CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`209089Orig1s000
` 209090Orig1s000
`
`
`
`SUMMARY REVIEW
`
`

`

`Division Director Review
`
`NDA 209089 (tablet) and NDA 209090 (oral solution)
`
`levocetirizine dihydrochloride
`
`Summary Review for Regulatory Action
`
` 1
`
`INTRODUCTION
`
`On behalf of UCB, Inc., Sanofi US Services, Inc. (Sanofi) submitted these 505(b)(2) new
`drug applications seeking approval for levocetirizine dihydrochloride tablets and oral
`solution (levocetirizine; proposed trade names Xyzal Allergy 24HR and Children’s Xyzal
`Allergy 24HR),
`M“) for OTC use for the temporary relief of symptoms due
`to hay fever or other respiratory allergies, including nmny nose; sneezing; itchy, watery
`eyes; and itching of the nose or throat.
`
`Levocetirizine is a histamine H1 -receptor antagonist, which is the R—enantiomer of the
`racemate, cetirizine. As such, the sponsor references not only the levocetirizine
`prescription NDAs 22064 (oral tablet) and NDA 22157 (oral solution), but also NDAs
`19835, 21621, and 20346 for the Zyrtec (cetirizine dihydrochloride) tablets, chewable
`tablets, and oral solution, respectively. Levocetirizine is approved as a prescription product
`for the management of symptoms of seasonal allergic rhinitis (SAR; adults and children
`ages 2 years and older), perennial allergic rhinitis G’AR; adults and children ages 6 months
`and older) and the treatment of uncomplicated skin manifestations of chronic idiopathic
`urticaria (CIU; adults and children ages 6 months and older). Dosing is 5 mg once daily in
`
`Reference ID: 4048782
`
`Theresa M. Michele, MD
`From Director, Division ofNonprescription Drug Products
`
`
`
`Subject
`
`NDA/BLA #
`
`Division Director Summary Review
`
`209089 (tablet), 209090 (oral solution)
`
`Union Chimique Belge, Inc. GJCB)
`Applicant Name
`Agent: Sanofi US Services Inc.
`
`Date of Submission
`
`March 31, 2016
`
`PDUFA Goal Date
`
`January 31, 2017
`
`Proprietary Name /
`Establ'shed (USAN) Na e
`l
`m
`
`Xyzal Allergy 24HR (levocetirlzme dihydrochloride)
`Children s Xyzal Allergy 24HR (levocetirlzme
`dihydrochloride)
`Allergic rhinitis (seasonal and perennial):
`
`o Tablet, 5 mg (adults and children 6—64 years
`of age)
`
`Dosage Forms / Route of
`Administration / Strength
`0 Oral solution 2.5 mg/5 mL (adults and
`
`children ages 2-64 years)
`Temporary relieves these symptoms due to hay fever
`or other respiratory allergies: runny nose; sneezing;
`Proposed Indication(s)
`
`itchy, watery eyes; itching of the nose or throat
`
`Recommended Regulatory
`Action
`
`Approval
`
`

