CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`
` 209089Orig1s000
` 209090Orig1s000
`
`
`
`CLINICAL REVIEW(S)
`
`

`

`Application Type
` Application Number(s)
`
`Priority or Standard
`
`Submit Date(s)
`Received Date(s)
` PDUFA Goal Date
`Division / Office
`
`CLINICAL REVIEW
`
`NDA (Rx to OTC switch)
`209-089 Xyzal Allergy 24 HR tablets
`209-090 Xyzal Allergy 24 HR solution
`Standard
`
`March 18, 2016
`March 31, 2016
` January 31, 2017
`DPARP/ODE 2/OND
`
`Reviewer Name(s)
` Review Completion Date
`
`Xu Wang, M.D., Ph.D.
`December 9, 2016
`
` Established Name
`Rx Trade Name
`OTC Trade Name
`
`Therapeutic Class
` Applicant
`
`Formulation(s)
` Dosing Regimen
`
`Indication(s)
`
` Intended Population(s)
`
`Template Version: March 6, 2009
`
`Reference ID: 4025819
`
`Levocetirizine dihydrochloride
`Xyzal tablets/solution
`Xyzal Allergy 24HR
`tablets/solution
`Antihistamine
`UCB Inc.
`
`tablets/solution
`≥12 years: One tablet (5 mg) daily/10 mL
`solution (5 mg) daily;
`6 – 11 years: 1/2 tablet (2.5 mg) daily/5 mL
`solution (2.5 mg) daily;
`2 – 5 years: 2.5 mL solution (1.25 mg)
`daily
`Temporarily relieve these symptoms due
`to hay fever or other upper respiratory
`allergies:
`• running nose,
`• sneezing,
`• itchy, watering eyes,
`• itching of nose or throat
`Tablets: ≥6 years of age
`Solution: ≥2 years of age
`
`

`

`Clinical Review
`Xu Wang, M.D., Ph.D.
`NDA 209-089/NDA 209-090 Rx to OTC switch
`Xyzal Allergy 24HR (levocetirizine dihydrochloride) tablets/solution
`
`2
`
`Table of Contents
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT .........................................4
`1.1 Recommendation on Regulatory Action ............................................................. 4
`1.2 Risk Benefit Assessment .................................................................................... 4
`INTRODUCTION AND REGULATORY BACKGROUND ........................................ 4
`2.1 Product Information ............................................................................................ 4
`2.2 Currently Available Treatments for Proposed Indications................................... 5
`2.3 Availability of Proposed Active Ingredient in the United States .......................... 5
`2.5 Summary of Presubmission Regulatory Activity Related to Submission ..............5
`3 ETHICS AND GOOD CLINICAL PRACTICES.........................................................6
`3.1 Submission Quality and Integrity ........................................................................ 6
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES ........................................................................................................... 6
`4.1 Chemistry Manufacturing and Controls .............................................................. 6
`4.3 Preclinical Pharmacology/Toxicology ................................................................. 7
`4.4 Clinical Pharmacology ........................................................................................ 7
`5 SOURCES OF CLINICAL DATA............................................................................ 7
`5.1 Tables of Studies/Clinical Trials ....................................................................... 8
`5.2 Review Strategy ............................................................................................... 8
`6 REVIEW OF EFFICACY ......................................................................................... 9
`Efficacy Summary...................................................................................................... 9
`6.1.4 Analysis of Primary Endpoint(s) .................................................................... 9
`7 REVIEW OF SAFETY............................................................................................. 14
`Safety Summary ........................................................................................................ 14
`9 APPENDICES ........................................................................................................ 14
`9.1
`Literature Review/References .......................................................................... 14
`9.2
`Labeling Recommendations ............................................................................. 15
`9.3 Advisory Committee Meeting............................................................................ 15
`
`Reference ID: 4025819
`
`2
`
`

