`
`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`
`
`
`APPLICATION NUMBER:
`
`212516Orig1s000
`
`
`MULTI-DISCIPLINE REVIEW
`Summary Review
`Office Director
`Cross Discipline Team Leader Review
`Clinical Review
`Non-Clinical Review
`Statistical Review
`Clinical Pharmacology Review
`
`

`

` NDA/BLA Multi-disciplinary Review and Evaluation NDA 212516
`
`Drizalma Sprinkle (Duloxetine Delayed-Release Capsules)
`
`
`
`NDA/BLA Multi-Disciplinary Review and Evaluation
`Application Type 505(b)(2) New Drug Application (NDA)
`Application Number(s) NDA 212516
`Priority or Standard Standard
`Submit Date(s) September 9, 2018
`Received Date(s) September 9, 2018
`
` PDUFA Goal Date
`July 19, 2019
`Division/Office Division of Psychiatry Products/ Office of Drug Evaluation I
`Review Completion Date
` Established/Proper Name Duloxetine Delayed-Release Capsules 20 mg, 30 mg, 40 mg, and
`60 mg
`(Proposed) Trade Name Drizalma Sprinkle
`Pharmacologic Class Serotonin (5-HT) and Norepinephrine Reuptake Inhibitor
`Code name
`Applicant Sun Pharma Global FZE
`Doseage form Oral Capsules
`Applicant proposed Dosing
` Dosing regimen varies by indication. Starting dose 30 mg/day to
`
`Regimen
`
` 60 mg/day; target dose
` mg/day to 60 mg/day; maximum
`dose 120 mg/day
` Major Depressive Disorder (MDD), Generalized Anxiety
`
` Disorder (GAD), Diabetic Peripheral Neuropathic Pain (DPNP),
`and Chronic Musculoskeletal Pain
`
` 370143000 Major depressive disorder (disorder)
`21897009 Generalized anxiety disorder (disorder)
`
`193184006 Chronic painful diabetic neuropathy (disorder)
`
`762452003 Chronic musculoskeletal pain (finding)
`
`
`
` Applicant Proposed
`
`Indication(s)/Population(s)
`
`
` Applicant Proposed
`
` SNOMED CT Indication
`Disease Term for each
`
`Proposed Indication
`
`Recommendation on
`Regulatory Action
`Recommended
`
`Indication(s)/Population(s)
`(if applicable)
`
`Recommended SNOMED
`CT Indication Disease
`
`Term for each Indication
`(if applicable)
`Recommended Dosing
`Regimen
`
`Approval
`
`Major Depressive Disorder: Adults
`Generalized Anxiety: Adults, Elderly, Children and Adolescents
`(7 to 17 years of age)
`Diabetic Peripheral Neuropathic Pain: Adults
`Chronic Musculoskeletal Pain: Adults
`
` 370143000 Major depressive disorder (disorder)
`21897009 Generalized anxiety disorder (disorder)
`
`193184006 Chronic painful diabetic neuropathy (disorder)
`
`762452003 Chronic musculoskeletal pain (finding)
` Dosing regimen varies by indication. Starting dose 30 mg/day to
`
`
` 60 mg/day; target dose
` mg/day to 60 mg/day; maximum
`dose 120 mg/day
`
`Reference ID: 4463875
`
`1
`
`(b)
`(4)
`
`(b)
`(4)
`
`

