CENTER FOR DRUG EVALUATION AND
`
`
`RESEARCH
`
`
`
`
`
`
`
`
`
`
`APPLICATION NUMBER:
`
`
`209472Orig1s000
`
`
`NON-CLINICAL REVIEW(S)
`
`
`
`
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`Application number:
`Supporting document/s:
`Applicant’s letter date:
`
`
` CDER stamp date:
`Product:
`Indication:
`Applicant:
`Review Division:
`
`NDA 209472
`0032
` August 9, 2019
`August 9, 2019
`Pemfexy (pemetrexed injection)
`
` Same indications as the Listed Drug, Alimta
`Eagle
`Division of Hematology Oncology Toxicology
`(Division of Oncology Products 2)
`Reviewer: Whitney S. Helms, PhD
`Supervisor/Team Leader: Whitney S. Helms, PhD
`Division Director:
`John Leighton, PhD
`(Patricia Keegan, MD)
`
` Meredith Libeg for Autumn Zack-Taylor
`
`Project Manager:
`
`Reference ID: 4502092
`
`

`

`Pharmacology/Toxicology Labeling Review:
`
`
`
` Eagle Pharmaceuticals submitted a Class 1 Resubmission for Pemfexy (pemetrexed injection).
`
` Eagle previously submitted this NDA for approval on December 30, 2016 and FDA granted a
`
`
` tentative approval on October 26, 2017 with final approval dependent on expiring patent and
`
` exclusivity periods and the lack of changes/new information/ new manufacturing or inspection
`
`
` issues at the end of these periods. No new nonclinical studies were submitted to support the
`
` current submission and major labeling recommendations from the pharmacology/toxicology
`
`
`perspective were included with the original approval. The Applicant submitted an updated label
`with the current resubmission. Current FDA recommendations were based on the original label
`
`with revisions to maintain consistency with the most current labeling practices. For a full
`assessment of the nonclinical data used to support the tentative approval and initial labeling,
`
`refer to the original NDA review by M. Anwar Goheer, PhD. From a pharmacology/toxicology
`
`perspective there are no new issues since the tentative approval that would prevent final
`
`approval of Pemfexy for treatment of the intended patient populations.
`
`Pemfexy Label:
`
`Reasoning
`
`FDA made minor revisions
`
`to maintain consistency
`
`with current labeling
`
`practices. Eagle accepted
`all changes
`
`
`
`
`
`FDA Recommends
`The Applicant Proposed
`Embryo-Fetal Toxicity
`Embryo-Fetal Toxicity
`
` Based on findings from animal
`
` Based on findings from animal
`studies and its mechanism of
`studies and its mechanism of
`action, pemetrexed can cause
`action, PEMFEXY can cause
`fetal harm when administered
`fetal harm when administered to
`
`to a pregnant woman. In
`
`a pregnant woman. In animal
`animal reproduction studies,
`reproduction studies,
`intravenous administration of
`intravenous administration of
`pemetrexed to pregnant mice
`
`during the period of
`
`pemetrexed to pregnant mice
`organogenesis was
`during the period of
`teratogenic, resulting in
`organogenesis was teratogenic,
`developmental delays and
`resulting in developmental
`increased malformations at
`
`delays and increased
`doses lower than the
`recommended human dose of malformations at doses lower
`
`
`than the recommended human
`500 mg/m2. Advise pregnant
`
`women of the potential risk to
`
`
`dose of 500 mg/m2. Advise
`the fetus. Advise females of
`
`pregnant women of the potential
`reproductive potential to use
`risk to the fetus. Advise females
`effective contraception during
`of reproductive potential to use
`treatment with PEMFEXY and
`effective contraception during
`for 6 months after the final
`treatment with PEMFEXY and
`dose. Advise males with
`
`for 6 months after the final dose.
`female partners of
`reproductive potential to use
`Advise males with female
`effective contraception during
`
`partners of reproductive potential
`2
`
`Reference ID: 4502092
`
`