`

`Clinical Review
`Xu Wang, M.D., Ph.D.
`NDA 209-089/NDA 209-090 Rx to OTC switch
`Xyzal Allergy 24HR (levocetirizine dihydrochloride) tablets/solution
`
`Table of Tables
`
`Table 1: Overview of 14 randomized, placebo-controlled studies for allergic rhinitis............... 8
`Table 2: Dose-ranging studies mean rT4SS change over treatment period ………………………..10
`Table 3: Efficacy results in studies A268 (SAR) and A266 (PAR)……………….. ..................11
`Table 4: Mean rT4SS change in pediatric study A303 (SAR)……………………………........ 12
`Table 5: Mean rT4SS change in pediatric study A304 (PAR)............................................... 12
`Table 6: MSC change in EEU study A379, Onset and duration of action………………...........14
`
`Reference ID: 4025819
`
`3
`
`

`

`Clinical Review
`Xu Wang, M.D., Ph.D.
`NDA 209-089/NDA 209-090 Rx to OTC switch
`Xyzal Allergy 24HR (levocetirizine dihydrochloride) tablets/solution
`1 Recommendations/Risk Benefit Assessment
`
`1.1 Recommendation on Regulatory Action
`
`The Applicant proposes a partial Rx to OTC switch of Xyzal (levocetirizine dihydrochloride). Xyzal
`tablets (NDA 22-064) and Xyzal solution (NDA 22-157) were approved on 05/25/2007 and 01/28/2008,
`respectively, for the treatment of seasonal and perennial allergic rhinitis, and chronic idiopathic urticaria
`(CIU) in patients 6 years of age and older (Xyzal tablets/solution prescription labeling). On
`02/24/2009, the Applicant submitted pediatric study reports, as requested in a pediatric Written Request,
`and on 08/24/2009 Xyzal was approved in pediatric patients 6 months to <6 years of age.
`
`The Applicant proposes an OTC switch for allergic rhinitis in patients 2 years of age and older. The
`proposed OTC labeling states that levocetirizine dihydrochloride (LCTZ) is “for temporarily relieves
`these symptoms due to hay fever or other upper respiratory allergies: ●running nose, ●sneezing, ●itchy,
`watering eyes, ●itching of nose or throat.” The proposed OTC dosing regimen is the same as that of the
`prescription drug Xyzal. For patients ≥12 years: One tablet (5 mg) daily/10 mL solution (5 mg) daily;
`Fro patients 6 – 11 years: 1/2 tablet (2.5 mg) daily or 5 mL solution (2.5 mg) daily; For patients 2 – 5
`years: 2.5 mL solution (1.25 mg) daily.
`
`The recommended action for this prescription (Rx) to over-the-counter (OTC) switch for
`Xyzal Allergy 24HR (levocetirizine dihydrochloride) tablets and solution is Approval.
`
`1.2 Risk Benefit Assessment
`
`Allergic rhinitis is a well-established OTC indication in the U.S., and both oral medications and nasal
`sprays are available OTC to treat this condition. Dose selection and efficacy of the product for adults
`and children ≥ 2 years of age were established during the prescription approval process, and efficacy is
`not expected to be different in the OTC setting. Thus, the benefit provided by LCTZ is well established
`and prior precedents exist for consumer self-selection for treatment of allergic rhinitis using oral drugs
`(Zyrtec, Claritin, and Allegra) in the OTC setting. It would benefit the public to have an additional oral
`antihistamine readily available as a nonprescription drug product. The safety of LCTZ is supported by
`the clinical development program for the prescription Xyzal, as well as by the post-marketing
`experience. Thus, the risk benefit assessment supports approval of LCTZ tablets and solution for the
`proposed partial OTC switch.
`
`2 Introduction and Regulatory Background
`
`2.1 Product Information
`
`Levocetirizine dihydrochloride (LCTZ) is an oral histamine H1-receptor antagonist (antihistamine) and
`the active R-enantiomer of the approved racemate, cetirizine (Zyrtec). In the United States, prescription
`drug Xyzal tablets, NDA 22-064, was approved 05/25/2007 with pediatric studies deferred. On
`01/28/2008 prescription drug Xyzal solution, NDA 22-157, was approved. On 01/24/2009 FDA issued a
`pediatric Written Request to NDAs 22-064 and 22-157. On 02/24/ 2009, study reports for the requested
`4
`
`Reference ID: 4025819
`
`

