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

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY NDA/BLA REVIEW AND EVALUATION
`
`Application number:
`Supporting document/s:
`Applicant’s letter date:
`CDER stamp date:
`Product:
`
`Indication:
`
`NDA 205-029
`0000
`December 4, 2012
`December 4, 2012
`Epinephrine (HCL) Injection
`USP, 1:1000 (1mg/mL)
` Treatment of increasing systemic arterial blood
` pressure in acute hypotensive states associated with
` septic shock
`
`
`Belcher Pharmaceuticals, LLC (Belcher)
` Applicant:
`Cardiovascular and Renal Products
`Review Division:
`Rama Dwivedi, Ph.D.
`Reviewer:
`Thomas Papoian, Ph.D.
`Supervisor/Team Leader:
`Norman Stockbridge, M.D., Ph.D.
`Division Director:
`Russell Fortney
`Project Manager:
`Template Version: September 1, 2010 (Modified by DCRP: December 12, 2012)
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and necessary for
`approval of NDA205-029 are owned by Belcher Pharmaceuticals or are data for which Belcher
`Pharmaceuticals, LLC (Belcher) has obtained a written right of reference. Any information or
`data necessary for approval of NDA205-029 that Belcher Pharmaceuticals, LLC (Belcher) does
`not own or have a written right to reference constitutes one of the following: (1) published
`literature, or (2) a prior FDA finding of safety or effectiveness for a listed drug, as reflected in
`the drug’s approved labeling. Any data or information described or referenced below from
`reviews or publicly available summaries of a previously approved application is for descriptive
`purposes only and is not relied upon for approval of NDA205-029
`
`Reference ID: 3339007
`
`1
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`

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`NDA# 205029
`
`
`
`
` Reviewer: Rama S. Dwivedi
`
`3
`
`4
`
`3.1
`3.2
`3.3
`
`TABLE OF CONTENTS
`1 EXECUTIVE SUMMARY .................................................................................................. 6
`1.1
`INTRODUCTION AND CLINICAL RATIONALE ...................................................... 6
`1.2
`BRIEF SUMMARY OF NONCLINICAL FINDINGS .................................................. 6
`1.3
` RECOMMENDATIONS .............................................................................................. 7
`1.3.1
`Approvability .......................................................................................................... 7
`1.3.2
`Additional Non Clinical Recommendations ........................................................... 7
`1.3.3
`Labeling .................................................................................................................. 7
`2 DRUG INFORMATION ...................................................................................................... 9
`2.1
`DRUG ............................................................................................................................... 9
`2.2
`RELEVANT NDAS. ........................................................................................................... 9
`2.3 DRUG FORMULATION..................................................................................................... 10
`2.4
`COMMENTS ON NOVEL EXCIPIENTS ............................................................................... 11
`2.5
`COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ............................................... 11
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN ............................................ 12
`2.7
`REGULATORY BACKGROUND ......................................................................................... 12
`STUDIES SUBMITTED ................................................................................................ 12
`STUDIES REVIEWED ....................................................................................................... 12
`STUDIES NOT REVIEWED ............................................................................................... 13
`PREVIOUS REVIEWS REFERENCED ................................................................................. 13
`PHARMACOLOGY ....................................................................................................... 13
`PRIMARY PHARMACOLOGY ............................................................................................ 13
`4.1
`PRIMARY PHARMACOLOGY: STUDIES FROM THE LITERATURE ....................................... 19
`4.2
`SAFETY PHARMACOLOGY .......................................................................................... 32
`4.3.1
`PHARMACOKINETICS/ADME/TOXICOKINETICS ................................................. 35
`5
`6 GENERALTOXICOLOGY ............................................................................................... 36
`6.1
`SINGLE-DOSE TOXICITY ................................................................................................ 36
