CENTER FOR DRUG EVALUATION AND
`
`
`RESEARCH
`
`
`
`
`
`
`
`
`
`
`APPLICATION NUMBER:
`
`
`210875Orig1s000
`
`
`NON-CLINICAL REVIEW(S)
`
`
`
`
`
`

`

`
`
`OF
` HEALTH
`
`
`
`
`
`
` & HUMAN
` SERVICES
`DEPARTMENT
`
`
`
`
`
` Public Health Service
`
`
`Food and Drug Administration
`
`
`
`
`
`
`
`______________________________________________________________________________
`
`Division of Neurology Products (HFD-120)
`Center for Drug Evaluation and Research
`
`
`Date: January 24, 2019
`
`From: Lois M. Freed, Ph.D.
`
`Supervisory Pharmacologist
`
`
`Subject: NDA 210-875 (Kynmobi, apomorphine hydrochloride sublingual film, APL-130277)
`______________________________________________________________________________
`
`NDA 210-875, a 505(b)(2) application, was submitted by Sunovion Pharmaceuticals on March
`29, 2018, to request marketing approval for apomorphine hydrochloride sublingual film for the
`“intermittent ‘OFF’ episodes associated with Parkinson’s disease
`
`MEMORANDUM
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`NDA 210-875 relies, in part, on findings of safety and effectiveness of a previously approved
`drug. The listed drug is Apokyn (apomorphine hydrochloride for subcutaneous injection),
`approved (NDA 21-264) for “the acute, intermittent treatment of hypomobility, ‘off’ episodes
`(‘end-of-dose wearing off’ and unpredictable ‘on/off’ episodes) associated with advanced
`Parkinson’s disease.” Clinical development was conducted under IND 110955.
`
`To support clinical development and an NDA, the sponsor conducted GLP studies to assess the
`local toxicity of apomorphine (28-day cheek pouch toxicity in hamster) and the toxicity and
`
`
`toxicokinetics of metabolite, apomorphine sulfate (13-week oral toxicity of apomorphine in rat).
`These (and preliminary dose-ranging studies) were reviewed by Dr. McKinney, who has
`concluded the nonclinical data support approval of the NDA (Pharmacology/Toxicology Review
`and Evaluation, NDA 210-875, LuAnn McKinney, DVM, January 24, 2019).
`
`The sponsor provided a scientific bridge to the listed drug in clinical studies, comparing the
`pharmacokinetics of apomorphine hydrochloride sublingual film to those of Apokyn and APO-g
`SC injection (approved in Europe). In humans, apomorphine sulfate, apomorphine glucuronide,
`and norapomorphine glucuronide are major human metabolites (metabolite-to-parent AUC ratios
`were 9.6, 131, and 10.4, respectively). Plasma AUC values for these major human metabolites
`were, “4.4, 15.8, and 9.1fold [respectively] greater following SL administration compared to
`SC…” (Office of Clinical Pharmacology Review, NDA 210875, Mariam Ahmed, PhD, Kevin
`Krudys, PhD, Sreedharan Sabarinath, PhD, December 28, 2018). Because these metabolites are
`conjugates, which were not considered of toxicological concern (e.g., not acyl glucuronides),
`additional nonclinical studies of these metabolites were not required. A local tolerance study was
`initially recommended, but it not required because the clinical team agreed the local effects of
`the product could be adequately evaluated in humans.
`
`
`
`
`
`Reference ID: 4380831Reference ID: 4613103
`
`1
`
`(b) (4)
`
`

`

`As noted, the sponsor assessed the toxicity of apomorphine sulfate (following oral administration
`of apomorphine) and the local tolerance of APL-130277 (sublingual film) in nonclinical studies.
`In the 28-day study in Sprague Dawley rat (10/sex/group + 9/sex/dose group for toxicokinetic
`analysis), apomorphine was administered by oral gavage at doses of 0, 3, 10, or 30 mg/kg QD.
`No drug-related effects were observed. At the high dose, plasma Cmax and AUC(0-24 h) for
`apomorphine sulfate were 2400-767 ng/mL and 11000-3150 ng*hr/mL, respectively. At the
`maximum recommended human dose (MRHD: 5 x 35 mg/day, 10 films/day), plasma Cmax and
`AUC(0-24 hr) for the metabolite were 1220 ng/mL and 13160 ng*hr/mL. In the local tolerance
`study, APL-130277 was applied to the buccal mucosa (cheek pouch) of Golden Syrian hamsters
`(8/sex/group) at a dose of 0 or 2.08 mg apomorphine TID for 28 days. No local irritation was
`detected. These studies did not provide adequate margins (based on metabolite exposure or local
`APL-130277 concentration) compared to humans; however, neither study was considered
`essential for clinical development or an NDA.
`
`
`An additional issue was the specification limit for one impurity, Impurity which was positive
`for bacterial mutagenicity in an adequate (Q)SAR evaluation. The specification limit would
`result in a total daily dose of
`at the MRHD. This is acceptable from a nonclinical standpoint
`because the anticipated human use for the proposed indication is ≤10 yrs, for which the daily
`limit for a mutagenic impurity is
` March 2018).
`
`
`Recommendation
`
`
`From a nonclinical standpoint, there is no objection to approval of the NDA.
`
`
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`Reference ID: 4380831Reference ID: 4613103
`
`2
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (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/
`------------------------------------------------------------
`
`LOIS M FREED
`01/24/2019 07:18:31 PM
`
`
`
`Reference ID: 4380831Reference ID: 4613103
`
`

