CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-3 04
`
`ENVIRONMENTAL ASSESSMENT
`
`

`

`1
`
`'-
`
`Food and‘Drug Administration
`Center for Drug Evaluation and Research
`Office of Pharmaceutical Science/Immediate Office
`
`
`Memorandum
`
`Date:
`
`From:
`
`To:
`
`July 07, 2008
`
`Raanan A. Bloom, Ph.D.
`OPS/IO/PARS
`
`Danae Christodoulou, Ph.D.
`OPS/ONDQA/DPAI
`
`Through:
`
`Jon Clark, Ms.
`OPS/IO/PARS
`
`Subject:
`
`NDA 22-304; Tapentadol HCl
`
`Johnson and Johnson Pharmaceutical Research and Development, L.L.C.
`920 Route 202
`
`Raritan, NJ 08869
`
`Background
`
`Johnson and Johnson Pharmaceutical Research and Development, L.L.C. is requesting
`approval of an NDA for tapentadol hydrochloride drug substance in immediate release (IR)
`tablets. An EA has been submitted pursuant to 21 CFR part 25.
`
`Discussion
`
`The review appended below was conducted by Ruth Ganunis, Ph.D., under contract to the
`Office of Pharmaceutical Science, Center for Drug Evaluation and Research (Completion
`date: May 19, 2008). Also attached are recommendations and an Executive Summary.
`
`Comments and Conclusions
`
`Based on an evaluation of the information provided in this EA and in FDA guidance, and on
`the scientific validity of the “no effects” conclusions of the EA, no significant adverse
`environmental impacts are expected from the introduction of tapentadol residues into the
`environment due to the use of tapentadol for the treatment of acute pain.
`
`

`

`Page 2 — NDA 22-304
`
`
`
`EXECUTIVE SUMMARY — ENVIRONMENTAL ASSESSMENT
`
`FONSI recommended.
`
`The maximum predicted amount of tapentadol hydrochloride drug substance manufactured for
`direct use in any of the next five years is C j kg/year. Assuming no metabolism or
`environmental depletion, the firm determines the EIC to be m
`
`[1(4)
`
`Tapentadol hydrochloride is fieely water soluble and has a log K0w <3.5. A' microbial inhibition
`test showed tapentadol hydrochloride to be relatively non-toxic, with an E050 of 586 mg/L. The
`firm provided the results of 3 acute toxicity studies, including fish, invertebrate and algal
`species. Of these, the most sensitive species is green algae with an assessment factor of
`No observed effects were seen at the MEEC. No potential adverse environmental effects
`resulting from the manufacture and use of tapentadol hydrochloride are identified.
`
`,—
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`

`

`Page 3 — NDA 22-304
`
`REVIEW OF ENVIRONMENTAL ASSESSMENT
`
`1.
`
`Date:
`
`EA dated November 7, 2007
`
`2.
`
`Name of applicant/petitioner:
`
`Johnson and Johnson Pharmaceutical Research and Development, L.L.C.
`
`ADEQUATE
`
`3.
`
`Address:
`
`920 Route 202
`
`Raritan, NJ 08869
`
`'ADEQUATE
`
`4.
`
`Description of the proposed action:
`
`a.
`
`Requested Approval:
`
`Johnson and Johnson Pharmaceutical Research and Development, L.L.C. is
`requesting approval of an NDA for tapentadol hydrochloride drug substance in
`immediate release (IR) tablets. An EA has been submitted pursuant to 21 CFR
`part 25.
`
`ADEQUATE
`
`Need for Action:
`
`Tapentadol hydrochloride tablets will be used for the treatment of acute pain.
`
`ADEQUATE
`
`Expected Locations of Use (Drug Product):
`
`The locations of use will typically be hospitals, clinics and/or patients in their
`homes.
`
`ADEQUATE
`
`Disposal Sites
`
`