`6.2
`REPEAT-DOSE TOXICITY STUDIES ................................................................................. 36
`7 GENETIC TOXICOLOGY ............................................................................................... 40
`8 CARCINOGENICITY ....................................................................................................... 40
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY.................................. 41
`10 SPECIAL TOXICOLOGY STUDIES ............................................................................. 42
`10.1 ASTM HEMOLYSIS-DIRECT CONTACT METHOD (ASTM F 756-08) ............................. 42
`11 INTEGRATED SUMMARY AND SAFETY EVALUATION ...................................... 46
`11.1
`INTRODUCTION .............................................................................................................. 46
`11.2 PHARMACOLOGY ........................................................................................................... 47
`11.3 TOXICOLOGY ................................................................................................................. 47
`11.4 GENOTOXICITY .............................................................................................................. 47
`11.5 CARCINOGENICITY ......................................................................................................... 48
`
`Reference ID: 3339007
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`NDA# 205029
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` Reviewer: Rama S. Dwivedi
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`11.6 DEVELOPMENTAL TOXICOLOGY .................................................................................... 48
`11.7 CONCLUSION .................................................................................................................. 48
`12
`REFERENCES ................................................................................................................ 49
`
`
`Reference ID: 3339007
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`NDA# 205029
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` Reviewer: Rama S. Dwivedi
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`Table of Tables
`
`
`Table 1: Effect of epinephrine on vital organ system ........................................................... 15
`Table 2: Time course of arterial metabolic parameters at baseline and 180 minutes in saline,
`epinephrine, or norepinephrine control groups, and endotoxemic rats treated with or without
`epinephrine or norepinephrine from 90 to 180 minutes (Sponsor’s table) ............................... 20
`Table 3: Course of tissue lactate (nmol/mg wet/weight) and lactate/pyruvate (L/R) ratio at
`baseline and 180 minutes in saline, epinephrine, or norepinephrine control groups, and
`endotoxemic rats treated with or without epinephrine or norepinephrine from 90 to 180 minutes
`(Sponsor’s table).............................................................................................................. 20
`Table 4: The Median Lethal Dose(s) of Epinephrine (Sponsor’s table) .................................. 36
`Table 5: Survival and Median Body Weights of Rats in the 14-Day In halation Study of
`Epinephrine Hydrochloride (NTP) ..................................................................................... 37
`Table 6: Survival and Median Body Weights of Mice in the 14-Day In halation Study of
`Epinephrine Hydrochloride (NTP) ..................................................................................... 37
`Table 7: Organ Weights for rat in the 13-Week Inhalation Study of Epinephrine Hydrochloride
`(a) .................................................................................................................................. 38
`Table 8: Change in Organ weights for mice in the 13-Week Inhalation studies of Epinephrine
`hydrochloride (a) ............................................................................................................. 39
`Table 9: Nasal Passage Lesions Observed in Mice in the 2-Year Inhalation Studies of
`Epinephrine Hydrochloride ............................................................................................... 40
`Table 10: Effect of epinephrine on early pregnancy of rabbit (Sponsor’s table) ...................... 41
`Table 11: Supplies (Sponsor’s table) ............................................................................ 43
`Table 12: Standard Hemoglobin Concentration (Sponsor’s table) ......................................... 44
`Table 13: Preparation of test article and controls (Sponsor’s table) ....................................... 44
`Table 14: Color Determinations (Sponsor’s table) .............................................................. 45
`Table 15: Hemolytic Grades ............................................................................................. 45
