60 countries
`initially as an Rx drug product, with levocetirizine tablets now available nonprescription in 12 countries, pharmacist only in 3 countries,
`and oral solution in Australia and the Ukraine (oral drops are available as Rx in 30 countries). To date, LCTZ tablets, drops, and oral
`solution have not been withdrawn in any country for safety reasons.
`
`Collectively, data from nonclinical, clinical pharmacology, and clinical safety studies, as well as postmarketing safety surveillance data
`demonstrate that levocetirizine has low toxicity, is well-tolerated, and results in minimal medically significant systemic effects when
`administered at reconnnended doses. Levocetirizine has few significant drug-drug interactions. The most common side effects are
`generally mild and reversible. Common adverse events in clinical trials and reports to postmarket databases include drug ineffective,
`fatigue, headache, nasopharyngitis, and somnolence. Serious events, including wheezing, bronchopneumonia, and febrile seizure were
`reported in clinical trials. In the sponsor’s postmarket database, SAEs reported include suicide attempt, seizures, dyspnea, and somnolence,
`loss of consciousness, angioedema, overdose, and anaphylaxis, all of which have been reported infrequently in adults.
`
`The proposed OTC labeling is similar to approved labeling for Xyzal and includes information regarding potential drug interactions.
`limitations of duration of use. and appropriate instructions regarding when to ask a doctor. and when to stop use.
`
`M“)
`
`
`
`seen less commonly with nocturnal dosing. The Rx drug is currently labeled to take: “once daily in the evening”. This reviewer
`recommends the proposed OTC Xyzal (tablet and oral solution) be dosed in the evening to match the current Rx label.
`
`In clinical trials, somnolence was
`
`Postmarket pharmacovigilance for any liver disorders may be warranted with OTC Xyzal given the occasional postmarket reports of liver-
`related adverse events, including the 3 deaths (no causal link, see p. 16 of this review) and the disproportionate AEs (weak association) for
`liver disorders from the sponsor’s FAERS analysis.
`
`Evidence and Uncertainties
`
`Conclusions and Reasons
`
`

`

`Cross Discipline Team Leader Review
`Dimension
`
`Evidence and Uncertainties
`
`• Allergic Rhinitis (AR) affects up to 30% of the adult population in the
`United States (Wallace DV et al, J Allergy Clin Immunol 2008;
`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)
`• Approximately 30% of patients with AR report that AR symptoms
`have caused them to miss work. Half (51%) reported that AR
`adversely affects their daily lives to a moderate extent (Blaiss MS,
`Allergy Asthma Proc. 2007b; 28 (2):145-52).
`• 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
`avoidance is not practical.
`• OTC pharmacological treatments for AR include oral antihistamines,
`antihistamine/decongestant combination products, oral and nasal
`decongestants, cromolyn nasal spray, antihistamine eye drops, and
`intranasal corticosteroids.
`
`Analysis of
`Condition
`
`Current
`Treatment
`Options
`
`Benefit
`
`• The efficacy and safety of levocetirizine for the treatment of nasal and
`ocular symptoms associated with AR has been established in the
`original NDA. The clinical studies supporting the efficacy and safety
`were reviewed for approval of prescription Xyzal. No new clinical data
`were submitted with this application.
`• There is over 8 years of experience with use of levocetirizine in the
`United States with an estimated 10.6 million patient-years exposure.
`For a benefit assessment in this application, the sponsor submitted a
`draft DFL a Label Comprehension Study, and an Integrated Summary
`of Effectiveness.
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`Reference ID: 4039504
`
`Conclusions and Reasons
`
`There is a significant negative impact of
`Allergic Rhinitis (AR) on quality of life.
`
`Significant economic loss is associated with
`AR due to missed work, decreased
`productivity, and frequent doctor visits.
`
`Pharmacotherapy has been the mainstay of
`treatment for SAR and PAR. The high
`prevalence and chronic nature of this condition,
`and the fact that most sufferers self-treat
`(Malone 1997, Conner 2002) highlight the
`importance of OTC allergy treatments with
`established efficacy and safety.
`Overall, the effectiveness of levocetirizine for
`treatment of AR was well established for the
`approval of the Rx product, Xyzal. The
`consumer is well-versed in the use of oral
`antihistamines in the OTC setting. Consumers
`can appropriately self-diagnose AR and use the
`product safely and effectively. In addition,
`levocetirizine provides an additional choice for
`consumers.
`
`4
`
`

