Application Type NDA Submission Number 22-157 Submission

CLINICAL REVIEW

Application Type NDA

Submission Number 22-157

Submission Code

Letter Date March 27, 2007

Stamp Date March 28, 2007

PDUFA Goal Date January 28, 2008

Reviewer Name Robert M. Boucher, MD, MPH

Review Completion Date October 4, 2007

Established Name Levocetirizine dihydrochloride

(Proposed) Trade Name Xyzal®

Therapeutic Class Antihistamine

Applicant UCB, Inc.

Priority Designation S

Formulation 0.5 mg/mL oral solution

Dosing Regimen 2.5 mg or 5 mg once daily

Indication SAR, PAR, CIU

Intended Population Six years and older

Clinical Review

Robert M. Boucher, MD, MPH

NDA 22-157

Xyzal oral solution (levocetirizine dihydrochloride)

TABLE OF CONTENTS1

.................................................................................EXECUTIVE SUMMARY

1.1 R

ECOMMENDATION ON REGULATORY ACTION ...........................................................................................4

1.2 R

ECOMMENDATION ON POSTMARKETING ACTIONS ....................................................................................4

1.2.1 Risk Management Activity ....................................................................................................................4

1.2.2 Required Phase 4 Commitments............................................................................................................4

1.3 S

UMMARY OF CLINICAL FINDINGS ..............................................................................................................5

1.3.1 Brief Overview of Clinical Program......................................................................................................5

1.3.2 Dosing Regimen and Administration.....................................................................................................5

1.3.3 Drug-Drug Interactions..........................................................................................................................5

1.3.4 Special Populations................................................................................................................................5

2 INTRODUCTION AND BACKGROUND......................................................................................................6

2.1 P

RODUCT INFORMATION .............................................................................................................................6

2.2 C

URRENTLY AVAILABLE TREATMENT FOR INDICATIONS............................................................................6

2.3 A

VAILABILITY OF PROPOSED ACTIVE INGREDIENT IN THE UNITED STATES ................................................6

2.4 I

MPORTANT ISSUES WITH PHARMACOLOGICALLY RELATED PRODUCTS.....................................................7

2.5 P

RESUBMISSION REGULATORY ACTIVITY ...................................................................................................7

2.6 O

THER RELEVANT BACKGROUND INFORMATION........................................................................................7

3 SIGNIFICANT FINDINGS FROM OTHER REVIEW DISCIPLINES ......................................................7

3.1 CMC (

AND PRODUCT MICROBIOLOGY, IF APPLICABLE) .............................................................................7

3.2 A

NIMAL PHARMACOLOGY/TOXICOLOGY ....................................................................................................8

4 DATA SOURCES, REVIEW STRATEGY, AND DATA INTEGRITY.......................................................8

4.1 S

OURCES OF CLINICAL DATA ......................................................................................................................8

4.2 T

ABLES OF CLINICAL STUDIES ....................................................................................................................8

4.3 R

EVIEW STRATEGY .....................................................................................................................................8

4.4 D

ATA QUALITY AND INTEGRITY .................................................................................................................8

4.5 C

OMPLIANCE WITH GOOD CLINICAL PRACTICES.........................................................................................9

4.6 F

INANCIAL DISCLOSURES............................................................................................................................9

5 CLINICAL PHARMACOLOGY .....................................................................................................................9

5.1 P

HARMACOKINETICS ...................................................................................................................................9

5.2 P

HARMACODYNAMICS...............................................................................................................................10

5.3 E

XPOSURE-RESPONSE RELATIONSHIPS .....................................................................................................11

6 INTEGRATED REVIEW OF EFFICACY ...................................................................................................11

6.1 I

NDICATION ...............................................................................................................................................11

7 INTEGRATED REVIEW OF SAFETY ........................................................................................................11

7.1 M

ETHODS AND FINDINGS ..........................................................................................................................11

8 ADDITIONAL CLINICAL ISSUES ..............................................................................................................12

8.1 D

OSING REGIMEN AND ADMINISTRATION .................................................................................................12