`

`Clinical Review
`three pediatric studies were submitted and pediatric exclusivity was granted for both NDAs on August
`25, 2009.
`Xu Wang, M.D., Ph.D.
`NDA 209-089/NDA 209-090 Rx to OTC switch
`Xyzal Allergy 24HR (levocetirizine dihydrochloride) tablets/solution
`
`LCTZ tablets and solution have been registered in many countries worldwide, including as prescription
`drugs in 60 countries and OTC drugs in 12 countries. To date, there have been no market withdrawals
`for LCTZ in any country due to safety reasons.
`
`
`
`2.2 Currently Available Treatments for Proposed Indications
`
`In addition to avoidance of allergens, antihistamines are the first-line treatment for symptoms of allergic
`rhinitis. Several antihistamines are currently marketed as OTC monograph drugs in the US, including
`first-generation agents such as brompheniramine, chlorpheniramine, diphenhydramine, and doxylamine.
`These products are indicated for the treatment of symptoms of “hay fever or other upper respiratory
`allergies” [21 CFR 341.72]. The first-generation antihistamines are characterized by sedation as an
`adverse effect. There are also antihistamines marketed OTC in the US that were initially approved as
`NDA products, such as clemastine, and the second-generation antihistamine, loratadine and
`loratadine/PSE. Loratadine and other second-generation antihistamines typically have limited
`penetration of the CNS and are associated with less or minimal sedation. There are numerous
`antihistamines which are available only by prescription in the US, including hydroxyzine,
`cyproheptadine, fexofenadine, and Xyzal tablets and solution.
`
`2.3 Availability of Proposed Active Ingredient in the United States
`
`Xyzal tablets (NDA 22-064) and Xyzal oral solution (NDA 22-157) are the only two drug products
`containing LCTZ that are currently available in the US. Both are currently available in the US as Rx
`drug products for the following approved Rx indications:
`
`•
`
`•
`
`•
`
`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 in adults and children 6 months of age and
`older.
`
`2.5 Summary of Presubmission Regulatory Activity Related to Submission
`
`On 05/29/2015, the sponsor submitted a Type B pre-IND meeting request for both Xyzal tablets (pre-
`IND 126,506) and Xyzal solution (pre-IND 126,507) to discuss the Rx to OTC switch for both Xyzal
`Rx NDAs. The meeting package was submitted on 08/20/2015 to both pre-INDs, and the meeting was
`held on 10/01/2015. Significant issues discussed during this meeting listed in the meeting minutes
`included:
`
`• One comprehensive Summary of Clinical Efficacy (SCE) located in the tablet NDA to support
`the switch of both LCTZ tablets and the solution formulation; An Integrated Summary of
`Efficacy (ISE) would not be required.
`
`Reference ID: 4025819
`
`5
`
`

`

`Clinical Review
`Xu Wang, M.D., Ph.D.
`NDA 209-089/NDA 209-090 Rx to OTC switch
`Xyzal Allergy 24HR (levocetirizine dihydrochloride) tablets/solution
`
`• One comprehensive Summary of Clinical Safety (SCS) and one Integrated Summary of Safety
`(ISS) located in the tablets NDA to support the switch of both LCTZ tablets and solution to
`OTC status.
`• Resubmit of the clinical study databases (i.e., SAS datasets of the clinical data of either
`individual studies or pooled studies) are not required if a listing indicating the location of the
`SAS datasets of the clinical data for each individual clinical study was provided. Sponsor was
`informed that if any SAS dataset could not be easily located, their submission may be requested.
`
`On 09/21/2015, two separate proprietary name requests for review (i.e., Xyzal® Allergy 24HR and
` were submitted to both pre-INDs. On 03/16/2016, the FDA notified the sponsor
`that the two proposed proprietary names were acceptable.
`
`On 12/11/2015, the sponsor submitted “General Correspondence”, amended the sponsor’s switch
`proposal for Xyzal tablets and solution to partially switch only two of the three approved Rx
`indications, i.e., SAR and PAR. On 12/22/2015, a tele-conference was held with sponsor and DNDP to
`clarify that the CIU (hives) indication would remain Rx for both Xyzal tablets and solution.
`
`3 Ethics and Good Clinical Practices
`
`3.1 Submission Quality and Integrity
`
`The NDA submission is adequately indexed, organized and complete to allow for review. There are no
`new clinical studies contained in this submission, instead the submission relies on previously reviewed
`clinical trial data for safety and efficacy. Therefore, data integrity is not an issue for this Rx to OTC
`switch.
`
`4 Significant Efficacy/Safety Issues Related to Other Review
`Disciplines
`4.1 Chemistry Manufacturing and Controls
`
`Per the Original NDA 209-089 LCTZ tablet 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 product specifications, drug substance and
`drug product manufacturers, container closure systems, and expiration dates associated with this Rx-to-
`OTC switch.
`
`•
`•
`•
`
`•
`
`inclusion of a debossed tablet (with updated appearance specification)
`new packaging configurations for HDPE bottles
`addition of a peel-push aluminum lidding
`blister packages
`addition of new packaging sites.
`
`Reference ID: 4025819
`
` to the
`
`6
`
`(b) (4)
`
`(b) (4)
`
`