`

`Page 4 — NDA 22-304
`
`Returned product will be disposed through high temperature incineration at
`licensed disposal facilities. US hospitals, pharmacies, or clinics will dispose of
`empty or partially empty packages according to their internal handling
`procedures. In the home, empty or partially empty packages will be disposed by a
`community’s solid waste management system, which may include landfills,
`incineration and recycling. Minimal quantities ofunused drug may be disposed
`in the sewer system. Where available, disposal ofunused medicines could also be
`through take-back programs in local community waste disposal systems or
`pharmacies.
`
`ADEQUATE
`
`5.
`
`Identification of chemicals that are the subject of the proposed action:
`
`Nomenclature:
`
`Established Name (USAN): Tapentadol hydrochloride
`Proposed Trade Name: Not applicable
`Chemical name: 3-[(1R,2R)—3-(dimethylamino)-l-ethyl-2-methylpropyl]pheno1
`monohydrochloride
`,
`Chemical Abstracts Service (CAS) Registration Number: 175591-09-0
`Molecular Formula: C14H23NO-HC1
`-
`Molecular Weight: 257.80 (221.34 + 36.46)
`Chemical Structure:
`
`OH .
`
`. HCI
`
`\
`
`(In
`
`ADEQUATE
`
`6.
`
`Environmental Issue:
`
`a.
`
`Environmental Fate of Released Substances
`
`i.
`
`Identification of Substances of Interest
`
`The firm does not mention or discuss metabolites, degradants, or any other
`structurally related compounds that may exist in the environment. It is
`assumed that the subject of interest is tapentadol hydrochloride. In their
`calculation of the environmental concentration, they assume no
`metabolism or degradation.
`
`ADEQUATE
`
`

`

`Page 5 — NDA 22-304
`
`ii.
`
`Physical and Chemical Characterization
`
`Dissociation Constants
`
`pKal: 9.34
`uKa2: 10.45
`2.87
`
`1704
`
`
` End . oint
`Water Solubility (at ambient
`380 mg/mL
`
`
`tem o erature
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Partition Coefficient n-
`
`.
`Octanol/Water 10 Km,
`Adsorption Coefficient (Koc)
`OECD Guideline 121
`
`.
`
`Tapentadol hydrochloride is freely soluble in water at ambient
`temperature. The Partition Coefficient n—Octanol/Water (log Kow) is 2.87.
`A value less than 3.5 indicates that the compound is not likely to
`bioaccumulate.
`
`Based on the test data, tapentadol hydrochloride is expected to enter the
`aquatic environment.
`
`Concern: The K0c is greater than 1000, indicating that it will adsorb to
`biosolids and mobilize in the environment. The firm makes no comments
`about this high value.
`
`iii.
`
`Environmental Depletion Mechanisms
`
`No rapid, complete depletion mechanisms are known (see introductory
`summary; supporting data not provided).
`
`ADEQUATE
`
`iv.
`
`Environmental Concentration
`
`The maximum predicted amount of tapentadol hydrochloride drug
`substance manufactured for direct use in any of the next five years is
`C 3kg/year. Assuming no metabolism or environmental depletion,
`the firm determines the EIC to be «\h
`
`5(4)
`
`ADEQUATE
`
`Summary
`
`

`

`Page 6 — NDA 22—304
`
`Tapentadol hydrochloride is expected to enter the aquatic environment
`through patient use. Based on the high water solubility and log
`octanol/water coefficient <3.5 (log Kow 2.87) no relevant partitioning into
`sewage sludge is expected.
`
`ADEQUATE
`
`b.
`
`Environmental Effects
`
` Condition
`
`Microbial
`
`t Factor
`
`Test Organism
`est Method
`
`Microbial inocula
`
`
`
`growth
`
`
`NOEC = 95.9 mg/L
`
`(OECD Guideline
`inhibition
`E050 = 586 mg/L
`
`
`
`209)
`
`
`
`
` Acute toxicity NOEC = 2.4 mg/L
`
`
`
`
`Algae
`
`(Pseudokirchneriella
`
`ECso = 4.5 mg/L (72 h)
`subcqpitata)
`
`(OECD Guideline
`
`
`
`
`201
`.
`
`
`
`Daphnids
`
`Acute toxicity NOEC = 4.4 mg/L
`
`
`(Daphnia magna)
`EC50 = 25 mg (48 h)
`
`
`OECD Guideline 202
`
`Zebra fish
`
`
`
`Acute toxicity NOEC = 12 mg/L
`
`(Brachydam‘o rerio)
`LC50 = 77 mg/L (96 h)
`
`
`(OECD Guideline
`
`
`
`
`The inhibitory effect of tapentadol hydrochloride on the respiration rate of aerobic
`wastewater microorganisms of activated sludge was investigated in a 3—hour
`respiration inhibition test following OECD Guideline 209. The 3 hour ECso of
`lacosamide in the activated sludge respiration test was (“mg/L. The 3 hour
`NOEC was 95.9 mg/L. The microbial inhibition test showed tapentadol
`hydrochloride to be relatively non-toxic.-
`
`The firm conducted a 72 hour static test following OECD Guideline 201 to assess
`the acute toxicity of tapentadol hydrochloride to freshwater green algae. The
`EC50 for growth rate was .’ ——';
`.; the EC50 for yield was 4.5 mg/L. The NOEC
`for both endpoints, growth rate and yield was 2.4 mg/L.
`
`The firm conducted a 48 hour static test following OECD Guideline 202 to assess
`the acute toxicity of tapentadol hydrochloride to the water flea (Daphnia magna).
`The 48 hour EC50 was estimated to be 25 mg/L. The NOEC was 4.4 mg/L.
`
`The firm conducted a 96 hour static test following OECD Guideline 203 to assess
`the acute toxicity of tapentadol hydrochloride to zebra fish. The LC50 (Median
`
`

