CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`212640Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`Date
`
`From
`
`Subject
`NDA/BLA #
`Suoolement#
`Applicant
`Date of Submission
`PDUF A Goal Date
`Proprietary Name I Non-
`Proprietary Name
`Dosage form(s) I Strength(s)
`Applicant Proposed
`Indication( s )/Population( s)
`Regulatory Action
`
`Summary Memorandum
`
`November 4, 2019
`Teresa Bmacchio, MD
`Eric Bastings, MD
`Summary Memorandum
`212640
`
`Aquestive Therapeutics
`1/31/2019
`11/30/2019
`Exservan (riluzole)
`
`Oral film, 50 mg
`Treatment of amyotrophic lateral sclerosis (ALS)
`
`Aooroval
`
`Reference ID: 45~S4
`
`1
`
`

`

`1. Background
`The applicant has submitted a New Drug Application (NDA) for Exservan (riluzole) 50-mg
`oral film. The applicant is seeking approval through the 505(b)(2) regulatory pathway and is
`relying on the findings of safety and effectiveness for the listed drug (LD), Rilutek (riluzole
`50-mg oral tablet), and on data from a relative bioavailability study for establishing a
`pharmacokinetic (PK) bridge between Exservan and the LD.
`
`Riluzole 50-mg oral tablet was approved for “the treatment of patients with amyotrophic
`lateral sclerosis (ALS)” on December 12, 1995 (NDA 020599). The applicant proposes the
`same indication as Rilutek. The recommended dosage for riluzole is 50 mg taken orally twice
`daily. The oral film formulation of riluzole will provide an equivalent dose of the 50-mg
`tablet.
`
`Riluzole oral film was granted orphan drug designation by FDA on January 23, 2018.
`
`Product Quality
`2.
`The technical lead on the Office of Product Quality (OPQ) review was Dr. Martha Heimann.
`Dr. Heimann’s review lists the entire OPQ team that was involved with the review of this
`application. Please refer to the OPQ review for details of the product quality assessment.
`
`According to the OPQ review, the drug substance is produced with adequate quality to
`support approval of the NDA.
`
`The drug product is a polymer-based film matrix that contains 50 mg of riluzole per film.
`The formulation is similar to previous products developed by the applicant (e.g., Zuplenz and
`Suboxone); however, the riluzole oral film formulation incorporates polacrilex resin and
`flavors
`. There are no novel
`excipients, and maximum daily exposures for excipients are within levels for FDA-approved
`products.
`
`Stability and release testing were found to be acceptable. The stability data provides adequate
`support for a shelf-life of 24 months, when stored at controlled room temperature (68°–77°
`F). OPQ determined that the manufacturing process for the drug product is satisfactory. All
`manufacturing facilities for this product were found to be acceptable. There were no
`outstanding issues identified in the OPQ review.
`
`OPQ recommends approval.
`
`3. Nonclinical Pharmacology/Toxicology
`There was no nonclinical information in the submission.
`
`2
`
`
`
`Reference ID: 4522611Reference ID: 4525554
`
`(b) (4)
`
`

`

`4. Clinical Pharmacology
`The Office of Clinical Pharmacology (OCP) review was performed by clinical pharmacology
`reviewer Dr. Gopichand Gottipati, with Dr. Sreedharan Sabarinath as Team Leader.
`
`Study 162020, the pivotal bioequivalence study, was a single-center, open-label, single-dose,
`randomized, 5-period, crossover, comparative bioavailability study. Healthy subjects were
`randomized to receive a single dose of study medication or the reference formulation (under
`fasting or fed conditions) according to the randomization scheme. The study enrolled 45
`subjects, and 30 subjects completed all treatment periods.
`
`Bioavailability/Bioequivalence Assessment
`The following table from the clinical study report for Study 162020 provides a summary of
`the comparative bioavailability data from the bioequivalence studies. Reference A refers to
`riluzole oral film and Reference B refers to riluzole tablets, both under fasting conditions.
`
`The results show that the geometric means for AUC0-t, AUC0-inf, and for Cmax were
`approximately 109%, 109%, and 116%, respectively. OCP notes that this indicates a similar
`extent and rate of riluzole absorption after a single dose of the test and reference products
`under fasting conditions, which meets bioequivalence criteria.
`
`Food Effects
`The LD, riluzole tablet, has significant food effects. As described in the prescribing
`information for the LD, the Cmax decreases by approximately 45% and the AUC decreases
`by approximately 20% when administered with a high fat meal. The prescribing information
`(PI) for the listed drug specifies that riluzole should be administered “at least 1 hour before or
`2 hours after a meal”.
`
`
`
`Reference ID: 4522611Reference ID: 4525554
`
`3
`
`

