CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`022396Orig1s000
`
`MEDICAL REVIEW(S)
`
`
`
`
`
`
`
`
`
`

`

`g“
`
`”a
`
`Food and Drug Administration
`
`:51 / CENTERFORDRUGEVALUATIONAND RESEARCH
`Division of Anesthesia, Analgesia, and Addiction Products
`i
`“34h
`10903 New Hampshire Ave.
`Silver Spring, MD 20993-0002
`
`Summar Review for Re_ulato Action
`
`
`December 23, 2013
`
`Rigoberto Roca, M.D.
`Deputy Division Director Summary Review
`
`022396/000
`NDA/Supplement No.
`
`Hospira, Inc.
`Applicant Name
`December 2, 2009
`Date of Original Submission
`
`Complete Response letter issued October 1, 2010
`J1me 28, 2013
`
`Date of Complete Response
`Submission
`
`PDUFA Goal Date
`December 28, 2013
`
`Proprietary Name /
`Established
`S .
`
`Solution for intravenous injection / 37.5 mg/mL
`Dosage Forms / Strength
`1. Management of acute mild to moderate to pain
`Proposed Indications
`
`Dyloject / diclofenac sodium
`
`Material Reviewed/Consulted
`
`
`
`OSE/DMEPA
`
`Rachna Kapoor, PhaimD / Morgan Walker, PharmD,
`MBA
`
`CDTL = Cross-Discipline Team Leader
`DGCPC = Division of Good Clinical Practice Compliance
`DGMPA = Division of GMP Assessment
`DMEPA = Division ofMedication Error Prevention and Analysis
`NDMAB = New Drug Manufacturing Assessment Branch
`ONIP = Office ofMedical Policy
`
`0MPQ=OtficeofManufictmingandProductQuality
`0ND = Oflice ofNew Drugs
`0NDQA = Ofice ofNew Drug Quality Assessment
`OPDP = Ofice of Professional Drug Promotion
`OSE = Ofice of Surveillance and Epidemiology
`
`Reference ID: 3426952
`
`

`

`NDA 022396/000
`
`Dyloject® (diclofenac sodium) Injection
`
`1. Introduction
`
`Dyloject, is an injectable formulation of diclofenac sodium, a nonsteroidal anti-inflammatory
`drug (NSAID) that is an inhibitor of both isoforms of cyclooxygenase (COX-1 and COX-2).
`It
`exhibits analgesic, anti-inflammatory and antipyretic effects. Diclofenac is approved and
`marketed in the United States in immediate-release and modified-release oral formulations, as
`
`well as a topical formulation. There are no approved intravenous formulations in the United
`States.
`
`This formulation was originally developed by Javelin Pharmaceuticals, Inc., under IND 65,048.
`The company was acquired by Hospira, Inc. (the Applicant), and a new drug application (NDA)
`was submitted on December 2, 2009, under section 505(b)(2) of the federal Food, Drug, and
`Cosmetic Act. The referenced drug was Cataflam (NDA 020142). The final assessment at the
`end of that review cycle resulted in a complete response letter, issued on October 1, 2010. This
`submission consists of the Applicant’s response to that complete response letter.
`
`This review will provide an overview of the regulatory and scientific facts of this application and
`issues that were identified during the course of the review of the submission. Aspects that will
`be touched upon include the regulatory history,
`the adequacy of the data to support
`the
`application, and the labeling requested by the Applicant.
`
`2. Background
`
`As noted in Dr. Lloyd’s review, the supporting data for the original NDA included 16 clinical
`studies, two of which were Phase 3 efficacy trials (DF—004 and DFC-005), and one Phase 3
`open-label safety study (DFC-010). The review team’s conclusion at the end of the first review
`cycle was that adequate information had been submitted to evaluate the drug product’s efficacy
`and safety. No concerns were identified related to the efficacy of the product. There was
`concern that the safety profile of one of the doses proposed by the Applicant did not result in a
`favorable riskzbenefit assessment; however, the team concluded that the data supported the
`riskzbenefit assessment of a lower dose regimen.
`
`From a drug quality perspective, the review team concluded that there was a lack of assurance of
`an acceptable manufacturing process.
`
`Both of these issues resulted in the NDA not being approved during the first review cycle. The
`Complete Response letter issued on October 1, 2010, identified two deficiencies as the reasons
`for the action:
`
`CLINICAL
`1. Data submitted do not support
`
`the proposed
`
`m4)
`
`Summary Review for Regulatory Action
`
`2
`
`Reference ID: 3426952
`
`

