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

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`Application number:
`Supporting document/s:
`Applicant’s letter date:
`CDER stamp date:
`Product:
`
`Indication:
`Applicant:
`
`Review Division:
`Reviewer:
`Team Leader:
`Division Director:
`Project Manager:
`
`209089 and 209090
`2 and 2
`31 March 2016
`31 March 2016
`Xyzal Allergy 24HR Tablets, 5 mg (209089) and
`Children’s Xyzal Allergy 24HR Oral Solution, 2.5
`mg/5 mL (209090) (levocetirizine
`dihydrochloride)
`Allergic rhinitis
`UCB, Inc.
`1950 Lake Park Drive
`Smyrna, GA 30080
`Sanofi US Services, Inc., Agent
`Nonprescription Drug Products
`D. Charles Thompson, RPh, PhD, DABT
`Jane J. Sohn, PhD
`Theresa Michele, MD
`Sherry A. Stewart, PharmD
`
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDAs 209089/209090 are owned by UCB, Inc. or are data for
`which UCB, Inc. has obtained a written right of reference. Any information or data
`necessary for approval of NDAs 209089/209090 that UCB, Inc. does not own or have a
`written right to reference constitutes one of the following: (1) published literature, or (2)
`a prior FDA finding of safety or effectiveness for a listed drug, as reflected in the drug’s
`approved labeling. Any data or information described or referenced below from reviews
`or publicly available summaries of a previously approved application is for descriptive
`purposes only and is not relied upon for approval of NDAs 209089/209090.
`
`Reference ID: 4021960
`
`1
`
`

`

`NDAs 209089/209090
`
`
`
`Reviewer: D. Charles Thompson
`
`TABLE OF CONTENTS
`
`1
`
`EXECUTIVE SUMMARY ......................................................................................... 3
`1.1
`INTRODUCTION .................................................................................................... 3
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 3
`1.3
`RECOMMENDATIONS ............................................................................................ 3
`2 DRUG INFORMATION ............................................................................................ 3
`2.1
`DRUG ................................................................................................................. 3
`2.2
`RELEVANT INDS, NDAS, BLAS AND DMFS ........................................................... 4
`2.3
`DRUG FORMULATION ........................................................................................... 4
`2.4
`COMMENTS ON NOVEL EXCIPIENTS ....................................................................... 6
`2.5
`COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ......................................... 6
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN ...................................... 6
`2.7
`REGULATORY BACKGROUND ................................................................................ 6
`STUDIES SUBMITTED ............................................................................................ 7
`3.3
`PREVIOUS REVIEWS REFERENCED........................................................................ 7
`INTEGRATED SUMMARY AND SAFETY EVALUATION ................................... 8
`11
`12
`APPENDIX/ATTACHMENTS ............................................................................. 10
`
`3
`
`Reference ID: 4021960
`
`2
`
`

`

`NDAs 209089/209090
`
`
`
`Reviewer: D. Charles Thompson
`
`Executive Summary
`1
`Introduction
`1.1
`The 505(b)(2) NDAs 209089 and 209090 propose partial Rx-to-OTC switches for,
`respectively, XYZAL 5 mg tablets (levocetirizine dihydrochloride) approved under NDA
`022064 (25 May 2007) and XYZAL 2.5 mg/5 mL oral solution approved under NDA
`022157 (28 January 2008). The Sponsor proposes
` in the
`nonprescription treatment of the symptoms of hay fever or other upper respiratory
`allergies in adults and children 2 years of age and older. The chronic idiopathic urticaria
`indication will remain prescription only.
`1.2 Brief Discussion of Nonclinical Findings
`No original data were included in the submission. All nonclinical pharmacology and
`toxicology data support for the applications is provided by way of cross reference to the
`Sponsor’s original applications for the corresponding, identical prescription drug
`products and to the Agency’s previous determinations of safety and efficacy for the
`related drug product, cetirizine HCl (NDA 019835). From a nonclinical perspective,
`these data are both sufficient and adequate to support the proposed Rx-to-OTC switch
`applications as approvable.
`1.3 Recommendations
`1.3.1 Approvability: Approvable
`
`1.3.2 Additional Non Clinical Recommendations: None
`
`2 Drug Information
`2.1 Drug
`CAS Registry Number: 130018-87-0
`
`Generic Name: Levocetirizine dihydrochloride
`
`Code Name: UCB 28556
`
`Chemical Name: (2-(4-((R)-(4-Chlorophenyl)phenylmethyl)piperazin-1-yl)ethoxy)acetic
`acid dihydrochloride
`
`Molecular Formula/Molecular Weight: C21H25ClN2O3•2ClH/461.8
`
`Reference ID: 4021960
`
`3
`
`(b) (4)
`
`