`

` FDA only made formatting
`
`changes; Eagle accepted
`
`treatment with PEMFEXY and
`for 3 months after the final
`dose [see Use in Specific
`
`Populations (0, Error!
`
`Reference source not
`found.)
`
`
`
`(0)].
`
`to use effective contraception
`during treatment with PEMFEXY
`and for 3 months after the final
`dose [see Use in Specific
`
`Populations (0, Error!
`Reference source not found.)]
`
`
`8.1 Pregnancy
`Risk Summary
`
`Based on findings in animal
`studies and its mechanism
`of action, pemetrexed can
`cause fetal harm when
`administered to a pregnant
`
`woman [see Clinical
`
`
`Pharmacology (0)]. There
`
`
`are no available data on
`pemetrexed use in pregnant
`women. In animal
`reproductive studies,
`intravenous administration
`
`of pemetrexed to pregnant
`
`mice during the period of
`organogenesis was
`teratogenic, resulting in
`developmental delays and
`malformations at doses
`lower than the
`
`recommended human dose
`of 500 mg/m2 [see Data].
`
`Advise pregnant women of
`
`
`
`the potential risk to a fetus.
`
`[see use in Specific
`Population (Error!
`Reference source not
`found.)]
`In the U.S. general
`population, the estimated
`background risk of major
`
`birth defects and
`miscarriage in clinically
`recognized pregnancies is 2
`
`to 4% and 15 to 20%,
`
`8.1 Pregnancy
`Risk Summary
`
`
`Based on findings from animal
`studies and its mechanism of
`action, PEMFEXY can cause
`fetal harm when administered
`to a pregnant woman [see
`Clinical Pharmacology (0)].
`
`There are no available data
`on pemetrexed use in
`
`pregnant women. In animal
`reproduction studies,
`intravenous administration of
`
`pemetrexed to pregnant mice
`during the period of
`organogenesis was
`teratogenic, resulting in
`developmental delays and
`malformations at doses lower
`than the recommended
`
`
`human dose of 500 mg/m2
`(see Data). Advise pregnant
`
`
`women of the potential risk to
`a fetus [see use in Specific
`Population (Error! Reference
`source not found.)].
`In the U.S. general
`population, the estimated
`background risk of major birth
`defects and miscarriage in
`clinically recognized
`
`
`pregnancies is 2 to 4% and 15
`to 20%, respectively.
`Data
`
`Animal Data
`
`3
`
`Reference ID: 4502092
`
`(b) (4)
`
`

`

`respectively.
`Data
`
`Animal Data
`
`Pemetrexed was
`teratogenic in mice. Daily
`dosing of pemetrexed by
`
`intravenous injection to
`
`
`pregnant mice during the
`period of organogenesis
`increased the incidence of
`fetal malformations (cleft
`
`palate; protruding tongue;
`enlarged or misshaped
`kidney; and fused lumbar
`
`vertebra) at doses (based
`on BSA) 0.03 times the
`human dose of 500 mg/m2.
`
`At doses, based on BSA,
`
`greater than or equal to
`
`
`0.0012 times the 500 mg/m2
`
`
`
`human dose, pemetrexed
`
`administration resulted in
`
`dose-dependent increases
`in developmental delays
`
`(incomplete ossification of
`
`talus and skull bone; and
`
`decreased fetal weight).
`
` Pemetrexed was teratogenic
`
`in mice. Daily dosing of
`pemetrexed by intravenous
`injection to pregnant mice
`
`during the period of
`organogenesis increased the
`incidence of fetal
`malformations (cleft palate;
`protruding tongue; enlarged or
`
`misshaped kidney; and fused
`lumbar vertebra) at doses
`
`(based on BSA) 0.03 times
`
`the human dose of
`500 mg/m2. At doses, based
`on BSA, greater than or equal
`to 0.0012 times the
`500 mg/m2 human dose,
`pemetrexed administration
`
`resulted in dose-dependent
`increases in developmental
`delays (incomplete
`ossification of talus and skull
`bone; and decreased fetal
`weight).
`
`8.2 Lactation
`
`Risk Summary
`
`8.2 Lactation
`
`Risk Summary
`
`Risk Summary
`There is no information
`regarding the presence of
`pemetrexed or its metabolites
`
`in human milk, the effects on
`
`the breastfed infant, or the
`effects on milk production.
`Because of the potential for
`serious adverse reactions in
`breastfed infants from
`
`pemetrexed, advise women not
`to breastfeed during treatment
`
`There is no information
`regarding the presence of
`pemetrexed or its metabolites in
`human milk, the effects on the
`breastfed infant, or the effects on
`milk production. Because of the
`potential for serious adverse
`reactions in breastfed infants
`from PEMFEXY, advise women
`not to breastfeed during
`treatment with PEMFEXY and
`
`4
`
`No changes
`
`Reference ID: 4502092
`
`