`

`Division Director Review
`NDA 209089 (tablet) and NDA 209090 (oral solution)
`
`levocetirizine dihydrochloride
`
`the evening for adults and children ages 12 years and older, 2.5 mg once daily in the
`evening for adults and children ages 6 to 11 years, and 1.25 mg once daily in the evening
`for children ages 6 months to 5 years. There are dose adjustments required for various
`degrees of renal impairment ranging from 2.5 mg once daily for adults with mild renal
`impairment to a contraindication in patients with end-stage renal disease. The sponsor is
`proposing a partial switch of the SAR and PAR indications down to age 2 years. The
`indication for CIU and PAR indication for children younger than 2 years would remain
`prescription.
`The indication that the sponsor is proposing “temporarily relieves these symptoms due to
`hay fever or other respiratory allergies: runny nose; sneezing; itchy, watery eyes; itching of
`the nose or throat” is consistent with other OTC products available for treatment of allergic
`rhinitis. However, Sanofi proposes that dosing of the product could occur
`
` in the evening to avoid somnolence as with the prescription product. To
`justify this dosing revision, Sanofi submitted analyses of clinical safety data from morning-
`dosed studies compared to evening-dosed studies.
`The allergic rhinitis indications of SAR and PAR are considered to be similar for both
`prescription and OTC use, and consumer ability to understand and use products in this
`category is well established. As such, no new nonclinical pharmacology and toxicology,
`human pharmacokinetics and bioavailability, clinical pharmacology, clinical efficacy or
`safety studies were submitted as part of this application. As part of this application, Sanofi
`conducted a label comprehension study in order to support warning language for kidney
`disease and urinary retention.
`This summary review provides an overview of the application with a focus on the new
`dosing instructions and labeling.
`
`2 BACKGROUND
`
`2.1 Allergic rhinitis (seasonal and perennial)
`Allergic rhinitis is a common IgE-mediated inflammatory condition characterized by one or
`more of the following symptoms: congestion, rhinorrhea (anterior and posterior), sneezing,
`and itching. Symptoms may significantly affect quality of life, and may be associated with
`sleep disturbance, fatigue, headache, cognitive impairment. Traditionally, allergic rhinitis is
`divided into two subsets, SAR and PAR, depending on the aeroallergens involved and
`persistence of symptoms. Although estimates vary, allergic rhinitis may affect as many as
`30-60 million people in the US, including 10-30% of adults and up to 40% of children.1
`Allergic rhinitis is a well-established OTC indication, with both monograph and NDA OTC
`products available in a variety of intranasal and oral formulations. These include first and
`second generation oral antihistamines, oral antihistamine/decongestant combination
`products, intranasal decongestants, and intranasal cromolyn. In addition, in October 2013,
`FDA approved the first intranasal corticosteroid as a prescription to OTC switch [Nasacort
`Allergy 24 HR (triamcinolone acetonide) nasal spray; NDA 20,468], with several
`
`1 The diagnosis and management of rhinitis: An updated practice parameter, Joint Task Force on
`Practice Parameters for Allergy and Immunology. 2008
`
`2
`
`Reference ID: 4048782
`
`(b) (4)
`
`(b) (4)
`
`

`

`Division Director Review
`NDA 209089 (tablet) and NDA 209090 (oral solution)
`
`levocetirizine dihydrochloride
`
`subsequent OTC approvals of other nasal steroid products. Professional guidelines for the
`treatment of adults with allergic rhinitis recommend nasal steroids as first line therapy for
`moderate-severe disease with or without a second generation antihistamine.
`The standard OTC indication language for allergic rhinitis, covering the prescription
`indications for both SAR and PAR, is derived from the OTC monograph indication for first
`generation antihistamines “temporarily relieves runny nose and sneezing, itching of the
`nose or throat, and itchy, watery eyes due to hay fever or other upper respiratory
`allergies.2” While consumers can generally recognize the symptoms of allergic rhinitis,
`diagnosis of PAR in infants and children under the age of 2 years is more complex and
`requires the evaluation of a physician.
`
`2.3 Relevant Regulatory History for fluticasone propionate
`As part of this application, one formal pre-submission meeting was held between
`Sanofi/UCB and FDA regarding the content and format of the planned NDAs for the
`prescription to OTC switch of levocetirizine.
`
`(cid:22) CHEMISTRY, MANUFACTURING, AND CONTROLS
`Levocetirizine 5 mg tablets are white to off-white film-coated, oval, scored tablets. They
`may be split in half to give a 2.5 mg dose for children ages 6 to 11 who are able to swallow
`tablets. The liquid formulation is a clear, colorless solution at a concentration of 0.5 mg/mL
`(2.5 mg/5 mL) which is bioequivalent to the tablet. The sponsor states that there are no
`changes to the prescription quality information except for inclusion of a debossed tablet,
`new packaging configurations,
` the blister packages, and
`addition of new packaging sites. There is a shelf life of 36 months under room temperature
`storage conditions. To be in compliance with the USP salt policy of the active moiety, the
`established name should contain the active moiety in the neutral form without the name of
`the salt. However, to avoid confusion with the prescription product, which will remain on
`the market for the CIU indication, the quality team recommends accepting the proposed
`established name of “levocetirizine dihydrochloride”. I concur with this recommendation as
`well as their recommendation for approval from a quality standpoint.
`
`4 NONCLINICAL PHARMACOLOGY/TOXICOLOGY
`No new nonclinical data were submitted as part of this application. As the OTC product is
`the same as the prescription product, there are no new excipients or impurities. There are no
`outstanding nonclinical pharmacology/toxicology issues.
`
`5 CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS
`No new clinical pharmacology data were submitted as part of this application. According to
`the prescription label, levocetirizine is rapidly and extensively absorbed following oral
`administration and has a peak plasma concentration 0.9 hour after administration of the oral
`tablet without a food effect. The drug is excreted primarily through the kidney by both
`
`2 21 CFR 341.72 Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug Products for Over-the-
`Counter Human Use; Labeling of antihistamine drug products (1992, as amended Dec 6, 2002).
`
`3
`
`Reference ID: 4048782
`
`(b) (4)
`
`

