CENTER FOR DRUG EVALUATION AND
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`RESEARCH
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`APPLICATION NUMBER:
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`209472Orig1s000
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`CLINICAL REVIEW(S)
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`File Memorandum
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`Memo Date
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`To NDA
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`Submission Date
`PDFUA Date
`Product
`Dosage Form
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`Sponsor
`From
`Via
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`Reference Drug
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`10/4/2019
`209472
`8/9/2019
`10/9/2019
`Pemfexy (Pemetrexed for Injection) Ready to Dilute Solution
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`500 mg vial for injection, (25 mg/mL)
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`Eagle Pharmaceuticals
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`Barb Scepura
` Erin Larkins, MD, Clinical Team Leader, DOP2
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`Alimta (NDA 021677and 021462)
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`Clinical Information
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`No clinical data was submitted in this application.
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`Background
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`This is a 505(b) (2) application by Eagle Pharmaceuticals. Eagle Pharmaceuticals is proposing a proprietary name
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`for their product Pemfexy (Pemetrexed for Injection). The reference drug product is Eli Lilly and Company’s Alimta
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`(pemetrexed disodium) for injection (NDAs 021677 and 021462). Alimta was initially granted traditional approval
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`on February 4, 2004. Eagle Pharmaceuticals Pemfexy (Pemetrexed for Injection) will have the same indications as
`Alimta.
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`Eagle Pharmaceuticals, Inc. (“Eagle”) requests a waiver of in vivo bioavailability studies to demonstrate the
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`bioequivalence of Eagle’s Ready-to-Dilute (RTD) aqueous solution formulation of Pemetrexed Injection, 25
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`mg/mL, to the listed drug Alimta.
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`Labeling
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`Please refer to the review by Associate Director for Labeling for details.
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`Summary of Findings
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`No clinical safety or efficacy data were submitted in this NDA application.
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`An Initial Pediatric Study Plan was submitted under IND 126831, with agreement on October 14, 2016.
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`Additional Background Information
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`Clinical studies have not been performed using Eagle’s PEMFEXY product. The prepared Eagle PEMFEXY product
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`contains relatively high levels of propylene glycol (PG), which are not present in the reference
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`Reference ID: 4500363Reference ID: 4553588
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`drug ALIMTA. Although PG is generally considered safe, potential toxicity concerns with infusion of high levels of
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`PG are renal, cardiac, neurologic, metabolic and hematologic.
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`Potential Safety Issues Related to PG
` Hemolysis related to osmolality.
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`o The Applicant submitted a toxicology study which demonstrated no safety concern for this
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`product.
`o Please refer to CMC review for details.
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`Lactic acidosis and renal toxicity reported with cumulative doses.
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`o Clinical reports of lactic acidosis and renal toxicity associated with PG have been in the setting of
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`cumulative exposure over time, mostly associated with continuous infusions over multiple days
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`of drug products containing PG as an excipient. A 2014 report from the European Medicines
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` Agency (EMA) regarding the use of PG as an excipient1 cites the report by Speth et al2 for a dose
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` escalation study of mitoquidone, in which the drug product had PG as an excipient. in this study,
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` patients with cancer received PG at doses of up to 15 g/m2 as a 4-hour IV infusion once every 3
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` weeks. This resulted in Cmax exposures as high as 425 g/mL (42.5 mg/dL). There was no
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` evidence of lactic acidosis or associated renal toxicity in this study.
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`o The following information is contained in the Nonclinical Review for this application: “On a
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` mg/m2 basis humans would receive no more than approximately 8 g/m2 delivered during the
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` recommended 10-minute infusion at the maximum anticipated level of 15.6 g, though a more
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` likely high dose would be no more than approximately 10 g, or 5.5 g/m2, based on typical
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` calculations using an average BSA of 1.8 m2 rather than 3”.
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` Reviewer comment: The anticipated maximum dose of 8 g/m2 is well below the highest dose of 15 g/m2 PG
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` administered in the Speth trial. Given this, and the once every 3-week dosing of PEMFEXY, lactic acidosis and renal
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` toxicity due to PG are not expected to be associated with use of this product.
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`  Cardiovascular effects with “rapid infusions”
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`o As referenced by the Applicant in a September 28, 2017 response to information request from
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`the FDA, the 2014 EMA report cites several publications describing cardiovascular effects of PG
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`at different dose levels in nonclinical studies. One study from the mid-1970s reports
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`antiarrhythmic effects observed in rats and dogs following IV injection of PG at doses between
` 193 to 289 mg/kg.3 Another study from the mid-1980s specifically evaluated the cardiovascular
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` effects of PG administered to dogs as an IV injection at doses of 160, 400, and 800 mg/kg.
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` Results from this second study showed transient decrease in heart rate and blood pressure at a
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`dose ≥400 mg/kg, with values returning to normal within 1 minute of PG administration.
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`Reviewer comment: These reports from nonclinical studies are for PG administered as an injection. PEMFEXY is
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`recommended to be administered as an IV infusion over 10 minutes. Literature searches performed by the clinical
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`reviewer and the clinical team lead revealed no clinical case reports of sudden death clearly or likely related to
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`receipt of propylene glycol as an excipient.
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`Reference ID: 4500363Reference ID: 4553588
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`

