CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`022410Orig1s000
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`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
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`22-410
`NDA
`Brand Name
`Generic Name
`Reviewer
`Team Leader
`OCP Division
`OND Division
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`Sponsor
`Submission Type; Code
`Formulation; Strength(s)
`
`Indication
`Proposed
`Regimen
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`Dosing
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`Oct 21, 2008
`
`Submission Date(s)
`Suboxone
`
`Buprenorphine (bup) and Naloxone (nal)
`Sheetal Agarwal, Ph.D.
`Suresh Doddapaneni, Ph.D.
`Division of Clinical Pharmacology-2
`Division of Anesthesia, Analgesia, and
`Rheumatology
`Reckitt Benckiser Pharmaceuticals Inc.
`505 (b) (1)
`S
`Sublingual film strips; 2 mg bup/0.5 nal and 8
`mg bup/2 mg nal
`Maintenance treatment of opioid dependence
`Recommended target dose for maintenance is
`16 mg bup/4 mg nal per day
`
`Addendum to the Primary Clinical Pharmacology Review Dated June 23, 2009
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`
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`This addendum addresses the two following specific issues that were not captured in
`the primary Clinical Pharmacology review authored by this reviewer dated June 23,
`2009; (1) Division of Scientific Investigations (DSI) inspection results of pivotal BA/BE
`Study 20-273-SA and (2) Implications on the bioavailability of the sublingual film strips if
`the strips were to be placed on the floor of the mouth
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` These two issues are discussed
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`below:
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`(1) DSI Inspection report of study 20-273-SA:
`At the time of signing off the primary review for NDA 22-410, report of the DSI
`inspection of Study 20-273-SA was pending. Subsequently, DSI finalized their report on
`June 29, 2009 (see review by Dr. Sean Kassim, Ph.D. dated 6/29/2009 for details).
`
`The conclusions from DSI report were:
`1. Accuracy of the reported naloxone concentrations for subjects 407 (period 2) and
`443 (all periods) has not been assured due to unresolved chromatographic
`interference in at least half the reportable naloxone values in each period. The
`naloxone data for these periods should be omitted and bioequivalence should be
`re-evaluated.
`2. The Clinical portion and the remaining analytical data from 20-273-SA are
`acceptable for review.
`
`
`This reviewer reanalyzed the data as suggested by DSI omitting the naloxone
`concentrations for subjects 407 and 443. The reanalysis showed no significant
`differences between
`the original and reanalyzed data (see
`table below) and
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`(b) (4)
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`(b) (4)
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`

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`consequently the conclusions made in the primary review dated June 23, 2009
`regarding the outcome of this study stand.
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`(2)
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` Although, not sought for approval, sponsor tested the
`buccal mode of administration as well in several of the PK studies. Although not
`reviewed in detail, a quick overview of the studies showed that the strips administered
`by buccal route were either bioequivalent (for example 2 mg, 4 mg, and 8 mg doses) or
`the bioavailability differences were minor (12 mg dose). Buccal and sublingual routes
`are considered to be two distinct routes of administration and the observation that these
`two routes of administration yielded similar bioavailability indicates lends further comfort
`that any bioavailability differences resulting from the potentially different ways in which
`the sublingual strips may have been used in the NDA database may not be clinically
`significant.
`
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`(b) (4)
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`

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`Linked Applications Submission
`Type/Number
`--------------------
`--------------------
`NDA 22410
`ORIG 1
`
`Sponsor Name
`
`Drug Name / Subject
`
`--------------------
`RECKITT
`BENCKISER
`PHARMACEUTICA
`LS INC
`
`------------------------------------------
`BUPRENORPHINE/NALOXONE
`2MG/8MG FILM STRP
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SHEETAL S AGARWAL
`07/28/2009
`
`SURESH DODDAPANENI
`07/28/2009
`
`

`

`CLINICAL PHARMACOLOGY REVIEW
`
`22-410
`NDA
`Brand Name
`Generic Name
`Reviewer
`Team Leader
`OCP Division
`OND Division
`
`Sponsor
`Submission Type; Code
`Formulation; Strength(s)
`
`Indication
`Proposed Dosing Regimen
`
`Oct 21, 2008
`
`Submission Date(s)
`Suboxone
`
`Buprenorphine (bup) and Naloxone (nal)
`Sheetal Agarwal, Ph.D.
