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

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`Reviewer: Elizabeth A. Bolan, Ph.D.
`
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`
` NDA 22-410
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`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
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`PHARMACOLOGY/TOXICOLOGY REVIEW AND EVALUATION
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`
`
`22-410
`
`
`NDA NUMBER:
`000
`
`
`SERIAL NUMBER:
`February 4, 2009
`DATE RECEIVED BY CENTER:
`Suboxone
` (buprenorphine and naloxone)
`PRODUCT:
`
`
`
`Treatment of opioid dependence
`INTENDED CLINICAL POPULATION:
`Reckitt Benckiser Pharmaceuticals, Inc.
`
`APPLICANT:
`
`
`
`All nonclinical information in the above
`
`DOCUMENTS REVIEWED:
`
`submission
`
`
`
`
`
`
`Division of Analgesia, Anesthesia and
`
`REVIEW DIVISION:
`
`
`
` Rheumatology Products (HFD-170)
`Elizabeth A. Bolan, Ph.D.
`PHARM/TOX REVIEWER:
`
`
`R. Daniel Mellon, Ph.D.
`PHARM/TOX SUPERVISOR:
`
`
`Bob Rappaport, M.D.
`DIVISION DIRECTOR:
`
`
`
`Matthew Sullivan
`PROJECT MANAGER:
`
`
`
`
`Date of review submission to Division File System (DFS): May 22, 2009
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`1
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`(b) (4)
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`

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`Reviewer: Elizabeth A. Bolan, Ph.D.
`
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`
` NDA 22-410
`
`
`TABLE OF CONTENTS
`
`EXECUTIVE SUMMARY .............................................................................................. 3
`
`2.6 PHARMACOLOGY/TOXICOLOGY REVIEW................................................... 9
`
`2.6.1 INTRODUCTION AND DRUG HISTORY................................................................... 9
`
`2.6.2 PHARMACOLOGY....................................................................................................... 15
`2.6.2.1
`Brief summary ...................................................................................................................... 16
`2.6.2.2
`Primary pharmacodynamics ................................................................................................. 16
`2.6.2.3
`Secondary pharmacodynamics ............................................................................................. 16
`2.6.2.4
`Safety pharmacology ............................................................................................................ 17
`2.6.2.5
`Pharmacodynamic drug interactions..................................................................................... 17
`
`2.6.3 PHARMACOLOGY TABULATED SUMMARY....................................................... 17
`
`2.6.4 PHARMACOKINETICS/TOXICOKINETICS .......................................................... 17
`2.6.4.1
`Brief summary ...................................................................................................................... 17
`2.6.4.2 Methods of Analysis............................................................................................................. 17
`2.6.4.3
`Absorption ............................................................................................................................ 18
`2.6.4.4
`Distribution........................................................................................................................... 18
`2.6.4.5 Metabolism........................................................................................................................... 18
`2.6.4.6
`Excretion............................................................................................................................... 18
`2.6.4.7
`Pharmacokinetic drug interactions........................................................................................ 18
`2.6.4.8
`Other Pharmacokinetic Studies............................................................................................. 18
`2.6.4.9
`Discussion and Conclusions ................................................................................................. 19
`2.6.4.10 Tables and figures to include comparative TK summary .......................................................... 19
`
`2.6.5 PHARMACOKINETICS TABULATED SUMMARY............................................... 19
`
`2.6.6 TOXICOLOGY .............................................................................................................. 19
`2.6.6.1
`Overall toxicology summary ................................................................................................ 20
`2.6.6.2
`Single-dose toxicity .............................................................................................................. 20
`2.6.6.3
`Repeat-dose toxicity ............................................................................................................. 20
`2.6.6.4
`Genetic toxicology................................................................................................................ 20
`2.6.6.5
`Carcinogenicity..................................................................................................................... 31
`2.6.6.6
`Reproductive and developmental toxicology........................................................................ 54
`2.6.6.8
`Special toxicology studies .................................................................................................... 54
`2.6.6.10 Tables and Figures..................................................................................................................... 54
`
`2.6.7 TOXICOLOGY TABULATED SUMMARY .............................................................. 54
`
`OVERALL CONCLUSIONS AND RECOMMENDATIONS............................................... 55
`
`APPENDIX/ATTACHMENTS ................................................................................................. 60
`
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`2
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`

`

`Reviewer: Elizabeth A. Bolan, Ph.D.