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` EMA Statement on PG
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` The 2014 EMA report regarding PG as an excipient concludes “the safe maximum daily dose of PG for adults is
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` 500 mg /kg”. 1 In a letter dated October 2, 2017 Eagle Pharmaceuticals confirmed that the maximum level of PG
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` to be delivered at the maximum expected pemetrexed dose of 1500 mg is 15.6 g, which is equivalent to
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`approximately 222 mg/kg, which is less than half the maximum daily dose considered safe for adults per the EMA
`report.
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`FDA Statement on PG
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`The FDA Inactive Ingredient Database (IID) for Drug Products includes a maximum potency of 30% for propylene
` glycol administered as an administered as an intravenous infusion.5 The anticipated maximum potency of PG
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` Pemetrexed Injection for the expected highest total dose of 1,500 mg of pemetrexed, administered IV as a 100­
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` mL admixture over a 10-minute infusion to a very large patient with 3 m2 BSA, is 15.6%. This potency of 15.6% is
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` approximately 50% lower than the IID-allowed maximum potency for an IV infusion (30%), and approximately
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` one fifth of the maximum potency IID-allowed for an IV
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`injection (82.04%).
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` Reviewer comment: The dose of PG in Eagle’s prepared PEMFEXY product is within the safety limits defined by
` both the FDA and the EMA.
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` Reviewer comment: Based on biopharmaceutical review, nonclinical assessment and literature references, Eagle’s
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` prepared PEMFEXY product contains safe levels of PG.
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`References
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`1. European Medicines Agency. Background review for the excipient propylene glycol. November 20, 2014,
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`available at:
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`http://www.ema.europa.eu/docs/en GB/document library/Report/2014/12/WC500177937.pdf
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`Accessed on September 28, 2017.
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`2. Speth P and Vree T. Propylene glycol pharmacokinetics and effects after intravenous infusion in humans.
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`Therapeutic Drug Monitoring, 1987, 9:255-258.
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`3. Eichbaum FW and Yasaka WJ. Antiarrhythmic effect of solvents: propylene glycol, benzyl alcohol. Basic
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`Res Cardiology, 1976, 71:355-370.
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`4. Al-Khudhairi D and Whitman JG. Autonomic reflexes and the cardiovascular effects of propylene glycol.
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`Br J Anaesth, 1986, 58:897-902.
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`5. U. S. Food and Drug Administration. Inactive Ingredient Search for Approved Drug Products. Available at:
`https://www.accessdata.fda.gov/scripts/cder/iig/getiigWEB.cfm
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`Accessed on October 3, 2017.
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`Reference ID: 4500363Reference ID: 4553588
`
`

`

`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/
`------------------------------------------------------------
`
`BARBARA A SCEPURA
`10/02/2019 11:06:04 AM
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`ERIN A LARKINS
`10/02/2019 12:20:53 PM
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`
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`Reference ID: 4500363Reference ID: 4553588
`
`

`

`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/
`------------------------------------------------------------
`
`BARBARA A SCEPURA
`01/29/2020 12:38:09 PM
`
`Reference ID: 4553588
`
`