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`Reference ID: 3339007
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`NDA# 205029
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`
`
`
` Reviewer: Rama S. Dwivedi
`
`Table of Figures
`
`
`
`Figure 1: Epinephrine structure and Space filling model (Wikipedia)...................................... 9
`Figure 2: Epinephrine Synthetic pathway (Goodman & Gillman, 2011) ................................ 13
`Figure 3: The mechanism of Epinephrine action ................................................................. 14
`Figure 4: Characteristics of the canine sepsis model with three different bacterial challenges in
`control animals receiving intravenous fluids and antibiotics without vasopressor therapy
`(Sponsor’s Figure) ........................................................................................................... 22
`Figure 5: Effects of vasopressors on survival. The odds ratios of survival (means, closed circles;
`±, horizontal lines) with vasopressor therapy averaged over all bacterial challenge and drug dose
`levels are shown. Overall, the effect of epinephrine on outcome was significantly different from
`the effects of norepinephrine and vasopressin (P = 0.03). Compared with controls, epinephrine
`had a harmful effect and norepinephrine and vasopressin had beneficial effects on survival. .... 23
`Figure 6: Effects of vasopressors on physiological parameters of cardiac index, ejection fraction,
`and systemic vascular resistance on canine sepsis models as differences from nonvasopressor
`treated controls (Sponsor’s Figure). ................................................................................... 24
`Figure 7: Effects of epinephrine, norepinephrine, and dopamine on cardiovascular parameters in
`a physiological ovine preparation (Sponsor’s figure) ........................................................... 25
`Figure 8: Graphic representation of the effect of hyperdynamic sepsis with vehicle (squares) and
`epinephrine (triangles) on MAP, heart rate, cardiac output, and total peripheral conductance ... 27
`Figure 9: Graphic representation of renal blood flow and renal conductance during
`hyperdynamic sepsis with vehicle (squares) and with epinephrine (triangles) ......................... 28
`Figure 10: Graphic representation of mesenteric blood flow and mesenteric conductance during
`hyperdynamic sepsis with vehicle (squares) and with epinephrine (triangles) ......................... 29
`Figure 11: Graphic representation of coronary blood flow and coronary conductance during
`hyperdynamic sepsis with vehicle (squares) and with epinephrine (triangles) ......................... 30
`Figure 12: Graphic representation of stroke volume and df/dt during hyperdynamic sepsis with
`vehicle (squares) and with epinephrine (triangles) ............................................................... 31
`Figure 13: Graphic representation of sagittal sinus blood flow during hyperdynamic sepsis with
`vehicle (squares) and with epinephrine (triangles) ............................................................... 31
`Figure 14: Effects of selected reference compounds on heart rate (HR) in anaesthetized guinea
`pigs after intravenous administration. Each curve represents the meanTS.E.M. *P <0.05, **P
`<0.01, ***P <0.001 versus pre-drug values......................................................................... 32
`Figure 15: Effects of selected reference compounds on (A) SAP and (B) DAP in anaesthetized
`guinea pigs after intravenous administration of different doses. Each curve represents the
`meanTS.E.M. *P <0.05, **P <0.01, ***P <0.001 versus pre-drug values............................... 33
`Figure 16: Effects of reference compounds on (A) LVP and (B) dp/dtmax in anaesthetized
`guinea pigs after intravenous administration of different doses. Each curve represents the
`meanTS.E.M. *P <0.05, **P <0.01, ***P <0.001 versus pre-drug values............................... 34
`
`Reference ID: 3339007
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`NDA# 205029
`
`
`
`
` Reviewer: Rama S. Dwivedi
`
`EXECUTIVE SUMMARY
`1
`INTRODUCTION AND CLINICAL RATIONALE
`1.1
`Belcher Pharmaceuticals, LLC, proposes that epinephrine USP, 1:1000 (1 mg/mL) Injection
`(0.05 to 2.0 μg/kg/min) will provide hemodynamic support for increasing systemic arterial blood
`pressure to achieve a desired MAP (cid:149) 70 mmHg in acute hypotensive states associated with septic
`shock.
`
`This submission is primarily based on published literature [i.e., a 505(b)(2) application] and
`safety information from the listed reference drug Twinject (NDA 020800; May 30, 2003). In
`addition, there are several (almost 39) approved epinephrine drug formulations currently being
`marketed as 1 mg/mL, (1:1000), 0.1 mg/mL (1:10,000), and 0.5 mg/mL (1:2000) solutions.
