CENTER FOR DRUG EVALUATION AND
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`RESEARCH
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`APPLICATION NUMBER:
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`210875Orig1s000
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`SUMMARY REVIEW
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` Summary Review
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` 5/21/20
` Gerald D. Podskalny, DO, and Eric Bastings, MD
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` Summary Review
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` 210875
` Response to CR letter
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` Kynmobi / Apomorphine hydrochloride sublingual film
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` Date
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` From
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` Subject
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` NDA/BLA #
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` Supp #
` Proprietary /
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`Established
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` (USAN) names
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` Dosage forms /
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` strength
` Proposed
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` Indication(s)
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` Action
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` 1. Background/Regulatory History/Previous Actions/Foreign Regulatory Actions/Status
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` Sunovion Pharmaceuticals Inc. (Applicant) submitted a response to the complete response
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` letter that was issued by the Agency on January 29, 2019, for their new drug application
`(NDA) for Kynmobi (apomorphine hydrochloride) sublingual film.
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` The proposed indication for Kynmobi is the acute, intermittent treatment of “off” episodes in
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` patients with Parkinson’s disease (PD). This 505(b)(2) NDA relies on nonclinical and clinical
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` pharmacology information from listed drug Apokyn (NDA 21-264). Apokyn is approved for
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` the treatment of “acute, intermittent treatment of hypomobility, off episodes (“end-of-dose
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` wearing off” and unpredictable “on/off” episodes) in patients with advanced Parkinson’s
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` disease.
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` As discussed in the summary review for the original application, the applicant conducted a
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` relative bioavailability study (CTH-200) designed to bridge Kynmobi and Apo-go, an
`apomorphine subcutaneous injection marketed outside of the United States. The applicant also
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`submitted in the original application interim results of a relative bioavailability study (CTH­
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`203) between Apokyn, Apo-go and Kynmobi that was ongoing at the time. In addition, the
`applicant attempted to establish sameness between Apo-go and Apokyn based on composition
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`and in vitro data.
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` The original application was issued a complete response (CR) letter because of deficiencies in
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` human factors evaluations, inadequate bridging to listed drug Apokyn, and inadequate
` characterization of the oropharyngeal adverse events that were observed in patients treated
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` with Kynmobi.
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`This new submission includes the applicant’s response to the deficiencies listed in the CR
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`action letter and to various issues that did not affect approvability of the original NDA.
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` Summary Review
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` Sublingual film / 10 mg, 15 mg, 20 mg, 25 mg and 30 mg
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` Acute, intermittent treatment of “off’ episodes in patients with
` Parkinson’s disease
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` Approval
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`Reference ID: 4611886Reference ID: 4613103
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`1
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`Summary Review
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`Of note, the efficacy of Kynmobi was established in the first review cycle.
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` 2. Chemistry, Manufacturing and Controls
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`Leah W. Falade, Ph.D. (Primary Reviewer), Ta-Chen Wu, Ph.D. (Secondary Reviewer), and
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` Martha Heimann, Ph.D. (Technical Lead) reviewed the CMC information.
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`There are no outstanding product quality issues precluding approval.
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`3. Clinical Pharmacology/Biopharmaceutics
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`The Office of Clinical Pharmacology review team included Mariam Ahmed, Ph.D. (Primary
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`Reviewer), Sreedharan Sabarinath, Ph.D. (Team Lead), and Mehul Mehta, Ph.D. (Division
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`Director).
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`505(b)(2) bridge
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`As discussed in the first-cycle summary review, insufficient information was provided by the
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`applicant to establish a bridge between Kynmobi and Apokyn. The final results of relative
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`bioavailability Study CTH-203 were needed to support the scientific bridge between the listed
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`drug and Kynmobi. This new submission includes the final study report for Study CTH-203.
`The study shows that following the maximum recommended dose of Kynmobi (i.e., 30 mg),
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`the extent of apomorphine exposure and Cmax is at least 10% and 40% lower, respectively,
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`than following a 6-mg dose of Apokyn. Therefore, the OCP review team concludes that an
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`acceptable bridge has been established between Kynmobi and Apokyn, allowing to rely on
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`Apokyn’s nonclinical safety information, and on applicable clinical pharmacology
`information from Apokyn.
