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`CENTER FOR DRUG EVALUATION AND
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`RESEARCH
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`APPLICATION NUMBER:
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`209388Orig1s000
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`MULTI-DISCIPLINE REVIEW
`Summary Review
`Clinical Review
`Non-Clinical Review
`Statistical Review
`Clinical Pharmacology Review
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`E DƵůƚŝͲŝƐĐŝƉůŝŶĂƌLJ ZĞǀŝĞǁ ĂŶĚ ǀĂůƵĂƚŝŽŶ
`
`NDA Multi-Disciplinary Review and Evaluation
`ƉƉůŝĐĂƚŝŽŶ dLJƉĞ E
`Appiiccticp type
`ƉƉůŝĐĂƚŝŽŶ EƵŵďĞƌ ϮϬϵϯϴϴ
`Appiiccticn ~tmpci
`WƌŝŽƌŝƚLJ Žƌ ^ƚĂŶĚĂƌĚ ^ƚĂŶĚĂƌĚ
`iiiciitycistcntait
`^Ƶďŵŝƚ ĂƚĞ;ƐͿ ϭϮͬϭϵͬϮϬϭϵ
`stpmit Date(s)
`
`ZĞĐĞŝǀĞĚ ĂƚĞ;ƐͿ ϭϮͬϭϵͬϮϬϭϵ
`
`Received Date(s)
`12/19/2019
`
`Wh& 'ŽĂů ĂƚĞ ϬϲͬϭϵͬϮϬϮϬ
`PDUFA Goal Date 06/19/2020
`
`ŝǀŝƐŝŽŶͬKĨĨŝĐĞ ŝǀŝƐŝŽŶ ŽĨ 'ĂƐƚƌŽĞŶƚĞƌŽůŽŐLJ ;'ͿͬKĨĨŝĐĞ ŽĨ /ŵŵƵŶŽůŽŐLJ ĂŶĚ
`Division/Office Division of Gastroenterology (DG)/Office of Immunology and
`
`
`/ŶĨůĂŵŵĂƚŝŽŶ ;K//Ϳ
`Inflammation (Oll)
`
`ZĞǀŝĞǁ ŽŵƉůĞƚŝŽŶ ĂƚĞ ϬϲͬϭϴͬϮϬϮϬ
`
`Review Completion Date 06/ 18/ 2020
`ƐƚĂďůŝƐŚĞĚͬWƌŽƉĞƌ EĂŵĞ DĞƚŽĐůŽƉƌĂŵŝĚĞ ŶĂƐĂů ƐƉƌĂLJ
`Established/Proper Name Metoclopramide nasal spray
`
`;WƌŽƉŽƐĞĚͿ dƌĂĚĞ EĂŵĞ 'ŝŵŽƚŝ
`(Proposed) Trade Name
`WŚĂƌŵĂĐŽůŽŐŝĐ ůĂƐƐ ŽƉĂŵŝŶĞͲϮ ƌĞĐĞƉƚŽƌ ĂŶƚĂŐŽŶŝƐƚ
`Pharmacologic Class
`ƉƉůŝĐĂŶƚ ǀŽŬĞ WŚĂƌŵĂ
`Applicant
`ŽƐĂŐĞ &Žƌŵ EĂƐĂů ƐƉƌĂLJ
`Dosage Form
`ƉƉůŝĐĂŶƚ WƌŽƉŽƐĞĚ ŽƐŝŶŐ
`dŚĞ ƌĞĐŽŵŵĞŶĚĞĚ 'ŝŵŽƚŝ ĚŽƐĞ ĨŽƌ ƚŚĞ ƚƌĞĂƚŵĞŶƚ ŽĨ ĂĐƵƚĞ ĂŶĚ
`Applicant Proposed Dosing The recommended Gimoti dose for the treatment of acute and
`ƌĞĐƵƌƌĞŶƚ ĚŝĂďĞƚŝĐ ŐĂƐƚƌŽƉĂƌĞƐŝƐ ŝƐ ϭϱ ŵŐ ϰ ƚŝŵĞƐ ĚĂŝůLJ ĨŽƌ Ϯ ƚŽ
`ZĞŐŝŵĞŶ
`Regimen
`recurrent diabetic gastroparesis is 15 mg 4 times daily for 2 to E5;
`ǁĞĞŬƐ͕ ĚĞƉĞŶĚŝŶŐ ŽŶ ƐLJŵƉƚŽŵĂƚŝĐ ƌĞƐƉŽŶƐĞ͘ ΀EŽƚĞ͗ ŽŶ :ƵŶĞ
`weeks, depending on symptomatic response. [Note: on June
`ϭϲ͕ ϮϬϮϬ͕ ƚŚĞ ƉƉůŝĐĂŶƚ ƌĞƋƵĞƐƚĞĚ ƚŽ ƌĞǀŝƐĞ ƚŚĞ ĚƵƌĂƚŝŽŶ ƚŽ Ϯ ƚŽ
`16, 2020, the Applicant requested to revise the duration to 2 to
`ϴ ǁĞĞŬƐ΁͘ &Žƌ ĂŶLJ ƐŝŶŐůĞ ĞƉŝƐŽĚĞ ŽĨ ŐĂƐƚƌŽƉĂƌĞƐŝƐ͕ ƚŚĞƌĞ ƐŚŽƵůĚ
`8 weeks]. For any single episode of gastroparesis, there should
`ďĞ ŶŽ ŵŽƌĞ ƚŚĂŶ ϭϮ ĐƵŵƵůĂƚŝǀĞ ǁĞĞŬƐ ŽĨ ŵĞƚŽĐůŽƉƌĂŵŝĚĞ
`be no more than 12 cumulative weeks of metoclopramide
`ĞdžƉŽƐƵƌĞ ;Ăůů ĚŽƐĂŐĞ ĨŽƌŵƐ ĂŶĚ ƌŽƵƚĞƐ ŽĨ ĂĚŵŝŶŝƐƚƌĂƚŝŽŶͿ
`ďĞĐĂƵƐĞ ŽĨ ƚŚĞ ŝŶĐƌĞĂƐĞĚ ƌŝƐŬ ŽĨ ĚĞǀĞůŽƉŝŶŐ d ǁŝƚŚ ůŽŶŐĞƌͲ
`because of the increased risk of developing TD with longer-
`ƚĞƌŵ ƵƐĞ͘ ĚŵŝŶŝƐƚĞƌ ƚŚĞ ĚŽƐĞ ϯϬ ŵŝŶƵƚĞƐ ďĞĨŽƌĞ ĞĂĐŚ ŵĞĂů
`term use. Administer the dose 30 minutes before each meal
`ĂŶĚ Ăƚ ďĞĚƚŝŵĞ͘ dŚĞ ŵĂdžŝŵƵŵ ƌĞĐŽŵŵĞŶĚĞĚ ĚĂŝůLJ ĚŽƐĞ ŝƐ
`and at bedtime. The maximum recommended daily dose is
`ϲϬ ŵŐ͘
`60 mg.
`ƉƉůŝĐĂŶƚ WƌŽƉŽƐĞĚ
`'ŝŵŽƚŝ ŝƐ ŝŶĚŝĐĂƚĞĚ ĨŽƌ ƚŚĞ ƌĞůŝĞĨ ŽĨ ƐLJŵƉƚŽŵƐ ŝŶ ĂĚƵůƚ ǁŽŵĞŶ
`/ŶĚŝĐĂƚŝŽŶ;ƐͿͬWŽƉƵůĂƚŝŽŶ;ƐͿ
`ǁŝƚŚ ĂĐƵƚĞ ĂŶĚ ƌĞĐƵƌƌĞŶƚ ĚŝĂďĞƚŝĐ ŐĂƐƚƌŽƉĂƌĞƐŝƐ
`lndication(s)/Population(s) with acute and recurrent diabetic gastroparesis
`ZĞĐŽŵŵĞŶĚĂƚŝŽŶ ŽŶ
`ƉƉƌŽǀĂů
`ZĞŐƵůĂƚŽƌLJ ĐƚŝŽŶ
`Regulatory Action
`ZĞĐŽŵŵĞŶĚĞĚ
`'ŝŵŽƚŝ ŝƐ ŝŶĚŝĐĂƚĞĚ ĨŽƌ ƚŚĞ ƌĞůŝĞĨ ŽĨ ƐLJŵƉƚŽŵƐ ŝŶ ĂĚƵůƚƐ ǁŝƚŚ
`Recommended Gimoti
`is indicated for the relief of symptoms in adults with
`/ŶĚŝĐĂƚŝŽŶ;ƐͿͬWŽƉƵůĂƚŝŽŶ;ƐͿ
`ĂĐƵƚĞ ĂŶĚ ƌĞĐƵƌƌĞŶƚ ĚŝĂďĞƚŝĐ ŐĂƐƚƌŽƉĂƌĞƐŝƐ͘
`lndication(s)/Population(s)
`acute and recurrent diabetic gastroparesis.
`;ŝĨ ĂƉƉůŝĐĂďůĞͿ
`(If appllcable) Limitations of Use:
`>ŝŵŝƚĂƚŝŽŶƐ ŽĨ hƐĞ͗
`'ŝŵŽƚŝ ŝƐ ŶŽƚ ƌĞĐŽŵŵĞŶĚĞĚ ĨŽƌ ƵƐĞ ŝŶ͗
`Gimoti is not recommended for use in:
`x ƉĞĚŝĂƚƌŝĐ ƉĂƚŝĞŶƚƐ ĚƵĞ ƚŽ ƚŚĞ ƌŝƐŬ ŽĨ ĚĞǀĞůŽƉŝŶŐ ƚĂƌĚŝǀĞ
`o pediatric patients due to the risk of developing tardive
`ĚLJƐŬŝŶĞƐŝĂ ;dͿ ĂŶĚ ŽƚŚĞƌ ĞdžƚƌĂƉLJƌĂŵŝĚĂů ƐLJŵƉƚŽŵƐ ĂƐ ǁĞůů
`dyskinesia (TD) and other extrapyramidal symptoms as well
`ĂƐ ƚŚĞ ƌŝƐŬ ŽĨ ŵĞƚŚĞŵŽŐůŽďŝŶĞŵŝĂ ŝŶ ŶĞŽŶĂƚĞƐ͘
`as the risk of methemoglobinemia in neonates.
