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`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`22-410/S006/S007
`
`
`
`
`SUBOXONE®
`
`buprenorphine hydrochloride; naloxone hydrochloride
`
`Reckitt Benckiser Pharmaceuticals, Inc.
`
`8/10/2012
`
`
`
`Trade Name:
`
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`
`
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`22-410/S006/S007
`
`
`
`
`CONTENTS
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
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`
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`
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`
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`
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`

`

`CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`APPLICATION NUMBER:
`22-410/S006/S007
`22-410/5006/5007
`
`
`APPLICA TI0N NUMBER:
`
`APPROVAL LETTER
`APPROVAL LETTER
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`NDA 022410/S-006
`NDA 022410/S-007
`
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`SUPPLEMENT APPROVAL
`
`
`
`Reckitt Benckiser Pharmaceuticals, Inc.
`10710 Midlothian Turnpike, Suite 430
`Richmond, VA 23235
`
`Attention: Clorey Toombs
`
`CMC Manager, Regulatory Affairs
`
`Dear Ms. Toombs:
`
`Please refer to your Supplemental New Drug Applications (sNDA) dated September 29 and 30,
`2011, and received September 30, 2011, and identified as S-006 and S-007, respectively. These
`sNDAs were submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act
`(FDCA) for Suboxone (buprenorphine and naloxone) sublingual film.
`
`
`We acknowledge receipt of your amendments dated January 26, March 8, and June 4, 2012, to
`Supplement S006, and January 27 and 31, March 8, and June 4, 2012, to Supplement S007, and
`to your risk evaluation and mitigation strategy (REMS) assessment dated August 29, 2011.
`
`These “Prior Approval” supplemental new drug applications provide for the following:
`S-006: addition of a 4 mg/1 mg (buprenorphine/naloxone) strength
`S-007: addition of a 12 mg/3 mg (buprenorphine/naloxone) strength
`
`These supplemental new drug applications also provide for proposed modifications to the
`approved risk evaluation and mitigation strategy (REMS).
`
`We have completed our review of these supplemental applications, as amended. They are
`approved, effective on the date of this letter, for use as recommended in the enclosed, agreed-
`upon labeling text.
`
`CONTENT OF LABELING
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`automated drug registration and listing system (eLIST), as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling (text for the package insert, text for the
`patient package insert, Medication Guide), with the addition of any labeling changes in pending
`
`Reference ID: 3172979
`
`

`

`NDA 022410/S-006
`NDA 022410/S-007
`Page 2
`
`
`“Changes Being Effected” (CBE) supplements, as well as annual reportable changes not
`included in the enclosed labeling.
`
`Information on submitting SPL files using eLIST may be found in the guidance for industry
`titled “SPL Standard for Content of Labeling Technical Qs and As” at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`The SPL will be accessible from publicly available labeling repositories.
`
`Also within 14 days, amend all pending supplemental applications for this NDA, including CBE
`supplements for which FDA has not yet issued an action letter, with the content of labeling
`[21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the changes approved in this
`supplemental application, as well as annual reportable changes and annotate each change. To
`facilitate review of your submission, provide a highlighted or marked-up copy that shows all
`changes, as well as a clean Microsoft Word version. The marked-up copy should provide
`appropriate annotations, including supplement number(s) and annual report date(s).
`
`We request that the labeling approved today be available on your website within 10 days of
`receipt of this letter.
`
`CARTON AND IMMEDIATE CONTAINER LABELS
`
`We acknowledge your June 4, 2012, submission containing final printed carton and container
`labels.
`
`We remind you of the following:
`
`
`Pouch Labels (Currently marketed strengths: 1 mg/0.5 mg, 8 mg/2 mg)
`At next printing revise the statement “Do not chew or swallow sublingual films”
`to read “Do not cut, chew or swallow sublingual film” and relocate to the
`Principal Display Panel to increase its prominence
`
`Carton Labeling (Currently marketed strengths: 1 mg/0.5 mg, 8 mg/2 mg)
`At next printing revise the statement “Do not chew or swallow sublingual films”
`to read “Do not cut, chew or swallow sublingual film” and relocate to the
`Principal Display Panel to increase its prominence.
`
`
`
`Reference ID: 3172979
`
`

