CENTER FOR DRUG EVALUATION AND
`
`‘
`
`RESEARCH
`
`APPLICATIONNUMBER:
`NDA 22-253 & 22-254
`
`ENVIRONMENTAL ASSESSMENT
`
`

`

`4
`
`'-
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Pharmaceutical Science/Immediate Office
`
`
`Memorandum
`
`Date:
`
`From:
`
`To:
`
`May 14, 2008
`
`Raanan A. Bloom, Ph.D.
`OPS/IO/PARS
`
`Prafull Shiromani, PhD.
`OPS/ONDQA/DPAI
`
`Through:
`
`Jon Clark, M.S.
`OPS/IO/PARS
`
`Subject:
`
`NDA 22-253; Lacosamide Tablets: For the treatment of Epilepsy as adjunctive therapy in
`patients with partial onset seizures aged 16 years and older. Letter Date 9/28/07
`
`NDA
`Lacosamide Tablets: For the management of neuropathic pain associated with
`diabetic peripheral neuropathy. M
`NDA 22-254; Lacosamide Injection: For the treatment of Epilepsy as adjunctive therapy1n
`patients with partial onset seizures aged 16 years and older when oral administration15
`temporarily not feasible. Letter Date 9/28/07
`
`~
`
`“(4)
`
`Schwarz Biosciences. Inc.
`PO. box 1'10167
`
`Research Triangle Park, NC 27709
`
`Background
`
`Schwarz Biosciences, Inc. requests approval for the marketing of lacosamide tablets for the
`treatment of epilepsy (NDA 22—253), lacosamide tablets for the management of neuropathic
`pain associated with diabetic peripheral neuropathy (NDA ‘—-‘ , lacosamide injection for
`
`the treatment of epilepsy(NDA 22-254)
`'—
`
`W.” In accordance with 21 CFR Part 25, Schwarz Biosciences, Inc. h?(4)
`submitted an Environmental Assessment (EA; dated June 2007) that evaluates the potentia
`environmental impacts due to use and disposal of these products The EA was submitted
`
`under NDA 22-253 and cross-referenced to NDAs 22—254
`_. The EA
`evaluates environmental introductions of lacosamide due to use and disposal of products to
`marketed under the “submitted NDAs.
`
`
`
`

`

`Page 2 — NDA 22-253, 22-254.
`
`hi4)
`
`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 11, 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 BA, no significant adverse V
`environmental impacts are expected from the introduction of lacosamide residues into the
`enVironment due to the use of lacosamide for the treatment of epilepsy and the management
`of neuropathic pain associated with diabetic peripheral neuropathy
`
`A Finding of No Significant Impact (FONSI) is recommended.
`
`APPEARS THlS WAY
`
`0N ORIGINAL
`
`

`

`Page 3 — NDA 22—253, 22-254 ”‘5'”
`
`M4) '
`
`
`
`EXECUTIVE SUMMARY — ENVIRONMENTAL ASSESSMENT
`
`FONSI recommended.
`
`After intake of lacosamide by patients for the treatment of partial-onset seizures or diabetic
`neuropathic pain, lacosamide is mainly excreted in human urine. There is one major metabolite,
`O-desmethyl lacosamide, which has no knewn activity. Lacosamide and the major metabolite
`O-d—esmethyl lacosamide are expected to reach the aquatic environment through POTWs.
`LacOsamide1s highly water soluble, and has a low octanol/water coefficient (log Kow= 0.25).
`Adsorption/desorption experiments show low adsorption to soils and river sediment. The
`physicochemical data provided demonstrate that lacosamide will remain in the aquatic
`compartment, and that expose to the terrestrial and atmospheric compartments is expected to be
`insignificant. Forced degradation studies suggest that lacosamide is not likely to significantly
`degrade.
`'
`
`The maximum predicted amount of lacosamide manufactured for direct use in any of the next
`five years is
`/—*—" year. Conservatively assuming no metabolism and no degradation in
`the environment for their analysis, the EIC is ~ ug/L.
`
`Wei
`
`The firm satisfied the requirements with tier 1 testing, which included microbial inhibition
`testing as well as acute testing on green algae. The BC50/MEEC ratio for green algae growth is
`>10,000, which is greater than the assessment factor of 1000. To satisfy EU requirements, the
`firm also conducted chronic testing on zebra fish and Daphnia, and provided those results here.
`The most sensitive species identified in the chronic study is zebra fish, where the NOEC/MEEC
`'ratio is >1000, which exceeds the tier 3 assessment factor of 10.
`-
`
`Based on the data, a FONSI can be recommended.
`
`Recommendations:
`
`A FONSI is recommended with the following qualifications:
`
`' It is noted that the agency has requested a resubmission of the EA‘ W
`W
`
`110‘s
`
`' The firm provided tier 1 testing for US requirements, and also provided tier 3 testing
`for EU requirements They use the tier 3 assessment factor of 10 for comparison,
`although I am not sure that that assessment factor18 appropriate because they did not
`provide the results of tier 2. The review is written assuming that use of the tier 3 factor in
`this case in appropriate. Either way they satisfy the tier 1 requirements and provide
`additional chronic studies for which the NOEC/MEEC ratio is significantly large that
`there is no environmental concern.
`
`-
`
`