`

`Page 7 — NDA 22-304
`
`Lethal Concentration) was estimated to be 77 mg/L. The NOEC was determined
`to be 12 mg/L.
`
`The firm provided the results of 3 acute toxicity studies. The calculated
`assessment factor for each is >1,000. No observed effects were seen at the
`MEEC.
`
`c.
`
`Summary
`
`The microbial inhibition test found tapentadol hydrochloride to be relatively non-
`toxic. The firm provided the results of 3 acute toxicity studies. The calculated
`assessment factor for each is >1,000. No observed effects were seen at the
`MEEC.
`
`ADEQUATE
`
`Mitigation Measures
`
`No adverse environmental effects have been identified.
`No mitigation measures are required.
`
`ADEQUATE
`
`Alternatives to the proposed action
`
`No potential effects have been identified for this proposed action.
`No alternatives to the proposed action are required.
`
`ADEQUATE
`
`List of Preparers
`
`Names and professional experience are provided.
`
`ADEQUATE
`
`10.
`
`References
`
`References are provided.
`
`ADEQUATE
`
`11.
`
`Appendices
`
`Provided.
`
`

`

`Page 8 — NDA 224304
`
`ADEQUATE
`
`Review by:
`
`Ruth Ganunis, Ph.D., May 19, 2008
`Under contract to:
`Office of Pharmaceutical Science
`
`Center for Drug Evaluation and Research
`
`
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Raanan Bloom
`7/7/2008 02:19:08 PM
`ENV ASSESSMENT
`
`Jon E. Clark
`7/11/2008 02:25:31 PM
`CHEMIST
`
`

`

`ENVIRONMENTAL ASSESSMENT
`
`and
`
`FINDING OF NO SIGNIFICANT IMPACT
`
`for
`
`Tapentadol Hydrochloride
`50, 75, and 100 mg Immediate Release Tablets
`
`NDA 22—304 1
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`
`Date Completed: May 19, 2008
`
`

`

`FINDING OF NO SIGNIFICANT IMPACT
`
`NDA 22-304
`
`Tapentadol Hydrochloride
`50, 75, and 100 mg Immediate Release Tablets
`
`The National Environmental Policy Act of 1969 (NEPA) requires all Federal agencies to assess the
`environmental impact oftheir actions. FDA is required under NEPA to consider the environmental
`‘impact of approving certain drug product applications as an integral part of its regulatory process.
`
`The Food and Drug Administration, Center for Drug Evaluation and Research, has carefully
`considered the potential environmental impact ofthis action and has concluded that this action will
`not have a significantimpact on the quality of the human environment and that an environmental
`impact statement, therefore, will not be prepared.
`
`In support of its new drug application for Tapentadol Hydrochloride Immediate Release Tablets,
`Johnson and Johnson Pharmaceutical Research and Development, L.L.C. prepared an environmental
`assessment (attached)
`in accordance with 21 CFR Part 25 which evaluates the potential
`environmental impacts of the use and disposal from use of the product.
`4
`
`Tapentadol hydrochloride tablets will be used for the treatment of acute pain.
`
`Tapentadol hydrochloride may enter the environment from patient use and disposal. It is expected to
`enter into the aquatic environment. Data indicate that the compound is unlikely to enter the
`terrestrial and atmospheric environments. The toxicity of tapentadol hydrochloride to aquatic
`organisms was characterized. The results indicate that the compound is not expected to be toxic to
`organisms at expected environmental concentrations.
`
`Empty or partially empty packages will be diSposed by a community’s solid waste management
`system that may include landfills, incineration and recycling. Minimalquantities ofthe unused drug
`may be disposed in the sewer system.
`
`The Center for Drug Evaluation and Research has concluded that the product can be used and
`disposed without any expected adverse environmental impacts. Adverse impacts are not anticipated
`upon endangered or threatened species or upon'property listed in or eligible for listing in the
`National Register of Historic Places.
`
`