`

`NDAs 209089/209090
`
`Reviewer: D. Charles Thompson
`
`Structure:
`
`HCI
`
`Pharmacologic Class: histamine-1 (H1) receptor antagonist
`
`2.2 Relevant INDs, NDAs, BLAs and DMFs
`
`NDA 022064; NDA 022157; NDA 019835; IND 72,233; DMF
`DMF
`03)“); DMF
`(5N4); DMF
`0M4); DMF
`tn“); DMF
`
`W”; DMF
`(5)“)
`
`“m;
`
`2.3 Drug Formulation
`
`NDA 209089: Xyzal Allergy 24HR Tablets, 5 mg
`
`The Sponsor provides drug product description and composition information for this
`product by way of cross reference to NDA 022064 for Xyzal® Tablets, 5 mg (approved
`25 May 2007). The levocetirizine dihydrochloride drug product will be supplied as an
`immediate release, white to off-white, film-coated, oval-shaped scored tablets for oral
`administration with each tablet containing 5 mg of levocetirizine dihydrochloride (see
`Sponsor’s Table 1 and figure below). The Sponsor states the following with respect to
`the proposed new OTC drug product:
`
`“There are 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 prescription-to-
`nonprescription switch. The proposed NDA does include the following
`changes:
`
`0
`
`0
`
`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
`and addition of new packaging sites."
`
`(ll) (4)
`
`Reference ID: 4021 960
`
`

`

`NDAs 209089/209090
`
`Reviewer: D. Charles Thompson
`
`Table 1 - Quantitative Composition of Levocetlrlzlne dihydrochloride Tablets. 5 mg
`
`
`Component
`Amount per tablet
`Function
`Reference to
`
`(mg)
`Standards
`
`Levocetinzne dihydrochloride
`
`500
`
`Active ingredient
`
`Microcrystalline cellulose
`
`Collordal anhydrous Silica
`
`Lactose monohydrate
`
`Magnesium stearate
`0!) (4)
`
`0)“)
`
`In “W”
`specification
`NF
`
`0)“)
`
`NF
`
`NF
`
`NF
`
`in house specification
`
`USP
`
`Proposed Tablet (debossed logo)
`
`00
`
`NBA 209090: Children’s Xyzal Allergy 24HR Oral Solution, 2.5 mgl5 mL
`
`The Sponsor provides drug product description and composition information for this
`product by way of cross reference to NBA 022157 for Xyzal® Oral Solution, 0.5 mglmL
`(approved 28 January 2008). The levocetirizine dihydrochloride drug product will be
`supplied as an immediate release, oral solution containing 0.5 mg of levocetirizine
`dihydrochloride per mL of product (see Sponsor’s Table 2.1 below). The Sponsor states
`the following with respect to the proposed new OTC drug product:
`
`"There are no changes to previously approved Chemistry, Manufacturing,
`and Controls (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 prescription-to-nonprescription switch.
`However, the proposed NDA includes an administration device (dosing
`cup)”
`
`Reference ID: 4021 960
`
`

`

`NDAs 209089/209090
`
`Reviewer: D. Charles Thompson
`
`Table 2:]
`
`Proposed Commercial Formulation for Levocetirizine Dihydrochloride 0.5
`mg/mL Oral Solution
`
`.
`Amount per
`
`Ingredient
`InL (mg)
`Functlon
`Levocetirizine dlh drochlonde
`0.50
`Active in edicnt
`
`Sodium acetate trihydrate,
`USP
`
`Glacial acetic acid. USP
`
`Maltitol Solution, NF
`61 win
`
`Purified water. USP
`
`I
`
`2.4 Comments on Novel Excipients
`
`Neither proposed drug product contains novel excipients.
`
`2.5 Comments on lmpuritieleegradants of Concern
`
`No changes are proposed from impurity and/or degradant specifications originally
`approved for the corresponding prescription drug products.
`
`2.6
`
`Proposed Clinical Population and Dosing Regimen
`
`The Sponsor proposes— dose in too
`nonprescription treatment of the symptoms of hay fever or omer upper respiratory
`allergies in adults and children 2 years of age and older. The recommended
`nonprescription dosing regimen is as follows:
`
`
`
`This dosing regimen and targeted patient population is consistent with that of the
`corresponding prescription drug products, except mat children <2 years of age and the
`chronic idiopathic urticaria (CIU) indication are excluded from the proposed
`nonprescription conditions and dosing is no longer recommended to be confined to the
`evening.
`
`2.7 Regulatory Background
`
`The 505(b)(2) NDAs 209089 and 209090 propose partial Rx-to-OTC switches for,
`respectively, XYZAL 5 mg tablets (Ievocetirizine dihydrochloride) approved under NDA
`022064 (25 May 2007) and XYZAL 2.5 mg/5 mL oral solution approved under NDA
`022157 (28 January 2008). A Type B Pre-IND meeting (PIND 126506 and 126507) was
`
`Reference ID: 4021960
`
`