`

`Cross Disci . line Team Leader Review
`
`Evidence and Uncertainties
`
`Conclusions and Reasons
`
`
`
`0 For a risk assessment in this application, the sponsor submitted an
`Integrated Summary of Safety (ISS), and Postrnarket safety data.
`0 Collectively, data from nonclinical, clinical pharmacology, and clinical
`safety studies, as well as postmarketing safety surveillance data
`demonstrate that levocetirizine has low toxicity, is well-tolerated, and
`results in minimal medically significant systemic effects when
`administered at recommended doses.
`
`0 Levocetirizine has few significant drug-drug interactions.
`0 The most common side effects are generally mild and reversible,
`including somnolence, fatigue, and asthenia.
`0 Serious adverse events, including wheezing, pneumonia, seizures,
`suicide attempt, and anaphylactic shock have been reported
`infrequently in adults, with no deaths in clinical trials. In the
`postmarket setting, 32 deaths have been reported, including cardiac
`arrest and liver failure, although there is no certain link between
`levocetirizine use and the events. Postmarket AEs of drug ineffective,
`asthenia, fatigue and somnolence, are the most common AEs, likely-
`related to levocetirizine use (see Clinical, Section 7 of this review and
`Dr. Gierhart’s review.
`
`0 The proposed OTC labeling has the essential warnings translated from
`the prescription label from Xyzal .
`
`0 Proposed OTC labeling includes information regarding potential drug
`interactions and instructions regarding when to ask a doctor, and when
`to stop use. Of note, the sponsor has proposed OTC labeling stratifying
`adults into two categories: “up to age 64” and “65 years and older”
`with different dosing recommendations for the two groups. However,
`there is no such differentiation in the Rx Xyzal labeling (i.e., the Rx
`Xyzal labeling recommending 5 mg once daily in the evening for
`“adults and children 12 years of age and older”).
`0 Pro osed OTC labelin for the oral solution directs to ask a doctor for
`
`H; whereas Rx labeling provides
`
`Levocetirizine has a favorable safety profile
`based on 8 years of clinical use and
`postmarketing experience in the United States
`and 15 years worldwide.
`The potential for somnolence, fatigue, and
`asthenia were seen more often with morning
`administration in clinical trials.
`
`Serious adverse events are uncommon with
`
`labeled use. Deaths with cardiac arrest or liver
`
`toxicity were confounded by preexisting
`disease and multiple drugs, making a causal
`link with levocetirizine use impossible.
`
`The information provided in proposed OTC
`labeling will mitigate the risks of serious
`adverse events. Specifically, the proposed
`recommendations to ask a doctorfor adults
`ages 65 and olderfor the ta: 3,,
`,,
`,
`,
`,
`solution and to ask a doctor
`
`‘
`groups.
`
`will help to minimize risks in these age
`
`

`

`Cross Disci - line Team Leader Review
`
`0 See Section 2.1, pages 12-13 of Dr. Gierhart’s clinical review.
`
`Evidence and Uncertainties
`
`Conclusions and Reasons
`
`