`

`
`Pregnancy Testing
`statement added
`consistent with current
`
`labelling practices and
`PLLR.
`
`with PEMFEXY and for one
`week after last dose.
`
`for one week after last dose.
`
`8.3 Females and Males of
`Reproductive Potential
`
`8.3 Females and Males of
`Reproductive Potential
`
`Females
`Pregnancy Testing
`Pemetrexed can cause fetal
`Verify pregnancy status of
`
`harm when administered to a
`females of reproductive potential
`pregnant woman [see Use in
`
`prior to initiating PEMFEXY
`Specific Populations (0)].
`
`[see Use in Specific Populations
`Because of the potential for
`(0)].
`genotoxicity, advise females of
`Contraception
`reproductive potential to use
`effective contraception during Females
`treatment with PEMFEXY for PEMFEXY can cause fetal harm
`at least 6 months after the
`when administered to a pregnant
`
`final dose
`.
`woman [see Use in Specific
`Populations (0)]. Because of the
`
`Males
`potential for genotoxicity, advise
`Because of the potential for
`females of reproductive potential
`genotoxicity, advise males
`to use effective contraception
`with female partners of
`during treatment with
`reproductive potential to use
`PEMFEXY and for 6 months
`effective contraception during
`treatment with PEMFEXY and after the final dose.
`for 3 months after the final
`Males
`dose [see Nonclinical
`Because of the potential for
`Toxicology (0)].
`genotoxicity, advise males with
`female partners of reproductive
`Infertility
`potential to use effective
`Males
`contraception during treatment
`Pemetrexed may impair
`with PEMFEXY and for 3
`fertility in males of
`reproductive potential. It is not months after the final dose [see
`Nonclinical Toxicology (0)].
`known whether these effects
`on fertility are reversible [see
`Infertility
`Nonclinical Toxicology (0)].
`Males
`
`PEMFEXY may impair fertility
`in males of reproductive
`potential. It is not known
`whether these effects on fertility
`are reversible [see Nonclinical
`Toxicology (0)].
`5
`
`Reference ID: 4502092
`
`(b) (4)
`
`