`

`Division Director Review
`NDA 209089 (tablet) and NDA 209090 (oral solution)
`
`levocetirizine dihydrochloride
`
`glomerular filtration and active tubular secretion, leading to a plasma half-life of
`approximately 8 to 9 hours after administration of either the tablet or oral solution.
`Excretion varies with renal function and the plasma blood levels increase approximately 6
`fold in persons with end-stage renal disease. Because the adverse effect of somnolence is
`known to increase with increasing dose, dosing in the prescription setting is based on renal
`function. Levocetirizine is contraindicated in persons with end-stage renal disease or who
`are on hemodialysis. For the OTC label, the sponsor recommends the following warning:
`“Do not use if you have kidney disease.” While an argument could potentially be made for
`a lesser warning of “ask a doctor before use if you have kidney disease,” the sponsor has
`taken a conservative approach, which is reasonable. Furthermore, this warning was tested
`in a label comprehension study, with reasonably good comprehension.
`There are no outstanding clinical pharmacology issues.
`
`6 CLINICAL MICROBIOLOGY
`Not applicable.
`
`7 CLINICAL AND STATISTICAL EFFICACY
`A large number of clinical trials have been conducted with levocetirizine, including a
`number of trials supporting the SAR and PAR, as well as pediatric dosing. The efficacy of
`levocetirizine for SAR and PAR has been previously established for the prescription
`product, so efficacy will be reviewed only briefly here, as the OTC indication is similar.
`The clinical program for the prescription NDAs included a total of 12 clinical trials in
`allergic rhinits: 6 efficacy and safety trials in adult and adolescents with SAR or PAR (3
`dose ranging, one pivotal trial in PAR, one pivotal trial in SAR, and one shorter duration
`trial), 2 efficacy and safety trials in children 6 to 12 years of age with SAR or PAR, 2
`environmental exposure unit trials, and 2 long term safety trials. Efficacy in children under
`age 6 was extrapolated based on pharmacokinetic data.
`Reflective total symptom scores (rTSS), a composite symptom score of rhinorrhea,
`sneezing, and nasal itching, and ocular itching) were evaluated over treatment periods of 2
`to 4 weeks for SAR and PAR, respectively. Subjects treated with fluticasone propionate
`aqueous nasal spray (FPANS) exhibited significantly greater decreases in rTSS than
`placebo-treated patients (see product prescription labeling). In environmental chamber
`studies evaluating onset of action, a decrease in nasal symptoms in treated subjects
`compared to placebo was shown to occur as soon as 1 hour after treatment.
`
`8 SAFETY
`The safety profile of levocetirizine is well-characterized, including a large clinical trial
`database (primarily in SAR and PAR) of more than 6000 subjects exposed to levocetirizine,
`and postmarketing data from prescription approval in over 60 countries worldwide and in
`12 countries as a nonprescription drug. The U.S. prescription label contains warnings and
`precautions related to sedation, avoiding concurrent use of alcohol or other CNS
`suppressants, and instructions to use with caution in patients with predisposing factors for
`urinary retention. As noted previously, dose adjustment for renal impairment (including
`
`Reference ID: 4048782
`
`4
`
`