8.2 D

RUG-DRUG INTERACTIONS .....................................................................................................................12

8.3 S

PECIAL POPULATIONS..............................................................................................................................12

8.4 P

EDIATRICS ...............................................................................................................................................12

8.5 A

DVISORY COMMITTEE MEETING .............................................................................................................12

8.6 L

ITERATURE REVIEW ................................................................................................................................13

8.7 P

OSTMARKETING RISK MANAGEMENT PLAN ............................................................................................13

8.8 O

THER RELEVANT MATERIALS .................................................................................................................13

Clinical Review

Robert M. Boucher, MD, MPH

NDA 22-157

Xyzal oral solution (levocetirizine dihydrochloride)

9 OVERALL ASSESSMENT.............................................................................................................................13

9.1 C

ONCLUSIONS ...........................................................................................................................................13

9.2 R

ECOMMENDATION ON REGULATORY ACTION .........................................................................................13

9.3 R

ECOMMENDATION ON POSTMARKETING ACTIONS ..................................................................................14

9.3.1 Risk Management Activity ..................................................................................................................14

9.3.2 Required Phase 4 Commitments..........................................................................................................14

9.3.3 Other Phase 4 Requests........................................................................................................................14

9.4 L

ABELING REVIEW ....................................................................................................................................14

9.5 C

OMMENTS TO APPLICANT........................................................................................................................14

10.1 R

EVIEW OF INDIVIDUAL STUDY REPORTS .................................................................................................15

10.2 L

INE-BY-LINE LABELING REVIEW.............................................................................................................15

REFERENCES ..........................................................................................................................................................19

List of Abbreviations

BA bioavailability

BE bioequivalence

CIU chronic idiopathic urticaria

LCTZ levocetirizine dihydrochloride

PAR perennial allergic rhinitis

PK pharmacokinetics

SAR seasonal allergic rhinitis

Clinical Review

Robert M. Boucher, MD, MPH

NDA 22-157

Xyzal oral solution (levocetirizine dihydrochloride)

1 EXECUTIVE SUMMARY

1.1 Recommendation on Regulatory Action

The recommended regulatory action for levocetirizine 0.5 mg/mL oral solution is approval, from

a clinical standpoint, for the relief of symptoms associated with seasonal and perennial allergic

rhinitis, and for the treatment of the uncomplicated skin manifestations of chronic idiopathic

urticaria, in patients 6 years of age and older.

The primary basis for approval of NDA 22-157, in addition to reference made to the approved

NDA 22-064 (levocetirizine tablets, 5 mg), is a single bioequivalence study (A00318) that

satisfactorily demonstrates the BE of LCTZ 10 ml (0.5 mg/mL) oral solution with LCTZ 5 mg

oral tablet. Based on substantial evidence from replicate adequate and well-controlled clinical

studies with levocetirizine 5 mg oral tablet, a review of which formed the basis of approval for

NDA 22-064 for SAR, PAR, and CIU), levocetirizine is safe and effective for the label

indications at a dose of 2.5 mg to 5 mg taken orally, once daily in the evening. In placebo-

controlled studies of patients 6 years and older with seasonal and perennial allergic rhinitis,

levocetirizine is effective in improving the total symptom score comprised of sneezing,

rhinorrhea, nasal pruritus, and ocular pruritus. In placebo-controlled studies of patients 18 years

and older with chronic idiopathic urticaria, levocetirizine is effective in improving the severity of

pruritus, wheal number, and wheal size.

While placebo-controlled trials in the pediatric development program (ages 6 to 11 years) for

NDA 22-064 using a dose of 5 mg once daily demonstrated that levocetirizine is effective in this

age group, information on PK from literature cited in the application indicated that the systemic

exposure (AUC) of levocetirizine 5 mg in pediatric patients 6 to 11 years of age is approximately

twice that of adults, and supported LCTZ 2.5 mg as the appropriate dose for children 6 to 11

years of age.