`
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`
` NDA 22-410
`
`EXECUTIVE SUMMARY
`
`Recommendations
`
`A. Recommendation on approvability
`This NDA can be approved from a nonclinical pharmacology/toxicology
`perspective.
`
`B. Recommendation for nonclinical studies
`There are no recommendations for nonclinical studies.
`
`
`I.
`
`
`
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`
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`C. Recommendations on labeling
`The table below contains the draft labeling submitted by the Applicant, the
`proposed changes and the rationale for the proposed changes. For the final
`version of the label, please refer to the Action Letter. Note: The recommended
`changes from the proposed labeling are in red or strikeout font.
`
`Applicant’s proposed labeling
`
`Rationale for changes
`
`no changes to this section.
`
`Reviewer’s proposed changes
`
` 8
`
` USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`Pregnancy Category C.
`
` 8
`
` USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`Pregnancy Category C.
`
`
`Teratogenic effects:
`Effects on embryo-fetal development
`were studied in Sprague-Dawley rats and
`Russian white rabbits following oral (1:1)
`and intramuscular (IM) (3:2)
`administration of mixtures of
`buprenorphine and naloxone. Following
`oral administration to rats and rabbits, no
`teratogenic effects were observed at
`buprenorphine doses up to 250
`mg/kg/day and 40 mg/kg/day, respectively
`(estimated exposure approximately 150
`times and 50 times, respectively, the
`recommended human daily sublingual
`dose of 16 mg on a mg/m² basis). No
`definitive drug-related teratogenic effects
`were observed in rats and rabbits at IM
`doses up to 30 mg/kg/day (estimated
`
`
`Teratogenic effects:
`Effects on embryo-fetal development
`were studied in Sprague-Dawley rats and
`Russian white rabbits following oral (1:1)
`and intramuscular (IM) (3:2)
`administration of mixtures of
`buprenorphine and naloxone. Following
`oral administration to rats and rabbits, no
`teratogenic effects were observed at
`buprenorphine doses up to 250
`mg/kg/day and 40 mg/kg/day, respectively
`(estimated exposure approximately 150
`times and 50 times, respectively, the
`recommended human daily sublingual
`dose of 16 mg on a mg/m² basis). No
`definitive drug-related teratogenic effects
`were observed in rats and rabbits at IM
`doses up to 30 mg/kg/day (estimated
`
`
`
`
`3
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`(b) (4)
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`

`

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` NDA 22-410
`
`Reviewer: Elizabeth A. Bolan, Ph.D.
`
`
`exposure approximately 20 times and 35
`times, respectively, the recommended
`human daily dose of 16 mg on a mg/m²
`basis). Acephalus was observed in one
`rabbit fetus from the low-dose group and
`omphacele was observed in two rabbit
`fetuses from the same litter in the mid
`dose group; no findings were observed in
`fetuses from the high dose group.
`Following oral administration of
`buprenorphine to rats, dose-related post-
`implantation losses, evidenced by
`increases in the numbers of early
`resorptions with consequent reductions in
`the numbers of fetuses, were observed at
`doses of 10 mg/kg/day or greater
`(estimated exposure approximately 6
`times the recommended human daily
`sublingual dose of 16 mg on a mg/m²
`basis). In the rabbit, increased post
`implantation losses occurred at an oral
`dose of 40 mg/kg/day. Following IM
`administration in the rat and the rabbit,
`post-implantation losses, as evidenced by
`decreases in live fetuses and increases in
`resorptions, occurred at 30 mg/kg/day. In
`rabbits, buprenorphine produced
`statistically significant pre-implantation
`losses at oral doses of 1 mg/kg/day or
`greater and post-implantation losses that
`were statistically significant at intravenous
`(IV) doses of 0.2 mg/kg/day or greater
`(estimated exposure approximately 0.3
`times the recommended human daily
`sublingual dose of 16 mg on a mg/m2
`basis).