`Suresh Doddapaneni, Ph.D.
`Division of Clinical Pharmacology-2
`Division of Anesthesia, Analgesia, and
`Rheumatology
`Reckitt Benckiser Pharmaceuticals Inc.
`505 (b) (1)
`S
`Sublingual film strips; 2 mg bup/0.5 nal and 8 mg
`bup/2 mg nal
`Maintenance treatment of opioid dependence
`Recommended target dose for maintenance is 16 mg
`bup/4 mg nal per day
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`1
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`(b) (4)
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`TABLE OF CONTENTS
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`Page Contents/Study Description
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`Cover page
`
`
`Table of Contents
`
`1.0
`Executive Summary
`1.1 Recommendation
`1.2 Phase 4 Commitment
`1.3 Summary of Important Clinical Pharmacology Findings
`1.4 Overall Summary and Conclusions
`Clinical Pharmacology Review (Question Based Review)
`2.1 General Attributes/Background
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`
`
`2.2 General Clinical Pharmacology
`2.3 General Biopharmaceutics
`2.4 Analytical Section
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`Labeling Comments
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`3.0
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`4.0 Appendices
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`
`4.1
`Individual Study Reviews
`4.1.1 Study 20-250-SA: Relative BA study for 2/0.5 mg Suboxone
`Suboxone® tablets
`4.1.2 Study 20-273-SA: Relative BA study for 8/25 mg Suboxone
`Suboxone® tablets
`4.1.3 Study 20-272-SA: Relative BA study for two of 2/0.5 mg Suboxone
` when administered at the same time vs. the same combination of
`Suboxone® tablets
`4.1.4 Study 20-B20-AU: Relative BA study for 12/3 mg Suboxone
`Suboxone® tablets
`4.1.5 Study 20-A90-AU: Relative BA study for 16/4 mg Suboxone
`Suboxone® tablets
`4.1.6 Study 1003395: Relative BA study for one of 8/2 and two of 2/0.5 mg
`Suboxone
` when administered at the same time vs. the same
`combination of Suboxone® tablets
`4.1.7 Study 20-291-SA: Dose Proportionality Study of 2/0.5, two of 2/0.5, 8/2,
`12/3 and 16/4 mg Suboxone
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`Filing Checklist
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`Page #
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`1
`2
`3
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`7
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`31
`35
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` vs.
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`2.0
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`4.2
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`2
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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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`Executive summary
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`1.0
`
`This is a 505 (b) (1) NDA for Suboxone
`C-III (buprenorphine and naloxone
`soluble film) for sublingual administration. The indication sought for the strips is
`maintenance of opioid withdrawal and the product was developed as an alternative to
`Suboxone® sublingual tablets (NDA 20-733, approved October 8, 2002, marketed in the
`US since January 2003 and currently approved in 39 countries).
`
`Per the sponsor, buprenorphine and naloxone soluble film is being developed as an
`alternative to Suboxone® tablets for the following reasons:
`• Mitigation against unintentional pediatric exposure by providing child-resistant
`packaging in unit dose format.
`• Improvement in patient convenience.
`• Protection against diversion by providing a dosage form that is very difficult for the
`patient to remove from the SL mucosa once it is administered. This will provide
`assurance to the caregiver that the dose has actually been taken appropriately.
`• Provision of a robust unit dose product form for hospital and institutional use.
`
`The sponsor proposes that the Suboxone® sublingual (SL) tablets be continued to be
`used for induction of therapy. The dosage strengths of Suboxone
` for which
`marketing approval is being sought are the same as those currently approved for
`Suboxone® sublingual tablets, i.e. buprenorphine 8 mg with naloxone 2 mg indicated as
`8/2 mg strips and buprenorphine 2 mg with naloxone 0.5 mg indicated as 2/0.5 mg strips.