`

`PREPARED BY:
`
`Ruth Ganunis, Ph.D.
`under contract to
`Office of Pharmaceutical Science
`
`Center for Drug Evaluation and Research
`
`CONCURRED BY:
`
`Raanan A. Bloom, Ph.D.
`Senior Environmental Officer
`Office of Pharmaceutical Science
`
`Center for Drug Evaluation and Research
`
`CONCURRED BY:
`
`Jon Clark, M.S.
`
`Associate Director for Policy
`Office of Pharmaceutical Science
`
`Center for Drug Evaluation and Research
`
`CONCURRED BY:
`
`Moheb Nasr, Ph.D.
`
`Director, Office of New Drug Quality Assessment
`Office of Pharrnaceutical Science
`'
`
`Center for Drug Evaluation and Research
`
`Attachment:
`
`Environmental Assessment dated June, 2007'
`Appended Electronic Signature Page
`
`

`

`TABLE OF CONTENTS
`
`IN-TEXT TABLES ...........................................................,. ........................................................ Ill
`
`SUMMARY............................................................................................................................. [V
`
`1.
`
`2.
`
`3.
`
`4.
`4.1.
`4.2.
`4.3.
`4.4.
`
`>5.
`5.1.
`
`5.2.
`5.3.
`5.4.
`5.5.
`
`6.
`6.1.
`
`6.2.
`
`7.
`
`8.
`
`9.
`
`DATE ............................................................................................................................ 1
`
`NAME ........................................................................................................................... 1
`
`ADDRESS OF APPLICANT ........................................................................................ 1
`
`DESCRIPTION OF THE PROPOSED ACTION .......................................................... 1
`Requested Approval ..................................................................................................... 1
`Need for Action ............................................................................................................. 1
`Locations of Use ........................................................................................................... 1
`Disposal Sites ............................................................................................................... 1
`
`IDENTIFICATION OF SUBSTANCES ......................................................................... 2
`Nomenclature ............................................................................................................... 2
`5.1.1.
`Established Name (U.S. Adopted Name—USAN) ......................................... 2
`5.1.2.
`Brand/Proprietary Name/Trade Name ......................................................... 2
`5.1.3.
`Chemical Name ............................................................................................ 2
`Chemical Abstracts Service (CAS) Registration Number ............................................ 2
`Molecular Formula ........................................................................................................ 2
`Molecular Weight .......................................................................................................... 2
`Structural (Graphic) Formula ........................................................................................ 2
`
`ENVIRONMENTAL ISSUES ........................................................................................ 2
`Assessing Toxicity to Environmental Organisms ......................................................... 3
`
`Microbial Inhibition Test ..................................................................... 4
`6.1.1.
`
`Acute Toxicity to Freshwater Green Algae ........................................ 4
`6.1.2.
`6.1.3.
`Acute Toxicity to the Water-Flea (Daphnia magna) ..................................... 4
`6.1.4.
`Acute Toxicity to Fish ................................................................................... 5
`Conclusion .................................................................................................................... 5
`
`MITIGATION MEASURES ..............................................................................., ........... 5
`
`ALTERNATIVES TO THE PROPOSED ACTION ................... 5
`
`LIST OF PREPARERS ................................................................................................ 5
`
`10.
`
`REFERENCES ............................................................................................................. 6
`
`CONFIDENTIAL APPENDICES .................................................................................. 8
`11 .
`APPENDIX 1 CONFIDENTIAL MEEC Calculation ................................................................... 9
`
`APPENDIX 2 CONFIDENTIAL Tiered Approach to Environmental Effects Testing
`Calculations ............................................................................................ 11
`
`Table APX 1:
`
`Calculation of Assessment Factors ............................................................ 12
`
`EAUS-FA-R331333-TAB-NDA-VOI/O7 November 2007/PDF
`
`[1
`
`Page 2
`
`