`x ŵŽĚĞƌĂƚĞ Žƌ ƐĞǀĞƌĞ ŚĞƉĂƚŝĐ ŝŵƉĂŝƌŵĞŶƚ ;ŚŝůĚͲWƵŐŚ  Žƌ Ϳ͕
`moderate or severe hepatic impairment (Child-Pugh B or C),
`ŵŽĚĞƌĂƚĞ Žƌ ƐĞǀĞƌĞ ƌĞŶĂů ŝŵƉĂŝƌŵĞŶƚ ;ĐƌĞĂƚŝŶŝŶĞ ĐůĞĂƌĂŶĐĞ
`moderate or severe renal impairment (creatinine clearance
`ůĞƐƐ ƚŚĂŶ ϲϬ ŵ>ͬŵŝŶƵƚĞͿ͕ ĂŶĚ ƉĂƚŝĞŶƚƐ ĐŽŶĐƵƌƌĞŶƚůLJ ƵƐŝŶŐ
`less than 60 mL/minute), and patients concurrently using
`ƐƚƌŽŶŐ zWϮϲ ŝŶŚŝďŝƚŽƌƐ ĚƵĞ ƚŽ ƚŚĞ ƌŝƐŬ ŽĨ ŝŶĐƌĞĂƐĞĚ ĚƌƵŐ
`strong CYP2D6 inhibitors due to the risk of increased drug
`ĞdžƉŽƐƵƌĞ ĂŶĚ ĂĚǀĞƌƐĞ ƌĞĂĐƚŝŽŶƐ͘
`exposure and adverse reactions.
`
`
`
` exposure (all dosage forms and routes of administration)
`
`sĞƌƐŝŽŶ ĚĂƚĞ͗ KĐƚŽďĞƌ ϭϮ͕ ϮϬϭϴ
`Version date: October 12, 2018
`
`Reference ID: 4628132
`Reference ID: 4628132
`
`(b)
`(4)
`
`

`

`E ϮϬϵϯϴϴ
`NDA 209388
`'ŝŵŽƚŝ ;ŵĞƚŽĐůŽƉƌĂŵŝĚĞ ŶĂƐĂů ƐƉƌĂLJͿ
`Gimoti (metoclopramide nasal spray)
`ZĞĐŽŵŵĞŶĚĞĚ ŽƐŝŶŐ ĚƵůƚƐ >ĞƐƐ dŚĂŶ ϲϱ zĞĂƌƐ ŽĨ ŐĞ͗ dŚĞ ƌĞĐŽŵŵĞŶĚĞĚ ĚŽƐĂŐĞ
`Recommended Dosing Adults Less Than 65 Years onge: The recommended dosage
`ZĞŐŝŵĞŶ ŽĨ 'ŝŵŽƚŝ ĨŽƌ ƚŚĞ ƚƌĞĂƚŵĞŶƚ ŽĨ ĂĐƵƚĞ ĂŶĚ ƌĞĐƵƌƌĞŶƚ ĚŝĂďĞƚŝĐ
`Regimen
`of Gimoti for the treatment of acute and recurrent diabetic
`ŐĂƐƚƌŽƉĂƌĞƐŝƐ ŝŶ ĂĚƵůƚƐ ŝƐ ϭ ƐƉƌĂLJ ;ϭϱ ŵŐͿ ŝŶ ŽŶĞ ŶŽƐƚƌŝů͕
`gastroparesis in adults is 1 spray (15 mg) in one nostril,
`ϯϬ ŵŝŶƵƚĞƐ ďĞĨŽƌĞ ĞĂĐŚ ŵĞĂů ĂŶĚ Ăƚ ďĞĚƚŝŵĞ ;ŵĂdžŝŵƵŵ ŽĨ ĨŽƵƌ
`30 minutes before each meal and at bedtime (maximum of four
`ƚŝŵĞƐ ĚĂŝůLJͿ ĨŽƌ Ϯ ƚŽ ϴ ǁĞĞŬƐ͕ ĚĞƉĞŶĚŝŶŐ ŽŶ ƐLJŵƉƚŽŵĂƚŝĐ
`times daily) for 2 to 8 weeks, depending on symptomatic
`ƌĞƐƉŽŶƐĞ͘
`response.
`ĚƵůƚƐ ϲϱ zĞĂƌƐ ŽĨ ŐĞ ĂŶĚ KůĚĞƌ͗ ůĚĞƌůLJ ƉĂƚŝĞŶƚƐ ŵĂLJ ďĞ ŵŽƌĞ
`Adults 65 Years of Age and Older: Elderly patients may be more
`ƐĞŶƐŝƚŝǀĞ ƚŽ ƚŚĞ ĂĚǀĞƌƐĞ ĞĨĨĞĐƚƐ ŽĨ ŵĞƚŽĐůŽƉƌĂŵŝĚĞ ĂŶĚ ƌĞƋƵŝƌĞ
`sensitive to the adverse effects of metoclopramide and require
`Ă ůŽǁĞƌ ƐƚĂƌƚŝŶŐ͘ 'ŝŵŽƚŝ ŝƐ ŶŽƚ ƌĞĐŽŵŵĞŶĚĞĚ ŝŶ ŐĞƌŝĂƚƌŝĐ
`a lower starting. Gimoti is not recommended in geriatric
`ƉĂƚŝĞŶƚƐ ĂƐ ŝŶŝƚŝĂů ƚŚĞƌĂƉLJ͘
`patients as initial therapy.
`'ĞƌŝĂƚƌŝĐ ƉĂƚŝĞŶƚƐ ƌĞĐĞŝǀŝŶŐ ĂŶ ĂůƚĞƌŶĂƚŝǀĞ ŵĞƚŽĐůŽƉƌĂŵŝĚĞ
`Geriatric patients receiving an alternative metoclopramide
`ƉƌŽĚƵĐƚ Ăƚ Ă ƐƚĂďůĞ ĚŽƐĂŐĞ ŽĨ ϭϬ ŵŐ ĨŽƵƌ ƚŝŵĞƐ ĚĂŝůLJ ĐĂŶ ďĞ
`product at a stable dosage of 10 mg four times daily can be
`ƐǁŝƚĐŚĞĚ ƚŽ 'ŝŵŽƚŝ ϭ ƐƉƌĂLJ ;ϭϱ ŵŐͿ ŝŶ ŽŶĞ ŶŽƐƚƌŝů͕ ϯϬ ŵŝŶƵƚĞƐ
`switched to Gimoti 1 spray (15 mg) in one nostril, 30 minutes
`ďĞĨŽƌĞ ĞĂĐŚ ŵĞĂů ĂŶĚ Ăƚ ďĞĚƚŝŵĞ ;ŵĂdžŝŵƵŵ ĨŽƵƌ ƚŝŵĞƐ ĚĂŝůLJͿ
`before each meal and at bedtime (maximum four times daily)
`ĨŽƌ Ϯ ƚŽ ϴ ǁĞĞŬƐ͕ ĚĞƉĞŶĚŝŶŐ ŽŶ ƐLJŵƉƚŽŵĂƚŝĐ ƌĞƐƉŽŶƐĞ͘ ǀŽŝĚ
`for 2 to 8 weeks, depending on symptomatic response. Avoid
`ƚƌĞĂƚŵĞŶƚ ǁŝƚŚ ŵĞƚŽĐůŽƉƌĂŵŝĚĞ ;Ăůů ĚŽƐĂŐĞ ĨŽƌŵƐ ĂŶĚ ƌŽƵƚĞƐ
`treatment with metoclopramide (all dosage forms and routes
`ŽĨ ĂĚŵŝŶŝƐƚƌĂƚŝŽŶͿ ĨŽƌ ůŽŶŐĞƌ ƚŚĂŶ ϭϮ ǁĞĞŬƐ͘
`of administration) for longer than 12 weeks.