`
`Epinephrine, a sympathomimetic (adrenergic) drug has been in the market for over 50 years in
`treating hypotension associated with septic shock. The mechanism to increase blood pressure is
`due to the activation of (cid:302) and (cid:533)-adrenergic receptors affecting myocardial stimulation leading to
`increased ventricular contraction (positive inotropic action) and heart rate (positive chronotropic
`action), and vasoconstriction in many vascular beds, including veins.
`
`1.2
`BRIEF SUMMARY OF NONCLINICAL FINDINGS
`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.
`
`Metabolic effects such as hyperlactemia, hyperglycemia and hypokalemia, decreased mesenteric,
`coronary and renal conductance were associated with epinephrine treatment (Levy 2003).
`
`Data from NTP studies (1990) have shown an equivocal response of epinephrine when tested in
`Salmonella typhimurium strain TA100 in the absence of metabolic activation system (S-9) and
`negative in the presence of metabolic activation (S9).
`
`The data from published reports suggest that epinephrine was not carcinogenic in 2-year rat
`studies. However, studies were considered inadequate (NTP, Report 380, 1990), in that doses
`were too low to have an adequate systemic challenge from the drug compound.
`
`Epinephrine has been shown to interfere with ovum implantation and fetus survival in rabbits
`(Auletta, 1971). Developmental effects have been observed in rabbits at a subcutaneous dose of
`1.2 mg/kg, in mice at a subcutaneous dose of 1 mg/kg, and in hamsters at a subcutaneous dose of
`0.5 mg/kg. Hemorrhages, edema and necrosis of distal extremities were observed when 5-50 μg
`of adrenalin was injected directly into rabbit fetuses at 18 to 22 days of gestational age (Shepard,
`1986).
`
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`Reference ID: 3339007
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`NDA# 205029
`
`Reviewer: Rama S. Dwivedi
`
`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.
`
`1.3
`
`RECOMMENDATIONS
`
`1.3.1 Approvability
`
`Approvable
`
`1.3.2 Additional Non Clinical Recommendations
`
`None
`
`1.3.3
`
`Labeling
`
`8.1 Pregnancy
`The sponsor did not address the loss in ovum implantation, fetus survival and teratogenic
`potential (gastroschisis in one fetus) of epinephrine in rabbits (Auletta, 1971). Epinephrine has
`been shown to affect the ovum transport and the motility of the rabbit oviduct (Longley et al
`1968) and impair implantation in rats (Crist & Hulka, 1970). A decreased number of
`implantations and fetuses were observed in rabbits treated with epinephrine on Days 6 to 7 and 7
`to 9 (P<0.01 and P<0.01 respectively). In addition to this, epinephrine has been shown to
`interfere with ovum implantation and fetus survival in rabbits and having a potential teratogenic
`activity as gastroschisis in one fetus Cl”able 10) at Day 6/7 (Auletta, 1971) and abnormally absent
`aortic arches related to dysrhythmogenesis (Rajala et a1, 1988).