`

`Clinical Review
`Xu Wang, M.D., Ph.D.
`NDA 209-089/NDA 209-090 Rx to OTC switch
`Xyzal Allergy 24HR (levocetirizine dihydrochloride) tablets/solution
`
`Per the Original NDA 209-090 LCTZ solution 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 209-090 includes an administration
`device (dosing cup).
`
`These minor CMC changes in the proposed OTC LCTZ tablets and solution are unlikely to affect the
`safety and effectiveness of the drugs.
`
`4.3 Preclinical Pharmacology/Toxicology
`
`No new preclinical and toxicological data were submitted in the Rx to OTC switch NDAs. The
`summary of nonclinical pharmacology and toxicology, including a cross-reference to previously
`submitted information, is provided in Module 2.4 of both NDAs. Summary review of the preclinical and
`toxicological data can be found in the DNDP Pharmacology/Toxicology NDA Review by D. Charles
`Thompson, R.Ph., Ph.D., D.A.B.T.
`
`4.4 Clinical Pharmacology
`
`No new clinical pharmacology studies were conducted in support of this submission. A clinical
`pharmacology summary, including cross-references to information previously submitted in the two Rx
`Xyzal tablets and solution (NDAs 22-064 and 22-157), is provided in Modules 2.7.1 “Summary of
`Biopharmaceutical Studies and Associated Analytical Methods (Allergic Rhinitis)” and 2.7.2
`“Summary of Clinical Pharmacology Studies (Allergic Rhinitis)”.
`
`The prescription Xyzal labeling recommends a dose of LCTZ for children 6 to 11 years of age is 2.5 mg
`and for children less than 6 years of age is 1.25 mg. The clinical pharmacology studies showed that a
`single dose of 5 mg LCTZ in children age 6 to 11 years of age resulted in Cmax and AUC values about
`2-fold greater than that reported in healthy adult subjects, and 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.
`
`5 Sources of Clinical Data
`The clinical program of Xyzal prescription NDA included 14 clinical studies to support the proposed
`indication. Of these studies, 6 are efficacy and safety studies in adult and adolescent patients with
`seasonal and perennial allergic rhinitis, 2 are efficacy and safety studies in pediatric patients 6 to 12
`years of age with seasonal and perennial allergic rhinitis, 2 are environmental exposure unit studies, and
`2 are long term safety studies (Table 1).
`
`Reference ID: 4025819
`
`7
`
`

`

`Clinical Review
`Xu Wang, M.D., Ph.D.
`NDA 209-089/NDA 209-090 Rx to OTC switch
`Xyzal Allergy 24HR (levocetirizine dihydrochloride) tablets/solution
`5.1 Tables of Studies/Clinical Trials
`
`Table 1 Overview of 14 randomized, placebo-controlled studies for allergic rhinitis
`
`5.2 Review Strategy
`
`The OTC switch application does not seek any new indications, and no new clinical trial data were
`included in the NDA. As efficacy was already established during the prescription approval process,
`this review only summarizes the efficacy data that have been reviewed previously. Additional
`sections and subsections of the standard NDA template that are redundant or not relevant to this Rx to
`OTC switch have been deleted from this review; per standard review practice the sections have not
`been renumbered1.
`
`This review is focused on the efficacy of LCTZ, because the safety of LCTZ, both from the clinical
`development program and from post-marketing experience, were reviewed by the Division of Non-
`prescription Drug Products (DNDP) Medical Officer [NDA 22-089/NDA 22-090, Medical Officer
`Review, Brenda S. Gierhart, M.D., 11/14/2016].
`
`1 MAPP 6010.3, effective date 12/10/2010
`
`Reference ID: 4025819
`
`8
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`