`
`
`
`sĞƌƐŝŽŶ ĚĂƚĞ͗ KĐƚŽďĞƌ ϭϮ͕ ϮϬϭϴ
`Version date: October 12, 2018
`
`Reference ID: 4628132
`Reference ID: 4628132
`
`

`

`E ϮϬϵϯϴϴ
`NDA 209388
`'ŝŵŽƚŝ ;ŵĞƚŽĐůŽƉƌĂŵŝĚĞ ŶĂƐĂů ƐƉƌĂLJͿ
`Gimoti (metoclopramide nasal spray)
`dĂďůĞ ŽĨ ŽŶƚĞŶƚƐ
`Table of Contents
`dĂďůĞ ŽĨ dĂďůĞƐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭ
`Table of Tables .................................................................................................................... 1
`dĂďůĞ ŽĨ &ŝŐƵƌĞƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ Ϯ
`Table of Figures ................................................................................................................... 2
`ZĞǀŝĞǁĞƌƐ ŽĨ DƵůƚŝͲŝƐĐŝƉůŝŶĂƌLJ ZĞǀŝĞǁ ĂŶĚ ǀĂůƵĂƚŝŽŶ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϯ
`Reviewers of Multi-Disciplinary Review and Evaluation .................................................... 3
`'ůŽƐƐĂƌLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϰ
`Glossary ............................................................................................................................... 4
`džĞĐƵƚŝǀĞ ^ƵŵŵĂƌLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϱ
`1. Executive Summary ....................................................................................................... 5
`WƌŽĚƵĐƚ /ŶƚƌŽĚƵĐƚŝŽŶ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϱ
`1.1. Product Introduction .............................................................................................. 5
`ŽŶĐůƵƐŝŽŶƐ ŽŶ ƚŚĞ ^ƵďƐƚĂŶƚŝĂů ǀŝĚĞŶĐĞ ŽĨ ĨĨĞĐƚŝǀĞŶĞƐƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϲ
`1.2. Conclusions on the Substantial Evidence of Effectiveness ..................................... 6
`ĞŶĞĨŝƚͲZŝƐŬ ƐƐĞƐƐŵĞŶƚ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϴ
`1.3. Benefit-Risk Assessment ......................................................................................... 8
`WĂƚŝĞŶƚ džƉĞƌŝĞŶĐĞ ĂƚĂ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϲ
`1.4. Patient Experience Data ........................................................................................ 16
`ZĞŐƵůĂƚŽƌLJ ĂĐŬŐƌŽƵŶĚ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϳ
`2. Regulatory Background ............................................................................................... 17
`h͘^͘ ZĞŐƵůĂƚŽƌLJ ĐƚŝŽŶƐ ĂŶĚ DĂƌŬĞƚŝŶŐ ,ŝƐƚŽƌLJ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϳ
`2.1. US. Regulatory Actions and Marketing History ................................................... 17
`^ƵŵŵĂƌLJ ŽĨ WƌĞƐƵďŵŝƐƐŝŽŶͬ^ƵďŵŝƐƐŝŽŶ ZĞŐƵůĂƚŽƌLJ ĐƚŝǀŝƚLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϳ
`2.2. Summary of Presubmission/Submission Regulatory Activity ............................... 17
`^ŝŐŶŝĨŝĐĂŶƚ /ƐƐƵĞƐ ĨƌŽŵ KƚŚĞƌ ZĞǀŝĞǁ ŝƐĐŝƉůŝŶĞƐ WĞƌƚŝŶĞŶƚ ƚŽ ůŝŶŝĐĂů
`3. Significant Issues from Other Review Disciplines Pertinent to Clinical
`ŽŶĐůƵƐŝŽŶƐ ŽŶ ĨĨŝĐĂĐLJ ĂŶĚ ^ĂĨĞƚLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϮϬ
`Conclusions on Efficacy and Safety ............................................................................. 20
`KĨĨŝĐĞ ŽĨ ^ĐŝĞŶƚŝĨŝĐ /ŶǀĞƐƚŝŐĂƚŝŽŶƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϮϬ
`3.1. Office of Scientific Investigations .......................................................................... 20
`WƌŽĚƵĐƚ YƵĂůŝƚLJ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϮϬ
`3.2. Product Quality ..................................................................................................... 20
`ůŝŶŝĐĂů DŝĐƌŽďŝŽůŽŐLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ Ϯϭ
`3.3. Clinical Microbiology ............................................................................................. 21
`ĞǀŝĐĞƐ ĂŶĚ ŽŵƉĂŶŝŽŶ ŝĂŐŶŽƐƚŝĐ /ƐƐƵĞƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ Ϯϭ
`3.4. Devices and Companion Diagnostic Issues ........................................................... 21
`EŽŶĐůŝŶŝĐĂů WŚĂƌŵĂĐŽůŽŐLJͬdŽdžŝĐŽůŽŐLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϮϮ
`4. Nonclinical Pharmacology/Toxicology ........................................................................ 22
`ůŝŶŝĐĂů WŚĂƌŵĂĐŽůŽŐLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϮϮ
`5. Clinical Pharmacology ................................................................................................. 22
`džĞĐƵƚŝǀĞ ^ƵŵŵĂƌLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϮϮ
`5.1. Executive Summary ............................................................................................... 22
