`• 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)
`
`
`
`• An opioid withdrawal syndrome is 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)
`
`
`
`
`• Buprenorphine/naloxone products are not recommended in patients
`
`with severe hepatic impairment and may not be appropriate for patients
`
`with moderate hepatic impairment (5.11)
`
`
`• Caution patients about the risk of driving or operating hazardous
`
`machinery. (5.12)
`
`
`-------------------------------------ADVERSE REACTIONS------------------------------------­
`Adverse events commonly observed with the sublingual administration of
`
`
`
`the SUBOXONE sublingual film were 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 or FDA at 1-800-FDA-1088 or
`
`
`
`
`
`www.fda.gov/medwatch.
`
`
`
`
`--------------------------------------DRUG INTERACTIONS----------------------------------­
`
`• Monitor patients starting or ending CYP3A4 inhibitors 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---------------------------­
`
`
`•
`Pregnancy: Based on animal data, may cause fetal harm. (8.1)
`
`
`
`•
`Nursing mothers: Caution should be exercised when administered to a
`
`
`
`nursing woman. (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)
`
`
`Buprenorphine/naloxone products are not recommended in patients
`
`with severe hepatic impairment and may not be appropriate for
`
`patients with moderate hepatic impairment. (8.6)
`
`
`
`•
`
`
`•
`
`
`•
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
`
`
`
`
`Revised: April 2014
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
` These highlights do not include all the information needed to use
` SUBOXONE safely and effectively. See full prescribing information for
`
`
`
` SUBOXONE.
`
`
` SUBOXONE® (buprenorphine and naloxone) sublingual film for sublingual
`administration CIII
`
`
`Initial U.S. Approval: 2002
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`----------------------------------RECENT MAJOR CHANGES--------------------------------­
`
`Dosage and Administration, Induction (2.1)
`04/2014
`
`
`
`Dosage and Administration, Patients With
`
`
`
`Hepatic Impairment (2.5)
`
`
`
`
`Warnings and Precautions, Use in Patients
`
`With Impaired Hepatic Function (5.11)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`04/2014
`
`
`04/2014
`
`
`
`
`----------------------------------INDICATIONS AND USAGE--------------------------------­
`
`SUBOXONE sublingual film is a partial-opioid agonist indicated for treatment
`
`
`
`
`
`of opioid dependence. Prescription use of this product is limited under the
`
`
`
`
`Drug Addiction Treatment Act. (1)
`
`
`
`
`
`------------------------------DOSAGE AND ADMINISTRATION----------------------------­
`
`
`
`• For patients dependent on short-acting opioid products who are in opioid
`
`
`withdrawal; on Day 1, administer up to 8 mg/ 2 mg SUBOXONE sublingual
`
`
`
`
`
`film (in divided doses). On Day 2, administer up to 16 mg/4 mg of
`
`SUBOXONE sublingual film as a single dose. (2.1)
`
`
`
`• For patients dependent on methadone or long-acting opioid products,
`
`
`
`induction onto sublingual buprenorphine monotherapy is recommended
`
`
`
`on Days 1 and 2 of treatment. (2.1)
`
`
`
`• For maintenance treatment, the target dosage of SUBOXONE sublingual
`
`
`
`
`
`
`film is usually 16 mg/4 mg as a single daily dose. (2.2)
`
`
`
`
`
`
`• Place the SUBOXONE sublingual film under the tongue, close to the base
`
`
`
`on the left or right side and allow to completely dissolve. Film should not
`
`
`be chewed, swallowed, or moved after placement. (2.3)
`
`
`
`-----------------------------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)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3496928
`
`