`

`
`
`
`
`
`
`
` 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
`
`
`
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`
`
`
`
`
`
`
` Indication:
`
` Applicant:
`
`
`
`
`
`
`
`
`
`
`
` 210875
`
`
` Application number:
`
`
`
` Supporting document/s:
`
` eCTD/SDN 0001
`
` Applicant’s letter date: MAR 29 2018
`
`
` CDER stamp date: MAR 29 2018
`
`
` Product:
`
` APL-130277 Sublingual Apomorphine Thin Film
`
`
` Strip
`
`Parkinson’s disease
` Sunovion Pharmaceuticals, Inc.
`
` 84 Waterford Drive
`
`
`
`
` Marlborough, MA 01752-7010
`
` Division of Neurology Products
`
` LuAnn McKinney, DVM, DACVP
`
`
` Lois M. Freed, PhD
`
` Billy Dunn, MD
` Jack Dan, PharmD
`
`
`
` Review Division:
`
` Reviewer:
`
` Supervisor:
`
` Division Director:
`
` Project Manager:
`Disclaimer
`
`
`
`
` Except as specifically identified, all data and information discussed below and
` necessary for approval of NDA 210875 are owned by Sunovion Pharmaceuticals, Inc. or
`
`
`
`
`
`
`
` are data for which Sunovion Pharmaceuticals, Inc. has obtained a written right of
` reference. Any information or data necessary for approval of NDA 210875 that
`
`
`
`
`
` Sunovion Pharmaceuticals, Inc. 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 are for descriptive purposes
`
`
`
` only and are not relied upon for approval of NDA 210875.
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4380423Reference ID: 4613103
`
`
`
` 1
`
`
`

`

`
`
` NDA # 210875
`
`
`
`
`
`
`
`
` LuAnn McKinney, DVM, DACVP
`
`
`
` TABLE OF CONTENTS
`
`
`
`
`
`
`
`
` 1
` EXECUTIVE SUMMARY ......................................................................................... 3
`
`
`
` INTRODUCTION .................................................................................................... 3
`
`
`1.1
`
` 1.2 BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 3
`
`
`
`
`
`
`
` 1.3 RECOMMENDATIONS ............................................................................................ 3
`
`
`
`
`
` 2
` DRUG INFORMATION ............................................................................................ 4
`
`
`
` 2.1 DRUG................................................................................................................. 4
`
`
`
`
` 2.2 RELEVANT INDS, NDAS, BLAS AND DMFS........................................................... 4
`
`
`
`
`
`
`
` 2.3 DRUG FORMULATION ........................................................................................... 5
`
`
`
`
`
` 2.4 COMMENTS ON NOVEL EXCIPIENTS....................................................................... 5
`
`
`
`
` 2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ......................................... 6
`
`
`
`
`
` 2.6 PROPOSED CLINICAL POPULATION AND DOSING REGIMEN ...................................... 7
`
`
`
`
`
` 2.7 REGULATORY BACKGROUND ................................................................................ 7
`
`
`
`
`
` 3 STUDIES SUBMITTED............................................................................................ 8
`
`
`
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` 3.1 STUDIES REVIEWED............................................................................................. 8
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` 3.2 STUDIES NOT REVIEWED: NA............................................................................... 8
`
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` 3.3 PREVIOUS REVIEWS REFERENCED........................................................................ 8
`
`
`
`
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` 4 PHARMACOLOGY.................................................................................................. 8
`
`
`
`
` 4.1 PRIMARY PHARMACOLOGY ................................................................................... 8
`
`
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`
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` 5 PHARMACOKINETICS/ADME/TOXICOKINETICS ................................................ 8
`
`
`
`
` 5.1 PK/ADME.......................................................................................................... 8
`
`
`
`
` 6 GENERAL TOXICOLOGY....................................................................................... 9
`
`
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`
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` 6.1 SINGLE-DOSE TOXICITY ....................................................................................... 9
`
`
`
`
` SPECIAL TOXICOLOGY STUDIES................................................................... 15
`
`
`
`10
`
`
` INTEGRATED SUMMARY AND SAFETY EVALUATION................................. 16
`
`
`
`
`11
`
`
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`
`
`Reference ID: 4380423Reference ID: 4613103
`
`
`
` 2
`
`
`

