CENTER FOR DRUG EVALUATION AND

RESEARCH

APPLICATION NUMBER:

205637Orig1s000

CROSS DISCIPLINE TEAM LEADER REVIEW

 Cross Discipline Team Leader Review

9. Advisory Committee Meeting............................................................................................23

10. Pediatrics.........................................................................................................................24
11. Other Relevant Regulatory Issues...................................................................................24
11.2 Risk Evaluation and Mitigation Strategy.......................................................................24
11.3 OSI Inspection ...............................................................................................................25
11.4 Cardiac Conduction Effects ...........................................................................................25
11.5 Financial Disclosures .....................................................................................................26
11. 5 Controlled Substances Staff Review.............................................................................26
12. Labeling ..........................................................................................................................26
13. Recommendations/Risk Benefit Assessment..................................................................27

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1. Introduction
This application is for a new buprenorphine/naloxone combination product for the
maintenance treatment of opioid dependence, referencing the approved product Suboxone
(buprenorphine/naloxone) tablets (NDA 20733) through the 505(b)(2) pathway1. The
proprietary name, Bunavail, has been found acceptable.

Unlike Suboxone, which is a sublingual tablet, Bunavail uses a bioerosive mucosal adhesive
(BEMA) technology for buccal delivery, a novel route for buprenorphine. Due to differences
in bioavailability, the nominal doses are lower than those in Suboxone. Comparative
pharmacokinetic studies have demonstrated exposure meeting criteria for bioequivalence using
the 4.2/0.7 mg strength, and the application rests on the Agency’s previous findings of safety
and efficacy of Suboxone.

Four dosage strengths were proposed for marketing. These are:

 mg buprenorphine/naloxone (corresponds to 2/0.5 mg Suboxone tablet)
(b) (4)

 2.1/0.35 mg buprenorphine/naloxone (corresponds to 4/1 mg (two 2/0.5 mg) as Suboxone

tablet
 4.2/0.7 mg buprenorphine/naloxone (corresponds to 8/2 mg Suboxone tablet)
 6.3/1.04 mg buprenorphine/naloxone (corresponds to 12/3 mg (two 2/0.5 mg and one 8/2
mg as Suboxone tablet)

A comparative bioavailability study was performed comparing the 4.2/0.7 mg dose to the 8/2
mg Suboxone tablet. Biowaivers were sought for the higher and lower strengths, but the
biowaiver for the lowest strength could not be granted. Therefore, only three strengths are
recommended for approval.

Bunavail should be used in patients who have already begun treatment using buprenorphine-
(b) (4)
only sublingual products. The recommended dose is is 8.4 mg buprenorphine (two 4.2/ mg
films) as a single daily dose, but may be adjusted for the individual patient.
This review will briefly summarize the clinical pharmacology findings, safety findings from
the pharmacokinetic studies in healthy, naltrexone-blocked volunteers, and findings from a
clinical pharmacology study supporting the adequacy of the naloxone dose.

1
Suboxone tablets have been withdrawn by the manufacturer, Reckitt Benckiser, from US marketing. However,
the Agency has determined that Suboxone tablets were not withdrawn from sale for reasons of safety or
effectiveness and the product is listed in the “Withdrawn Applications” section of the Orange Book.

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2. Background
Buprenorphine is a partial agonist at the μ-opiate receptor. A parenteral formulation of
buprenorphine was approved in 1981 for the treatment of pain2, two sublingual tablet
formulations were approved in 2002 for the treatment of opioid dependence3, and a sublingual
film formulation for opioid dependence4 and an extended-release transdermal film formulation
for pain5 were approved in 2010.

Buprenorphine was developed as a treatment for opioid dependence because some of its
pharmacological properties suggested it could serve as a safer alternative to methadone, a full
agonist at the μ-receptor. Like methadone, buprenorphine’s activity at the μ-receptor was
expected to relieve patients’ urge to use illicit opioids, but like methadone, the long duration of
action would allow patients to achieve a steady state, without the alternating highs and lows
associated with opioid abuse that impair daily functioning. Additionally, at sufficiently high
doses, buprenorphine blocks full opioid full agonists from achieving their full effects, further
deterring abuse of these substances for buprenorphine-maintained patients.

Due to its partial agonist properties, the euphorigenic effects of buprenorphine are understood
to reach a “ceiling” at moderate doses, beyond which increasing doses of the drug do not
produce the increased effect that would result from full opioid agonists. This was expected to
limit its attractiveness as a drug of abuse relative to full agonists.