`

`Cross Discipline Team Leader Review
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`
`
`Cross-Discipline Team Leader Review
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`
`Date
`From
`Subject
`NDA
`Type of Application
`Applicant
`Date of Receipt
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`PDUFA Goal Date
`Proposed
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`Proprietary/Established Name
`Dosage forms / Strength
`Route of Administration
`Proposed Indication(s)
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`Recommended:
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`October 03, 2019
`Anamitro Banerjee, Ph.D.
`Cross-Discipline Team Leader Review
`2084742
`505(b)(2)
`Eagle Pharmaceuticals, Inc.
`August 09, 2019 (original submission: (December 30,
`2016)
`October 09, 2019
`PEMFEXY (pemetrexed injection)
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`Injection/ 25 mg/mL (500 mg/vial)
`Intravenous injection
`Pemetrexed for injection is a folate analog metabolic
`inhibitor indicated for:
`• Locally Advanced or Metastatic Nonsquamous Non-
`Small Cell Lung Cancer:
`• Initial treatment in combination with cisplatin.
`• Maintenance treatment of patients whose disease has
`not progressed after four cycles of platinum-based
`first-line chemotherapy.
`• After prior chemotherapy as a single-agent.
`•Mesothelioma: in combination with cisplatin.
`
`TENTATIVE APPROVAL
`
`This cross-discipline team leader review is based on the primary reviews, memos and documented
`review input of:
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` Product Quality (Xing Wang), dated October 03, 2019
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` Clinical (Barbara Scepura); in DARRTS, dated October 02, 2019
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` Pharmacology/Toxicology (M. Anwar Goheer, NAI); in DARRTS, dated September 30,
`2019
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` Pharmacology/Toxicology Labeling Review (Whitney Helms); in DARRTS, dated October
`04, 2019
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` Clinical Labeling Review (Stacy Shord); in DARRTS, dated October 04, 2019
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` OPDP (Susan Redwood), dated September 27, 2019
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`Page 1 of 4
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`Reference ID: 4502319
`
`1
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`