`

`Page 4 — NDA 22-253, 22-254,
`
`
`
`hi4)
`
`REVIEW OF ENVIRONMENTAL ASSESSMENT
`
`1.
`
`2.
`
`Date: EA dated June 2007
`
`Name of applicant/petitioner: Schwarz Biosciences, Inc
`
`ADEQUATE
`
`Address:
`
`P.O. BOX 110167
`
`Research Triangle Park, NC 27709
`
`ADEQUATE
`
`Description of the proposed action:
`
`a.
`
`Requested Approval:
`
`-
`
`NDA 22-253; Lacosamide Tablets, For the treatment of Epilepsy as adjunctive
`therapy in patients with partial onset seizures aged 16 years and older
`NDA =" _ Lacosamide Tablets, For the management of neuropathic pain
`associated with diabetic peripheral neuropathy
`NDA 22-254; Lacosamide Injection, For the treatment of Epilepsy as adjunctive
`therapy in patients with partial onset seizures aged 16 years and older when oral
`administration is temporarily not feasible
`'33—ng
`
`Lacosamide tablets will be marketed in 50 mg, 100 mg, 150 mg, 200 mg, 250 mg
`and 300 mg strengths packaged in HDPE bottles and PVC/PVDC aluminum
`blisters. Lacosamide 10 mg/ml solution for infusion will be packaged in clear
`glass vials with a rubber stopper and aluminum cap. Lacosamide 15 mg/ml syrup
`will be packaged in brown glass or PET bottles. An EA has been submitted
`pursuant to 21 CFR part 25.
`'
`
`ADEQUATE
`
`Need for Action:
`
`Lacosamide is intended for use as a drug for adjunctive therapy in the treatment
`of partial-onset seizures in patients with epilepsy, and management of neuropathic
`pain associated with diabetic peripheral neuropathy.
`
`ADEQUATE
`
`

`

`Page 5 —NDA 22-253, 22-254,
`
`..——-—-—=—==—-—’
`
`h?“
`
`c.
`
`Expected Locations of Use (Drug Product):
`The locations of use will typically be hospitals, clinics and/or patients in their
`homes. The intravenous solution for infusion may also be used in emergency
`settings.
`I
`
`ADEQUATE
`
`d.
`
`Disposal Sites
`
`Empty orpartially empty packages containing lacosamide will be disposed by a
`community’s solid waste management system, which may include landfills,
`incineration and recycling. Minimal quantities of unused drug may—be disposed in
`the sewer system.
`
`ADEQUATE
`
`5.
`
`Identification of chemicals that are the subject of the proposed action:
`
`Nomenclature
`
`Established Name (USAN): Lacosamide
`Proposed Trade Name: Not yet available
`Chemical abstracts index name: Propanamide, 2-(acetylamino)-3-
`methoxy-N-(phenyl methy1)—, (2R)—
`.
`Systematic Chemical Name (IUPAC): (R)-2-Acetamido-N-benzyl-3-
`methoxypropionamide
`Chemical Abstracts Service (CAS) Registration Number: 175481—‘36-4
`Molecular Formula: C13 H18N203
`
`Molecular Weight: 250.3
`Chemical Structure:
`
`I
`
`'m\
`
`Lacosamide is the single (R)-enantiomer.
`
`ADEQUATE
`
`6.
`
`Environmental Issue:
`
`3.
`
`Environmental Fate of Released Substances
`
`i.
`
`Identification of Substances of Interest
`
`

