CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`022410Orig1s000
`
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`
`

`

`
`
`
`
`
`
`
`NDA 22-410
` Suboxone ®
`
` (buprenorphine and naloxone)
`sublingual film 2 mg/0.5 mg and 8 mg/2 mg
`
`Summary of the Basis for the Recommended Action
` from Chemistry, Manufacturing, and Controls
`
`
`
`
`
`
`Applicant: Reckitt Benckiser Pharmaceuticals Inc.
`
`
`Indication: Suboxone is indicated for maintenance treatment of opioid
`
`dependence.
`
`
`Presentation: The drug product is two different film formulations: 2
`mg/0.5 mg and 4 mg/2 mg (buprenorphine/naloxone). The drug product
`is supplied in individual child-resistant polyester/foil laminated pouches
`available in a lower strength (2mg/0.5 mg/film) and a higher strength (8
`mg/2 mg/film). Each strength will be available in 30 pouches per carton.
`
`
`EER Status: Recommendations:
`Consults:
`EA –
`
`
`
`CDRH-
`
`
`
`Statistics –
`
`
`
`Methods Validation –
`
`DMEPA-
`
`
`Biopharm–
`
`
`Microbiology –
`
`Pharm/toxicology –
`
`acceptable
`Categorical exclusion provided
`N/A
`N/A
`Not recommended
`Completed
`N/A
`N/A
`N/A
`
`20-October-2008
`N/A
`None.
`
`
`
`
`
`Original Submission:
`Re-submissions:
`
`
`
`Post-Approval CMC PMC/PMR:
`
`Background:
`This NDA is submitted under 505b2. The drug product, Suboxone ®, a soluble
`film designed for sublingual delivery, is a combination of buprenorphine and
`naloxone indicated for maintenance treatment of opioid dependence. Naloxone
`is an opioid receptor antagonist. Suboxone is an alternative to the currently
`marketed Suboxone® (buprenorphine/naloxone) sublingual tablet (NDA 20-
`733).
`
`
`

`

`Drug Substances:
`There are two drug substances for this NDA:
`-
`Buprenorphine hydrochloride is manufactured the applicant. The
`information on the chemistry, manufacturing, and controls (CMC) for
`buprenorphine hydrochloride drug substance is referred to Type II Drug Master
`File (DMF) 12412. DMF 12412 was reviewed and found satisfactory.
`The specifications for Buprenorphine HCl Drug Substance include Physical
`Description (visual), Identification (NIR, UV, Chlorides), pH (aqueous
`suspension), Water (Karl Fischer), Residue on Ignition
`, Specific
`Optical Rotation
` Residual Solvents
`
` by GC), Assay (HPLC, titration), Ion Chloride determination,
`Purity (HPLC) and Particle Size Distribution. Each known impurity
`
`) and any individual unspecified
` and their total no more than
` The
`impurity can not exceed
`specifications for Buprenorphine HCl comply and exceed those required by USP.
`A
` re-test period is established at the time of manufacture and the
`expiration date is extended in six monthly units up to a shelf life of
` subject to the material meeting the specification criteria.
`
`
`
`
`
`
`
` -
`
`Naloxone hydrochloride dihydrate
`
`There are two suppliers of naloxone hydrochloride dihydrate drug substance; the
`first supplier is
` CMC information is referred to their DMF
`.
`DMF
` was reviewed and found satisfactory.The second supplier is
` CMC information is referred to their DMF
`. DMF
` was
`reviewed and found satisfactory. The Reckitt Benckiser’s naloxone HCl
`dihydrate purchasing specifications have been agreed with both suppliers. These
`specifications, which comply and exceed those required by both USP and Ph Eur,
`include Physical Description (visual), Identification (IR, TLC, Chloride), Acidity
`or alkalinity (titrimetric), Water content (Karl Fischer), Residue on Ignition
` Optical Rotation
`, Residual Solvents
` by GC), Assay (HPLC, titration), Ion
`
`
`
`
`
`2
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`.
`
` each NMT
` NMT
` and
` NMT
` each NMT
`impurities, including Ph Eur impurities
`(known and unknown related substances) can not exceed
`
`The supporting shelf-life support
`hydrochloride dihydrate.
`
`
`
`
`
`
` Other
` and the total
`
`Chloride determination, Appearance of solution (visual), Loss on drying
`(gravimetric), and Purity (HPLC). Known impurities
`
`
`
` storage re-test period naloxone
`
`The drug substances are satisfactory
`
`Conclusion:
`
`Drug Product:
`The manufacture process comprises
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The drug product is manufactured in two different film formulations: 2 mg/0.5
`mg and 4 mg/2 mg (buprenorphine/naloxone). Both dosage strengths have the
`same width and length, 0.875” x 0.5”, but differ in weight, 40 mg for the lower
`strength and 50 mg for the higher. Although both formulations share the same
`excipients, their composition is different. Those differences in formulation,
`obtained during product development, assure that each formulation has the
`desired properties (flexibility, disintegration and pharmacokinetic properties).
`Drug product specifications include Appearance (visual), Identification (HPLC),
`Assay (buprenorphine and naloxone each
` by HPLC), Dissolution
`(currently Q =
` in 7 minutes for buprenorphine and Q =
` in 7 minutes
`for naloxone), Moisture content uniformity (NMT
`), Microbial limits
`
`
`
`3
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`(USP<905>), and Purity (HPLC). Purity requirements for Buprenorphine Related
`Substances include
`
`
` any Individual
` and their total can not exceed
` Purity
`Unidentified Impurity NMT
`requirements for Naloxone Related Substance include
`
`
`
`
`
`, and for
` Any Individual Unidentified Impurity NMT
` each NMT
` and the total of impurities can not exceed
`
`Based on the provided stability data, 12 months of expiry dating is granted for
`the drug product
`
`
`
`The drug product is satisfactory.
`
`Conclusion:
`
`Overall Conclusion:
`From a CMC perspective, the application is recommended for approval.
`
`Ali Al-Hakim, Ph.D.
`Branch Chief,
`DPA I/ONDQA
`
`
`
`4
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`1 Page of Draft Labeling has been Withheld in Full
`as b4 (CCI/TS) immediately following this page.
`
`