`

`
`
`
`
`
`
`
` DRUG INTERACTIONS
`
`
` 7.1
`
` Cytochrome P-450 3A4 (CYP3A4) Inhibitors and
`
`
` Inducers
`
`
` Antiretrovirals
`
`
`
` 7.2
`
` Benzodiazepines
`
`
`
` 7.3
`
` USE IN SPECIFIC POPULATIONS
`
` 8.1
`
`
` Pregnancy
`
`
` 8.3 Nursing Mothers
`
`
`
` 8.4
`
`
` Pediatric Use
`
`
` 8.5 Geriatric Use
`
`
`
`
`
` 8.6 Hepatic Impairment
`
`
`
` 8.7
`
`
`
` Renal Impairment
`
` DRUG ABUSE AND DEPENDENCE
`
`
` Controlled Substance
`
` 9.1
`
`
`
` 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
`
`
`
` 17.2 Disposal of Unused SUBOXONE Sublingual Films
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` *
`
`
`
` Sections and subsections omitted from the full
`
`
` prescribing information are not listed.
`
`
`
`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
` 1
` INDICATIONS AND USAGE
`
`
` 2
` DOSAGE AND ADMINISTRATION
`
`
` 2.1
`
`
` Induction
`
`
`
`
` 2.2 Maintenance
`
`
`
`
` 2.3 Method of Administration
`
`
`
`
` 2.4
`
`
` Clinical Supervision
`
`
`
` 2.5
`
` Patients With Hepatic Impairment
`
`
`
` 2.6 Unstable Patients
`
`
`
`
` 2.7
`
` Stopping Treatment
`
`
`
` 2.8
`
`Switching Between Buprenorphine and
`
` Naloxone Sublingual Tablets and SUBOXONE
`
`
`
` Sublingual Film
`
` Switching Between SUBOXONE Sublingual Film
`
`
` Strengths
`
`
` 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
`
`
`
`
` 5.9 Neonatal Withdrawal
`
`
`
` 5.10 Use in Opioid Naïve Patients
`
`
`
` 5.11 Use in Patients With Impaired Hepatic Function
`
`
`
` 5.12
`
`
`
` Impairment of Ability to Drive or Operate
`
`
`Machinery
`
`
`
`
` 5.13 Orthostatic Hypotension
`
`
`
` 5.14 Elevation of Cerebrospinal Fluid Pressure
`
`
` 5.15 Elevation of Intracholedochal Pressure
`
`
`
`
` 5.16 Effects in Acute Abdominal Conditions
`
`
`
`
` 5.17 General Precautions
`
`
`
` ADVERSE REACTIONS
`
`
` Clinical Trials Experience
`
` 6.1
`
`
`
`
` 6.2
`
`Postmarketing Experience
`
`
`
` 2.9
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 3
`
` 4
`
` 5
`
`
`
` 6
`
`
`
` 7
`
`
`
`
` 8
`
`
`
`
`
`
` 9
`
`
`
`
` 10
`
` 11
`
` 12
`
`
`
` 13
`
`
`
`
` 16
`
` 17
`
`
`
`Reference ID: 3496928
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
`
` 1
`
`
` INDICATIONS AND USAGE
` SUBOXONE sublingual film is indicated for 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 2
` DOSAGE AND ADMINISTRATION
`
`
`
` 2.1
` Induction
`
`
`
`
` Prior to induction, consideration should be given to the type of opioid dependence (i.e., long- or short-acting
` opioid products), the time since last opioid use, and the degree or level of opioid dependence. To avoid
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` precipitating an opioid withdrawal syndrome, the first dose of buprenorphine/naloxone should be started only
` when objective signs of moderate withdrawal appear.
`
`
`
`
`
`
`
`
`
`
`
` On Day 1, an induction dosage of up to 8 mg /2 mg SUBOXONE sublingual film is recommended. Clinicians
` should start with an initial dose of 2 mg/ 0.5 mg or 4 mg/1 mg buprenorphine/naloxone and may titrate
`
`
`
`
`
`
`
` upwards in 2 or 4 mg increments of buprenorphine, at approximately 2-hour intervals, under supervision, to 8
`
`
`
` mg/2 mg buprenorphine/naloxone based on the control of acute withdrawal symptoms.
`
`
`
`
`
` On Day 2, a single daily dose of up to 16 mg/4 mg SUBOXONE sublingual film is recommended.
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
` Patients dependent on methadone or long-acting opioid products
`
`
`
`
`
`
`
`
`
`
`
` Patients dependent upon methadone or long-acting opioid products may be more susceptible to precipitated
` and prolonged withdrawal during induction than those on short-acting opioid products.
`
`
`
`
` Buprenorphine/naloxone combination products have not been evaluated in adequate and well-controlled
`
`
`
` studies for induction in patients on long-acting opioid products, and contain naloxone, which is absorbed in
`
`
`
`
`
`
` small amounts by the sublingual route and could cause worse precipitated and prolonged withdrawal. For this
`
`
`
`
`
` reason, buprenorphine monotherapy is recommended in patients taking long-acting opioids when used
`
`
`
`
` according to approved administration instructions. Following induction, the patient may then be transitioned
`
`
`
`
` to once-daily SUBOXONE sublingual film.
`
`
`
`
`
`
`
` Patients dependent on heroin or other short-acting opioid products
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Patients dependent on heroin or short-acting opioid products may be inducted with either SUBOXONE sublingual
` film or with sublingual buprenorphine monotherapy. The first dose of SUBOXONE sublingual film or
`
`
`
`
`
`
`
` buprenorphine should be administered when objective signs of moderate opioid withdrawal appear, and not less
`
`
`
`
` than 6 hours after the patient last used an opioid.
`
`
`
`
`
`
`
` It is recommended that an adequate maintenance dose, titrated to clinical effectiveness, be achieved as rapidly
` as possible. In some studies, a too-gradual induction over several days led to a high rate of drop-out of
`
`
`
`
`
`
` buprenorphine patients during the induction period.
`
`
`
`
`
`
`
`Reference ID: 3496928
`
`