`^ƵŵŵĂƌLJ ŽĨ ůŝŶŝĐĂů WŚĂƌŵĂĐŽůŽŐLJ ƐƐĞƐƐŵĞŶƚ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ Ϯϰ
`5.2. Summary of Clinical Pharmacology Assessment .................................................. 24
`WŚĂƌŵĂĐŽůŽŐLJ ĂŶĚ ůŝŶŝĐĂů WŚĂƌŵĂĐŽŬŝŶĞƚŝĐƐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ Ϯϰ
`5.2.1. Pharmacology and Clinical Pharmacokinetics ............................................... 24
`'ĞŶĞƌĂů ŽƐŝŶŐ ĂŶĚ dŚĞƌĂƉĞƵƚŝĐ /ŶĚŝǀŝĚƵĂůŝnjĂƚŝŽŶ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ Ϯϱ
`5.2.2. General Dosing and Therapeutic Individualization ....................................... 25
`ŽŵƉƌĞŚĞŶƐŝǀĞ ůŝŶŝĐĂů WŚĂƌŵĂĐŽůŽŐLJ ZĞǀŝĞǁ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ Ϯϳ
`5.3. Comprehensive Clinical Pharmacology Review .................................................... 27
`ZĞǀŝĞǁ ŽĨ ƚŚĞ ZŽŽƚ ĂƵƐĞ ŶĂůLJƐŝƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ Ϯϳ
`5.3.1. Review of the Root Cause Analysis ................................................................ 27
`ZĞĂŶĂůLJƐŝƐ ŽĨ WŚĂƌŵĂĐŽŬŝŶĞƚŝĐƐ ŽĨ DdKͲ/EͲϬϬϲ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϯϬ
`5.3.2. Reanalysis of Pharmacokinetics of METO-IN-006 ......................................... 30
`ůŝŶŝĐĂů WŚĂƌŵĂĐŽůŽŐLJ YƵĞƐƚŝŽŶƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϯϯ
`5.3.3. Clinical Pharmacology Questions ................................................................... 33
`^ŽƵƌĐĞƐ ŽĨ ůŝŶŝĐĂů ĂƚĂ ĂŶĚ ZĞǀŝĞǁ ^ƚƌĂƚĞŐLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϯϰ
`6. Sources of Clinical Data and Review Strategy............................................................. 34
`^ŽƵƌĐĞƐ ŽĨ ůŝŶŝĐĂů /ŶĨŽƌŵĂƚŝŽŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϯϰ
`6.1. Sources of Clinical Information ............................................................................. 34
`ZĞǀŝĞǁ ^ƚƌĂƚĞŐLJ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϯϱ
`6.2. Review Strategy .................................................................................................... 35
`ůŝŶŝĐĂů ƐƐĞƐƐŵĞŶƚƐ ŽĨ Z /ƐƐƵĞƐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϯϱ
`7. Clinical Assessments of CR Issues ............................................................................... 35
`ZĞǀŝĞǁ ŽĨ ƚŚĞ ZŽŽƚ ĂƵƐĞ ŶĂůLJƐŝƐ ZĞƉŽƌƚ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϯϱ
`7.1. Review of the Root Cause Analysis Report ........................................................... 35
`WĂƚŝĞŶƚ džƉĞƌŝĞŶĐĞ ^ƵŵŵĂƌLJ ZĞƉŽƌƚ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϯϲ
`7.1.1. Patient Experience Summary Report ............................................................. 36
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`sĞƌƐŝŽŶ ĚĂƚĞ͗ KĐƚŽďĞƌ ϭϮ͕ ϮϬϭϴ
`Version date: October 12, 2018
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`Reference ID: 4628132
`Reference ID: 4628132
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`E ϮϬϵϯϴϴ
`NDA 209388
`'ŝŵŽƚŝ ;ŵĞƚŽĐůŽƉƌĂŵŝĚĞ ŶĂƐĂů ƐƉƌĂLJͿ
`Gimoti (metoclopramide nasal spray)
`ŝƌĞĐƚŝŽŶƐ ĨŽƌ hƐĞ ĂŶĚ ŽƐĞ ĚŵŝŶŝƐƚƌĂƚŽƌ dƌĂŝŶŝŶŐ ŝŶ ƚŚĞ
`7.1.2. Directions for Use and Dose Administrator Training in the
`ŽŵƉĂƌĂƚŝǀĞ ŝŽĂǀĂŝůĂďŝůŝƚLJ ^ƚƵĚLJ ;DdKͲ/EͲϬϬϲͿ WƌŽƚŽĐŽů͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϯϵ
`Comparative Bioavailability Study (METO-lN-006) Protocol ......................... 39
`ůŝŶŝĐĂů džƉĞƌŝĞŶĐĞͶdƌĂŝŶŝŶŐ ĨŽƌ WŚĂƐĞ ϯ ůŝŶŝĐĂů dƌŝĂů WĂƚŝĞŶƚƐ ĨŽƌ
`7.1.3. Clinical Experience—Training for Phase 3 Clinical Trial Patients for
`^ĞůĨͲĂĚŵŝŶŝƐƚƌĂƚŝŽŶ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϰϬ
`Self-ad ministration ........................................................................................ 40
`ŽŶĐůƵƐŝŽŶƐ ŽŶ ƚŚĞ ZŽŽƚ ĂƵƐĞ ŶĂůLJƐŝƐ &ŝŶĚŝŶŐƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϰϮ
`7.1.4. Conclusions on the Root Cause Analysis Findings ......................................... 42
`ůŝŶŝĐĂů ǀĂůƵĂƚŝŽŶ ŽĨ ^ĂĨĞƚLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϰϮ
`8. Clinical Evaluation of Safety ........................................................................................ 42
`ZĞǀŝĞǁ ŽĨ ^ĂĨĞƚLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϰϮ
`8.1. Review of Safety.................................................................................................... 42
`ŽŶĐůƵƐŝŽŶƐ ĂŶĚ ZĞĐŽŵŵĞŶĚĂƚŝŽŶƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϰϯ
`8.2. Conclusions and Recommendations ..................................................................... 43