`

`Page ‘6 — NDA 22-253, 22—254 «.7...
`
`31(4)
`
`Afier both oral and intravenous administration of lacosamide, 95% is
`recovered in urine and less than 0.5% in the feces. The major compounds
`excreted were unchanged lacosamide (40% of dose), O-desmethyl-
`metabolite (30% of dose), and a polar fraction (20%). Small amounts
`(0.5% to 2%) of finther metabolites were found in the urine (listed page
`9). The major metabolite, the O-desmethyl-metabolite, has no known
`pharmacological activity. The exact chemical structure of the polar
`fraction could not be determined, but it is likely that they are small polar
`molecules close to the R-serine backbone. It is assumed that the polar
`traction has no pharmacological activity.
`
`Additional stereo-specific analysis of urine samples showed that there is
`no enantiomeric interconversion of lacosamide.
`
`Unchanged lacosamide, the O-desmethyl-metabolite, and the polar
`fraction account for approximately 90% of the dose. Since it is assumed
`that the metabolites do not have activity, and because the major
`metabolite, the 0-desmethyl-metabolite, is expected to have comparable
`or higher water solubility than the parent compound, only the parent
`compound was studied in this EA as the substance relevant for the
`environmental risk assessment.
`
`ADEQUATE
`
`AWEARS lHlS WAY
`0N ORlGli‘lAL
`
`

`

`Page 7 —— NDA 22-253, 22—254, M
`
`M4)
`
`ii.
`
`Physical and Chemical Characterization
`
`
`
`Endpoint
`
`
`
`Water solubility (25°C)
`
`
`in phosphate buffer, pH 4.5
`
`Modification 1 : 28.4 mg/mL
`
`Modification 2 : 28.9 mg/mL
`
`
`
` in phosphate buffer, pH 7.5
`Modification 1 : 20.1 mg/mL
`Modification 2 : 20.8 mg/mL
`
`
`
`'
`
`Modification 1 : 30.2 mg/mL
`Modification 2 : 30.8 m /mL
`
`
`
` in pure water
`0.25 (mean, n=6)
`Log Kow (n—octanol / water
`
`partition coefficient)
`(OECD 107, shake flask
`
`
`
`Koc (adsorption / desorption
`9 mL/g (adsorption)
`
`coefficient normalized for
`12 mL/g (desorption)
`
`organic carbon content oftest
`
`
` Dissociation constant
`
`
`No dissociation at environmentally
`relevant pH (pKa outside pH range of
`
`
`1.5 to 12
`
`
`
`93 10 Pa calculated
`Hen ’5 Law Constant act 25°C 1.14 * 10”atm*m3/mol calculated
`
`Investigations on polymorphism of lacosamide show that the drug can be
`present in four different crystalline structures and one amorphous form.
`Two of the crystalline structures (modifications 1 and 2) are routinely
`formed in the regular synthesis of lacosamide drug substance and only
`these modifications are existent in lacosamide drug substance batches.
`Crystalline modifications 3 and 4, and the amorphous state only form
`under unique conditions or are not stable, and are not present in drug
`substance batches.
`\_’—-——————~—\
`m
`
`b“)
`
`The log Kow was determined to be 0.25. A value less than 3 indicates that
`the compound is not likely to adsorb to the organic fraction of soil,
`sediment, or biosolids (i.e., sludge).
`
`Although not required for EA submissions in the US, the
`adsorption/desorption coefficient was determined to satisfy the EU
`requirements and the data was reported in this EA. The adsorption value
`of 9 mg/g indicates a low potential of lacosamide to bind to the organic
`fraction of soils. The desorption values were slightly higher than the
`adsorption values, indicating reversibility of the adsorption process.
`
`