Because it is a partial agonist, buprenorphine has the potential to precipitate withdrawal

symptoms when used by an individual who is dependent on full opioid agonists such as heroin,
methadone, or oxycodone. This product references the application for Suboxone, NDA 20733
(Reckitt Benckiser), a sublingual tablet formulation of buprenorphine that also contains
naloxone. The naloxone is intended to be inactive when the product is used as intended, but to
add an additional measure of abuse deterrence by precipitating more severe withdrawal if the
product is crushed and injected by an individual dependent on full agonists.

The product was developed under IND 110267. BDSI originally met with the Division in a
pre-IND meeting in January, 2011. At that time, they were advised that no clinical efficacy or
safety data would be required, provided that the buprenorphine exposure was bioequivalent to
the reference product. Regarding naloxone, the Applicant was advised that the naloxone
exposure could be lower than the reference product when used as intended, but that they would
need to provide information to show that the product would release sufficient naloxone under
conditions of misuse to precipitate withdrawal in persons dependent on full agonist opioids.
BDSI was also informed that additional safety data, collected in at least 200 patients for a
minimum of 12 weeks, would need to be submitted addressing the potential for local toxicity.

2
Buprenex, NDA 18401 Reckitt Benckiser
3
Subutex (buprenorphine sublingual tablets), NDA 20732 and Suboxone (buprenorphine/naloxone sublingual
tablets), NDA 20733, Reckitt Benckiser
4
Suboxone (buprenorphine naloxone) film, NDA 22410, Reckitt Benckiser
5
Butrans, NDA 21306

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2.1 Role of Naloxone

As noted above, although buprenorphine has the potential to precipitate withdrawal symptoms
in individuals dependent on full agonists, naloxone was included in the Suboxone formulation
with the aim of providing an additional measure of deterrence to intravenous misuse. The
naloxone was intended to be inactive when the product is used as intended, sublingually. Some
transmucosal absorption of naloxone is possible, however, and for this reason, it is
recommended that patients transitioning from full opioids at the beginning of treatment be
treated initially with a few days of a buprenorphine-only product (e.g. Subutex or generics).
Because naloxone competes poorly with buprenorphine at the mu receptor, once a patient is
maintained on buprenorphine, the combination product can be introduced.6 Naloxone is
intended to produce aversive symptoms if the product is crushed and injected.

The current Agency approach to evaluating the abuse deterrent properties of drug products was
not in place in 2002, when Suboxone tablets were approved. Because both buprenorphine and
naloxone have the potential to precipitate withdrawal in opioid-dependent individuals, the
contribution of naloxone to abuse-deterrence has not been definitively established. However,
the referenced application provided evidence from laboratory studies that the amount of
naloxone included in the formulation was capable of producing aversive effects when given in
combination with buprenorphine. Ratios of 4:1, and (buprenorphine:naloxone) were
(b) (4) (b) (4)

evaluated and the 4:1 ratio was commercialized by Reckitt Benckiser. However, it is likely that
even if the ratio were to be maintained, there are doses of naloxone which are too low to cause
significant aversive effects.

During the IND stage, BDSI was told that as long as the naloxone exposure was no higher than
in the reference product when used as intended, no safety or efficacy issues would arise.
However, because of the increased biovailability of the BDSI product compared to the
reference product, the naloxone content would need to be reduced to yield plasma levels no
higher than the reference when the product was used as intended. Therefore, information
would be needed showing that the amount of naloxone in the final formulation was sufficient
to produce an aversive effect under conditions of misuse. They sought and received comment
on the study that they intended to use to provide this information and it was found acceptable.

6
Studies supporting the reference product, Suboxone, either used a buprenorphine-only sublingual solution (no
naloxone at all in the study), or, in one study, introduced Suboxone after two days of Subutex. Therefore, the
labeling recommends this approach. It is becoming more common in clinical practice to perform direct induction
(treatment initiation) with Suboxone, and several sponsors of buprenorphine/naloxone combination products,
including Orexo, are pursuing studies to show that Suboxone is as well-tolerated in initial use as Subutex.
However, at this time, combination products are labeled for use after initial treatment with buprenorphine-only
products.