`

`
`
`Maintenance
`2.2
`
`
`
`
`
`The dosage of SUBOXONE sublingual film from Day 3 onwards 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.
`
`
`
`After treatment induction and stabilization, 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 and clinical response. The recommended target dosage of SUBOXONE sublingual film
`
`
`
`
`during maintenance is 16 mg/4 mg buprenorphine/naloxone/day as a single daily dose. Dosages higher than 24
`
`
`
`mg/6 mg daily have not been demonstrated to provide a clinical advantage.
`
`
`
`Method of Administration
`2.3
`
`
`
`
`
`
`Do not cut, chew, or swallow SUBOXONE sublingual film. Place the SUBOXONE sublingual film under the tongue,
`
`
`
`
`
`
`close to the base on the left or right side. If an additional sublingual film is necessary to achieve the prescribed
`
`
`
`
`
`
`dose, place the 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
`2.4
`
`
`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.
`
`
`
`
`
`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).
`
`
`Reference ID: 3496928
`
`

`

`
` If treatment goals are not being achieved, the physician should re-evaluate the appropriateness of continuing
`
`
` the current treatment.
`
`
`
`
`
` 2.5
`
`
`
` Patients With Hepatic Impairment
` Because the doses of this fixed combination product cannot be individually titrated, severe hepatic impairment
`
`
`
`
`
`
`
` results in a reduced clearance of naloxone to a much greater extent than buprenorphine, and moderate
` hepatic impairment also results in a reduced clearance of naloxone to a greater extent than buprenorphine,
`
`
`
`
`
` the combination product should generally be avoided in patients with severe hepatic impairment and may not
` be appropriate for patients with moderate hepatic impairment [see Warnings and Precautions (5.11)].
`
`
`
`
`
`
`
`
`
` Unstable Patients
` 2.6
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Stopping Treatment
` 2.7
`
`
`
`
` The decision to discontinue therapy with SUBOXONE sublingual film after a period of maintenance should be
` made as part of a comprehensive treatment plan. Taper patients to avoid opioid withdrawal signs and
`
`
`
`
`
`
` symptoms.
`
` 2.8
`
`
`
` Switching Between Buprenorphine or Buprenorphine and Naloxone Sublingual Tablets and
`
` SUBOXONE Sublingual Film
`
`
`
` Patients being switched between buprenorphine and naloxone or buprenorphine only sublingual tablets and
` SUBOXONE sublingual film should be started on the corresponding dosage of 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 (buprenorphine and
`
`
`
` naloxone) 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 film or vice-versa. Patients should be monitored for symptoms related to over-dosing or under-
`
`
`
`
`
`dosing.
`
`
`
`
`
`2.9
` 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/1 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 Sublingual Film Strengths by Dimensions and Drug
`
`Concentrations.
`
`
`
`
`Reference ID: 3496928
`
`

`

` SUBOXONE sublingual film unit strength
`
`
`
`(buprenorphine/naloxone)
`
`
`
`
`
`
`
` 2 mg/0.5 mg
`
` 4 mg/1 mg
`
` (2 times the length of the 2 mg/0.5 mg unit)
`
`
`
`
`
`
` 8 mg/2 mg
`
` SUBOXONE sublingual
`
`
`film unit dimensions
`
`
`
`
`
` 22.0 mm x 12.8 mm
`
`
`
`
`
` 22.0 mm x 25.6 mm
`
`
`
`
`
` 22.0 mm x 12.8 mm
`
`
`
` 12 mg/3 mg
`
` (1.5 times the length of the 8 mg/2 mg unit)
`
`
`
`
`
`
`
`
`
` 22 mm X 19.2 mm
`
`
`
`
`
`
` Buprenorphine
`
` Concentration
`
`% (w/w)
`
` 5.4
`
` Naloxone
`
`
` Concentration
`
`% (w/w)
`
` 1.53
`
`
`
` 5.4
`
`
`
` 17.2
`
`
`
` 17.2
`
`
`
` 1.53
`
`
`
` 4.88
`
`
`
` 4.88
`
` 3
` DOSAGE FORMS AND STRENGTHS
`
`
`
`
` 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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 4
`
`
` CONTRAINDICATIONS
`
`
`
` 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)].
`
`
`
`
`Respiratory Depression
`5.2
`
`
`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)].
`
`
`Reference ID: 3496928
`
`