`

`Linked Applications Submission
`Type/Number
`--------------------
`--------------------
`NDA 22410
`ORIG 1
`
`Sponsor Name
`
`Drug Name / Subject
`
`--------------------
`RECKITT
`BENCKISER
`PHARMACEUTICA
`LS INC
`
`------------------------------------------
`SUBOXONE
`(BUPRENORPHINE/NALOXONE
`) sublingual film
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ALI H AL HAKIM
`08/21/2009
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`CHEMISTRY REVIEW
`
`NDA 22-410
`
`
`Suboxone
`(buprenorphine and naloxone)
`Sublingual Film
`2 mg/0.5 mg and 8 mg/2 mg
`
`
`Reckitt Benckiser Pharmaceuticals Inc.
`
`
`
`
`
`
`
`
`
`Xavier Ysern, PhD
`ONDQA/ DPA I/ Branch II
`
`
`
`Clinical Review Division: DAARP (HFD-170)
`
`
`
`NDA 22-410 CMC Review # 2 Page 1 of 12
`
`

`

`
`
`
`
`
`
`CHEMISTRY REVIEW
`
`
`Table of Contents...........................................................................................................................................................2
`
`Table of Contents
`
`Chemistry Review Data Sheet .......................................................................................................................................3
`
`The Executive Summary ...............................................................................................................................................6
`
`I. Recommendations ..................................................................................................................................................6
`A. Recommendation and Conclusion on Approvability.......................................................................................6
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk Management
`Steps, if Approvable........................................................................................................................................6
`
`II. Summary of Chemistry Assessments .....................................................................................................................6
`A. Description of the Drug Product(s) and Drug Substance(s)..............................................................................6
`B. Description of How the Drug Product is Intended to be Used..........................................................................8
`C. Basis for Approvability or Not-Approval Recommendation ............................................................................9
`
`III. Administrative ........................................................................................................................................................9
`A. Reviewer’s Signature........................................................................................................................................9
`B. Endorsement Block...........................................................................................................................................9
`C. CC Block ..........................................................................................................................................................9
`
`Chemistry Assessment See CMC Review # 1
`Attachments……………………………………………………………………………………………….10
`
`NDA 22-410 CMC Review # 2 Page 2 of 12
`
`