`
`Non-teratogenic effects:
`Dystocia was noted in pregnant rats
`treated intramuscularly with
`buprenorphine 5 mg/kg/day
`(approximately 3 times the recommended
`human daily sublingual dose of 16 mg on
` fertility, peri-, and
`a mg/m² basis).
`post-natal development studies with
`buprenorphine in rats indicated increases
`in neonatal mortality after oral doses of
`0.8 mg/kg/day and up (approximately 0.5
`times the recommended human daily
`sublingual dose of 16 mg on a mg/m²
`basis), after IM doses of 0.5 mg/kg/day
`and up (approximately 0.3 times the
`recommended human daily sublingual
`dose of 16 mg on a mg/m² basis), and
`after subcutaneous doses of 0.1
`
`exposure approximately 20 times and 35
`times, respectively, the recommended
`human daily dose of 16 mg on a mg/m²
`basis). Acephalus was observed in one
`rabbit fetus from the low-dose group and
`omphacele was observed in two rabbit
`fetuses from the same litter in the mid
`dose group; no findings were observed in
`fetuses from the high dose group.
`Following oral administration of
`buprenorphine to rats, dose-related post-
`implantation losses, evidenced by
`increases in the numbers of early
`resorptions with consequent reductions in
`the numbers of fetuses, were observed at
`doses of 10 mg/kg/day or greater
`(estimated exposure approximately 6
`times the recommended human daily
`sublingual dose of 16 mg on a mg/m²
`basis). In the rabbit, increased post
`implantation losses occurred at an oral
`dose of 40 mg/kg/day. Following IM
`administration in the rat and the rabbit,
`post-implantation losses, as evidenced by
`decreases in live fetuses and increases in
`resorptions, occurred at 30 mg/kg/day. In
`rabbits, buprenorphine produced
`statistically significant pre-implantation
`losses at oral doses of 1 mg/kg/day or
`greater and post-implantation losses that
`were statistically significant at intravenous
`(IV) doses of 0.2 mg/kg/day or greater
`(estimated exposure approximately 0.3
`times the recommended human daily
`sublingual dose of 16 mg on a mg/m2
`basis).
`
`Non-teratogenic effects:
`Dystocia was noted in pregnant rats
`treated intramuscularly with
`buprenorphine 5 mg/kg/day
`(approximately 3 times the recommended
`human daily sublingual dose of 16 mg on
` fertility, peri-, and
`a mg/m² basis).
`post-natal development studies with
`buprenorphine in rats indicated increases
`in neonatal mortality after oral doses of
`0.8 mg/kg/day and up (approximately 0.5
`times the recommended human daily
`sublingual dose of 16 mg on a mg/m²
`basis), after IM doses of 0.5 mg/kg/day
`and up (approximately 0.3 times the
`recommended human daily sublingual
`dose of 16 mg on a mg/m² basis), and
`after subcutaneous doses of 0.1
`
`
`
`
`4
`
`(b) (4)
`
`(b) (4)
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`

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` NDA 22-410
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`Alderley is misspelled
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`AUC comparisons were
`added
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` carcinogenicity study of
`buprenorphine/naloxone (4:1 ratio of the
`free bases) was performed in Alderley
`Park rats. Buprenorphine/naloxone was
`administered in the diet at doses of
`approximately 7, 31, and 123 mg/kg/day
`for 104 weeks (estimated exposure was
` 4, 18 and
`approximately
`44 times the
` recommended
`human sublingual dose of
` 16/4 mg
`buprenorphine/naloxone based on
`buprenorphine AUC comparisons
`
`
`
` A
`statistically significant increase in Leydig
`cell adenomas was observed in all dose
`
`groups.