`
`Based on the developmental efl'ects of epinephrine, the Sponsor’s version of 8.1 Pregnancy
`section as cited below:
`
`Pregnancy Category C:
`Epinephrine has been shown to have developmental eflects in rabbits at a subcutaneous dose of
`1.2 mg/kg (approximately 30 times the maximum recommended daily subcutaneous or
`intramuscular dose on a mg/m2 basis), in mice at a subcutaneous dose of 1 mg/kg
`(approximately 7 times the maximum recommended daily subcutaneous or intramuscular dose
`on a mg/mZ basis), and in hamsters at a subcutaneous dose of0.5 mg/kg (approximately 5 times
`the maximum recommended daily subcutaneous or intramuscular dose on a mg/mZ basis). These
`@fects were not seen in mice at a subcutaneous dose of0.5 mg/lrg (approximately 3 times the
`maximum recommended daily subcutaneous or intramuscular dose on a mg/mZ basis). Although
`there are no adequate and well-controlled studies in pregnant women, epinephrine crosses the
`placenta
`ut not the blood-brain barrier and could lead to etal anoxia, s ontaneous abortion
`
`orboth.*
`
`Should be revised as:
`
`Pregnancy Category C:
`Epinephrine has been shown to have developmental effects in rabbits at a subcutaneous dose of
`1.2 mg/kg (approximately 30 times the maximum recommended daily subcutaneous or
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`NDA# 205029
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`Reviewer: Rama S. Dwivedi
`
`intramuscular dose on a mg/m2 basis), in mice at a subcutaneous dose of 1 mg/kg
`(approximately 7 times the maximum recommended daily subcutaneous or intramuscular dose
`on a mg/m2 basis), and in hamsters at a subcutaneous dose of 0.5 mg/kg (approximately 5 times
`the maximum recommended daily subcutaneous or intramuscular dose on a mg/m2 basis). These
`effects were not seen in mice at a subcutaneous dose of 0.5 mg/kg (approximately 3 times the
`maximum recommended daily subcutaneous or intramuscular dose on a mg/m2 basis). In rabbits,
`epinephrine interferes with ovum implantation and fetus survival. Although there are no
`adequate and well—controlled studies in pregnant women, epinephrine crosses the placenta (but
`not the blood-brain banier) and could lead to fetal anoxia, spontaneous abortion or both.
`Therefore, epinephrine should be used in pregnancy only if considered essential by the physician
`and the potential benefit justifies the potential risk to the fetus.
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`Based on the data from mutagenicity and carcinogenicity studies (# page 40) the first paragraph
`of the Sponsor’s version of 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`section as cited below:
`
`
`
`Should be revised as:
`
`Epinephrine has been shown to have an equivocal response when tested in the bacterial reverse
`mutation (Ames) test. No carcinogenic efl'ects of epinephrine were observed in rats or mice when
`exposed by the inhalation route. However, systemic exposures were considered inadequate.
`There are no data available from either animal or human studies regarding efi'ects of epinephrine
`on fertility.
`
`Reference ID: 3339007
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`NDA# 205029
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`
`Drug Information
`2
`Drug
`
`
`2.1
`EPIVAS
`
`
`
`
`
`
`CAS Registry Number (Optional)
`
`Generic Name
`
`Chemical Name
`
`
`
`
`
`
`
` Reviewer: Rama S. Dwivedi
`
`
`
`
`
`
`
`
`
`
`Epinephrine Injection, USP 1:1000) 1 mg/mL
`
`51-43-4
`
`Epinephrine (Adrenaline)
`
`1, 2-Benzenediol, 4-[1-hydroxy-2-(methylamino)
`ethyl]-, (R)-(-)-1-(3, 4-Dihydroxyphenyl)-2-
`(methylamino)-ethanol
`
`1-hydroxy-2 (methylamino) ethyl]-1,2 benzenediol
`
`
`C9H13NO3
`
`183.2044
`
`
`Other name
`
`
`
`Molecular Formula
`
`Molecular Weight
`
`Structure or Biochemical Description
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Figure 1: Epinephrine structure and Space filling model (Wikipedia)
`
`
`
`
`
`
`
`Sympathomimetic Catecholamine
`
`
`
`
`
`
`Pharmacologic Class
`
`2.2
`
`Relevant NDAs.
`Adrenalin (N-204200), Septocane (N-022010, N-020971), Intocaine (N-020530),
`Twinject (N-020800), Auvi-Q(N-201739), Xylocaine (N-021381, N-006488), Epipen (N-
`019430), Orabloc (N-022466), Citanest (N-021383), Levophed (N-007513), Lidosite (N-
`021504).
`
`Reference ID: 3339007
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`NDA# 205029
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`Reviewer: Rama S- Dwivedi
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`2.3 Drug Formulation
`
`Refer toHDMF No.
`
`information concermng man
`
`cture of the
`
`for all Active Ingredient Manufacturer (AIM)
`
`g substance.