`

`Following the administration of riluzole oral film to healthy subjects under fed conditions
`with a high-fat meal, Cmax decreased by approximately 45%, and AUC decreased by about
`15%. The food effects were comparable to the LD; therefore, OCP recommends that the
`dosing instructions for riluzole oral film should remain the same as for the LD.
`
`OCP Recommendation:
`OCP recommends approval based on the bioequivalence demonstrated between riluzole oral
`film and the LD.
`
`5. Clinical- Efficacy
`The effectiveness of riluzole oral film is based on the demonstration of bioequivalence to the
`LD.
`
`6. Clinical- Safety
`The safety of Exservan is based on the demonstration of bioequivalence to the LD. Dr.
`Rainer Paine, the clinical reviewer for this application, reviewed the new safety data in this
`submission. The safety review focused on the clinical studies conducted with riluzole oral
`film; however, Dr. Paine also reviewed safety data from the published literature and post-
`marketing safety reports for riluzole.
`
`The review of safety evaluated the three studies conducted by the applicant: pilot study 1897,
`pivotal study 162020, and swallowing safety study 17M01R-0012.
`
`There were no deaths, serious adverse events, or discontinuations in the clinical development
`program.
`
`A new safety signal of oral hypoesthesia was identified for the oral film formulation of
`riluzole. In the pivotal study (162020), oral hypoesthesia occurred in both the fasting and fed
`riluzole oral film groups (38% and 10%, respectively), compared with no occurrences in
`subjects taking riluzole tablets. The hypoesthesia was transient and resolved during the study.
`Circumoral paresthesia is described in the label for the LD. The rates of hypoesthesia
`observed with the riluzole oral film may potentially be related to greater contact with the oral
`mucosa than with the tablet formulation. All other adverse events were generally consistent
`with the established safety profile of riluzole.
`
`A swallowing study, 17MO1R-0012, was a single-site, single-dose, open-label safety study
`in nine individuals with ALS. The study was terminated early due to enrollment challenges,
`and an interim analysis of 9 patients showed no evidence of swallowing dysfunction on
`videofluoroscopy.
`
`In a review of the postmarketing safety data for Rilutek from 12/17/17 to 11/12/18, Dr. Paine
`identified two cases of acute pancreatitis. Additionally, a published literature review also
`
`4
`
`
`
`Reference ID: 4522611Reference ID: 4525554
`
`

`

`identified a journal article describing two cases of acute pancreatitis associated with riluzole
`use (de Campos & de Carvalho, 20171). Pancreatitis was identified in the original riluzole
`clinical studies as an infrequent adverse event, occmTing in 11100 to 111000 patients.
`<bnsr
`Pancreatitis is not mentioned in the cmTent riluzole label.
`
`Clinical recommendation: Dr. Paine identified oral hypoesthesia as a new safety signal
`observed with this oral film fonnulation of riluzole. This will be described in Section 6 of the
`PI. Dr. Paine recommends approval of this supplement and I agree with his recommendation.
`A newly identified potential safety signal for pancreatitis will be further assessed under the
`originator product.
`
`7. Advisory Committee Meeting
`
`None required as drng is not a new molecular entity.
`
`8. Pediatrics
`
`The submission did not include any pediatric data. Because the product has 01phan drng
`designation, Pediatric Research Equity Act (PREA) requirements were not ti·iggered.
`
`9. Labeling
`
`Please refer to the final negotiated product label. Labeling negotiations with the applicant
`have been completed and the applicant has accepted all recommended changes.
`
`The Division of Medication Enor and Prevention Analysis (DMEP A) and the Office of
`Prescription Dmg Promotion (OPDP) provided consultations on the product labeling,
`including the proposed instructions for use (IFU).
`
`10. Recommendations/Risk-Benefit Assessment
`
`As the applicant has provided an adequate bridge to Rilutek, the findings of safety and
`efficacy of Rilutek, along with the new safety info1mation provided by the applicant, suppo1i
`the approval of Exservan (riluzole oral film)
`
`1 de Campos, C., & de Carvalho, M. Riluzole-induced recurrent pancreatitis J Clin Neurosci. 201;45:153-154.
`
`Reference ID: 45~S4
`
`5
`
`

`

`Oral hypoesthesia was identified as a new safety signal obse1ved with this oral suspension
`fo1mulation of riluzole in the pivotal bioequivalence study and will be described in labeling.
`This new safety finding does not impact the risk-benefit assessment of riluzole. A potential
`safety signal of pancreatitis was identified in a review of the postmarketing safety repo1is for
`<b><5
`riluzole and in a review of the published literature.
`f
`
`Specific postmarketing risk management activities are not needed.
`
`I agree with the review team that this NDA should be approved.
`
`Reference ID: 45~S4
`
`6
`
`

`

`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/
`------------------------------------------------------------
`
`TERESA J BURACCHIO
`11/20/2019 10:43:13 AM
`
`ERIC P BASTINGS
`11/22/2019 02:29:39 PM
`
`
`
`Reference ID: 4522611Reference ID: 4525554
`
`