1.2 Recommendation on Postmarketing Actions

1.2.1 Risk Management Activity

The clinical review does not reveal the need for any risk management activity.

1.2.2 Required Phase 4 Commitments

No Phase 4 commitments are sought for LCTZ oral solution.

Clinical Review

Robert M. Boucher, MD, MPH

NDA 22-157

Xyzal oral solution (levocetirizine dihydrochloride)

1.3 Summary of Clinical Findings

With the exception of BE study A00318 no additional clinical trials were conducted to support

NDA 22-157 and the applicant references the approved NDA 22-064 for pertinent clinical

findings. Refer to section 1.3 of the clinical review of NDA 22-064 (LCTZ 5 mg tablet) for a

summary of clinical findings.

1.3.1 Brief Overview of Clinical Program

The clinical program is comprised of one single-dose bioequivalence study in healthy volunteers

designed to compare the bioequivalence of levocetirizine solution to levocetirizine oral tablets.

Clinical efficacy and safety data for the proposed indications are referenced from NDA 22-064

(LCTZ 5 mg tablet).

1.3.2 Dosing Regimen and Administration

The recommended dose is 2.5 mg ( 5 mL) once daily in the evening in children 6 to 11 years of

age and 5 mg (10 mL) in adults and adolescents 12 years of age and older once daily in the

evening

1.3.3 Drug-Drug Interactions

No formal drug-drug interaction studies with levocetirizine have been conducted. References of

drug-drug interactions are to cetirizine the racemic mixture for which an interaction with

probenicid has been reported. Refer to section 1.3.5 of the clinical review of NDA 22-064

(LCTZ 5 mg tablet).

1.3.4 Special Populations

There are no safety or efficacy issues based on age, gender, or race with levocetirizine. Refer to

section 1.3.6 of the clinical review of NDA 22-064 (LCTZ 5 mg tablet) for more details.

Clinical Review

Robert M. Boucher, MD, MPH

NDA 22-157

Xyzal oral solution (levocetirizine dihydrochloride)

2 INTRODUCTION AND BACKGROUND

(USAN: levocetirizine dihydrochloride). Levocetirizine hydrochloride is the the R-enantiomer

of the racemate cetirizine, is an H

-receptor antagonist proposed for use in the symptomatic

treatment of seasonal allergic rhinitis (SAR), perennial allergic rhinitis (PAR), and chronic

idiopathic urticaria (CIU) in adults and children six years of age and older. The applicant has

developed an oral solution Xyzal® 0.5 mg/mL oral solution for the same indication. The

recommended dose is 2.5 mg (5 mL) in children 6 to 11 years of age and 5 mg (10 mL) once

daily in adults and adolescents 12 years of age and older. An oral tablet formulation of

levocetirizine dihydrochloride (Xyzal® tablets) was approved on May 25, 2007 (NDA 22-064).

UCB, Inc. submits NDA 22-157 for LCTZ 0.5 mg/mL oral solution under section 505(b)(2)

referencing NDA 22-064 (LCTZ 5 mg oral tablet) for drug substance, nonclinical,

biopharmaceutics and clinical data. The development program for levocetirinze solution is based

on demonstration of bioequivalence of the oral solution to the oral tablet. With the establishment

of bioequivalence, clinical efficacy and safety data are not required to support approval of the

oral solution.

The applicant’s rationale for developing LCTZ in an oral formulation is that liquid dosage forms

are well-suited for use by children, the elderly, and patients with dysphagia.

2.1 Product Information

The product is an oral solution containing 0.5 mg/mL formulated with glycerin and

maltitol (USP) sodium acetate, glacial acetic acid, and

sodium acetate trihydrate methylparaben and propylparaben

saccharin sodium Tutti frutti flavor 501103A7; and purified water

2.2 Currently Available Treatment for Indications

Several products of the antihistamine class are available for the proposed indications. Refer to

section 2.2 of the clinical review of NDA 22-064 (LCTZ 5 mg tablet) for a full list.

Currently marketed long-acting antihistamines available in liquid oral formulations include

cetirizine, loratadine, desloratadine, and fexofenadine.