`
`Buprenorphine, the primary active compound in Suboxone
`(as well as in
`Suboxone® sublingual tablets), is a partial opioid agonist with a high affinity for the mu-
`opioid receptor and lower intrinsic activity than full opioid agonists. Naloxone (an
`antagonist at the mu-opioid receptor) is included in the formulation to discourage
`diversion and abuse of Suboxone® Tablets
`. The primary purpose of inclusion
`of naloxone in these products is to prevent the intravenous misuse of buprenorphine
`(concept originally used in currently marketed pentazocine product, Talwin® NX). This
`could be done because naloxone exhibits poor oral and sublingual bioavailability.
`Therefore, if Suboxone
` is misused or abused by injection, the naloxone
`component is expected to antagonize the opioid agonist effects of buprenorphine and
`potentially precipitate withdrawal in an individual dependent on full opioid agonists and
`therefore discourage the individual to abuse the product.
`
`1.1
`
`The Office of Clinical Pharmacology / Division of Clinical Pharmacology 2 (OCP/DCP-
`
`C-III (buprenorphine and naloxone
`2) has reviewed NDA 22-410 for Suboxone
`soluble film) for sublingual administration and finds it acceptable provided that (a) the
`DSI audit report for the BE study (Study 20-273 SA) finds the study acceptable and (b)
`the Agency and the sponsor agree on the labeling.
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`Recommendation
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`3
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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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`Phase 4 Commitments
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`Summary of Important Clinical Pharmacology Findings
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`1.2
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`None.
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`1.3
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`The Clinical Pharmacology package submitted for this NDA consisted of 19 Phase 1 PK
`studies conducted in healthy adult volunteers (including pilot, pivotal BE and dose and
`dosage form proportionality studies, studies with other strengths of Suboxone
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`and 1 clinical study in a patient population to determine local oral tolerability with the
`soluble film dosage form. The primary support for the clinical safety and efficacy of the
`Suboxone
` 8mg/2mg and 2mg/0.5mg formulations comes from the established
`safety and efficacy data on Subutex® (NDA 20-732) and Suboxone® sublingual tablets
`(NDA 20-733). No special population or drug-drug interaction studies were conducted in
`this NDA. The Sponsor is relying on Agency’s previous findings for Suboxone®
`sublingual tablets to construct their labeling for special populations (e.g., renal and
`hepatic impairment patients, elderly patients) and drug-drug interactions. Refer to
`Clinical Pharmacology review by Dr. Suresh Doddapaneni for NDA 20-733 for details.
`
`Out of the 19 PK studies submitted, 7 were deemed relevant for this NDA and were
`reviewed. Out of the 7 studies reviewed, 4 were thoroughly reviewed because they form
`the basis of approval for the subject matter of this NDA and the other 3 are considered
`additional supportive studies. The other 10 PK studies submitted included testing of
` the buccal route of administration for
` Conclusions from the four relative BA studies
` Suboxone
`employing the two film strips for which approval is sought are presented below:
`
`Study 20-250-SA (Buprenorphine and Naloxone 1 x 2 mg/0.5 mg Soluble Film v/s
`Tablet)
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`The upper 90% CI limit for buprenorphine just misses the upper limit of 125% for Cmax
`(131.43) but the 90% CI limits are within 80-125% of the reference treatment for
`AUClast and AUCinf for SL strips indicating that the SL strips are not equivalent with
`respect to (w.r.t) the rate of absorption but are equivalent w.r.t the extent of absorption of
`buprenorphine to the reference product, SL tabs. In addition, the two treatments are
`equivalent w.r.t rate of absorption of naloxone. Since naloxone plasma concentrations
`were below the limit of quantification for a number of subjects, its AUC values are
`unreliable. Nonetheless, the 90% CI limits for naloxone are within 80-125% of the
`reference treatment for AUClast and AUCinf.
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`Study 20-273-SA (Buprenorphine and Naloxone 1 x 8 mg/2 mg Soluble Film v/s
`Tablet)
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`The upper 90% CI limits for buprenorphine and naloxone are slightly above 125% for all
`the three PK parameters measured Cmax, AUClast and AUCinf for SL strips indicating
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` the
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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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`that the SL strips are not bioequivalent based on both, the rate and extent of absorption,
`of buprenorphine or naloxone, to the reference product, SL tabs.