`ĚǀŝƐŽƌLJ ŽŵŵŝƚƚĞĞ DĞĞƚŝŶŐ ĂŶĚ KƚŚĞƌ džƚĞƌŶĂů ŽŶƐƵůƚĂƚŝŽŶƐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϰϰ
`9. Advisory Committee Meeting and Other External Consultations .............................. 44
`WĞĚŝĂƚƌŝĐƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϰϰ
`10. Pediatrics ..................................................................................................................... 44
`>ĂďĞůŝŶŐ ZĞĐŽŵŵĞŶĚĂƚŝŽŶƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϰϰ
`11. Labeling Recommendations ........................................................................................ 44
`WƌĞƐĐƌŝƉƚŝŽŶ ƌƵŐ >ĂďĞůŝŶŐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϰϰ
`11.1.Prescription Drug Labeling .................................................................................... 44
`KƚŚĞƌ WƌĞƐĐƌŝƉƚŝŽŶ ƌƵŐ >ĂďĞůŝŶŐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϰϳ
`11.2.0ther Prescription Drug Labeling ......................................................................... 47
`ZŝƐŬ ǀĂůƵĂƚŝŽŶ ĂŶĚ DŝƚŝŐĂƚŝŽŶ ^ƚƌĂƚĞŐŝĞƐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϰϳ
`12. Risk Evaluation and Mitigation Strategies .................................................................. 47
`WŽƐƚŵĂƌŬĞƚŝŶŐ ZĞƋƵŝƌĞŵĞŶƚƐ ĂŶĚ ŽŵŵŝƚŵĞŶƚ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϰϴ
`13. Postmarketing Requirements and Commitment ........................................................ 48
`ĞƉƵƚLJ ŝǀŝƐŝŽŶ ŝƌĞĐƚŽƌ ĨŽƌ ^ĂĨĞƚLJ ;ůŝŶŝĐĂůͿ ŽŵŵĞŶƚƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϰϵ
`14. Deputy Division Director for Safety (Clinical) Comments ........................................... 49
`ƉƉĞŶĚŝĐĞƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϱϬ
`15. Appendices .................................................................................................................. 50
`KW ƉƉĞŶĚŝĐĞƐ ;dĞĐŚŶŝĐĂů ŽĐƵŵĞŶƚƐ ^ƵƉƉŽƌƚŝŶŐ KW
`15.1.0CP Appendices (Technical Documents Supporting OCP
`ZĞĐŽŵŵĞŶĚĂƚŝŽŶƐͿ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϱϬ
`Recommendations) ............................................................................................... 50
`ďĞƌƌĂŶƚ W< WƌŽĨŝůĞƐ ĐƌŽƐƐ ^ƚƵĚŝĞƐ tŝƚŚ W< ĂƚĂ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϱϬ
`15.1.1. Aberrant PK Profiles Across Studies With PK Data ........................................ 50
`ZĞĂŶĂůLJƐŝƐ ŽĨ DdKͲ/EͲϬϬϲ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϱϰ
`15.1.2. Reanalysis of METO-lN-006 ........................................................................... 54
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`sĞƌƐŝŽŶ ĚĂƚĞ͗ KĐƚŽďĞƌ ϭϮ͕ ϮϬϭϴ
`Version date: October 12, 2018
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`ŝŝ
`ll
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`Reference ID: 4628132
`Reference ID: 4628132
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`

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`E ϮϬϵϯϴϴ
`'ŝŵŽƚŝ ;ŵĞƚŽĐůŽƉƌĂŵŝĚĞ ŶĂƐĂů ƐƉƌĂLJͿ
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` Table of Tables
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`dĂďůĞ ϭ͘ ZĞĐŽŵŵĞŶĚĞĚ ŽƐĞ ĚũƵƐƚŵĞŶƚ ĨŽƌ 'ŝŵŽƚŝ ŽŵƉĂƌĞĚ ƚŽ ZĞŐůĂŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ Ϯϲ
`dĂďůĞ Ϯ͘ /ŶĐŝĚĞŶĐĞ ŽĨ >Žǁ džƉŽƐƵƌĞ ĐƌŽƐƐ ůŝŶŝĐĂů ^ƚƵĚŝĞƐ ŽĨ 'ŝŵŽƚŝ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ Ϯϵ
`dĂďůĞ ϯ͘ ^ƵŵŵĂƌLJ ŽĨ <ĞLJ W< WĂƌĂŵĞƚĞƌƐ ĨŽƌ DĞƚŽĐůŽƉƌĂŵŝĚĞ ŝŶ DdKͲ/EͲϬϬϲ
`džĐůƵĚŝŶŐ ϭϭ W< WƌŽĨŝůĞƐ tŝƚŚ ŵĂdž фϱ ŶŐͬŵ> ŝŶ ŽŵƉĂƌŝƐŽŶ ƚŽ ƚŚĞ KƌŝŐŝŶĂů
`ZĞƐƵůƚƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϯϬ
`dĂďůĞ ϰ͘ ŝŽĞƋƵŝǀĂůĞŶĐĞ ŶĂůLJƐŝƐ džĐůƵĚŝŶŐ ϭϭ W< WƌŽĨŝůĞƐ tŝƚŚ ŵĂdž фϱ ŶŐͬŵ> ŝŶ
`ŽŵƉĂƌŝƐŽŶ ƚŽ ƚŚĞ KƌŝŐŝŶĂů  ŶĂůLJƐŝƐ ŝŶ DdKͲ/EͲϬϬϲ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϯϮ
`dĂďůĞ ϱ͘ ^ƵŵŵĂƌLJ ŽĨ ŽƐĞƐ ĚŵŝŶŝƐƚĞƌĞĚ ĂŶĚ EƵŵďĞƌ ŽĨ W< WƌŽĨŝůĞƐ ǁŝƚŚ >Žǁ ƌƵŐ
`ďƐŽƌƉƚŝŽŶͶŽŵƉĂƌĂƚŝǀĞ  ^ƚƵĚLJ DdKͲ/EͲϬϬϲ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϯϵ
`dĂďůĞ ϲ͘ WĂƚŝĞŶƚƐ tŝƚŚ WŽƐƚͲĚŽƐĞ ŽŶĐĞŶƚƌĂƚŝŽŶ фϱ ŶŐͬŵ> ŝŶ DdKͲ/EͲϬϬϮ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϱϯ
`dĂďůĞ ϳ͘ WĂƚŝĞŶƚƐ tŝƚŚ WŽƐƚͲĚŽƐĞ ŽŶĐĞŶƚƌĂƚŝŽŶ фϱ ŶŐͬŵ> ŝŶ DdKͲ/EͲϬϬϯ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϱϰ
`dĂďůĞ ϴ͘ dŚĞ W< ĂƚĂƐĞƚ ŝŶ ƚŚĞ KƌŝŐŝŶĂů ŶĂůLJƐŝƐ ŽĨ DdKͲ/EͲϬϬϲ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϱϱ
`dĂďůĞ ϵ͘ dŚĞ W< ĂƚĂƐĞƚ ŝŶ ƚŚĞ ZĞĂŶĂůLJƐŝƐ ŽĨ DdKͲ/EͲϬϬϲ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϱϲ
`dĂďůĞ ϭϬ͘ ZĞǀŝĞǁĞƌ͛Ɛ ŶĂůLJƐŝƐ ĨŽƌ DĞƚŽĐůŽƉƌĂŵŝĚĞ ŝŽĞƋƵŝǀĂůĞŶĐĞ ŶĂůLJƐĞƐ