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`Cross Discipline Team Leader Review
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`
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` OPDP (Fatima Nazia), dated September 26, 2019
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` Clinical Pharmacology (Safaa Burns), dated October 02, 2019
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` 1. Introduction
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` The proposed Pemetrexed (as diacid) for Injection is a sterile single dose ready to dilute solution
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` with a concentration of 25 mg/mL (500 mg/vial), intended for IV use. The solution is further
` diluted with 5% Dextrose in Water to a maximum of final pemetrexed concentration of 15 mg/mL
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`prior to administration. The submission is a 505(b)(2) application, referencing the lyophilized
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`formulation, Alimta (NDA 021462). The listed drug (LD) Alimta is available in 100 mg and 500
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`mg single dose vials. The therapeutic active moiety (pemetrexed), route of administration
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`of the proposed drug product is identical to the listed rug product. However, the listed and
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`the proposed drug product differ in salt form of the active moiety, excipients, dosage form, and the
`solution for dilution. In support of the equivalence of the LD and the proposed drug product, the
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`applicant provided comparative physicochemical properties and a bio-waiver request. Clinical data
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`was not submitted in the application. Other than the pemetrexed in disodium salt form, Alimta
`contains mannitol, and hydrochloric acid or sodium hydroxide for pH adjustment
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`Alimta is
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`reconstituted with 0.9% sodium chloride injection solution followed by further dilution prior to
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`administration. The proposed drug product contains pemetrexed (as diacid), propylene glycol as
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`stabilizer, tromethamine and hydrocholic acid as pH adjusters, and water for injection
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`The proposed Eagle product may be diluted with 5% Dextrose Injection while the
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`LD may only be diluted with 0.9% Sodium Chloride Injection.
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`2. Background
`The current application relies on the Agency’s determination of human safety and efficacy for the
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`pemetrexed lyophilized powder for injection (Alimta), which has been previously approved for
`marketing under NDA 021462 and NDA 021677.
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`This NDA was given a tentative approval on October 26, 2017. In this resubmission, the applicant
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`is seeking full approval of the ready to dilute solution of pemetrexed ditromethamine for the same
`indication granted for Alimta. Alimta is indicated for the initial treatment of nonsquamous non-
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`small cell lung cancer in combination with cisplatin, as a single agent treatment for nonsquamous
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`non-small cell lung cancer after prior chemotherapy, and for the treatment of mesothelioma in
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`combination with cisplatin.
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`3. Chemistry, Manufacturing and Controls (CMC)
` Labeling and strength
`The drug substance for NDA 208472 is pemetrexed diacid
`, consistent with the listed product, Alimta.
`designation is on the basis of the pemetrexed
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`Chemical Name: (4-(2-(2-amino-4-oxo-4,7-dihydro-1H-pyrrolo[2,3-d]pyrimidin-5­
`yl)ethyl)benzoyl)-L-glutamic acid.
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`Page 2 of 4
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`Reference ID: 4502319
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`2
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`(b) (4)
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`(b) (4)
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`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Cross Discipline Team Leader Review
`
`
`
`N 3
`2
`
`O
`
`4
`
`1
`N
`H
`
`H2N
`
`1
`
`2
`
`6
`
`5
`
`N
`7
`H
`
`34
`5
`
`6
`
`2
`1
`
`CO2H
`
`H
`N
`
`S
`L
`
`O
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`HO2C
`(4-(2-(2-amino-4-oxo-4,7-dihydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)benzoyl)-L­
`glutamic acid
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`Chemical Formula: C20H21N5O6
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`Molecular Weight: 427.4170
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`The applicant did not provide any new CMC information in this resubmission. No CMC
`deficiencies were identified in the previous review cycle.
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`Overall CMC recommendation
`The Office of Pharmaceutical Quality recommendation remains APPROVAL action for NDA
`208472.
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`4. Pharmacology/Toxicology
`No new information provided in this resubmission
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`5. Clinical
`No clinical safety or efficacy data were submitted in this NDA application.
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`6. Clinical Pharmacology
`This NDA does not contain any clinical or clinical pharmacology studies as the Applicant requested
`a biowaiver. No new information submitted in this resubmission.
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`7. Advisory Committee Meeting
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`N/A
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`9. Other Relevant Regulatory Issues
`The application may not be approved for marketing until patent/s for the listed drug expires or the
`current patent infringement lawsuit is settled.
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`10. Labeling
`The applicant updated the label as suggested by the review team. The label is now acceptable.
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`Page 3 of 4
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`Reference ID: 4502319
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`3
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`

`

`Cross Discipline Team Leader Review
`
`
`
`14. Recommendations/Risk Benefit Assessment
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` Recommended Regulatory Action
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`This drug product differs with the listed drug, Alimta, in the salt form of active moiety and in the
`composition of the product. No clinical studies were conducted to assure safety and efficacy and a
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`bio-waiver request will be granted for this 505(b)(2) application when it can be approved. The cross
`disciplinary team lead recommendation is for a Tentative Approval for this NDA. The drug
`product may not be approved for marketing until pertinent patents for the listed drug “Alimta”
`expire or the current patent infringement lawsuit is settled in Eagles’s favor.
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` Risk Benefit Assessment
`Please refer to NDA 021462
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`Page 4 of 4
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`Reference ID: 4502319
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`4
`
`

`

`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/
`------------------------------------------------------------
`
`ANAMITRO BANERJEE
`10/04/2019 04:36:56 PM
`
`Reference ID: 4502319
`
`