`

`lN-TEXT TABLES
`
`Table 1:
`
`Physical/Chemical Characterization ...................................................................... 3
`
`Table 2:
`
`Toxicity Testing of Tapentadol Hydrochloride Drug Substance with
`Representative Environmental Organisms ............................................................ 4
`
`APPEARSTHlSW '
`we: 0mm Ay
`
`I
`
`BAUS-FA<R33 l 333-TAB-NDA-V0 l/07 November 2007/PDF
`
`‘
`
`[II
`
`Page 3
`
`

`

`Chemistry, Manufacturing & Controls
`Report No.: EAUS-FA—R331333-TAB—NDA-V01
`
`NDA Environmental Assessment for Tapentadol Hydrochloride Drug Substance
`in 50-, 75-, and IUD-mg Immediate Release (IR) Tablets
`
`SUMMARY
`
`Potential environmental impacts of tapentadol hydrochloride IR tablets have been
`evaluated in this environmental assessment according to 21 CFR Part 25.
`
`The calculated Maximum Expected Environmental Concentration (MEEC, Expected
`Introduction Concentration, or BIC-aquatic based on use) was more than 1 part per
`billion (ppb, based on the fifth year projection forecast), therefore, fate and acute
`effects testing results were reported.
`
`In accordance with the Tier 1 Testing Criteria described in the Guidance for Industry
`Environmental Assessment of Human Drug and Biologics Applications{l}, if no
`rapid, complete depletion mechanisms are known, then a microbial inhibition test
`should be done; and if the Log K0w <3.5, then an acute toxicity study should be done.
`If the results demonstrate that the acute ECso (Median Effective Concentration) or the
`acute LCso (Median Lethal Concentration), divided by the MEEC is 21,000, then no
`further testing should be conducted unless sublethal effects are observed at the
`MEEC.
`
`For tapentadol hydrochloride, no rapid, complete depletion mechanisms are known. A
`microbial inhibition test showed tapentadol hydrochloride to be relatively non-toxic
`with an ECso of 586 mg/L. The Log K0“, is <35. The calculated assessment factors for
`algae, daphnids, and zebra fish were each greater than 1,000 according to the
`calculation described above, and sublethal effects" were not seen at the MEEC;
`therefore additional
`testing is not required. No potential adverse environmental
`effects resulting from the manufacture and use of tapentadol hydrochloride have been
`identified.
`-
`
`'1. Guidance for industry-environmental assessment of human drugs and biologics
`applications. US FDA - Food and Drug Administration, Washington, DC,
`July 1998.
`
`EAUS—FA-R33 l 333-TAB-NDA-V0 l/07 November 2007/PDF
`
`[V
`
`Page 4
`
`

`

`1.
`
`DATE
`
`07 Nov 2007
`
`2.
`
`NAME
`
`Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
`
`3.
`
`ADDRESS OF APPLICANT
`
`920 Route 202
`
`Raritan, NJ 08869, U.S.A.
`
`4.
`
`DESCRIPTION OF THE PROPOSED ACTION
`
`, 4.1. Requested Approval
`
`Johnson & Johnson Pharmaceutical Research & Development, L.L.C.,
`
`is
`
`submitting an NBA pursuant to Section 505(b) of the Federal Food, Drug,
`
`and Cosmetic Act for tapentadol hydrochloride drug substance in IR tablets.
`
`An environmental assessment
`21 CFR Part 25.
`
`(EA)
`
`is being submitted pursuant
`
`to
`
`4.2. Need for Action
`
`This EA supports a New Drug Application (NDA)
`
`for
`
`tapentadol
`
`hydrochloride IR tablets. This drug will be used for the treatment of acute
`
`pain.
`
`4.3. Locations of Use
`
`This drug will be used in‘hospitals and private homes across the US. It will
`be available by prescription only.
`I
`
`4.4.
`
`' Disposal Sites
`
`Disposal of prescribed product will be through use, with returned product
`
`disposed through high temperature incineration at licensed disposal facilities.
`
`US hospitals, pharmacies, or clinics will dispose of empty or partially empty
`
`packages according to their internal handling procedures.
`
`In the home,
`
`disposal will be through community solid waste management systems, which
`
`may include
`
`landfills,
`
`incineration, and recycling, although minimal '
`
`quantities of the unused drug could be disposed of in the sewer system.
`
`Where available, disposal of unused medicines could also be through
`
`take—back programs
`pharmacies.
`
`in local community waste disposal
`I
`
`systems or
`
`EAUS—FA-R33l333-TAB-NDA-VO 1/07 November 2007/PDF
`
`1
`
`Page 5
`
`