`
`Function
`
`Quantity
`
`Quantity
`
`Reference
`
`mglml
`
`mg/l ml
`
`ampoule
`
`
`_pinephrineBase
`
`So—diumChloride
`
`Drug Substance
`TonicityAgent
`
`mg
`
`Water forInjection
`
`Specification:
`Ingredients are in compliance wiflI USP monograph.
`
`Epinephrine Identification
`
`(Colorimetric test)
`
`Complies
`
`Optical rotation
`
`(on dried substance)
`
`Loss on drying
`E inc IIrine Assn
`’T
`l’
`(TItratIon)
`
`’
`
`l
`
`USP
`USP
`
`USP
`
`USP
`
`USP
`USP
`
`USP
`usp
`
`WWW-MC) —-
`
`ln-house Method
`
`Reference ID: 3339007
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`NDA# 205029
`
`Reviewer: Rama 8. Dwivedi
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`2.4
`
`Comments on Novel Excipients
`
`All excipients are in compliance with pharmacopoeial monograph requirements as below:
`
`m Pharmacopoeia“ reference
`
`2.5
`
`Comments on Impurities/Degradants of Concern
`
`ismmregardtoepmepmne impmiues——, and
`
`is in accordance to approved listed drug (Twinject).
`
`
`
`In-house Method
`
`
`
`How supplied! route
`of administration
`
`Single use auto-
`injector for
`subcutaneous or
`intramuscular
`injection
`
`Listed Drug
`
`Twinject (0.3 mg
`epinephrine/mL)
`Shionogi lnc
`distributed by
`Greenstone LLC (label
`date 1/2010
`
`NDA 020800;
`Approval 5/2003
`
`Indications
`
`Dosage
`
`Epinephrine auto-injector is
`indicated in the emergency
`treatment of severe allergic
`reactions (Type 1).
`
`The dosage is 0.3 mg delivered
`inl mL and is for use by patients
`who weigh 30 kg (approx. 65
`pounds) or greater.
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`Reference ID: 3339007
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`NDA# 205029
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`Reviewer: Rama S. Dwivedi
`
`2.6
`
`Proposed Clinical Population and Dosing Regimen
`
`Epinephrine injection USP, 121000 (1 mg/mL) is proposed for intravenous infilsion in
`increasing the systemic arterial blood pressure in acute hypotensive states associated with septic
`shock. The dosing regimen for intravenous administration of epinephrine is 0.05 to 2.0
`pg/kg/min in hypotension associated septic shock, and is titrated to achieve a desired mean
`arterial
`ressure GVIAP) of 270 mmHg. A periodic adjustment of dosage
`
`‘inincrements, such as by0.05 to 0.2 pg/kg/min, isnecessaryto achieve the desired
`
`goa . Epinephrine should be titrated closely and the minimum dose should be used as required.
`Once the hemodynamics is stabilized for several hours, the dosage may be weaned down
`incrementally over time.
`
`2.7
`
`Regulatory Background
`
`
`acka e
`IND
`for
`Belcher Pharmaceuticals, LLC, submitted a re-IND meetin
`Based
`intravenous administration of epinephrine
`on the information in its PIND package (dated Dec. 4, 2012), Belcher proposed epinephrine
`USP, 1:1000 (1 mg/mL) Injection (0.05 to 2.0 pg/kg/min) to provide hemodynamic support for
`increasing systemic arterial blood pressure (to achieve a desired M AP 2 70 mmHg) in acute
`hypotensive states associated with septic shock. This current NDA submission is primarily based
`on published literature [i.e., a 505(b)(2) application)] and safety information from the listed
`reference drug Twinject (NDA 020800; May 30, 2003).