`

` NDA/BLA Multi-disciplinary Review and Evaluation NDA 212516
`
`
`Drizalma Sprinkle (Duloxetine Delayed-Release Capsules)
`
`
`2
`
`3
`
`Table of Contents
`
`Table of Tables................................................................................................................................4
`
`Table of Figures ..............................................................................................................................5
`
`Reviewers of Multi-Disciplinary Review and Evaluation.................................................................6
`
`Glossary ........................................................................................................................................10
`
`1
`Executive Summary ...............................................................................................................12
`
`1.1. Product Introduction......................................................................................................12
`
`1.2. Conclusions on the Substantial Evidence of Effectiveness.............................................12
`
`1.3. Benefit-Risk Assessment ................................................................................................13
`
`1.4. Patient Experience Data.................................................................................................15
`
`Therapeutic Context..............................................................................................................16
`
`2.1. Analysis of Condition......................................................................................................16
`
`2.2. Analysis of Current Treatment Options .........................................................................16
`
`Regulatory Background .........................................................................................................19
`
`3.1. U.S. Regulatory Actions and Marketing History.............................................................19
`
`3.2. Summary of Presubmission/Submission Regulatory Activity ........................................19
`
`Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on
`
`
`Efficacy and Safety ................................................................................................................21
`
`4.1. Office of Scientific Investigations (OSI) ..........................................................................21
`
`4.2. Product Quality ..............................................................................................................21
`
`4.3. Clinical Microbiology......................................................................................................21
`
`4.4. Devices and Companion Diagnostic Issues ....................................................................21
`
`5 Nonclinical Pharmacology/Toxicology ..................................................................................22
`
`5.1. Executive Summary........................................................................................................22
`
`Clinical Pharmacology ...........................................................................................................23
`
`6.1. Executive Summary........................................................................................................23
`
`6.1.1. Recommendations..................................................................................................23
`
`
`6.1.2. Post-Marketing Requirements and Commitments .................................................23
`
`6.2. Summary of Clinical Pharmacology Assessment............................................................23
`
`6.2.1. Pharmacology and Clinical Pharmacokinetics.........................................................24
`
`6.2.2. General Dosing and Therapeutic Individualization.................................................24
`
`6.3. Comprehensive Clinical Pharmacology Review..............................................................25
`
`
`6.3.1. Overview of the Product and Regulatory Background ...........................................25
`
`6.3.2. General Pharmacology and Pharmacokinetic Characteristics ................................25
`
`6.3.3. Clinical Pharmacology Questions............................................................................26
`
`
`4
`
`6
`
`Reference ID: 4463875
`
`2
`
`
`

`

` NDA/BLA Multi-disciplinary Review and Evaluation NDA 212516
`
`
`Drizalma Sprinkle (Duloxetine Delayed-Release Capsules)
`
`
`8
`
`7
`
`Sources of Clinical Data and Review Strategy .......................................................................30
`
`7.1. Table of Clinical Studies .................................................................................................30
`
`7.2. Review Strategy .............................................................................................................31
`
`Statistical and Clinical and Evaluation ...................................................................................31
`
`8.1. Review of Relevant Individual Trials Used to Support Efficacy ......................................31
`
`8.1.1. [DLT_60C-0324_16] ................................................................................................31
`
`8.1.2. Study Results ..........................................................................................................33
`
`8.2. Review of Safety.............................................................................................................37
`
`8.2.1. Safety Review Approach .........................................................................................37
`
`8.2.2. Review of the Safety Database ...............................................................................37
`
`8.2.3. Adequacy of Applicant’s Clinical Safety Assessments.............................................38
`
`8.2.4. Safety Results..........................................................................................................38
`
`8.2.5. Analysis of Submission-Specific Safety Issues.........................................................44
`
`8.2.6. Specific Safety Studies/Clinical Trials......................................................................44
`
`
`8.2.7. Safety in the Postmarket Setting ............................................................................44
`
`8.3. Conclusions and Recommendations ..............................................................................45
`
`9 Advisory Committee Meeting and Other External Consultations .........................................46
`
`10 Pediatrics...............................................................................................................................47
`
`11 Labeling Recommendations ..................................................................................................48
`
`11.1.
`Prescription Drug Labeling .........................................................................................48
`
`
`12 Risk Evaluation and Mitigation Strategies (REMS) ................................................................50
`
`
`13 Postmarketing Requirements and Commitment ..................................................................51
`
`14 Appendices............................................................................................................................52
`
`14.1.
`References..................................................................................................................52
`
`14.2.
`Financial Disclosure ....................................................................................................52
`
`14.3.
`Nonclinical Pharmacology/Toxicology........................................................................53
`
`14.4. OCP Appendices (Technical documents supporting OCP recommendations)............54
`
`14.4.1. OSIS Memo ......................................................................................................54
`
`14.4.2.
`Individual Study Review...................................................................................55
`
`
`Reference ID: 4463875
`
`3
`
`
`