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2.2 Legal and Regulatory Issues Constraining Buprenorphine

Treatment
Buprenorphine is a Schedule III Controlled Substance and physicians prescribing Bunavail
must comply with the relevant aspects of the Controlled Substances Act. In addition, the
provision of agonist treatment of opioid addiction is governed by certain legal requirements.
Unlike methadone, buprenorphine may be prescribed by physicians meeting certain
requirements.

Methadone treatment of opioid addiction is delivered in a closed distribution system (opioid

treatment programs, OTPs) that originally required special licensing by both Federal and State
authorities, under the Narcotic Addict Treatment Act of 1974. The current regulatory system is
accreditation-based, but OTPs must still comply with specific regulations that pertain to the
way clinics are run, the credentials of staff, and the delivery of care. To receive methadone
maintenance, patients are required to attend an OTP, usually on a daily basis, with the
possibility of earning the privilege of taking home doses as their treatment stability increases.
Buprenorphine may also be administered to patients at OTPs.

Buprenorphine treatment is covered Title XXXV of the Children’s Health Act of 2000 (P.L.
106-310), which provides a “Waiver Authority for Physicians Who Dispense or Prescribe
Certain Narcotic Drugs for Maintenance Treatment or Detoxification Treatment of Opioid-
Dependent Patients.” This part of the law is known as the Drug Addiction Treatment Act of
2000 (DATA 2000). Under the provisions of DATA 2000, qualifying physicians may obtain a
waiver from the special registration requirements in the Narcotic Addict Treatment Act of
1974, and its enabling regulations, to treat opioid addiction with Schedule III, IV, and V opioid
medications that have been specifically approved by FDA for that indication, and to prescribe
and/or dispense these medications in treatment settings other than licensed OTPs, including in
office-based settings. At present, the only products covered by DATA 2000 (i.e., Schedule III-
IV, approved for the indication) are buprenorphine sublingual tablets and
buprenorphine/naloxone sublingual tablets and films.

To qualify for a DATA 2000 waiver, physicians must have completed at least 8 hours of
approved training in the treatment of opioid addiction or have certain other qualifications
defined in the legislation (e.g., clinical research experience with the treatment medication,
certification in addiction medicine) and must attest that they can provide or refer patients to
necessary, concurrent psychosocial services. The 8 hour training courses are provided by
various physician organizations (e.g. APA) and delivered in-person, in web-based formats, or
through other mechanisms. Physicians who obtain DATA 2000 waivers may treat opioid
addiction with products covered by the law in any appropriate clinical settings in which they
are credentialed to practice medicine.

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3.1.5 Extraction Studies

Although not required (because no claim of abuse deterrence other than the language already
in the referenced label is proposed), BDSI performed a number of extraction studies as
described in the FDA Guidance on development of abuse-deterrent opioids. The applicant
compared Suboxone tablets with Bunavail films. Such studies were not performed when
Suboxone tablets were under development nor when the Suboxone film product was
developed. Various conditions and various media were used, with the objective of identifying
methods that yielded differential extraction of buprenorphine and naloxone. The studies show
that buprenorphine can be selectively extracted in from both Bunavail films and
(b) (4)

Suboxone tablets, leaving the naloxone behind and yielding a solution of buprenorphine
dissolved in . However, unlike the tablet, which disintegrates into the solution
(b) (4)

although the naloxone does not dissolve, the film remains intact and could be removed, taking
the naloxone with it. It is noted, however, that there are also methods of separating the
naloxone from buprenorphine in the reference tablet product.

3.2 Facilities review/inspection

Per Dr. Shaw’s review, all inspections are satisfactory.

3.3 Biowaiver Requests

To support approval of the proposed product, BDSI conducted a bioequivalence study
comparing the Bunavail 4.2/0.7 mg strength to the referenced 8/2 mg Suboxone sublingual
tablet and conducted a relative bioavailability study between the 4.2/0.7 mg strength and the
6.3/1.04 mg strength to demonstrate dose proportionality. BDSI requested a waiver from
conducting bioavailability/bioequivalence studies to support approval of the Bunavail film
dosage strengths below 4.2/0.7 mg. The biowaiver request was reviewed by Kareen Riviere,
Ph.D., supervised by Tapash Ghosh, Ph.D.