`

`NDA 022396/000
`
`Dyloject® (diclofenac sodium) Injection
`
`CHEMISTRY MANUFACTURING AND CONTROLS
`
`
`2.
`
`
`
`te September 23,
`in
`ta provr e
`curren y avar a e
`2010, we are recommendin a “For Cause Ins ection” of the dru
`roduct
`manufacturer’s facili
`
`Based on the
`
`An inspection
`must be performed and a satisfactory recommendation issued for all
`manufacturing sites by the Oflice of Compliance prior to marketing of this
`product.
`
`
`
`Summary Review for Regulatory Action
`
`Reference ID: 3426952
`
`

`

`NDA 022396/000
`
`Dyloject® (diclofenac sodium) Injection
`
`3. Chemistry, Manufacturing, and Controls (CMC)
`General Product Considerations
`
`The drug product is an aqueous solution, presented in a l-mL fill volume in a 2- mL USP Type I
`flint glass vial. The stopper is a 13—mm
`(m4) rubber stopper, and there is an
`aluminum overseal.
`
`SQecific Issues Identified in the Course of the Review
`No new data related to the drug substance or drug product were submitted in this application.
`The primary issue that needed to be evaluated during this review cycle
`mm
`was
`w: w
`
`sufficient to address the concerns
`
`Outstanding or Unresolved Issues
`I concur with the conclusions reached by Dr. Peri that the application’s approvability is
`dependent on the inspection of the drug product manufacturing facility, and final assessment and
`recommendation of the Office of Compliance.
`
`4. Nonclinical Pharmacology/Toxicology
`
`There were no new nonclinical data submitted during this review cycle.
`
`Outstanding or Unresolved Issues
`There were no outstanding or unresolved pharmacology/toxicology issues that precluded
`approval during the first review cycle, and there are none during this review cycle.
`
`5. Clinical Pharmacologleiopharmaceutics
`
`There were no new clinical pharmacology data submitted during this review cycle.
`
`Outstanding or Unresolved Issues
`There were no outstanding or unresolved clinical pharmacology issues that precluded approval
`during the first review cycle, and there are none during this review cycle.
`
`6. Clinical Microbiology
`
`is not a therapeutic antimicrobial;
`Dyloject
`required or submitted for this application.
`
`therefore, clinical microbiology data were not
`
`7. Clinical/Statistical — Efficacy
`
`There were no new clinical data submitted during this review cycle. As noted above, the review
`team concluded that the Applicant had submitted adequate data to support efficacy of the product
`during the review cycle.
`
`Outstanding or Unresolved Issues
`Although the conclusion of the review team during the first review cycle was that efficacy had
`been demonstrated, there was the concern
`m4)
`
`Summary Review for Regulatory Action
`
`4
`
`Reference ID: 3426952
`
`