`

`Clinical Review
`Xu Wang, M.D., Ph.D.
`NDA 209-089/NDA 209-090 Rx to OTC switch
`Xyzal Allergy 24HR (levocetirizine dihydrochloride) tablets/solution
`
`6 Review of Efficacy
`Efficacy Summary
`The proposed OTC dosing and indication for LCTZ are consistent with the dosing and indications
`approved for the prescription drug product. The proposed OTC indication is as follows: “temporarily
`relieves these symptoms due to hay fever or other upper respiratory allergies: runny nose, sneezing,
`itchy, watering eyes, and itching of nose or throat.” As no new claims or changes in dosing are
`proposed, the efficacy data previously submitted in support of the prescription drug are adequate to
`support the proposed OTC LCTZ drug. No additional trials are required.
`6.1.4 Analysis of Primary Endpoint(s)
`
`The primary efficacy variables were the mean 24 hours reflective composite scoring of rhinitis
`symptoms (T4SS) over the treatment period by the subjects with SAR and PAR. T4SS is the sum of the
`scores for sneezing, rhinorrhea, nasal pruritus and ocular pruritus. In 2 environment exposure unit
`studies (A379 and A412) the major symptoms complex (MSC) score (running nose, itchy nose, sniffles,
`nose blows, sneezes, and watery eyes) was used as the primary efficacy variable. Each symptom was
`rated on a 0 - 3 scale.
`
`0 = no symptoms
`1 = mild symptoms - present but not troublesome
`2 = moderate symptoms -frequently troublesome, but not sufficient to interfere with normal
`daily activity or night-time sleep
`3 = severe symptoms - sufficiently troublesome to interfere with normal daily activity or night-
`time sleep
`
`A Clinical Summary of Efficacy was submitted to support the OTC indication of this Rx to OTC switch
`NDA. The original efficacy data were reviewed at the prescription drug clinical development program
`and not resubmitted to this NDA. Following are summaries of the clinical data used to support efficacy
`labeling in the OTC Drug Facts Label.
`
`Efficacy – adults and adolescents 12 years of age and older
`
`Efficacy in this patient population was assessed from 5 placebo-controlled clinical studies. Of these, 3
`were dose-ranging studies and 2 were confirmatory efficacy studies.
`
`Dose-ranging studies
`
`The 3 dose-ranging studies were identical in design except that study A217 was conducted in patients
`with SAR and the other two studies (A265 and A219) were conducted in patients with PAR. 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).
`
`Reference ID: 4025819
`
`9
`
`

`

`Clinical Review
`Xu Wang, M.D., Ph.D.
`NDA 209-089/NDA 209-090 Rx to OTC switch
`Xyzal Allergy 24HR (levocetirizine dihydrochloride) tablets/solution
`A total of 470 patients 18 - 72 years of age with SAR were enrolled in study A217 whereas, 5211 PAR
`subjects were randomized in A265, and 421 PAR patients were randomized in study A219. SAR
`patients had a positive skin test or radioallergosorbent test (RAST) to grass and/or weed pollen and had
`a history of SAR for at least 2 years. Patients with PAR had at least a 2-year history of PAR due to
`house dust mites and a positive skin test or RAST to house dust mites.
`
`Following a screening period of approximately 7 days, patients were randomized to treatment with
`LCTZ 2.5, 5, 10 mg or placebo once daily in the evening for 14 days (study A217) or 4 weeks (study
`A265, A219). Patients recorded the severity of four symptoms (runny nose, itchy nose, sneezing, and
`ocular pruritus) once daily in a diary based on a severity scale of 0 to 3 to reflect how they felt over the
`entire 24 hour treatment period and recorded that score in their diary just before taking the next dose of
`study medication (reflective score). 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. The baseline score was the mean of the daily reflective T4SS (assessed in the evening)
`over the 7-day screening period (period from the day of the initial visit to the day preceding the
`randomization visit). The results were analyzed using an analysis of covariance (ANCOVA).
`
`The efficacy results for the dose-ranging studies are shown in Table 2. There was evidence of a dose-
`ordering effect in studies A217 and A265 but not in study A219 where the 5 mg dose did not reach
`statistical significance level. However, the change from baseline in symptom scores was numerically
`better than placebo. A dose effect was seen in study A217 across all three doses. In study A265 all three
`doses had a statistically significantly greater improvement compared to placebo, but the effect size was
`similar in all 2 doses.
`
`Table 2 Dose-ranging studies mean rT4SS change over treatment period
`
`Source: From 2.7.3 Clinical Summary of Efficacy (Allergic Rhinitis) and the Biostatistics Review of prescription drug Xyzal
`tablets.
`
`Reference ID: 4025819
`
`10
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`