`

`Cross Discipline Team Leader Review
`
`2.
`
`Background
`
`UCB, Inc. (Agent: Sanofi US Services Inc.) submitted a supplemental 505 b(1)NDA seeking
`over-the-counter (OTC) marketing approval for its levocetirizine dihydrochloride 5 mg tablet
`and 2.5 mg/S m1 oral solution, currently marketed as the prescription (Rx) products, named
`Xyzal. This product would be the fourth-in—class OTC second generation antihistamine,
`following loratadine (2002), cetirizine (2007), and fexofenadine (2011).
`
`Prior use of levocetirizine as an Rx drug
`The sponsor submitted sales data available from IMS Health for levocetirizine from January 1,
`2006 through June 30, 2015 for 5 mg tablets and oral solution, and estimated that
`(m4) tablets and
`m" of oral solution and oral drops were
`distributed globally. These distributed amounts equate to approximately 10,726,521 patient—
`years of worldwide exposure to levocetirizine 5 mg tablets, and 491,351 patient-years of
`worldwide exposure to levocetirizine oral solution and oral drops.
`
`Proposed OTC Indications and Dose
`The proposed indications for levocetirizine are similar or identical to the claims of other OTC
`antihistamines, are consistent with the Prescribing Information of Rx Xyzal, and are expressed
`in the proposed OTC product labeling as follows:
`
`0 Temporarily relieves («ii symptoms 3i hay fever or other upper respiratory allergies:
`my nose, sneezing, itchy, watery eyes, itching of the nose or throat
`
`In the proposed Drug Facts Label (DFL) for the 5 mg tablet , adults and children age 12—64
`years of age
`”(4)
`
`For the oral solution, adults and children 12-64 years of age
`
`M“)
`
`Proposed OTC Name
`On March 16, 2016, the FDA notified Sanofi US that the two proposed proprietary names
`Xyzal Allergy 24HR (5 mg tablet) and Children’s Xyzal Allergy 24I-IR (oral solution 2.5 mg/S
`ml) were both conditionally acceptable.
`
`Presubmission Regglatory Activity
`As noted in Dr. Gierhart’s review, presubmission regulatory activity was conducted under the
`two pre-investigational new drug development programs (preINDs). On May 29, 2015, Sanofi
`US Services Inc. (Agent for UCB Inc., holder of the two Xyzal Rx NDAs 022064 and 022157)
`submitted a Type B preIND meeting request to both preINDs (126506 0(yzal tablets and
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9. 2015. For initial rollout (NldEl‘ofiginal BLA reviews)
`
`7
`
`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
`Name of Discipline Primary Reviewer
`Materials Reviewed
`Grace P. Jones, PharmD, BCPS
`DMEPA Human Factors Study Review
`Karen Livornese, MSN
`DNDP Labeling Review
`Brenda Gierhart, M.D.
`DNDP Medical Officer Review
`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
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`8
`
`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
`•
` 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.
`
`Nonclinical Pharmacology/Toxicology
`4.
`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
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`9
`
`Reference ID: 4039504
`
`(b) (4)
`
`(b) (4)
`
`

`

`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 tablets and
`solution may be considered approvable from a nonclinical perspective”
`
`Clinical Pharmacology
`5.
`The Clinical Pharmacology review was conducted by Dr. Bhawana Saluja, who recommended
`approval.
`
`No new clinical pharmacology data or information was submitted in NDAs 209089 and
`209090. No new biopharmaceutical or clinical pharmacology studies were conducted in
`support of the switch from Rx to OTC status. The sponsor provided a clinical pharmacology
`summary, including cross-references to information previously submitted in the two Rx NDAs
`022064 and 022157, in Modules 2.7.1 “Summary of Biopharmaceutic Studies and Associated
`Analytical Methods (Allergic Rhinitis)” and 2.7.2 “Summary of Clinical Pharmacology
`Studies (Allergic Rhinitis)” of NDAs 209089 and 209090.
`
`Dr. Saluja noted no significant clinical pharmacology issues except for the potential for
`reduced renal excretion in patients with renal impairment, ranging from a doubling in plasma
`levels for mild renal impairment to a 6-fold increase in end stage renal disease. However, Dr.
`Saluja stated that the proposed DFL warning: do not use in consumers with kidney disease
`covered the potential for reduced excretion with renal impairment and no further warning is
`needed.
`
`For the purpose of analyzing somnolence TEAEs from Phase 1 and 2 studies, Dr. Gierhart also
`provided a list of the 31 Clinical Pharmacology studies summarized in Modules 2.7.1 and
`2.7.2 and/or listed in the “Tabular listing of all clinical studies” located in Module 2.7.6
`
`Clinical Microbiology
`6.
`A Microbiology Review was not needed for this application.
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`10
`
`Reference ID: 4039504
`
`