`

`Page 8 —NDA 22-253, 22-254. ff .
`
`”(4)
`
`The physico-chemical data indicate that lacosamide is predominately
`present in the aqueous phase in undissociated form in the aquatic
`environment.
`‘
`
`ADEQUATE
`
`iii.
`
`Environmental Depletion Mechanisms '
`
`Forced degradation studies were performed and their results are summarized below.
`
`Environmental Depletion Mechanisms
`
`Hydrolysis
`
`Photolysis
`
`
`
`
`
`Aerobic biodegradation
`(OECD 301 B, modified
`Stumi test
`
`'
`
`
`
`
`
`Hydrolytically stable at environmentally
`relevant conditions;
`hydrolysis Tl/z > 24 hours
`
`
`
`
`
`
`No significant degradation in solid state
`or aqueous solution afier irradiation with
`20,000 kJ/m2 (1.2 million lux hours) or
`
`
`100.000 kJ/m2 (6 million qu hours) in
`
`ueous solution.
`
`
`Not readily biodegradable to carbon
`dioxide within 28 days under the
`
`strin ent test conditions
`
`Lacosamide is very stable at elevated temperatures and high humidity. Open and closed
`storage under accelerated conditions (40°C and 75% relative humidity) for 12 weeks showed
`no significant degradation of the substance.
`
`Lacosamide is stable under environmentally relevant conditions. Abiotic
`degradation processes like hydrolysis, photolysis and thermal
`decomposition are not expected to contribute significantly to rapid
`dissipation of lacosamide from aquatic and terrestrial compartments.
`
`Since no significant degradation processes were identified, no rapid
`depletion was assumed as a worst-case for assessment of the fate of
`lacosamide in the aquatic environment.
`
`ADEQUATE
`
`iv.
`
`Environmental Concentration
`
`

`

`Page 9 —NDA 22—253, 22-254, m 3(4)
`
`The maximum predicted amount of lacosamide manufactured for direct
`
`use in any of the next five years is :’
`year. Assuming no
`metabolism or environmental depletion, the firm determines the EIC to be
`*” lug/L.
`
`Taking a conservative approach, the firm assumes no dilution into surface
`waters after passage through POTWs. Therefore, the maximum expected
`environmental concentration (MBEC) was set to be equivalent to the EEC
`or EIC.
`
`ADEQUATE
`
`v.
`
`Summary
`
`Lacosamide is expected to enter the aquatic environment through patient
`use. Based on the high water solubility and low octanol/water coefficient
`(log Kow 0.25) no relevant partitioning into sewage sludge is expected.
`
`Exposure in the terrestrial compartment is expected to be insignificant.
`Due to the low Kow of 0.25 and mean Koc of 9 mL/g no further testing on
`fate and effects in the terrestrial environment is indicated.
`
`Due to the high water solubility of lacosamide and its low calculated
`vapor pressure and Henry’s Law Constant there will be no substantive
`partitioning from the aquatic to the atmospheric compartment.
`
`ADEQUATE
`
`APPEARS was way
`on ORIGINAL
`
`