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`Study 20-272-SA (Buprenorphine and Naloxone two of 2 mg/0.5 mg Soluble Films
`v/s Tablets for a total dose of 4 mg buprenorphine/ 1 mg naloxone)
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`The 90% CI limits for buprenorphine and naloxone are all within 80-125% for all the
`three PK parameters measured Cmax, AUClast and AUCinf for the SL strips indicating
`that the SL strips are bioequivalent based on both, the rate and extent of absorption, of
`buprenorphine or naloxone to the reference product, SL tabs for a total dose of 4 mg
`buprenorphine and 1 mg naloxone when administered as a combination of two 2/0.5 mg
`strips together.
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`Study 1003395 (Buprenorphine and Naloxone one of 8 mg/2 mg and two of 2 mg/0.5
`mg Soluble Films v/s Tablets for a total dose of 12 mg buprenorphine/ 3 mg
`naloxone)
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`The 90% CI limits for buprenorphine and naloxone are all within 80-125% for all the
`three PK parameters measured Cmax, AUClast and AUCinf for the SL strips indicating
`that the SL strips are bioequivalent based on both, the rate and extent of absorption, of
`buprenorphine or naloxone to the reference product, SL tabs for a total dose of 12 mg
`buprenorphine and 3 mg naloxone when administered as a combination of one 8/2 mg
`and two 2/0.5 mg strips together.
`
` are or are close
`Therefore, overall the 2/0.5, 4/1 and 12/3 doses of the Suboxone
` fails the
`to being bioequivalent to the tablets. The 8/2 mg dose of the Suboxone
`BE test on both rate and extent of absorption for both the buprenorphine and opioid
`components; however the levels overall are only slightly higher than the tablets.
`
`For the 2/0.5 and 8/2 doses, since the failure in BE for buprenorphine and naloxone is on
`the higher end, the therapeutic efficacy of the new product (strips) w.r.t buprenorphine
`and naloxone is not expected to be compromised. However, safety implications of the
`higher exposure with SL strips relative to the approved SL tablets (and the clinical trial
`formulation of aqueous ethanolic solution in the SL Tablets NDAs) has to be considered.
`It should be noted that the exposure of buprenorphine from Suboxone® SL film strips is
`much lower than that for the aqueous ethanolic solution of buprenorphine which was
`employed as the Clinical Trial formulation supporting the original NDAs 20-732 and 20-
`733. For the Suboxone® SL tablet NDA, the Division Director’s Review of NDA and
`Basis for Action concluded that the relative bioavailability for the 8 mg/2 mg Suboxone®
`tablet relative to the solution was 0.66 (66%). Thus, relative to the approved Suboxone®
`tablet, the bioavailability of the solution was 1.52 (the reciprocal of 0.66 is 152%).
`Therefore, even though the bioavailability of buprenorphine from the buprenorphine and
`naloxone soluble film (Suboxone
` is somewhat higher than the tablets (overall,
`about 20% higher than the tablets), it is still less than that observed for the aqueous
`ethanolic solution. So applying the same basis of acceptance of safety of higher
`buprenophine levels from Suboxone® tablets when compared to the ethanolic solution as
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`employed in NDA # 20-733 (for Suboxone® tablets), the relative bioavailability for the 8
`mg/2 mg Suboxone
` relative to the solution can be considered as 0.84 (0.66 +
`20% of 0.66) which is still lower than the solution and therefore the safety of the higher
`bioavailability of buprenorphine from Suboxone
` is covered by the available data
`from NDAs 20-732 and 20-733.
`
`Naloxone plasma levels though higher when Suboxone® film strips were administered
`when compared to Suboxone® tablets, are still below those that can precipitate
`withdrawal symptoms and compromise efficacy and therefore are deemed not to be of
`concern. In clinical study RB-US-07-0001, submitted in the current NDA, despite the
`sub-optimal design of the study, (refer to the review by Dr. Celia Winchell for additional
`details), it did not appear that there was significant concern about precipitation of
`withdrawal from the SL strips, lending additional support that the slightly higher
`naloxone exposure is not high enough to cause precipitation of withdrawal.