`

`Division Director Review
`
`NDA 209089 (tablet) and NDA 209090 (oral solution)
`
`levocetirizine dihydrochloride
`
`mild impairment) is required. Levocetirizine is contraindicated in patients with a known
`hypersensitivity, end-stage renal disease, or hemodialysis.
`
`8.1
`
`Safety in clinical trials
`
`The sponsor provided an analysis of 62 clinical trials conducted with levocetirizine at doses
`ranging from 1.25 mg/day to 30 mg/day. The most common adverse events in adult studies
`occurring more often in the levocetirizine group than placebo in short term studies were
`somnolence and fatigue. In long-term studies, somnolence, fatigue, and dry mouth occurred
`more frequently in the levocetirizine group compared to placebo. In children, infectious
`adverse events were more frequent, potentially confounding drug associations.
`
`Efi'ect on QT interval
`
`A QT study performed using a single dose of 30 mg (6 times the recommended dose) did
`not show a significant QT effect. In general, multiple dose QT studies are required to assure
`that the study is performed at steady state; however, the clinical reviewer notes that PK data
`demonstrate that steady state is reached after 2 days of dosing, with only a slight increase in
`blood levels from day one to day 2. In addition, four clinical studies conducted with 30 mg
`of cetirizine in healthy males did not demonstrate QT prolongation. While there are a few
`cases of potential QT prolongation/torsades in post-marketing data, the clinical team
`determined that there were confounding factors and a clear signal is not seen. As such, they
`concluded that QT prolongation is not a significant concern with levocetirizine, and I
`concur.
`
`Sedation
`
`In short-term studies in adults, somnolence occurred in 5.3% of subjects receiving
`levocetirizine compared to 1.6% of the placebo group, and fatigue occurred in 3.1% versus
`1.4%. In long-term studies, somnolence occurred in 4.7% of the levocetirizine group versus
`1.7% of the placebo group, and fatigue occurred in 5.8% versus 4.8%. A small cross-over
`study evaluating cognitive and psychomotor function demonstrated no significant
`differences between levocetirizine, cetirizine, loratadine, and placebo. In addition, a
`randomized, double—blind driving study 1.5 hours after dosing found that diphenhydramine
`reduced driving ability while levocetirizine did not.
`
`Sedation (combining the preferred terms of lethargy, neonatal oversedation, sedation,
`somnolence, somnolence neonatal, stupor, sopor, and narcosis) was found to be dose
`related, increasing with increasing dose, which is not surprising.
`mm
`M w
`
`"m" the sponsor compared
`3 studies in which levocetirizine was dosed in the morning with 8 studies dosed in the
`evening, and concluded that there was no significant difl'erence in somnolence between the
`groups. Of note, the total daily dose of the morning studies was 5 mg per day, while the
`total daily dose of the evening studies was variable, with some subjects receiving 10 mg.
`To address the concern that the studies chosen by the sponsor may not be representative of
`the overall clinical database, Dr. Gierhart reviewed all available clinical studies, including
`32 studies dosed only in the morning and 17 studies dosed only in the evening. When
`subjects receiving doses of 5 mg or less were compared, it appears that sedation occurred
`
`Reference ID: 4048782
`
`

`

`Division Director Review
`
`NDA 209089 (tablet) and NDA 209090 (oral solution)
`
`levocetirizine dihydrochloride
`
`more frequently with morning dosing than evening dosing, which is further supported by
`the phannacokinetics showing a peak serlnn level approximately 1 hour after dosing.
`Although cross-study comparisons are fraught with difficulty, the overall data
`om)
`(b) m
`
`ow)
`
`Geriatric population
`
`Limited clinical study data are available in the geriatric population. Given the risk of
`sedation and the increasing risk of renal impairment with increasing age, the sponsor
`proposes to limit use in the OTC setting to consumers less than 65 years of age. The clinical
`team agreed with this conservative approach, and I concur.
`
`8.2 Consumer studies
`
`The sponsor conducted a single label comprehension study enrolling 417 adults and
`adolescents ages 16 years and older, including 28% of subjects with low literacy. Self-
`selection, human factors, and actual use studies were not required for this switch
`application given that the antihistamine category and indication of allergic rhinitis
`(SAR/PAR) are already established for OTC use. The label comprehension study was a
`multi-site, single-visit, study to evaluate comprehension of warnings and directions related
`to kidney disease and urinary retention. See Table 2 for results.
`
`Table 1: Label comprehension primary objectives: normal versus low literacy
`
`(Question 3) Objective
`
`(Q 5) Stop l‘se and Ask a Doctor It
`You have trouble minatmgor
`M1118 your bladder
`
`Normal Literacy
`3‘40]
`PE%
`
`95% Cl
`
`n
`
`Low Liter“?
`_\'=1 16
`PE%
`
`95% CI
`
`n
`
`193
`
`97.3
`
`94.8. 98 9
`
`113
`
`97.4
`
`92.6. 99.5
`
`(Q 4) Do Not l'se
`disease
`lt'you have In!
`(Q 2) Ask a Doctor before l'se It You
`
`,
`-86
`
`S
`9- 0
`
`,
`91 9. 97 _
`
`98
`
`84.5
`
`76.6. 90 5
`
`"m
`ever had trouble urinating or
`Mug your bladder
`
`204
`
`67 s
`
`62 z. 73 o
`
`72
`
`62.1
`
`52.6. 70 9
`
`Overall, consumers showed generally good comprehension of these first two warnings,
`“stop use and ask a doctor if you have trouble urinating or emptying your bladder” and “do
`not use if you have kidney disease.” The relatively low comprehension of the kidney
`disease warning (Lower Bound of the Confidence Interval @BCI) for the low literacy
`population of 77%) is potentially concerning; however, the majority of incorrect answers
`were from consumers who stated that they would ask a doctor before use, which is a safe
`alternative. Likewise, consumers scored relatively poorly on the warning to “ask a doctor
`before use if you have ever had trouble urinating or emptying your bladder”, but when
`mitigated to include subjects who responded with other safe alternatives of “do not use” or
`“ask a doctor” without a correct rationale, the overall results improved from 66% correct to
`89%. Further, since the warning to stop use if urinary retention occurs was well understood,
`it seems unlikely that consumers will have an unacceptable level of risk when using this
`product. The social science reviewer notes that the response pattern and verbatim
`
`Reference ID: 4048782
`
`