`

`6
`
`Reference ID: 4502092
`
`
`APPEARS THIS WAY ON ORIGINAL
`
`

`

`No changes
`
`No changes
`
`12.1 Mechanism of
`Action
`Pemetrexed is a folate analog
`metabolic inhibitor that disrupts
`folate-dependent metabolic
`processes essential for cell
`replication. In vitro studies show
`that pemetrexed inhibits
`thymidylate synthase (TS),
`dihydrofolate reductase (DHFR),
`and glycinamide ribonucleotide
`formyltransferase (GARFT),
`which are folate-dependent
`
`enzymes involved in the de novo
`biosynthesis of thymidine and
`purine nucleotides. Pemetrexed
`is taken into cells by membrane
`carriers, such as the reduced
`folate carrier and membrane
`folate binding protein transport
`systems. Once in the cell,
`pemetrexed is converted to
`polyglutamate forms by the
`enzyme folylpolyglutamate
`synthetase. The polyglutamate
`forms are retained in cells and
`are inhibitors of TS and GARFT.
`
`12.1 Mechanism of
`Action
`Pemetrexed is a folate analog
`metabolic inhibitor that
`disrupts folate-dependent
`metabolic processes essential
`for cell replication. In vitro
`
`studies have shown that
`
`pemetrexed inhibits
`thymidylate synthase (TS),
`dihydrofolate
`reductase (DHFR), and
`glycinamide ribonucleotide
`formyltransferase (GARFT),
`which are folate-dependent
`
`enzymes involved in the
`de novo biosynthesis of
`thymidine and purine
`nucleotides. Pemetrexed is
`taken into cells by membrane
`carriers such as the reduced
`folate carrier and membrane
`folate binding protein transport
`systems. Once in the cell,
`pemetrexed is converted to
`polyglutamate forms by the
`enzyme folylpolyglutamate
`synthetase. The polyglutamate
`forms are retained in cells and
`are inhibitors of TS and
`GARFT.
`
`13.1
`Carcinogenesis,
`Mutagenesis,
`Impairment of Fertility
`
` No carcinogenicity studies
`
` have been conducted with
`pemetrexed. Pemetrexed was
`clastogenic in an in vivo
`micronucleus assay in mouse
`bone marrow but was not
`mutagenic in multiple in vitro
`
`13.1 Carcinogenesis,
`Mutagenesis,
`Impairment of Fertility
`No carcinogenicity studies have
`been conducted with pemetrexed.
`Pemetrexed was clastogenic in an
`in vivo micronucleus assay in
`mouse bone marrow but was not
`mutagenic in multiple in vitro
`tests (Ames assay, Chinese
`Hamster Ovary cell assay).
`
`7
`
`Reference ID: 4502092
`
`

`

`tests (Ames assay, Chinese
`Hamster Ovary cell assay).
`Pemetrexed administered
`intraperitoneally at doses of
`
`≥0.1 mg/kg/day to male
`mice (approximately 0.006
`times the recommended human
`dose based on BSA) resulted
`in reduced fertility,
`hypospermia, and testicular
`atrophy.
`
`Pemetrexed administered
`intraperitoneally at doses of
`
`≥0.1 mg/kg/day to male
`mice (approximately 0.006 times
`
`the recommended human dose
`based on BSA) resulted in
`reduced fertility, hypospermia,
`and testicular atrophy.
`
`8
`
`Reference ID: 4502092
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`WHITNEY S HELMS
`10/04/2019 12:45:13 PM
`
`Reference ID: 4502092
`
`

`

`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:
`
`Applicant:
`
`Review Division:
`
`209472
`NDA 021462
`December 30, 2016
`December 30, 2016
`
` Pemetrexed Injection (PEMFEXY)
`Advanced or metastatic nonsquamous non-
`
`small cell lung cancer (NSCLC) and
`Mesothelioma in combination with cisplatin
`(same as Alimta)
`
` Eagle Pharmaceuticals, Inc.
`50 Tice Boulevard, Woodcliff Lake,
`New Jersey 07677, USA
`
`Division of Hematology Oncology Toxicology
`(Division of Oncology Products 2)
`M. Anwar Goheer, Ph.D.
`Reviewer:
`Supervisor/Team Leader: Whitney S. Helms, Ph.D.
`Division Director:
`John Leighton, Ph.D., D.A.B.T.
`(Patricia Keegan, M.D.)
`Autumn Zack-Taylor
`
`Project Manager:
`Disclaimer
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 209472 are owned by Eagle Pharmaceuticals or are
`
`data for which Eagle Pharmaceuticals has obtained a written right of reference.
`
`Any information or data necessary for approval of NDA 209472 that Eagle
`
`
`Pharmaceuticals 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 NDA 209472.
`
`Reference ID: 4161663
`
`1
`
`
`