`

`
`File Memorandum
`
`
`Memo Date
`
`To NDA
`
`Submission Date
`PDFUA Date
`Product
`Dosage Form
`
`Sponsor
`From
`Via
`
`Reference Drug
`
`10/4/2019
`209472
`8/9/2019
`10/9/2019
`Pemfexy (Pemetrexed for Injection) Ready to Dilute Solution
`
`
`
`
`
`
`
`500 mg vial for injection, (25 mg/mL)
`
`
`
`Eagle Pharmaceuticals
`
`Barb Scepura
` Erin Larkins, MD, Clinical Team Leader, DOP2
`
`
`
`
`
`
`
`
`
`Alimta (NDA 021677and 021462)
`
`
`
`
`Clinical Information
`
`
`
`No clinical data was submitted in this application.
`
`Background
`
`
`
`
`
`
`
`
`
`
`
`
`This is a 505(b) (2) application by Eagle Pharmaceuticals. Eagle Pharmaceuticals is proposing a proprietary name
`
`
`
`
`
`
`
`
`
`
`
`
`
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`for their product Pemfexy (Pemetrexed for Injection). The reference drug product is Eli Lilly and Company’s Alimta
`
`
`
`
`
`
`
`
`
`
`
`
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`(pemetrexed disodium) for injection (NDAs 021677 and 021462). Alimta was initially granted traditional approval
`
`
`
`
`
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`on February 4, 2004. Eagle Pharmaceuticals Pemfexy (Pemetrexed for Injection) will have the same indications as
`Alimta.
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`Eagle Pharmaceuticals, Inc. (“Eagle”) requests a waiver of in vivo bioavailability studies to demonstrate the
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`bioequivalence of Eagle’s Ready-to-Dilute (RTD) aqueous solution formulation of Pemetrexed Injection, 25
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`mg/mL, to the listed drug Alimta.
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`Labeling
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`Please refer to the review by Associate Director for Labeling for details.
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`Summary of Findings
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`No clinical safety or efficacy data were submitted in this NDA application.
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`An Initial Pediatric Study Plan was submitted under IND 126831, with agreement on October 14, 2016.
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`Additional Background Information
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`Clinical studies have not been performed using Eagle’s PEMFEXY product. The prepared Eagle PEMFEXY product
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`contains relatively high levels of propylene glycol (PG), which are not present in the reference
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`Reference ID: 4500363
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`

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`drug ALIMTA. Although PG is generally considered safe, potential toxicity concerns with infusion of high levels of
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`PG are renal, cardiac, neurologic, metabolic and hematologic.
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`Potential Safety Issues Related to PG
` Hemolysis related to osmolality.
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`o The Applicant submitted a toxicology study which demonstrated no safety concern for this
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`product.
`o Please refer to CMC review for details.
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`Lactic acidosis and renal toxicity reported with cumulative doses.
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`o Clinical reports of lactic acidosis and renal toxicity associated with PG have been in the setting of
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`cumulative exposure over time, mostly associated with continuous infusions over multiple days
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`of drug products containing PG as an excipient. A 2014 report from the European Medicines
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` escalation study of mitoquidone, in which the drug product had PG as an excipient. in this study,
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` patients with cancer received PG at doses of up to 15 g/m2 as a 4-hour IV infusion once every 3
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` weeks. This resulted in Cmax exposures as high as 425 g/mL (42.5 mg/dL). There was no
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` evidence of lactic acidosis or associated renal toxicity in this study.
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`o The following information is contained in the Nonclinical Review for this application: “On a
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` mg/m2 basis humans would receive no more than approximately 8 g/m2 delivered during the
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` recommended 10-minute infusion at the maximum anticipated level of 15.6 g, though a more
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` likely high dose would be no more than approximately 10 g, or 5.5 g/m2, based on typical
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` calculations using an average BSA of 1.8 m2 rather than 3”.
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` Reviewer comment: The anticipated maximum dose of 8 g/m2 is well below the highest dose of 15 g/m2 PG
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` administered in the Speth trial. Given this, and the once every 3-week dosing of PEMFEXY, lactic acidosis and renal
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` toxicity due to PG are not expected to be associated with use of this product.
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`  Cardiovascular effects with “rapid infusions”
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`o As referenced by the Applicant in a September 28, 2017 response to information request from
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`the FDA, the 2014 EMA report cites several publications describing cardiovascular effects of PG
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`at different dose levels in nonclinical studies. One study from the mid-1970s reports
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`antiarrhythmic effects observed in rats and dogs following IV injection of PG at doses between
` 193 to 289 mg/kg.3 Another study from the mid-1980s specifically evaluated the cardiovascular
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` effects of PG administered to dogs as an IV injection at doses of 160, 400, and 800 mg/kg.
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` Results from this second study showed transient decrease in heart rate and blood pressure at a
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`dose ≥400 mg/kg, with values returning to normal within 1 minute of PG administration.
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`Reviewer comment: These reports from nonclinical studies are for PG administered as an injection. PEMFEXY is
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`recommended to be administered as an IV infusion over 10 minutes. Literature searches performed by the clinical
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`reviewer and the clinical team lead revealed no clinical case reports of sudden death clearly or likely related to
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`receipt of propylene glycol as an excipient.
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`Reference ID: 4500363
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`