`

`Page 10 —,NDA 22-253, 22-254, __._2:___=_
`
`will
`
`b.
`
`Environmental Effects
`
`__
`Inhibition of microbial respiration
`3-hour EC50> 1000 mg/L ‘
`>100,000
`rate of activated sludge
`3-hour NOEC (E05) 2 1000 mg/L
`
`(OECD 209)
`Effects on algal growth of green
`alga Scenedesmus subspicatus
`
`72-hour ErCSO/EbCSO > 100 mg/L
`
`>10,000 '
`
`
`
`Fish Early Life Stage,
`Chronic test
`OECD 210
`
`Daphnia Reproduction,
`Chronic test
`OECD 211
`
`NOEC for all parameters tested 2 10
`mg/L
`
`>1.,000
`
`‘
`
`21-day NOEC was 32 mg/L on
`survival and reproduction rates of
`Dahnia ma; na
`
`>10,000
`
`.
`
`The inhibitory effect of lacosamide 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 EC50 of lacosamide in
`the activated sludge respiration test was >1000. The 3 hour NOEC (EC15) was
`21000 mg/L.
`
`Based on the log Kow <35 and the environmental fate data suggesting that
`lacosamide will remain in the aqueous phase, tier 1 acute toxicity testing in one
`aquatic species is appropriate. The firm provided the results of a 72 hour test on
`the growth of the green algal species Scenedesmus subspicatus. The test was
`conducted following OECD Guideline 201. The study found the 72-hour EC“)
`and EC50 are >100 mg/L. There were no sublethal effects observed at any dose
`tested; the NOEC was 2100 mg/L. The ECso/MEEC ratio for lacosamide is
`>10,000, which is larger than the tier 1 assessment factor of 1000.
`
`To satisfy EU requirements, the firm included the results of chronic tests on
`Daphm'a and zebra fish. An early life stage toxicity test on zebra fish was
`performed according to OECD Guideline 210. The test parameters assessed were
`egg development and hatching rate, time to hatch/development rate, survival of
`larvae and juvenile fish, and fish length and weight. For each test, the NOEC was
`210 mg/L and the LOEC > 10 mg/L. Overall, the NOEC of lacosamide for early
`life stages of zebrafish was determined to be at least the highest test concentration
`of 10 mg/L. The NOEC/MEEC ratio for lacosamidein this test was 1,000, which
`is larger than the tier 3 assessment factor of 10.
`
`The effect of lacosamide on the survival and reproduction of Daphnia magna was
`investigated according to OECD guideline'Zl l. The test parameters assessed
`were mortality after 21 days and mean reproduction rate. The NOEC of
`lacosamide to Daphnia magna survival and reproduction was 32 mg/L. The
`
`

`

`Page 11 — NDA 22—253, 22—254,
`
`——==—-——-'
`
`M4}
`
`lowest concentration tested with toxic effects was 100 mg/L, the concentration
`where a statistically significant reduced mean reproduction rate was found. The
`NOEC/MEEC ratio for lacosamide in this chronic toxicity test was >l0,000,
`which is significantly larger than the tier 3 assessment factor of 10.
`
`c.
`
`.
`
`Summary
`
`After intake of lacosamide by patients for the treatment of partial-onset seizures
`or diabetic neuropathic pain, lacosamide is mainly excreted in human urine.
`Lacosamide and the major metabolite O-desmethyl lacosamide (which has no
`known activity) are expected to reachthe aquatic environment through POTWs.
`The physicochemical data provided demonstrate that lacosamide will remain in
`the aquatic compartment, and that exposure of the terrestrial and atmospheric
`- compartments is expected to be insignificant. Forced degradation studies suggest
`that lacosamide is not likely to significantly degrade. The firm takes a
`conservative approach by assuming no metabolism and no degradation in the
`environment for their analysis. While only tier 1 testing was required, the firm
`provided the results of chronic testing as well. The most sensitive species in the
`chronic test is zebra fish, where the NOEC/MEEC ratio is >1000, which far
`exceeds the tier 2 assessment factor of 10.
`
`Based on the data, a FONSI can be recommended.
`
`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
`
`

`

`Page 12 —— NDA 22-253, 22-254,
`
`b6”
`
`References are provided.
`
`ADEQUATE
`
`11.
`
`Appendices
`
`Provided.
`
`_ADEQUATE
`
`Review by:
`
`Ruth Ganunis, Ph.D., May 11, 2008
`Under contract to:
`Office of Pharmaceutical Science
`
`Center for Drug Evaluation and Research
`
`Wares m;s w
`Orv ORIGINAL AY
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Raanan Bloom
`
`5/15/2008 01:08:37 PM
`ENV ASSESSMENT
`
`Jon E. Clark
`5/15/2008 02:08:15 PM
`CHEMIST
`
`

`

`ENVIRONMENTAL ASSESSMENT
`
`and
`
`FINDING OF NO SIGNIFICANT IMPACT
`
`for
`
`Lacosamide Tablets
`
`NDA 22-253
`
`Food and Drug Administration -
`Center for Drug Evaluation and Research
`
`Date Completed: May 11, 2008
`
`
`
`