`
`
`1.4 Overall conclusions
`
` exhibited enhanced
`1.4.1 Although the 2/0.5 mg and the 8/2 mg Suboxone
`bioavailability of buprenorphine in two out of the four studies employing these
`strips, the levels are lower than those established for a safe and effective
`sublingual solution of buprenorphine that was employed as a Clinical Trial
`formulation for approval of precursor Subutex® and Suboxone® tablets.
`1.4.2 Higher naloxone levels seen for SL
` relative to those seen with SL tablets
`are still considered low to cause precipitation of opioid withdrawal.
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`(b) (4)
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`(b) (4)
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`2.0 Question Based Review
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`2.1 General Attributes of the Drug
`
`2.1.1 What pertinent regulatory background or history contributes to the current
`assessment of the clinical pharmacology and biopharmaceutics of this drug?
`
`
`Buprenorphine is a thebaine-derived partial agonist of the opioid (morphine-type) µ-
`receptor and an antagonist of the opioid (dynorphin-type) κ-receptor initially approved by
`the FDA (1982) in an injectable formulation, Buprenex®, for the treatment of moderate
`to severe pain.
`
`Since initial approval, addiction researchers have explored buprenorphine’s utility in
`maintenance treatment for opiate addiction. Most of the research on buprenorphine in this
`clinical context was performed through NIH funding (National Institute on Drug Abuse)
`through individual research grants. Reckitt & Colman Pharmaceuticals Inc. and National
`Institute on Drug Abuse (NIDA) have been engaged in a Cooperative Research and
`Development Agreement (CRADA) to develop buprenorphine alone (Subutex®) and in
`combination with naloxone (Suboxone®) for the treatment of opiate dependence.
`
`The development of buprenorphine in high doses as a treatment for opiate dependence
`began with a sublingual ethanolic solution. Indeed most of the clinical research that has
`been conducted with this drug substance used that formulation.
`
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`
`
` Thus, the
`sponsor initiated a new development program using a sublingual tablet. Since alcohol
`increases the bioavailability of buprenorphine, it was soon discovered that the new
`sublingual tablet was not bioequivalent to the sublingual solution, milligram for
`milligram. The ensuing development program for the tablet formulation, therefore,
`focused on three factors (1) establishing a relationship between the tablet and the
`sublingual solution which, in the absence of bioequivalence, would allow for the treating
`physician to accurately approximate the dosing regimen shown to be effective and safe in
`clinical trials using the solution (2) absent the above relationship, adequate and well
`controlled studies demonstrating the efficacy of the sublingual buprenorphine tablet in
`the treatment of opiate addiction and (3) the development of a combination product with
`naloxone and buprenorphine which would have equivalent efficacy but would, by virtue
`of the small dose of naloxone present, and the poor sublingual bioavailability, be a
`deterrent to intravenous abuse, therefore improving its safety profile. Pursuant to this,
`Subutex® and Suboxone® tablets were approved under NDA 20-732 and 20-733
`respectively. The safety and efficacy claims for buprenorphine and buprenorphine and
`naloxone for both Subutex® and Suboxone® sublingual tablets respectively, came from
`buprenorphine sublingual solution.
`
`The NDA (20-732) for Subutex® was submitted in 1997 and an approvable action was
`taken in 1998 pending resolution of several deficiencies. Although the clinically tested
`sublingual 30% alcoholic solution and the to-be-marketed Subutex® sublingual tablet
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`7
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`(b) (4)
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`(strengths of 2 and 8 mg) dosage forms were not found to be bioequivalent with respect
`to buprenorphine (the solution being more bioavailable as compared to the tablets),
`available data permitted adequate conversion of tablet doses achieved to corresponding
`efficacious solution doses; the main consideration being that since the tablets have a
`lower bioavailability relative to the solution and the highest tablet dose proposed is 24
`mg, there is a considerable safety margin with the tablet in the proposed dosage regimen.