`

`Division Director Review
`NDA 209089 (tablet) and NDA 209090 (oral solution)
`
`levocetirizine dihydrochloride
`
`responses suggest that consumers may be confused between kidney and bladder; however,
`this may be of lesser import if they choose a safe course of action based on the label.
`
`Post-marketing data
`8.3
`As part of this application, post-marketing safety data for levocetirizine were submitted and
`reviewed from the following sources: the sponsor’s pharmacovigilance database, FDA’s
`Adverse Event Reporting System (FAERS), the American Association of Poison Control
`Centers’ National Poison Data System (NPDS), the Drug Abuse Warning Network
`(DAWN), and the published literature. The sponsor also reviewed the French
`Pharmacovigilance Database for the racemate cetirizine. All of these sources are subject to
`a number of limitations, primarily due to issues inherent in spontaneous reporting. Overall,
`the adverse events reported in the post-market setting are consistent with the clinical trials
`database and the known adverse event profile of antihistamines.
`
`9 ADVISORY COMMITTEE MEETING
`An advisory committee meeting was not held for this application as this is not a first in class
`switch and there were no novel or controversial issues raised by the application.
`
`10 PEDIATRICS
`Levocetirizine is approved in the prescription setting down to age 2 years for SAR and age
`6 months for PAR and CIU. The CIU indication will remain prescription. Because this
`application does not involve a new indication, dosage form, route of administration, or
`dosing regimen, PREA is not triggered. The sponsor fulfilled PREA obligations with the
`prescription product by conducting pediatric trials. Diagnosis of allergic rhinitis may be
`complex in infants and young children, with a variety of other more serious conditions such
`as pharyngonasal reflux resulting from prematurity, neuromuscular disease, or cleft palate,
`adenoidal hypertrophy, congenital syphilis, and otitis media, to be considered.3 As such, it
`is appropriate for indications for infants and children less than 2 years of age to remain
`prescription.
`
`11 OTHER RELEVANT REGULATORY ISSUES
`
`11.1 OSI Audits
`OSI site inspections were not conducted for this application.
`
`11.2 Financial Disclosure
`Not applicable.
`
`11.3 Environmental Assessment
`A categorical exclusion was granted for this application.
`
`3 The diagnosis and management of rhinitis: An updated practice parameter, Joint Task Force on
`Practice Parameters for Allergy and Immunology. 2008
`
`Reference ID: 4048782
`
`7
`
`