BDSI provided multi-point dissolution profile comparisons with f2 testing results for the lower
two strengths versus the 4.2/0.7 mg strength using multi-media pHs. These data support a
biowaiver for the 2.1/0.35 mg strength and not the mg strength.
(b) (4)

(b) (4)

Since the 4.2/0.696 mg strength was used in the pivotal BE study, the Applicant used this
strength as the reference rather than the 6.3/1.044mg strength in the dissolution studies
supporting the biowaiver for the lower strengths. This approach is acceptable.

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Bond concluded that three repeated doses daily doses to the same buccal dose site did not
result in any overt local toxicity.

In Dr. Bond’s review of the composition of the drug substances and drug product and
consultation with ONDQA, no nonclinical-based safety issues related to impurities,
degradants, and excipients were identified.

In the label, text was added to sections describing non-clinical findings to link the exposure
margins described in the existing text to the corresponding doses as delivered by Bunavail.

5. Clinical Pharmacology/Biopharmaceutics
5.1 General Background
This overview of buprenorphine and buprenorphine/naloxone clinical pharmacology is taken
largely from the approved labeling for NDA 20-723 and 20-733.
Pharmacokinetics of buprenorphine and naloxone (as Suboxone) show wide inter-patient
variability in the sublingual absorption of buprenorphine and naloxone, but within subjects the
variability is low. Both Cmax and AUC of buprenorphine show dose linearity in the range of 4
to 16 mg, but not dose proportionality. The table below from the labeling for Suboxone and
Subutex shows the PK parameters. Buprenorphine has a mean elimination half-life of 37
hours; naloxone has a half-life of 1.1 hours. Naloxone does not affect the PK

Pharmacokinetic parameters of buprenorphine after the administration of 4 mg, 8mg,

and 16 mg Suboxone doses and 16mg Subutex dose (mean (%CV)).
Pharmacokinetic Suboxone 4 mg Suboxone 8 mg Suboxone16 mg Subutex 16 mg
Parameter
Cmax, ng/mL 1.84 (39) 3.0 (51) 5.95 (38) 5.47 (23)
AUC0-48, 12.52 (35) 20.22 (43) 34.89 (33) 32.63 (25)
hour.ng/mL

Buprenorphine is approximately 96% protein bound, primarily to alpha and beta globulin.
Naloxone is approximately 45% protein bound, primarily to albumin.

Buprenorphine undergoes both N-dealkylation to norbuprenorphine and glucuronidation. The

N-dealkylation pathway is mediated by cytochrome P-450 3A4 isozyme. Norbuprenorphine,
an active metabolite, can further undergo glucuronidation. Cytochrome P-450 3A4 (CYP3A4)
inhibitors may increase plasma concentrations of buprenorphine.

Naloxone undergoes direct glucuronidation to naloxone 3-glucuronide as well as N-

dealkylation, and reduction of the 6-oxo group. Buprenorphine is eliminated in urine (30%,
primarily conjugated) and feces (69%, primarily free buprenorphine and norbuprenorphine).

Recently-reviewed data demonstrates that hepatic impairment differentially affects the PK of

buprenorphine and naloxone. In subjects with mild hepatic impairment, the changes in mean
Cmax, AUC0-last, and half-life values of both buprenorphine and naloxone are not clinically

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5.2.2 Data Supporting Other Doses

BDSI submitted support for the additional proposed doses in the form of several PK studies of
dose proportionality and dosage form equivalence, some of which used the final to-be-
marketed film sizes and some of which did not. No studies used the proposed mg
(b) (4)

dose.

Study BNX-106
The dose-proportionality of buprenorphine and naloxone pharmacokinetics following single-
dose administration of BEMA buprenorphine/naloxone film was assessed in 20 healthy
subjects under naltrexone block in Study BNX-106. The study used the following doses (not
the doses proposed for marketing):
 0.875/0.15 mg
 3.5/0.6 mg
 5.25/0.9 mg
Each dose was administered as a single buccal film.

Dr. Qiu’s review describes the results as follows:

Based on the power model, definitive dose proportionality of buprenorphine and naloxone PK
parameters following the administration of BEMA Buprenorphine NX films (1 x 0.875/0.15 mg,
1 x 3.5/0.6 mg, and 1 x 5.25/0.9 mg) was not demonstrated over the buprenorphine dose range
of 0.875 mg to 3.5 mg and naloxone dose range of 0.15 to 0.9 mg because the estimates of
beta 1, the slopes of the power model, were significantly different from unity (1.0000).
Buprenorphine and naloxone PK parameters (e.g., Cmax, AUC0-24, AUClast, and AUCinf)
increased slightly less than proportional with dose over the buprenorphine dose range of 0.875
mg to 3.5 mg and naloxone dose range of 0.15 mg to 0.9 mg, respectively.