`
`The NDA (20-733) for Suboxone® was submitted in 1999 and approved in 2002. In this
`NDA, proposed maintenance dosing range of 4 mg to 24 mg with Suboxone® tablets
`approximated the buprenorphine sublingual solution doses of 2.8 mg to 16.8 mg applying
`a constant relative bioavailability of 0.7 throughout the dose range. 16 mg dose of
`Suboxone® and Subutex® were found to result in similar Cmax and AUC values
`indicating that naloxone does not affect the pharmacokinetics of buprenorphine. This
`combined with the fact that the two formulations are compositionally similar led to the
`conclusion that Suboxone® and Subutex® will deliver similar buprenorphine
`concentrations. In part, the basis for accepting the buprenorphine SL solution efficacy
`data in support of the Suboxone® application was the premise that the naloxone in
`Suboxone® was inactive when used as directed. It was known that there were extremely
`low but detectable levels of naloxone associated with the 8:2 and16:4 doses of
`Suboxone®. The application had to therefore demonstrate that these low levels did not
`affect the overall efficacy of the product. The efficacy of both Suboxone® and Subutex®
`in Study 1008a was established with a placebo control and the success rate, albeit for one
`month of treatment, was comparable. In addition, the absence of precipitated withdrawal
`in patients treated with Suboxone® or in patients switching from Subutex to Suboxone®
`(following induction) was the most compelling evidence in support of this premise.
`Naloxone in buprenorphine/naloxone is not significantly absorbed sublingually, and
`therefore, most of the dose is available for GI absorption. There has not been a robust
`evaluation of the chronic oral toxicity of naloxone, which was initially developed as a
`single-use agent for intravenous administration. The development plan for
`buprenorphine/naloxone should, therefore, have included a up to a minimum of 6-months
`to a year of safety data for the combination product doses of naloxone of up to 6 mg/day
`(more typically 2 mg/day). In the open label extension, Study 1008(b) approximately 250
`patients were exposed to naloxone for up to 6 months in doses for which this product will
`be labeled. No unexpected adverse events were noted in this experience. In addition,
`naloxone plasma concentrations were in general found to be very low, when
`Suboxone® was administered in the dose range of 4 to 16 mg.
`
`The objective of the clinical development program for buprenorphine and naloxone
`soluble film, Suboxone
` (the subject of this NDA # 22-410) was to generate
`comparative pharmacokinetic (PK) data between the approved Suboxone® sublingual
`tablet and the soluble film dosage forms. This comparison was then to be used to connect
`the established safety and efficacy of Suboxone® SL tablets (NDA #20-733) to
`buprenorphine and naloxone soluble film dosage forms (NDA #22-410).
`
` A
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` and 75,811 on
` type B pre-NDA meeting was held for this product under IND #s
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`June 24, 2008. This 505 (b) (1) NDA for Suboxone
`C-III (buprenorphine and
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`8
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`(b) (4)
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`(b) (4)
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`(b) (4)
`
`

`

`naloxone soluble film) for sublingual administration was submitted to FDA on October
`21, 2008. A standard review status was granted for this NDA.
`
`The indication sought for the strips is maintenance of opioid withdrawal and the product
`was developed as an alternative to Suboxone® sublingual tablets (NDA 20-733,
`approved October 8, 2002, marketed in the US since January 2003 and currently
`approved in 39 countries). FDA’s Office of Orphan Product Development has determined
`that buprenorphine qualifies for orphan designation for the treatment of opiate addiction
`in opiate users based on the projected low commercial potential. Because of the orphan
`drug status, the sponsor is exempt from pediatric study requirements under PREA.
`
`2.1.2 What are the highlights of the properties of the drug or the formulation as they
`relate to clinical pharmacology review?
`
`
`
`
`Buprenorphine is a weak base with a pKa of 8.4. As such, pH of the saliva will
`play a role in the amount of buprenorphine absorbed from the oral mucosa. The solubility
`of buprenorphine is 1.1 mg/mL at pH 6 but only 0.11 at pH 7, a 10-fold decrease. It is
`highly lipid soluble (log partition coefficient of octanol/pH 6.6 is 3.37). Buprenorphine
`occurs as a white to off-white, crystalline powder, sparingly soluble in water, freely
`soluble in methanol, soluble in alcohol and practically insoluble in cyclohexane.