`

`NDA # 209472
`
`Reviewer: Anwar Goheer, Ph.D.
`
`TABLE OF CONTENTS
`
`
`1
` EXECUTIVE SUMMARY...........................................................................................4
`
`INTRODUCTION: ....................................................................................................4
`
`1.1
`1.2 BRIEF DISCUSSION OF NONCLINICAL FINDINGS .......................................................4
`
`
`1.3 RECOMMENDATIONS .............................................................................................5
`
`2
` DRUG INFORMATION..............................................................................................6
`
`2.1 DRUG ..................................................................................................................6
`
`2.2 RELEVANT INDS, NDAS, BLAS AND DMFS............................................................6
`
`
`
`2.3 DRUG FORMULATION ............................................................................................6
`
`
`2.4 COMMENTS ON NOVEL EXCIPIENTS ........................................................................7
`
`2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN..........................................8
`
`3 STUDIES SUBMITTED.............................................................................................9
`
`3.1 STUDIES REVIEWED..............................................................................................9
`
`3.2 STUDIES NOT REVIEWED.......................................................................................9
`
`3.3 PREVIOUS REVIEWS REFERENCED.........................................................................9
`
`5 PHARMACOKINETICS/ADME/TOXICOKINETICS .................................................9
`
`5.1 PK/ADME ...........................................................................................................9
`
`6 GENERAL TOXICOLOGY......................................................................................11
`
`6.2 REPEAT-DOSE TOXICITY .....................................................................................11
`
`10
`SPECIAL TOXICOLOGY STUDIES....................................................................17
`
`12
`APPENDIX/ATTACHMENTS ..............................................................................18
`
`
`Reference ID: 4161663
`
`2
`
`
`

`

`NDA # 209472
`
`Reviewer: Anwar Goheer, Ph.D.
`
`
`
` Table of Tables
`
`
`
` Table 1: Composition of Pemetrexed Injection, 25 mg/mL (500 mg/vial) .........................6
`
`Table 2: LD50s for PG........................................................................................................7
`
`
`Table 3: Protein Binding of Pemetrexed Injection and Alimta in Human Plasma ...........10
`
`
`
`
`
`Table 4: Protein Binding of Pemetrexed Injection and Alimta in Human Albumin ..........10
`
`
`
`
`
`Table 5: Protein Binding of Pemetrexed Injection and Alimta in Human α1-Acid
`
`
`
`
`
`
`Glycoprotein.....................................................................................................11
`
`Table 6: Treatment Groups.............................................................................................12
`
`
`Table 7: Summary of Mortality of mice ...........................................................................13
`
`
`
`
`Table 8: Gross pathology................................................................................................14
`
`
`Table 9: Organ Weight Changes –Terminal Sacrifice ....................................................14
`
`
`
`Table 10: Histological Findings.......................................................................................15
`
`
`
`Table 11: Toxicokinetics .................................................................................................15
`
`
`Table 12: Hemolytic potential of Pemetrexed and Alimta...............................................18
`
`
`
`Table 13: Plasma Compatibility ......................................................................................18
`
`
`
` Table of Figures
`
` Figure 1: Mean Body Weights of Male and Female Mice...............................................13
`
`
`
`
`Reference ID: 4161663
`
`3
`
`
`

