CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`205029Orig1s000
`
`MEDICAL REVIEW(S)
`
`
`
`
`
`
`
`
`
`

`

`
`
`DIVISION OF CARDIOVASCULAR & RENAL PRODUCTS
`Divisional Memo
`
`
`NDA:
`205029 Epinephrine injection for raising blood pressure
`in the hypotension associated with septic shock.
`Sponsor:
`Belcher Pharmaceuticals
`Review date: 25 April 2014
`
`
`Reviewer:
`N. Stockbridge, M.D., Ph.D., HFD-110
`This memo conveys the Division’s recommendation to issue an Approval letter for this
`application.
`This application was previously the subject of a Complete Response (4 October 2014). The
`resubmission (29 January 2014) has been the subject of reviews of CMC (Bhamidipati; 14
`July 2014) and DMEPA (Stewart; 16 July 2014). There is a comprehensive CDTL memo
`(Targum; 17 July 2014) with which I am in full agreement. I highlight a few matters here.
`Numerous CMC issues raised in the CR letter were all satisfactorily addressed. However,
`the agreed-upon shelf life of 12 months is supported by data from only one commercial
`batch. The sponsor commits to providing data from 3 commercial batches post-marketing.
`Numerous recommendations on carton and container labeling were addressed. There are
`no remaining issues.
`The only other deficiency noted in the CR letter pertained to pediatric data. The sponsor
`addressed the issue with a literature review. Dr. Targum reviewed these materials and did
`not find additional references upon her independent literature search. Dr. Targum
`concludes, and I concur, that the sparse literature does not provide adequate information
`about the effectiveness and safety of epinephrine to raise blood pressure in children with
`sepsis. The sponsor, Dr. Targum, and I concur that study of epinephrine for this use is
`highly impractical, given the incidence, so we will waive the PREA requirement for further
`study.
`
`C:\Users\STOCKBRIDGEN\Documents\NDA\N205029 Epinephrine\Epinephrine-DD2.doc Last
`saved
`
`
`08:30 Friday, July 25, 2014
`
`(cid:127)1(cid:127)
`
`Reference ID: 3599130
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`NORMAN L STOCKBRIDGE
`07/25/2014
`
`Reference ID: 3599130
`
`

`

`Cross-Discipline Team Leader Review
`
`Date
`28 September 2013
`
`
`From
`
`Norman Stockbridge
`
`Cross-Discipline Team Leader Review/
`Subject
`Division Director memo
`
`
`NDA/BLA #
`
`Supplement#
`
`205029
`
`000
`
`
`
`Applicant
`Belcher Pharmaceuticals
`
`
`Date of Submission
`
`4 December 2012
`
`PDUFA Goal Date
`
`4 October 2013
`
`
`
`Proprietary Name /
`Established (USAN) names
`
`”(a (DMEPA approved 7 August 2013)
`Epinephrine
`
`Dosage forms / Strength
`
`Intravenous solution 1 mg/mL
`
`Proposed Indication(s)
`
`1.
`
`Pressor in patients with septic shock
`
`Action:
`
`Complete response
`
`Page 1 of 3
`
`Reference ID: 3380847
`
`