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` No other drug-related
`increases in tumors were noted.
`
`Carcinogenicity studies of buprenorphine
`were conducted in Sprague-Dawley rats
`and CD-1 mice. Buprenorphine was
`administered in the diet to rats at doses of
`0.6, 5.5, and 56 mg/kg/day (estimated
`exposure was approximately 0.4, 3, and
`35 times the recommended human daily
`sublingual dose of 16 mg on a mg/m2
`basis) for 27 months. As in the
`buprenorphine/naloxone carcinogenicity
`study in rat, statistically significant dose-
`
`
`
`
`5
`
`Reviewer: Elizabeth A. Bolan, Ph.D.
`
`
`mg/kg/day and up (approximately 0.06
`times the recommended human daily
`sublingual dose of 16 mg on a mg/m²
`basis). Delays in the occurrence of
`righting reflex and startle response were
`noted in rat pups at an oral dose of 80
`mg/kg/day (approximately 50 times the
`recommended human daily sublingual
`dose of 16 mg on a mg/m² basis).
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis,
`Impairment of Fertility
`
`Carcinogenicity:
`Carcinogenicity data on SUBOXONE
` are not available.
`
`mg/kg/day and up (approximately 0.06
`times the recommended human daily
`sublingual dose of 16 mg on a mg/m²
`basis). Delays in the occurrence of
`righting reflex and startle response were
`noted in rat pups at an oral dose of 80
`mg/kg/day (approximately 50 times the
`recommended human daily sublingual
`dose of 16 mg on a mg/m² basis).
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis,
`Impairment of Fertility
`
`Carcinogenicity:
`Carcinogenicity data on SUBOXONE
` are not available.
`
` A
`
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Reviewer: Elizabeth A. Bolan, Ph.D.
`
`
`
`
`
`
` In an 86-week study in CD-1
`mice, buprenorphine was not
`carcinogenic at dietary doses up to 100
`mg/kg/day (estimated exposure was
`approximately 30 times the recommended
`human daily sublingual dose of 16 mg on
`a mg/m2 basis).
`
`
`
`
`Mutagenicity:
`The 4:1 combination of buprenorphine
`and naloxone was not mutagenic in a
`bacterial mutation assay (Ames test)
`using four strains of S. typhimurium and
`two strains of E. coli. The combination
`was not clastogenic in an in vitro
`cytogenetic assay in human lymphocytes,
`or in an intravenous micronucleus test in
`the rat.
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`Impairment of Fertility:
`Dietary administration of buprenorphine in
`the rat at dose levels of 500 ppm or
`greater (equivalent to approximately 47
`mg/kg/day or greater; estimated exposure
`approximately 28 times the recommended
`
`
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`6
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`Buprenorphine
`mutagenicity data from the
`Suboxone/Subutex label
`were added in because they
`include additional positive
`findings
`
`
`
`
`
`
`related increases in
` Leydig cell tumors occurred. ,
`
`
`
`
`
` In an 86-week
`study in CD-1 mice, buprenorphine was
`not carcinogenic at dietary doses up to
`100 mg/kg/day (estimated exposure was
`approximately 30 times the recommended
`human daily sublingual dose of 16 mg on
`a mg/m2 basis).
`
`Mutagenicity:
`The 4:1 combination of buprenorphine
`and naloxone was not mutagenic in a
`bacterial mutation assay (Ames test)
`using four strains of S. typhimurium and
`two strains of E. coli. The combination
`was not clastogenic in an in vitro
`cytogenetic assay in human lymphocytes,
`or in an intravenous micronucleus test in
`the rat.
`
`Buprenorphine was studied in a series of
`tests utilizing gene, chromosome, and
`DNA interactions in both prokaryotic and
`eukaryotic systems. Results were
`negative in yeast (S. cerevisiae) for
`recombinant, gene convertant, or forward
`mutations; negative in Bacillus subtilis
`“rec” assay, negative for clastogenicity in
`CHO cells, Chinese hamster bone
`marrow and spermatogonia cells, and
`negative in the mouse lymphoma L5178Y
`assay.