`

`
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`
`Submission(s) Reviewed
`Original
`Amendments:
` 0002
` 0005
` 0009
` 0014
`
`Document Date
`20-Oct-2008
`
`30-Oct-2008 (Proposed proprietary name Suboxone
`08-Dec-2008 (Environmental Assessment)
`03-Mar-2009 (Updated stability data)
`28-Apr-2009 (Change of secondary packaging facility)
`
`
`
`
`
`7. NAME & ADDRESS OF APPLICANT:
`
`
`
`
`
`
`CHEMISTRY REVIEW
`
`
`Chemistry Review Data Sheet
`
`
`
`
`
`
`
`22-410
`
`2
`
`20-Aug-2009
`
`Xavier Ysern, PhD
`
`
`
`1. NDA :
`
`2. REVIEW #:
`
`3. REVIEW DATE:
`
`4. REVIEWER:
`
`5. PREVIOUS DOCUMENTS:
`
`
`Previous Documents
`--
`
`
`
`
`
`
`
`Document Date
`--
`
`
`
`
`
`Name: Reckitt Benckiser Pharmaceuticals Inc.
`Address: 10710 Midlothian Turnpike, Suite 430
`Richmond, VA23235
`Representative: Deborah C. Moffitt
`Manager, Regulatory Affairs Operations
`Telephone: 804 423-6970
`
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name:
`Suboxone
`
`
`b) Non-Proprietary Name (USAN):
`(buprenorphine and naloxone) sublingual film (established name)
`c) Code Name/# (ONDC only):
`--
`
`· Chem. Type:
`d) Chem. Type/Submission Priority:
` · Submission Priority:
`
`
`
`
`
`9. LEGAL BASIS FOR SUBMISSION:
`
`10. PHARMACOL. CATEGORY:
`
`11. DOSAGE FORM:
`
`12. STRENGTH/POTENCY:
`
`13. ROUTE OF ADMINISTRATION:
`
`
`
`
`
`
`
`
`
`
`S
`
`4
`
`
`505(b)(1)
`
`Treatment of opiod dependence
`
`Sublingual film
`
`2 mg/0.5 mg and 8 mg/2 mg (buprenorphine/naloxone)
`
`Sublingual
`
` route
`
`NDA 22-410 CMC Review # 2 Page 3 of 12
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`CHEMISTRY REVIEW
`
`
`
`
`
`Rx
`
`Naloxone hydrochloride dihydrate
`
`C19H21NO4·HCl·2H2O
`
`CAS RN:
`
`
`
`
`
`465-65-6 Naloxone.
`357-08-4 Naloxone hydrochloride anhydrous
`51481-60-8 Naloxone hydrochloride dihydrate
`
`Not a SPOTS product
`
`OH
`
`O
`
`O
`
`.
`
`.
`HCl H2O
`
`N
`
`OH
`
`4,5α-Epoxy-3,14-dihydroxy-17-(prop-2-enyl)morphinan-6-one hydrochloride dihydrate
`
`
`
`14. Rx/OTC DISPENSED:
`
`15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA, MOLECULAR WEIGHT:
`
`
`
`
`
` MW: 399.9
`
`
`
`
`
`
`
`
`
`2
`
`OH
`
`3
`
`O
`
`4
`
`5
`
`15
`
`12
`
`13
`
`18
`
`19
`
`O
`
`6
`
`7
`
`OH
`
`1
`
`11
`
`14
`
`8
`
`10
`
`16
`
`9
`
`N
`17
`
`.
`
`HCl
`
`Buprenorphine hydrochloride
`
`Laboratory Code: RX6029M.HCl
`
`C29H41NO4·HCl
`
`MW: 467.6 (base) 504.1 (salt)
`
`CAS Registry number: 53152-21-9
`
`(2S)-2-[17-Cyclopropylmethyl-4,5α-epoxy-3-hydroxy-6-methoxy-6α,14-ethano-14α-morphinan-7α-yl]-3,3-
`dimethylbutan-2-ol hydrochloride
`
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`
`A. DMFs:
`
`Holder
`
`Item Referenced
`
`Code1
`
`Status2
`
`1 Action codes for DMF Table:
` 1 – DMF Reviewed.
`
`Other codes indicate why the DMF was not reviewed, as follows:
`4 – Sufficient information in application
`2 –Type 1 DMF.
`3 – Reviewed previously and no revision since last review.
`7 – Other (explain under "Comments")
` 5 – Authority to reference not granted.
`6 – DMF not available.
`
`2 Adequate, Inadequate, or N/A (There is enough data in the application, therefore the DMF did not need to be reviewed)
`
`Date Review
`Completed
`
`05-Feb-2009
`21-Jan-2009
`24-Feb-2009
`
`
`
`Comments
`
`CMC Review # 9
`CMC Review # 4
`CMC Review # 1
`
`
`LOA 09-Sep-2008
`LOA 17-Sep-2007
`
`Adequate
`Adequate
`Adequate
`
`
`
`Adequate
`Adequate
`
` 1
`
`
`1
`1
`
`
` 4
`
`
`4
`
`
`DMF #
`
`Type II
`
`
`
`
`
`12412
`
`Reckitt Benckiser Healthcare (UK) Ltd.
`
`Buprenorphine HCl
`
`
`Type IV
`
`
`
`
` lime flavor
`White Ink
`
`)
`
`
`
`NDA 22-410 CMC Review # 2 Page 4 of 12
`
`(
`
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`CHEMISTRY REVIEW
`
`
`
`
`
`B. Other Documents:
`
`Application #
`20-732
`20-733
`
`Description
`Subutex (Buprenorphine) Tablets 2 mg and 8 mg
`Suboxone (Buprenorphine and Naloxone) sublingual tablet 2/0.5 mg and 8/2 mg
`
`
`Document
`NDA
`NDA
`
`
`18. STATUS:
`
`
`
`CONSULTS
`Biometrics
`EES
`Pharm/Tox
`Biopharm
`Labeling
`
`Methods Validation
`EA
`Microbiology
`
`
`DATE
`
`REVIEWER
`
`
`
`
`20-Aug-2009
`
`
`
`
`08-Aug-2009 Multidisciplinary
`
`
`
`
`
`
`Part of this review
`Part of this review
`
`
`RECOMMENDATION
`
`--
`Acceptable recommendation
`--
`--
`OSE does not object the use of the tradename Suboxone.
`The drug product should be referred as “Suboxone
`(Buprenorphine and Naloxone) sublingual film”
`throughout all labels and labeling documentation.
`Revalidation by Agency laboratories is not recommended
`Acceptable
`--
`
`NDA 22-410 CMC Review # 2 Page 5 of 12
`
`