`

`Cross Discipline Team Leader Review
`
`1. Introduction
`
`Epinephrine has been marketed for over 50 years. This would be its first approval as a pressor,
`although it is approved to treat anaphylaxis and induction and maintenance of mydriasis during
`intraocular surgery.
`
`2. Background
`
`The application is literature-based.
`
`3. CMC/Device
`
`
`
`I refer to the CMC review by Dr. Bhamidipati (21 August 2013). There are no issues with
`regard to drug substance or dru
`roduct, and stabili
`data su 011 a
`The
`
`s onsor seeks a
`The CMC team does not a
`ee with this and
`
`recommends that the product be
`The CMC team does not consider the proposed assays for drug and degradants to be
`adequately validated for use at release or on stability.
`
`Establishment inspections are currently incomplete.
`
`The CMC deficiencies are the sole bases for a Complete Response.
`
`4. Nonclinical Pharmacology/1'oxicology
`
`I refer to Dr. Dwivedi’s review (19 June 2013). Epinephrine is a fairly non-selective systemic
`vasoconstrictor, raising blood pressure in septic shock or other vasodilatory states. At some
`point, mesenteric, renal, and coronary circulations are compromised. Pulmonary resistance
`seems relatively unafl'ected.
`
`Metabolic effects include hypokalemia and hyperglycemia. The latter of these leads to
`increased lactic acid as metabolism shifis more aerobic. The effect does not appear to reflect
`hypoxia; oxygen utilization generally increases slightly.
`
`Epinephrine leads to impaired implantation and increased fetal loss in rabbits, supporting
`pregnancy class C labeling.
`
`5. Clinical Pharmacologleiopharmaceutics
`
`I refer to the review by Dr. Hariharan (9 September 2013). The effective half-er of
`epinephrine is about 5 minutes. The pressor effect has little or no latency. There is enormous
`between-subject variability in response, probably reflecting various vasoconstrictive
`influences. This variability supports the proposed dose range of 0.05 to 2 mcg/kg/min.
`
`6. Clinical Microbiology
`I refer to Dr. Donald’s review (15 February 2013). The sponsor’s—
`procedure was considered adequate from a microbiological point of View. By personal
`communication, the microbiology team supports the decision to have the sponsor switch to
`
`Page 2 of3
`
`Reference ID: 3380847
`
`

`

`Cross Discipline Team Leader Review
`
`7. Clinical/Statistical- Efficacy
`I refer to reviews by Drs. Bai (statistical; 9 September 2013) and Moreschi (clinical; 19
`September 2013). The literature supporting approval comes from many small studies over
`many years. Dr. Bai calls them “exploratory”, but they tell a consistent story of epinephrine’s
`not very subtle hemodynamic effects.
`The Bollaert (1990) results are typical. Thirteen subjects with dopamine-resistant sepsis-
`related hypotension underwent uncontrolled treatment with epinephrine 0.5 or 1 mcg/kg/min
`and right heart catheterization at about 1 h. Systolic pressure increased from a mean of 73 to a
`mean of 120 mmHg and cardiac index increased from about 5.5 to about 6.7 L/min/m2.
`Systemic vascular resistance increased by about 20%, but pulmonary vascular resistance was
`unchanged. VO2 increased by about 10%. Mortality was greater than 50%.
`Similar results are seen in many other studies reviewed by Dr. Moreschi, with doses ranging
`from 0.025 to 18 mcg/kg/min and administered for a week or more.
`8. Safety
`The safety database is little better than anecdotal. Invasive monitoring is routine, with the goal
`of optimizing perfusion of critical organs. Epinephrine does not appear to be proarrhythmic.
`9. Advisory Committee Meeting
`None.
`Pediatrics
`10.
`The PeRC recommended that the Division advise the sponsor that its pediatric plan is deficient
`and ask the sponsor to submit information from all available sources, including literature, to
`appropriately label the product for the pediatric population. I concur.
`11.
`Other Relevant Regulatory Issues
`DSI inspected nothing.
`Financial disclosure information was not available, but none of the cited studies was sponsored
`by Belcher.
`Labeling
`12.
`Labeling will look similar to that of other recently approved agents for vasodilatory shock. Dr.
`Moreschi cites published guidelines that suggest that epinephrine be used after norepinephrine
`or dopamine, but neither the authors nor Dr. Moreschi finds the data persuasive for calling
`epinephrine second-line.
`
`Recommendations/Risk Benefit Assessment
`13.
`But for CMC issues, epinephrine is approvable to increase the blood pressure in the setting of
`septic shock.
`
`Page 3 of 3
`
`Reference ID: 3380847
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`NORMAN L STOCKBRIDGE
`09/28/2013
`
`Reference ID: 3380847
`
`

`

`
`
`
`
`
`CLINICAL REVIEW
`
`Application Type 505(b)(2)
`Application Number(s) 205-029
`Priority or Standard
`Standard
`
`
`
`
`Submit Date(s) November 30, 2012
`Received Date(s) December 4, 2012
`PDUFA Goal Date October 4, 2013
`Division / Office DCRP/OND I
`
`Reviewer Name(s) Gail Moreschi, MD, MPH
`Review Completion Date September 19, 2013
`
`Established Name Epinephrine (HCL) Injection
`(Proposed) Trade Name
`
`Therapeutic Class Sympathomimetic (adrenergic)
`Applicant Belcher Pharmaceuticals, LLC
`
`Formulation(s) 1:1000 (1 mg/mL)
`Dosing Regimen IV
`Indication(s)
`Increase Blood Pressure
`Intended Population(s) Hypotensive States with Septic
`Shock
`
`
`
`Template Version: March 6, 2009
`
`Reference ID: 3376064
`
`(b) (4)
`
`