2.3 Availability of Proposed Active Ingredient in the United States

Levocetirizine dihydrochloride was approved for marketing in the on May 25, 2007. The product

has not yet been launched.

157

L.-

. .

;::s

. I

Clinical Review

Robert

Boucher, MD,

MPH

Xyzal oral solution (levocetirizine dihydrochloride)

2.4

Important

Issues With Pharmacologically Related Products

Refer to section 2.4

the clinical review

ofNDA

22-064 (LCTZ 5 mg tablet).

2.5 Presubmission Regulatory Activity

the applicant submits NDA

22-157 for a single oral liquid formulation, seeking the same age range and indications as the

approved LCTZ 5 mg tablet, and references NDA 22-064 for clinical efficacy and safety data to

support the current NDA.

2.6

Other

Relevant Background Information

The applicant's LCTZ pe.diatric development although

its current safety database for the pediatric age group less than 6 years

age does not support

use in children less than 6 years old,

J includes a request for deferral

data submission . - in

NDA

22-157.

For additional relevant background information refer to section 2.6

the clinical review

NDA 22-064 (LCTZ 5

tablet).

3 SIGNIFICANT FINDINGS FROM OTHER REVIEW DISCIPLINES

3.1

CMC (and

Product

Microbiology,

Applicable)

The CMC review

forthis

NDA is by Dr. Craig Bertha who notes that the applicant references

NDA 22-064 for all drug substance information and data.

From a CMC standpoint, the application

recommended for approval.

Levocetirizine oral solution is an aqueous-based product containing 0.5 mg LCTZ/mL

formulated

a target pH

5.0. The drug product

I Isodium acetate/acetic acid and

includes maltilol solution, glycerin, saccharin sodium, tutti frutti flavoring, and

I I

methyl- and propylparaben. The solution is packaged in 5 ounce l I

glass!

I Ibottles and

demonstrated to have adequate stability to support a 24 month shelf

life.

Clinical Review

Robert M. Boucher, MD, MPH

NDA 22-157

Xyzal oral solution (levocetirizine dihydrochloride)

and 2) microbiology

consultation reviewing microbial testing and preservative effectiveness studies).

3.2 Animal Pharmacology/Toxicology

Pharmacology/toxicology data for levocetirizine is referenced for the most part for cetirizine the

racemic mixture. Refer to section 3.2 of the clinical review of NDA 22-064 (LCTZ 5 mg tablet)

for further details.

4 DATA SOURCES, REVIEW STRATEGY, AND DATA INTEGRITY

4.1 Sources of Clinical Data

The primary basis for approval of NDA 22-157 and the source of clinical data for this review is

the clinical pharmacology BE study A00318, conducted by the applicant. This is a Phase 1

randomized, open-label, crossover, single-dose BE study of LCTZ 5 mg oral tablet and LCTZ 10

mL oral solution (0.5 mg/mL) in 24 healthy, fasting, male and female adults.

4.2 Tables of Clinical Studies

Refer to section 4.2 of the clinical review of NDA 22-064 for the table of clinical studies

supporting the efficacy and safety of LCTZ 5 mg tablets that formed most of the basis for

approval, from a clinical standpoint, of LCTZ for SAR, PAR, and CIU.

4.3 Review Strategy

Notwithstanding referencing the approved NDA 22-064 for clinical findings of safety and

efficacy supporting LCTZ use in SAR, PAR, and CIU, the review strategy for this NDA is

weighted towards the CMC and Clinical Pharmacology review disciplines given that the the

development program is based on a single BE study and the applicant is not seeking a new

indication or age group.

4.4 Data Quality and Integrity

The review does not find any significant data quality or integrity issues; no DSI audit is

requested.

Clinical Review

Robert M. Boucher, MD, MPH

NDA 22-157

Xyzal oral solution (levocetirizine dihydrochloride)

4.5 Compliance with Good Clinical Practices

The title page of study A00318 states that the trial was conducted in accordance with the ICH E6

Note for Guidance on Good Clinical Practice.