`

`
`
`
`
`
`CHEMISTRY REVIEW
`
`
`
`The Chemistry Review for NDA 22410
`
`Recommendations
`
`
`The Executive Summary
`
` I.
`
`
`A.
`
`B.
`
`Recommendation and Conclusion on Approvability
`
`From the CMC point of view, the application is recommended for approval.
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable
`
`
`
`
`
`
`II.
`
`None
`
`
`Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`
` a soluble film designed for sublingual delivery, is a combination of
`The drug product, Suboxone
`
`buprenorphine and naloxone indicated for maintenance treatment of opioid dependence. Buprenorphine is a mu-
`opioid receptor partial agonist and a kappa-opioid receptor antagonist. Naloxone is an opioid receptor antagonist.
`Suboxone
` is an alternative to the currently marketed Suboxone® (buprenorphine/naloxone) sublingual tablet
`(NDA20-733).
`
`
`(cid:130) Drug Substance(s)
`
`
`
`
`Buprenorphine hydrochloride, chemical name (2S)-2-[17-Cyclopropylmethyl-4,5α-epoxy-3-hydroxy-6-
`
`methoxy-6α,14-ethano-14α-morphinan-7α-yl]-3,3-dimethylbutan-2-ol hydrochloride, has the molecular formula
`C29H41NO4·HCl and a molecular weight of 504.10 g/mol. It is a white or off-white crystalline powder, sparingly
`soluble in water, freely soluble in methanol, soluble in alcohol and practically insoluble in cyclohexane.
`
`Buprenorphine, the active component of buprenorphine hydrochloride, is a partial agonist at the mu-opioid
`
`receptor and an antagonist at the kappa-opioid receptor. Buprenorphine is a thebaine (paramorphine an opiate
`alkaloid) derivative with powerful analgesia approximately twenty-five to forty times as potent as morphine.
`Buprenorphine also has very high binding affinity for the µ receptor such that opioid receptor antagonists (e.g.
`naloxone) only partially reverse its effects.
`
`Buprenorphine hydrochloride is manufactured by the applicant at their facility, “Fine Chemical Plant”
`
`(Reckitt Benckiser Healthcare Limited), located in Hull, United Kingdom. The information on the chemistry,
`manufacturing, and controls (CMC) for buprenorphine hydrochloride drug substance is referred to Reckitt Benckiser
`Healthcare (UK) Limited’ Type II Drug Master File (DMF) 12412.
`
`
`
`
`Buprenorphine hydrochloride
`
`The specifications for Buprenorphine HCl Drug Substance include Physical Description (visual),
`
`Identification (NIR, UV, Chlorides), pH (aqueous suspension), Water (Karl Fischer), Residue on Ignition
`
`, Specific Optical Rotation (
`), Residual Solvents (
` by GC),
`Assay (HPLC, titration), Ion Chloride determination, Purity (HPLC) and Particle Size Distribution. Each known
`impurity
` and any individual unspecified impurity
` and their total no more than
`can not exceed
` Reckitt Benkiser’s specifications for Buprenorphine
`HCl comply and exceed those required by USP.
`
`
`
`NDA 22-410 CMC Review # 2 Page 6 of 12
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`CHEMISTRY REVIEW
`
`
`
`
`
`Naloxone hydrochloride dihydrate
`
`
`
`
`
`drug substance is stored in
`Bulk
`
` re-test data is applied at the time of manufacture and the expiration date is extended in six monthly units
`A
` subject to the material meeting the specification criteria.
`up to a shelf life of
`
`
`
`