`

`Clinical Review
`Xu Wang, M.D., Ph.D.
`NDA 209-089/NDA 209-090 Rx to OTC switch
`Xyzal Allergy 24HR (levocetirizine dihydrochloride) tablets/solution
`
`Confirmatory studies
`Two confirmatory efficacy studies were conducted in the clinical program of prescription drug LCTZ.
`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 study treatment (LCTZ 5 mg) or placebo for 2 weeks. Patients
`in study A266 had a history of PAR to house dust mites for at least 2 years, and were randomized to
`study treatment (LCTZ 5 mg) or placebo for 6 weeks.
`
`A total of 237 and 294 patients 12 to 71 years of age were randomized to study treatment or placebo in
`study A268 and A266, respectively. 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, excluded score of ocular pruritus). In study A268, the subjects were also asked how they felt
`over the last hour of the treatment period (instantaneous score, iT3SS) as a secondary endpoint. This
`was the only allergic rhinitis study that provides an assessment of the end-of-dosing interval efficacy.
`Table 3 below showed evidence of efficacy for LCTZ 5 mg daily dose in SAR and PAR comparing
`with the placebo. Study A268 also showed that LCTZ 5 mg was efficacious at the end of 24-hour
`dosing interval in the treatment of SAR.
`
`Table 3 Efficacy results in studies A268 (SAR) and A266 (PAR)
`
`Source: From 2.7.3 Clinical Summary of Efficacy (Allergic Rhinitis) and the Biostatistics Review of prescription drug Xyzal
`tablets.
`
`Efficacy – 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 study was conducted in France
`and Germany. A total of 177 subjects, male or female, were randomized to receive LCTZ 5 mg or
`
`Reference ID: 4025819
`
`11
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`

`

`Clinical Review
`Xu Wang, M.D., Ph.D.
`NDA 209-089/NDA 209-090 Rx to OTC switch
`Xyzal Allergy 24HR (levocetirizine dihydrochloride) tablets/solution
`
`placebo daily 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.
`
`Table 4 Mean rT4SS change in pediatric study A303 (SAR)
`
`Source: Table excerpted from NDA 22-064 Xyzal tablets, MO Review, Robert M. Boucher, M.D., M.P.H., 04/03/2007
`
`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
`(Table 5).
`
`Table 5 Mean rT4SS change in pediatric study A304 (PAR)
`
`Source: Table excerpted from NDA 22-064 Xyzal tablets, MO Review, Robert M. Boucher, M.D., M.P.H., 04/03/2007
`
`UCB did not conduct efficacy studies with lower doses of Xyzal. 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. Dosing recommendation based on
`pharmacokinetic measures for systemically active drugs for allergic rhinitis is reasonable because
`allergic rhinitis is the same disease in adults and children and the effect of drug on the disease is
`expected to be similar between adults and children. The Division had used the rationale in the past for
`other oral antihistamines. The two studies A303 and A304 provide ample safety data for Xyzal in the
`group of 6 to <12 years of age.
`
`Efficacy – children less than 6 years of age
`
`There were no efficacy studies in children less than 6 years of age. UCB filed a supplemental NDA
`(sNDA 22-064) on 02/24/2009, to extend the age range of the approved indications down to 2 years for
`SAR and 6 months for PAR and CIU. Efficacy studies conducted in adults and adolescents 12 years of
`age and older have previously demonstrated that LCTZ is effective for treatment of the symptoms of
`
`Reference ID: 4025819
`
`12
`
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`