`

`IDENTIFICATION OF SUBSTANCES
`5.
`_ 5.1. Nomenclature
`
`Established Name (U.S. Adopted Name-USAN)
`5.1.1.
`Tapentadol hydrochloride
`
`5.1.2.
`
`Brand/Proprietary Namefl'rade Name
`
`Not applicable
`
`5.1.3.
`
`Chemical Name
`
`3~[( 1 R,2R)-3-(dimethylamino)— 1 -ethyl-2-methylpropyl]phenol
`monohydrochloride
`
`5.2. Chemical Abstracts Service (CAS) Registration Number
`'
`175591-09—0
`
`5.3. Molecular Formula
`
`C14H23NO-HCI
`
`5.4. Molecular Weight
`257.80 (221.34 + 36.46)
`
`5.5.
`
`Structural (Graphic) Formula
`
`'
`
`OH
`
`. HCI
`
`R
`
`.
`
`N
`
`6.
`
`ENVIRONMENTAL ISSUES
`
`The manufacture and use of tapentadol hydrochloride tablets are not
`expected to result
`in significant environmental
`releases of the active
`
`ingredient or excipients. No potential adverse environmental effects resulting
`from the manufacture and use of tapentadol hydrochloride have been
`identified.
`
`The physical and chemical characterizations used to evaluate potential
`adverse effects in the environment are presented in Table l.
`
`EAUS-FA-R33 I 333-TAB-NDA-V0 I/O7 November 2007/PDF
`
`2
`
`Page 6
`
`

`

`Table 1:
`
`Physical/Chemical Characterization
`Property
`Water Solubility (at ambient temperature)
`
`Value
`380 mg/mL
`
`Source
`Section 3.2.8.1.3{ l}
`
`Dissociation Constants
`
`pKal: 9.34
`pKa2: 10.45
`
`Section 3.2.S.1.3{ l}
`
`Partition Coefficient n-Octanol/Water (log KW)‘
`
`2.87
`
`Section 3.2.3.1.3 {1}
`
`Adsorption Coefficient (KM)
`Log K0,
`
`1704
`3.23
`
`Report
`13674.6123j2}
`
`The water solubility of tapentadol hydrochloride at ambient temperature is
`
`380 mg/mL. Tapentadol hydrochloride can be considered freely soluble in
`
`water according to current United States Pharmacopeia. {1}
`
`The dissociation constant
`
`(pKa)
`
`indicates the tendency of an organic
`
`chemical to ionize and is related to the adsorption of the chemical
`
`into
`
`biological membranes. The pKal of tapentadol hydrochloride was
`
`determined to be 9.34, pKa2 was determined to be 10.45. {1}
`
`The partition coefficient (log Kow)
`
`indicates the tendency of an organic
`
`chemical to partition into lipids or fats, sorb to particulates such as soils or
`
`sediments, sorb to biomass and sludge, and distribute among the various
`
`environmental compartments. According to the Tier
`
`1 Testing Criteria
`
`described in the Guidance for Industry Environmental Assessment ofHuman
`
`Drug and Biologics Applications (July 1998), chemicals with log K0“, <3.5
`
`do not have potential
`
`to bioaccumulate.{7} The log Kow for tapentadol
`
`hydrochloride is 2.87, which is below 3.5, therefore, tapentadol does not
`
`show a potential to bioaccumulate.{ 1}
`
`indicates the tendency of an organic
`The adsorption coefficient. (K00)
`chemical
`to mobilize
`in the environment. The K0c
`for
`tapentadol
`
`hydrochloride was evaluated in a study according to OECD Guideline 121.
`
`Based on the results of this study, the K06 was 1704. {2}
`
`Information related to the Maximum Expected Environmental Concentration
`
`(MEEC, Expected Introduction Concentration, or BIC-Aquatic, based on
`
`use) calculation is confidential and is provided in Confidential Appendices,
`Section 11, APPENDIX 1.
`‘
`
`6.1. Assessing Toxicity to Environmental Organisms
`The following environmental effect studies have been conducted with
`
`tapentadol hydrochloride drug substance;
`Table 2.
`
`the results are summarized in
`
`EAUS-FA-R33 l 333-TAB—NDA—V0 l /07 November 2007/PDF
`
`D)
`
`Page 7
`
`