`

`NDA 022410/S-006
`NDA 022410/S-007
`Page 3
`
`
`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
`
`The REMS for Suboxone (buprenorphine and naloxone) sublingual film was originally approved
`on August 30, 2010. The REMS consists of a Medication Guide, elements to assure safe use,
`implementation system, and a timetable for submission of assessments of the REMS. Your
`proposed modifications to the REMS consists of revised REMS and REMS materials to include
`the following two new dosage strengths as follows:
`
`
` 4mg/1mg buprenorphine/naloxone
` 12mg/3mg buprenorphine/naloxone
`
`
`Your proposed modified REMS, submitted on June 04, 2012, and appended to this letter, is
`approved.
`
`The timetable for submission of assessments of the REMS will remain the same as that approved
`on August 30, 2010, but
` has been removed from the REMS
`document.
`
`There are no changes to the REMS assessment plan described in our August 30, 2010, letter.
`
`In addition to the assessments submitted according to the timetable included in the approved
`REMS, you must submit a REMS assessment and may propose a modification to the approved
`REMS when you submit a supplemental application for a new indication for use as described in
`section 505-1(g)(2)(A) of FDCA.
`
`If you currently distribute or plan to distribute an authorized generic product under this NDA,
`you must submit a complete proposed REMS that relates only to the authorized generic product.
`Submit a proposed REMS, REMS supporting document, and any required appended documents
`as a prior approval supplement. Approval of the proposed REMS is required before you may
`market your authorized generic product.
`
`Prominently identify the submission containing the REMS assessments or proposed
`modifications of the REMS with the following wording in bold capital letters at the top of the
`first page of the submission as appropriate:
`
`
`NDA 022410 REMS ASSESSMENT
`
`NEW SUPPLEMENT FOR NDA 022410
`PROPOSED REMS MODIFICATION
`REMS ASSESSMENT
`
`NEW SUPPLEMENT (NEW INDICATION FOR USE)
`FOR NDA 022410
`REMS ASSESSMENT
`PROPOSED REMS MODIFICATION (if included)
`
`Reference ID: 3172979
`
`(b) (4)
`
`

`

`NDA 022410/S-006
`NDA 022410/S-007
`Page 4
`
`
`If you do not submit electronically, please send 5 copies of REMS-related submissions.
`
`PROMOTIONAL MATERIALS
`
`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory
`comments, (2) the proposed materials in draft or mock-up form with annotated references, and
`(3) the package insert(s) to:
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion (OPDP)
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`You must submit final promotional materials and package insert(s), accompanied by a Form
`FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form
`FDA 2253 is available at http://www.fda.gov/opacom/morechoices/fdaforms/cder.html;
`instructions are provided on page 2 of the form. For more information about submission of
`promotional materials to the Office of Prescription Drug Promotion (OPDP), see
`http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`All promotional materials that include representations about your drug product must be promptly
`revised to be consistent with the labeling changes approved in this supplement, including any
`new safety information [21 CFR 314.70(a)(4)]. The revisions in your promotional materials
`should include prominent disclosure of the important new safety information that appears in the
`revised package labeling. Within 7 days of receipt of this letter, submit your statement of intent
`to comply with 21 CFR 314.70(a)(4) to the address above or by fax to 301-847-8444.
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`
`Reference ID: 3172979
`
`

`

`NDA 022410/S-006
`NDA 022410/S-007
`Page 5
`
`
`If you have any questions, call Matthew Sullivan, Senior Regulatory Project Manager, at (301)
`796-1245.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Bob A Rappaport, MD
`Director
`Division of Anesthesia, Analgesia,
` and Addiction Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
`
`ENCLOSURE(S):
`Content of Labeling
`Medication Guide
`Carton and Container Labeling
`REMS
`REMS materials
`• REMS Introductory Letter to Prescribers
`• REMS Introductory Letter to Pharmacists
`• Appropriate Use Checklist
`• Physician Brochure, “Important Information for Physicians-Frequently Asked
`Questions”
`• Pharmacist Brochure, “Important Information for Pharmacists-Frequently Asked
`Questions”
`
`Reference ID: 3172979
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`BOB A RAPPAPORT
`08/10/2012
`
`Reference ID: 3172979
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`APPLICATION NUMBER:
`22-410/S006/S007
`22-410/5006/5007
`
`
`APPLICA TI0N NUMBER:
`
`
`LABELING
`LABELING
`
`
`
`
`
`
`
`
`
`