`

`
`
`
`
`
`
`
`
` LuAnn McKinney, DVM, DACVP
`
`
`
` NDA # 210875
`
` Executive Summary
` 1
`
` Introduction
`
`
` 1.1
` Sunovion Pharmaceuticals, Inc. submitted this NDA for Kynmobi®, a sublingual film
`
`
`
`
` formulation of apomorphine HCl, for the acute, intermittent treatment of “off” episodes in
`
`Parkinson’s disease patients.
`
` Pursuant to Section 505 (b)(2) of the Federal Food, Drug, and Cosmetic Act, Sunovion
`
` Pharmaceuticals is relying on the Agency’s finding of safety for the listed drug,
`
`
`
`
` APOKYN® injectable apomorphine (NDA 21264, approved on APR 20, 2004). The
`
`
`
`
` sponsor submitted clinical data to establish a pharmacokinetic bridge to the listed drug.
`
`
`
` 1.2 Brief Discussion of Nonclinical Findings
`
`
`
`
`
` In nonclinical studies in rabbit and golden hamster, the sublingual drug product
`
`
`
` produced no irritation to oral or cheek pouch mucosa. In a 90-day toxicity study in rat,
`
`
`
` oral administration of apomorphine resulted in circulating levels of the major metabolite,
`
`
` apomorphine sulfate, similar to those seen clinically at the MRHD. No adverse in-life or
`
`
`
` post mortem findings were reported and there should be little or no toxicologic risk from
`
`
`
`
`
`
` clinical administration via the sublingual route.
`
`
`
`
`
`
`
` Pyridoxine HCl
` film and at the MRHD of
`
` one 20 mg plus one 15 mg strip, five times daily, the daily dose of pyridoxine would be
`
`
`
`
`
` . Although this exceeds the dietary dose of
` per day and is slightly
`
`
`
` daily dose administered for pyridoxine-dependent seizures,
`
`
`
`higher than the
` the clinical team finds
`
` to be acceptable.
`
`
`
`
`
`
` In stability studies, three degradant impurities were identified. Two are structurally
`
`
`
` similar to apomorphine and are not considered to be of concern; the third, a
`
`
`
`
` is specified at an acceptable intake based on the advanced
`
`
`
` age of the patient population.
`
`
`
`
` 1.3 Recommendations
` 1.3.1 Approvability
`
`
`
` This New Drug Application is approvable from a nonclinical perspective.
`
`
`
` 1.3.3 Labeling
`
`
`
`
`
`
` Labeling largely reflects that approved for the listed drug; however, the comparisons of
`
` nonclinical doses are to the MRHD for subcutaneously administered APOKYN® (20
`
`
`
`
` mg/day). These should be corrected to reflect exposures at the MRHD of the sublingual
`
`
`
`
`
` drug product
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`
`
`Reference ID: 4380423Reference ID: 4613103
`
`
`
` 3
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
` NDA # 210875
`
`
`
`Sponsor’s table:
`
`
`
`
`
`
`
`
` LuAnn McKinney, DVM, DACVP
`
`
`
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`
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`
`
`
`
` 2 Drug Information
`
`
`
` 2.1 Drug
`
` CAS Registry Number: 41372-20-7
`
`
`
` Generic Name: Apomorphine hydrochloride
`
`
` Code Name: APL 130277
`
`
`Chemical Name: 4H-Dibenzo [de, g] quinoline-10, 11-diol, 5, 6, 6a, 7-tetrahydro-6­
`
` methyl hydrochloride, hemihydrate (salt)
`
`
`Molecular Formula: C17 H17 NO2 • HCl • ½ H2O (salt)
`
`
` Molecular Mass: 312.79 (apomorphine hydrochloride hemihydrate)
`
` Structure:
`
`Sponsor’s figure:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Pharmacologic Class: Non-ergoline dopamine agonist
`
` 2.2 Relevant INDs, NDAs, BLAs and DMFs
`
`
` IND 110955
`
` NDA 21264 (Apokyn ®)
`
`
`
`
`
`
`Reference ID: 4380423Reference ID: 4613103
`
`
`
` 4
`
`
`
`
`
`