`Results were equivocal in the Ames test:
`negative in studies in two laboratories, but
`positive for frame shift mutation at a high
`dose (5mg/plate) in a third study. Results
`were positive in the Green-Tweets (E.
`coli) survival test, positive in a DNA
`synthesis inhibition (DSI) test with
`testicular tissue from mice, for both in vivo
`and in vitro incorporation of [3H]thymidine,
`and positive in unscheduled DNA
`synthesis (UDS) test using testicular cells
`from mice.
`
`Impairment of Fertility:
`Dietary administration of buprenorphine in
`the rat at dose levels of 500 ppm or
`greater (equivalent to approximately 47
`mg/kg/day or greater; estimated exposure
`approximately 28 times the recommended
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Reviewer: Elizabeth A. Bolan, Ph.D.
`
`
`human daily sublingual dose of 16 mg on
`a mg/m2 basis) produced a reduction in
`fertility demonstrated by reduced female
`conception rates. A dietary dose of 100
`ppm (equivalent to approximately 10
`mg/kg/day; estimated exposure
`approximately 6 times the recommended
`human daily sublingual dose of 16 mg on
`a mg/m2 basis) had no adverse effect on
`fertility.
`
`
`
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`
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`
` NDA 22-410
`
`human daily sublingual dose of 16 mg on
`a mg/m2 basis) produced a reduction in
`fertility demonstrated by reduced female
`conception rates. A dietary dose of 100
`ppm (equivalent to approximately 10
`mg/kg/day; estimated exposure
`approximately 6 times the recommended
`human daily sublingual dose of 16 mg on
`a mg/m2 basis) had no adverse effect on
`fertility.
`
`
`
`II.
`
`
`Summary of nonclinical findings
`
` is
`
`A. Brief overview of nonclinical findings
`The majority of the nonclinical data relied upon in NDA 22-410 for Suboxone
`found in NDAs 20-732 (Subutex) and 20-733 (Suboxone).
`
`, an
`The naloxone (NLX) drug substance contains
`impurity with a structural alert for mutagenicity. As a post approval commitment for
`Suboxone (NDA 20-733), the Division requested adequate qualification of
` In
`studies submitted to this NDA,
` was not mutagenic in the Ames test but was
`found to be clastogenic in an in vitro cytogenetic assay in human lymphocytes. Because
`of the positive finding for clastogenicity, the levels of
` in the drug substance
`should be reduced to the currently acceptable threshold for known genotoxic impurities
`of NMT 1.5 mcg/day. The specification set by the Applicant for
` would result
`in levels NMT
` mcg/day when Suboxone
` is used as labeled, and are therefore
`acceptable.
`
`The Applicant has conducted an in vitro study assessing the interaction of buprenorphine
`(BUP) and its metabolite norbuprenorphine (nor-BUP) with several cytochrome P450s in
`human liver and in cDNA expressed microsomes. At micromolar levels, BUP inhibited
`CYP2D6 and CYP3A and nor-BUP inhibited CYP2D6. However, plasma concentrations
`of BUP in the therapeutic range are unlikely to cause clinically significant inhibition of
`CYP2D6 or CYP3A in patients. The Applicant also demonstrated that BUP and nor-
`BUP do not bind to either central or peripheral benzodiazepine receptors. The current
`label for Subutex and Suboxone as well as reports in the literature (Ibrahim RB, et al.,
`2000b; Megarbane B, et al., 2006; Megarbane B, et al., 2005c) state that there is a
`pharmacodynamic interaction between BUP and benzodiazepines. Although the
`mechanism for this interaction remains unknown, in light of data submitted by the
`Applicant it is most likely not due to PK interactions or direct action of BUP or nor-BUP
`on central or peripheral benzodiazepine receptors.