`

`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`SUBOXONE® sublingual film safely and effectively. See full
`prescribing information for SUBOXONE sublingual film.
`SUBOXONE (buprenorphine and naloxone) sublingual film for
`sublingual administration CIII.
`
`
`Initial U.S. Approval: 2002
`
`-------------------------INDICATIONS AND USAGE-----------------------
`SUBOXONE sublingual film is indicated for maintenance
`treatment of opioid dependence. Prescription use of this product
`is limited under the Drug Addiction Treatment Act. (1)
`--------------------DOSAGE AND ADMINISTRATION-------------------
`Administer SUBOXONE sublingual film sublingually as a single
`daily dose. (2)
`The recommended daily dose for maintenance treatment is 16
`mg/4mg buprenorphine and naloxone. Advise patients not to cut,
`chew, or swallow SUBOXONE sublingual film
`-----------------DOSAGE FORMS AND STRENGTHS------------------
`Sublingual film: 2 mg buprenorphine with 0.5 mg naloxone, 4 mg
`
`buprenorphine with 1 mg naloxone ,8 mg buprenorphine with 2
`mg naloxone, and 12 mg buprenorphine with 3 mg naloxone. (3)
`--------------------------CONTRAINDICATIONS----------------------------
`Hypersensitivity to buprenorphine or naloxone. (4)
`-------------------WARNINGS AND PRECAUTIONS--------------------
` Buprenorphine can be abused in a similar manner to other
`
`opioids. Clinical monitoring appropriate to the patient’s level
`
`of stability is essential. Multiple refills should not be
`prescribed early in treatment or without appropriate patient
`follow-up visits. (5.1)
` Significant respiratory depression and death have occurred in
`
`
`association with buprenorphine, particularly when taken by
`
`the intravenous (IV) route in combination with
`benzodiazepines or other CNS depressants (including
`alcohol). (5.2)
` Consider dose reduction of CNS depressants, SUBOXONE
`
`sublingual film, or both in situations of concomitant
`prescription. (5.3)
` Store SUBOXONE sublingual film safely out of the sight and
`
`reach of children. Buprenorphine can cause severe, possibly
`
`fatal, respiratory depression in children. (5.4)
` Chronic administration produces opioid-type physical
`
`dependence. Abrupt discontinuation or rapid dose taper may
`result in opioid withdrawal syndrome. (5.5)
` Monitor liver function tests prior to initiation and during
`
`treatment and evaluate suspected hepatic events. (5.6)
` Do not administer SUBOXONE sublingual film to patients with
`
`known hypersensitivity to buprenorphine or naloxone. (5.7)
`
` A marked and intense opioid withdrawal syndrome is highly
`
`
`likely to occur with parenteral misuse of SUBOXONE
`sublingual film by individuals physically dependent on full
`opioid agonists or by sublingual administration before the
`agonist effects of other opioids have subsided. (5.8)
` Neonatal withdrawal has been reported following use of
`
`buprenorphine by the mother during pregnancy. (5.9)
` SUBOXONE sublingual film is not appropriate as an
`
`
`analgesic. There have been reported deaths of opioid naïve
`individuals who received a 2 mg sublingual dose. (5.10)
` Caution patients about the risk of driving or operating
`
`hazardous machinery. (5.11)
`
`
`---------------------------ADVERSE REACTIONS--------------------------
`Adverse events commonly observed with the sublingual
`administration of the SUBOXONE sublingual film was oral
`hypoesthesia, glossodynia, oral mucosal erythema, headache,
`nausea, vomiting, hyperhidrosis, constipation, signs and
`symptoms of withdrawal, insomnia, pain, and peripheral edema.
`(6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact Reckitt
`Benckiser Pharmaceuticals Inc. at 1-877-782-6966,FDA at 1­
`800-FDA-1088, or www.fda.gov/medwatch.
`
`---------------------------DRUG INTERACTIONS--------------------------
` Monitor patients starting or ending CYP3A4 inh bitors or
`
`inducers for potential over or under dosing. (7.1)
`
` Use caution in prescribing SUBOXONE sublingual film for
`
`patients receiving benzodiazepines or other CNS depressants
`and warn patients against concomitant self­
`administration/misuse. (7.3)
`-------------------USE IN SPECIFIC POPULATIONS-------------------
` SUBOXONE sublingual film is not indicated for use during
`
`pregnancy unless potential benefit justifies potential risk. (8.1)
` Buprenorphine passes into the mother’s milk. Breast-feeding
`
`is not advised while taking SUBOXONE sublingual film. (8.3)
` Safety and effectiveness of SUBOXONE sublingual film in
`
`patients below the age of 16 has not been established. (8.4)
` Administer SUBOXONE sublingual film with caution to elderly
`
`
`or debilitated patients. (8.5)
`
` Administer SUBOXONE sublingual film with caution to
`
`patients with liver dysfunction. (8.6)
`See 17 for PATIENT COUNSELING
`INFORMATION and Medication Guide
`
`Revised August 2012
`
`Reference ID: 3172979
`
`