`

`NDA 022396/000
`
`Dyloject® (diclofenac sodium) Injection
`
`0’) (4)
`
`Therefore, I concur with the overall conclusion reached by the review team that the data
`submitted are adequate to demonstrate the efficacy of the product and that, from an efficacy
`standpoint, there are no outstanding issues or concerns that would preclude approval.
`
`8. Safety
`
`There were no new clinical data submitted during this review cycle. As noted above, the
`conclusion of the review team during the first review cycle was that the Applicant had
`successfully demonstrated that the drug product had a favorable risk:benefit profile for the lower
`dose (37.5 mg]
`mm) The Applicant was advised in the Complete
`Response letter of October 1, 201
`M“)
`
`(b) (4)
`
`It was noted in Dr. Lloyd’s review that the review team had identified other safety issues during
`the first review cycle, which were felt to not impede the approvability of the application, but
`could potentially be addressed with labeling.
`
`These issues are summarized in Dr. Lloyd’s review and consist of the following: bleeding events,
`thromboembolic events, wound healing, safety profile in patients with renal impairment.
`I
`concur with his assessment and recommendations regarding how these issues should be
`addressed in the package insert.
`
`Outstanding or Unresolved Issues
`
`M“) the Applicant addressed the clinical
`deficiency identified in the Complete Response letter of October 1, 2010. Therefore, I concur
`with the review team that there are no outstanding safety issues that would preclude approval.
`
`9. Advisory Committee Meeting
`
`An advisory committee meeting was not convened for this supplemental application, as there
`were no issues in this supplemental application that required presentation or discussion at an
`advisory committee meeting.
`
`10. Pediatrics
`
`the
`The Applicant has not conducted any clinical trials in pediatric patients. At present,
`Applicant’s proposed pediatric plan is to request a waiver from studying pediatric patients
`between the ages of birth and 12 months of age, and a deferral for studying pediatric patients
`
`Summary Review for Regulatory Action
`
`5
`
`Reference ID: 3426952
`
`

`

`NDA 022396/000
`
`Dyloject® (diclofenac sodium) Injection
`
`between the ages of 1 year and 17 years of age. The Applicant’s plan includes the following
`studies:
`Study 1:
`An open-label pharmacokinetic and safety study or studies of an age appropriate
`formulation of Dyloject in pediatric patients 2 to <17 years of age with acute pain.
`
`Study 2:
`A pharmacokinetic, safety, and efficacy study or studies of an age-appropriate formulation
`of Dyloject in pediatric patients 1 to <2 years of age with acute pain.
`
`The pediatric study plan was presented at the Pediatric Research Committee (PeRC) meeting of
`November 6, 2013. The following text, reproduced from Dr. Lloyd’s review, summarizes the
`committee’s recommendations:
`
`PeRC noted that the variability in development of metabolic pathways for this
`product have not been clearly established and would not preclude studies in
`pediatric patients birth to <12 months of age. Therefore, PeRC did not agree with
`the Applicant’s partial waiver request in that age group. However, due to the
`theoretical concerns associated with immature metabolic pathways, PeRC
`recommended that even though the Applicant will be required to conduct studies
`in all pediatric age ranges, that studies should be conducted sequentially in older
`age groups first. If studies in older age groups reveal safety concerns, studies in
`younger age groups could be waived at that time. Additionally, if more commonly
`used NSAIDs (e.g., ibuprofen) receive approval down to birth, a waiver in
`patients less than one year of age could be considered at that time. PeRC
`recommended that the postmarketing requirements (PMRs) under the Pediatric
`Research Equity Act (PREA) be issued such that each pediatric age group has
`sequential, non-overlapping protocol submission and study completion dates.
`
`I concur with Dr. Lloyd’s recommendation that studies should be conducted in all the pediatric
`age groups, that these studies may be deferred on the basis that studies in adults have been
`completed and that the drug development program has progressed to the point that the drug is
`ready for approval, and that efficacy may be extrapolated from adults to pediatric patients two
`years of age and older. The studies to be requested as post-marketing requirements, as noted in
`Dr. Lloyd’s review, are as follows:
`
`Summary Review for Regulatory Action
`
`6
`
`Reference ID: 3426952
`
`(b) (4)
`
`