`
`Naloxone is white, or almost white crystalline powder and is hygroscopic. It is freely
`soluble in water, soluble in alcohol; practically insoluble in toluene.
`
`(buprenorphine/ naloxone) soluble film is a pale orange film strip,
`Suboxone
`imprinted with a logo identifying the product and strength in white ink. Suboxone
`is available in the following strengths/dimensions:
`
` •
`
` (8 mg buprenophine/2 mg naloxone), soluble film contains 8 mg
` Suboxone
`buprenorphine (as 8.64 mg buprenorphine hydrochloride [HCl]) and 2 mg naloxone (as
`2.44 mg naloxone HCl dihydrate); dimensions 0.875 inch x 0.5 inch
`
` •
`
` (2 mg buprenophine/0.5 mg naloxone), soluble film contains 2 mg
` Suboxone
`buprenorphine (as 2.16 mg buprenorphine HCl) and 0.5 mg naloxone (as 0.61 mg
`naloxone HCl dihydrate); dimensions 0.875 inch x 0.5 inch
`
`strength utilizes a different formulation and these are designated
`Each Suboxone
`‘high strength’ and ‘low strength’ for the 8 mg/ 2 mg and 2 mg/ 0.5 mg products
`respectively.
`
`
`
`
`
`
`
`
`
`
`9
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Quantitative Formula for Suboxone
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`10
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Although at this time, approval is sought only for the 2/0.5 and the 8/2 mg strips, the 12/3
`and the 16/4 mg strips were employed in relative BA studies 20-B90-AU and 20-A90-
`AU respectively and also in Study 20-291-SA, a dose proportionality study, reviewed in
`this NDA.
`
`
`
`
` The following two tables list the strip dimensions and the compositions.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`11
`
`(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)
`
`

`

`2.1.3 What are the proposed mechanism(s) of action and therapeutic indication(s)?
`
` (as well as in
`Buprenorphine, the primary active compound in Suboxone
`Suboxone® sublingual tablets), is a partial opioid agonist with a high affinity for the mu-
`opioid receptor and lower intrinsic activity than full opioid agonists.
`
`Naloxone (USP monograph name naloxone hydrochloride) is used by the injection route
`to reverse opioid overdose or opioid side effects such as respiratory depression. As an
`antagonist, the naloxone binds to the receptor but does not give resultant pharmacological
`effects. When full agonists are occupying the receptors in the brain and exerting an effect,
`the naloxone displaces the agonist and binds to the receptor, thereby removing the effect
`of the agonist and allowing the body to recover. The net effect is a reversal of the opioid
`agonist effects. Naloxone is poorly bioavailable by the sublingual route but has increased
`bioavailability when injected. The inclusion of naloxone with buprenorphine in the
`Suboxone® product is designed to reduce the abuse potential compared to a
`buprenorphine only product.
`
`The therapeutic indication is for maintenance treatment of opioid dependence.
`
`2.1.4 What are the proposed dosage and route of administration?
`
` for which marketing approval is being sought
`The dosage strengths of Suboxone
`are the same as those currently approved for Suboxone® sublingual tablets, i.e.
`buprenorphine 8 mg with naloxone 2 mg indicated as 8/2 mg strips and buprenorphine 2
`mg with naloxone 0.5 mg indicated as 2/0.5 mg strips.
`
`2.2 General Clinical Pharmacology
`
`The Clinical Pharmacology package submitted for this NDA consisted of 19 Phase 1 PK
`studies conducted in healthy adult volunteers (including pilot, pivotal BE and dose and
`dosage form proportionality studies) and 1 clinical study in a patient population to
`determine local oral tolerability with the soluble film dosage form. The primary support
`for the clinical safety and efficacy of the Suboxone
` 8mg/2mg and 2mg/0.5mg
`formulations comes from the established safety and efficacy data on Suboxone®
`sublingual tablets (NDA 20-733). No special population or drug-drug interaction studies
`were conducted in this NDA. The Sponsor is relying on Agency’s previous findings for
`Suboxone® sublingual tablets to construct their labeling for special populations (e.g.,
`renal and hepatic impairment patients, elderly patients) and drug-drug interactions. Refer
`to Clinical Pharmacology review by Dr. Suresh Doddapaneni for NDA 20-733 for all
`General Clinical Pharmacology details (including information related to ADME, Intrisic
`and Extrinsic factors).
