CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`205029Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`

`

`Cross Discipline Team Leader Review
`
`Primary Medical and Cross-Discipline Team Leader Review
`
`
`
`u , M.D.
`Shari L. Tar.
`From
`m_——
`
`Proprietary Name /
`Established
`S ‘
`
`names
`
`Dosa_e forms/Stren_ h
`Proposed Indication(s)
`
`Epinephrine injection, USP
`
`1m mL1:1000
`Increase mean arterial blood pressure in hypotension
`associated with septic shock.
`
`
`
`Recommended:
`
`Approvalpending DMEPA review and acceptance oflabel
`
`The DMEPA review of revised carton and container labels and insert labeling is pending at
`this time.
`
`1. Introduction
`
`The applicant has submitted a response to the Agency’s Complete Response action for NDA
`#205029 (see Background, below). This review will address two outstanding issues from the
`original application review: CMC deficiencies and pediatric information.
`
`2. Background
`
`Epinephrine has been marketed for over 50 years. Epinephrine injection, USP auto-injector
`(each unit delivers 0.15 mg or 0.3 mg of epinephrine) is approved in the emergency treatment
`of severe allergic reactions (Type 1). However, intravenous epinephrine, while marketed, is
`not approved for use in septic shock.
`
`In 2006, the Agency began an initiative to remove imapproved drugs from the market and
`issued the guidance, “Marketed Unapproved Drugs—Compliance Policy Guide (CPG).” The
`applicant submitted NDA #205029 on December 4, 2012, for approval of epinephrine in septic
`shock, based on support from published literature [505(b) (2) submission].
`
`Page 1 of 7
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`Reference ID: 3594820
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`1
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`