`

`NDA 022396/000
`
`Dyloject® (diclofenac sodium) Injection
`
`
`
`11. Other Relevant Regulatory Issues
`
`
`
`The final recommendation fiom the Office of Compliance was to withhold approval of the
`application due to the following observed deficiency (as noted in the memo dated December 17,
`2013):
`
`
`
`Outstanding or Unresolved Issues
`In View of the results of the inspection of the manufacturing facilities, and the final
`recommendation fiom the Office of Com liance,
`there is still a concern
`
`and, therefore,
`
`s app 1cation cannot e approve at
`
`s time.
`
`12.Labefing
`
`The Pediatric and Maternal Health Staff (PMHS) recently provided recommended language for
`the nursing mothers section of the package inserts of another diclofenac-containing product. The
`recommended language was based on published literature, and the ability to incorporate that
`language into this product’s package insert, based on potential 505(b)(2) regulatory implications,
`is currently being evaluated.
`
`Summary Review for Regulatory Action
`
`7
`
`Reference ID: 3426952
`
`

`

`NDA 022396/000
`
`Dyloject® (diclofenac sodium) Injection
`
`In addition, the Division of Medication Error Prevention and Analysis (DMEPA) provided
`recommendations for modifications to the package insert, container labels, and carton labeling.
`The Office of Prescription Drug Products (OPDP) also provided comments on the package
`insert.
`13. Decision/Action/Risk Benefit Assessment
`Regulatory Action
`Complete Response.
`
`Risk:Benefit Assessment
`The Applicant has submitted adequate information and data to demonstrate
`the safety and effectiveness of the product. However, the inspection of the
`manufacturing facilities identified significant issues that preclude approval of
`this application at this time.
`
`The package insert, container labels, and carton labeling have been reviewed
`extensively during this cycle. Recommendations regarding the carton and
`container labels have been conveyed to the Applicant during the course of this
`review cycle; the modifications to the package insert will be conveyed to the
`Applicant with the action letter and discussed during the next review cycle.
`
`Recommendation for Postmarketing Risk Management Activities
`The review team’s assessment of the Applicant’s proposed pediatric plan will be
`conveyed with the action letter.
`
`Recommendation for other Postmarketing Study Commitments
`None.
`
`Summary Review for Regulatory Action
`
`8
`
`Reference ID: 3426952
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`RIGOBERTO A ROCA
`12/23/2013
`
`Reference ID: 3426952
`
`

`

`Cross Discipline Team Leader Review
`NDA 22396 Dyloject
`Joshua M. Lloyd. MD
`
`Cross-Discipline Team Leader Review
`
`December 11. 2013
`
`
`Sub'ect
`
`Cross-Disci 0 line Team Leader Review
`
`
`
`June 28, 2013
`Date of Submission
`
`PDUFA Goal Date
`December 28, 2013
`
`
`Proprietary Name /
`Established
`S ‘
`
`Dyloject/
`diclofenac sodium
`
`Proposed Indications
`
`Recommended Action:
`
`1. Management of acute mild to moderate pain
`2. Management of acute moderate to severe pain alone
`or in combination with opioid analgesics
`Approval pending a final acceptable recommendation from
`the Office of Compliance for all manufacturing and testing
`facilities
`
`1. Introduction
`
`Javelin Pharmaceuticals, Inc., (subsequently purchased by Hospira; also referred to as “the
`Applicant”) developed Dyloject, an injectable drug product containing diclofenac sodium,
`under IND 65,048 for the short-term management of acute moderate to severe pain. The
`Applicant submitted a New Drug Application (NDA) under section 505(b)(2) of the Federal
`Food, Drug, and Cosmetic Act, on December 2, 2009 (received December 3, 2009),
`referencing the Agency’s prior findings of efficacy and safety for diclofenac potassium
`(Cataflam; NDA 20142).
`
`The Applicant has submitted this NDA for Dyloject (administered as a 37.5 mg intravenous
`bolus injection) as a response to the Complete Response (CR) action issued by the Division on
`October 1, 2010. The deficiencies cited in the CR letter were related to both the clinical and
`the chemistry, manufacturing, and controls (CMC) disciplines, as well as labeling. The
`clinical and CMC deficiencies are reproduced below:
`
`CLINICAL
`1. Data submitted do not support the proposed
`
`mm
`
`Page 1 of 10
`
`Reference ID: 3420441
`
`1
`
`