`
` A
`
` 2-year carcinogenicity study with Suboxone was conducted in the rat using doses
`yielding human exposure margins of 4, 18 and 44 times the human sublingual dose of
`16/4 mg/mg BUP/NLX based on BUP AUC values. Treatment-related unilateral benign
`Leydig cell (testes) adenomas were observed at the high dose and bilateral benign Leydig
`cell (testes) adenomas were observed at all doses. These neoplasms are considered
`
`
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`7
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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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`

`

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` NDA 22-410
`
`Reviewer: Elizabeth A. Bolan, Ph.D.
`
`
`treatment-related will be described in the product label. No other treatment-related
`neoplasms were observed in males and no treatment-related neoplasms were observed in
`females. This study confirms the findings of Leydig cell tumors that were seen in a prior
`carcinogenicity assessment in rats conducted with BUP alone for the Subutex NDA. The
`findings of Leydig cell tumors from the BUP study as well as negative findings from a
`mouse carcinogenicity study with BUP are described in the current Suboxone/Subutex
`label.
`
`The results from the Suboxone carcinogenicity study as well as the BUP rat and mouse
`studies will be included in the Suboxone
` label. It is recommended that the
`Suboxone/Subutex label be updated to include results from the Suboxone carcinogenicity
`study.
`
`
`B. Pharmacologic activity
`Buprenorphine is a synthetic opioid agonist that is 10-20 times more potent than
`
`morphine with a very long duration of action. It acts as a partial mu opioid receptor
`agonist and a kappa opioid receptor antagonist. Naloxone is a nonspecific opioid
`receptor antagonist. At low doses BUP produces sufficient agonist effect to enable
`opioid-addicted individuals to discontinue the misuse of opioids without experiencing
`withdrawal symptoms. The NLX component of the formulation serves to attempt to
`prevent abuse of the product. Naloxone is rapidly metabolized via the oral and
`sublingual routes resulting in low bioavailability, however, with parenteral
`administration, as in an abuse situation, the NLX is bioavailable to block the effects of
`BUP.
`
`
`C. Nonclinical safety issues relevant to clinical use
`The Suboxone carcinogenicity assessment in rat submitted with this NDA
`
`confirms the findings of Leydig cell tumors that were seen in a carcinogenicity
`assessment in rats conducted with BUP for the Subutex NDA. The findings of Leydig
`cell tumors from the BUP study are described in the current Suboxone/Subutex label.
`The findings of Leydig cell tumors from the Suboxone carcinogenicity study as well as
`the BUP study will be included in the Suboxone
` label. The relevance of these
`findings to clinical use of Suboxone
` is unknown. No new clinical safety issues with
`Suboxone
` as compared to the currently marketed Suboxone/Subutex products have
`arisen.
`
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`8
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
`
`

`

`Reviewer: Elizabeth A. Bolan, Ph.D.
`
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`
` NDA 22-410
`
`2.6 PHARMACOLOGY/TOXICOLOGY REVIEW
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`2.6.1 INTRODUCTION AND DRUG HISTORY
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`NDA number: 22-410
`Review number: 1
`Sequence number/date/type of submission: 000/February 4, 2009/original submission
`Information to sponsor: Yes ( ) No (X)
`Sponsor and/or agent: Reckitt Benckiser Pharmaceuticals, Inc. Richmond, VA
`Manufacturer for drug substance: Buprenorphine HCl: Reckitt Benckiser Healthcare
`(UK) Limited, Hull UK; Naloxone HCl:
` and
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`Reviewer name: Elizabeth A. Bolan, Ph.D.
`Division name: Division of Anesthesia, Analgesia, and Rheumatology Products
`HFD #: 170
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`Review completion date: May 14, 2009
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`Drug:
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`Trade name: Suboxone
`
`Generic name: Buprenorphine HCl and Naloxone HCl
`
`Code name: NA
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`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
`
`CAS registry number: 53152-21-9
`Molecular formula/molecular weight: C29H41NO4 HCl MW=504.1
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`
`Structure:
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`9
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` NDA 22-410
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`Reviewer: Elizabeth A. Bolan, Ph.D.