Study BNX-107
The relative bioavailabilities of buprenorphine and naloxone between two of the doses
proposed for marketing were evaluated in 24 healthy subjects under naltrexone block in Study
BNX-107. The study used the following doses:
 Bunavail 4.2/0.7 mg
 Bunavail 6.2/1.04 mg
Each dose was administered as a single buccal film.

This study demonstrated dose-proportionality between the two highest doses proposed for
marketing. Dr. Qiu concluded:

Statistical analysis of the dose normalized log transformed Cmax, AUClast and AUCinf
between the 6.3/1.04 mg (1 x 6.3/1.04 mg) and 4.2/0.7 mg (1 x 4.2/0.7 mg) doses of BEMA
Buprenorphine NX films found that the 90% CI for all PK parameters for both buprenorphine
and naloxone were within the 80-125% range implies that the increase in buprenorphine and
naloxone exposure is proportional to dose between the 4.2/0.7 mg and 6.3/1.04 mg BEMA
Buprenorphine NX dose strengths.

This study provides support for the 6.3/1.04 mg dose.

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7. Clinical/Statistical- Efficacy
No new data on the clinical efficacy of buprenorphine were submitted.

The adequacy of the naloxone dose to perform as intended—that is, to cause aversive effects if
the product is crushed and injected—was supported by a double-blind, placebo-controlled,
four-treatment, four-period crossover study to determine the lowest dose of naloxone that
would produce a withdrawal response when administered with buprenorphine in opioid-
dependent subjects (Study LCR-04-01-01).

The design of the study is summarized in Dr. Horn’s review and briefly described below:

Subjects with chronic moderate-to-severe non-cancer pain requiring at least 100 mg per day of
oral morphine for at least 3 months were to continue to receive opioid at the same dose on the
same schedule and receive four test articles administered intravenously (buprenorphine 0.75
mg; buprenorphine 0.75 mg + naloxone 0.1 mg; buprenorphine 0.75 mg + naloxone 0.2 mg;
placebo) intended to induce withdrawal symptoms consecutively in random order, with three
days between test articles to minimize any carryover effects. Withdrawal in response to the
test articles was to be measured using the Clinical Opiate Withdrawal Scale, physiologic, and
subject rated-measurements. The primary analysis comparing test articles was to be performed
on the COWS scores.

To be eligible, subjects also had to display signs and symptoms of withdrawal (as evidenced
by A COWS score of ≥5) in response to a challenge of naloxone, administered in 0.05 mg
increments every five minutes until the target COWS was reached or a total of 0.2 mg had
been administered.

Fifteen subjects enrolled and completed the study. There was no planned formal testing or
sample size calculation.

Subjects had a mean age of 50 (range 24-63) and were 40% female. Baseline opioid use is
summarized in the table below from Dr. Horn’s review.

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Subject ID Opioid regimen Total Daily Morphine

Equivalent Dose (mg)
1002 Morphine and oxycodone 120
1003 Oxycodone 120
1005 Morphine and oxycodone 225
1006 Morphine and hydrocodone 90
1007 Fentanyl and oxycodone 587
1009 Morphine and oxycodone 100
1012 Oxycodone 300
1013 Methadone 1050
1015 Methadone 180
1016 Methadone 1260
1017 Morphine 420
1020 Morphine 520
1021 Morphine and hydrocodone 150
1023 Fentanyl and oxycodone 450
1024 Morphine 180
Source: CM dataset and CSR Table 6

Assessments included pharmacodynamics measures (COWS, Drug Effect Questionnaire,

Opioid Agonist Scale) and physiologic measures, including vital signs and pupil diameter.
Rescue treatment of withdrawal was protocol-specified to occur for COWS score >13. Many
of the assessments were not recorded prior to rescue, and are therefore less meaningful to
interpret. However, the proportion of subjects requiring rescue, and the mean COWS scores
recorded prior to rescue, provide evidence that 0.1 mg and 0.2 mg naloxone was sufficient to
precipitate withdrawal in most subjects.