`

`Cross Discipline Team Leader Review
`
`Clinical Efficacy
`7.
`Xu Wang, MD from the Division of Pulmonary Allergy, and Rheumatology Products
`(DPARP) reviewed the efficacy of the two Rx-to-OTC switch NDAs and recommended
`approval.
`
`In his review, Dr. Wang noted that no new clinical trial data were submitted with this
`application and the efficacy of LCTZ was previously established in the original NDAs and is
`described in Xyzal prescription labeling as follows:
`• Seasonal Allergic Rhinitis (SAR): Xyzal is indicated for the relief of symptoms
`associated with seasonal allergic rhinitis in adults and children 2 years of age and older
`• Perennial Allergic Rhinitis (PAR): Xyzal is indicated for the relief of symptoms
`associated with perennial allergic rhinitis in adults and children 6 months of age and
`older
`• Chronic Idiopathic Urticaria (CIU): Xyzal is indicated for the treatment of the
`uncomplicated skin manifestations of chronic idiopathic urticaria (CIU) in adults and
`children 6 months of age and older (the CIU indication will remain Rx)
`
`CDTL Comment
`For OTC, the sponsor proposes use in children down to age 2 rather than down to age 6
`months. Below age 2, it is appropriate to have a physician diagnose PAR and oversee use of
`LCTZ. For a comparator, loratadine is also indicated down to age 2.
`
`Dr. Wang noted that 12 clinical studies supported the original NDA, of which 6 are efficacy
`and safety studies in adult and adolescent patients with SAR and PAR, 2 are efficacy and
`safety studies in pediatric patients 6 to 12 years of age with SAR and PAR, 2 are
`environmental exposure unit studies, and 2 are long term safety studies (shown in the Table 2
`below from Dr. Xu’s review).
`
`Dr. Wang noted the sponsor’s studies supported efficacy in adults and adolescents 12 years of
`age and older and, separately through 2 pediatric studies, efficacy in children 6 to less than 12
`years of age. Efficacy for pediatric patients under 6 years of age was extrapolated from the
`adult and adolescent data.
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`11
`
`Reference ID: 4039504
`
`

`

`Cross Discipline Team Leader Review
`
`Table 2. Efficacy studies of levocetirizine that supported original Rx approval
`
`Table 2 above is taken from Dr. Xu’s review.
`
`For adults and adolescents 12 years of age and older:
`Study A217 was conducted in patients with SAR and the other two studies (A265 and A219)
`were conducted in patients with PAR. The primary efficacy variables were the change from
`baseline in the average of the reflective total symptom score (rT4SS) over the first week and
`over the entire treatment period. All three studies A217, A219, and A265, evaluated three
`doses of LCTZ 2.5, 5, and 10 mg compared to placebo for the treatment of the symptoms of
`SAR (study A217) and PAR (studies A219 and A265).
`
`Two confirmatory efficacy studies were conducted. The primary efficacy variables were the
`change from baseline in the average of the reflective total symptom (4) score (rT4SS) and
`reflective total symptom (3) score (rT3SS). In study A268, patients who had a history of SAR
`for at least 2 years and a positive allergen skin test to grass or weed pollen were randomized to
`LCTZ 5 mg or placebo for 2 weeks. Patients in study A266 had a history of PAR to house dust
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`12
`
`Reference ID: 4039504
`
`