`

`Clinical Review
`Gail Moreschi, MD, MPH
`NDA 20-5029
` Epinephrine
`
`
`
`Table of Contents
`
`2
`
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ......................................... 6
`1.1 Recommendation on Regulatory Action ............................................................. 6
`1.2 Risk Benefit Assessment .................................................................................... 6
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies ... 6
`1.4 Recommendations for Postmarket Requirements and Commitments ................ 6
`INTRODUCTION AND REGULATORY BACKGROUND ........................................ 6
`2.1 Product Information ............................................................................................ 7
`2.2 Currently Available Treatments for Proposed Indications ................................... 7
`2.3 Availability of Proposed Active Ingredient in the United States .......................... 7
`2.4
`Important Safety Issues With Consideration to Related Drugs ........................... 8
`2.5 Summary of Presubmission Regulatory Activity Related to Submission ............ 8
`2.6 Other Relevant Background Information ............................................................ 9
`3 ETHICS AND GOOD CLINICAL PRACTICES ......................................................... 9
`
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES ........................................................................................................... 9
`4.1 Chemistry Manufacturing and Controls .............................................................. 9
`4.2 Clinical Microbiology ........................................................................................... 9
`4.3 Preclinical Pharmacology/Toxicology ................................................................. 9
`4.4 Clinical Pharmacology ...................................................................................... 10
`5 SOURCES OF CLINICAL DATA............................................................................ 11
`5.1 Tables of Studies/Clinical Trials ....................................................................... 11
`5.2 Review Strategy ............................................................................................... 11
`5.3 Discussion of Individual Studies/Clinical Trials ................................................. 11
`6 REVIEW OF EFFICACY ......................................................................................... 11
`Efficacy Summary ...................................................................................................... 11
`Indication .......................................................................................................... 11
`6.1
`6.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations .... 35
`7 REVIEW OF SAFETY ............................................................................................. 35
`Safety Summary ........................................................................................................ 35
`7.1 Methods ............................................................................................................ 35
`7.1.1 Studies/Clinical Trials Used to Evaluate Safety ......................................... 43
`7.2 Adequacy of Safety Assessments .................................................................... 43
`7.3 Major Safety Results ........................................................................................ 43
`7.3.1 Deaths ........................................................................................................ 43
`7.3.2 Nonfatal Serious Adverse Events .............................................................. 44
`7.3.3 Dropouts and/or Discontinuations .............................................................. 44
`
`Reference ID: 3376064
`
`2
`
`(b) (4)
`
`

`

`Clinical Review
`Gail Moreschi, MD, MPH
`NDA 20-5029
` Epinephrine
`
`
`
`7.3.4 Significant Adverse Events ........................................................................ 45
`7.3.5 Submission Specific Primary Safety Concerns .......................................... 45
`7.4 Supportive Safety Results ................................................................................ 45
`7.4.1 Common Adverse Events .......................................................................... 45
`7.4.2
`Laboratory Findings ................................................................................... 45
`7.4.3 Vital Signs .................................................................................................. 48
`7.4.4 Electrocardiograms (ECGs) ....................................................................... 48
`7.5 Other Safety Explorations ................................................................................. 48
`7.5.3 Drug-Demographic Interactions ................................................................. 48
`7.5.4 Drug-Disease Interactions .......................................................................... 48
`7.5.5 Drug-Drug Interactions ............................................................................... 49
`7.6 Additional Safety Evaluations ........................................................................... 50
`7.6.1 Human Carcinogenicity .............................................................................. 50
`7.6.2 Human Reproduction and Pregnancy Data ................................................ 50
`7.6.3 Pediatrics and Assessment of Effects on Growth ...................................... 51
`7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound ...................... 51
`7.7 Additional Submissions / Safety Issues ............................................................ 51
`8 POSTMARKET EXPERIENCE ............................................................................... 51
`
`9 APPENDICES ........................................................................................................ 52
`9.1
`Literature Review/References .......................................................................... 52
`9.2
`Labeling Recommendations ............................................................................. 54
`9.3 Advisory Committee Meeting ............................................................................ 54
`
`Reference ID: 3376064
`
`3
`
`(b) (4)
`
`