`

`Division Director Review
`
`NDA 209089 (tablet) and NDA 209090 (oral solution)
`
`levocetirizine dihydrochloride
`
`12 LABELING
`
`12.1 Proprietary name
`
`The proposed proprietary names, Xyzal Allergy 24HR (5 mg tablet) and Children’s Xyzal
`Allergy 24HR (oral solution 2.5 mg/S ml), were deemed acceptable by the Division of
`Medication Error Prevention and Analysis (DMEPA).
`
`12.2 Consumer labeling
`
`Sanofi submitted Drug Facts label, outer carton labels, and immediate container labels for a
`variety of count sizes ranging from 10-count to a 110-count club pack for the tablets and a
`5 ounce bottle of the oral solution.
`
`Specific labeling reviews were completed by DMEPA and DNDP in addition to labeling
`reviews completed by the various review disciplines. For the most part, the proposed
`labeling reflects standard language for other second generation antihistamines, including
`specific sedation wamings as follows: “When using this product: drowsiness may occur,
`avoid alcoholic drinks; alcohol, sedatives, and tranquilizers may increase drowsiness; and
`be careful when driving a motor vehicle or operating machinery.” As noted previously, the
`Drug Facts label includes warnings related to kidney disease as well as urinary retention,
`which were tested in a label comprehension study. The kidney disease warning is more
`conservative than the dose adjustments permitted on the prescription label, which is
`reasonable for the OTC setting and tested well in label comprehension.
`
`(m4) taking the
`The sponsor proposed
`om)- This was the subject of
`product in the evening
`a comprehensive review by the clinical team, with the ultimate decision that the data
`support retaining evening dosing schedule. After discussion with the sponsor, the
`instructions for use will state “take once daily in the evening” for consistency with the
`prescription labeling.
`
`The other labeling issue that was discussed extensively by the review team was the
`sponsor’s proposal to add the phrase “Original Prescription Strength” 011 the PDP for the 5
`mg tablet. In general, DNDP has allowed this phrase only for full switch programs in order
`to avoid consumer and physician confusion with other indications and dosing strengths that
`remain prescription. The racemate Zyrtec (cetiiizine) was permitted to have this flag on
`labeling because it was a full switch application. In this case, the sponsor proposed that
`while Xyzal is not a full switch for the 5 mg tablet because the CIU indication did not
`switch, there would be no confusion because there are no other tablet strengths available in
`either the prescription or the OTC setting. This is a reasonable argument provided that the 5
`mg tablet remains the only strength available for both prescription and OTC use.
`
`13 DECISION/ACTION/BENEFIT RISK ASSESSMENT
`
`13.1 Regulatory action
`
`Sanofi has submitted adequate data to support approval of Xyzal (levocetiiizine) 5 mg
`tablet and oral solution for OTC use for seasonal and perennial allergic rhinitis. This
`
`Reference ID: 4048782
`
`

`

`Division Director Review
`NDA 209089 (tablet) and NDA 209090 (oral solution)
`
`levocetirizine dihydrochloride
`
`approval will constitute a partial switch of the SAR and PAR indications down to age 2
`years. The CIU indication for all age groups as well as PAR for children ages 6 months to
`under 2 years will remain prescription.
`
`13.2 Risk Benefit Assessment
`The overall risk-benefit assessment supports approval of Xyzal (levocetirizine) tablets and
`oral solution for the indication “temporarily relieves these symptoms of hay fever or other
`respiratory allergies: runny nose, sneezing, itchy, watery eyes, and itching of the nose or
`throat” in adults and children 2 to 64 years of age. The efficacy and safety of allergic
`rhinitis indications (SAR and PAR) have been established for prescription use. It is
`expected that this second generation antihistamine product would have similar efficacy in
`the OTC setting, as the allergic rhinitis indication is similar for both prescription and OTC.
`No new safety signals were identified as part of this application, including evaluation of the
`safety database of 62 clinical trials and an extensive post-marketing database. Given the
`contraindication for use in severe renal impairment or in patients on hemodialysis on the
`prescription label and complex dosing algorithm for patients with lesser degrees of renal
`impairment, OTC labeling will contain the more conservative warning of “Do not use if
`you have kidney disease.” This warning along with warnings related to urinary retention
`were tested in a label comprehension study. Further, the labeling will contain class labeling
`warnings related to sedation.
`
`13.3 Recommendation for Postmarketing Risk Evaluation and Mitigation
`Strategies
`None.
`
`13.4. Recommendation for other Postmarketing Requirements and
`Commitments
`None.
`
`Reference ID: 4048782
`
`9
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`THERESA M MICHELE
`01/30/2017
`
`Reference ID: 4048782
`
`