`

`
`
`
`
`
`
`
`
` LuAnn McKinney, DVM, DACVP
`
`
`
`
`
`, Type II
`
`
`
` NDA # 210875
`
` Right of Reference to DMF
`
`
` 2.3 Drug Formulation
`
` dissolving film strip
` containing apomorphine
` The drug product
`
`
`
`
`
`
`
` pyridoxine HCl/sodium hydroxide. Six strengths of APL­
`HCl and
` 130277 (10, 15, 20, 25, 30 mg), are individually packaged into foil laminate pouches.
`
`
`
`
`
`
`
`
`
`
`
`Sponsor’s table:
`
` 2.4 Comments on Novel Excipients
`
`
` There are no novel excipients.
`
`
`Sponsor’s table:
`
`
`
`
`
`
`
`Reference ID: 4380423Reference ID: 4613103
`
`
`
`
`
` 5
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
`
`

`

`
`
`
`
`
`
`
`
` LuAnn McKinney, DVM, DACVP
`
` NDA # 210875
`
`
`
` .
` Pyridoxine HCl
`
`
` The MRHD of one 15 mg and one 20 mg strips, to be taken five times daily, results in a
`
`
`
` pyridoxine.
`daily dose of
`
`Sponsor’s table:
`
`
`
`
`
`
`
`
`
`
`
`was
`
`
`
` 2.5 Comments on Impurities/Degradants of Concern
`
`
`
`There are three identified degradant impurities in the drug product films. Degradants
` have structural similarity to apomorphine
`
`
`
`
` In
`
`
`
`
` stability studies, the maximum level of Impurity
` per film, after long term
`
` (31 months) storage at room temperature. An
`
`
`
`is an oxidation product with a structural alert
`
`degradant impurity
` for mutagenicity and a proposed acceptance criterion of
`
`
`
`
`
`
`
` /film.
`
`
`
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`
`
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`
`
`Reference ID: 4380423
`Reference ID: 4613103
`
`
`
`
` 6
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) ( )
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`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
` NDA # 210875
`
` Sponsor’s figure:
`
`
`
`
`
`
`
`
`
` LuAnn McKinney, DVM, DACVP
`
`
` results in an acceptable daily
`
`
` per film for Impurity
`The proposed criterion of
`
` from 5 daily single films of 10, 15, 20, or 25 mg. The MRHD of 35 mg
`
`
`
`
`
`
` intake of
` consists of one 15 mg plus one 20 mg film resulting in a daily application of 10 films; this
`
`
`
`
`
`
`
`yields a daily intake of
` This exceeds the acceptable
`
`
`
` daily intake specified for a treatment duration of greater than 10 years’; however, it a
`
`
` clinical judgement that patients in advanced stages of the disease would be unlikely to
`
`
` take the drug for ten or more years. As such,
` per film is acceptable.
`
`
`
`
`
` 2.6 Proposed Clinical Population and Dosing Regimen
`
`
`
`
`
`
`
` The dosing regimen is sublingual administration for the acute, intermittent treatment of
` “off” episodes in Parkinson’s disease patients, every two hours, not to exceed 5 doses
`
`
`
`
` dose results in a total daily dose of
`
`
`
`
`
`
`
` daily. The highest dosage of
`of
`
`
` apomorphine HCl.
` 2.7 Regulatory Background
`
`
` The sponsor submitted IND 110995 on June 15, 2014, and a May Proceed letter was
`
`
`
`
`
`
`
`
` issued on August 7, 2014. Fast Track designation was granted on August 25, 2016.
`
`
`
`
`
`Reference ID: 4380423Reference ID: 4613103
`
`
`
` 7
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
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`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`
`
`
`
` LuAnn McKinney, DVM, DACVP
`
` NDA # 210875
`
` This NDA (210875) was submitted on March 29, 2018. The proprietary name,
`
`
`
`
`
`
`
`
`
` Kynmobi®, was found to be conditionally acceptable (letter dated June 15, 2018).
` Studies Submitted
`
`
` 3
` 3.1 Studies Reviewed
`
`
` Oral local irritation studies were submitted and reviewed under the IND (110955).
`
`
` Submitted to the NDA and reviewed were the following:
` 1) TK of oral dose apomorphine by sublingual administration into male New
`
`
`
`
`
`
`Zealand white (NZW) rabbits. NPS1637-RPT001: Toxicokinetic report from
`
` 11C46Q1G12.
`
`
` 2) Tolerability and toxicokinetic assessment of apomorphine by oral gavage in Rats.
`
` 3) Oral gavage toxicity and toxicokinetic study of a metabolite of apomorphine
`
`
`