`

` NDA/BLA Multi-disciplinary Review and Evaluation NDA 212516
`
`
`Drizalma Sprinkle (Duloxetine Delayed-Release Capsules)
`
`
`Table of Tables
`
`Table 1: FDA-Approved Antidepressant Medications ..................................................................17
`
`Table 2: Alternative Formulations of FDA-Approved Antidepressant Medications .....................17
`
`Table 3: Summary of Pharmacokinetic Parameters for Duloxetine .............................................27
`
`
`Table 4: Ratios of LSM for Log-transformed Pharmacokinetic Parameters [Cmax, AUC0-t and
`
`AUC0-inf] for Duloxetine (90% Confidence Interval)....................................................................28
`
`Table 5: Listing of Clinical Trials Relevant to this NDA..................................................................30
`
`Table 6: Material Reviewed..........................................................................................................31
`
`Table 7: Schedule of Study Assessments - Study DLT_60C-0324_16............................................33
`
`Table 8: Number of Patients Exposed to Duloxetine Delayed-Release per Treatment Period ....35
`
`Table 9: Study DLT_60C_0324_16 - Demographics......................................................................36
`
`Table 10: Rescue Medication Use.................................................................................................36
`
`Table 11: Safety Population, Size and Denominators...................................................................37
`
`Table 12: Dropouts or Discontinuations.......................................................................................38
`
`Table 13: Adverse Events By Treatment Condition ......................................................................39
`
`
`
`Table 14: Reference Ranges for Laboratory Assessments............................................................40
`
`Table 15: Elevations in Liver Function Tests .................................................................................41
`
`: Participants Experiencing Change in Heart Rate ≥ 20 Beats per Minute from Baseline
`
`
`Table 16
`......................................................................................................................................................42
`
`
`
`
`Table 17 Summary of Subject Demographic (Left) and Subjects Completing the Bioequivalence
`
`Study (Right) .................................................................................................................................58
`
`
`
`Table 18 Summary of Pharmacokinetic Parameters for Duloxetine ............................................60
`
`
`Table 19 Ratios of LSM for log-transformed pharmacokinetic parameters [Cmax, AUC0-t and
`
`AUC0-∞ ] for Duloxetine (90% Confidence Interval) ....................................................................61
`
`
`Reference ID: 4463875
`
`4
`
`
`

`

` NDA/BLA Multi-disciplinary Review and Evaluation NDA 212516
`
`Drizalma Sprinkle (Duloxetine Delayed-Release Capsules)
`
`Table of Figures
`
`Figure 1 Linear and Semi-log Plot or Mean Plasma Duloxetine Concentration (ng/ml) Versus
`
`Time (hr) .......................................................................................................................................28
`
`
`Figure 2: Systolic Blood Pressure by Treatment Condition...........................................................43
`
`Figure 3: Diastolic Blood Pressures by Treatment Condition .......................................................44
`
`Figure 4 Subject Enrollment and Disposition by Treatment Sequence ........................................58
`
`Figure 5 linear and Semi-log Plot or Mean Plasma Duloxetine Concentration (ng/ml) Versus
`
`Time (hr) .......................................................................................................................................61
`
`
`Reference ID: 4463875
`
`
`5
`
`
`