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`Cross Discipline Team Leader Review
`
`However, CMC deficiencies in the review ofNBA #205029 led to the issuance of a Complete
`
`ResinseiCRi actioni4October2013i. TheailicantiroisedaF
`Howeve ,
`e CMC rev1ew team
`e pro uct un ergo
`t
`not agree an recommen e
`
`In addition, the CMC reviewers do not consider the
`proposed assays for drug and degradants to be adequately validated for use at release or on
`stability.
`(Establishment inspections were also incomplete).
`
`
`
`The Agency also did not agree with the applicant’s request for a full waiver of pediatric
`studies; the Agency instead requested that the applicant submit information from all available
`sources, including literature, in order to appropriately label epinephrine for the pediatric
`population.
`
`3. CMC/Device
`
`In the current review, the CMC reviewer has recommended approval for NBA 205029. The
`applicant has agreed to submit long-term storage stability data for three commercial batches
`for expiration dating extension of the drug product as a post-approval supplement.
`
`0 General product quality considerations
`
`
`In this resubmission, the
`
`
`
`The CMC reviewer considered this
`
`
`
`
`The drug product specification was revised for assa to
`and included acceptance limits of no more than
`an
`
`
`
`
`at release and on stability respectively.
`
`Stability data were provided for one batch of drug product manufactured with revised
`formulation and manufacturing rocess stored at long term storage conditions (25°C) up to 9
`
`months. Based on the levels of_ observed on stability, the applicant proposed a
`shelf-er of. months for the drug product. However, based on stability data showing that
`the drug product maintains the critical quality attributes up to 12 months, the CMC reviewer
`recommended a 12 month shelf-er for the drug product.
`
`0 Facilities review/inspection
`
`The Office of Compliance has provided an overall acceptable recommendation for
`manufacturing and testing facilities for this NDA.
`
`Page 2 of 7
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`Reference ID: 3594820
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`2
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`Cross Discipline Team Leader Review
`
`4. Nonclinical Pharmacology/Toxicology
`
`In their review of the original application, the nonclinical pharmacology/toxicology reviewers
`found the NDA to be approvable; there are no new nonclinical pharmacology/toxicology data.
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`In their review of the original application, the clinical pharmacology/biopharmaceutics
`reviewers recommended approval of epinephrine based on its effect on mean arterial pressure
`(MAP) in septic shock patients. The proposed dosing regimen in septic shock patients is 0.05
`to 2.0 μg/kg/min continuous intravenous (IV) infusion titrated to achieve a target MAP.
`
`A summary of key features from Dr. Hariharan’s review:
`! When administered intravenously, epinephrine rapidly disappears from plasma with an
`effective half-life of < 5 minutes. Time to pharmacokinetic steady state following
`continuous intravenous (IV) infusion is about 10 minutes.
`! Following intravenous (IV) infusion, epinephrine has a quick onset of blood pressure
`response (< 5 minutes). The time to offset of effect is about 10-15 minutes.
`! There is a trend for dose-dependent increase in blood pressure and heart rate with
`increasing doses of epinephrine (0.001 to 0.2 μg/kg/min) in healthy subjects.
`In septic shock patients, there is an increase in MAP with IV infusions of epinephrine.
`However, results of a naïve-pooled analysis suggest a high degree of inter-patient
`variability.
`Intrinsic factors such as age, body weight and disease severity may affect
`pharmacokinetics of epinephrine. However, due to the rapid onset and offset
`characteristics, close monitoring, and dose titration to a target response, no dose
`adjustments are warranted.
`
`!
`
`!
`
`6. Clinical Microbiology
`
`The microbiology reviewer recommended approval based on the original submission; there is
`no new microbiology information.
`
`Page 3 of 7
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`Reference ID: 3594820
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`Cross Discipline Team Leader Review
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`7. Clinical/Statistical- Efficacy
`
`Dr. Moreschi recommended approval of epinephrine for the treatment of hypotension in septic
`shock. The basis of her approval recommendation was the consistent increase in mean
`arterial blood pressure supported by publication-based evidence. Dr. Moreschi had no
`recommendations for postmarketing requirements or commitments.
`
`Dr. Bai concluded that the literature-based evidence was exploratory. I concur with Dr. Bai,
`but conclude that the consistent results in different publications over time support a role for
`epinephrine to increase mean arterial blood pressure in hypotensive patients with septic shock.
`
`8. Safety
`
`In reviewing the original application, Dr. Moreschi used the Twinject label, published
`literature provided by the sponsor, and references cited in Goodman and Gilman and
`Ellenhorn’s Medical Toxicology to find case reports of the side effects from the use of
`epinephrine for longer periods of time.
`
`In her review, Dr. Moreschi noted the high background mortality rate in septic shock and the
`resulting difficulty of calculating deaths from epinephrine use. She has also noted the lack of
`safety data with prolonged use of intravenous epinephrine. I concur. Intravenous pressors are
`routinely used in the intensive care unit, under close monitoring and telemetry. Moreover,
`intravenous epinephrine has a short half-life; thus, the drug can be stopped with rapid
`disappearance of plasma levels in the event of an adverse effect.
`
`Epinephrine use was associated with palpitations (Illi 1995), tachycardia (Myburgh 2008), and
`cardiac arrhythmias (Mackie 1991, Brock 2003, Annane 2007) and metabolic effects such as
`lactic acidosis (Day 1996, Myburgh 2008), increase in blood sugar (Beck 1985) and increase
`in insulin requirement (Myburgh 2008).
`
`Other events from published literature included: limb ischemia, stroke, myocardial ischemia
`and infarction, pulmonary edema, renal insufficiency. While these events could have been
`related to underlying conditions and/or concomitant medications, it is also plausible that these
`events resulted from epinephrine’s pharmacologic effects and appropriate mention should
`appear in labeling.
`
`9. Advisory Committee Meeting
`
`This application was not presented to an advisory committee.
`
`Page 4 of 7
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`Reference ID: 3594820
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`Cross Discipline Team Leader Review
`
`10.
`
`Pediatrics
`
`In the Complete Response letter, the Agency requested that the applicant submit information
`from all available sources, including literature, to appropriately label this product for the
`pediatric population.
`
`The applicant has submitted 5 published studies in infants and children, along with clinical
`practice guidelines for hemodynamic support of pediatric and neonatal septic shock from the
`American College of Critical Care Medicine (ACCM). A pharmacokinetic study in ill infants
`and children (Fisher 1993), some of whom had septic shock, revealed linear dose-proportional
`pharmacokinetics of epinephrine infusion that correspond with the pharmacokinetics observed
`in adult septic shock patients.
`
`Table 1. Studies in pediatric patients provided by the applicant
`Study
`Design
`Epinephrine
`Duration of
`dose
`dosing
`
`Results
`
`Heckmann
`2002
`
`Retrospective chart
`review
`
`0.05 to 2.6
`μg/kg/min for
`first 24 hours
`
`Median
`17.25 (range:
`3-124 hours)
`
`Not stated
`
`Ceneviva
`1998
`
`Case series
`
`Han 2003
`
`Retrospective cohort
`study
`
`↑ MABP +7
`(-1 to 13) mm
`Hg, p <
`0.001; ↑ HR
`+10 (-10 to
`42) bpm, p <
`0.001
`No results
`specific to
`epinephrine
`
`0.13 + 0.04
`μg/kg/min
`(inotrope) or
`0.48 + 0.22
`μg/kg/min
`(vasopressor)
`Not stated; epinephrine was included in
`treatment guidelines and not the primary
`intervention
`Not stated; epinephrine was included in
`treatment guidelines and not the primary
`intervention
`
`Unblinded,
`randomized
`(ACCM/PALS
`guidelines with and
`without goal-
`directed therapy to
`* >
`achieve ScvO2
`70%)
`Not stated; epinephrine was included in
`Unblinded
`treatment guidelines
`observational study
`*ScvO2 = superior vena cava oxygen saturation
`
`De Oliveira
`2008
`
`Brierley
`2008
`
`Page 5 of 7
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`Reference ID: 3594820
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`Population/N
`exposed to
`epinephrine
`Very low birth
`weight
`infants/31
`
`Fluid-refractory
`septic shock/9
`(vasopressor) +
`9 (inotrope)
`
`Septic shock
`
`Severe sepsis
`or fluid-
`refractory
`septic shock
`
`Fluid-resistant
`septic shock/12
`
`5
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`