Dr. Horn’s review reproduces the following figure from the study report

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Dr. Horn concluded:

The results in change from baseline in COWS scores support the effectiveness of
buprenorphine and buprenorphine with naloxone at the two doses studied in causing clinically
significant withdrawal in a substantial proportion of subjects. Naloxone appeared to worsen
withdrawal symptoms in a dose-dependent fashion above what was observed with
buprenorphine alone. The results on the COWS were supported by the trends observed in the
physiological measures, even though many of the physiological measures were taken after
rescue medication administration.

The COWS results are well-supported by the pattern of rescue medication use, which was
administered based on COWS scores above 13 and indicated that subjects were experiencing
withdrawal in a pattern consistent with the overall COWS data.

The subjects were on clinically relevant opioid maintenance doses in this study and the results
can be reasonably be generalized to those with a physical dependence to full opioid agonists
who would attempt to inject this product. Buprenorphine and naloxone in a ratio of 7.5 to 1 at a
naloxone dose of 0.1 mg resulted in more withdrawal than buprenorphine alone, indicating that
this ratio of buprenorphine to naloxone and this amount of naloxone is sufficient to increase the
aversive effects of the product when injected. The amount of naloxone in the lowest
[proposed] dose of the product is (b) (4) , which is more than 0.1 mg and it is combined with (b) (4)
mg buprenorphine in a 6:1 ratio, which is a lower ratio than the 7.5:1 ratio in the study.

8. Safety
Because this is a novel dosage form and route of administration for buprenorphine, a study
evaluating local tolerability was conducted to address potential differences between the oral
mucosal tolerability of Bunavail and the reference product. During development, BDSI was
also advised that the oral mucosal evaluations in their tolerability study should be performed
by dentists. However, they did not incorporate this advice. In subsequent discussions at the
pre-NDA stage, the Division concluded that we were primarily concerned about symptomatic
oral mucosal effects, and not those too subtle to be detected by a trained, but non-dentist,
observer. The buccal mucosa is considered less vulnerable than the sublingual mucosa;
therefore, although the route of administration is novel and some experience with the
tolerability of the product is needed, there is considerable experience with transmucosal
delivery of buprenorphine via a more vulnerable surface

Because the systemic exposure is the same as the reference product, the systemic safety of this
product rests primarily on previous Agency findings for Suboxone.

Dr. Horn’s review describes the study of local tolerability, Study BNX-201. It is briefly
summarized here.

The study was a 12-week, open-label study in patients who had been maintained on Suboxone
tablets at doses between 8 mg and 32 mg for at least 30 days, and who had no baseline
abnormalities of buccal mucosa that could affect drug absorption. Based on the conversion
scheme in the table below, patients were to be switched from Suboxone tablets to the BDSI
buccal film as a single daily dose to be administered for 12 weeks. Dose adjustments could be
made during the treatment period.

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BNX-201 Subject Disposition

Source: CSR Table 14.1.1

Consistent with the subsequent finding that the dose conversion was too low by about 20%,
many patients required dose increases during the study. Regardless of the dose of Suboxone
the patients converted from, 30-40% required upward titration during the study, with the
exception of the 8 patients converting from Suboxone 32/8 mg/day, who all required a dose
increase. Only one subject had a dose decrease.

There were no deaths in the study or in the development program. There were two SAEs, one
case of osteomyelitis and one case of suicidal ideation.

Adverse events that led to discontinuation were the two SAEs discussed above, headache, two
positive urine toxicology screens and an oral ulcer in a subject whose urine was negative for
buprenorphine.

The results of the oral mucosal examinations did not reveal any local toxicity concerns. Three
subjects had mild mucosal redness during the study, which resolved without discontinuing
treatment. Two subjects were observed to have swelling or raised lesions, which also resolved
without discontinuing treatment. There was one subject with a mild mouth ulceration at the
Day 7 visit. However, no buprenorphine or norbuprenorphine was detected in the subject’s
urine on Day 7, indicating that the subject was not taking the product.

Other treatment-emergent adverse events (occurring in more than two subjects) are shown in
the table below from Dr. Horn’s review. However, because this is an open-label study in
patients already on buprenorphine, the findings are difficult to interpret. The most common
event was drug withdrawal, attributable to the incorrect dose conversion scheme used in the
study.

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TEAEs Occurring in more than 2 Subjects

Source: Table 20 BNX-201 CSR

There were no findings of concern in lab, vital sign, or EKG evaluations.