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` EMA Statement on PG
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` The 2014 EMA report regarding PG as an excipient concludes “the safe maximum daily dose of PG for adults is
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` 500 mg /kg”. 1 In a letter dated October 2, 2017 Eagle Pharmaceuticals confirmed that the maximum level of PG
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` to be delivered at the maximum expected pemetrexed dose of 1500 mg is 15.6 g, which is equivalent to
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`approximately 222 mg/kg, which is less than half the maximum daily dose considered safe for adults per the EMA
`report.
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`FDA Statement on PG
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`The FDA Inactive Ingredient Database (IID) for Drug Products includes a maximum potency of 30% for propylene
` glycol administered as an administered as an intravenous infusion.5 The anticipated maximum potency of PG
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` Pemetrexed Injection for the expected highest total dose of 1,500 mg of pemetrexed, administered IV as a 100­
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` mL admixture over a 10-minute infusion to a very large patient with 3 m2 BSA, is 15.6%. This potency of 15.6% is
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` approximately 50% lower than the IID-allowed maximum potency for an IV infusion (30%), and approximately
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` one fifth of the maximum potency IID-allowed for an IV
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`injection (82.04%).
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` Reviewer comment: The dose of PG in Eagle’s prepared PEMFEXY product is within the safety limits defined by
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` Reviewer comment: Based on biopharmaceutical review, nonclinical assessment and literature references, Eagle’s
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` prepared PEMFEXY product contains safe levels of PG.
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`References
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`1. European Medicines Agency. Background review for the excipient propylene glycol. November 20, 2014,
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`available at:
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`http://www.ema.europa.eu/docs/en GB/document library/Report/2014/12/WC500177937.pdf
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`Accessed on September 28, 2017.
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`2. Speth P and Vree T. Propylene glycol pharmacokinetics and effects after intravenous infusion in humans.
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`Therapeutic Drug Monitoring, 1987, 9:255-258.
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`3. Eichbaum FW and Yasaka WJ. Antiarrhythmic effect of solvents: propylene glycol, benzyl alcohol. Basic
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`Res Cardiology, 1976, 71:355-370.
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`4. Al-Khudhairi D and Whitman JG. Autonomic reflexes and the cardiovascular effects of propylene glycol.
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`Br J Anaesth, 1986, 58:897-902.
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`5. U. S. Food and Drug Administration. Inactive Ingredient Search for Approved Drug Products. Available at:
`https://www.accessdata.fda.gov/scripts/cder/iig/getiigWEB.cfm
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`Accessed on October 3, 2017.
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`Reference ID: 4500363
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`

`

`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/
`------------------------------------------------------------
`
`BARBARA A SCEPURA
`10/02/2019 11:06:04 AM
`
`ERIN A LARKINS
`10/02/2019 12:20:53 PM
`
`Reference ID: 4500363
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
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`MEMORANDUM
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`Date:
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`January 22, 2018
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`From: Autumn Zack-Taylor, M.S., Regulatory Health Project Manager
`DOP2/0HOP/CDER
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`Subject: Financial Disclosure Review
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`Financial disclosures were not required for review of this application because there were no
`clinical studies submitted supporting the application.
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`Reference ID: 4662511
`
`