`

`2.7
`
`7
`
`
`
`8
`
`
`
`
`9
`
`10
`11
`12
`
`
`
`13
`
`16
`
`17
`
`
`
`
`
`DRUG INTERACTIONS
`Cytochrome P-450 3A4 (CYP3A4)
`7.1
`Inhibitors and Inducers
`
`
` Antiretrovirals
`7.2
`7.3
` Benzodiazepines
`USE IN SPECIFIC POPULATIONS
`8.1
` Pregnancy
`8.3
` Nursing Mothers
` Pediatric Use
`8.4
`
` Geriatric Use
`8.5
`
` Hepatic Impairment
`8.6
`8.7
`Renal Impairment
`DRUG ABUSE AND DEPENDENCE
`9.1
` Controlled Substance
`9.2
` Abuse
`9.3
` Dependence
`
`OVERDOSAGE
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`
`12.2
`Pharmacodynamics
`
`12.3
`Pharmacokinetics
`
`NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis,
`
`Impairment of Fertility
`HOW SUPPLIED / STORAGE AND
`HANDLING
`
`PATIENT COUNSELING INFORMATION
`17.1
`Safe Use
`
`
`* Sections and subsections omitted from
`the full prescribing information are not
`listed.
`
`FULL PRESCRIBING INFORMATION:
`CONTENTS*
`
`INDICATIONS AND USAGE
`1
`2
`DOSAGE AND ADMINISTRATION
` Maintenance
`2.1
`
`
`Method of Administration
`2.2
`
`2.3
` Clinical Supervision
`2.4
` Unstable Patients
`2.5
` Stopping Treatment
`2.6
`Switching between SUBOXONE
`(buprenorphine and naloxone)
`Sublingual Tablets and
`SUBOXONE Sublingual Film
`Switching between different
`
`strengths of SUBOXONE
`Sublingual Film
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`
`WARNINGS AND PRECAUTIONS
` Abuse Potential
`5.1
`5.2
`Respiratory Depression
`5.3
`CNS Depression
`5.4
` Unintentional Pediatric Exposure
`5.5
` Dependence
`5.6
`Hepatitis, Hepatic Events
`5.7
`Allergic Reactions
`5.8
`Precipitation of Opioid Withdrawal
`Signs and Symptoms
` Neonatal Withdrawal
`5.9
`5.10 Use in Opioid Naïve Patients
`
`5.11
`Impairment of Ability to Drive and
`
`Operate Machinery
`5.12 Orthostatic Hypotension
`5.13
`Elevation of Cerebrospinal Fluid
`
`Pressure
`Elevation of Intracholedochal
`Pressure
`Effects in Acute Abdominal
`Conditions
`5.16 General Precautions
`
` ADVERSE REACTIONS
`Adverse Events in Clinical Trials -
`6.1
`SUBOXONE Sublingual Film
`Adverse Events – Post-marketing
`Experience with SUBOXONE
`Sublingual Tablets
`
`3
`4
`5
`
`6
`
`5.14
`
`
`5.15
`
`
`6.2
`
`Reference ID: 3172979
`
`