` (apomorphine sulfate) in rats.
`
`
`
` 3.2 Studies Not Reviewed: NA
`
`
` 3.3 Previous Reviews Referenced
` IND 110955: Pharmacology/Toxicology review of local irritation studies in hamster
`
`
`
`
` cheek pouches. February 3, 2017. LuAnn McKinney, DVM, DACVP.
` Pharmacology
`
`
` 4
`
`
` 4.1 Primary Pharmacology
` Per the APOKYN® label:
`
`
`
`
` “[Apomorphine HCl] is a non-ergoline dopamine agonist with high in vitro binding affinity
` for the dopamine D4 receptor, and moderate affinity for the dopamine D2, D3, and D5,
`
`
` and adrenergic α1D, α2B, α2C receptors. The precise mechanism of action of APOKYN
`
`
`
`
` as a treatment for Parkinson’s disease is unknown, although it is believed to be due to
`
` stimulation of post-synaptic dopamine D2-type receptors within the caudate-putamen in
`
`
` the brain.”
`
`
` Pharmacokinetics/ADME/Toxicokinetics
`
` 5
` 5.1 PK/ADME
`
`
` When administered sublingually, apomorphine that is not absorbed through the oral
`
`
`
`
`
`
`
` mucosa is presumed to be swallowed. Based on published literature (Vietri M, et al.,
` Xenobiotica, 32(7):587-594, 2002) the sponsor reported that orally administered
`
`
`
`
`
`
` apomorphine undergoes rapid sulfation in the duodenum and in the liver resulting in
` high circulating levels of the major metabolite apomorphine sulfate.
`
`
`
`
`
`
`
` The sponsor reported that exposure levels of apomorphine sulfate were higher in
`
`
`
`
`healthy volunteers and PD patients after sublingual administration than after
` subcutaneous administration of apomorphine. Although the bioavailability of
`
`
`
`
`
`
`
` apomorphine is reduced when administered by the sublingual route (15% relative to the
` subcutaneous route), exposure (AUC) to the metabolite, apomorphine sulfate, was
`
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`Reference ID: 4380423Reference ID: 4613103
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` 8
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` LuAnn McKinney, DVM, DACVP
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` NDA # 210875
`
` approximately 4.35-fold higher following a sublingual dose of 15 mg compared to a
`
`
`subcutaneous dose of 2 mg (1550 versus 356 h*ng/mL).
`
` 6 General Toxicology
`
`
`
`
` 6.1 Single-Dose Toxicity
` 11C46Q1G12: Dosing of Apomorphine by Sublingual Administration into Male New
`
`
`
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`
`
` Zealand White (NZW) Rabbits and Collection of Blood Samples for Analysis
`
`
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` films of
` Anesthetized male NZW rabbits (8/group) were administered sublingual
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`
`
`
`
` 1.19 mg apomorphine, with either meglumine or with pyridoxine
`,
` followed immediately by 500 µL of deionized water. On Study Day 1, animals were
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` administered one strip and sampled for TK analysis (0, 10, 20, 30, 40 minutes and 1,2,
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` and 4 hours post dose). On Study Day 2, three strips were administered at 0, 2, and 4
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` hours, after which the animals were necropsied and examined for gross and/or
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` microscopic evidence of local irritation.
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` Local irritation assessment:
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`
` No macroscopic or microscopic effects on the sublingual tissues were reported.
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`
` Toxicokinetics:
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` (pyridoxine or meglumine) had little effect on systemic
`
`The
`
` exposures to apomorphine.
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`Sponsor’s table:
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`Reference ID: 4380423Reference ID: 4613103
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` 9
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