`

`FINDING OF NO SIGNIFICANT IMPACT
`
`NDA 22-253
`
`Lacosamide Tablets
`
`The National Environmental Policy Act of 1969 (NEPA) requires all Federal agencies to assess the
`environmental impact of their 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 carefiilly
`considered the potential environmental impact of this action and has concluded that this action will
`not have a significant impact 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 Lacosamide, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg and
`300 mg tablets, Schwarz Bioscience, Inc. prepared an environmental assessment (attached) in
`accordance with 21 CFR Part 25 which evaluates the potential environmental impacts ofthe use and
`disposal from use of the product.
`
`Lacosamide is intended for use as a drug for adjunctive therapy in the treatment of partial-onset
`seizures in patients with epilepsy, and management of neuropathic pain associated with diabetic
`peripheral-neuropathy.
`-
`
`Lacosamide 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 lacosamide 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. Minimal quantities of the 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 Pharmaceutical Science
`
`Center for Drug Evaluation and Research
`
`Attachment:
`
`Environmental Assessment dated June, 2007
`Appended Electronic Signature Page
`
`

`

`EA
`
`Lacosamide
`
`RCC Ltd.
`
`ENVIRONMENTAL ASSESSMENT (EA)
`
`OF LACOSAMIDE
`
`EXPERT REPORT
`
`
`
`
`
`Page 1
`
`

`

`EA
`
`Lacosamide
`
`RCC Ltd.
`
`TABLE OF CONTENTS
`
`SIGNATURES .......................................... '. ................................................................................ 4
`
`1
`
`2
`
`3
`4
`
`4.1
`
`4.2
`
`4.3
`
`4.4
`
`5
`
`5.1
`
`5.1.1
`
`5. 1.2
`
`5.1.3
`
`5.2
`
`5.3
`
`5.4
`
`5.5
`
`6
`
`6.1
`
`DATE ................................................................................................................. 5
`
`NAME OF APPLICANT OR PETITIONER....................................................... 5
`
`_ ADDRESS .......................................................................................................... 5
`DESCRIPTION OF PROPOSED ACTION ........................................................ 6
`
`Requested Approval ............................................................‘................ -. ............... 6
`
`Need forAction ........................ 6
`
`Locations of Use ................................................................................................. 6
`
`Disposal Sites
`
`............................................................................................... 6
`
`IDENTIFICATION OF SUBSTANCE THAT IS THE SUBJECT OF
`THE PROPOSED ACTION ................................................................................ 7
`
`Nomenclature...............................................................................t....................... 7
`
`Established Name (INN/USAN/Laboratory Codes and Previous
`Names) ............................................................................................................... 7
`
`Brand/Proprietary Name/Trade Name ................................................................. 7
`
`Chemical Names................................................................................................. 7
`
`Chemical Abstracts Service (CAS) Registration Number .................................... 7
`
`Molecular Formula .............................................................................................. 7
`
`Molecular Weight ............................................................................................... 7
`
`Structural Formula .............................................................................................. 8
`
`ENVIRONMENTAL ISSUES ................................................. -. .......................... 9
`
`Environmental Fate ofReleased Substances........................................; ............... 9
`
`‘ 6.1.1
`
`Identification of Substances of Interest ........................... -. .................................... 9
`
`6.1.2
`
`6.1.3
`
`6. 1 .4
`
`6.1.5
`
`6.2
`
`6.2.1
`
`Physical and Chemical Characterization ......................................... . ................... 10
`
`Environmental Depletion Mechanisms ............................................................... 13
`
`Environmental Concentrations ........................................................................... 15
`
`Summary on Environmental Fate of Released Substances .............A..................... 16.
`
`Environmental Effects of Released Substances ...........................
`
`..... 18
`
`Microbial Inhibition Testing .......................... '. .................................................... 18
`
`Page 2
`
`