`

` NDA/BLA Multi-disciplinary Review and Evaluation NDA 212516
`
`Drizalma Sprinkle (Duloxetine Delayed-Release Capsules)
`
`Reviewers of Multi-Disciplinary Review and Evaluation
`
`Kofi Ansah, PharmD
`Regulatory Project Manager
`Arippa Ravindran, PhD
`
` Nonclinical Reviewer
`Ikram Elayan, PhD
`
` Nonclinical Team Leader
`Di Zhou, PhD
`Office of Clinical Pharmacology Reviewer(s)
`Luning (Ada) Zhuang, PhD
`Office of Clinical Pharmacology Team Leader(s)
`
` Martine Solages, MD
`Clinical Reviewer
`Bernard Fischer, MD
`Clinical Team Leader
`N/A
`Statistical Reviewer
`N/A
`Statistical Team Leader
`Luning (Ada) Zhuang, PhD
` Cross-Disciplinary Team Leader
`
`N/A
`
` Division Director (DHOT)
`N/A
`
` Division Director (OCP)
`N/A
`
` Division Director (OB)
`N/A
`
` Division Director (OHOP)
`Office Director (or designated signatory authority) N/A
`
`Additional Reviewers of Application
`
`Wendy Wilson, PhD (Branch Chief)
`OPQ
`N/A
`Microbiology
`Domenic D’Alessandro, PharmD
`OPDP
`N/A
`OSI
`N/A
`OSE/DEPI
`Loretta Holmes, BSN, PharmD
`OSE/DMEPA
`Leah Hart, PharmD
`OSE/DRISK
`Shawna Hutchins, PharmD
`Other: DMPP/PLT
`OPQ=Office of Pharmaceutical Quality
`
`OPDP=Office of Prescription Drug Promotion
`
`OSI=Office of Scientific Investigations
`OSE= Office of Surveillance and Epidemiology
`DEPI= Division of Epidemiology
`DMEPA=Division of Medication Error Prevention and Analysis
`DRISK=Division of Risk Management
`
`Reference ID: 4463875
`
`6
`
`
`

`

` NDA/BLA Multi-disciplinary Review and Evaluation NDA 212516
`
`Drizalma Sprinkle (Duloxetine Delayed-Release Capsules)
`
`Signatures
`
`DISCIPLINE
`
`REVIEWER
`
`OFFICE/DIVISION
`
`SECTIONS
`AUTHORED/
`APPROVED
`
`Nonclinical
`Reviewer
`
`Nonclinical
`Supervisor
`
`Clinical
`Pharmacology
`Reviewer
`
`Division of Psychiatry Products
`
`Sections:
`
`Arippa
`Ravindran
`
`Signature:
`
`Ikram Elayan
`
`Division of Psychiatry Products
`
`Sections:
`
`Signature:
`
`Di Zhou
`
`Office of Clinical Pharmacology Sections
`
`Signature:
`
`AUTHORED/
`APPROVED
`Select one:
`___ Authored
`___ Approved
`
`Select one:
`___ Authored
`___ Approved
`
`Select one:
`___ Authored
`___ Approved
`
`Reference ID: 4463875
`
`7
`
`

`

` NDA/BLA Multi-disciplinary Review and Evaluation NDA 212516
`
`Drizalma Sprinkle (Duloxetine Delayed-Release Capsules)
`
`SECTIONS
`AUTHORED/
`APPROVED
`
`Section:
`
`AUTHORED/
`APPROVED
` Select one:
`___ Authored
`
`___ Approved
`
`Select one:
`___ Authored
`___ Approved
`
`Select one:
`___ Authored
`___ Approved
`
`Select one:
`___ Authored
`___ Approved
`
`DISCIPLINE
`
`REVIEWER
`
`OFFICE/DIVISION
`
`Luning Zhuang
`
` Office of Clinical
`
`Pharmacology
`
`Signature:
`
`Clinical
`Pharmacology
`Team Leader
`
`Clinical
`Pharmacology
`Division Director
`
`Mehul Melta
`
` Office of Clinical
`
`Pharmacology
`
`Section:
`
`Signature:
`
`N/A
`
`Pharmacometrics
`Reviewer
`
`Signature:
`
`N/A
`
`Pharmacometrics
`Team Leader
`
`Signature:
`
`Section:
`
`Section:
`
`Reference ID: 4463875
`
`8
`
`