4.6 Financial Disclosures

UCB certifies on FDA Form 3454 that it does not enter into any financial arrangement with the

clinical investigators that could affect study outcome as defined in 21 CFR 54.2(a), that clinical

investigators required to disclose a proprietary interest in the product deny such interests, and

that no investigator is the recipient of significant payment of other sorts.

5 CLINICAL PHARMACOLOGY

Dr. Partha Roy conducted the clinical pharmacology review of NDA 22-157 (and NDA 22-064)

and, from a clinical pharmacology standpoint, recommends approval for the application.

5.1 Pharmacokinetics

The pharmacokinetic data most pertinent for this NDA submission are from the applicant’s BE

study A00318, a comparison of the PK profiles of LCTZ 0.5 mg/mL oral solution and LCTZ 5

mg oral tablet. The results of that clinical pharmacology study form the primary clinical basis for

approval of NDA 22-157.

Study A00318 is a randomized, open-label, 2-way crossover, single dose BE study of LCTZ oral

solution and tablet in 24 healthy subjects which satisfactorily demonstrates the PK comparability

of the two formulations. Two groups of 12 healthy adult male and female subjects received a

single dose of either 10 mL of LCTZ 0.5 mg/mL oral solution or 5 mg LCTZ oral tablet under

fasting conditions. A minimum 7-day washout period occurred prior to crossover. The 90%

confidence intervals for the test to reference ratio calculated for the primary PK parameters

(AUC [0-t], AUC, and C

max

) are fully included within the 80% to 125% bioequivalence limits,

thereby demonstrating bioequivalence of the oral solution to the oral tablet. The time to C

max

was

reached more rapidly after administration of the oral solution than the tablet (0.50h and 0.67h,

respectively). Other PK parameters were consistently comparable between the two formulations.

Figure 1 compares mean plasma concentration-time profiles of the 2 formulations and Table 1

summarizes key findings from the study.

Figure 1. Mean plasma concentration-time profiles of LCTZ formulations

Clinical Review

Robert M. Boucher, MD, MPH

NDA 22-157

Xyzal oral solution (levocetirizine dihydrochloride)

Table 1. Summary of LCTZ oral tablet and oral solution PK comparisons

(Study A00318)

Parameter Reference:

LCTZ oral

tablet

(a)

Test:

LCTZ oral

solution

(a)

(b)

(%)

Test/Reference ratio

Point estimate 90% CI

AUC (0-t)

(ng.h/mL)

1944 ± 484

1887 (1723-2066)

1954 ± 556

1884 (1721-2063) 7.7 99.9 96 – 104

AUC (ng.h/mL)

2044 ± 513

1943 (1771-2131)

2020 ± 593

1944 (1771-2132) 7.3 100.0 96 – 104

max

(ng/mL)

208 ± 40

204 (190-219)

227 ± 49

223 (207-239) 13.4 109.1 102 – 117

max

(h)

0.67 (0.50-4.00) 0.50 (0.33-2.00) -0.30 -0.42 - -0.17

(a): Values are arithmetic means ± standard deviation (SD) on first line, geometric mean (Exp(mean ± SD, ln data)) on second

line. t

max

values are median (range).

(b): Intra-individual coefficient of variation (CV) (%).

Refer to section 5.1 of the clinical review of NDA 22-064 (LCTZ 5 mg tablet) as well as Dr.

Partha Roy’s Clinical Pharmacology review of NDA 22-064 for additional relevant PK

information.

5.2 Pharmacodynamics

Refer to section 5.2 of the clinical review of NDA 22-064 (LCTZ 5 mg tablet) as well as Dr.

Partha Roy’s Clinical Pharmacology review of NDA 22-064.

Clinical Review

Robert M. Boucher, MD, MPH

NDA 22-157

Xyzal oral solution (levocetirizine dihydrochloride)

5.3 Exposure-Response Relationships

There is no linear PK/PD relationship for levocetirizine. Refer to section 5.3 of the clinical

review of NDA 22-064 (LCTZ 5 mg tablet) as well as Dr. Partha Roy’s Clinical Pharmacology

review of NDA 22-064.