`

`EA
`
`6.2.2
`
`6.2.3
`
`6.2.4
`
`6.3
`
`10
`
`11
`
`11.1
`
`11.1.1
`
`11.2
`
`11.2.1
`
`11.2.2
`
`1 1.2.3
`
`1 1.2.4
`
`Lacosamide
`
`RCC Ltd.
`
`Effects on Aquatic Organisms: Tier 1 Testing ...................................‘..........i.......20
`
`Effects on Aquatic Organisms: Higher Tier Testing ...........................................22
`
`Summary on Assessment Factors in Environmental Effect Studies .....................27
`Summary on Environmental Fate and Effect of Released Substances .................28
`MITIGATION MEASURES ..............................................................................29
`
`ALTERNATIVES TO THE PROPOSED ACTION ...........................................29
`
`LIST OF PREPARERS........................ 30
`
`REFERENCES .....................................31
`
`APPENDICES ...................................................................................................32
`
`Non-confidential Information .................................................................... . ........ 32
`
`Data Summary Table ......................................................................................... 32
`
`y Confidential/ Proprietary Information................................................................34
`Sales Forecast for Lacosamide for Years 2008 to 2012 ............ '. .......................... 34
`
`Calculation of BIG for Lacosamide based on Sales Forecast for Years
`2008 to 2012 .............._........................................................................................34
`
`Calculation ofEEC and MEI-3C
`
`............................................................. 35
`
`Calculation of Risk Characterization Ratios .......................................................35
`
`Page 3
`
`

`

`
`
`EA RCC Ltd. Lacosamide
`
`
`
`SIGNATURES
`
`The present Environmental Assessment Expert Report was prepared by:
`
`Environmental Expert:
`
`
`Mflflw.......... ................................
`
`Date
`
`Dr. Enrico Kjefer
`RCC Ltd.
`
`Sponsor’s Representative:
`
`pwmtr.....................................
`
`Date
`
`'
`
`Dr. Niels Krebsfanger, D.A.B.T.
`SCHWARZ BIOSCIENCES GmbH
`
`
`
`
`
`

`

`
`Lacosamide
`
`RCC Ltd.
`
`EA
`
`1
`
`DATE
`
`Date of EA preparation:
`
`June, 2007
`
`Date of subsequent amendment(s):
`
`--
`
`2
`
`NAME OF APPLICANT OR PETITIONER
`
`'SCHWARZ BIOSCIENCES, Inc.
`
`3
`
`ADDRESS
`
`PO. Box 110167
`
`Research Triangle Park, NC 27709
`
`8010 Arco Corporate, Suite 100
`
`Raleigh, NC 27617
`USA
`
`Page 5
`
`

`

`EA
`
`4
`
`4.1
`
`Lacosamide
`
`RCC Ltd.
`
`DESCRIPTION OF PROPOSED ACTION
`
`Requested Approval
`
`Schwarz Biosciences, Inc. has filed an NBA pursuant to section 505 (b) of the Federal Food,
`Drug, and Cosmetic Act for lacosamide tablets (50 mg, 100 mg, 150 mg, 200 mg, 250 mg, and
`300 mg) packaged in HDPE bottles and PVC/PVDC aluminum blisters, lacosamide 10 mg/ml
`solution for infusion packaged in clear glass vials with rubber stopper and aluminum cap, and
`lacosamide 15 mg/ml syrup packaged in brown glass or PET bottles. An EA has been submitted
`pursuant to 21 CFR part 25.
`’
`
`’ 4.2
`
`Need for Action
`
`Lacosamide is intended for use as drug for adjunctive therapy in the treatment of partial—onset
`seizures in patients with epilepsy, and management of neuropathic pain associated with diabetic
`peripheral neuropathy.
`
`4.3
`
`Locations of Use
`
`The locations of usewill typically be hospitals, clinics and/or patientsin their homes. The
`intravenous solution for infusion may also be used in emergency settings.
`
`4.4
`
`Disposal Sites
`
`At US. hospitals, pharmacies, or clinics, empty or partially empty packages will be disposed of
`according to hospital, pharmacy, or clinic procedures in accordance with local requirements. In
`the home, empty or partially empty containers will typically be disposed of by a community's
`solid waste management system, which may include landfills, incineration, and recycling,
`although minimal quantities ofthe unused drug could be disposed of in the sewer system.
`
`Page 6
`
`