`

`NDAs 209089/209090
`
`
`
`Reviewer: D. Charles Thompson
`
`held on 1 October 2015, during which the Sponsor was informed that, “In general, it is
`acceptable to cross-reference to previously submitted information” in providing support
`for the nonclinical safety of the proposed products (Meeting Minutes, 9 November
`2015). A second teleconference was held with the Sponsor on 22 December 2015 to
`discuss possible scenarios for inclusion or not of the CIU, or hives, indication for the
`proposed OTC products (Internal Meeting Minutes, 13 January 2016). The Sponsor
`elected not to include the CIU indication in either of the current Rx-to-OTC switch
`applications.
`
`In addition to the levocetirizine dihydrochloride studies sponsored and conducted by the
`Sponsor in support of the prescription NDAs, the Sponsor also references the Agency’s
`prior determinations of the safety and clinical efficacy of ZYRTEC® (cetirizine
`dihydrochloride) [5 mg and 10 mg tablets in NDA 019835, oral syrup (5 mg/mL) in NDA
`020346, and chewable tablets (5 mg and 10 mg) in NDA 021621] (see Section 3 below).
`
`Studies Submitted
`3
`No nonclinical studies were included in the current submissions for NDA 209089 or
`NDA 209090. Rather, the Sponsor cross referenced nonclinical data submitted under its
`own NDA 022064 for the prescription oral tablet levocetirizine dihydrochloride drug
`product. These same data had previously been referenced by the Sponsor in support of
`NDA 022157. Pivotal nonclinical data submitted under NDA 022064 have been
`reviewed previously (see Section 3.3 below) and are only discussed in summary herein.
`A tabular listing of all nonclinical safety data referenced by the Sponsor is provided in
`the Sponsor’s Table 1 reproduced in Appendix 1.
`
`As noted above, the Sponsor references prior Agency determinations of nonclinical
`safety under the cetirizine dihydrochloride NDA 019835 as the source for some pivotal
`nonclinical data, including chronic toxicity studies in rats and dogs, 2-year dietary
`carcinogenicity studies in rats and mice, and some developmental and reproductive
`toxicity study data. A specific letter of authorization (LoA) granting the Sponsor rights to
`reference data contained in NDA 019835 was not included in the current submission.
`Relevant nonclinical portions of previously approved Zyrtec prescription drug product
`labeling under NDA 019835 and also for the current prescription Xyzal prescription drug
`product under NDA 022064 are appended for reference (see Appendix 2).
`
`3.3 Previous Reviews Referenced
`(cid:120) NDA 22-064: Pharmacology/Toxicology Review and Evaluation, L.F. Sancilio,
`PhD, 8 May 2007.
`(cid:120) NDA 22-157: Pharmacology/Toxicology Review and Evaluation, L.F. Sancilio,
`PhD, 21 August 2007.
`(cid:120) NDA 22-064/S-017 and NDA 22-157/S003: Pharmacology/Toxicology Review
`and Evaluation, L.F. Sancilio, PhD, 23 July 2009.
`
`Reference ID: 4021960
`
`7
`
`