6 INTEGRATED REVIEW OF EFFICACY

Efficacy studies were not required and were not conducted in this development program.

Efficacy is supported based on establishment of bioequivalence and reference to efficacy studies

conducted with the oral tablet submitted in NDA 22-064. Efficacy studies conducted in adults

and adolescents 12 years of age and older confirm that levocetirizine 5 mg tablet is effective for

the symptoms of SAR, PAR, and CIU. Efficacy for pediatric patients under 12 years of age is

extrapolated from the adult and adolescent data for SAR and PAR, and from the adult data

(patients 18 years of age and older) for CIU. Refer to section 6 of the clinical review of NDA

22-064 (LCTZ 5 mg tablet) for further details.

6.1 Indication

The relief of symptoms associated with seasonal and perennial allergic rhinitis and the treatment

of the uncomplicated skin manifestations of chronic idiopathic urticaria.

7 INTEGRATED REVIEW OF SAFETY

7.1 Methods and Findings

The safety data in the bioequivalence study comes for 24 subjects who each received a total of 2

doses of 5 mg levocetirizine dihydrochloride. There were not serious adverse events reported.

A total of 51 adverse events were reported in the study. None of these were considered severe.

The most frequent adverse events reported were somnolence (n = 8 [33.3%]), and (7[29.2%])

following administration of the oral tablet and the oral solution respectively, and headache

reported by 6 (25%) of subjects after both the oral tablet and the oral solution. Somnolence and

headache are two of the most frequently reported adverse events reported in the clinical

development program for levocetirizine dihydrochloride tablets and are described in the label.

There was one report each of dry mouth, nasopharyngitis, diarrhea NOS, and syncope following

administration of the oral tablet. With the exception of diarrhea, these adverse events are

described in the label for levocetirizine oral tablets. There was one report of pharyngitis

following administration of the oral solution. One patient (49 year old male athlete) experience

elevated CK (up to 23,650 U/L), and elevated liver enzymes following strenuous physical

activity (weight lifting). The enzymes were normal with repeat testing and rechallenge with

lecovetirizine 5 mg following a 2-week period of avoidance of strenuous physical activity.

Clinical Review

Robert M. Boucher, MD, MPH

NDA 22-157

Xyzal oral solution (levocetirizine dihydrochloride)

These enzyme abnormalites are not likely related to the study medication. There were no deaths

or serious adverse events reported in the single dose BE study. For additional safety information

on levocetirizine dihydrochloride refer to NDA 22-064.

8 ADDITIONAL CLINICAL ISSUES

As the reason for this NDA submission for LCTZ is a new formulation (oral solution) of an

approved product (the oral tablet) proposed for use in the same population and for the same

indications as the LCTZ tablet, there are no new or additional clinical issues addressed in this

review with the exception of the clinical pharmacology BE study of the 2 product formulations

that forms the basis of approval of NDA 22-157.

8.1 Dosing Regimen and Administration

The dosing of levocetirizine dihydrochloride oral solution is 2.5 mg (5 mL) once daily in the

evening for children 6 to 11 years of age and 5 mg (10 mL) once daily in the evening for adults

and adolescents 12 years of age and older. Some adult and adolescent patients may be

adequately controlled with 2.5 mg (5 mL)

8.2 Drug-Drug Interactions

Refer to section 8.2 of the clinical review of NDA 22-064 (LCTZ 5 mg tablet).

8.3 Special Populations

Refer to section 8.3 of the clinical review of NDA 22-064 (LCTZ 5 mg tablet).

8.4 Pediatrics

8.5 Advisory Committee Meeting

The clinical review does not identify issues that warrant advisory committee action.