`Naloxone hydrochloride dihydrate, chemical name 17-Allyl-4,5α -epoxy-3, 14-dihydroxymorphinan-6-one
`
`hydrochloride dihydrate, has the molecular formula C19H21NO4·HCl·2H2O and a molecular weight of 399.87 g/mol.
`It is a white to slightly off-white powder and is freely soluble in water, soluble in alcohol; practically insoluble in
`toluene and ether.
`
`Naloxone, the active component of naloxone hydrochloride dihydrate, is a potent antagonist at mu-opioid
`
`receptors and produces opioid withdrawal effects in individuals physically dependent on full opioids. Naloxone is
`included in the Suboxone
` formulation to deter users from diverting its use to intravenous injection by producing
`opioid antagonist effects of short duration in subjects dependent on full opioid agonists.
`
`
`
`.
`
`
`There are two suppliers of naloxone hydrochloride dihydrate drug substance,
` naloxone
` and
`
`hydrochloride dihydrate is manufactured in their
` facility. The pertinent CMC information is
`referred to their proprietary Type II DMF DMF
` naloxone hydrochloride dihydrate is
`manufactured at their facility in
` The CMC information is referred to their proprietary
`Type II DMF
`
`
`
`
`The Reckitt Benckiser’s naloxone HCl dihydrate purchasing specifications have been agreed with both
` (main drug substance supplier) and
` (alternate supplier). These specifications, which
`comply and exceed those required by both USP and Ph Eur, include Physical Description (visual), Identification (IR,
`TLC, Chloride), Acidity or alkalinity (titrimetric), Water content (Karl Fischer), Residue on Ignition
`),
`), Residual Solvents
` by GC), Assay
`Optical Rotation
`(HPLC, titration), Ion Chloride determination, Appearance of solution (visual), Loss on drying (gravimetric), and
`Purity (HPLC). Known impurities
`
`
` Other impurities, including Ph Eur
` NMT
` and the total (known and unknown related substances) can not exceed
`
`
`
`r
`
` containers and in
` in
`Naloxone hydrochloride dihydrate is supplied by
` containers by
` The supporting shelf-life given by the suppliers exceed the
`storage period before re-test applied by Reckitt Benckiser.
`
`
`
`(cid:130) Drug Product
`
`
` is a pale orange soluble film strip imprinted with a logo identifying the product and
`Suboxone
`
`strength in white ink designed to provide immediate release of buprenorphine and naloxone in a 4:1 w/w ratio
`sublingually.
`
`
`
`In addition to the active components buprenorphine and naloxone, the film contains polyethylene oxide
` hydroxypropyl methylcellulose
` maltitol
`), acesulfame potassium
`), lime flavor
` citric acid
`,
`(
`, FD&C yellow # 6 (colorant) and white ink (print ink). All excipients, with the exception of
`sodium citrate
` Lime Flavor
`lime flavor, FD&C yellow # 6 and white ink, meet compendial requirements. The lime flavor,
`, is the same used in approved Suboxone Tablets (NDA 20-733), complies with food additives as per 21
`CFR §172.510. FD&C Yellow # 6 is a FDA certified colorant permitted for food use as per 21 CFR §74.706, also
`
`NDA 22-410 CMC Review # 2 Page 7 of 12
`
` each NMT
`
`impurities
`%.
`
`
`
`(b) (4)
`
`(b) (4)
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`(b) (4)
`
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`
`