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`Apomorphine metabolites
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`The Agency recommended that the applicant conduct in vitro studies to evaluate the drug-
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`drug interaction (DDI) potential of two major inactive metabolites of Kynmobi, apomorphine
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`glucuronide and norapomorphine glucuronide. The applicant submitted results from DDI
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`studies of apomorphine glucuronide. The DDI potential of apomorphine glucuronide (through
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`inhibition of major transporters) is considered minimal.
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`A postmarketing requirement will be issued to conduct in vitro studies to evaluate the DDI
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`potential of the norapomorphine glucuronide major metabolite as a perpetrator for major CYP
`enzymes and transporters.
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`Office of Study Integrity and Surveillance (OSIS) inspections
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`) were
`Two clinical study sites and the analytical laboratory facility (
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`inspected by the Office of Study Integrity and Surveillance (OSIS). The data from Study
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`CTH-203 were found to be reliable.
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`Reference ID: 4611886Reference ID: 4613103
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`2
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`(b) (4)
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`Recommendation
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`The Office of Clinical Pharmacology recommends approval.
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`4. Clinical
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` Kenneth Bergmann, MD, was the primary clinical reviewer for the original NDA submission,
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` and for the submission under review.
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`The efficacy of Kynmobi for the acute, intermittent treatment of “off” episodes was
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`established during the first NDA review cycle.
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`The applicant did not adequately characterize in the original application the oropharyngeal
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`adverse events that were observed in patients treated with Kynmobi. The applicant was
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`requested to provide a comprehensive discussion and summary of oropharyngeal adverse
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`events with Kynmobi, including an expert review from a qualified dermatologist. For both
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`Study 300 (controlled efficacy study) and Study 301 (open-label safety study), the applicant
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`was asked to reexamine the safety database, and pool all related oropharyngeal adverse events
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`in appropriate clusters (e.g., oropharyngeal edema, pain, ulceration, hypoesthesia, etc.).
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`The applicant was also requested to present analyses of the time to onset of the events after
`treatment initiation, evolution, time course, time to resolution after treatment discontinuation,
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`and relationship to the dose of Kynmobi. In addition, the applicant was asked to present
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`analyses of the association between oropharyngeal adverse events and systemic
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`hypersensitivity, including the temporal relationship between oropharyngeal and systemic
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`hypersensitivity events, if any. All patients reporting new oropharyngeal adverse events in
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`Study 301, which was ongoing during the first review cycle, were to be examined by a
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`qualified dermatologist/dentist with photographs taken of all relevant oral mucosal and skin
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`abnormalities needing to be included in a case summary.
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`New safety information was added for 105 patients, who were treated between the 120-day
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`update cut off (May 10, 2018) and the cutoff date for the resubmission (May 10, 2019).
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`The size of the overall safety database of Kynmobi is adequate. As Kynmobi is an
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`intermittent-use drug intended to be taken during an acute “off” episode, the number of daily
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`uses of the drug varies from day to day. The applicant could only provide daily dosing as an
`average daily dose (Table 1). Most patients took an average 0-2 doses of Kynmobi per day.
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`The available safety information is limited for doses greater than 30 mg, which will be the
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`highest recommended dose.
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`Summary Review
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`Reference ID: 4611886Reference ID: 4613103
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`3
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` Summary Review
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`Table 1. Imputed average number of doses per day by highest dose level recorded during
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`the maintenance phase of Study 300 and 301
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`0 to <1 1 to <2 2 to <3 3 to <4 4 to <5 ≥5 Total N
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` 20
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` 23
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` 27
`24
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`14
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` 7
` 115
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` 5
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` 10
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` 8
`6
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`4
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` 4
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` 37
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` 2
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` 4
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` 3
`6
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`3
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` 1
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` 19
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` 1
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` 2
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` 2
`2
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`0
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`
` 1
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` 8
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` 0
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` 0
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` 0
`1
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`0
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` 0
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` 1
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` 64
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` 83
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` 77
`65
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`37
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` 31
` 357
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` APL-130277 Dose level
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` 36
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` 10 mg
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` 44
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` 15 mg
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` 37
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` 20 mg
`26
`25 mg
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`16
`30 mg
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` 18
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` 35 mg
` 177
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` Total
`Source: FDA Clinical Review
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` There is no significant new safety information related to deaths, serious adverse events and
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` adverse dropouts in additional patients presented in this submission.