`

`NDAs 209089/209090
`
`
`
`Reviewer: D. Charles Thompson
`
`Integrated Summary and Safety Evaluation
`11
`With NDAs 209089 and 209090, the Sponsor proposes partial Rx-to-OTC switches for,
`respectively, XYZAL 5 mg tablets (levocetirizine dihydrochloride) and XYZAL 2.5 mg/5
`mL oral solution. The Sponsor proposes
` the nonprescription
`treatment of the symptoms of hay fever or other upper respiratory allergies in adults and
`children 2 years of age and older. The CIU indication of the prescription products will be
`excluded from nonprescription use for the time being as will dosing in patients less than
`two years of age.
`
`Importantly, for both the proposed nonprescription drug products, there are no CMC-
`related changes from the corresponding prescription drug products, including tablet size
`and shape, drug substance and drug product specifications, drug substance and drug
`product manufacturers, and container closure systems.
`
`The proposed dosing regimen for the nonprescription drug products remains identical to
`that of the corresponding prescription drug products, with the exception that children
`less than two years of age are excluded from the nonprescription target population and
`dosing is
` to be confined to the evening.
`
`In support of the proposed applications, nonclinical data have been provided by way of
`cross reference to data submitted under the Sponsor’s own corresponding prescription
`NDA 022064 for the oral tablet levocetirizine dihydrochloride drug product, data which
`were previously referenced in support of NDA 022157 (oral solution). The Sponsor has
`also referenced the Agency’s prior determination of safety of ZYRTEC® (cetirizine
`dihydrochloride) under NDA 019835 for some pivotal nonclinical safety data. All of these
`nonclinical data have been reviewed internally by Dr. Lawrence Sancilio, DPARP, and
`his executive summary is reproduced below.
`
`“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, 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 mice, cetirizine did not affect fertility
`and early development and embryofetal development; in the prenatal and
`postnatal developmental study, there was lower pup weight. In
`embryofetal development studies in rats and rabbits, cetirizine was not
`teratogenic although increased skeletal anomalies/variants were observed
`
`Reference ID: 4021960
`
`8
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDAs 209089/209090
`
`
`
`Reviewer: D. Charles Thompson
`
`in rabbits. In a 4-week oral toxicity study in rats with levocetirizine, the
`target organ was the liver. There were hepatic hypertrophy and
`vacuolation, increased liver weight, induced liver enzymes and fat
`deposition. Enzyme induction in the rat is not toxicologically relevant. In a
`13-week oral toxicity study in rats with levocetirizine alone, the target
`organ again was the liver. There were hypertrophy and vacuolation,
`induced liver enzymes and fat deposition. A second 13-week oral toxicity
`study in rats was a bridging study with levocetirizine and cetirizine. Both
`compounds at comparable doses produced similar liver effects, increased
`enzymes, hypertrophy and central fat deposition.
`
`In a 4-week oral toxicity study in dogs, a bridging study was made with
`cetirizine. At the HD dose, both levocetirizine and cetirizine were toxic
`putting the animals in a moribund condition which required a reduction in
`dose. Both compounds induced emesis and produced fecal impaction.
`The target organ was the gastrointestinal tract.
`
`In a 13-week oral toxicity study in dogs, a bridging study was conducted
`with cetirizine. Both compounds produced emesis at comparable doses.
`Based on the toxicity studies in rats and dogs, there was no difference in
`the toxicity profile of levocetirizine and cetirizine.
`
`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....
`
`Levocetirizine, the R-enantiomer of cetirizine is a potent and competitive
`H1 receptor antagonist. In vitro H1 receptor binding studies using different
`tissues [sic], levocetirizine was 2-3 times more potent than cetirizine; in
`blocking the isolated guinea pig ileum and tracheal response to histamine,
`levocetirizine was 1-3 times more potent than cetirizine. In the in vivo
`histamine induced skin wheal assay in mice and rats, orally levocetirizine
`was 2-4 times more potent than cetirizine.”
`
`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.
`
`Reference ID: 4021960
`
`9
`
`

`

`NDAs 209089/209090
`
`
`
`Reviewer: D. Charles Thompson
`
`12 Appendix/Attachments
`Appendix 1
`Table 1 - Cross Reference Table of Nonclinical Study Reports from Xyzal®
`(levocetirizine dihydrochloride) Tablets NDA 22-064 [excerpted from Sponsor]
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4021960
`
`10
`
`

`

`NDAs 209089/209090
`
`
`
`Reviewer: D. Charles Thompson
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4021960
`
`11
`
`

`

`NDAs 209089/209090
`
`
`
`Reviewer: D. Charles Thompson
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4021960
`
`12
`
`

`

`NDAs 209089/209090
`
`
`
`Reviewer: D. Charles Thompson
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4021960
`
`13
`
`

`

`NDAs 209089/209090
`
`
`
`Reviewer: D. Charles Thompson
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4021960
`
`14
`
`

`

`NDAs 209089/209090
`
`
`
`Reviewer: D. Charles Thompson
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4021960
`
`15
`
`