`

`A. Microbial growth inhibition (activated sludge respiration inhibition){3}
`
`B. Algae (Pseudokz'rchnerz'ella subcapitata) acute toxicity{4}
`
`C. Daphnids (Daphnia magna) acute toxicity{5} g
`
`D. Zebra fish (Brachydanio rerio) acute toxicity{6}
`
`Table 2:
`
`Toxicity Testing of Tapentadol Hydrochloride Drug Substance with Representative
`Environmental Organisms
`Test Organism
`Microbial inocula
`
`Conditions
`Microbial growth
`inhibition
`Acute toxicity
`
`Source
`Results
`Report
`NOEC = 95.9 mg/L
`13674.6122{3}
`EC5o = 586 mg/L
`Report
`NOEC = 2.4 mg/L
`Algae
`13674.61 l9{4}
`EC50= 4.5 mg/L (72 h)
`(Pseudokirchneriella subcapitata)
`Report
`NOEC = 4.4 mg/L
`Daphnids
`13674.6120{5}
`ECso = 25 mg (48 h)
`(Daphnia magna)
`Report
`NOEC = 12 mg/L
`Acute toxicity
`Zebra fish (Brachydanio rerio)
`
`LCso = 77 mg/L (96 h) [3674.612] {6}
`ECso = median effective concentration
`NOEC = no observed effect concentration
`LCso = median lethal concentration
`
`Acute toxicity
`
`_
`Microbial Inhibition Test
`6.1.1.
`The
`influence of tapentadol hydrochloride on ‘ microorganisms was
`
`determined by measuring the respiration rate under defined conditions in a
`
`3—hour respiration inhibition—activated sludge study according to OECD
`Guideline 209.
`
`Based on the results of this test, the ECso (Median Effective Concentration)
`was calculated to be 586 mg/L. The No-Observed-Effect Concentration
`
`(NOEC, determined as the calculated 3-hour EC15) was 95.9 mg/L. {3}
`
`6.1.2.
`
`Acute Toxicity to Freshwater Green Algae
`
`The influence of tapentadol hydrochloride on the green algal species
`
`Pseudokirchneriella subcapitata was investigated in a 72—hour static test,
`
`according to OECD Guideline 201.
`
`Based on the results,
`
`the EC50 for growth rate was determined to be
`
`9.8 mg/L. The EC50 for yield was determined to be 4.5 mg/L. The NOEC for
`
`both endpoints, grth rate and yield, was determined to be 2.4 'mg/L. {4}
`
`6.1.3.
`
`Acute Toxicity to the Water-Flea (Daphnia magna)
`
`The acute toxicity of tapentadol hydrochloride to Daphnia magna was
`
`determined in a 48-hour static test according to OECD Guideline 202.
`
`EAUS-FA-R331333-TAB-NDA-V01/07 November 2007/PDF
`
`V
`
`4
`
`Page 8
`
`