`

`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`1
`SUBOXONE sublingual film is indicated for maintenance treatment of opioid dependence and should be used as
`part of a complete treatment plan to include counseling and psychosocial support.
`
`Under the Drug Addiction Treatment Act (DATA) codified at 21 U.S.C. 823(g), prescription use of this
`product in the treatment of opioid dependence is limited to physicians who meet certain qualifying
`
`requirements, and who have notified the Secretary of Health and Human Services (HHS) of their intent to
`prescribe this product for the treatment of opioid dependence and have been assigned a unique
`
`identification number that must be included on every prescription.
`
`DOSAGE AND ADMINISTRATION
`2
`
`SUBOXONE sublingual film is administered sublingually as a single daily dose. SUBOXONE sublingual film
`should be used in patients who have been initially inducted using SUBUTEX® (buprenorphine) sublingual tablets.
`
`
`2.1
`Maintenance
`
`
`
`
` SUBOXONE sublingual film is indicated for maintenance treatment. The recommended target dosage of
`
`
`SUBOXONE sublingual film is 16 mg/4 mg buprenorphine/naloxone/day as a single daily dose.
`
`
`
` The dosage of SUBOXONE sublingual film should be progressively adjusted in increments/decrements of
`
`
`2 mg/0.5 mg or 4 mg/1 mg buprenorphine/naloxone to a level that holds the patient in treatment and
`suppresses opioid withdrawal signs and symptoms.
`
`
` The maintenance dose of SUBOXONE sublingual film is generally in the range of 4 mg/1 mg
`
`buprenorphine/naloxone to 24 mg/6 mg buprenorphine/naloxone per day depending on the individual patient.
`Dosages higher than this have not been demonstrated to provide any clinical advantage.
`
`
`
`2.2
`Method of Administration
`
`
`Do not cut, chew, or swallow SUBOXONE sublingual film. Place a sublingual film under the tongue. If an
`
`
`additional sublingual film is necessary to achieve the prescribed dose, place an additional sublingual film
`
`
`sublingually on the opposite side from the first film. Place the sublingual film in a manner to minimize overlapping
`
`
`as much as possible. The sublingual film must be kept under the tongue until the film is completely dissolved.
`
`
`SUBOXONE sublingual film should NOT be moved after placement.
`
`Proper administration technique should be demonstrated to the patient.
`
`Clinical Supervision
`2.3
`Treatment should be initiated with supervised administration, progressing to unsupervised administration as the
`
`patient’s clinical stability permits. SUBOXONE sublingual film is subject to diversion and abuse. When
`determining the prescription quantity for unsupervised administration, consider the patient’s level of stability, the
`security of his or her home situation, and other factors likely to affect the ability to manage supplies of take-home
`medication.
`
`Ideally patients should be seen at reasonable intervals (e.g., at least weekly during the first month of treatment)
`based upon the individual circumstances of the patient. Medication should be prescribed in consideration of the
`frequency of visits. Provision of multiple refills is not advised early in treatment or without appropriate patient
`follow-up visits. Periodic assessment is necessary to determine compliance with the dosing regimen,
`effectiveness of the treatment plan, and overall patient progress.
`
`Once a stable dosage has been achieved and patient assessment (e.g., urine drug screening) does not indicate
`illicit drug use, less frequent follow-up visits may be appropriate. A once-monthly visit schedule may be
`reasonable for patients on a stable dosage of medication who are making progress toward their treatment
`objectives. Continuation or modification of pharmacotherapy should be based on the physician’s evaluation of
`treatment outcomes and objectives such as:
`
`1. Absence of medication toxicity.
`
`
`Reference ID: 3172979
`
`