`

` NDA/BLA Multi-disciplinary Review and Evaluation NDA 212516
`
`Drizalma Sprinkle (Duloxetine Delayed-Release Capsules)
`
`DISCIPLINE
`
`REVIEWER
`
`OFFICE/DIVISION
`
`Martine
`Solages
`
`
`
` Division of Psychiatry
`Products
`
`Clinical Reviewer
`
`Signature:
`
`SECTIONS
`AUTHORED/
`APPROVED
`
`Sections:
`
` Bernard
`
`Fischer
`
`
`
` Division of Psychiatry
`Products
`
`Sections:
`
`Clinical Team
`Leader
`
`Signature:
`
`Signature:
`
`Javier Muniz
`
`
`
` Division of Psychiatry
`Products
`
`Sections:
`
`Signature:
`
` Tiffany
`
`Farchione
`
`
`
` Division of Psychiatry
`Products
`
`Sections:
`
`Deputy Division
`Director
`(Clinical)
`
`Division Director
`(Clinical)
`
`Signature:
`
`AUTHORED/
`APPROVED
`Select one:
`___ Authored
`___ Approved
`
`Select one:
`___ Authored
`___ Approved
`
`Select one:
`___ Authored
`___ Approved
`
`Select one:
`___ Authored
`___ Approved
`
`Reference ID: 4463875
`
`9
`
`

`

` NDA/BLA Multi-disciplinary Review and Evaluation NDA 212516
`
`Drizalma Sprinkle (Duloxetine Delayed-Release Capsules)
`
`Glossary
`
`AC
`ADME
`AE
`AR
`BLA
`BPCA
`BRF
`CBER
`CDER
`CDRH
`CDTL
`CFR
`CMC
`COSTART
`CRF
`CRO
`CRT
`CSR
`CSS
`DHOT
`DMC
`ECG
`eCTD
`ETASU
`FDA
`FDAAA
`FDASIA
`GCP
`GRMP
`ICH
`IND
`ISE
`ISS
`ITT
`MedDRA
`mITT
`NCI-CTCAE
`NDA
`NME
`OCS
`
`advisory committee
`absorption, distribution, metabolism, excretion
`adverse event
`adverse reaction
`biologics license application
`Best Pharmaceuticals for Children Act
`Benefit Risk Framework
`Center for Biologics Evaluation and Research
`Center for Drug Evaluation and Research
`Center for Devices and Radiological Health
`Cross-Discipline Team Leader
`Code of Federal Regulations
`chemistry, manufacturing, and controls
`
`Coding Symbols for Thesaurus of Adverse Reaction Terms
`
`case report form
`contract research organization
`clinical review template
`clinical study report
`Controlled Substance Staff
`Division of Hematology Oncology Toxicology
`data monitoring committee
`electrocardiogram
`electronic common technical document
`elements to assure safe use
`Food and Drug Administration
`Food and Drug Administration Amendments Act of 2007
`Food and Drug Administration Safety and Innovation Act
`good clinical practice
`good review management practice
`International Conference on Harmonisation
`Investigational New Drug
`integrated summary of effectiveness
`integrated summary of safety
`intent to treat
`Medical Dictionary for Regulatory Activities
`
`modified intent to treat
`National Cancer Institute-Common Terminology Criteria for Adverse Event
`new drug application
`new molecular entity
`Office of Computational Science
`
`10
`
`
`Reference ID: 4463875
`
`

`

` NDA/BLA Multi-disciplinary Review and Evaluation NDA 212516
`
`Drizalma Sprinkle (Duloxetine Delayed-Release Capsules)
`
`OPQ
`OSE
`OSI
`PBRER
`PD
`PI
`PK
`PMC
`PMR
`PP
`PPI
`PREA
`PRO
`PSUR
`REMS
`SAE
`SAP
`SGE
`SOC
`TEAE
`
`Office of Pharmaceutical Quality
`Office of Surveillance and Epidemiology
`Office of Scientific Investigation
`Periodic Benefit-Risk Evaluation Report
`pharmacodynamics
`prescribing information
`pharmacokinetics
`postmarketing commitment
`postmarketing requirement
`per protocol
`patient package insert (also known as Patient Information)
`Pediatric Research Equity Act
`patient reported outcome
`Periodic Safety Update report
`risk evaluation and mitigation strategy
`serious adverse event
`statistical analysis plan
`special government employee
`standard of care
`treatment emergent adverse event
`
`Reference ID: 4463875
`
`11
`
`
`