`

`The 48-hour ECso value was estimated to be 25 mg/L. The NOEC was
`
`determined to be 4.4 mg/L. {5}
`
`6.1.4.
`
`Acute Toxicity to Fish
`
`The
`
`acute
`
`toxicity
`
`of
`
`tapentadol
`
`hydrochloride
`
`to
`
`zebra
`
`fish
`
`(Brachydanz‘o rerio) was determined in a 96-hour static renewal
`
`test,
`
`according to OECD Guideline 203.
`
`Based on the results from this study, the 96-hour LC50 (Median Lethal
`
`Concentration) was estimated to be 77 mg/L. The NOEC was determined to
`
`be 12 mg/L. {6}
`
`6.2. Conclusion
`
`In accordance with the Tier 1 Testing Criteria described in the Guidance for
`
`Industry Environmental Assessment of Human Drug and Biologics
`
`testing is required. After the
`Applications (July 1998) {7}, no further
`microbial inhibition test found tapentadol’hydrochloride to have an ECso of
`
`586 mg/L,
`
`the log K0“, was determined to be <35, after which acute
`
`ecotoxicity studies were reported. The calculated assessment factor for each
`
`of the 3 acute toxicity studies is >1,000. No observed effects were seen at the
`
`MEEC, therefore no further testing is required. The original assumption that
`
`tapentadol hydrochloride has no known environmental effects remains valid.
`
`Information related to the tiered approach to environmental effects testing is
`
`confidential and is provided in Confidential Appendices, Section 11,
`APPENDIX 2.
`
`7.
`
`MITIGATION MEASURES
`
`Section 7 is not required when there have been no adverse environmental
`effects identified.
`
`8.
`
`ALTERNATIVES TO THE PROPOSED ACTION
`
`Section 8 is not required when there have been no adverse environmental
`effects identified.
`
`9. .
`
`LIST OF PREPARERS
`
`Edward Nowak, QEP, CHMM
`Director, Global Pharma R&D Environmental Health & Safety
`Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
`1000 US. Route 202 South
`
`Raritan, NJ 08869—0602
`
`EAUS-FA-R33 I 333—TAB—NDA-V0 1/07 November 2007/PDF
`
`5
`
`Page 9
`
`

`

`More than 25 years of environmental experience;
`
`15 years with the
`
`telecommunications research and development
`
`industry, 8 years with the
`
`States Environmental
`United
`pharmaceutical industry.
`
`Protection Agency,
`
`and
`
`6 with
`
`the
`
`Bachelor of Science in Civil Engineering, New Jersey Institute of
`Technology
`
`Master of Science in Environmental Engineering, New Jersey Institute of
`Technology
`
`Kelly Quinlan
`Environmental Engineer
`Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
`1000 US. Route 202 South
`
`Raritan, NJ 08869-0602
`
`More than 2 years of environmental experience with the pharmaceutical
`
`industry.
`
`Bachelor of Science in Environmental Science, Rutgers University
`
`Master of Science in Environmental Science, Rutgers University (Pursuing)
`
`1'0.
`
`REFERENCES
`
`1. Section3..2S. 1.3 of
`hydrochloride
`
`J&JPRD Drug Master File
`
`for
`
`tapentadol
`
`following
`2. Tapentadol HCl— determination of the K00 coefficient
`OECD Guideline 121;—
`j OECD Guldellne 121 Z ‘
`r
`f;
`jReport 136746123 (01 Nov 2007)
`7’
`3. Tapentadol HCl- activated sludge respiration inhibition. 1C
`j
`OECD Guideline 209; g”; _
`-
`7
`EReport
`13674 6122. (02 Mar 2007)
`
`“‘43
`
`4. Tapentadol HCl
`-
`acute
`toxicity to the
`C
`jOECD Guideline 201; C:
`Report 136746119. (07 Feb 2007).
`
`7
`
`freshwater green alga.
`
`j]
`
`‘1‘”
`
`5. Tapentadol HCl - acute toxicity to water fleas (Daphnia magna) under
`static conditions, following OECD draft guideline #202.Q
`OECD Guideline 202; C:
`.
`:1 Report
`1374.6120. (29 Mar 2007)
`
`:l
`
`EAUS-FA-R33 l 333-TAB-NDA-VOl/07 November 2007/PDF
`
`.
`
`6
`
`Page 10
`
`

`

`6. Tapentadol HCl — acute tozfflicity to zebra fish (Brachydanio refjo), uncle;
`static-renewal conditions. C;
`:(l'OECD Guideline 203;C
`j
`W‘
`(’1
`jReport 13674.6121. (30 Mar 2007)
`
`-b(4)
`
`7. Guidance for industry-environmental assessment of human drugs and
`biologics applications. US FDA - Food and Drug Administration,
`Washington, DC, Jul 1998.
`
`EAUS—FA—R331333-TAB-NDA-VO1/07 November 2007/PDF
`
`'
`
`7
`
`Page 11
`
`

`

`---------~----------------------------------------------------------------------------------------------------------
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Jon E. Clark
`7/11/2008 02:25:57 PM
`
`Moheb Nasr
`
`7/18/2008 08:15:58 AM
`
`