`

`2. Absence of medical or behavioral adverse effects.
`
`3. Responsible handling of medications by the patient.
`
`4. Patient’s compliance with all elements of the treatment plan (including recovery-oriented activities,
`
`psychotherapy, and/or other psychosocial modalities).
`
`
`5. Abstinence from illicit drug use (including problematic alcohol and/or benzodiazepine use).
`
`If treatment goals are not being achieved, the physician should re-evaluate the appropriateness of continuing the
`current treatment.
`
`Unstable Patients
`2.4
`Physicians will need to decide when they cannot appropriately provide further management for particular
`
`patients. For example, some patients may be abusing or dependent on various drugs, or unresponsive to
`psychosocial intervention such that the physician does not feel that he/she has the expertise to manage the
`patient. In such cases, the physician may want to assess whether to refer the patient to a specialist or more
`intensive behavioral treatment environment. Decisions should be based on a treatment plan established and
`agreed upon with the patient at the beginning of treatment.
`
`Patients who continue to misuse, abuse, or divert buprenorphine products or other opioids should be provided
`with, or referred to, more intensive and structured treatment.
`
`
`2.5
`Stopping Treatment
`The decision to discontinue therapy with SUBOXONE sublingual film after a period of maintenance should be
`made as part of a comprehensive treatment plan. Both gradual and abrupt discontinuation of buprenorphine has
`been used, but the data are insufficient to determine the best method of dose taper at the end of treatment.
`
`Switching between SUBOXONE Sublingual Tablets and SUBOXONE Sublingual Film
`2.6
`
`Patients being switched between SUBOXONE sublingual tablets and SUBOXONE sublingual film should be
`
`started on the same dosage as the previously administered product. However, dosage adjustments may be
`necessary when switching between products. Not all strengths and combinations of the SUBOXONE sublingual
`films are bioequivalent to the SUBOXONE sublingual tablets as observed in pharmacokinetic studies [see
`Clinical Pharmacology (12.3)]. Therefore, systemic exposures of buprenorphine and naloxone may be different
`when patients are switched from tablets to strips or vice-versa. Patients should be monitored for symptoms
`
`related to over-dosing or under-dosing.
`
`
`2.7
`Switching between SUBOXONE Sublingual Film strengths
`As indicated in Table 1, the sizes and the compositions of the four units of SUBOXONE sublingual films, i.e.,
`2 mg/0.5 mg, 4 mg/2 mg, 8 mg/2 mg and the 12 mg/3 mg units, are different from one another. If patients switch
`between various combinations of lower and higher strength units of SUBOXONE sublingual films to obtain the
`
`same total dose, (e.g., from three 4 mg/1 mg units to a single 12 mg/3 mg unit, or vice-versa), systemic
`exposures of buprenorphine and naloxone may be different and patients should be monitored for over-dosing or
`under-dosing. For this reason, pharmacist should not substitute one or more film strengths for another without
`approval of the prescriber.
`
`Table 1. Comparison of available Suboxone film strengths by dimensions and drug concentrations.
`
`Suboxone film unit strength
`(buprenorphine/naloxone)
`
`Suboxone film unit
`
`dimensions
`
`
`
`Buprenorphine Naloxone
`Concentration
`Concentration
`% (w/w)
`% (w/w)
`
`2 mg/0.5 mg
`
`22.0 mm x 12.8 mm 5.4
`
`1.53
`
`Reference ID: 3172979
`
`

`

`4 mg/1 mg
`(2 times the length of the 2
`
`mg/0.5 mg unit)
`
`22.0 mm x 25.6 mm 5.4
`
`1.53
`
`8 mg/2 mg
`
`22.0 mm x 12.8 mm 17.2
`
`12 mg/3 mg
`(1.5 times the length of the 8
`mg/2 mg unit)
`
`22 mm X 19.2 mm
`
`17.2
`
`4.88
`
`4.88
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`SUBOXONE sublingual film is supplied as an orange rectangular sublingual film with a white printed logo in four
`
`dosage strengths:
` buprenorphine/naloxone 2 mg/0.5 mg,
`
` buprenorphine/naloxone 4 mg/1 mg,
`
` buprenorphine/naloxone 8 mg/2 mg, and
`
`
` buprenorphine/naloxone 12 mg/3 mg
`
`
`CONTRAINDICATIONS
`4
`SUBOXONE sublingual film should not be administered to patients who have been shown to be hypersensitive
`to buprenorphine or naloxone as serious adverse reactions, including anaphylactic shock, have been reported
`[see Warnings and Precautions (5.7)].
`
`5
`
`WARNINGS AND PRECAUTIONS
`
`
`Abuse Potential
`5.1
`Buprenorphine can be abused in a manner similar to other opioids, legal or illicit. Prescribe and dispense
`buprenorphine with appropriate precautions to minimize risk of misuse, abuse, or diversion, and ensure
`appropriate protection from theft, including in the home. Clinical monitoring appropriate to the patient’s level of
`stability is essential. Multiple refills should not be prescribed early in treatment or without appropriate patient
`
`follow-up visits. [see Drug Abuse and Dependence (9.2)].
`
`
`
`5.2
`Respiratory Depression
`Buprenorphine, particularly when taken by the IV route, in combination with benzodiazepines or other CNS
`depressants (including alcohol), has been associated with significant respiratory depression and death. Many,
`
`but not all, post-marketing reports regarding coma and death associated with the concomitant use of
`buprenorphine and benzodiazepines involved misuse by self-injection. Deaths have also been reported in
`association with concomitant administration of buprenorphine with other depressants such as alcohol or other
`
`CNS depressant drugs. Patients should be warned of the potential danger of self-administration of
`benzodiazepines or other depressants while under treatment with SUBOXONE sublingual film. [see Drug
`Interactions (7.3)].
`
`
`In the case of overdose, the primary management should be the re-establishment of adequate ventilation
`with mechanical assistance of respiration, if required. Naloxone may be of value for the management of
`
`buprenorphine overdose. Higher than normal doses and repeated administration may be necessary.
`SUBOXONE sublingual film should be used with caution in patients with compromised respiratory function (e.g.,
`chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, or
`pre-existing respiratory depression).
`
`Reference ID: 3172979
`
`