`

`NDA # 209472
`
`Reviewer: Anwar Goheer, Ph.D.
`
`Executive Summary
`1
`Introduction:
`1.1
`
` Eagle Pharmaceuticals has submitted NDA 209472 for PEMFEXY (Pemetrexed
`Injection) under the 505(b)(2) pathway and is relying primarily on FDA’s prior findings of
`safety and effectiveness for the listed drug Alimta to support the pharmacology and
`
`toxicology requirements for a new drug application. Pemetrexed Injection is a ready-to­
`dilute formulation of pemetrexed with different excipients than the listed drug, Alimta.
`
`
`
`Eagle has submitted limited pharmacokinetic and toxicology studies comparing its
`
`
`Pemetrexed Injection (PEMFEXY) to Alimta in order to help support the safety of the
`
`
`
`formulation and to qualify any novel impurities present in the Eagle pemetrexed
`
`
`formulation.
`1.2 Brief Discussion of Nonclinical Findings
`Pemetrexed is a folate analog metabolic inhibitor that exerts its action by disrupting
`
`
`folate-dependent metabolic processes essential for cell replication. The Applicant
`
`conducted several pharmacology/toxicology studies comparing the two products to help
`
`support the safety of the differences in formulation, including high levels of propylene
`glycol, and to qualify impurities in the Eagle product at levels above the ICHQ3B limits.
`
`
`
`To investigate whether changes to the formulation would result in any changes in
`
`plasma protein binding which might affect the PK of the active pharmaceutical
`
`ingredient (API), pemetrexed, the Applicant tested pemetrexed injection and Alimta at
`final assay concentrations of 10, 100, and 1000 μg/mL in an equilibrium dialysis assay
`
`
`
`system. Results showed that protein binding of Pemetrexed Injection and Alimta to
`
`human plasma, human serum albumin, and human α1-acid glycoprotein was
`
`
`comparable. In a safety study investigating the hemolytic potential of the Eagle
`
`
`
`formulation of pemetrexed, Pemetrexed Injection diluted in 5% Dextrose Injection to 15
`
`
`
`mg/mL had no hemolytic potential in human whole blood and was negative for protein
`
`
`
`precipitation and aggregation in human plasma at a final pemetrexed concentration of
`
`
`7.5 mg/mL, similar to Alimta.
`
`The toxicities of pemetrexed injection compared to Alimta were assessed in a repeat
`
`
`dose toxicity study in Crl:CD1 (IRC) mice. Animals (15/sex/group) received 315 mg/kg
`
`(945 mg/m2) of pemetrexed injection or Alimta given once weekly for a total of 7 doses.
`
`While several deaths occurred in the pemetrexed injection and vehicle arms, the
`
`
`
`pathologist attributed these deaths to the infusion procedure rather than the drug and no
`
`
`treatment-related effects were noted in body weight, food consumption, clinical
`observations, and ophthalmic examinations in either early death animals or animals that
`
`survived until sacrifice. Similar procedural deaths also occurred in Alimta-treated
`
`animals in the toxicokinetic groups. No propylene glycol was present in the vehicle
`
`control formulation, suggesting that the high levels of this excipient were also not related
`
`
`
`
`to these mortalities. Clinical pathology findings were generally comparable between the
`
`
`pemetrexed injection and Alimta groups. Findings included minor hepatocellular effects
`
`in pemetrexed-treated females indicated by mild increases in alanine aminotransferase
`
`Reference ID: 4161663
`
`4
`
`
`

`

`NDA # 209472
`
`Reviewer: Anwar Goheer, Ph.D.
`
` (ALT) and aspartate aminotransferase (AST) activities, as well as minimal to mild
`
`
`
` decreases in neutrophil and/or lymphocyte counts in both sexes of the Alimta-treated
` group and in females in the pemetrexed injection-treated group. Treatment-related
`
`
`
` changes occurred in the testes and epididymides of mice given Alimta or pemetrexed
`injection; the incidence and intensity of these findings were comparable for both groups
`and correlated with reduction in testes weights.
`
`Systemic exposure (Cmax and AUC0-24hr) following once weekly IV administration of
`pemetrexed injection or Alimta for seven doses was similar between the two treatment
`
`
`
`groups. Overall, the results of this study were comparable to those results previously
`
`reported for pemetrexed and indicate that pemetrexed injection administered weekly for
`
`seven doses is comparable to Alimta administered weekly for seven doses. No clear
`
`
`
`pemetrexed injection-related local tolerance effects or impurity-related toxicities (Section
`2.5) were observed in this study, providing safety data to support the requested
`
`specifications.
`
`From a pharmacology/toxicology perspective the submitted studies are supportive of the
`
`
`comparability of pemetrexed-related toxicity and exposure between the listed drug and
`
`
`
`Eagle’s pemetrexed injection and sufficient to support the final impurity specifications.
`
`While the nonclinical data is also reasonably supportive of the safety of the high levels
`
`
`
`of propylene glycol included in this formulation of pemetrexed, there is clinical data in
`
`
`
`
`the literature suggesting that such high levels of propylene glycol may represent an
`added risk to patients. While there is no additional nonclinical data needed to support
`
`
`
`
`this formulation, given the literature suggesting the potential for propylene glycol
`
`mediated toxicity (primarily metabolic acidosis and hyperosmolarity, and sequalae of
`those toxicities) at clinical pharmacokinetic concentrations above 25 mg/dL1, and
`
`potential propylene glycol Cmax concentrations that exceed this level even in patients
`with a small BSA at the recommended pemetrexed injection dose of 500 mg/m2, a
`
`
`
`determination of the safety of the levels of propylene glycol in the currently proposed
`
`
`
`
`formulation cannot be made on the basis of nonclinical data alone.
`
`1.3 Recommendations
`1.3.1 Approvability
`There are no outstanding issues from a pharmacology/toxicology perspective that would
`
`
`prevent approval of Pemfexy.
`1.3.2 Additional Non Clinical Recommendations
`None
`
`
`
` 1 Background Review for the Excipient Propylene Glycol, European Medicines Agency (EMA) Report, 20 November
`2014
`
`
`
`Reference ID: 4161663
`
`5
`
`
`