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` LuAnn McKinney, DVM, DACVP
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` NDA # 210875
`
`
` 6.2 Repeat-Dose Toxicity
`
` 6.2.1
`
` Study title: A tolerability and toxicokinetic assessment of apomorphine by oral
`
`gavage in rats
`
`
` Study no.:
`
`
` Study report location:
`
`
` Conducting
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`
` laboratory and
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`
` location:
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` 277-802
` eCTD 4.2.3.2
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`
` Date of study
`
` initiation:
`
`
` GLP compliance: No
`
`
` QA statement: No
` Apomorphine/IR00012/85.5% (chloride salt form)
`
`
` Drug/ lot #/ % purity:
`
` Key Study Findings
`
`
`
` • The NOEL was the HD in M and F.
`
`
` • Apomorphine sulfate levels greatly exceeded parent apomorphine levels.
`
` • Apomorphine exposures increased with dose in a slightly greater than
`
`
` proportional manner. The AUC(0.25-6h) was approximately 1.5- to 3-fold higher in
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`
`
` males than in females; Cmax: (HDM) 38.3 and (HDF) 43.9 ng/mL; Tmax was
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`
`
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` approximately 0.25 hr post-dose
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`
`
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` • Apomorphine sulfate exposures increased with dose in a greater than
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`
`
`
` proportional manner and the Tmax ranged from 0.5 - 6 hr post-dose. The AUC
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` (0.25-6h), was approximately 4.5 to 5-fold higher in males than in females and Cmax
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`was 3-fold higher in HDM than in HDF.
`
`
` Methods
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`
` JUL 10, 2017
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` Doses: 0, 3, 10, or 30 mg/kg/day
`
`
` Frequency of dosing: Once daily for three days
`
`
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` Route of administration: Oral gavage
`
`
`
`
` Dose volume: 10 mL/kg
`
`
`
`
` Formulation/Vehicle: 50 mM citrate buffer in DIO water
`
`
` Species/Strain: CrL:CD(SD) rat
`
`
` Number/Sex/Group: Main study: 3/sex/group; TK: 6/sex/group
`
` Age: 6 weeks
`
`
` Weight: M: 175-226g; F: 150-195g
`
` Satellite groups: NA
`
`
` Unique study design:
` In-life observations were limited to body weight,
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`
`
`
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` food consumption, and clinical signs. All animals
` were euthanized and discarded on Study Day 2.
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`Reference ID: 4380423Reference ID: 4613103
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`
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` 10
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`(b) (4)
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`

`

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` LuAnn McKinney, DVM, DACVP
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` NDA # 210875
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` Observations and Results
`
`
` Mortality: None
`
` Clinical Signs: No test article effects were reported.
`
`
` Body Weights: No test article effects were reported.
`
` Feed Consumption: No test article effects were reported.
`
` Histopathology: NA
`
` All animals were euthanized on Study Day 2 and tissues were discarded.
`
`
` Toxicokinetics:
`
`
` Exposure to apomorphine sulfate (AUC(0.25-6h)) was 14- to 20-fold (M) and 5- to 10-fold
`
`
`
` (F) greater that of apomorphine.
`
` Apomorphine:
`
`
` • Exposure (AUC(0..25-6h) and Cmax) was similar-to or slightly greater-than dose-
`
`
`
`
`
`
`
`
` proportional. A 10-fold increase in dose resulted in 16-fold (M) and 9-fold (F)
`
` increases in AUC(0.25-6h) and 10-fold (M) and 9-fold (F) increases in Cmax.
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`
`
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`
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` • AUC(0..25-6h), was 1.5-fold (LD), 2.3-fold (MD), and 2.7-fold (HD) higher in M than
`
`
`
`F.
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`
` • Tmax was 5 minutes post-dose, except for HDM, in which the Tmax was at 2 hours
`
`
` post-dose
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` Apomorphine Sulfate:
`
`
`
` • Exposure (AUC(0.25-6h) and Cmax) was greater than dose-proportional. A 10-fold
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` increase in dose (3 to 30 mg/kg/day apomorphine) resulted in 17-fold (M) and 15­
` fold (F) increases in AUC(0..25-6h) and 21-fold(M) and 27-fold (F) increases in Cmax
`
`
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` • AUC(0..25-6h) was 4.5-5.1 fold higher in M than in F.
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` • Tmax ranged from 0.5 to 6 hours post-dose in M and F.
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`
`Sponsor’s table: Apomorphine
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`Reference ID: 4380423Reference ID: 4613103
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`
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` 11
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`