`

`CNS Depression
`5.3
`Patients receiving buprenorphine in the presence of opioid analgesics, general anesthetics, benzodiazepines,
`phenothiazines, other tranquilizers, sedative/hypnotics, or other CNS depressants (including alcohol) may exhibit
`increased CNS depression. Consider dose reduction of CNS depressants, SUBOXONE sublingual film, or both
`in situations of concomitant prescription. [see Drug Interactions (7.3)].
`
`Unintentional Pediatric Exposure
`5.4
`
`Buprenorphine can cause severe, possibly fatal, respiratory depression in children who are accidentally exposed
`
`to it. Store buprenorphine-containing medications safely out of the sight and reach of children.
`
`
`5.5
`Dependence
`Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical
`dependence of the opioid type, characterized by withdrawal signs and symptoms upon abrupt discontinuation or
`
`rapid taper. The withdrawal syndrome is typically milder than seen with full agonists and may be delayed in
`
`onset. Buprenorphine can be abused in a manner similar to other opioids. This should be considered when
`prescribing or dispensing buprenorphine in situations when the clinician is concerned about an increased risk of
`
`misuse, abuse, or diversion. [see Drug Abuse and Dependence (9.3)]
`
`Hepatitis, Hepatic Events
`5.6
`Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving
`buprenorphine in clinical trials and through post-marketing adverse event reports. The spectrum of
`abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of death,
`
`hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy. In many cases, the
`presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant
`
`usage of other potentially hepatotoxic drugs, and ongoing injecting drug use may have played a causative or
`contributory role. In other cases, insufficient data were available to determine the etiology of the abnormality.
`Withdrawal of buprenorphine has resulted in amelioration of acute hepatitis in some cases; however, in other
`cases no dose reduction was necessary. The possibility exists that buprenorphine had a causative or
`
`contributory role in the development of the hepatic abnormality in some cases. Liver function tests, prior to
`initiation of treatment is recommended to establish a baseline. Periodic monitoring of liver function during
`treatment is also recommended. A biological and etiological evaluation is recommended when a hepatic event
`is suspected. Depending on the case, SUBOXONE sublingual film may need to be carefully discontinued to
`
`prevent withdrawal signs and symptoms and a return by the patient to illicit drug use, and strict monitoring of the
`
`patient should be initiated.
`
`
`
`Allergic Reactions
`5.7
`Cases of hypersensitivity to buprenorphine and naloxone containing products have been reported both in clinical
`trials and in the post-marketing experience. Cases of bronchospasm, angioneurotic edema, and anaphylactic
`shock have been reported. The most common signs and symptoms include rashes, hives, and pruritus. A
`history of hypersensitivity to buprenorphine or naloxone is a contraindication to the use of SUBOXONE
`sublingual film.
`
`5.8
`Precipitation of Opioid Withdrawal Signs and Symptoms
`
`Because it contains naloxone, SUBOXONE sublingual film is highly likely to produce marked and intense
`
`withdrawal signs and symptoms if misused parenterally by individuals dependent on full opioid agonists such as
`heroin, morphine, or methadone. Because of the partial agonist properties of buprenorphine, SUBOXONE
`sublingual film may precipitate opioid withdrawal signs and symptoms in such persons if administered
`sublingually before the agonist effects of the opioid have subsided.
`
`Reference ID: 3172979
`
`

`

`Neonatal Withdrawal
`5.9
`Neonatal withdrawal has been reported in the infants of women treated with buprenorphine during pregnancy.
`From post-marketing reports, the time to onset of neonatal withdrawal signs ranged from Day 1 to Day 8 of life
`with most cases occurring on Day 1. Adverse events