`

`
`
`
`employed in Suboxone Tablets. The ink is an edible grade supplied by
`all components are compendial.
`
`The drug product is manufactured in two different film formulations: 2 mg/0.5 mg and 4 mg/2 mg
`
`(buprenorphine/naloxone), referred as lower and higher strengths respectively. Both dosage strengths have the same
`width and length, 0.875” x 0.5”, but differ in weight, 40 mg for the lower strength and 50 mg for the higher.
`Although both formulations share the same excipients, their composition is different. Those differences in
`formulation, obtained during product development, assure that each formulation has the desired properties
`(flexibility, disintegration and pharmacokinetic properties).
`
`
`
`
`CHEMISTRY REVIEW
`
`The manufacture process comprises
`
`
`
` and
`
`
`
`
`
`
`
`
`
`
`Unidentified Impurity NMT
`Substance include
`
` and their total can not exceed
`
`
`Drug product specifications include Appearance (visual), Identification (HPLC), Assay (buprenorphine and
`
`naloxone each
` by HPLC), Dissolution (currently Q =
` in 7 minutes for buprenorphine and Q =
`
`in 7 minutes for naloxone), Moisture content uniformity (NMT
`), Microbial limits (USP<905>), and Purity
`(HPLC). Purity requirements for Buprenorphine Related Substances include
`
` any Individual
` Purity requirements for Naloxone Related
`
`
` and for
` and the total of impurities can not exceed
`
`each NMT
`
`
` Any Individual Unidentified Impurity NMT
`
`
`Both buprenorphine and naloxone are susceptible to radical oxidative degradation processes. The
`
`degradation products forming in Suboxone
` appear consistent with those observed in the sublingual tablets,
`although there is some difference in their relative rates of formation. Based on the provided stability data, a 12
`months expiration dating is granted.
`
`The drug product is supplied in individual child-resistant polyester/foil laminated pouches available in a
`
`lower strength (buprenorphine/naloxone 2 mg/0.5 mg/strip) 30 pouches per carton (NDC 12496-1402-3), and a
`higher strength (buprenorphine/naloxone 8 mg/2 mg/strip; content expressed in terms of free base) 30 pouches per
`carton (NDC 12496-1408-3). The product is recommended to be stored at room temperature, “Store at 25 °C (77
`°F), excursions permitted to 15 - 30 °C (59 - 86 °F) [see USP Controlled Room Temperature]”, and advised to store
`it out of sight and reach of children.
`
`
`
`B. Description of How the Drug Product is Intended to be Used
`
`Suboxone
`
` is indicated for maintenance treatment of opioid dependence. The drug product is designed
`to deliver buprenorphine by the sublingual
` route; it is an alternative to the currently marketed
`Suboxone® sublingual tablet (NDA20-733).
`
`
`NDA 22-410 CMC Review # 2 Page 8 of 12
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
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`(b) (4)
`
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`
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`
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`
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`
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`
`