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` NDA # 210875
`
` Apomorphine Sulfate: Sponsor’s table
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` LuAnn McKinney, DVM, DACVP
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` 6.2.2
`
` Study title: A 13-week oral gavage toxicity and toxicokinetic study of a
`
`
`
` metabolite of apomorphine (apomorphine sulfate) in rats.
` 277-800
`
`
`
` Study no.:
`
` Study report location:
`
` eCTD: 4.2.3.4
`
` Conducting laboratory and location:
`
`
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`
` Key Study Findings:
`
`
` The NOEL was the HD in M and F.
`
`
`
` • Study Day 91: Apomorphine sulfate
`
`
`
` o AUC(0-24hr) - M: 11000 and F: 3150 ng•h/mL
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`
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` o Cmax - M: 2400 and F: 767 ng/mL
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` o Tmax - M: 0.5- 1 hr; F: 0.5 hr
`
`
`
` • Study Day 91: Apomorphine
`
`
` o AUC(0-24hr) - M: 84.2 and F: 83.8 ng•h/mL
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` o Cmax - M: 13.1 and F: 14.3 ng/mL Day 91
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` o Tmax - M and F: 0.25-0.5 hr
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`Reference ID: 4380423Reference ID: 4613103
`
`
`
` 12
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`
` JUL 27, 2017
`
` Date of study initiation:
`
`
` GLP compliance: Yes
`
`
` QA statement: Yes
`
` Drug, lot #, and % purity:
`Apomorphine HCl,
`
` /IR00012/100.5%
`
`
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`
`
`
`
` LuAnn McKinney, DVM, DACVP
`
` NDA # 210875
`
` Methods
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`
`
` Doses: 0, 3, 10, 30 mg/kg/day
`
` Frequency of dosing: Once daily
`
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` Route of administration: Oral gavage
`
`
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` Dose volume: 10 mL/kg
`
`
`
` Formulation/Vehicle: Citrate buffer monohydrate (pH 3.5)
`
` Species/Strain: Crl:CD(SD) rat
`
`
` Number/Sex/Group: 10/sex
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`
`
` Age: 7 weeks
`
`
` Weight: 170-272 g.
`
`
` Satellite groups: TK: 3/sex C; 9/sex dosed
`
` Unique study design: Rats were dosed with parent in order to assess
`
`
` toxicity of the major metabolite.
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` Deviation from study protocol: None.
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`
`
` Dose selection: The HD was chosen to target the likely clinical apomorphine sulfate
`
`
` levels after administration of the maximum recommended human dose.
`
`
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`
`
` Observations and Results
`
`
` Mortality:
`
` Two moribund LDF were euthanized subsequent to dosing (gavage) error.
`
`
` Clinical Signs:
`
`
` There were no reported test article effects on clinical signs, body weights, food
`
`
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`
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` consumption, ophthalmoscopic examination, clinical chemistry values, hematology or
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` coagulation values, urinalysis, organ weights, or macroscopic pathology.
`
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` Histopathology
`
`
`
` Signed, dated pathology report: Yes
` Adequate Battery: Yes (Standard battery)
`
`
` Peer Review: Yes (Contracted to an outside CRO)
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`
` Histological Findings:
`No test article histomorphologic effects were reported.
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`Toxicokinetics:
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` Study Day 1: 0.25, 0.5, 1, 2, 6 hours post-dose; Study Days 31 and 91: 0.5, 1, 2, 6, 12,
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` and 24 hours post-dose
`
`
`Apomorphine sulfate:
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`
`
`
`
` • Exposure to apomorphine sulfate increased with dose in a greater than dose-
`
` proportional manner. A 10-fold increase in apomorphine dose from 3 to 30
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` mg/kg/day resulted in increase of 11- to 29-fold in AUC and 15- to 45-fold in Cmax
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` in both M and F.
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` • AUC(0-6h) was 2- to 8-fold higher in M than F.
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` • Tmax ranged from 0.5 to 4 hours in M and was generally 0.5 hours in F.
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` • Apomorphine sulfate accumulated over time: from Study Day 1, AUC(0-6h),
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` increased 2- to 3-fold on Study Day 31 and was 2- to 6-fold higher on Study Day
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`Reference ID: 4380423Reference ID: 4613103
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`
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` 13
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`

`

`
`
` NDA # 210875
`
`
`
`
`
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`
`
` LuAnn McKinney, DVM, DACVP
`
`
`
` 91. AUC (0-24h) was not reported on Study Day 1 but increased 2- to 3-fold from
`
`Study Day 31 to Study Day 91.
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`Sponsor’s table:
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`
` Apomorphine:
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`
`
`
` • Exposure generally increased with dose in a variably dose-proportional manner.
` A 10-fold increase in apomorphine dose resulted in 10- to 17-fold increases in
`
`
`
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` AUC (excluding Day 91 for LDM) and 4- to 39-fold increases in Cmax for M and F.
`
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` • There was no apparent accumulation in either M or F
`
`
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` • Tmax was generally 0.25 hours on Study Day 1 and 0.5 hours on Study Days 31
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` and 91 in both M and F.
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`Sponsor’s table:
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`Reference ID: 4380423Reference ID: 4613103
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` 14
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`