Clinical Review

Robert M. Boucher, MD, MPH

NDA 22-157

Xyzal oral solution (levocetirizine dihydrochloride)

8.6 Literature Review

A literature review was not conducted for this NDA. Refer to list of references following section

10 in the clinical review of NDA 22-064 (LCTZ 5 mg tablet)

8.7 Postmarketing Risk Management Plan

The clinical review does not identify concerns that warrant a postmarketing risk management

plan.

8.8 Other Relevant Materials

None

9 OVERALL ASSESSMENT

9.1 Conclusions

Levocetirizine 0.5 mg/mL oral solution taken as a 2.5 mg or 5 mg dose once daily in the evening

is safe and effective for the treatment of symptoms of seasonal, perennial allergic rhinitis, and

chronic idiopathic urticaria in patients 6 years of age and older. The bases for this conclusion are

the findings of safety and efficacy for the same indications and patient populations of the

approved LCTZ 5 mg oral tablet contained in NDA 22-064 and the finding of bioequivalence

between the oral solution and oral tablet LCTZ formulations.

Refer to section 9.1 of the clinical review of NDA 22-064 (LCTZ 5 mg tablet) for additional

discussion of specific efficacy and safety findings demonstrated in the LCTZ oral tablet clinical

development program.

The primary basis for approval of the LCTZ oral solution formulation is the applicant’s BE study

A00318 which satisfactorily demonstrates comparable BE between the oral solution and oral

tablet formulations of LCTZ in 24 healthy male and female adults. The study results show that

10 mL of the LCTZ 0.5 mg/mL solution has a PK profile similar to that of the LCTZ 5 mg tablet

based on the extent and rate of absorption assessed by the primary parameters AUC

(0-t)

, AUC,

and C

max

9.2 Recommendation on Regulatory Action

The recommended regulatory action from a clinical standpoint for Levocetirizine 0.5 mg/mL oral

solution is for approval at a dose of 2.5 mg or 5 mg once daily in the evening for the relief of

symptoms of SAR, PAR, and the treatment of the uncomplicated skin manifestations of CIU in

patients 6 years and older.

Clinical Review

Robert M. Boucher, MD, MPH

NDA 22-157

Xyzal oral solution (levocetirizine dihydrochloride)

9.3 Recommendation on Postmarketing Actions

The clinical review does not identify a need for specific risk management activities or Phase 4

studies.

9.3.1 Risk Management Activity

Refer to section 9.3.

9.3.2 Required Phase 4 Commitments

Refer to section 9.3.

9.3.3 Other Phase 4 Requests

Refer to section 9.3.

9.4 Labeling Review

Refer to section 10.2 for specific details of the preliminary labeling review.

9.5 Comments to Applicant

There are no comments based on the clinical review to be conveyed to the applicant.

Clinical Review

Robert M. Boucher, MD, MPH

NDA 22-157

Xyzal oral solution (levocetirizine dihydrochloride)

10 Appendices

10.1 Review of Individual Study Reports

Refer to section 10.1 of the clinical review of NDA 22-064 (LCTZ 5 mg oral tablet).

10.2 Line-by-Line Labeling Review

Clinical Review

Robert M. Boucher, MD, MPH

NDA 22-157

Xyzal oral solution (levocetirizine dihydrochloride)

Clinical Review

Robert M. Boucher, MD, MPH

NDA 22-157

Xyzal oral solution (levocetirizine dihydrochloride)

Clinical Review

Robert M. Boucher, MD, MPH

NDA 22-157

Xyzal oral solution (levocetirizine dihydrochloride)

Clinical Review

Robert M. Boucher, MD, MPH

NDA 22-157

Xyzal oral solution (levocetirizine dihydrochloride)

REFERENCES

Refer to the References section of the clinical review of NDA 22-064 (LCTZ 5 mg oral tablet).

---------------------------------------------------------------------------------------------------------------------

---------------------

This is a representation of an electronic record that was signed electronically and

this page is the manifestation of the electronic signature.

/s/

Robert M Boucher

10/4/2007 10:13:07 AM

MEDICAL OFFICER

Lydia McClain

10/4/2007 11:42:45 AM

MEDICAL OFFICER

I concur