`

`Cross Discipline Team Leader Review
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`Cross-Discipline Team Leader Memo
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`
`Date
`From
`Subject
`NDA
`Type of Application
`Applicant
`Date of Receipt
`PDUFA Goal Date
`Proposed
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`Proprietary/Established Name
`Dosage forms / Strength
`Route of Administration
`Proposed Indication(s)
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`Recommended:
`
`October 26, 2017
`Okpo Eradiri, Ph.D.
`Cross-Discipline Team Leader Review
`209472
`505(b)(2)
`Eagle Pharmaceuticals, Inc.
`December 30, 2016
`October 30, 2017
`PEMFEXY (pemetrexed injection)
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`Injection/ 25 mg/mL (500 mg/vial)
`Intravenous injection
`Pemetrexed for injection is a folate analog metabolic
`inhibitor indicated for:
`• Locally Advanced or Metastatic Nonsquamous Non-
`Small Cell Lung Cancer:
`• Initial treatment in combination with cisplatin.
`• Maintenance treatment of patients whose disease has
`not progressed after four cycles of platinum-based
`first-line chemotherapy.
`• After prior chemotherapy as a single-agent.
`•Mesothelioma: in combination with cisplatin.
`TENTATIVE APPROVAL
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`This cross-discipline team leader review is based on the primary reviews, memos and documented
`review input of:
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` Drug Substance (Haripada Sarker), dated September 18, 2017
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` Drug Product (Xing Wang), dated September 05, 2017
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` Microbiology (Denise Miller), dated July 28, 2017
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` Manufacturing Facilities (Wenzheng Zhang), dated September 28, 2017
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` Manufacturing Process (Zhaoyang Meng), dated August 28, 2017
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` Biopharmaceutics (Zhuojun Zhao), dated August 24, 2017
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` Clinical (Barbara Scepura); in DARRTS, dated October 20, 2017
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` Pharmacology/Toxicology (M. Anwar Goheer); in DARRTS, dated October 03, 2017
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`Page 1 of 6
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`Reference ID: 4172494
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`1
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`

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`Cross Discipline Team Leader Review
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`
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` Patient Labeling (Susan Redwood); in DARRTS, dated October 20, 2017
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` Medication Error Prevention and Analysis (Janine Stewart), dated October 25, 2017
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` 1. Introduction
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` The proposed Pemetrexed (as diacid) for Injection is a sterile single dose ready to dilute solution
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` with a concentration of 25 mg/mL (500 mg/vial), intended for IV use. The solution is further diluted
`with 5% Dextrose in Water to a maximum final pemetrexed concentration of 15 mg/mL prior to
`administration. The submission is a 505(b)(2) application, referencing the lyophilized
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`formulation, Alimta (NDA 021462). The listed drug (LD), Alimta, is available in 100 mg and 500
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`mg single dose vials. The therapeutic active moiety (pemetrexed), route of administration
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`of the proposed drug product are identical to the listed drug product. However, the listed
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`and the proposed drug products differ in salt form of the active moiety, excipients, dosage form, and
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`the solution for dilution. In support of the equivalence of the LD and the proposed drug product, the
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`applicant provided comparative physicochemical properties and a bio-waiver request. Clinical data
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`were not submitted in the application. Other than the pemetrexed in disodium salt form, Alimta
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`contains mannitol and hydrochloric acid or sodium hydroxide for pH adjustmen
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`Alimta is
`reconstituted with 0.9% sodium chloride injection solution followed by further dilution prior to
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`administration. The proposed drug product contains pemetrexed (as diacid), propylene glycol as
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`stabilizer, tromethamine and hydrochloric acid as pH adjusters, and water for injection
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`. The proposed Eagle product may be diluted with 5% Dextrose Injection while the
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`LD may only be diluted with 0.9% Sodium Chloride Injection.
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`2. Background
`The current application relies on the Agency’s determination of human safety and efficacy for the
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`pemetrexed lyophilized powder for injection (Alimta), which has been previously approved for
`marketing under NDA 021462 and NDA 021677; Alimta was granted traditional approval on
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`February 4, 2004.
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`The applicant is seeking approval of a ready to dilute solution of pemetrexed ditromethamine for the
`same indications granted for Alimta. Alimta is indicated for the initial treatment of nonsquamous
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`non-small cell lung cancer in combination with cisplatin, as a single agent treatment for
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`nonsquamous non-small cell lung cancer after prior chemotherapy, and for the treatment of
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`mesothelioma in combination with cisplatin.
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`3. Chemistry, Manufacturing and Controls (CMC)
`). Labeling and strength
`The drug substance for NDA 208472 is pemetrexed diacid
`designation are based on the pemetrexed
`, consistent with the listed product, Alimta.
`Chemical Name: (4-(2-(2-amino-4-oxo-4,7-dihydro-1H-pyrrolo[2,3-d]pyrimidin-5­
`yl)ethyl)benzoyl)-L-glutamic acid.
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`Page 2 of 6
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`Reference ID: 4172494
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`2
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`(b)