`

`NDA # 209472
`
`Reviewer: Anwar Goheer, Ph.D.
`
`1.3.3 Labeling
`The nonclinical recommendations to the Applicant’s proposed labeling are primarily
`
`
`
`based on the listed drug, were discussed internally, and will be communicated to the
`Applicant.
`2 Drug Information
`2.1 Drug
`Generic Name
` Pemetrexed Injection
`
`
` Code Name
`None
`Chemical Name
`N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5­
`yl)ethyl]benzoyl]-L-glutamic acid
`Molecular Formula/Molecular Weight
`C20H21N5O6 / 427.41
`Structure or Biochemical Description:
`
`Folate antimetabolite
`Pharmacologic Class:
`2.2 Relevant INDs, NDAs, BLAs and DMFs
`NDA 021462
`2.3 Drug Formulation
`Table 1: Composition of Pemetrexed Injection, 25 mg/mL (500 mg/vial)
`
`
`
`(Excerpted from Applicant’s submission)
`
`Reference ID: 4161663
`
`6
`
`(b) (4)
`
`(b) (4
`
`(b) (4
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA # 209472
`
`Reviewer: Anwar Goheer, Ph.D.
`
`2.4 Comments on Novel Excipients
` The maximum level of tromethamine to be delivered at the maximum pemetrexed dose
`
`. This amount of tromethamine is significantly lower than the dose
`of 1500 mg is
`
`. Thus, there is sufficient clinical
`given as a drug for acidosis (Tham), which is
`
`
`
`safety data to justify the potential levels of tromethamine administered in Pemetrexed
`
`
`Injection.
`
`The maximum level of propylene glycol (PG) to be delivered at the maximum expected
`pemetrexed dose of 1500 mg is 15.6 g (~222 mg/kg). In an email communication on
`
`September 15, 2017, the Applicant confirmed that PG was present in the pemetrexed
`
`injection formulation used in their comparative mouse toxicology study
`
`
`and, in a follow-up communication on
`
`September 25, 2017, that PG was not present in the vehicle control administered in the
`
`
`same study. In the Applicant’s toxicology study mice received 21 mL/kg of
`
`pemetrexed—which would result in approximately 98 mg of PG using an average
`
`
`
`mouse weight of 30 g (21 mL/kg*0.03 kg=0.63 mL; 0.63 mL* 156 mg/mL PG= 98 mg
`
`
`PG) or approximately 9.8 g/m2 (3200 mg/kg),. Per the protocol, injections in this
`toxicology study occurred over 5 minutes. Compared to the listed drug, there were no
`
`significant differences in clinical observations or changes in clinical chemistry recorded
`
`in this study; while transient changes in clinical chemistry immediately after infusion
`
`cannot be excluded based on the study design, no effects were apparent by scheduled
`
`
`
`sacrifice. On an mg/m2 basis humans would receive no more than approximately 8 g/m2
`
`delivered during the recommended 10 minute infusion at the maximum anticipated level
`
`
`
`of 15.6 g, though a more likely high dose would be no more than approximately 10 g, or
`
`
`
`5.5 mg/m2, based on typical calculations using an average BSA of 1.8m2 rather than 3.
`Thus, there is nonclinical data with the formulation to support the high levels of PG
`
`delivered in the 10 minute time interval, though based on the EMA background review
`
`for propylene glycol1, saturation of propylene glycol metabolism occurs at lower doses
`
`for humans than for rats/rabbits (0.2 g/kg vs. 2 g/kg, respectively). In response to a
`
`
`nonclinical information request, the Applicant submitted additional supportive nonclinical
`
`information based on literature reports that LD50s for IV administration of propylene
`
`glycol in multiple animal species occurred at doses greater than 6 g/kg (Error!
`
`
`