`

`Cross Discipline Team Leader Review
`
`The applicant also referred to Fisher (1993) which evaluated pharmacokinetic data in six
`hemodynamically stable ill patients, 0.5 to 16 years-old, who were receiving an epinephrine
`intravenous infusion. I reviewed and discussed the Fisher publication with the clinical
`pharmacology reviewer (Dr. Sudarshan Hariharan); we did not find adequate
`pharmacodynamic data in the publication to guide instructions for use in pediatric patients.
`
`Only one retrospective chart review (Heckmann) specifically mentions dosing and blood
`pressure results in one pediatric subgroup (e.g., very low birth weight infants). We are lefl
`with scant information regarding safety in pediatric patients.
`I therefore recommend that the
`applicant’s proposed labeling in pediatric patients be modified to the standard language for
`“insufficient evidence.” Accordingly, epinephrine should be approved for use in the adult
`population only.
`
`The applicant made a “good faith” attempt to provide literature support for epinephrine use in
`pediatric patients.
`I also searched Pubmed (e.g., “epinephrine” “shock” “hypotension”
`“pediatric” “children”) and could find no additional relevant publications. Based on previous
`literature searches ofpressor use in pediatric patients with septic shock, I do not think that it
`will be easy, practical or feasible for the applicant to conduct a clinical trial of intravenous
`epinephrine use in this population. I therefore recommend that the applicant be granted a
`waiver from the requirement for pediatric studies.
`
`11.
`
`Other Relevant Regulatory Issues
`
`There were no DSI inspections or financial disclosures.
`
`12.
`
`Labefing
`
`o
`
`In a letter dated April 3, 2013, The Division of Medication Error Prevention and
`Analysis (DMEPA) concluded that the a
`licant’s r0 osed ro riet
`was unacce table due to
`
`
`
`The a
`
`licant’s alternate ro riet
`
`
`
`In the current submission, the applicant has submitted carton and container and
`labeling for Epinephrine Injection, USP, without a proprietary name.
`
`
`
`0
`
`In their May 28, 2014 review of the proposed container label, carton, and insert
`labeling, DMEPA made several recommendations to improve the proposed container
`label and carton labeling to increase the readability and prominence of important
`information on the label and labeling. The applicant revised the carton and container
`labels and DMEPA’s review is currently pending.
`o Labeling will be revised to reflect additional adverse events reported in the literature.
`
`Page 6 of 7
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`Reference ID: 3594820
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`

`

`Cross Discipline Team Leader Review
`
`13.
`
`Recommendations/Risk Benefit Assessment
`
`! Recommended Regulatory Action
`
`Pending acceptance of the revised carton and container labels and labeling, I recommend
`approval of epinephrine to increase mean arterial blood pressure in adult patients with septic
`shock.
`
`The available literature appears insufficient to support efficacy and safety and provide
`guidance for dosing in pediatric patients. I think that it would be challenging for the
`applicant to conduct a randomized controlled clinical trial of epinephrine in this population. I
`therefore recommend that the sponsor be granted a waiver from the requirement for pediatric
`studies.
`
`! Risk Benefit Assessment
`
`The main benefit of epinephrine lies in its ability to increase mean arterial blood pressure and
`thereby maintain hemodynamic stability and adequate tissue perfusion in hypotensive patients
`with septic shock. Known risks of epinephrine appear to be related to its pharmacologic
`activity (e.g., hypertension, arrhythmias, tachycardia, hyperglycemia). Providers could
`monitor for these risks as intravenous pressors are routinely administered in intensive care
`units.
`
`! Recommendation for other Postmarketing Requirements and Commitments:
`
`None other than the stability study as agreed to by the applicant and CMC reviewers.
`
`! Recommended Comments to Applicant:
`
`Revised labeling should be sent to the applicant.
`
`Page 7 of 7
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`Reference ID: 3594820
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`7
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`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`SHARI L TARGUM
`07/17/2014
`
`Reference ID: 3594820
`
`