`

` NDA/BLA Multi-disciplinary Review and Evaluation NDA 212516
`
`Drizalma Sprinkle (Duloxetine Delayed-Release Capsules)
`
`1 Executive Summary
`
`Product Introduction
`
`1.1.
`
`
`
` Sun Pharma Global FZE has submitted a 505(b)(2) application for duloxetine delayed-release
`capsules (proposed proprietary name Drizalma Sprinkle). Duloxetine is a serotonin and
`
`norepinephrine reuptake inhibitor.
`
`
`Cymbalta (duloxetine delayed-release capsules) (NDA 021427), the listed drug for this
`
`application, is currently available in 20 mg, 30 mg, and 60 mg delayed-release capsules that
`
`cannot be crushed, chewed, or opened. The Applicant has developed a delayed-release capsule
`which may be opened and sprinkled over food or given via a nasogastric tube. The Applicant
`believes that this formulation will be beneficial to patients who have difficulties swallowing
`
`capsules. The Applicant has also developed a 40 mg capsule, which would provide more options
`for dose titration.
`
`
`
` Conclusions on the Substantial Evidence of Effectiveness
`
`
`
`1.2.
`
`This Application relies on the Agency’s findings of safety and effectiveness for Cymbalta, the
`listed drug, as well as a single-dose, crossover, four-treatment, four-sequence bioequivalence
`study. The submitted bioequivalence study demonstrates that duloxetine delayed-release
`
`capsules are bioequivalent to Cymbalta.
`
`Reference ID: 4463875
`
`12
`
`
`

`

`1.3.
`
` NDA/BLA Multi-disciplinary Review and Evaluation NDA 212516
`
`Drizalma Sprinkle (Duloxetine Delayed-Release Capsules)
`
`Benefit-Risk Assessment
`
`Benefit-Risk Summary and Assessment
`
` The Applicant has demonstrated bioequivalence to the listed drug (Cymbalta). No new safety findings were identified that would indicate a
`
`clinically significant difference in the risk-benefit considerations for this form of duloxetine to treat the proposed indications and patients who
`
`are unable to swallow pills would have an alternative formulation; therefore, the review team recommends approval of this application.
`
`Dimension
`
`Analysis of
`Condition
`
`Current
`
`Treatment
`Options
`
`Benefit
`
`Evidence and Uncertainties
`
`Conclusions and Reasons
`
` Major Depressive Disorder (MDD), Generalized Anxiety Disorder (GAD),
`
`
`
` diabetic peripheral neuropathic pain (DPNP), and chronic musculoskeletal
` pain are associated with psychiatric and physical health co-morbidities and
`
`poor functional outcomes. These conditions frequently co-occur.
`
` Among the available treatments for MDD, GAD, DPNP, and chronic
` musculoskeletal pain, medications with serotonergic and noradrenergic
`
`effects─namely, serotonin norepinephrine reuptake inhibitors (SNRIs) and
`
`tricyclic antidepressants (TCAs)─play an important role for patients who suffer
`from overlapping symptoms. However, the safety profile of TCAs is
`
`unfavorable when compared with SNRIs such as duloxetine. Furthermore, no
`SNRIs are currently available in a formulation that can be administered to
`patients who are unable to swallow pills.
` The Applicant submitted a single-dose, cross-over, four-treatment,
`
`four-period, four-sequence study to assess whether this product is
`bioequivalent to the listed drug, Cymbalta.
`
`Effective treatment of MDD, GAD, DPNP, and
`chronic musculoskeletal pain may reduce
`distress and disability.
`
`The development of a duloxetine formulation
`that can be administered to patients who are
`unable to swallow pills addresses an unmet
`
`clinical need.
`
`
`
` Study results indicate that this product is
`bioequivalent to the listed drug.
`
`Reference ID: 4463875
`
`13
`
`

`

` NDA/BLA Multi-disciplinary Review and Evaluation NDA 212516
`
`Drizalma Sprinkle (Duloxetine Delayed-Release Capsules)
`
`Dimension
`
`Evidence and Uncertainties
`
`Conclusions and Reasons
`
` Analysis of safety data for this product including vital signs, laboratory
`
`
` assessments, and adverse events did not reveal any unexpected safety
`
` signals.
`
`
`
` Risk and Risk
`
`
`
`Management
`
`
` The safety profile of this product is consistent
`
` with that of the listed drug, Cymbalta. A
`medication guide will be included in labeling
`
`for this product. No Risk Evaluation and
`Mitigation Strategy (REMS) is required.
`
`Reference ID: 4463875
`
`14
`
`