`Reference source not found.), or approximately 36 g/m2 in rats, 18 g/m2 in mice.
`
`
`
`
` Animal Species
`
`Mouse
`Rabbit
`Rat
`N.A.: not applicable
`
`
`Table 2: LD50s for PG
`
`EMA Report
` Expert Panel Report
`(mg/kg)
`(mg/kg)
`5,000-8,000
`6,081
`4,000-6,000
`N.A.
`N.A.
`5,985
`
`(Excerpted from Applicant’s submission)
`
`
`
`(mg/kg)
`N.A
`6,500
`6,800
`
`There is, however, also clinical data regarding PG administration by the IV route
`available in the published scientific literature. At a PG dose of 213 g/day for 7 days
`
`
`
`
`
`given by continuous infusion (1699 g total) some clinical toxicity (confusion,
`
`
`
`Reference ID: 4161663
`
`7
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA # 209472
`
`Reviewer: Anwar Goheer, Ph.D.
`
`hyperosmolality, lactic acidosis, and acute kidney injury) occurred, but the effects were
` recoverable2. In the same review documenting this clinical high dose PG toxicity, animal
`
`LD50 doses were
`g/kg by oral administration in all species tested. The 2014 EMA
`
`
`
`
`review on propylene glycol toxicity suggests limits in patients ≥5 years old of up to 500
`
`
`mg/kg/day based on clinical data described by Yaucher et al3 and Yahwak et al4. This
`
`
`document also refers to a study described by Speth et al5,6 in which patients with cancer
`
`
`
`received propylene glycol at a once every 3 week dose of up to 15 g/m2 over a 4 hour
`
`IV infusion resulting in Cmax exposures as high as 425 μg/mL (42.5 mg/dL) as a part of
`a Phase 1 study of mitoquidone (600 mg/m2) with no evidence of lactic acidosis,
`hemolysis, or increase in osmolarity.
`
`2.5 Comments on Impurities/Degradants of Concern
`The pharmacology/toxicology team received questions from the CMC review team
`
`
`regarding the safety of the levels propylene glycol (PG) and tromethamine that will be
`
`
`
`delivered to patients at the maximum pemetrexed dose in the Eagle formulation as well
`as questions about the justification of the specifications for Impurities
`in
`
`the drug product. Impurities
` were present at levels of
`% in the toxicology
`
`batch for the Pemetrexed Injection lot used in the repeat dose toxicology study
`
`comparing Pemetrexed Injection and Alimta. There were no clear differences in toxicity
`
`
`between animals treated weekly with Pemetrexed Injection versus Alimta at doses
`
`
`approximately twice the recommended once every 3 weeks human dose in this study
`
`
`and no drug-related deaths (reviewed below). For this reason, the proposed
`
`
`
`specifications for Impurities
`of no more than % are justified based on the
`
`submitted nonclinical data.
`
`
` as stereoisomers of a
`The Applicant identified the structure of Impurities
`
`
`published metabolite of pemetrexed. This pemetrexed metabolite is present following
`administration of the drug in both animal and human samples at levels higher than the
`
`proposed specification of no more than %. Consistent with the recommendations in
`
`
`
`
` 2 Fowles JR, Banton MI, Pottenger LH. A toxicological review of the propylene glycols. Crit Rev Toxicol.
`
`
` 2013 Apr;43(4):363-90.
`
`
`3 Yaucher, N. and Fish, J. (2003). Propylene Glycol-Associated Renal Toxicity from Lorazepam Infusion.
`
`Pharmacotherapy 23, 1094–1099.
`
`
`4 Yahwak, J., Riker, R. and Fraser, G. (2008). Determination of a lorazepam dose threshold for using the
`
`
`
`
`
`osmol gap to monitor for propylene glycol toxicity. Pharmacotherapy 28, 984–991.
`
`
`5 Speth, P. and Vree, T. (1987). Propylene glycol pharmacokinetics and eff