`

`
`
`
`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).
`
`
`
`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.
`
`
`
`Dependence
`5.5
`
`
`
`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 are 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.
`
`Reference ID: 3496928
`
`

`

` Precipitation of Opioid Withdrawal Signs and Symptoms
` 5.8
`
`
`
`
`
` Because it contains naloxone, SUBOXONE sublingual film is likely to produce 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.
`
`
`
` 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 associated with the neonatal withdrawal
`
`
`
`
`
`
`
`
` syndrome included hypertonia, neonatal tremor, neonatal agitation, and myoclonus, and there have been
`
`
`
` reports of convulsions, apnea, respiratory depression, and bradycardia.
`
`
`
`
`
`
`
`
` 5.10 Use in Opioid Naïve Patients
`
`
`
`
`
`
`
`
`
` There have been reported deaths of opioid naive individuals who received a 2 mg dose of buprenorphine as a
` sublingual tablet for analgesia. SUBOXONE sublingual film is not appropriate as an analgesic.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 5.11 Use in Patients With Impaired Hepatic Function
` Buprenorphine/naloxone products are not recommended in patients with severe hepatic impairment and may
`
`
`
`
`
`
` not be appropriate for patients with moderate hepatic impairment. Because hepatic impairment results in a
` reduced clearance of naloxone to a much greater extent than buprenorphine, the doses of buprenorphine and
`
`
`
` naloxone in this fixed-dose combination product cannot be individually titrated. Therefore, patients with
`
`
`
`
`
`
` severe hepatic impairment will be exposed to substantially higher levels of naloxone than patients with normal
`
`
` hepatic function. This may result in an increased risk of precipitated withdrawal at the beginning of treatment
`
`
`
`
` (induction) and may interfere with buprenorphine’s efficacy throughout treatment. In patients with moderate
`
`
`
`
`
` hepatic impairment, the differential reduction of naloxone clearance compared to buprenorphine clearance is
`
` not as great as in subjects with severe hepatic impairment. Therefore, buprenorphine/naloxone products are
`
`
`
`
`
`
` not recommended for initiation of treatment (induction) in patients with moderate hepatic impairment due to
`
`
`
` the increased risk of precipitated withdrawal. However, buprenorphine/naloxone products may be used with
`
`
`
`
`
` caution for maintenance treatment in patients with moderate hepatic impairment who have initiated
`
`
`
` treatment on a buprenorphine product without naloxone. However, patients should be carefully monitored
`
`
` and consideration given to the possibility of naloxone interfering with buprenorphine’s efficacy [see Use in
`
`
`
`
`
` Specific Populations (8.6)].
`
`
`
`
`
`
` 5.12
`
`
` Impairment of Ability to Drive or Operate Machinery
` SUBOXONE sublingual film may impair the mental or physical abilities required for the performance of
`
`
`
`
`
`
`
` potentially dangerous tasks such as driving a car or operating machinery, especially during treatment induction
`
` and dose adjustment. Patients should be cautioned about driving or operating hazardous machinery until they
`
`
`
` are reasonably certain that SUBOXONE sublingual film therapy does not adversely affect his or her ability to
`
`
`
`
`
`
`
` engage in such activities.
`
` 5.13 Orthostatic Hypotension
`
`
`
`
`
` Like other opioids, SUBOXONE sublingual film may produce orthostatic hypotension in ambulatory patients.
`
`
`
`
`
` 5.14
` Elevation of Cerebrospinal Fluid Pressure
`
`
`
`
`
`
`
` Buprenorphine, like other opioids, may elevate cerebrospinal fluid pressure and should be used with caution in
`
` patients with head injury, intracranial lesions, and other circumstances when cerebrospinal pressure may be
`
`
`
`
`
`
`
`
`Reference ID: 3496928
`
`

`

`
`
`
`
`
`
`
`increased. Buprenorphine can produce miosis and changes in the level of consciousness that may interfere
`
`with patient evaluation.
`
`
`
`Elevation of Intracholedochal Pressure
`5.15
`
`
`
`Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus should be
`
`
`
`
`administered with caution to patients with dysfunction of the biliary tract.
`
`
`
`
`
`Effects in Acute Abdominal Conditions
`5.16
`
`
`
`
`
`As with other opioids, buprenorphine may obscure the diagnosis or clinical course of patients with acute
`
`abdominal conditions.
`
`
`
`5.17 General Pr