`
`Listed Drug
`
`How supplierl/ route
`of administration
`
`Approval 51’2003
`
`Twinject (0.3 mg
`cpinephrincltnL)
`Shionogi Inc
`distributed by
`Grecnstone LLC (label
`date 120“)
`
`NDA 0208001
`
`Single use auto—
`injector for
`subcutaneous or
`intramuscular
`injection
`
`Epinephrine auto-injector is
`indicated in the emergency
`treatment of severe allergic
`reactions (Type 1).
`
`The dosage is 0.3 mg delivered
`inl mL and is for use by patients
`who weigh 30 kg (approx. ()5
`pounds) or greater.
`
`In addition, there are several (almost 39) approved epinephrine drug formulations currently being
`marketed as 1 mg/mL, (l : 1000), 0.1 mg/mL (110,000), and 0.5 mg/mL (1 :2000) solutions for
`intramuscular or subcutaneous administration for the treatment of anaphylactic shock OEpiPen
`and Twinject), and anesthetic combination products that contain epinephrine at low doses (such
`as Septocaine; Octocaine; Xylocaine with epinephrine).
`
`3.
`
`STUDIES SUBNIITTED
`
`3.1
`
`Studies Reviewed
`
`Levy et al. (2003). Effects of epinephrine and norepinephrine on hemodynamics, oxidative
`metabolism, and organ energetics in endotoxemic rats
`Minneci et al. (2004). Differing effects of epinephrine, norepinephrine, and vasopressin on
`survival in a canine model of septic shock (in vivo study in dogs)
`
`Reference ID: 3339007
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`
`
` Reviewer: Rama S. Dwivedi
`
`NDA# 205029
`
`Myburgh et al, (2006). An appraisal of selection and use of catecholamines in septic shock - old
`becomes new again (in vitro study using a sheep preparation)
`Di Giantomasso (2005). The hemodynamic and metabolic effects of epinephrine in
`experimental hyperdynamic septic shock (in vivo study in sheep)
`ASTM Hydrolysis (ASTM F 756-08)
`3.2
`Studies Not Reviewed
`None
`Previous Reviews Referenced
`3.3
`NDA 020800 (Twinject)
`4.
`PHARMACOLOGY
`4.1
`Primary Pharmacology
`Biosynthesis: Epinephrine (also known as adrenaline) is a hormone belonging to group of
`catecholamines and synthesized in adrenals from the amino acid tyrosine under the control of
`CNS in response to a physiological stress (Fig. 2). Once the dopamine and norepinephrine are
`synthesized, norepinephrine is methylated and finally converted to epinephrine by
`phenylethanolamine N-methyltransferase (PNMT) in the cytosol of adrenergic neurons using the
`S-adenosylmethionine (SAMe) as methyl donor. Circulating epinephrine is rapidly inactivated by
`catechol O-methyltransferase (COMT) and monoamine oxidase (MAO) that is highly present in
`the liver.
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`Figure 2: Epinephrine Synthetic pathway (Goodman & Gillman, 2011)
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`NDA# 205029
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`Mechanism of Action: Epinephrine (adrenaline), an endogenous sympathomimetic
`catecholamine targets adrenergic receptors ((cid:302)- and (cid:533)-adreno-receptors belonging to a class of G-
`protein coupled receptors), and causes vasoconstriction through its binding with (cid:302)-receptors ((cid:302)1
`and (cid:302)2) at high concentration and vasodilation via (cid:533)-receptors ((cid:533)1, (cid:533)2, and (cid:533)3) at low
`concentration.
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`Epinephrine binds its receptor that associates with heterotrimeric G protein. The G protein
`associates with adenylate cyclase that converts ATP to cAMP. This initiates a chain of chemical
`reactions to ultimately signal a cellular response (Fig. 3).
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`Figure 3: The mechanism of Epinephrine action
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`Effect of epinephrine on vital organ system is presented as below (Table 1) Goodman & Gillman
`12e, Section II.