`

`Cross Discipline Team Leader Review
`NDA 22396 Dyloject
`Joshua M. Lloyd, MD
`
`CHEMISTRY MANUFACTURING AND CONTROLS
`
`
`
` An inspection
`
`i B
`
`ased on the
`
`currently available data provided in the amendment dated September 23,
`2010, we are recommendin a “For Cause Ins ection” of the dru
`roduct
`
`
`must be performed and a satisfactory recommendation issued for all
`manufacturing sites by the Office of Compliance prior to marketing of this
`product.
`
`The Applicant responded with a CR submission to address the deficiencies outlined in the CR
`letter and, s ecificall , has res onded to the clinical deficiency
`
`Therefore, they are
`e m gs or
`e 37.5 mg ose, and this is accepta e given
`pursuing
`the 37.5 mg dose documented in Dr. Larissa Lapteva’s combined cross-discipline team leader
`review (CDTL)-Division Deputy Director memo dated October 1, 2010. The Applicant’s
`
`Page 2 of 10
`
`Reference ID: 3420441
`
`2
`
`

`

`Cross Discipline Team Leader Review
`NDA 22396 Dyloject
`Joshua M. Lloyd, MD
`
`responses to the deficiencies are discussed further in this review, as are relevant data and
`conclusions regarding the proposed labeling.
`
`I have concluded that this application should receive an Approval action pending a final
`acceptable recommendation from the Office of Compliance for all manufacturing and testing
`facilities as discussed in Section 13 below.
`
`2. Background
`
`Diclofenac is a nonsteroidal anti—inflammatory drug (NSAID) that exhibits anti—inflammatory,
`analgesic, and antipyretic activities and is a potent inhibitor of both COX-1 and COX—2.
`Diclofenac is approved and marketed in the United States as various salt forms in oral
`(immediate-release and modified-release) and topical
`formulations for multiple painful
`conditions. There are no approved intravenous (IV) formulations of diclofenac in the United
`States.
`
`The original NDA for Dyloject was submitted on December 2, 2009. The basis for the NDA
`was 16 clinical studies including two Phase 3 efficacy trials (DFC-004 and DFC-005) and one
`Phase 3 open-label safety study (DFC-010). Details regarding the safety and efficacy reviews
`are available in Dr. Larissa Lapteva’s combined CDTL-Division Deputy Director memo dated
`October 1, 2010. Also refer to Dr. Lapteva’s review for a discussion of the relevant pre-
`submission regulatory history.
`
`3. CMC/Device
`
`Dr. Peri noted in his review that:
`
`Javelin Pharmaceuticals Inc. originally submitted an NDA on 3-Dec-2009 for
`their drug product diclofenac sodium injection.
`m4)mm)
`
`recommended a withhold
`“m" Office of Compliance
`recommendation for
`the manufacturing facility and hence a Complete
`Response action was taken for the NDA.
`
`The drug product manufacturing facility has undergone inspection and a final recommendation
`fiom the Office of Compliance is pending. The CMC team recommends approval of the NDA
`pending a final acceptable recommendation from the Office of Compliance for all
`manufacturing and testing facilities.
`
`4. Nonclinical Pharmacology/Toxicology
`
`Page 3 of 10
`
`Reference ID: 3420441
`
`3
`
`

`

`Cross Discipline Team Leader Review
`NDA 22396 Dyloject
`Joshua M. Lloyd, MD
`
`No new nonclinical pharmacology/toxicology data were submitted with this CR submission.
`
`5. Clinical Pharmacologleiopharmaceutics
`
`No new clinical pharmacology/biopharmaceutics data were submitted with this CR
`submission.
`
`6. Clinical Microbiology
`
`N/A
`
`7. Clinical/Statistical- Efficacy
`
`No new efficacy data were submitted with this CR submission.
`
`The Applicant’s proposed indications in this submission are slightly different than what was
`recommended by the Division in the first review cycle. The Applicant’s proposed indication
`appears below with their changes from the Division’s recommendations indicated in red font
`(additions) and red strikethrough font (deletions).
`
`m4) management of
`Dyloject is an NSAID indicated in adults for the
`mm) mild to moderate pain and :i management of mo moderate to severe
`pain alone or in combination with
`M“, opioid analgesics.
`
`I recommend that the indication be further modified to:
`
`Dyloject is an NSAID indicated in adults for the management of mild to
`moderate pain and management of moderate to severe pain alone or in
`combination with opioid analgesics.
`
`This indication is consistent with recently approved injectable non-opioid analgesics and the
`results of the pivotal Phase 3 clinical trials. Additional information about the pivotal clinical
`trials will be included in the clinical trials section of the labeling (Section 14) to communicate
`basic study population characteristics and to further guide prescribers on proper patient
`selection for therapy with Dyloject.
`
`8. Safety
`
`No new safety data were submitted with this CR submission.
`
`Page 4 of 10
`
`Reference ID: 3420441
`
`4
`
`