`

`
`
`
`
`
`CHEMISTRY REVIEW
`
`
`
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`The pending issue, an acceptable recommendation for the overall cGMP status of the manufacturing,
`
`testing and packaging facilities by the Office of Compliance, has been satisfactorily resolved (EER summary report,
`dated 20-Aug-2009, is attached).
`
`Adequate CMC information has been submitted to allow a satisfactory evaluation of the quality of both
`
`drug substance
` DMF
` and
` DMF
` for Noloxone Hydrochloride
`Dihydrate, and DMF 12412 for Buprenorphine Hydrochloride) and drug product manufactured, tested and packaged
`in accordance with the procedures and recommendations given in the original submission and pertinent
`amendments.
`
`
`
`From the CMC standpoint NDA 22-410 is recommended for approval.
`
`
`
`
`
`
`III. Administrative
`
`
`
`
`
`
`
`
`A. Reviewer’s Signature Xavier Ysern, PhD
`
`Review Chemist/ ONDQA/ DPA I/ Branch II
`
`B. Endorsement Block
`
`
`C. CC Block
`
`
`
`Ali Al-Hakim, PhD
`
`Branch Chief/ ONDQA/ DPA I/ Branch II
`
`Matthew Sullivan
`
`Project Manager/ OND/ ODE II/ DAARP
`
`NDA 22-410 CMC Review # 2 Page 9 of 12
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`3 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page.
`
`

`

`Linked Applications Submission
`Type/Number
`--------------------
`--------------------
`NDA 22410
`ORIG 1
`
`NDA 22410
`
`ORIG 1
`
`Sponsor Name
`
`Drug Name / Subject
`
`--------------------
`RECKITT
`BENCKISER
`PHARMACEUTICA
`LS INC
`RECKITT
`BENCKISER
`PHARMACEUTICA
`LS INC
`
`------------------------------------------
`SUBOXONE
`(BUPRENORPHINE/NALOXONE
`)
`
`SUBOXONE
`(BUPRENORPHINE/NALOXONE
`)
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`XAVIER J YSERN
`08/20/2009
`
`ALI H AL HAKIM
`08/20/2009
`
`

`

`
`
`
`
`CHEMISTRY REVIEW
`
`NDA 22-410
`
`
`*
`Suboxone
`(buprenorphine and naloxone) sublingual film
`2 mg/0.5 mg and 8 mg/2 mg
`
`
`Reckitt Benckiser Pharmaceuticals Inc.
`
`
`
`
`
`
`
`
`
`Xavier Ysern, PhD
`Office of New Drug Quality Assurance
`
`
`
`Division of Analgesia, Anesthesia, and Rheumatology Products (HFD-170)
`
`
`
`
`
` *
`
` The originally proposed tradename is used throughout the review. The proposed tradename is not acceptable.
`
`
`
`
`
`
`
`
`(b) (4)
`
`