`

`
`
` EA Lacosamide RCC Ltd.
`
`
`
`5
`
`5.1
`
`5.1.1
`
`IDENTIFICATION OF SUBSTANCE THAT IS THE SUBJECT
`OF THE PROPOSED ACTION
`
`Nomenclature '
`
`Established Name (lNNIUSANILaboratory Codes and Previous
`Names)
`
`International Nonproprietary Name (INN):
`Lacosamide
`-
`
`United States Adopted Name (USAN):
`Lacosamide
`
`Laboratory Codes and Previous Names:
`SPM 927, ADD 234037, harkoseride
`
`5.1.2
`
`Brand/Proprietary Name/Trade Name
`
`Not yet available.
`
`5.1.3
`
`Chemical Names
`
`Chemical Abstracts (CA) Index Name:
`Propanamide, 2-(acetylamino)-3-methoxy-N-(pheny1methyl)-, (2R)-
`
`Systematic Chemical Name (l'UPAC):
`(R)-2-Acetamido-N—benzyl-3-methoxypropionamide
`
`5.2
`
`Chemical Abstracts Service (CAS) Registration Number
`
`175481-36-4
`
`5.3
`
`Molecular Formula
`
`C13 H18N203
`
`5.4
`
`250.3
`
`'
`
`Molecular Weight
`
`Page 7
`
`

`

`
`
`EA RCC Ltd. Lacosamide
`
`
`
`5.5 ’
`
`Structural Formula
`0
`
`'
`
`H
`
`/\©0
`N
`
`IC
`
`H
`
`H
`N
`
`H30
`
`‘
`
`o
`\n/
`
`-
`
`-
`
`.
`
`Lacosamide is the single (R)-enantiomer.
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`
`
`Page 8
`
`

`

`EA
`
`6
`
`6.1
`
`6.1.1
`
`
`
`Lacosamide RCC Ltd. .
`
`
`
`ENVIRONMENTAL ISSUES
`
`Environmental Fate of Released Substances
`
`Identification of Substances of Interest
`
`Human metabolism and excretion of lacosamide is described in CTD Module 2.7.2.3.3 and
`CTD Module 2.7.2.3.4, respectively, and briefly summarized below.
`
`After oral and intravenous administration of 100 mg [”CHacosamide (45 uCi) in healthy
`subjects, approximately 95% of radioactivity administered was recovered in the urine and less
`than 0.5% in the feces. The major compounds eXcreted were unchanged lacosamide (SPM 927,
`approximately 40% of the dose) and its O-desmethyl-metabolite (SPM 12809, approximately
`30%). A polar fiaction accounted for approximately 20%. Small amounts (0.5 to 2%) of further
`metabolites were found in the urine: the p-hydroxy-, the O-desmethyl—p-hydroxy-, O-desmethyl-
`m-hydroxy—, and the desacetyl derivatives of lacosamide. In addition, a N-carbamoyl-O-B—D—
`glucuronide of the desacetyl metabolite has been identified. In plasma the O-desmethyl
`_
`metabolite SPM 12809 represents approximately 10% of the parent compound. In conclusion the
`major human metabolite is SPM 12809. This metabolite has no known pharmacological activity.
`
`Additional stereo-specific analysis of urine samples showed that there is no enantiomeric
`interconversion of lacosamide.
`
`With regard to the structure of the polar fraction, the analytical results do not allow evident
`proposals for exact chemical structures, though they indicate small polar molecules close to the
`R—serine backbone. This seems to be most probable since larger molecules could not be observed
`in the respective MS-spectra and the expressed polar chromatographic behavior indicates loss of
`lipophilic structural elements.
`'
`
`The findings ofthe metabolism/excretion study show that excretion of unchanged Iacosamide
`and the metabolites formed mainly occurs via urine (approximately 95% of applied dose). Thus,
`the substances of interest for the environmental assessment are besides unchanged Iacosamide
`the major O—desmethyl metabolite SPM 12809 and a polar fraction, which potentially can reach
`surface waters (aquatic environment) via sewage systems. These compounds account for
`approximately 90% of the dose. The major metabolite (O-desmethyl metabolite, SPM 12809) in
`humans has no known pharmacological activity. All other metabolites found in urine were below
`2% and are like the polar fi'action assumed to be also pharmacologically not active. Physico-
`chemical data on the major human metabolite SPM 12809 (O—desmethyl Iacosamide) are not
`available. But concluding from its chemical structure (i.e., due to de-masking of a polar hydroxy
`group) and the retention times in HPLC-runs the substance is considered more polar than
`Iacosamide, and therefore expected to have a comparable or higher water solubility than the
`parent c