`Clinical Review
`Xu Wang, M.D., Ph.D.
`NDA 209-089/NDA 209-090 Rx to OTC switch
`Xyzal Allergy 24HR (levocetirizine dihydrochloride) tablets/solution
`
`SAR and PAR. Efficacy for pediatric patients under 6 years of age was extrapolated from the adult and
`adolescent data. This is acceptable as the indicated conditions (SAR, PAR, and CIU) share the same
`pathophysiology and behave similarly from a clinical perspective in both children and adults. In the
`pediatric program, the safety and clinical pharmacology of LCTZ in children <6 years of age were
`evaluated. 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..
`
`Efficacy – Onset of action, environmental exposure (EEU) studies
`
`Onset of action was evaluated in two environmental exposure unit (EEU) studies A379 and A412. Both
`studies were conducted in Kingston, Ontario Canada. Both were double-blind placebo and active-
`controlled studies in patients with SAR. Cetirizine 10 mg tablets were used in study A379 and cetirizine
`5mg (oral drops 10 mg/ml) and 10 mg tablets were used in A412 as active controls. Levocetirizine 5 mg
`was used in study A379 whereas LCTZ 2.5 (oral drops 5 mg/ml) and 5 mg (tablet) were used in study
`A412. Study A412 was conducted with the primary objective to serve as a PD link to LCTZ and
`cetirizine to provide data in support of the Applicant’s assertion that half the dose of LCTZ had
`equivalent efficacy to 2x the dose of cetirizine. The assertion is based on the acknowledgement that
`cetirizine is a racemic mixture of R and S enantiomers and that only the R enantiomer (LCTZ) is active
`therefore, the efficacious dose of LCTZ should be half that of cetirizine (CTZ).
`
`The primary objective of the study was therefore to compare the efficacy of LCTZ 2.5 mg, 5mg, and
`CTZ 5mg, 10 mg vs. placebo. The design of the study also allowed it to be used to support an onset an
`duration of action claim. Male and female patients age 16 years of age and older with a history of SAR,
`allergic to ragweed pollen confirmed by positive skin prick testing performed at screening or within 12
`months prior to screening, were enrolled in these 2 EEU studies. Symptoms were recorded every 30
`minutes during the 2 study periods. A complex of symptoms called the major symptom complex (MSC)
`was used as the primary efficacy variable. The MSC (Major symptom complex) consisted of 6
`individual symptoms – runny nose, itchy nose, sniffles, nose blows, sneezes, and watery eyes. Four
`additional symptoms (itchy eyes and ears, itchy throat, cough, and postnasal drip) were combined with
`the MSC to form the Total Symptom Complex (TSC). In terms of severity, the individual symptoms
`with the exception of nose blows and sneezes were scored on a scale of 0 – 5 (0 = none, 1 = a little, 2 =
`moderate, 3 = quite a bit, 4 – severe, 5 = very severe). Severity of nose blows and sneezes were scored 1
`-8 based on the number where 8 represents >15. The subjects also reported nasal congestion as a
`separate symptom using a separate severity score (0 -4).
`
`The individual time point analyses showing the onset and duration of action for study A379 was
`summarized in Table 6 below. Both LCTZ and CTZ doses were statistically superior to placebo in
`improving allergic rhinitis symptom scores and suggested that both drugs had an onset of action within
`one hours and duration of effect of at least 24 hours. For study A412, UCB did not provide specific time
`point comparisons between LCTZ and placebo. The approved Xyzal prescription labeling (section
`14.1) carries the sentence “Xyzal 5 mg was found to have an onset of action 1 hour after oral intake”.
`
`Reference ID: 4025819
`
`13
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`

`

`Clinical Review
`Xu Wang, M.D., Ph.D.
`NDA 209-089/NDA 209-090 Rx to OTC switch
`Xyzal Allergy 24HR (levocetirizine dihydrochloride) tablets/solution
`
`Table 6 MSC change in EEU study A379, Onset and duration of action
`
`Source: From 2.7.3 Clinical Summary of Efficacy (Allergic Rhinitis) and the Biostatistics Review of prescription drug Xyzal
`tablets.
`
`7 Review of Safety
`Safety Summary
`The safety of levocetirizine is supported by the clinical development prog