`

` NDA/BLA Multi-disciplinary Review and Evaluation NDA 212516
`
`Drizalma Sprinkle (Duloxetine Delayed-Release Capsules)
`
`1.4.
`
`Patient Experience Data
`
`
`
`Patient Experience Data Relevant to this Application (check all that apply)
`□ The patient experience data that were submitted as part of the
`
`
`
`
` Section of review where
`application include:
`
` discussed, if applicable
`
`□ Clinical outcome assessment (COA) data, such as
`□ Patient reported outcome (PRO)
`□ Observer reported outcome (ObsRO)
`□ Clinician reported outcome (ClinRO)
`□ Performance outcome (PerfO)
`□ Qualitative studies (e.g., individual patient/caregiver
`
`interviews, focus group interviews, expert interviews, Delphi
`Panel, etc.)
`□ Patient-focused drug development or other stakeholder
`
`
` meeting summary reports
`□ Observational survey studies designed to capture patient
`experience data
`□ Natural history studies
`□ Patient preference studies (e.g., submitted studies or
`
`scientific publications)
`□ Other: (Please specify):
`□ Patient experience data that were not submitted in the application, but were considered
`in this review:
`□
`Input informed from participation in meetings with patient
`stakeholders
`□ Patient-focused drug development or other stakeholder
`
`
` meeting summary reports
`□ Observational survey studies designed to capture patient
`experience data
`□ Other: (Please specify):
`x Patient experience data was not submitted as part of this application.
`
`Reference ID: 4463875
`
`15
`
`

`

` NDA/BLA Multi-disciplinary Review and Evaluation NDA 212516
`
`Drizalma Sprinkle (Duloxetine Delayed-Release Capsules)
`
`
`
` 2 Therapeutic Context
`
`2.1. Analysis of Condition
`
`Cymbalta, the listed drug, is indicated for the treatment of Major Depressive Disorder (MDD),
`
`Generalized Anxiety Disorder (GAD), diabetic peripheral neuropathic pain (DPNP), fibromyalgia,
`
`and chronic musculoskeletal pain. The Applicant is not seeking a fibromyalgia indication for
`
`duloxetine delayed-release capsules due to patent exclusivity limitations.
`
`MDD is the second leading cause of disability worldwide and is associated with increased risk of
`physical illnesses such as diabetes mellitus, cardiovascular disease, and cancer, as well as
`
`
`increased risk of suicide. In a given year, 6% of the adult population will experience MDD.
`
`Lifetime prevalence of MDD in the United States may approach 20%, though estimates vary
`
`widely (Otte et al. 2016). GAD has been associated with an increased risk of physical health
`conditions, problematic use of drugs and alcohol, increased suicide risk, and poor social and
`occupational functioning (Stein and Sareen 2015). DPNP occurs in 12% to 50% of individuals
`
`with diabetes and may lead to significant morbidity, including foot ulcers, skin and bone
`infections, and amputation. The total annual cost of DPNP in the United States is between $4.6
`and $13.7 billion (Gordois et al. 2003). Chronic musculoskeletal pain afflicts between 11% and
`
`24% of the population and affects workforce participation, other functional outcomes,
`
`psychological health, and quality of life (Cimmino and Ferrone 2011). MDD, GAD, and chronic
`
`pain syndromes are frequently co-morbid, and the presence of one of these disorders may
`
`exacerbate the symptoms of any co-occurring disorders.
`
`Analysis of Current Treatment Options
`
`2.2.
`
`Current treatment options for Major Depressive Disorder include psychotherapy,
`antidepressant medications, combined regimens of psychotherapy and medication, and
`
`interventional therapies such as electroconvulsive therapy and transcranial magnetic
`
`stimulation. Table 1 lists the FDA-approved antidepressant medications that are available for
`
`the treatment of MDD and other depressive disorders. Selective Serotonin Reuptake Inhibitors
`
`(SSRIs) and Serotonin-norepinephrine reuptake inhibitors (SNRIs) have a more favorable safety
`
`profile than tricyclic antidepressants (TCAs) and have replaced TCAs as first-line medications for
`Major Depressive Disorder (Otte et al. 2016). Monoamine Oxidase Inhibitors (MAOIs) require
`
`strict dietary restrictions and also have a less favorable safety profile compared with SSRIs and
`SNRIs.
`
`In addition to cognitive behavioral therapy and other psychotherapy interventions,
`
`antidepressant medications are also used in the treatment of GAD. SSRIs and SNRIs are
`
`considered first line treatments for GAD in clinical practice, although only escitalopram,
`
`
`duloxetine, paroxetine, and venlafaxine have FDA-approved indications for treatment of anxiety
`
`disorders. Duloxetine is the only FDA-approved medication for treatment of GAD in the
`pediatric population.
`
`Reference ID: 4463875
`
`16
`
`
`