`
`
`
`
`
`
`
`
`12
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`2.2.1 What are the design features of the clinical pharmacology and clinical studies
`used to support dosing or claims?
`
`Nineteen PK studies were submitted in the Clinical Pharmacology package of this NDA.
`Out of the 19, 7 were deemed relevant and reviewed for this NDA. The design features of
`those 7 studies are presented below in a tabular format:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`13
`
`

`

`Study No.
`
`Study Objective(s)
`
`Study Design
`
`Treatment, Dose
`[Lot or Product ID]
`
`No. Subjects
`Age Range
`(Mean)
`Buprenorphine and Naloxone Pivotal Bioequivalence Studies (All studies conducted in healthy volunteers under naltrexone block)
`45
`OL, R, single-dose,
`20-250-SA
`Compare the rate and extent of
`Suboxone® SL tablet
`(31M/14F)
`3-period, 3-treatment
`1 x 2 mg/0.5 mg
`both SL and buccal absorption of an
`[Lot #723403]
`Completed:
`(14-day washout),
`investigational formulation of buprenorphine
`39
`balanced crossover
`and naloxone soluble film dosage 2 mg/0.5
`Test 1
`18-43 (30)
`SL and buccal
`mg to
`SL buprenorphine and naloxone
`following an overnight
`an equivalent SL dose of the
`soluble film C-III
`fast of at least 10 hours
`commercially available reference product,
`1 x 2 mg/0.5 mg
`Suboxone® tablets.
`[Lot #H07DW101-288]
`Test 2
`Buccal buprenorphine and
`naloxone
`soluble film C-III
`1 x 2 mg/0.5 mg
`[Lot #H07DW101-288]
`Ref
`Suboxone® SL tablet
`2 x 2 mg/0.5 mg tablet
`[Lot #730901]
`Test 1
`SL buprenorphine and naloxone
`soluble film C-III
`2 x 2 mg/0.5 mg
`[Lot #A08DW101-024]
`Test 2
`Buccal buprenorphine and
`naloxone
`soluble film C-III2 x 2 mg/0.5
`mg
`[Lot #A08DW101-024]
`
`20-272-SA
`
`Compare the rate and extent of
`both SL and buccal absorption of an
`investigational formulation of buprenorphine
`and naloxone soluble film dosage (4 mg/1 mg
`administered as two 2 mg/0.5 mg soluble
`films) to an equivalent SL dose of the
`commercially available
`reference product, Suboxone®
`tablets.
`
`Single-dose, OL, R,
`3-period, 3-treatment
`(14-day washout),
`3-way balanced crossover
`study SL and buccal
`following an overnight
`fast of at least 10 hours
`
`Enrolled:
`48
`(39M/9F)
`Completed:
`37
`19-45 (32)
`
`
`
`14
`
`

`

`20-273-SA
`
`Compare the rate and extent of
`both SL and buccal absorption of an
`investigational formulation of buprenorphine
`and naloxone 12 mg/3 mg soluble film, to an
`equivalent SL dose of the commercially
`available reference product, (one 8 mg/2 mg
`plus two
`2 mg/0.5 mg tablets), Suboxone®
`tablets.
`
`Single-dose, OL, R,
`3-period, 3-treatment
`(14-day washout), 3-way
`balanced crossover SL and
`buccal following an overnight
`fast of at least 10 hours
`
`Enrolled:
`48
`(26M/22F)
`Completed:
`42
`18-45 (30)
`
`20-B20-AU
`
`Compare the rate and extent of
`both SL and buccal absorption of an
`investigational formulation of buprenorphine
`and naloxone 12 mg/3 mg