`

`Clinical Review
`Gail Moreschi, MD, MPH
`NDA 20-5029
` Epinephrine
`
`
`
`Table of Tables
`Table 1: Hemodynamic and metabolic parameters in 13 dopamine-resistant patients at
`baseline and after 1 hour epinephrine infusion .............................................. 13
`Table 2: Hemodynamic and oxygen transport changes with epinephrine from baseline14
`Table 3: Hemodynamic variables prior to epinephrine administration, at maximum
`administration, and following administration .................................................. 15
`Table 4: Hemodynamic and oxygen transport variables ................................................ 17
`Table 5: Hemodynamic data and blood gas values at baseline and during epinephrine
`infusions ......................................................................................................... 18
`Table 6: Effects of epinephrine and norepinephrine-dobutamine on hemodynamic
`parameters ..................................................................................................... 19
`Table 7: Hemodynamic variables before (control) and during epinephrine infusion in 14
`patients in refractory septic shock (mean ± SD) ............................................. 20
`Table 8: The hemodynamic variables before (control) and during epinephrine infusion
`according to the presence (group A) or absence (group B) of right ventricular
`failure in refractory septic shock..................................................................... 21
`Table 9: Evolution of the investigated parameters among the different treatments In the
`same patients ................................................................................................ 22
`Table 10: Systemic and pulmonary hemodynamics, gastric mucosal blood flow, and
`indocyanine green clearance between epinephrine and dobutamine-
`norepinephrine groups ................................................................................... 23
`Table 11: Arterial and mixed venous blood gas values and arterial lactate values
`between epinephrine and dobutamine-norepinephrine groups ...................... 24
`Table 12: Type and dosage ((cid:541)g/kg/min) of catecholamine in dopamine-sensitive and
`dopamine resistant groups ............................................................................. 25
`Table 13: Effects of epinephrine and dopexamine-norepinephrine on hemodynamic and
`oxygenation parameters and gastric mucosal blood flow ............................... 27
`Table 14: Outcomes between all patients, patients with severe sepsis and patients with
`acute circulatory failure treated with epinephrine or norepinephrine ............. 33
`Table 15: Multivariate logistic regression modeling ....................................................... 34
`Table 16: 6 Principal hemodynamic data between the 3 agents ................................... 39
`Table 17: Serious adverse events ................................................................................. 41
`
`
`Reference ID: 3376064
`
`4
`
`(b) (4)
`
`

`

`Clinical Review
`Gail Moreschi, MD, MPH
`NDA 20-5029
` Epinephrine
`
`
`
`Table of Figures
`Figure 1: Structure of epinephrine ................................................................................... 7
`Figure 2: Drug doses over time of epinephrine or norepinephrine ................................ 29
`Figure 3: Effects of treatment on mean arterial pressure .............................................. 30
`Figure 4: Kaplan-Meier plots of time to (A) hemodynamic success and (B) vasopressor
`withdrawal ...................................................................................................... 31
`Figure 5: Survival from Day 90 ...................................................................................... 32
`Figure 6: Comparisons between the epinephrine and norepinephrine on heart rate (top
`panel); and arterial lactate (middle panel) from baseline during the initial 16
`hours (1–16 h) of infusion and the maximum daily level during the initial 4
`days (D1–D4) of infusion period..................................................................... 42
`Figure 7: Effects of treatment on arterial ph and arterial lactate concentration ............. 47
`
`
`Reference ID: 3376064
`
`5
`
`(b) (4)
`
`