`

` NDA/BLA Multi-disciplinary Review and Evaluation NDA 212516
`
`Drizalma Sprinkle (Duloxetine Delayed-Release Capsules)
`
`Table 1: FDA-Approved Antidepressant Medications
`
`Pharmacologic Class
`Selective Serotonin Reuptake Inhibitors
`(SSRIs)
`
`Serotonin-norepinephrine Reuptake
`Inhibitors (SNRIs)
`Tricyclic Antidepressants (TCAs)
`
`Monoamine Oxidase Inhibitors (MAOI)
`
`Other Antidepressants
`
`
`
`
`
`
`
`Drug Names
`
` citalopram, escitalopram, fluoxetine,
` fluvoxamine, paroxetine, sertraline,
`
`vilazodone
` desvenlafaxine, duloxetine, levomilnacipran,
`
`venlafaxine
` amitriptyline, amoxapine, clomipramine,
`
` desipramine, doxepin, imipramine,
` maprotiline, protriptyline, nortriptyline,
`trimipramine
` isocarboxazid, phenelzine, selegiline,
`tranylcypromine
` buproprion, mirtazapine, nefazodone,
`trazodone, vortioxetine
`
`
`
`
`
` Table 2 lists the FDA-approved antidepressant medications that are available in alternative
`
`formulations and that may be prescribed for patients who are unable to swallow pills. FDA-
`
`
`issued Prescribing Information and Medication Guides do not necessarily include guidance
`
`
`about whether oral tablets may be crushed. In clinical practice, antidepressants are frequently
`crushed and administered with food or through nasogastric tubes (Bostwick and Demehri
`2014). However, all currently approved SNRIs appear on the Institute for Safe Medication
`Practices’ list of Oral Dosage Forms That Should Not Be Crushed (Institute for Safe Medication
`
`Practices 2019).
`
`
`Table 2: Alternative Formulations of FDA-Approved Antidepressant Medications
`
`Alternative Formulation
`Oral solution or concentrate
`
`Topical Patch
`Orally Disintegrating Tablet
`
`
`
`Drug Names
` citalopram (10mg/5ml), doxepin (10mg/ml),
`
` escitalopram (5mg/5ml), fluoxetine
`(20mg/5ml), nortriptyline (10mg/5ml),
`
`paroxetine (10mg/5ml), sertraline (20mg/ml)
`selegiline
`mirtazapine, selegiline
`
`Duloxetine and pregabalin are FDA-approved for treatment of diabetic neuropathic pain.
`Pregabalin is available as a capsule and as an oral solution (20mg/ml). The label and medication
`
`
`
`guide for pregabalin do not provide guidance about whether the capsule may be opened.
`
`
`Available non-pharmacologic treatments for chronic pain syndromes include cognitive
`
`behavioral therapy, mindfulness-based stress reduction, exercise therapy, acupuncture, and
`massage (Kligler et al. 2018). Other available treatments for chronic musculoskeletal pain
`
`Reference ID: 4463875
`
`17
`
`
`

`

` NDA/BLA Multi-disciplinary Review and Evaluation NDA 212516
`
`Drizalma Sprinkle (Duloxetine Delayed-Release Capsules)
`
`include nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, tramadol, and muscle
`
`relaxants. Tricyc