`

`Cross Discipline Team Leader Review
`NDA 22396 Dyloject
`Joshua M. Lloyd, MD
`
`Dr. Lapteva noted several safety concerns with Dyloject in her combined CDTL-Division
`Deputy Director Memo, including bleeding-related events, thromboembolic events, and
`anticoagulation therapy; wound healing; and safety in patients with renal impairment. Please
`refer to her review dated October 1, 2010, for additional information. Although these safety
`concerns were not approvability issues during the first cycle, they were handled in the context
`of labeling. These issues continue to not be approvability issues; however, I will explore them
`further as they relate to the current proposed labeling.
`
`Bleeding Events
`Dr. Lapteva raised the concern of bleeding events with Dyloject, particularly in patients on
`concomitant anticoagulation therapy. The labeling sent to the Applicant at the end of the first
`review cycle included cautionary language in the highlights section
`
`
`
`Applicant proposes removing the language from the highlights section.
`
`Dr. Lapteva notes that fewer patients were receiving concurrent anticoagulation therapy in the
`controlled trials compared to the open-label safety study. Two patients on concurrent
`anticoagulation therapy in the controlled Phase 3 clinical trials developed bleeding events (i.e.,
`epistaxis and rectal bleeding). However, 5.5% of patients treated with Dyloject and
`concomitant anticoagulation therapy in the open-label safety study developed bleeding-related
`events. Dr. Neuner, the primary clinical reviewer during the first cycle, notes in her review
`dated September 3, 2010, that the observed rates of bleeding events in the open-label study are
`comparable with the incidence of bleeding events described with anticoagulating agents
`reported in the literature. Additionally, the Applicant noted in the CR submission that of the
`seven subjects who reported incision site hemorrhage, six received anticoagulants at some
`point during the study. Only two of those subjects received Dyloject and anticoagulants
`concurrently. The remaining 4 subjects received anticoagulants 10 to 15 hours after the last
`dose of Dyloject, including 2 that had resolution of the adverse event prior to administration of
`anticoagulants and 3 who received anticoagulants greater than 5 half-lives after Dyloject.
`
`The small numbers of patients who developed incisional site hemorrhage with concurrent
`Dyloject and anticoagulation therapy limit the ability to conclude that there is increased risk
`with Dyloject beyond what is already described for NSAIDs in general. Dyloject labeling,
`consistent with NSAID class labeling, already contains adequate information about NSAIDs
`and the increased risk of bleeding with concomitant anticoagulation therapy. Therefore, I
`concur that the language
`
` be removed from the highlights section of Dyloject labeling.
`
`Thromboembolic Events
`Dr. Lapteva expressed concern that the use of Dyloject influenced clinicians’ choice of deep
`venous thrombosis (DVT) and pulmonary embolism (PE) prophylaxis in clinical trials due to
`the known and labeled interaction between NSAIDs and anticoagulant therapies. I reviewed
`the amendments to this application dated September 30, 2010, that were sent in response to the
`review team’s inquiries during the first review cycle.
`
`Page 5 of 10
`
`Reference ID: 3420441
`
`5
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Cross Discipline Team Leader Review
`NDA 22396 Dyloject
`Joshua M. Lloyd, MD
`
`Fourteen patients developed serious adverse events of DVT or PE in Phase 3 trials with ten of
`those receiving anticoagulant therapy at various doses and durations for DVT/PE prophylaxis.
`The remaining four patients who did not receive DVT/PE prophylaxis with anticoagulant
`therapy underwent laparoscopic cholecystectomy, open reduction of the fifth metatarsal, ankle
`surgery, or rotator cuff repair. In patients not considered to be at higher risk for DVT/PE, the
`routine use of pharmacologic DVT/PE prophylaxis is not considered standard of care for these
`procedures.
`Two of the four patients who developed DVT/PE and did not receive