`

`Clinical Review
`Gail Moreschi, MD, MPH
`NDA 20-5029
` Epinephrine
`
`
`
`1 Recommendations/Risk Benefit Assessment
`
`1.1 Recommendation on Regulatory Action
`
`
`Epinephrine has been utilized worldwide for many years as a pressor in
`hypotensive states. Studies from the literature document and confirm
`epinephrine’s efficacy in the treatment of hypotension. The literature however is
`incomplete as to all the possible adverse events that can occur with the use of
`epinephrine in septic shock during the hours or days that it might be utilized. By
`knowing the pharmacology of epinephrine it is possible to address these potential
`side effects. Patients treated for septic shock must be closely monitored for
`cardiac, vascular, respiratory, and metabolic events. Epinephrine should be
`approved for treatment of hypotension in septic shock.
`
`
`
`1.2 Risk Benefit Assessment
`
`Septic shock is a very serious illness necessitating fluids and antibiotics in addition
`to the treatment of hypotension. Epinephrine is valuable in the treatment of this
`serious often fatal illness.
`
`
`
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies
`
`None
`
`
`
`1.4 Recommendations for Postmarket Requirements and Commitments
`
` None
`
`2
`
`Introduction and Regulatory Background
`
`In June 2006, the Agency announced a new drug safety initiative to remove unapproved
`drugs from the market, including a final guidance entitled “Marketed Unapproved
`Drugs - Compliance Policy Guide (CPG).” Epinephrine has been utilized for years for
`the treatment of hypotension associated with septic shock. Epinephrine for intravenous
`use for the treatment of hypotension has not yet received FDA approval.
`
`
`
`Reference ID: 3376064
`
`6
`
`(b) (4)
`
`

`

`Clinical Review
`Gail Moreschi, MD, MPH
`NDA 20-5029
` Epinephrine
`
`
`2.1 Product Information
`
`Epinephrine (Adrenaline) is a sympathomimetic (adrenergic) agent. Its structural
`formula is presented in the following figure.
`
`
`Figure 1: Structure of epinephrine
`
`
`
`
`
`
`
`2.2 Currently Available Treatments for Proposed Indications
`
`Both dopamine and norepinephrine have been approved by the FDA in the treatment of
`septicemia. Dopamine hydrochloride was originally approved as Intropin in 1974 and is
`currently available generically for the correction of hemodynamic imbalances present in
`the shock syndrome due to myocardial infarctions, trauma, endotoxic septicemia, open
`heart surgery, renal failure, and chronic cardiac decompensation as in congestive
`failure.
`
`Norepinephrine bitartrate was originally approved in 1950 as Levophed for blood
`pressure control in certain acute hypotensive states (e.g., pheochromocytomectomy,
`sympathectomy, poliomyelitis, spinal anesthesia, myocardial infarction, septicemia,
`blood transfusion, and drug reactions).
`
`Recently, 20 December 2012, phenylephrine hydrochloride was approved for the
`treatment of vasodilatory shock, including septic shock.
`
`
`
`2.3 Availability of Proposed Active Ingredient in the United States
`
`There are several unapproved and more than 39 approved drug formulations containing
`epinephrine currently marketed. Epinephrine injection is currently available in 1 mg/mL,
`(1:1000), 0.1 mg/mL (1:10,000), and 0.5 mg/mL (1:2,000) solutions.
`
`
`Reference ID: 3376064
`
`7
`
`(b) (4)
`
`

`

`Clinical Review
`
`Gail Moreschi, MD, MPH
`NDA 20-5029
`- Epinephrine
`
`2.4 Important Safety Issues With Consideration to Related Drugs
`
`The Surviving Sepsis Campaign program of 2008 has recommended norepinephrine
`and dopamine to be the initial vasopressors of choice for maintaining a mean arterial
`pressure (MAP) of at least 65 mmHg in septic shock patients with epinephrine as the
`alternative vasopressor when there is a poor response to norepinephrine or dopamine.
`However, this Campaign admits there is not enough evidence to recommend one
`vasopressor over another.
`
`Dopamine increases the mean arterial pressure and the cardiac output due to an
`increase in stroke volume and heart rate, but has a minimal effect on the systemic
`vascular resistance. Therefore dopamine fails to increase the MAP when systemic
`vascular resistance is low (Levy 2005c). Dopamine causes more tachycardia and
`maybe more arrhythmogenic than epinephrine. Additionally dopamine may influence the
`endocrine response via the hypothalamicpituitary axis and may have
`immunosuppressive effects.
`
`Compared with dopamine, norepinephrine increases mean arterial pressure due to its
`vasoconstrictive effects and has little change in heart rate and less of an increase in
`stroke volume. Other side effects may be similar to epinephrine.
`
`Phenylephrine can cause angina, tissue necrosis, allergic reactions, peripheral and
`visceral vasoconstriction, and the need for renal replacement therapy.
`
`2.5 Summary of Presubmission Regulatory Activity Related to Submission
`
`for epinephrine to be
`The s onsor submitted a Pre-IND
`responded stating that
`e
`used
`increasing the blood pressure in patients in shock may serve as a basis for approval.
`On 3 February 2012 in a teleconference the sponsor informed the FDA that they were
`interested in pursuing the indication of increasing blood pressure in certain hypotensive
`states. The FDA agreed that this may be an appropriate indication.
`
`on
`
`On 25 July 2012 the sponsor met with the FDA for an End-of Phase 1 (EOP1) meeting.
`The Agency stated that a literature only NDA for epinephrine to increase the blood
`pressure in patients with septic shock was acceptable provided that the sponsor note
`and consider the limitations in the assay methodology in the published PK and PD
`studies for epinephrine.
`
`On 18 September 2012 the sponsor submitted questions to the Agency which were
`answered by the FDA regarding the clinical pharmacology studies.
`
`Reference ID: 3376064
`
`