`džĐůƵĚŝŶŐ ϭϭ W< WƌŽĨŝůĞƐ ǁŝƚŚ ŵĂdž фϱ ŶŐͬŵ>͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϱϳ
`dĂďůĞ ϭϭ͘ ZĞǀŝĞǁĞƌ͛Ɛ ŶĂůLJƐŝƐ ĨŽƌ DĞƚŽĐůŽƉƌĂŵŝĚĞ ŝŽĞƋƵŝǀĂůĞŶĐĞ ŶĂůLJƐĞƐ tŝƚŚ
`ĂƚĂ &ƌŽŵ ^ƵďũĞĐƚƐ tŚŽ ŽŵƉůĞƚĞĚ ůů &ŽƵƌ WĞƌŝŽĚƐ KŶůLJ͕ džĐůƵĚŝŶŐ ϭϭ W<
`WƌŽĨŝůĞƐ tŝƚŚ ŵĂdž фϱ ŶŐͬŵ> ŝŶ ŽŵƉĂƌŝƐŽŶ ƚŽ ƚŚĞ KƌŝŐŝŶĂů ZĞƐƵůƚƐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϱϳ
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`sĞƌƐŝŽŶ ĚĂƚĞ͗ KĐƚŽďĞƌ ϭϮ͕ ϮϬϭϴ
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`ϭ
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`Reference ID: 4628132
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`

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`E ϮϬϵϯϴϴ
`'ŝŵŽƚŝ ;ŵĞƚŽĐůŽƉƌĂŵŝĚĞ ŶĂƐĂů ƐƉƌĂLJͿ
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` Table of Figures
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`&ŝŐƵƌĞ ϭ͘ ^ƉĂŐŚĞƚƚŝ WůŽƚƐ ŽĨ /ŶĚŝǀŝĚƵĂů dŝŵĞͲDĞƚŽĐůŽƉƌĂŵŝĚĞ ŽŶĐĞŶƚƌĂƚŝŽŶ WƌŽĨŝůĞƐ
`ŝŶ DdKͲ/EͲϬϬϭ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϱϬ
`&ŝŐƵƌĞ Ϯ͘ ^ƉĂŐŚĞƚƚŝ WůŽƚƐ ŽĨ /ŶĚŝǀŝĚƵĂů dŝŵĞͲŽŶĐĞŶƚƌĂƚŝŽŶ WƌŽĨŝůĞƐ ŝŶ DdKͲ/EͲϬϬϱ͘͘͘͘͘ ϱϭ
`&ŝŐƵƌĞ ϯ͘ ^ƉĂŐŚĞƚƚŝ WůŽƚƐ ŽĨ /ŶĚŝǀŝĚƵĂů dŝŵĞͲDĞƚŽĐůŽƉƌĂŵŝĚĞ ŽŶĐĞŶƚƌĂƚŝŽŶ WƌŽĨŝůĞƐ
`ŝŶ DdKͲ/EͲϬϬϲ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϱϮ
`&ŝŐƵƌĞ ϰ͘ ŝƐƚƌŝďƵƚŝŽŶ ŽĨ ŵĂdž ĂŶĚ h ďLJ dƌĞĂƚŵĞŶƚ ŝŶ DdKͲ/EͲϬϬϲ džĐůƵĚŝŶŐ ϭϭ W<
`WƌŽĨŝůĞƐ tŝƚŚ ŵĂdž фϱ ŶŐͬŵ>͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϱϴ
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`sĞƌƐŝŽŶ ĚĂƚĞ͗ KĐƚŽďĞƌ ϭϮ͕ ϮϬϭϴ
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`Ϯ
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`Reference ID: 4628132
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`

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`E ϮϬϵϯϴϴ
`'ŝŵŽƚŝ ;ŵĞƚŽĐůŽƉƌĂŵŝĚĞ ŶĂƐĂů ƐƉƌĂLJͿ
`Reviewers of Multi-Disciplinary Review and Evaluation
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`ZĞŐƵůĂƚŽƌLJ WƌŽũĞĐƚ DĂŶĂŐĞƌ
`KĨĨŝĐĞ ŽĨ ůŝŶŝĐĂů WŚĂƌŵĂĐŽůŽŐLJ ZĞǀŝĞǁĞƌ;ƐͿ
`KĨĨŝĐĞ ŽĨ ůŝŶŝĐĂů WŚĂƌŵĂĐŽůŽŐLJ dĞĂŵ >ĞĂĚĞƌ;ƐͿ
`ůŝŶŝĐĂů ZĞǀŝĞǁĞƌ
`ůŝŶŝĐĂů dĞĂŵ >ĞĂĚĞƌ
`ƌŽƐƐͲŝƐĐŝƉůŝŶĂƌLJ dĞĂŵ >ĞĂĚĞƌ
`ŝǀŝƐŝŽŶ ŝƌĞĐƚŽƌ ;KWͿ
`ĞƉƵƚLJ ŝƌĞĐƚŽƌ ĨŽƌ ^ĂĨĞƚLJ ;ŝǀŝƐŝŽŶ ŽĨ
`'ĂƐƚƌŽĞŶƚĞƌŽůŽŐLJͿ
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`DĂƵƌĞĞŶ ĞǁĞLJ
`^ŽũĞŽŶŐ zŝ
`/ŶƐŽŽŬ <ŝŵ
`^ĂŶĚŚLJĂ ƉƉĂƌĂũƵ
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`Additional Reviewers of Application
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`EŽŶĐůŝŶŝĐĂů ZĞǀŝĞǁĞƌ
`<ĞŶƌŝĐŬ ^ĞŵƉůĞ
`EŽŶĐůŝŶŝĐĂů dĞĂŵ >ĞĂĚĞƌ
`^ƵƐŚĂŶƚĂ ŚĂŬĚĞƌ
`KWY
`ĂƌŽůŝŶĞ ^ƚƌĂƐŝŶŐĞƌ͖ <ĂƚŚĞƌŝŶĞ ƵŶĐĂŶ
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`WĞƚĞƌ <ƌŽŵŵĞŶŚŽĞŬ
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`ĂƌŽůLJŶ zĂŶĐĞLJ͖ dĂŵŵLJ >ĂƐŬLJ͖ <ƌŝƐƚĞŶ ĂŝƐĚĞŶ
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`Reference ID: 4628132
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`E ϮϬϵϯϴϴ
`'ŝŵŽƚŝ ;ŵĞƚŽĐůŽƉƌĂŵŝĚĞ ŶĂƐĂů ƐƉƌĂLJͿ
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` Glossary
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`ĐƚŝǀĞ ZŝƐŬ /ĚĞŶƚŝĨŝĐĂƚŝŽŶ ĂŶĚ ŶĂůLJƐŝƐ
`ĂƌĞĂ ƵŶĚĞƌ ƚŚĞ ĐƵƌǀĞ
`ďŝŽĂǀĂŝůĂďŝůŝƚLJ
`ďŝŽĞƋƵŝǀĂůĞŶĐĞ
`ĞŶƚĞƌ ĨŽƌ ĞǀŝĐĞƐ ĂŶĚ ZĂĚŝŽůŽŐŝĐĂů ,ĞĂůƚŚ
`ŵĂdžŝŵƵŵ ƉůĂƐŵĂ ĐŽŶĐĞŶƚƌĂƚŝŽŶ
`ĐĞŶƚƌĂů ŶĞƌǀŽƵƐ ƐLJƐƚĞŵ
`ŽŵƉůĞƚĞ ZĞƐƉŽŶƐĞ
`ŽĐƵŵĞŶƚ ƌĐŚŝǀŝŶŐ͕ ZĞƉŽƌƚŝŶŐ ĂŶĚ ZĞŐƵůĂƚŽƌLJ dƌĂĐŬŝŶŐ ^LJƐƚĞŵ
`ŝǀŝƐŝŽŶ ŽĨ ƉŝĚĞŵŝŽůŽŐLJ
`ĞdžƚƌĂƉLJƌĂŵŝĚĂů ƐLJŵƉƚŽŵƐ
`&ŽŽĚ ĂŶĚ ƌƵŐ ĚŵŝŶŝƐƚƌĂƚŝŽŶ
`ŐĂƐƚƌŽŝŶƚĞƐƚŝŶĂů
`ŐĂƐƚƌŽƉĂƌĞƐŝƐ
`/ŶǀĞƐƚŝŐĂƚŝŽŶĂů EĞǁ ƌƵŐ
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`ŶĞǁ ĚƌƵŐ ĂƉƉůŝĐĂƚŝŽŶ
`ŶĞƵƌŽůĞƉƚŝĐ ŵĂůŝŐŶĂŶƚ ƐLJŶĚƌŽŵĞ
`KĨĨŝĐĞ ŽĨ ůŝŶŝĐĂů WŚĂƌŵĂĐŽůŽŐLJ
`ƉŚĂƌŵĂĐŽŬŝŶĞƚŝĐƐ
`ƉŽƐƚŵĂƌŬĞƚŝŶŐ ĐŽŵŵŝƚŵĞŶƚ
`ƉŽƐƚŵĂƌŬĞƚŝŶŐ ƌĞƋƵŝƌĞŵĞŶƚ
`ƚĂƌĚŝǀĞ ĚLJƐŬŝŶĞƐŝĂ
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`sĞƌƐŝŽŶ ĚĂƚĞ͗ KĐƚŽďĞƌ ϭϮ͕ ϮϬϭϴ
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`Reference ID: 4628132
`
`

`

`E ϮϬϵϯϴϴ
`'ŝŵŽƚŝ ;ŵĞƚŽĐůŽƉƌĂŵŝĚĞ ŶĂƐĂů ƐƉƌĂLJͿ
`
` Executive Summary
`
`Product Introduction
`
`E ϮϬϵϯϴϴ ĨŽƌ 'ŝŵŽƚŝ ;ŵĞƚŽĐůŽƉƌĂŵŝĚĞ ŚLJĚƌŽĐŚůŽƌŝĚĞͿ ŶĂƐĂů ƐƉƌĂLJ ǁĂƐ ŝŶŝƚŝĂůůLJ ƐƵďŵŝƚƚĞĚ ŽŶ
`:ƵŶĞ ϭ͕ ϮϬϭϴ ĂŶĚ ƌĞĐĞŝǀĞĚ Ă ŽŵƉůĞƚĞ ZĞƐƉŽŶƐĞ ;ZͿ ĂĐƚŝŽŶ ŽŶ Ɖƌŝů ϭ͕ ϮϬϭϵ͘ &Žƌ ĨƵůů ĚĞƚĂŝůƐ ŽĨ
`ƚŚĞ ĨŝƌƐƚ ƌĞǀŝĞǁ ĐLJĐůĞ͕ ƌĞĨĞƌ ƚŽ ƚŚĞ ŵƵůƚŝĚŝƐĐŝƉůŝŶĂƌLJ ƌĞǀŝĞǁ ŵĞŵŽ͕ ĚĂƚĞĚ DĂƌĐŚ Ϯϵ͕ ϮϬϭϵ͘ dŚĞ
`ĨŽĐƵƐ ŽĨ ƚŚŝƐ ŵĞŵŽ ŝƐ ƚŚĞ ƌĞƐƵďŵŝƐƐŝŽŶ ŽĨ E ϮϬϵϯϴϴ͕ ƌĞĐĞŝǀĞĚ ŽŶ ĞĐĞŵďĞƌ ϭϵ͕ ϮϬϭϵ͕ ƚŚĂƚ
`ƌĞƐƉŽŶĚƐ ƚŽ ƚŚĞ ĚĞĨŝĐŝĞŶĐŝĞƐ ŝĚĞŶƚŝĨŝĞĚ ŝŶ ƚŚĞ Z >ĞƚƚĞƌ͘ dŚĞ ƉƌŽƉŽƐĞĚ ƌĞŐƵůĂƚŽƌLJ ƉĂƚŚǁĂLJ ĨŽƌ