`

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` NDA # 210875
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` Sponsor’s tables: Homogeneity
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` LuAnn McKinney, DVM, DACVP
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` 10 Special Toxicology Studies
`
`
`
` Pharmacology/Toxicology review of local irritation studies in hamster cheek pouches.
`
`
` Reviewed for IND 110955; FEB 3, 2017 by LuAnn McKinney, DVM, DACVP.
`
`
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`
`
` “The sponsor submitted 2 pilot studies and one 28-day pivotal study of the local
`
`
` tissue irritating effects of the clinical drug product on cheek pouch epithelium. All
`
`studies were conducted in Golden Syrian hamsters.”
`
`
`
`
` “In the pivotal local irritation study, 0 or 2.08 mg apomorphine (in a 5.5 x 7.5 mm
`
` piece of the clinical film) was applied three times daily to the right cheek pouch of
`
`
` hamsters (8/sex/group) for 28 days.”
`
`
` “There were neither gross nor histologic changes observed in either the control
`
`
` or test-article exposed cheek pouches.”
`
`
`
` “The dose tested was an MTD and a NOAEL for local irritation. Increased
` activity, decreased food consumption, and mild to moderate weigh loss were
`
`
`
` noted in M and F from Days 1 to 15, with lesser effects through Day 28. By Day
`
` 28, dosed M lost an average of 2% (≤5%) of starting body weight and dosed F
`
`
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`had lost an average of 3% (≤8%) of starting body weight.”
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`Reference ID: 4380423Reference ID: 4613103
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`
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` 15
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`

`

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`
` NDA # 210875
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` LuAnn McKinney, DVM, DACVP
`
`
`
` Integrated Summary and Safety Evaluation
`
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` 11
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` APL 30277/KYNMOBI® is a sublingual film formulation of apomorphine HCl developed
`
`
`
`
`
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` for the acute, intermittent treatment of “off” episodes in Parkinson’s disease patients.
`
` Submitted under Section 505(b)(2), of the CFR 314.50, this NDA relies the findings of
`
`
`
`
`
`
` safety and efficacy for the listed drug, APOKYN® injectable apomorphine (NDA 21264
` approved on April 20, 2004). In clinical trials submitted to this NDA, the sponsor
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`
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`
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`
` established a pharmacokinetic bridge to APOKYN®.
`
`
`
` consisting
`
`
` The drug product
` apomorphine HCl
`
` of pyridoxine HCl and flavorings and
`
`
`
`
` By varying the size of the film, the drug is available in
`
`dose strengths (10, 15, 20, and 25 mg);
`
` The films are to be taken to effect but
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`
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`
`
`
` not more than 5 times daily.
`
` apomorphine
`
`
`
`
`
` There are no novel excipients; however, the maximum dose of
`
` pyridoxine. This is greater than
` 5 times daily) results in a daily dose of
`
`
`(
` per day or the dose of
`
` the recommended dietary dose of
`
`
`
`
` for
`
` Vitamin B6 Dependency Syndrome and is slightly higher than the
` daily dose
`
`
` administered for pyridoxine-dependent seizures. Although not inactive, pyridoxine is
`
`
`
` listed as GRAS, is a common ingredient in oral vitamin supplements, and the clinical
`
` review team find the amount of pyridoxine at the maximal daily dose to be acceptable
`
`
`
` (See the Clinical Team Leader Review of this NDA).
`
`
`
` In stability testing, three degradant impurities of apomorphine were identified. Of the
`
`
`three impurities,
` have sufficient structural similarity to apomorphine (a
`
`) to be of no concern.
`
`
`
`
`Degradant impurity
`alerting structure
`
`is an
`
`
`
`
`
`
`
` product that contains a mutagenic
`
`
`
` product of apomorphine
`
`
`
`
`
`ave shown that a similar
` is mutagenic in S. typhimurium and E. coli.
`
`
`
` and this
`
` At the MRHD of 10 films a day, the dose of impurity
`
`
` for potential Class 3 substance
`exceeds the allowable limit in ICH M7(R1) of
`
`
`
`
` impurities that are administered for longer than 10 years.
`
`
`
` However, the maximum dose of
`
`
`
`
` would be needed by Parkinson’s disease
` patients in the advanced stages of the disease and it is unlikely that this elderly patient
`
`
`
`
`
`
`
` population would be taking that dose level for more than 10 years. The ICH M7 (R1)
` recommended daily intake of individual mutagenic impurities for a duration of 1-to-10
`
`
`
` and the daily intake of
`at the MRHD is well below that limit.
`
`
`years is
`
`
`
`
`
`Reference ID: 4380423Reference ID: 4613103
`
`
`
` 16
`
`
`(b) (4)
`
`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
`
`(b) (4)
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`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4