`

`Clinical Review
`Gail Moreschi, MD, MPH
`NDA 20-5029
` Epinephrine
`
`
`2.6 Other Relevant Background Information
`
`Intravenous epinephrine has been used as a vasopressor for over 50 years in treating
`hypotension associated with septic shock. Both the published clinical studies and the
`algorithms of numerous medical organizations around the world recommend epinephrine
`for the management of hemodynamic support.
`
`Ethics and Good Clinical Practices
`
` 3
`
`
`
`Since this is a literature-based application, this reviewer has no access to raw data or
`site inspections and cannot, therefore, make any assertion regarding the integrity of an
`individual trial cited in this review. There are no financial disclosures to review.
`
`Significant Efficacy/Safety Issues Related to Other Review Disciplines
`
` 4
`
`
`
`
`
`4.1 Chemistry Manufacturing and Controls
`
`The chemistry review by Shastri Bhamidipati, Ph.D., is not recommending approval due
`to significant issues in regards to the quality of the drug product resulting from the
`proposed commercial manufacturing process. Please refer to his review for a detailed
`account.
`
`
`4.2 Clinical Microbiology
`
`No product quality microbiology deficiencies were identified based upon the
`information provided. NDA 205029 is recommended for approval.
`
`
`4.3 Preclinical Pharmacology/Toxicology
`
`Rama S. Dwivedi, Ph.D., states in his review that epinephrine is approvable.
`Additionally he has the following comments:
`
`“Results from nonclinical septic model studies have shown that administration of
`epinephrine has significantly improved the mean arterial pressure (MAP) and
`myocardial performance in a dose dependent manner, by increasing contractility, stroke
`volume, and cardiac output. However, nonclinical data are limited in reproducing the
`severe sepsis seen in humans.
`
`
`Reference ID: 3376064
`
`9
`
`(b) (4)
`
`

`

`Clinical Review
`Gail Moreschi, MD, MPH
`NDA 20-5029
` Epinephrine
`
`
` Metabolic effects such as hyperlactemia, hyperglycemia and hypokalemia, decreased
`mesenteric, coronary and renal conductance were associated with epinephrine
`treatment (Levy 2003).”
`
`“The data from published reports suggest that epinephrine was not carcinogenic in 2-
`year rat studies.”
`
`“Epinephrine has been shown to interfere with ovum implantation and fetus survival in
`rabbits (Auletta, 1971).”
`
`“In addition to this, implantation loss, incidence of arrested fetuses and gastroschisis
`were observed in epinephrine-treated Dutch-Belted rabbits, showing a teratogenic
`potential of epinephrine.”
`
`
`4.4 Clinical Pharmacology
`
`In a draft review by Sudharshan Hariharan, Ph.D., “the key clinical pharmacology
`features of epinephrine are summarized below:
`
`
`(cid:120) When administered intravenously, epinephrine rapidly disappears from the
`plasma with an effective half-life of <5 min. Time to reach pharmacokinetic
`steady state following continuous i.v infusion is in the range of 10 min.
`
`
`
`
`
`
`
`
`
`
`
`(cid:120) Epinephrine has a rapid onset and offset of blood pressure effect.
`
`(cid:120) There is a trend for dose-dependent increase in blood pressure and heart rate
`with increasing doses of epinephrine in healthy subjects. However, the
`experience is relatively at the lower dose range [0.001 to 0.2 μg/kg/min] when
`compared to the proposed dosing regimen [0.05 to 2.0 μg/kg/min] in septic shock
`patients.
`
`(cid:120)
`
`(cid:120)
`
`In septic shock patients, there is an increase in mean arterial pressure with
`intravenous infusions of epinephrine. However, from a naïve-pooled analysis
`there is no trend for a relationship between epinephrine dose and mean change
`from baseline due to high inter-patient variability in response.
`
`Intrinsic factors such as age, body weight and disease severity may affect the
`pharmacokinetics of epinephrine. However, dose-adjustment based on exposure
`changes is not necessary as epinephrine is to be administered in a controlled
`clinical setting titrated to a target response. For similar reasons, drug interactions
`affecting the pharmacokinetics or pharmacodynamics of epinephrine also do not
`warrant any dose adjustment.”
`
`Reference ID: 3376064
`
`10
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`
`