`

`
`
`
`
`
`
`CHEMISTRY REVIEW
`
`
`Table of Contents...........................................................................................................................................................2
`
`Table of Contents
`
`Chemistry Review Data Sheet .......................................................................................................................................3
`
`The Executive Summary ...............................................................................................................................................6
`
`I. Recommendations ..................................................................................................................................................6
`A. Recommendation and Conclusion on Approvability.......................................................................................6
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk Management
`Steps, if Approvable........................................................................................................................................6
`
`II. Summary of Chemistry Assessments .....................................................................................................................6
`A. Description of the Drug Product(s) and Drug Substance(s)..............................................................................6
`B. Description of How the Drug Product is Intended to be Used..........................................................................8
`C. Basis for Approvability or Not-Approval Recommendation ............................................................................9
`
`III. Administrative ........................................................................................................................................................9
`A. Reviewer’s Signature........................................................................................................................................9
`B. Endorsement Block...........................................................................................................................................9
`C. CC Block ..........................................................................................................................................................9
`
`Chemistry Assessment.................................................................................................................................................10
`
`I. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data ....................................10
`S
` DRUG SUBSTANCE(S) ............................................................................................................................10
`Naloxone Hydrochloride Dihydrate,
`………………………………....11
`Naloxone Hydrochloride Dihydrate,
`……………………………………………………..20
`Buprenorphine Hydrochloride, Reckitt Benckiser Healthcare Ltd. ………………………………………..34
`
`
`
`
`
`
`P
`A
`R
`
` DRUG PRODUCT.......................................................................................................................................52
` APPENDICES…………………………………………………………………………………………….125
` REGIONAL INFORMATION.................................................................................................................1255
`
`II. Review of Common Technical Document-Quality (Ctd-Q) Module 1 ..............................................................127
`A. Labeling & Package Insert...........................................................................................................................127
`B. Environmental Assessment or Claim Of Categorical Exclusion...................................................................129
`C. Establishment of Inspection………………………………………………………………………………...129
`
`III. List of Deficiencies To Be Communicated None
`Attachments……………………………………………………………………………………………...130
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`
`Submission(s) Reviewed
`Original
`Amendments:
` 0002
` 0005
` 0009
` 0014
`
`Document Date
`20-Oct-2008
`
`30-Oct-2008 (Proposed proprietary name Suboxone
`08-Dec-2008 (Environmental Assessment)
`03-Mar-2009 (Updated stability data)
`28-Apr-2009 (Change of secondary packaging facility)
`
`
`
`
`
`7. NAME & ADDRESS OF APPLICANT:
`
`
`
`
`
`
`CHEMISTRY REVIEW
`
`
`Chemistry Review Data Sheet
`
`
`
`
`
`
`
`22-410
`
`1
`
`06-Jul-2009
`
`Xavier Ysern, PhD
`
`
`
`1. NDA :
`
`2. REVIEW #:
`
`3. REVIEW DATE:
`
`4. REVIEWER:
`
`5. PREVIOUS DOCUMENTS:
`
`
`Previous Documents
`--
`
`
`
`
`
`
`
`Document Date
`--
`
`
`
`
`
`Name: Reckitt Benckiser Pharmaceuticals Inc.
`Address: 10710 Midlothian Turnpike, Suite 430
`Richmond, VA23235
`Representative: Deborah C. Moffitt
`Manager, Regulatory Affairs Operations
`Telephone: 804 423-6970
`
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name:
` (proposed by the applicant)
`Suboxone
`
`
`b) Non-Proprietary Name (USAN):
`(buprenorphine and naloxone) sublingual film (established name)
`c) Code Name/# (ONDC only):
`--
`
`· Chem. Type:
`d) Chem. Type/Submission Priority:
` · Submission Priority:
`
`
`
`
`
`9. LEGAL BASIS FOR SUBMISSION:
`
`10. PHARMACOL. CATEGORY:
`
`11. DOSAGE FORM:
`
`12. STRENGTH/POTENCY:
`
`13. ROUTE OF ADMINISTRATION:
`
`
`
`
`
`
`
`
`
`
`S
`
`4
`
`
`505(b)(1)
`
`Treatment of opiod dependence
`
`Sublingual film
`
`2 mg/0.5 mg and 8 mg/2 mg (buprenorphine/naloxone)
`
`Sublingual
`
` route
`
`NDA 22-410 CMC Review # 1 Page 3 of 132
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`CHEMISTRY REVIEW
`
`
`
`
`
`Rx
`
`Naloxone hydrochloride dihydrate
`
`C19H21NO4·HCl·2H2O
`
`CAS RN:
`
`
`
`
`
`465-65-6 Naloxone.
`357-08-4 Naloxone hydrochloride anhydrous
`51481-60-8 Naloxone hydrochloride dihydrate
`
`Not a SPOTS product
`
`OH
`
`O
`
`O
`
`.
`
`.
`HCl H2O
`
`N
`
`OH
`
`4,5α-Epoxy-3,14-dihydroxy-17-(prop-2-enyl)morphinan-6-one hydrochloride dihydrate
`
`
`
`14. Rx/OTC DISPENSED: