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

`

`NDA Number
`Submissions Date
`Submission Type
`
`Proposed Brand Name
`
`Generic Name
`
`Sponsor
`Route of Administration
`
`Dosage Form
`
`Dosage Strength
`
`Proposed Dosing
`Regimen
`
`CLINICAL PHARMACOLOGY REVIEW
`209089 and 209090 (related INDs - 126506 & 126507)
`03/31/2016
`505(b)(2) – Partial Rx-to-OTC switch
`XYZAL® Allergy 24HR (NDA 209089)
`Children’s XYZAL® Allergy 24HR (NDA 209090)
`Levocetirizine Dihydrochloride Tablets (NDA 209089), 5 mg
`Levocetirizine Dihydrochloride Oral Solution (NDA 209090),
`2.5 mg/5 mL
`UCB Inc.
`Oral
`Immediate release scored tablet: 5 mg (NDA 209089)
`Solution: 2.5 mg/5 ml (NDA 209090)
`Tablet: 5 mg (NDA 209089)
`Solution: 2.5 mg/5 ml (NDA 209090)
`Adults and children 12 years of age and older: 5 mg qd
`Children 6 to 11 years of age: 2.5 mg qd
`Children 2-5 years of age: 1.25 mg qd
`Temporarily relieves these symptoms due to hay fever or other
`respiratory allergies:
`• runny nose
`• sneezing
`• itchy, watery eyes
`• itching of the nose or throat
`Adults and children 12 years of age and older
`Children 6 to 11 years of age
`Children 2-5 years of age
`Nonprescription Clinical Evaluation, and
`Pulmonary, Allergy, and Rheumatology Products
`Clinical Pharmacology II
`Bhawana (Bavna) Saluja, Ph.D.
`Anshu Marathe, Ph.D.
`
`Proposed Indication(s)
`
`Proposed Population(s)
`
`OND Divisions
`
`OCP Division
`Reviewer
`Team Leader
`
`Molecular Structure
`
`Reference ID: 4032282
`
`

`

`Office of Clinical Pharmacology Recommendation
`
`Office of Clinical Pharmacology/Division of Clinical Pharmacology II, has reviewed NDA 209089 and
`209090 submitted by UCB, Inc., requesting partial prescription (Rx) to over-the-counter (OTC) switch of
`XYZAL® (levocetirizine dihydrochloride) tablet (NDAs 022064) and oral solution (NDA 022157), and
`found the proposed drug product acceptable from a clinical pharmacology perspective.
`
`FDA Regulatory History of XYZAL® Tablet (NDA 022064) & Oral Solution (NDA 022157)
`
`• On May 25, 2007, XYZAL® (levocetirizine dihydrochloride) 5mg Tablet was first approved under
`NDA 022064 for the relief of symptoms associated with seasonal allergic rhinitis (SAR) and
`perennial allergic rhinitis (PAR), and for the treatment of the uncomplicated skin manifestations of
`chronic idiopathic urticarial (CIU) in adults and children 6 years of age or older.
`
`• On January 25, 2008, XYZAL® (levocetirizine dihydrochloride) 0.5mg/mL oral solution was first
`approved for the relief of symptoms associated with SAR and PAR, and treatment of
`uncomplicated skin manifestations of CIU for patients 6 years of age and older.
`
`• On August 21, 2009, the pediatric supplemental NDA for XYZAL® (levocetirizine
`dihydrochloride) 0.5mg/mL oral solution was approved for the relief of symptoms associated with
`SAR in children 2 years of age and older, and for the relief of symptoms of PAR and treatment of
`uncomplicated skin manifestations of CIU for children 6 months of age and older.
`
`Background of This Submission
`
`XYZAL® (levocetirizine dihydrochloride) 5mg tablet and 2.5 mg/5 mL oral solution is currently available
`in the U.S. as a prescription treatment for SAR, PAR, and CIU. The current submission requests a change
`of status from prescription to nonprescription use of levocetirizine dihydrochloride tablets (5 mg) and oral
`solution (2.5 mg/5 mL) for the temporary relief of symptoms due to hay fever or other respiratory
`allergies (runny nose, sneezing, itchy, watery eyes and itching of the nose or throat).
`
`There is no new human pharmacokinetics and bioavailability or clinical pharmacology studies submitted
`to support of this Rx-to-OTC switch application. A label comprehension study (CONCENTRICS
`PROTOCOL #15060) was submitted in support of this switch.
`
`General Pharmacokinetics Information of Levocetirizine Hydrochloride1
`
`• Absorption:
`Levocetirizine is rapidly and extensively absorbed following oral administration. In adults, peak
`plasma concentrations are achieved 0.9 hour after administration of the oral tablet. The
`accumulation ratio following daily oral administration is 1.12 with steady state achieved after 2
`days. Peak concentrations are typically 270 ng/mL and 308 ng/mL following a single and a
`repeated 5 mg once daily dose, respectively. Food had no effect on the extent of exposure (AUC)
`of the levocetirizine tablet, but Tmax was delayed by about 1.25 hours and Cmax was decreased
`by about 36% after administration with a high fat meal; therefore, levocetirizine can be
`administered with or without food. A dose of 5 mg (10 mL) of XYZAL® oral solution is
`bioequivalent to a 5 mg dose of XYZAL® tablets. Following oral administration of a 5 mg dose of
`
`1 Prescribing information, NDA 022064 (revised 11/2016)
`
`Reference ID: 4032282
`
`2
`
`

`

`XYZAL® oral solution to healthy adult subjects, the mean peak plasma concentrations were
`achieved approximately 0.5 hour post-dose.
`
`• Distribution: The mean plasma protein binding of levocetirizine in vitro ranged from 91 to 92%,
`independent of concentration in the range of 90-5000 ng/mL, which includes the therapeutic
`plasma levels observed. Following oral dosing, the average apparent volume of distribution is
`approximately 0.4 L/kg, representative of distribution in total body water.
`
`• Metabolism: The extent of metabolism of levocetirizine in humans is less than 14% of the dose
`and therefore differences resulting from genetic polymorphism or concomitant intake of hepatic
`drug metabolizing enzyme inhibitors are expected to be negligible. Metabolic pathways include
`aromatic oxidation, N-and O-dealkylation, and taurine conjugation. Dealkylation pathways are
`primarily mediated by CYP 3A4 while aromatic oxidation involves multiple and/or unidentified
`CYP isoforms.
`
`• Elimination: The plasma half-life in adult healthy subjects was about 8 to 9 hours after
`administration of oral tablets and oral solution, and the mean oral total body clearance for
`levocetirizine was approximately 0.63 mL/kg/min. The major route of excretion of levocetirizine
`and its metabolites is via urine, accounting for a mean of 85.4% of the dose. Excretion via feces
`accounts for only 12.9% of the dose. Levocetirizine is excreted both by glomerular filtration and
`active tubular secretion. Renal clearance of levocetirizine correlates with that of creatinine
`clearance. In patients with renal impairment the clearance of levocetirizine is reduced.
`
`• Drug Interaction: In vitro data on metabolite interaction indicate that levocetirizine is unlikely to
`produce, or be subject to metabolic interactions. Levocetirizine at concentrations well above Cmax
`level achieved within the therapeutic dose ranges is not an inhibitor of CYP isoenzymes 1A2, 2C9,
`2C19, 2A1, 2D6, 2E1, and 3A4, and is not an inducer of UGT1A or CYP isoenzymes 1A2, 2C9
`and 3A4. No formal in vivo drug interaction studies have been performed with levocetirizine.
`
`•
`
`
`o Pediatric Patients –
`Data from a pediatric pharmacokinetic study with oral administration of a single dose of 5
`mg levocetirizine in 14 children age 6 to 11 years with body weight ranging between 20
`and 40 kg show that Cmax and AUC values are about 2-fold greater than that reported in
`healthy adult subjects in a cross-study comparison. The mean Cmax was 450 ng/mL,
`occurring at a mean time of 1.2 hours, weight-normalized, total body clearance was 30%
`greater, and the elimination half-life 24% shorter in this pediatric population than in adults.
`Dedicated pharmacokinetic studies have not been conducted in pediatric patients younger
`than 6 years of age. A retrospective population pharmacokinetic analysis was conducted in
`323 subjects (181 children 1 to 5 years of age, 18 children 6 to 11 years of age, and 124
`adults 18 to 55 years of age) who received single or multiple doses of levocetirizine
`ranging from 1.25 mg to 30 mg. Data generated from this analysis indicated that
`administration of 1.25 mg once daily to children 6 months to 5 years of age results in
`plasma concentrations similar to those of adults receiving 5 mg once daily.
`o Geriatric Patients – Limited pharmacokinetic data are available in elderly subjects.
`Following once daily repeat oral administration of 30 mg levocetirizine for 6 days in 9
`elderly subjects (65–74 years of age), the total body clearance was approximately 33%
`lower compared to that in younger adults. The disposition of racemic cetirizine has been
`
`Reference ID: 4032282
`
`3
`
`(b) (4)
`
`

`

`shown to be dependent on renal fimction rather than on age. This finding would also be
`applicable for levocetirizine, as levocetirizine and cetirizine are both predominantly
`excreted in urine. Therefore, the XYZAL® dose should be adjusted in accordance with
`renal fimction in elderly patients.
`
`0
`
`Renal Impairment — Levocetirizine exposure (AUC) exhibited 1.8-, 3.2-, 4.3—, and 5.7-fold
`increase in mild, moderate, severe, renal impaired, and end-stage renal disease patients,
`respectively, compared to healthy subjects. The corresponding increases of half-er
`estimates were 1.4-, 2.0-, 2.9-, and 4—fold, respectively.
`The total body clearance of levocetirizine after oral dosing was correlated to the creatinine
`clearance and was progressively reduced based on severity of renal impairment. Therefore,
`it is recommended to adjust the dose and dosing intervals of levocetirizine based on
`creatinine clearance in patients with mild, moderate, or severe renal impairment. In end-
`stage renal disease patients (CLCR < 10 mL/min) levocetirizine is contraindicated. The
`amount of levocetirizine removed during a standard 4—hour hemodialysis procedure was
`<10%. The dosage of XYZAL® should be reduced in patients with mild renal impairment.
`Both the dosage and frequency of administration should be reduced in patients with
`moderate or severe renal impairment. mm
`M“)
`
`I Mild renal impairment (creatinine clearance [CLCR] = 50-80 mL/min): a dose of 2.5
`mg once daily
`I Moderate renal impairment (CLCR = 30-50 mL/min): a dose of 2.5 mg once every
`other day
`Severe renal impairment (CLCR = 10-30 mL/min): a dose of 2.5 mg twice weekly
`(administered once every 3—4 days)
`End—stage renal disease patients (CLCR < 10 mL/min) or patients undergoing
`hemodialysis should not receive levocetirizine
`
`I
`
`I
`
`1b) (4)
`
`o Hepatic Impainnent — XYZAL‘D has not been studied in patients with hepatic impairment.
`The non-renal clearance (indicative of hepatic contribution) was found to constitute about
`28% of the total body clearance in healthy adult subjects alter oral administration.
`As levocetirizine is mainly excreted unchanged by the kidney, it is unlikely that the
`clearance of levocetirizine is significantly decreased in patients with solely hepatic
`impairment.
`
`Detailed Labe
`
`ling Recommendations
`
`XYZALO tablet and oral solution are being proposed for a partial OTC switch. The relevant clinical
`discussion is below -
`pharmacology
`
`1.
`
`In the
`
`the
`XYZALO Allergy 24HR and Children’s XYZAL® Allergy 24HR Drug Facts,
`recommendation for patients who have kidney disease is “Do not use”. This is reasonable as it is
`known that apparent clearance of levocetirizine correlates with that of creatinine clearance, and is
`progressively reduced with the severity of renal impairment. Systemic exposure, represented by
`AUC, exhibited 1.8-, 3.2-, 4.3-, and 5.7-fold increase in mild, moderate, severe renal impaired and
`end—stage renal disease (ESRD) patients, respectively, compared to healthy subjects. There was a
`corresponding increase in half-life estimates of 1.4-, 2.0-, 2.9-, and 4-fold,
`respectively.
`Accordingly, the current label of prescribing XYZAL® recommends adjustment of the dose and
`
`Reference ID: 4032282
`
`

`

`dosing intervals of levocetirizine based on creatinine clearance in patients aged 12 years and older
`with mild, moderate, or severe renal impairment (see “Patients with Renal Impairment” under
`special populations in the section above). In addition, levocetirizine is contraindicated in end-stage
`renal disease patients (CLCR < 10 mL/min) and in children 6 months to 11 years of age with renal
`impairment.
`
`2. The Drug Facts under “Directions” section splits the adult patient population into two categories of
`“adults and children 12- 64 years of age” and “adults 65 years of age and older” with different
`dosing recommendations for the two groups for both XYZAL® Allergy 24HR and Children’s
`XYZAL® Allergy 24HR (see attached drug facts label in the attachment). This is reasonable as the
`current label of prescribing XYZAL® states the following in Section 12.3 for “Geriatric Patients” –
`
`“Limited pharmacokinetic data are available in elderly subjects. Following once daily repeat oral
`administration of 30 mg levocetirizine for 6 days in 9 elderly subjects (65–74 years of age), the
`total body clearance was approximately 33% lower compared to that in younger adults. The
`disposition of racemic cetirizine has been shown to be dependent on renal function rather than on
`age. This finding would also be applicable for levocetirizine, as levocetirizine and cetirizine are
`both predominantly excreted in urine. Therefore, the XYZAL dose should be adjusted in
`accordance with renal function in elderly patients.”
`
`In addition, the current label of prescribing XYZAL® also states that “Some patients may be
`adequately controlled by 2.5 mg (1/2 tablet or 1 teaspoon [5 mL] oral solution) once daily in the
`evening” under Section 2 (Dosage and administration). Therefore, this reviewer concurs with the
`recommendation to have adults 65 years of age and older to “ask a doctor”.
`
`3. The current label of prescribing XYZAL® recommends dosing “once daily in the evening”,
`whereas the XYZAL® Allergy 24HR and Children’s XYZAL® Allergy 24HR Drug Facts
`. Please note prescription XYZAL® is recommended to be dosed
`recommends
`once daily in the evening (QDPM) primarily because all of the confirmatory and supportive
`clinical trials dosed XYZAL® in the evening, and sedation-related effects of daytime use were not
`characterized in the application. The clinical reviewer has raised safety concerns
`
` dosing recommendation for the proposed OTC tablet and oral solution. Detailed discussion
`on this issue can be found in Clinical Safety Review by Dr. Brenda S. Gierhart, M.D.
`
`4. Since the extent of metabolism of levocetirizine in humans is less than 14% of the dose,
`differences resulting from genetic polymorphism or concomitant intake of hepatic drug
`metabolizing enzyme inhibitors are expected to be negligible. In addition, levocetirizine, at
`concentrations well above Cmax level attained after administration of therapeutic doses, is not an
`inhibitor of CYP enzymes 1A2, 2C9, 2C19, 2A1, 2D6, 2E1, and 3A4, and is also not an inducer of
`CYP enzymes 1A2, 2C9 and 3A4 and UGT1A1. Therefore, levocetirizine is unlikely to produce,
`or is subject to metabolic interactions with concomitant medications.2
`
`2 Prescribing information, NDA 022064 (revised 11/2016)
`
`Reference ID: 4032282
`
`5
`
`4 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following
`this page
`
`(b) (4)
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`BHAWANA SALUJA
`12/22/2016
`
`ANSHU MARATHE
`12/22/2016
`
`Reference ID: 4032282
`
`

`

`CLINICAL PHARMACOLOGY FILING FORM
`
`NDA Number
`
`
`
`sneezing
`0
`itchy, watery eyes
`o
`
`0
`itching of the nose or throat
`Adults and children 12 years of age and older: 5 mg qd
`Children 6 to 11 years of age: 2.5 mg qd
`
`Children 2-5 years of age: 1.25 mg qd
`Immediate release scored
`Route of
`
`Dosage Regimen
`
`Dosage Form
`
`Administration
`tablet: 5 mg
`
`Solution: 2.5 mg/S ml
`DCP 11
`
`OND Division
`
`
`
`209089 and 208090 (related
`1ND - 126506 & 126507
`Submission Date 03/3 1/2016
`Sanofi-Aventis
`Applicant
`Generic Name
`Levocetirizine
`Brand Name
`XYZAL®
`dih drochloride
`
`Oral Hl-histamine receptor antagonist
`Drug Class
`Indication
`Temporarily relieves these symptoms due to hay fever or other respiratory
`allergies:
`o
`runny nose
`
`
`
`
`OCP Division
`
`OCP Review Team
`Primary Reviewer(s)
`Secondary Reviewer/ Team Leader
`
`Division
`Anshu Marathe, Ph.D.
`Bhawana Saluja, Ph. D.
`
`Pharmacometrics
`
`Genomics
`
`Review Classification
`Standard [:1 Priori D E edited
`
`05/30/2016
`74-Day Letter Date
`06/13/2016
`Filing Date
`Review Due Date
`12/27/2016
`PDUFA Goal Date
`01/31/2017
`
`Is the Clinical Pharmacology section of the application fileable?
`Yes
`
`Application Fileability
`
`E] No
`
`If no list reason(s)
`Are there any potential review issues/ comments to be forwarded to the Applicant in the 74-day
`letter?
`
`C] Yes
`No
`
`If yes list comment(s)
`Is there a need for clinical trial(s) inspection?
`DYes
`
`No
`
`If yes explain
`
`Reference ID: 3934723
`
`

`

`Clmlcal Pharmacology Package
`
`Tabular Listing of All Human
`Studies
`
`Bioanalytical and Analytical
`Methods
`
`Yes [:1 No Clinical Pharmacology Summary
`
`Yes I] No
`
`ClYes No
`
`Labeling
`
`Yes [I No
`
`Clinical Pharmacolo 3 Studies
`Count
`Comment 5
`
`In Vitro Studies
`
`Characterization
`
`Characterization
`
`
`
`In Vivo Studies
`
`Biopharmaceutics
`El Absolute Bioavailabili
`
`El Relative Bioavailabili
`
`
`E] Food Effect
`
`El Bioanal
`
`'cal methods
`
`
`Human Pharmacokinetics
`
`Healthy
`subjects
`
`El Sin le Dose
`[I Multi . le Dose
`
`
`El Multiple Dose
`
`El Mass Balance Study
`
`El Other (e.g. dose
`. o . monah
`
`Intrinsic Factors
`
`El Race
`
`
`E] Pediatrics
`
`El Hepatic Impairment
`[1 Renal Im u ailment
`——
`Extrinsic Factors
`
`[1 Effects on Prim Dru
`
`DEffects of ' u. Dru-
`
`Reference ID: 3934723
`
`

`

`Pharmacod . amics
`
`El Health Sub'ects
`
`
`E] Patients
`
`Pharmacokinetics/Pharmacod namics
`
`I] Health Sub'ects
`
`
`[1 QT
`Pharmacometrics
`
`
`
`
`
`E] Patients
`
`E] Population
`Pharmacokinetics
`
`E] Exposure-Efficacy
`
`El Exposure—Safety
`Total Number of Studies/Re I orts
`
`Total Number of Studies/Reports to be
`Reviewed
`
`Reference ID: 3934723
`
`

`

`Comments
`
`This is a 505(b)(2) submission, where the
`sponsor is seeking approval for a
`prescription to over-the-counter (Rx-to-
`OTC) switch [Listed Drug(s) – Xyzal®
`Tablets, NDA 022064 & Xyzal® Oral
`Solution, NDA 022157]
`
`This is a 505(b)(2) submission.
`
`Criteria for Refusal to File (RTF)
`Assessment
`
`RTF Parameter
`1. Did the applicant submit bioequivalence
`data comparing to-be-marketed product(s)
`and those used in the pivotal clinical trials?
`2. Did the applicant provide metabolism and
`drug-drug interaction information? (Note:
`RTF only if there is complete lack of
`information)
`3. Did the applicant submit pharmacokinetic
`studies to characterize the drug product, or
`submit a waiver request?
`4. Did the applicant submit comparative
`bioavailability data between proposed drug
`product and reference product for a 505(b)(2)
`application?
`
`(cid:2)Yes (cid:2)No (cid:2)N/A
`
`(cid:2)Yes (cid:2)No (cid:2)N/A
`
`(cid:2)Yes (cid:2)No (cid:2)N/A
`
`(cid:2)Yes (cid:2)No (cid:2)N/A
`
`(cid:2)Yes (cid:2)No (cid:2)N/A
`
`(cid:2)Yes (cid:2)No (cid:2)N/A
`
`(cid:2)Yes (cid:2)No (cid:2)N/A
`
`(cid:2)Yes (cid:2)No (cid:2)N/A
`
`(cid:2)Yes (cid:2)No (cid:2)N/A
`
`(cid:2)Yes (cid:2)No (cid:2)N/A
`
`4
`
`5. Did the applicant submit data to allow the
`evaluation of the validity of the analytical
`assay for the moieties of interest?
`6. Did the applicant submit study
`reports/rationale to support dose/dosing
`interval and dose adjustment?
`7. Does the submission contain PK and PD
`analysis datasets and PK and PD parameter
`datasets for each primary study that supports
`items 1 to 6 above (in .xpt format if data are
`submitted electronically)?
`8. Did the applicant submit the module 2
`summaries (e.g. summary-clin-pharm,
`summary-biopharm, pharmkin-written-
`summary)?
`9. Is the clinical pharmacology and
`biopharmaceutics section of the submission
`legible, organized, indexed and paginated in
`a manner to allow substantive review to
`begin?
`If provided as an electronic submission, is the
`electronic submission searchable, does it
`have appropriate hyperlinks and do the
`hyperlinks work leading to appropriate
`sections, reports, and appendices?
`Complete Application
`10. Did the applicant submit studies
`including study reports, analysis datasets,
`source code, input files and key analysis
`output, or justification for not conducting
`
`Reference ID: 3934723
`
`

`

`studies, as agreed to at the pre-NDA or pre-
`BLA meeting? If the answer is ‘No’, has the
`sponsor submitted a justification that was
`previously agreed to before the NDA
`submission?
`Criteria for Assessing Quality of an NDA (Preliminary Assessment of Quality) Checklist
`
`(cid:2)Yes (cid:2)No (cid:2)N/A
`
`(cid:2)Yes (cid:2)No (cid:2)N/A
`
`(cid:2)Yes (cid:2)No (cid:2)N/A
`
`(cid:2)Yes (cid:2)No (cid:2)N/A
`
`Data
`1. Are the data sets, as requested during pre-
`submission discussions, submitted in the
`appropriate format (e.g., CDISC)?
`2. If applicable, are the pharmacogenomic
`data sets submitted in the appropriate format? (cid:2)Yes (cid:2)No (cid:2)N/A
`Studies and Analysis
`3. Is the appropriate pharmacokinetic
`information submitted?
`4. Has the applicant made an appropriate
`attempt to determine reasonable dose
`individualization strategies for this product
`(i.e., appropriately designed and analyzed
`dose-ranging or pivotal studies)?
`5. Are the appropriate exposure-response (for
`desired and undesired effects) analyses
`conducted and submitted as described in the
`Exposure-Response guidance?
`6. Is there an adequate attempt by the
`applicant to use exposure-response
`relationships in order to assess the need for
`dose adjustments for intrinsic/extrinsic
`factors that might affect the pharmacokinetic
`or pharmacodynamics?
`7. Are the pediatric exclusivity studies
`adequately designed to demonstrate
`effectiveness, if the drug is indeed effective?
`General
`8. Are the clinical pharmacology and
`biopharmaceutics studies of appropriate
`design and breadth of investigation to meet
`basic requirements for approvability of this
`product?
`9. Was the translation (of study reports or
`other study information) from another
`language needed and provided in this
`submission?
`
`(cid:2)Yes (cid:2)No (cid:2)N/A
`
`(cid:2)Yes (cid:2)No (cid:2)N/A
`
`(cid:2)Yes (cid:2)No (cid:2)N/A
`
`(cid:2)Yes (cid:2)No (cid:2)N/A
`
`Reference ID: 3934723
`
`5
`
`

`

`CLINICAL PHARMACOLOGY
`FILING MEMO FOR NDA 209089 & 209090
`
`Regulatory History
`Sanofi-aventis submitted NDA 209089 and NDA 209090 under 505(b)(2) seeking approval for a partial
`Rx-to-OTC switch. The listed drug(s) (original approved Rx) NDA 022064 levocetirizine dihydrochloride
`tablet and NDA 022157 levocetirizine dihydrochloride oral solution are indicated for the relief of
`symptoms associated with seasonal and perennial allergic rhinitis, and for the treatment of uncomplicated
`skin manifestations of chronic idiopathic urticaria in adults and pediatric patients 6 months of age and
`older.
`
`The major change proposed in this OTC NDA is that the proposed OTC label will omit hives indication
`(i.e., chronic idiopathic urticaria), which will remain on Rx status.
`
`The sponsor proposes debossed tablets in NDA 209089, while the listed drug is a printed tablet (See
`Figure 1 below).
`
`Figure 1. Comparison of the listed drug and proposed tablets
`
`, and indicated that this
`The sponsor states that this change needed minor modifications
`modification had no impact on quality of the product. The sponsor also submitted comparative multiple-
`time point dissolution profiles for whole printed tablets (listed drug) and whole debossed tablets.
`
`No new clinical pharmacology studies were conducted in the two NDA submissions; however, the
`submission is cross-referenced to NDA 022064 (levocetirizine dihydrochloride tablet) and NDA 022157
`(levocetirizine dihydrochloride oral solution). The clinical pharmacology review for the NDA submissions
`will focus on the adequacy of the drug facts label from a clinical pharmacology perspective.
`
`These two NDAs are considered fileable from the clinical pharmacology perspective.
`
`Reference ID: 3934723
`
`6
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`BHAWANA SALUJA
`05/20/2016
`
`ANSHU MARATHE
`05/20/2016
`
`Reference ID: 3934723
`
`