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`Naloxone hydrochloride
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`Chemical name: 4,5α-Epoxy-3,14-dihydroxy-17-(prop-2-enyl)morphinan-6-one
`
`hydrochloride
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`CAS registry number: 357-08-4
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`Molecular formula/molecular weight: C19H21NO4 HCl 2H2O MW=399.9
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`Structure:
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`
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`drug/compound
`Suboxone
`
`Subutex
`Suboxone
`buprenorphine
`naloxone
`naloxone
`
`Sponsor
`Reckitt Benckiser
`Reckitt Benckiser
`Reckitt Benckiser
`Reckitt Benckiser
`
`Division
`DAARP
`DAARP
`DAARP
`NA
`NA
`NA
`
`status
`active
`approved 10/8/02
`approved 10/8/02
`reviewed by CMC
`reviewed by CMC
`reviewed by CMC
`
`
`Relevant INDs/NDAs/DMFs:
`
`IND/NDA/MF
`IND 75,811
`NDA 20-722
`NDA 20-733
`MF 12412
`MF
`MF
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`Drug class: Buprenorphine is a partial mu opioid receptor agonist and a kappa opioid
`receptor antagonist. Naloxone is a nonspecific opioid receptor antagonist.
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`Intended clinical population: Suboxone
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`Clinical formulation: The Suboxone
` drug product is a soluble sublingual film strip
`containing a fixed ratio of 4:1 buprenorphine: naloxone. The product will be available in
`8/2 and 2/0.5 buprenorphine/naloxone strengths. The high strength (8/2) and low
`strength (2/0.5) strips utilize slightly different formulations as outlined in Table 1. All
`excipients can be found in approved drug products at equal or greater levels and therefore
`do not pose any unique toxicological concerns.
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`Excipients
`
`Table 1. Quantitative Formula for Suboxone
`(reproduced from NDA)
`
`
` is indicated for treatment of opioid abuse.
`
` High and Low Strengths
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`10
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`Reviewer: Elizabeth A. Bolan, Ph.D.
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` NDA 22-410
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`Impurities in the drug substances
`The qualification threshold according to the ICH Q3A(R2) guideline for impurities in the
`drug substances for a MDD of BUP or NLX of < 2 g/day is 0.15% or 1 mg/day intake,
`whichever is lower. The identification threshold as per ICH Q3A(R2) guideline for
`impurities in the drug substances for a MDD of BUP or NLX of < 2 g/day is 0.1% or 1
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`11
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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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` NDA 22-410
`
`Reviewer: Elizabeth A. Bolan, Ph.D.
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`mg/day intake, whichever is lower. The Applicant has set the specifications for
`impurities in the buprenorphine drug substance obtained from Reckitt Benckiser (MF
`12412) at NMT
` (Table 2) and no further identification or qualification will be
`necessary. The Applicant has set the specifications for impurities in the naloxone drug
`substances obtained from
` and
`
`below the thresholds for identification or qualification (unless otherwise noted, see Table
`3) and no further qualification will be necessary. Specific impurities are discussed
`below. The specifications for the buprenorphine drug substance and two naloxone drug
`substances are acceptable from a pharmacology/toxicology perspective.
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`
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`Specifications of buprenorphine hydrochloride drug substance impurities
`from Reckitt Benckiser
`Specification limit
`NMT
`NMT
`NMT
`NMT
`NMT
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`Impurity
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`Acceptable?
`YES
`YES
`YES
`YES
`YES
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`Table 2
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`Table 3
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`Impurity
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`Specifications of naloxone hydrochloride drug substance impurities
`from
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`Specification limit
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`max
`max
`max
`max
`max
`max
`max
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` max
` max
` max
` max
` max
` max
` max
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`Acceptable?