`

`NDAs 209089/209090
`
`
`
`Reviewer: D. Charles Thompson
`
`Appendix 2
`Relevant excerpts from approved prescription labeling for ZYRTEC (cetirizine
`hydrochloride) (NDA 019835/S-020, approved 4 April 2006) are reproduced below:
`
`ZYRTEC® (cetirizine hydrochloride)
`Tablets, Chewable Tablets and Syrup for Oral Use
`
`CLINICAL PHARMACOLOGY
`Mechanism of Action: Cetirizine, a human metabolite of hydroxyzine, is an
`antihistamine; its principal effects are mediated via selective inhibition of peripheral H1
`receptors. The antihistaminic activity of cetirizine has been clearly documented in a
`variety of animal and human models. In vivo and ex vivo animal models have shown
`negligible anticholinergic and antiserotonergic activity. In clinical studies, however, dry
`mouth was more common with cetirizine than with placebo. In vitro receptor binding
`studies have shown no measurable affinity for other than H1 receptors.
`Autoradiographic studies with radiolabeled cetirizine in the rat have shown negligible
`penetration into the brain. Ex vivo experiments in the mouse have shown that
`systemically administered cetirizine does not significantly occupy cerebral H1 receptors.
`
`Carcinogenesis, Mutagenesis and Impairment of Fertility: In a 2-year
`carcinogenicity study in rats, cetirizine was not carcinogenic at dietary doses up to 20
`mg/kg (approximately 15 times the maximum recommended daily oral dose in adults on
`a mg/m2 basis, or approximately 7 times the maximum recommended daily oral dose in
`infants on a mg/m2 basis). In a 2-year carcinogenicity study in mice, cetirizine caused
`an increased incidence of benign liver tumors in males at a dietary dose of 16 mg/kg
`(approximately 6 times the maximum recommended daily oral dose in adults on a
`mg/m2 basis, or approximately 3 times the maximum recommended daily oral dose in
`infants on a mg/m2 basis). No increase in the incidence of liver tumors was observed in
`mice at a dietary dose of 4 mg/kg (approximately 2 times the maximum recommended
`daily oral dose in adults on a mg/m2 basis, or approximately equivalent to the maximum
`recommended daily oral dose in infants on a mg/m2 basis). The clinical significance of
`these findings during long-term use of ZYRTEC is not known.
`
`Cetirizine was not mutagenic in the Ames test, and not clastogenic in the human
`lymphocyte assay, the mouse lymphoma assay, and in vivo micronucleus test in rats.
`
`In a fertility and general reproductive performance study in mice, cetirizine did not impair
`fertility at an oral dose of 64 mg/kg (approximately 25 times the maximum
`recommended daily oral dose in adults on a mg/m2 basis).
`
`Pregnancy Category B: In mice, rats, and rabbits, cetirizine was not teratogenic at oral
`doses up to 96, 225, and 135 mg/kg, respectively (approximately 40, 180 and 220 times
`the maximum recommended daily oral dose in adults on a mg/m2 basis). There are,
`however, no adequate and well-controlled studies in pregnant women. Because animal
`reproduction studies are not always predictive of human response, ZYRTEC should be
`used during pregnancy only if clearly needed.
`
`Reference ID: 4021960
`
`16
`
`

`

`NDAs 209089/209090
`
`
`
`Reviewer: D. Charles Thompson
`
`Nursing Mothers: In mice, cetirizine caused retarded pup weight gain during lactation
`at an oral dose in dams of 96 mg/kg (approximately 40 times the maximum
`recommended daily oral dose in adults on a mg/m2 basis). Studies in beagle dogs
`indicated that approximately 3% of the dose was excreted in milk. Cetirizine has been
`reported to be excreted in human breast milk. Because many drugs are excreted in
`human milk, use of ZYRTEC in nursing mothers is not recommended.
`
`OVERDOSAGE
`Overdosage has been reported with ZYRTEC. In one adult patient who took 150 mg of
`ZYRTEC, the patient was somnolent but did not display any other clinical signs or
`abnormal blood chemistry or hematology results. In an 18 month old pediatric patient
`who took an overdose of ZYRTEC (approximately 180 mg), restlessness and irritability
`were observed initially; this was followed by drowsiness. Should overdose occur,
`treatment should be symptomatic or supportive, taking into account any concomitantly
`ingested medications. There is no known specific antidote to ZYRTEC. ZYRTEC is not
`effectively removed by dialysis, and dialysis will be ineffective unless a dialyzable agent
`has been concomitantly ingested. The acute minimal lethal oral doses were 237 mg/kg
`in mice (approximately 95 times the maximum recommended daily oral dose in adults
`on a mg/m2 basis, or approximately 40 times the maximum recommended daily oral
`dose in infants on a mg/m2 basis