`

`Cross Discipline Team Leader Review
`
`mites for at least 2 years, and were randomized to LCTZ 5 mg or placebo for 6 weeks. Study
`A268 also showed that LCTZ 5 mg was efficacious at the end of 24-hour dosing interval in the
`treatment of SAR.
`
`CDTL Comment
`1. Study A268 validates one of the sponsor’s claims of 24-hour relief of symptoms of SAR.
`
`For children 6 to less than 12 years of age
`The clinical program of LCTZ included 2 pediatric studies in children 6 to <12 years of age.
`
`Study A303 was “A double-blind, placebo-controlled, randomized, multicenter Phase 4 trial:
`evaluation of the efficacy and safety, for children from 6 years to 12 years old, suffering from
`SAR, of LCTZ 5 mg tablets, administered orally once daily in the evening for 6 weeks.” The
`data summarized in Table 4 below showed that LCTZ 5 mg was statistically superior to
`placebo in relieving the symptoms of SAR in children 6 to 12 years of age.
`
`Study A304 was “A double-blind, placebo-controlled randomized multicenter Phase 3 trial:
`Evaluation of the efficacy and safety, on 6 to 12 year old children suffering from PAR due to
`house dust mites, of LCTZ 5 mg tablets, administered orally once daily in the evening for four
`weeks.” The study was conducted in South Africa. A total of 306 subjects, male or female,
`were randomized to receive LCTZ 5 mg or placebo daily for 4 weeks. This study showed that
`LCTZ 5 mg was statistically superior to placebo in relieving the symptoms of PAR caused by
`house dust mites in children 6 to 12 years of age.
`
`Clinical pharmacology studies showed that a single dose of 5 mg LCTZ in children age 6 to
`<12 years of age resulted in Cmax and AUC values about 2-fold greater than that reported in
`healthy adult subjects. Based on pharmacokinetic measures it is expected that 2.5 mg in
`patients 6 to <12 years would provide exposure comparable to 5 mg in patients less than 12
`years of age and older. Therefore, the dosing approved for ages 6 to <12 years was 2.5 mg
`rather than the 5 mg dose that was studied.
`
`For children less than 6 years of age
`There were no efficacy studies in children less than 6 years of age. Efficacy for pediatric
`patients under 6 years of age was extrapolated from the adult and adolescent data as the
`indicated conditions (SAR, PAR) share the same pathophysiology and behave similarly from a
`clinical perspective in both children and adults.
`
`LCTZ dosing of 1.25 mg was approved for allergic rhinitis in children 2 to < 6 years of age
`because pharmacology studies showed that administration of 1.25 mg once daily to children 6
`months to 5 years of age resulted in plasma concentrations similar to those of adults receiving
`5 mg once daily
`
`CDTL Comments
`
`1. Dr. Wang’s review focused on the 12 studies in Table 2 above and how these studies
`supported efficacy in SAR and PAR, which are the proposed OTC indications. Dr. Wang
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`13
`
`Reference ID: 4039504
`
`

`

`Cross Discipline Team Leader Review
`
`commented on the specific efficacy endpoints in these studies and these details can be found
`in his review.
`
`2. Dr. Gierhart discusses 31 clinical pharmacology studies and another 31 studies that the
`sponsor completed involving levocetirizine for other purposes or in in foreign countries . This
`explains the difference between the 12 studies discussed by Dr. Wang for efficacy and the
`remaining 49 studies Dr. Gierhart mentions in her safety review.
`8. Safety
`
`This safety information is taken from Dr. Gierhart’s NDA Rx-to-OTC switch review, which
`includes safety data from all 62 of the studies in the sponsor’s Summary of Clinical Safety
`(SCS), which are noted in Table 3 below, as well as data from the postmarket setting and the
`literature.
`
`This section summarizes:
`• Listing and categorization of sponsor’s 62 studies
`deaths in clinical trials or postmarket
`•
`common adverse events
`•
`potential safety issues for drugs in the same class
`•
`focus on somnolence
`•
`postmarket experience
`•
`
`62 studies
`The 62 studies, collated in Table 3 below, were conducted by UCB with levocetirizine
`formulations in the range from 1.25 mg/day to 30 mg/day. Of note, the sponsor’s SCS is
`essentially identical for both NDAs, the tablet (NDA 209089) and oral solution (NDA209090).
`
`Table 3: Categorization of study groups for 62 studies
`Study group
`Study numbers
`Clinical pharmacology studies (n=31)
`
`Clinical pharmacology (n=29)
`
`A184, A190, A221, A232, A233, A238,
`A245, A246, A252, A254, A256,
`A00260, A00263, A00280, A00297,
`A00305, A00318, A00324, A00331,
`A00340a b, A00351, A00373, A00379,
`A00380, A00412b, A00414b, A00415b,
`A00419b, A00428b
`A230, A234
`Studies in special populations (n=2)
`Phase 2-3-4 studies in adults 12 years old and older (n=22)
`A217, A219, A222, A00265, A00266,
`A00268, A00269, A00270, A00299,
`A00333, A00334, A00348, A00349,
`A00391b, A00