`
`YES
`YES
`YES
`YES
`YES
`YES
`YES
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`The naloxone drug substance from both suppliers contains
`, an impurity with a structural alert for mutagenicity. As a post approval
`commitment for Suboxone (NDA 20-733; see approval letter), the Division requested
`adequate qualification of
` by either demonstrating that it is a significant
`metabolite or by genotoxicity testing (one point mutation assay and one cytogenetic assay
`with the impurity tested up to the limit dose for each assay). The Division also stated that
`if
` is determined to be genotoxic, it must be limited via in-process controls or by
`drug substance acceptance criteria to
` For this NDA, the Applicant has submitted
`two genetic toxicology studies with
` was not
` YV62423) but was found to be clastogenic in an in
`mutagenic in the Ames test (
`vitro cytogenetic assay in human lymphocytes (
` SV1200). The current acceptable
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`12
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` NDA 22-410
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`Reviewer: Elizabeth A. Bolan, Ph.D.
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`threshold for known genotoxic impurities is NMT 1.5 mcg/day. The Applicant has set
`the specification of
` at
`. At
` for a total daily dose of 8 mg of NLX,
`the total daily intake would be
` mcg of the impurity. The specification of
` for
` in the drug substance is acceptable.
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`
`
`
` (also referred to as
`The Applicant has limited the naloxone impurity
`) to
` in the drug substances obtained from both
` and
`. Although this level is above ICH Q3A(R2) guidelines, the Applicant has
`previously conducted a safety evaluation which qualifies the compound to a level of
`. For the Suboxone NDA (NDA 20-733), the applicant had conducted a 3-month
`dietary general toxicology study with the impurity as well as a carcinogenicity
`assessment with Suboxone using a batch of naloxone containing the impurity
`. These studies were reviewed by Dr. Timothy McGovern (NDA 20-733;
`Supplement review dated October 7, 2002). Dr. McGovern determined that the
` was qualified up to a level of
`. The specification of
` for
` in the naloxone drug substances is considered acceptable.
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`Impurities in the drug product
`The Suboxone
` drug product contains the same impurity/degradant profile as
`Suboxone SL tablets (NDA 20-733)
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`The qualification threshold according to the ICH Q3B(R2) guidelines for
`impurities/degradants in the drug product for a maximum daily dose (MDD) between 10
`mg and 100 mg of BUP administered per day is 0.5% or 200 mcg TDI, whichever is
`lower. The Applicant has set the stability specifications for BUP-derived
`impurities/degradation products at levels which exceed this threshold: however, the four
`of the five impurities have been previously qualified for the Applicant’s Suboxone NDA
`(NDA 20-733; Table 4). The Applicant conducted a 28-day dietary toxicology study as
`well as in vitro and in vivo genetic toxicology studies with ethanol extracts of Suboxone
`which had been degraded under accelerated conditions. These studies were reviewed and
`found to be acceptable by Dr. Thomas Papoian (NDA 20-733, Supplement review dated
`December 11, 2001). For the Suboxone
` product, the levels of the four impurities
`assayed in the submitted studies are below qualified levels (Table 4). The impurity
` is unique to the Suboxone
` product. The levels are below
`ICH Q3B(R2) guidelines for qualification for the high strength (8/2 mg/mg BUP/NLX)
`dose. However, the Applicant has set different impurity specifications for two of the
`impurities in the high strength (8/2 mg/mg BUP/NLX) and low strength (2/0.5 mg/mg
`BUP/NLX) dosages (Table 4). The specification for
` is
`set at
` for the high strength and
` for the low strength. The specification for the
`low strength exceeds ICH Q3B(R2) thresholds. The Applicant makes the argument that
`the low strength strips are unlikely to be utilized to achieve doses greater than the 8 mg
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`13
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`
` NDA 22-410
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`Reviewer: Elizabeth A. Bolan, Ph.D.
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`BUP dose of the high strength strips. I agree with this justification. The maximum daily
`dose for the low dose product would be < 10 mg so the limit of
` or
` mcg TDI,
`whichever is lower, would therefore not be exceeded by the specification of
`. The
`specifica