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` In the original submission, oropharyngeal adverse events were reported in an excessively
` granular fashion. Often, adverse events describing similar symptoms were presented as
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` different preferred terms (e.g., oropharyngeal swelling and pharyngeal edema). The applicant
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` was asked to reexamine the safety database, and pool all related oropharyngeal adverse events
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` in appropriate clusters. The clinical review team also reanalyzed the applicant’s safety data
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` (Table 2). Terms for similar oropharyngeal adverse reactions were combined into clusters of
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` related preferred terms (see Table 2) for oropharyngeal swelling, pain/paresthesia, and
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` ulceration. Each patient was counted only once in a cluster, in each study phase.
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` Nausea and somnolence were the most common adverse reactions during the titration and the
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` maintenance phase. Oral soft tissue swelling (lips, tongue, gingiva, and mouth) was reported
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` as adverse reaction in 15% of patients treated with Kynmobi during the maintenance phase of
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`Study 300, compared with 0% of patients who received placebo; 11% of patients discontinued
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`Kynmobi because of this event.
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`Swelling of the face, oral allergy syndrome, hypersensitivity, or urticaria were reported as an
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`adverse reaction in 6% of patients treated with Kynmobi during the maintenance phase of
`Study 300, compared with 0% of patients who received placebo; 4% of patients discontinued
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`Kynmobi because of this event.
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`During the titration phase of Study 300, oral mucosal ulceration or stomatitis were reported as
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`adverse reactions in 2% of patients treated with Kynmobi. During the maintenance phase of
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`Study 300, oral mucosal ulceration or stomatitis were reported as adverse reactions in 7% of
`patients treated with Kynmobi, compared with 0% of patients who received placebo. During
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` the titration of Study 300, oral soft tissue pain or paresthesia were reported as adverse
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`reactions in 2% of patients treated with Kynmobi. During the maintenance phase of Study
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`300, oral soft tissue pain or paresthesia were reported as adverse reactions in 13% of patients
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`treated with Kynmobi, compared with 2% of patients who received placebo.
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`Reference ID: 4611886Reference ID: 4613103
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`4
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` Summary Review
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`In general, oral mucosal irritation reactions were mild to moderate severity, and usually
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`resolved with treatment discontinuation.
`Table 2: Adverse reactions reported in at least 5% of patients treated with Kynmobi
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`and with an incidence greater than placebo in Study 300 (Titration and Maintenance
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`Phase)
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`Reference ID: 4611886Reference ID: 4613103
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`5
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` Maintenance
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` Titration
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` Placebo
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` Kynmobi
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` Kynmobi
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` (N=55)
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` (N=54)
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` (N=141)
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` %
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` %
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` %
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` Gastrointestinal disorders
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` 21
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` Nausea
`28
`4
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` 1
`Oral/pharyngeal soft tissue swelling1
`15
`0
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` Oral/pharyngeal soft tissue pain and paraesthesia2
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` 2
`11
`2
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`Oral ulceration and stomatitis3
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` 3
`7
`2
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` Oral mucosal erythema
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` 4
`7
`4
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` Vomiting
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` 4
`7
`0
` Dry mouth
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` 1
`6
`0
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` Nervous system disorders
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` 11
` Somnolence
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`13
`2
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` 11
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` Dizziness
`9
`0
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` 8
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` Headache
`6
`0
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` Respiratory, thoracic and mediastinal disorders
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` 0
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` 7
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` 6
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` Rhinorrhea
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` General disorders and administration site
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` conditions
`0
`7
`3
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` Fatigue
`0
`4
`6
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` Chills
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` Injury, poisoning and procedural complications
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` 2
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` 6
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` 4
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` Fall
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` Skin and subcutaneous tissue disorders
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` 4
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` 6
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` 4
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` Hyperhidrosis
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` Injury, poisoning and procedural complications
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` 0
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` 6
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` 1
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` Laceration
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` Immune system disorders
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` 0
` 6
` 0
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`Hypersensitivity4
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` 1 Includes lip swelling, lip edema, oropharyngeal swelling, gingival edema, edema mouth, swollen tongue, and
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` pharyngeal edema
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`2 Includes throat irritation, glossodynia, oral paresthesia, oral pain, oropharyngeal pain, gingival pain, and oral
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`hypoesthesia
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`3 Includes lip ulceration, oral mucosal blistering, cheilitis, stomatitis, and tongue ulceration
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`4 Includes hypersensitivity, swelling face, oral allergy syndrome and urticaria
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` Evolution of oral/pharyngeal adverse events
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`Figure 1 and Figure 2 show the prevalence of oropharyngeal adverse events and the
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`prevalence of hypersensitivity-related adverse events as a percent of the safety population
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`over time. Reports of mild to moderate oropharyngeal adverse events started in the first week
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`of treatment. The prevalence, shown as a percentage of the study population, remained under
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`10% until Week 8. Between Week 8 and Week 16, the prevalence of oral adverse events
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` Summary Review
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`exceeded 15% of the study population, with a higher percentage of events classified as
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`moderate to severe than earlier in the study.
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` Hypersensitivity-related adverse events generally occurred soon after treatment initiation, and
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` remained mild in intensity.
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`Figure 1: Time-to-Event distribution of prevalence for oral/pharyngeal adverse event
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`clusters (cumulative safety population)
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` Figure 2: Time-to-Event distribution of prevalence for the hypersensitivity adverse event
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` cluster (cumulative safety population)
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` Of the 500 oropharyngeal adverse events reported for the combined titration and maintenance
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` phase of Study 300/301, 12% had not resolved by the data cutoff. The clusters with events
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`Reference ID: 4611886Reference ID: 4613103
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`6
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`Summary Review
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`most commonly not resolved at cutoff (as a proportion of total events) were alterations in
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`taste, oropharyngeal numbness/changes in sensation, and salivary complaints/oral dryness.
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` A trend towards a dose-response was observed for some oropharyngeal clusters, but a clear
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` interpretation was precluded by the titration of study medication to tolerance.
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`Anaphylaxis, angioedema, and hypersensitivity reactions
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`The applicant and Dr. Bergmann found no cases that fulfilled the criteria for anaphylaxis.
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`Both broad and narrow search criteria were used and identified cases of local oral or
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`pharyngeal swelling that were primarily localized to the mouth and face, without other signs
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`of anaphylaxis. There were few cases associated with systemic hypersensitivity (e.g.,
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`urticaria) that were not temporally related to the oral adverse event. None of the events were
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`associated with life-threatening outcomes, and symptoms resolved with discontinuation of
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`Kynmobi. The applicant’s expert consultant (David Margolis, MD) came to a similar
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`conclusion in his report.
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`Consultation by the Division of Dermatology and Dentistry
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`The review team consulted the Division of Dermatology and Dentistry (DDD) for assistance
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`in interpreting photographs for oropharyngeal adverse events included in the applicant’s
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`complete response. Assistance was also requested in evaluating the applicant’s expert opinion
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`about oropharyngeal adverse events associated with Kynmobi.
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`Natalia Chalmers, DDS, PhD, was the primary dental reviewer for this consult. David Kettl,
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`MD, was the team leader, and supervisory concurrence was provided by Kendall Marcus,
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`MD, Division Director.
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`The dental reviewer agreed that the applicant addressed the issues listed in the complete
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`response letter. Overall, the conclusions of the DDD consultants are similar to those of the
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`applicant. The consultant agreed that oral adverse events were generally were mild to
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`moderate in severity, and the symptoms (swelling and mucosal ulcers) resolved with
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`interruption or discontinuation of Kynmobi. The oropharyngeal adverse events do not appear
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`to be related to systemic hypersensitivity.
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`Safety conclusion
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`The applicant has adequately addressed the deficiencies that precluded approval included in
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`the Complete Response letter.
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`The clinical safety information supports the safety of Kynmobi up to a maximum
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`recommended dose of 30 mg.
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`A thorough analysis of oropharyngeal adverse events finds that the events were generally mild
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`to moderate in severity, remained localized, and resolved when Kynmobi was withheld or
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`discontinued. There is no evidence linking Kynmobi with more serious or life-threatening
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`Reference ID: 4611886Reference ID: 4613103
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`7
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`

`

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` Summary Review
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`hypersensitivity reactions (e.g., anaphylaxis or serious skin reactions). Prescribers will be
`prominently warned about the risk for oropharyngeal adverse reactions in the Kynmobi label.
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` 7. Other Relevant Regulatory Issues
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`
`Human Factors Validation Study
`Ebony Whaley, PharmD, BCPPS, Safety Evaluator, Lolita White, Pharm.D., Team leader,
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`
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`QuynhNhu Nguyen, MS, Associate Director for human factors, and Danielle Harris,
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`Pharm.D., Deputy Director, Division of Medication Error Prevention and Analysis (DMEPA),
`reviewed the human factor study information in the resubmission.
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`Deficiencies in the original human factors validation (HFV) study discovered during the
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`original NDA review were sent to the applicant in a Discipline Review letter and in the
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`Complete Response letter. Multiple participants committed use errors and experienced close
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`calls while performing critical tasks.
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`The applicant conducted a root cause analysis to determine the factors that underlie the errors
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`and close calls. The instructions for use were revised to combine the instruction for the
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`administration of the drug product and instructions for operating the child-resistant packaging
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`in a single document. These changes were evaluated in a supplemental HFV study to
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`demonstrate that the revisions were effective in mitigating the errors and did not introduce
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`new risks. Upon review of the study results, DMEPA found that close calls and errors in both
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`critical and noncritical tests that were similar to those found in the initial study. Most errors
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`occurred during administration of the 35-mg dose. Subjects took the 20-mg and 15-mg film at
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`the same time, or improperly took the 15-mg film followed by the 20-mg film. Some users
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`still had difficulty opening the child-resistant packaging due to problems with dexterity.
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`DMEPA concluded the applicant addressed the residual risk to the extent feasible. Users had
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`other means to open the child-resistant packaging or could ask a caregiver for assistance.
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`Most study participants knew to store the product away from children. DMEPA
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`recommended revisions to the instructions for use, the proposed labels and the prescribing
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`information, which were sent to the applicant. The applicant can implement these
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`recommendations without additional HFV testing.
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`DMEPA concluded that no additional mitigation strategies are necessary and that the residual
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`risk is acceptable.
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`Controlled Substance Staff
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`The applicant referenced information describing the potential for abuse and dependence for
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`the listed drug (Apokyn) under the 505(b)(2) pathway. CSS concluded that apomorphine does
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`not have abuse potential and should not be controlled under the Controlled Substances Act
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`(CSA).
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`CSS found reports in the literature of people trying to use apomorphine for abuse. In some of
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`the cases, this appears to be because apomorphine contains ‘morphine’ in the name, and
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`individuals believe it will produce opioid-like effects. Apomorphine is actually a non-specific
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`Reference ID: 4611886Reference ID: 4613103
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`8
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` Summary Review
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`dopamine agonist, and many individuals stop using the drug when it does not produce the
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`desired effects.
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` 8. Labeling
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`Proprietary name
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` The Division of Medication Error Prevention and Analysis sent a letter to the applicant, dated
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` April 29, 2020, stating the proposed proprietary name, Kynmobi is conditionally acceptable.
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`Physician labeling
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` The Office of Prescription Drug Promotion (OPDP) and Division of Medical Policy Programs
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` (DMPP) comments and edits were included in the division’s review of the label. Final
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` labeling was agreed upon with the applicant.
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` Carton and immediate container labels
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`The Office of Prescription Drug Promotion (OPDP) and the Office of Product Quality (OPQ)
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`reviewed the final revisions to the carton and container labels proposed by the applicant.
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`OPDP and OPQ have no additional edits for the carton and container labels.
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`Patient labeling
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` The Division of Medical Policy Programs (DMPP) and the Office of Prescription Drug
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` Promotion (OPDP) provided labeling edits and recommendations.
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` 11. Conclusions and Recommendations
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` The efficacy of Kynmobi for the acute treatment of “off” episodes in patients with
` Parkinson’s Disease was established in the first review cycle.
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` The applicant has adequately addressed the deficiencies that led to the Complete Response
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` letter issued after the first review cycle.
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`The data support approval of Kynmobi with a maximum recommended single dose of 30 mg,
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`taken up to 5 times a day.
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`The most common adverse reactions associated with Kynmobi are nausea, somnolence and
`oropharyngeal adverse reactions.
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`Postmarketing studies
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`A postmarketing requirement for a drug-drug interaction study is described in the Clinical
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`Pharmacology section of this review.
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`Reference ID: 4611886Reference ID: 4613103
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`9
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`(b) (4)
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` Summary Review
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`Comments to be conveyed to the applicant in the regulatory action letter
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` None other than the postmarketing requirement.
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`Reference ID: 4611886
`Reference ID: 4613103
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`10
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`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`GERALD D PODSKALNY
`05/20/2020 03:01:47 PM
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`ERIC P BASTINGS
`05/21/2020 08:46:43 AM
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`
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`Reference ID: 4611886Reference ID: 4613103
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`