9. Advisory Committee Meeting

N/A

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10. Pediatrics
BDSI requested a full waiver of the pediatric studies required under the Pediatric Research
Equity Act (PREA). The justification provided was based on safety concerns in the neonatal
age group, where buprenorphine may be used to treat symptoms of neonatal abstinence
syndrome (NAS). Although there is increasing research interest in the use of buprenorphine
for NAS, this product contains naloxone, which serves no purpose in the treatment of neonatal
abstinence syndrome and might present a safety concern. Therefore, the Division agreed that a
waiver in this age group was appropriate.
(b) (4)
Waivers for Ages to 16 years were requested on the grounds
that studies would be impossible or highly impracticable, due to the low prevalence of opioid
abuse and dependence.

The Division concurred that based on the most recent prevalence estimates and current and
previous feasibility assessments, studies would be highly impracticable. This information was
provided to the Pediatric Review Committee (PeRC), who agreed that a waiver should be
granted.

11. Other Relevant Regulatory Issues

11.2 Risk Evaluation and Mitigation Strategy
Prior to market withdrawal, the reference product, Suboxone tablets, was marketed subject to a
Risk Evaluation and Mitigation Strategy (REMS). Suboxone film continues to be marketed
under the Suboxone/Subutex REMS. Although the REMS provisions under FDAAA call for a
single shared system, a waiver was granted because Reckitt Benckiser declined to participate
in a single shared system, and the Agency determined that the benefits of the waiver (access to
medication) outweighed the burden of having multiple programs. All ANDA-holders are
obliged to participate in the shared system, known as the BTOD (buprenorphine-containing
transmucosal products for opioid dependence) REMS, but NDA holders are not subject to this
requirement. One other NDA holder, Orexo, marketing Zubsolv buprenorphine/naloxone
sublingual tablets under NDA 204242, joined the BTOD REMS at the time of approval of
their application in 2012.

The Agency requested that BDSI join the shared system REMS to reduce the burden on the
healthcare system by limiting the number of REMS for this class of products to two, and BDSI
has arranged to do so.

The goals of the REMS are to:

1. Mitigate the risks of accidental overdose, misuse, and abuse
2. Inform patients of the serious risks associated with buprenorphine-containing products

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REMS Elements:
1. Medication Guide
2. Elements to Assure Safe Use
 Safe use Conditions
 Monitoring
3. Implementation System
4. Timetable for Submission of Assessments

Materials for Prescribers:

1. Dear Prescriber Letter
2. Office-Based Buprenorphine Therapy for Opioid Dependence: Important Information
for Prescribers
3. Appropriate Use Checklist
Materials for Pharmacists:
1. Dear Pharmacist Letter
2. Office-Based Buprenorphine Therapy for Opioid Dependence: Important Information
for Pharmacists
Materials for Patients:
1. Medication Guide

The materials have been updated to include a description of the Bunavail products, including a
table showing the correspondence between Bunavail doses and Suboxone tablet doses.

For administrative reasons, the REMS materials approved for Bunavail will not include the
information about hepatic effects, as the BTOD group will be concurrently modifying its
REMS materials to include this information, and thus Bunavail’s product information as well
as the hepatic information can will be incorporated into the same modification. From a
practical standpoint, materials will not actually be created or distributed without this
information because the BTOD group will be immediately notified and the changes will be
rapidly incorporated into the group’s materials..

11.3 OSI Inspection

OSI’s Division of Bioequivalence and GLP Compliance (DBGLPC) audited the clinical and
analytical portions of Study BNX-110, the pivotal bioequivalence study and concluded that the
data from the study were acceptable.

11.4 Cardiac Conduction Effects

BDSI was informed during the IND stage that a signal for QT prolongation meeting criteria for
regulatory significance had been identified in a study of another buprenorphine product, at a
dose significantly lower than the dose used for treating drug addiction. A study of the potential
for doses of buprenorphine used for the treatment of opioid dependence to prolong the QT
interval has been requested of Reckitt Benckiser as post-marketing requirement (PMR), but
has not yet been completed. BDSI was informed that a TQT study would be required for their
NDA if the information was not available to be incorporated by reference at the time of
submission, but that the study could be performed post-approval.

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This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
---------------------------------------------------------------------------------------------------------
/s/
----------------------------------------------------
CELIA J WINCHELL
05/15/2014

Reference ID: 3507740