`anticoagulation therapy for prophylaxis as part of their treatment plan were assigned to the
`placebo or active control treatment arms and not the Dyloject treatment arm.
`
`Given the limited numbers and lack of a clear, definitive clinical indication for pharmacologic
`DVT/PE prophylaxis in patients who developed DVT/PE and were not treated with such
`prophylactic therapy, I cannot conclude with certainty that the use of an injectable NSAID in
`postoperative pain management influenced the decision to treat or not treat patients with
`pharmacologic DVT/PE prophylaxis in the Phase 3 clinical study population. Therefore, I
`have no further recommendations beyond what has already been included in labeling for this
`product during the first review cycle.
`
`Wound Healing
`Dr. Lapteva noted in her review that the observed occurrence of adverse events related to
`wound healing was higher in the NSAID-treated patients and that although interpretation of
`these data was limited, knowledge of these data will be important
`to communicate to
`prescribers. Given the concern for wound healing impairment with NSAID therapy, the
`review team made recommendations to include this information in labeling during the first
`review cycle.
`mm
`
`The retrospective wound healing analysis was based on a review of adverse events related to
`wound healing and was conducted using data from the controlled and open-label Phase 3
`studies.
`In contrast,
`the prospective wound healing analysis consisted of a six—item
`questionnaire related to wound healing that included an assessment of the extent of healing and
`extent and degree of inflammation in relation to the clinician’s expectations and assessments
`of incisional separation,
`infection at the surgical site, and use of postoperative systemic
`antibiotics. The prospective assessment was carried out in one of the pivotal Phase 3 clinical
`trials and in the open-label safety study following a request by the Division during drug
`development to collect information on any possible negative effects on wound healing.
`
`Adverse events related to wound healing were overall more frequent in the Dyloject—treated
`groups compared to placebo. Although the results from the prospective wound healing
`analysis appear to contradict those of the retrospective analysis, the clinical significance of the
`wormd healing questionnaire is uncertain as it relates to the observations seen in the
`retrospective analysis and it may be potentially impacted by clinician’s perceptions of their
`own practice. Therefore, information regarding adverse reactions related to wound healing
`remains important information that should be communicated to prescribers in labeling as
`recommended during the first review cycle.
`
`Page 6 of 10
`
`Reference ID: 3420441
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`6
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`Cross Discipline Team Leader Review
`NDA 22396 Dyloject
`Joshua M. Lloyd, MD
`
`Safefl in Patients with Renal Impairment
`The Applicant proposes
`
`mu)
`
`Cases of acute renal failure in the Phase 3 trial population are summarized in the table below.
`
`Table 1. Acute renal
`
`failure in patients treated in trials DFC—004, DFC—005, and DFC-010.
`DIC075V
`
`Total
`Impaired
`(N=8)
`
`Total Not
`Impaired
`(N= 139)
`
`18.75 mg
`Impaired
`(N=8)
`
`Combined
`37. 5 mg
`and 50 mg
`Impaired
`N=60
`
`Total
`Impaired
`(N=68)
`
`Total Not
`Impaired
`(N=1216)
`
`
`
`MedDRA
`System Organ
`Class/
`Preferred
`'l‘erm
`Acute Renal
`Failure
`
`1 (0.7%)
`
`l (l2.5%)
`
`2 (3.3%)
`
`3 (4.4%)
`
`8 (0.66%)
`
`Source: Table 15 from Dr. Lapteva’s review.
`
`Among patients with pre—existing renal impairment (including 60 patients with mild renal
`impairment and 8 patients with moderate renal impairment) who were treated with Dyloject,
`4.4% developed acute renal failure as compared to 0.66% of patients without pre-existing renal
`impairment. The frequency of acute renal failure in patients without pre-existing renal
`impairment was similar between Dyloject groups and placebo. According to Dr. Lapteva’s