`

`Clinical Review
`Gail Moreschi, MD, MPH
`NDA 20-5029
` Epinephrine
`
`
`5
`
`Sources of Clinical Data
`
`The entire clinical submission was a literature review.
`
`
`5.1 Tables of Studies/Clinical Trials
`
`NA
`
`5.2 Review Strategy
`
`No clinical studies were completed and submitted by the sponsor. The sponsor
`submitted articles documenting the efficacy of epinephrine. However, the sponsor
`essentially used the label of Twinject, NDA 020800, for safety which has a different
`indication, the emergency treatment of severe allergic reactions (Type I), different dose,
`and route of administration. Therefore, this reviewer looked for adverse effects from the
`longer use of epinephrine for hours and/or days. Essentially not much is published in
`the literature regarding the long term adverse effects of epinephrine.
`
`
`5.3 Discussion of Individual Studies/Clinical Trials
`
`These studies varied in their design, whether or not they were controlled studies and
`how long they observed and treated septic shock patients. Some studies even included
`shock from other causes.
`
`Review of Efficacy
`
` 6
`
`
`
`Efficacy Summary
`
`The literature review submitted by the sponsor documents the efficacy of
`epinephrine in the treatment of hypotension from septic shock. This treatment
`has been used for years without FDA approval which they are seeking with this
`submission.
`
`
`6.1
`
`Indication
`
`The indication the sponsor is seeking is for use in increasing systemic arterial blood
`pressure in acute hypotensive states associated with septic shock. Currently there is no
`FDA approved intravenous epinephrine for hemodynamic stabilization in septic shock.
`
`Reference ID: 3376064
`
`11
`
`(b) (4)
`
`

`

`Clinical Review
`Gail Moreschi, MD, MPH
`NDA 20-5029
` Epinephrine
`
`
`
`In 1991 the American College of Chest Physicians (ACCP) and the Society of Critical
`Care Medicine (SCCM) held a consensus conference to define the pathophysiology of
`sepsis. “Sepsis” is the clinical syndrome defined by the presence of both infection and a
`systemic inflammatory response in response to the infection. In the U.S more than
`200,000 persons die annually from sepsis. "Septic shock" in adults refers to a state of
`acute circulatory failure characterized by persistent arterial hypotension unexplained by
`other causes.
`
`In 2001 the signs and symptoms for sepsis were expanded to include hemodynamic
`instability, arterial hypoxemia, oliguria, coagulopathy and altered liver function tests.
`These signs and symptoms may be indicative of organ dysfunction.
`
`Arterial hypotension is the main hemodynamic parameter of sepsis, and occurs when
`systolic blood pressure drops below 90 mmHg; when mean arterial pressure (MAP)
`drops below 70 mmHg; or when systolic blood pressure decreases more than 40 mmHg
`in adults or in children.
`
`The treatment of septic shock includes many parameters but hypotension is extremely
`important. For a patient to survive this critical illness all the parameters must be treated.
`The studies involving the use of epinephrine for the treatment of hypotension in septic
`shock have developed historically and this historical time frame will be used in the
`following efficacy section. The sponsor has submitted 14 published studies