`ĂƉƉƌŽǀĂů ŝƐ ^ĞĐƚŝŽŶ ϱϬϱ;ďͿ;ϮͿ ŽĨ ƚŚĞ &ĞĚĞƌĂů &ŽŽĚ ƌƵŐ ĂŶĚ ŽƐŵĞƚŝĐ Đƚ͕ ƌĞůLJŝŶŐ ƵƉŽŶ ƚŚĞ
`ŐĞŶĐLJ͛Ɛ ƉƌĞǀŝŽƵƐ ĨŝŶĚŝŶŐƐ ŽĨ ƐĂĨĞƚLJ ĂŶĚ ĞĨĨĞĐƚŝǀĞŶĞƐƐ ĨŽƌ ƚŚĞ ůŝƐƚĞĚ ĚƌƵŐ͕ ZĞŐůĂŶ
`;ŵĞƚŽĐůŽƉƌĂŵŝĚĞ ŚLJĚƌŽĐŚůŽƌŝĚĞͿ ϭϬ ŵŐ ŽƌĂů ƚĂďůĞƚƐ ;E ϭϳϴϱϰͿ͘
`
`DĞƚŽĐůŽƉƌĂŵŝĚĞ͕ Ă ƐLJŶƚŚĞƚŝĐ ƐƵďƐƚŝƚƵƚĞĚ ďĞŶnjĂŵŝĚĞ ĂŶĚ ŝƐ Ă ĚŽƉĂŵŝŶĞͲϮ ƌĞĐĞƉƚŽƌ ĂŶƚĂŐŽŶŝƐƚ͕
`ŝƐ ĂƉƉƌŽǀĞĚ ĨŽƌ ƚŚĞ ƚƌĞĂƚŵĞŶƚ ŽĨ ĚŝĂďĞƚŝĐ ŐĂƐƚƌŽƉĂƌĞƐŝƐ ĂŶĚ ŝƐ ĂǀĂŝůĂďůĞ ĂƐ ĂŶ ŽƌĂů ƚĂďůĞƚ͕ ŽƌĂů
`ƐŽůƵƚŝŽŶ͕ ŝŶũĞĐƚĂďůĞ͕ ĂŶĚ ĂƐ ĂŶ ŽƌĂůůLJ ĚŝƐƐŽůǀŝŶŐ ƚĂďůĞƚ ĨŽƌŵƵůĂƚŝŽŶ͘ DĞƚŽĐůŽƉƌĂŵŝĚĞ ŝƐ ƚŚŽƵŐŚƚ
`ƚŽ ďĞ Ă ƐƚŝŵƵůĂŶƚ ŽĨ ƵƉƉĞƌ ŐĂƐƚƌŽŝŶƚĞƐƚŝŶĂů ;'/Ϳ ŵŽƚŝůŝƚLJ͖ ŚŽǁĞǀĞƌ͕ ƚŚĞ ĞdžĂĐƚ ŵĞĐŚĂŶŝƐŵ ŽĨ
`ĂĐƚŝŽŶ ŽĨ ŵĞƚŽĐůŽƉƌĂŵŝĚĞ ŝŶ ƚŚĞ ƚƌĞĂƚŵĞŶƚ ŽĨ ĂĐƵƚĞ ĂŶĚ ƌĞĐƵƌƌĞŶƚ ĚŝĂďĞƚŝĐ ŐĂƐƚƌŽƉĂƌĞƐŝƐ ŚĂƐ
`ŶŽƚ ďĞĞŶ ĨƵůůLJ ĞƐƚĂďůŝƐŚĞĚ͘ DĞƚŽĐůŽƉƌĂŵŝĚĞ ƐĞĞŵƐ ƚŽ ƐĞŶƐŝƚŝnjĞ ƚŝƐƐƵĞƐ ƚŽ ƚŚĞ ĂĐƚŝŽŶ ŽĨ
`ĂĐĞƚLJůĐŚŽůŝŶĞ͕ ŝŶĐƌĞĂƐĞƐ ƚŚĞ ƚŽŶĞ ĂŶĚ ĂŵƉůŝƚƵĚĞ ŽĨ ŐĂƐƚƌŝĐ ;ĞƐƉĞĐŝĂůůLJ ĂŶƚƌĂůͿ ĐŽŶƚƌĂĐƚŝŽŶƐ͕
`ƌĞůĂdžĞƐ ƚŚĞ ƉLJůŽƌŝĐ ƐƉŚŝŶĐƚĞƌ ĂŶĚ ĚƵŽĚĞŶĂů ďƵůď͕ ĂŶĚ ŝŶĐƌĞĂƐĞƐ ƉĞƌŝƐƚĂůƐŝƐ ŽĨ ƚŚĞ ĚƵŽĚĞŶƵŵ ĂŶĚ
`ũĞũƵŶƵŵ͕ ƚŚƵƐ ƌĞƐƵůƚŝŶŐ ŝŶ ĂĐĐĞůĞƌĂƚĞĚ ŐĂƐƚƌŝĐ ĞŵƉƚLJŝŶŐ ĂŶĚ ŝŶƚĞƐƚŝŶĂů ƚƌĂŶƐŝƚ͘ϭ
`
`dŚĞ ůĂďĞůŝŶŐ ĨŽƌ ĂƉƉƌŽǀĞĚ ŵĞƚŽĐůŽƉƌĂŵŝĚĞ ƉƌŽĚƵĐƚƐ ŝŶĐůƵĚĞƐ Ă ŽdžĞĚ tĂƌŶŝŶŐ ĨŽƌ ƚĂƌĚŝǀĞ
`ĚLJƐŬŝŶĞƐŝĂ ;dͿ͘ d ŝƐ Ă ĐĞŶƚƌĂů ŶĞƌǀŽƵƐ ƐLJƐƚĞŵ ;E^Ϳ ĂĚǀĞƌƐĞ ĞǀĞŶƚ ĂŶĚ ŝƐ Ă ƐLJŶĚƌŽŵĞ ŽĨ
`ƉŽƚĞŶƚŝĂůůLJ ŝƌƌĞǀĞƌƐŝďůĞ ĂŶĚ ĚŝƐĨŝŐƵƌŝŶŐ ŝŶǀŽůƵŶƚĂƌLJ ŵŽǀĞŵĞŶƚƐ ŽĨ ƚŚĞ ĨĂĐĞ Žƌ ƚŽŶŐƵĞ͕ ĂŶĚ
`ƐŽŵĞƚŝŵĞƐ ŽĨ ƚŚĞ ƚƌƵŶŬ ĂŶĚͬŽƌ ĞdžƚƌĞŵŝƚŝĞƐ͘ dŚĞ ƌŝƐŬ ŽĨ ĚĞǀĞůŽƉŝŶŐ d ĂŶĚ ƚŚĞ ůŝŬĞůŝŚŽŽĚ ƚŚĂƚ d
`ǁŝůů ďĞĐŽŵĞ ŝƌƌĞǀĞƌƐŝďůĞ ŝŶĐƌĞĂƐĞƐ ǁŝƚŚ ĚƵƌĂƚŝŽŶ ŽĨ ƚƌĞĂƚŵĞŶƚ ĂŶĚ ƚŽƚĂů ĐƵŵƵůĂƚŝǀĞ ĚŽƐĂŐĞ ŽĨ
`ŵĞƚŽĐůŽƉƌĂŵŝĚĞ͘ dŚĞ ĐƵŵƵůĂƚŝǀĞ ƵƐĞ ŽĨ ŵĞƚŽĐůŽƉƌĂŵŝĚĞ ƐŚŽƵůĚ ŶŽƚ ĞdžĐĞĞĚ ϭϮ ǁĞĞŬƐ ĚƵĞ ƚŽ
`ƚŚĞ ƌŝƐŬ ŽĨ d͘ /Ŷ ĂĚĚŝƚŝŽŶ͕ ŵĞƚŽĐůŽƉƌĂŵŝĚĞ ŵĂLJ ĂůƐŽ ĐĂƵƐĞ ŽƚŚĞƌ ĞdžƚƌĂƉLJƌĂŵŝĚĂů ƐLJŵƉƚŽŵƐ
`;W^Ϳ ƐƵĐŚ ĂƐ ĂĐƵƚĞ ĚLJƐƚŽŶŝĐ ƌĞĂĐƚŝŽŶƐ͕ ƉĂƌŬŝŶƐŽŶŝĂŶ ƐLJŵƉƚŽŵƐ ;ďƌĂĚLJŬŝŶĞƐŝĂ͕ ƚƌĞŵŽƌ͕ ĐŽŐǁŚĞĞů
`ƌŝŐŝĚŝƚLJ͕ ŵĂƐŬͲůŝŬĞ ĨĂĐŝĞƐͿ͕ ĂŶĚ ŵŽƚŽƌ ƌĞƐƚůĞƐƐŶĞƐƐ ;ĂŬĂƚŚŝƐŝĂͿ͘ϭ
`
`dŚĞ ƌĞĐŽŵŵĞŶĚĞĚ ŝŶĚŝĐĂƚŝŽŶ ĨŽƌ 'ŝŵŽƚŝ ŝƐ ĨŽƌ ƚŚĞ ƌĞůŝĞĨ ŽĨ ƐLJŵƉƚŽŵƐ ŝŶ ĂĚƵůƚƐ ǁŝƚŚ ĂĐƵƚĞ ĂŶĚ
`ƌĞĐƵƌƌĞŶƚ ĚŝĂďĞƚŝĐ ŐĂƐƚƌŽƉĂƌĞƐŝƐ ǁŝƚŚ ƚŚĞ ĨŽůůŽǁŝŶŐ >ŝŵŝƚĂƚŝŽŶƐ ŽĨ hƐĞ͗
`
`'ŝŵŽƚŝ ŝƐ ŶŽƚ ƌĞĐŽŵŵĞŶĚĞĚ ĨŽƌ ƵƐĞ ŝŶ͗
`x ƉĞĚŝĂƚƌŝĐ ƉĂƚŝĞŶƚƐ ĚƵĞ ƚŽ ƚŚĞ ƌŝƐŬ ŽĨ ĚĞǀĞůŽƉŝŶŐ ƚĂƌĚŝǀĞ ĚLJƐŬŝŶĞƐŝĂ ;dͿ ĂŶĚ ŽƚŚĞƌ
`ĞdžƚƌĂƉLJƌĂŵŝĚĂů ƐLJŵƉƚŽŵƐ ĂƐ ǁĞůů ĂƐ ƚŚĞ ƌŝƐŬ ŽĨ ŵĞƚŚĞŵŽŐůŽďŝŶĞŵŝĂ ŝŶ ŶĞŽŶĂƚĞƐ͘
`x ŵŽĚĞƌĂƚĞ Žƌ ƐĞǀĞƌĞ ŚĞƉĂƚŝĐ ŝŵƉĂŝƌŵĞŶƚ ;ŚŝůĚͲWƵŐŚ  Žƌ Ϳ͕ ŵŽĚĞƌĂƚĞ Žƌ ƐĞǀĞƌĞ ƌĞŶĂů
`
`ϭ ZĞŐůĂŶ ƉƌĞƐĐƌŝďŝŶŐ ŝŶĨŽƌŵĂƚŝŽŶ ;ƐŽƵƌĐĞ͗ ĚƌƵŐƐΛĨĚĂ͖ ĂĐĐĞƐƐĞĚ ϬϰͬϭϯͬϮϬϮϬͿ
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`sĞƌƐŝŽŶ ĚĂƚĞ͗ KĐƚŽďĞƌ ϭϮ͕ ϮϬϭϴ
`
`Reference ID: 4628132
`
`

`

`E ϮϬϵϯϴϴ
`'ŝŵŽƚŝ ;ŵĞƚŽĐůŽƉƌĂŵŝĚĞ ŶĂƐĂů ƐƉƌĂLJͿ
`ŝŵƉĂŝƌŵĞŶƚ ;ĐƌĞĂƚŝŶŝŶĞ ĐůĞĂƌĂŶĐĞ ůĞƐƐ ƚŚĂŶ ϲϬ ŵ>ͬŵŝŶƵƚĞͿ͕ ĂŶĚ ƉĂƚŝĞŶƚƐ ĐŽŶĐƵƌƌĞŶƚůLJ
`ƵƐŝŶŐ ƐƚƌŽŶŐ zWϮϲ ŝŶŚŝďŝƚŽƌƐ ĚƵĞ ƚŽ ƚŚĞ ƌŝƐŬ ŽĨ ŝŶĐƌĞĂƐĞĚ ĚƌƵŐ ĞdžƉŽƐƵƌĞ ĂŶĚ ĂĚǀĞƌƐĞ
`ƌĞĂĐƚŝŽŶƐ͘
`
`dŚĞ ƌĞĐŽŵŵĞŶĚĞĚ 'ŝŵŽƚŝ ĚŽƐŝŶŐ ŝƐ ĂƐ ĨŽůůŽǁƐ͗
`ĚƵůƚƐ >ĞƐƐ dŚĂŶ ϲϱ zĞĂƌƐ ŽĨ ŐĞ͗ dŚĞ ƌĞĐŽŵŵĞŶĚĞĚ ĚŽƐĂŐĞ ŽĨ 'ŝŵŽƚŝ ĨŽƌ ƚŚĞ ƚƌĞĂƚŵĞŶƚ ŽĨ ĂĐƵƚĞ
`ĂŶĚ ƌĞĐƵƌƌĞŶƚ ĚŝĂďĞƚŝĐ ŐĂƐƚƌŽƉĂƌĞƐŝƐ ŝŶ ĂĚƵůƚƐ ŝƐ ϭ ƐƉƌĂLJ ;ϭϱ ŵŐͿ ŝŶ ŽŶĞ ŶŽƐƚƌŝů͕ ϯϬ ŵŝŶƵƚĞƐ ďĞĨŽƌĞ
`ĞĂĐŚ ŵĞĂů ĂŶĚ Ăƚ ďĞĚƚŝŵĞ ;ŵĂdžŝŵƵŵ ŽĨ ĨŽƵƌ ƚŝŵĞƐ ĚĂŝůLJͿ ĨŽƌ Ϯ ƚŽ ϴ ǁĞĞŬƐ͕ ĚĞƉĞŶĚŝŶŐ ŽŶ
`ƐLJŵƉƚŽŵĂƚŝĐ ƌĞƐƉŽŶƐĞ͘
`ĚƵůƚƐ ϲϱ zĞĂƌƐ ŽĨ ŐĞ ĂŶĚ KůĚĞƌ͗ ůĚĞƌůLJ ƉĂƚŝĞŶƚƐ ŵĂLJ ďĞ ŵŽƌĞ ƐĞŶƐŝƚŝǀĞ ƚŽ ƚŚĞ ĂĚǀĞƌƐĞ ĞĨĨĞĐƚƐ
`ŽĨ ŵĞƚŽĐůŽƉƌĂŵŝĚĞ ĂŶĚ ƌĞƋƵŝƌĞ Ă ůŽǁĞƌ ƐƚĂƌƚŝŶŐ ĚŽƐĂŐĞ͘ 'ŝŵŽƚŝ ŝƐ ŶŽƚ ƌĞĐŽŵŵĞŶĚĞĚ ŝŶ ŐĞƌŝĂƚƌŝĐ
`ƉĂƚŝĞŶƚƐ ĂƐ ŝŶŝƚŝĂů ƚŚĞƌĂƉLJ͘
`'ĞƌŝĂƚƌŝĐ ƉĂƚŝĞŶƚƐ ƌĞĐĞŝǀŝŶŐ ĂŶ ĂůƚĞƌŶĂƚŝǀĞ ŵĞƚŽĐůŽƉƌĂŵŝĚĞ ƉƌŽĚƵĐƚ Ăƚ Ă ƐƚĂďůĞ ĚŽƐĂŐĞ ŽĨ ϭϬ ŵŐ
`ĨŽƵƌ ƚŝŵĞƐ ĚĂŝůLJ ĐĂŶ ďĞ ƐǁŝƚĐŚĞĚ ƚŽ 'ŝŵŽƚŝ ϭ ƐƉƌĂLJ ;ϭϱ ŵŐͿ ŝŶ ŽŶĞ ŶŽƐƚƌŝů͕ ϯϬ ŵŝŶƵƚĞƐ ďĞĨŽƌĞ ĞĂĐŚ
`ŵĞĂů ĂŶĚ Ăƚ ďĞĚƚŝŵĞ ;ŵĂdžŝŵƵŵ ĨŽƵƌ ƚŝŵĞƐ ĚĂŝůLJͿ ĨŽƌ Ϯ ƚŽ ϴ ǁĞĞŬƐ͕ ĚĞƉĞŶĚŝŶŐ ŽŶ ƐLJŵƉƚŽŵĂƚŝĐ
`ƌĞƐƉŽŶƐĞ͘ ǀŽŝĚ ƚƌĞĂƚŵĞŶƚ ǁŝƚŚ ŵĞƚŽĐůŽƉƌĂŵŝĚĞ ;Ăůů ĚŽƐĂŐĞ ĨŽƌŵƐ ĂŶĚ ƌŽƵƚĞƐ ŽĨ ĂĚŵŝŶŝƐƚƌĂƚŝŽŶͿ
`ĨŽƌ ůŽŶŐĞƌ ƚŚĂŶ ϭϮ ǁĞĞŬƐ͘
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` Conclusions on the Substantial Evidence of Effectiveness
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`dŚĞ ĂƉƉƌŽǀĂů ŽĨ 'ŝŵŽƚŝ ;ŵĞƚŽĐůŽƉƌĂŵŝĚĞͿ ŶĂƐĂů ƐƉƌĂLJ ŝƐ ƵŶĚĞƌ ƚŚĞ ϱϬϱ;ďͿ;ϮͿ ƌĞŐƵůĂƚŽƌLJ
`ƉĂƚŚǁĂLJ͕ ďĂƐĞĚ ŽŶ ĐŽŵƉĂƌĂƚŝǀĞ ďŝŽĂǀĂŝůĂďŝůŝƚLJ ;Ϳ ƚŽ ZĞŐůĂŶ ;ŵĞƚŽĐůŽƉƌĂŵŝĚĞͿ ϭϬ ŵŐ ŽƌĂů
`ƚĂďůĞƚ ;ůŝƐƚĞĚ ĚƌƵŐͿ͘ dŚĞ ŝŶĨŽƌŵĂƚŝŽŶ ƉƌŽǀŝĚĞĚ ŝŶ ƚŚĞ ůĂƐƐ Ϯ ƌĞƐƵďŵŝƐƐŝŽŶ ŽĨ E ϮϬϵϯϴϴ͕
`ƌĞĐĞŝǀĞĚ ŽŶ ĞĐĞŵďĞƌ ϭϵ͕ ϮϬϭϵ͕ ĂĚĞƋƵĂƚĞůLJ ĂĚĚƌĞƐƐĞƐ ƚŚĞ ĐŽŶĐĞƌŶƐ ƌĂŝƐĞĚ ĚƵƌŝŶŐ ƚŚĞ ĨŝƌƐƚ
`ƌĞǀŝĞǁ ĐLJĐůĞ͕ ĨŽƌ ǁŚŝĐŚ Ă Z ĂĐƚŝŽŶ ǁĂƐ ƚĂŬĞŶ͘
`
`dŽ ĞƐƚĂďůŝƐŚ Ă ďƌŝĚŐĞ ďĞƚǁĞĞŶ 'ŝŵŽƚŝ ĂŶĚ ZĞŐůĂŶ͕ ƚŚĞ ƉƉůŝĐĂŶƚ ĐŽŶĚƵĐƚĞĚ Ă  ƐƚƵĚLJ͕ DdKͲ
`/EͲϬϬϲ͖ Ăƚ Ăůů ƚŚƌĞĞ ĚŽƐĞƐ ŽĨ ŶĂƐĂů ƐƉƌĂLJ ĞǀĂůƵĂƚĞĚ ;ϭϱ͕ ϭϲ ĂŶĚ ϭϳ ŵŐͿ͕ 'ŝŵŽƚŝ ƐŚŽǁĞĚ