`review, the vast majority of patients with acute renal failure were volume-depleted when they
`developed the event.
`
`These results demonstrate a risk for developing acute renal failure in patients with pre—existing
`renal impairment who are treated with Dyloject. Therefore, I recommend that Dyloject be
`contraindicated in patients with moderate to severe renal insufficiency. As an injectable
`NSAID will likely be used in hospitalized and perioperative patients who are at risk for the
`development of acute renal failure and the majority of patients who developed acute renal
`failure in the clinical development program were volume-depleted, I recommend that, to
`further inform prescribers on the appropriate patient population for whom the risk—benefit
`profile would be favorable, the contraindication be further qualified to patients with moderate
`and severe renal insufficiency in the perioperative period and who are at risk for volume
`depletion.
`
`Additional Safefl Concerns
`The Pediatric and Maternal Health Staff (PMHS) were recently consulted on another
`diclofenac—containing product, and they provided recommended language for the nursing
`mothers section of the labeling to be applied to all diclofenac-containing products. Their
`recommended language was based upon the published literature, however, the Division is
`currently exploring the 505(b)(2) implications with respect to the inclusion of this language.
`The recommended information from PMHS represents important safety information and
`
`Page 7 of 10
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`Reference ID: 3420441
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`Cross Discipline Team Leader Review
`NDA 22396 Dyloject
`Joshua M. Lloyd, MD
`
`should be included in labeling to inform prescribers, pending resolution of any potential
`505(b)(2) issues.
`
`9. Advisory Committee Meeting
`
`An Advisory Committee meeting was not convened for this application.
`
`10.
`
`Pediatrics
`
`No studies have been carried out in pediatric patients. The Applicant submitted a pediatric
`study plan that includes the following studies:
`
`!
`
`!
`
`Study 1: An open-label pharmacokinetic and safety study or studies of an age-
`appropriate formulation of Dyloject in pediatric patients 2 to <17 years of age with
`acute pain
`Study 2: A pharmacokinetic, safety, and efficacy study or studies of an age-appropriate
`formulation of Dyloject in pediatric patients 1 to <2 years of age with acute pain
`
`The Applicant requested a deferral for pediatric patients ages 1 to <17 years. The Applicant
`also requested a partial waiver for pediatric patients birth to <12 months of age because the
`product would be ineffective and/or unsafe in this age group due to immaturity of the enzymes
`required for metabolism.
`
`The Applicant’s pediatric study plan was discussed at a meeting of the Pediatric Research
`Committee (PeRc) on November 6, 2013, and the PeRC had the following recommendations:
`PeRC noted that the variability in development of metabolic pathways for this product have
`not been clearly established and would not preclude studies in pediatric patients birth to <12
`months of age. Therefore, PeRC did not agree with the Applicant’s partial waiver request in
`that age group. However, due to the theoretical concerns associated with immature metabolic
`pathways, PeRC recommended that even though the Applicant will be required to conduct
`studies in all pediatric age ranges, that studies should be conducted sequentially in older age
`groups first. If studies in older age groups reveal safety concerns, studies in younger age
`groups could be waived at that time. Additionally, if more commonly used NSAIDs (e.g.,
`ibuprofen) receive approval down to birth, a waiver in patients less than one year of age could
`be considered at that time. PeRC recommended that the postmarketing requirements (PMRs)
`under the Pediatric Research Equity Act (PREA) be issued such that each pediatric age group
`has sequential, non-overlapping protocol submission and study completion dates.
`
`I recommend issuing PMRs for the pediatric studies outlined in Section 1