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`Table 1: Effect of epinephline on vital organ system
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`4.2
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`Primary Pharmacology: Studies from the Literature
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`Pharmacodynamics
`Non-clinical studies (one in vivo study in rats, one in vivo study dogs, and two studies in sheep
`(one in vitro and one in vivo) submitted by the Sponsor were reviewed and discussed herein to
`determine the pharmacological effects of epinephrine in animals.
`
`Levy et al. 2003
`Effects of epinephrine and norepinephrine on hemodynamics, oxidative metabolism, and organ
`energetics in endotoxemic rats
`
`Key Findings
`The hyperlactemia is not related to cellular hypoxia in sepsis model of Wistar rats following
`epinephrine treatment.
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`Purpose
`To determine whether an increased lactate concentration in sepsis model of Wistar rats is the
`result of hypoxia, thermogenic or any other metabolic pathway triggered by epinephrine.
`
`Method
`Sepsis was developed in rats following an intravenous infusion of 15 mg/kg Escherichia
`coli O127:B8 endotoxin.
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`After 90 minutes, sepsis and time matched saline treated control rats were treated for 90 to 180
`min with epinephrine (0.2 and 1(cid:541)g/kg/min) or norepinephrine (0.2 and 1(cid:541)g/kg/min).
`
`The mean arterial pressure (MAP), aortic, renal, mesenteric and femoral blood flow, arterial
`blood gases, lactate, pyruvate, and nitrate were measured at baseline and 90 and 180 min after
`endotoxin exposure.
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`NDA# 205029
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`Results
`MAP decreased (from 115 ± 11 to 76 ± 8 mmHg, p < 0.01) while heart rate increased (from 369
`± 9 to 430 ± 14 bpm, p < 0.05) in endotoxin treated sepsis rats. The lactate concentration
`increased with a high lactate/pyruvate (L/P) ratio (Table 2). The mean efficient dose of
`epinephrine (2.8(cid:541)g/kg/min) or norepinephrine (3.1(cid:541)g/kg/min) increased heart rate (from 370 ± 8
`and 360 ± 9 to 431 ± 10 and 420 ± 12 bpm, respectively, p < 0.05). Epinephrine and
`norepinephrine treatment in sepsis rats increased MAP over baseline values. Epinephrine
`increased aortic blood flow while renal blood low decreased with both drugs.
`
`Table 2: Time course of arterial metabolic parameters at baseline and 180 minutes in saline,
`epinephrine, or norepinephrine control groups, and endotoxemic rats treated with or without
`epinephrine or norepinephrine from 90 to 180 minutes (Sponsor’s table)
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`Plasma lactate concentration increased with a stable L/P ratio with epinephrine and did not
`change with norepinephrine compared to endotoxin values. Epinephrine and norepinephrine did
`not change tissue L/P ratios concentration in muscle, heart, gut, or liver when compared to base
`line endotoxin values (Table 3).
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`Table 3: Course of tissue lactate (nmol/mg wet/weight) and lactate/pyruvate (L/R) ratio at
`baseline and 180 minutes in saline, epinephrine, or norepinephrine control groups, and
`endotoxemic rats treated with or without epinephrine or norepinephrine from 90 to 180 minutes
`(Sponsor’s table)
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`NDA# 205029
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`
`Minneci et al. 2004
`Differing effects of epinephrine, norepinephrine, and vasopressin on survival in a canine model
`of septic shock (in vivo study in dogs)
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`Key Findings
`Epinephrine infusion caused a decrease in the 28-day survival in a dog model of septic shock,
`and norepinephrine and vasopressin did not show any significant improvement.
`
`Purpose
`To study the effects of epinephrine, norepinephrine, and vasopressin on survival in canine septic
`shock model.
`
`Methods
`Beagle dogs (n=78, 12-28 months old weighing 10-12 kg) were induced with sepsis by
`implantation of a fibrin clot containing live Escherichia coli 0111:B4 into the abdominal cavity.
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`After 6 hrs of implantation, dogs with varying degree of sepsis were randomized and given
`epinephrine (0.2, 0.8, or 2.0 μg/kg/min