`ĐŽŵƉĂƌĂďůĞ ĂƌĞĂ ƵŶĚĞƌ ƚŚĞ ĐƵƌǀĞ ;hͿ ƚŽ ZĞŐůĂŶ ϭϬͲŵŐ ƚĂďůĞƚ͕ ďƵƚ ĚĞŵŽŶƐƚƌĂƚĞĚ ŽŶ ĂǀĞƌĂŐĞ͕
`Ă ϭϲ ƚŽ ϮϬй ůŽǁĞƌ ŵĂdžŝŵƵŵ ƉůĂƐŵĂ ĐŽŶĐĞŶƚƌĂƚŝŽŶ ;ŵĂdžͿ͕ ǁŚŝĐŚ ǁĂƐ ƉƌŝŵĂƌŝůLJ ĚƵĞ ƚŽ ĂďĞƌƌĂŶƚ
`ƉŚĂƌŵĂĐŽŬŝŶĞƚŝĐƐ ;W<Ϳ ƉƌŽĨŝůĞƐ ŝŶ ϰ͘ϱй ŽĨ ƚŚĞ ƐƚƵĚLJ ƐƵďũĞĐƚƐ͘ ƵƌŝŶŐ ƚŚĞ ĨŝƌƐƚ ƌĞǀŝĞǁ ĐLJĐůĞ͕ ƚŚĞ
`ƌĞĂƐŽŶ ĨŽƌ ƚŚĞ ĂďĞƌƌĂŶƚ W< ƉƌŽĨŝůĞƐ ǁĂƐ ŶŽƚ ĞŶƚŝƌĞůLJ ĐůĞĂƌ͘  Z ǁĂƐ ŝƐƐƵĞĚ ĚƵĞ ƚŽ ƵŶĐĞƌƚĂŝŶƚLJ ĂƐ
`ƚŽ ǁŚĞƚŚĞƌ 'ŝŵŽƚŝ ǁĂƐ ĂďůĞ ƚŽ ĚĞůŝǀĞƌ ŵĞƚŽĐůŽƉƌĂŵŝĚĞ ŝŶ Ă ƌĞůŝĂďůĞ ĂŶĚ ĐŽŶƐŝƐƚĞŶƚ ŵĂŶŶĞƌ
`ŐŝǀĞŶ ƚŚĂƚ Ă ĐůĞĂƌ ĞdžƉůĂŶĂƚŝŽŶ ǁĂƐ ůĂĐŬŝŶŐ ĨŽƌ ƚŚĞ ůŽǁĞƌ ŵĂdž ŽďƐĞƌǀĞĚ ŝŶ ƚŚĞ  ƐƚƵĚLJ͕ ĂŶĚ ƚŚĞƌĞ
`ǁĂƐ ŝŶƐƵĨĨŝĐŝĞŶƚ ĞǀŝĚĞŶĐĞ ƚŽ ĞŶƐƵƌĞ ƚŚĂƚ ƚŚĞ ƋƵĂůŝƚLJ ĐŽŶƚƌŽů ĂŶĚ ĞƐƐĞŶƚŝĂů ƉĞƌĨŽƌŵĂŶĐĞ
`ĐŚĂƌĂĐƚĞƌŝƐƚŝĐƐ ŽĨ ƚŚĞ ĐŽŵďŝŶĂƚŝŽŶ ƉƌŽĚƵĐƚ ĚŝĚ ŶŽƚ ĐŽŶƚƌŝďƵƚĞ ƚŽ ƚŚĞ ŽďƐĞƌǀĞĚ ĐůŝŶŝĐĂů
`ǀĂƌŝĂďŝůŝƚLJ͘
`
`/Ŷ ƚŚĞ ƌĞƐƵďŵŝƐƐŝŽŶ͕ ƚŚĞ ƉƉůŝĐĂŶƚ ĂĚĚƌĞƐƐĞĚ ƚŚĞ ĚĞĨŝĐŝĞŶĐŝĞƐ ƌĞůĂƚĞĚ ƚŽ ƚŚĞ ƋƵĂůŝƚLJ ĐŽŶƚƌŽů ĂŶĚ
`ĞƐƐĞŶƚŝĂů ƉĞƌĨŽƌŵĂŶĐĞ ĐŚĂƌĂĐƚĞƌŝƐƚŝĐƐ ŽĨ ƚŚĞ ĐŽŵďŝŶĂƚŝŽŶ ƉƌŽĚƵĐƚ ďLJ ƌĞĞǀĂůƵĂƚŝŶŐ ƚŚĞ
`ĂĐĐĞƉƚĂŶĐĞ ĐƌŝƚĞƌŝĂ ĨŽƌ ƚŚĞ ƐƉĞĐŝĨŝĐĂƚŝŽŶ ƵƐŝŶŐ ďĂƚĐŚĞƐ ŵĂŶƵĨĂĐƚƵƌĞĚ Ăƚ ƚŚĞ ƉƌŽƉŽƐĞĚ
`ĐŽŵŵĞƌĐŝĂů ƐƚƌĞŶŐƚŚ͕ ŝŶĐůƵĚŝŶŐ ĨŽƌ ƐƉƌĂLJ ƉĂƚƚĞƌŶ ĂŶĚ ĚƌŽƉůĞƚ ƐŝnjĞ͕ ĂŶĚ ĂĚĚŝŶŐ Ă ƚĞƐƚ ĂŶĚ
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`sĞƌƐŝŽŶ ĚĂƚĞ͗ KĐƚŽďĞƌ ϭϮ͕ ϮϬϭϴ
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`Reference ID: 4628132
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`E ϮϬϵϯϴϴ
`NDA 209388
`'ŝŵŽƚŝ ;ŵĞƚŽĐůŽƉƌĂŵŝĚĞ ŶĂƐĂů ƐƉƌĂLJͿ
`Gimoti (metoclopramide nasal spray)
`ĂĐĐĞƉƚĂŶĐĞ ĐƌŝƚĞƌŝŽŶ ĨŽƌ ĂĐƚƵĂƚŝŽŶ ĨŽƌĐĞ ƚŽ ƚŚĞ ĨŝŶŝƐŚĞĚ ƉƌŽĚƵĐƚ ƐƉĞĐŝĨŝĐĂƚŝŽŶ͘ ĚĚŝƚŝŽŶĂůůLJ͕ ƚŚĞ
`acceptance criterion for actuation force to the finished product specification. Additionally, the
`ƉƉůŝĐĂŶƚ ƐƵďŵŝƚƚĞĚ ĨŝŶĚŝŶŐƐ ĨƌŽŵ Ă ƌŽŽƚ ĐĂƵƐĞ ĂŶĂůLJƐŝƐ ǁŚŝĐŚ ǁĂƐ ĚĞƐŝŐŶĞĚ ƚŽ ŝĚĞŶƚŝĨLJ ƚŚĞ
`Applicant submitted findings from a root cause analysis which was designed to identify the
`ƉŽƚĞŶƚŝĂů ƐŽƵƌĐĞ;ƐͿ ŽĨ ƚŚĞ ĂďĞƌƌĂŶƚ W< ƉƌŽĨŝůĞƐ͘ ZĞǀŝĞǁ ŽĨ ƚŚĞ ƌŽŽƚ ĐĂƵƐĞ ĂŶĂůLJƐŝƐ ƌĞƉŽƌƚ͕ ŝŶ
`potential source(s) of the aberrant PK profiles. Review of the root cause analysis report, in
`ĐŽŶũƵŶĐƚŝŽŶ ƐĂƚŝƐĨĂĐƚŽƌLJ ƌĞƐŽůƵƚŝŽŶ ŽĨ ƚŚĞ ƉƌŽĚƵĐƚ ƋƵĂůŝƚLJ ĂŶĚ ĚĞǀŝĐĞͲƌĞůĂƚĞĚ ŝƐƐƵĞƐ ƐƵƉƉŽƌƚ ƚŚĂƚ
`conjunction satisfactory resolution of the product quality and device-related issues support that
`ƚŚĞ ĂďĞƌƌĂŶƚ W< ƉƌŽĨŝůĞƐ ƌĞƐƵůƚŝŶŐ ŝŶ Ă ůŽǁĞƌ ŵĂdž ŽŶ ĂǀĞƌĂŐĞ͕ ǁĞƌĞ ůŝŬĞůLJ ĚƵĞ ƚŽ ĞƌƌŽŶĞŽƵƐ
`the aberrant PK profiles resulting in a lower Cmax on average, were likely due to erroneous
`ŝŶƚƌĂŶĂƐĂů ĂĚŵŝŶŝƐƚƌĂƚŝŽŶ ŽĨ ƚŚĞ ƐƚƵĚLJ ĚƌƵŐ ďLJ ƐƚƵĚLJ ƐƚĂĨĨ ŝŶ ƚŚĞ ĐŽŵƉĂƌĂƚŝǀĞ  ƐƚƵĚLJ DdKͲ
`intranasal administration of the study drug by study staff in the comparative BA study METO-
`/EͲϬϬϲ ƌĞƐƵůƚŝŶŐ ŝŶ ůŝƚƚůĞ ƚŽ ŶŽ ƐLJƐƚĞŵŝĐ ĞdžƉŽƐƵƌĞ ŝŶ ƐŽŵĞ ƐƵďũĞĐƚƐ ĂĐƌŽƐƐ Ăůů ƚŚƌĞĞ ĚŽƐĞ ŐƌŽƵƉƐ͘
`lN-006 resulting in little to no systemic exposure in some subjects across all three dose groups.
`
`/Ŷ ůŝŐŚƚ ŽĨ ŝĚĞŶƚŝĨLJŝŶŐ Ă ƉůĂƵƐŝďůĞ ĞdžƉůĂŶĂƚŝŽŶ ĨŽƌ ƚŚĞ ĂďĞƌƌĂŶƚ W< ƉƌŽĨŝůĞƐ ĂŶĚ ƐŝŶĐĞ ƚŚĞ ƋƵĂůŝƚLJ
`In light of identifying a plausible explanation for the aberrant PK profiles and since the quality
`ĚĞĨŝĐŝĞŶĐŝĞƐ ǁĞƌĞ ĂĚĚƌĞƐƐĞĚ͕ ŝƚ ŝƐ ƌĞĂƐŽŶĂďůĞ ƚŽ ĐŽŶĐůƵĚĞ ƚŚĂƚ ƚŚĞ ƌĞƐƵůƚƐ ŽĨ ƚŚĞ ƌĞůĂƚŝǀĞ
`deficiencies were addressed, it is reasonable to conclude that the results of the relative
`ďŝŽĂǀĂŝůĂďŝůŝƚLJ ƐƚƵĚLJ͕ DdKͲ/EͲϬϬϲ͕ ƉƌŽǀŝĚĞ ƐƵƉƉŽƌƚ ĨŽƌ ƌĞůLJŝŶŐ ŽŶ ƚŚĞ ĨŝŶĚŝŶŐƐ ŽĨ ĞĨĨŝĐĂĐLJ ĂŶĚ
`bioavailability study, METO-lN-006, provide support for relying on the findings of efficacy and
`ƐĂĨĞƚLJ ĨŽƌ ƚŚĞ ůŝƐƚĞĚ ĚƌƵŐ ;ZĞŐůĂŶ ϭϬͲŵŐ ƚĂďůĞƚͿ͘
`safety for the listed drug (Reglan 10-mg tablet).
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`sĞƌƐŝŽŶ ĚĂƚĞ͗ KĐƚŽďĞƌ ϭϮ͕ ϮϬϭϴ
`Version date: October 12, 2018
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`ϳ
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`Reference ID: 4628132
`Reference ID: 4628132
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`

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`E ϮϬϵϯϴϴ
`'ŝŵŽƚŝ ;ŵĞƚŽĐůŽƉƌĂŵŝĚĞ ŶĂƐĂů ƐƉƌĂLJͿ
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`Benefit-Risk Assessment
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`Reference ID: 4628132
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`ĞŶĞĨŝƚͲZŝƐŬ ^ƵŵŵĂƌLJ ĂŶĚ ƐƐĞƐƐŵĞŶƚ
`E ϮϬϵϯϴϴ ĨŽƌ 'ŝŵŽƚŝ ;ŵĞƚŽĐůŽƉƌĂŵŝĚĞ ŚLJĚƌŽĐŚůŽƌŝĚĞͿ ŶĂƐĂů ƐƉƌĂLJ ǁĂƐ ŝŶŝƚŝĂůůLJ ƐƵďŵŝƚƚĞĚ ŽŶ :ƵŶĞ ϭ͕ ϮϬϭϴ ĂŶĚ ƌĞĐĞŝǀĞĚ Ă ŽŵƉůĞƚĞ
`ZĞƐƉŽŶƐĞ ;ZͿ ĂĐƚŝŽŶ ŽŶ Ɖƌŝů ϭ͕ ϮϬϭϵ͘ dŚĞ ƌĞƐƵďŵŝƐƐŝŽŶ ǁĂƐ ƌĞĐĞŝǀĞĚ ŽŶ ĞĐĞŵďĞƌ ϭϵ͕ ϮϬϭϵ ĂŶĚ ƌĞƐƉŽŶĚƐ ƚŽ ƚŚĞ ĚĞĨŝĐŝĞŶĐŝĞƐ ŝĚĞŶƚŝĨŝĞĚ ŝŶ
`ƚŚĞ Z >ĞƚƚĞƌ͘ dŚĞ ƉƌŽƉŽƐĞĚ ƌĞŐƵůĂƚŽƌLJ ƉĂƚŚǁĂLJ ĨŽƌ ĂƉƉƌŽǀĂů ŝƐ ^ĞĐƚŝŽ