`
`
`sublingual film. (5.2, 5.3)
`
`
`
` Unintentional Pediatric Exposure: 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)
`
`
` Neonatal Opioid Withdrawal Syndrome: Neonatal opioid withdrawal
`syndrome (NOWS) is an expected and treatable outcome of prolonged
`use of opioids during pregnancy (5.5)
`
` Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of
`corticosteroids, and wean patient off of the opioid. (5.6)
`
` Risk of Opioid Withdrawal with Abrupt Discontinuation: If treatment is
`
`temporarily interrupted or discontinued, monitor patients for withdrawal
`
`and treat appropriately. (5.7)
`
` Risk of Hepatitis, Hepatic Events: Monitor liver function tests prior to
`initiation and during treatment and evaluate suspected hepatic events.
`
`(5.8)
`
` Precipitation of Opioid Withdrawal Signs and Symptoms: 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 or buccal administration before the
`
`agonist effects of other opioids have subsided. (5.10)
`
` Risk of Overdose in Opioid‐Naïve Patients: 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. (5.11)
`
`‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ADVERSE REACTIONS‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
`
`Adverse events commonly observed with the sublingual/buccal
`administration of the SUBOXONE sublingual film are oral hypoesthesia,
`
`glossodynia, oral mucosal erythema, headache, nausea, vomiting,
`hyperhidrosis, constipation, signs and symptoms of withdrawal, insomnia,
`
`pain, and peripheral edema. (6)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Indivior Inc. at 1‐877‐
`
`782‐6966 or FDA at 1‐800‐FDA‐1088 or www.fda.gov/medwatch.
`
`‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐DRUG INTERACTIONS‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
`
`
` Benzodiazepines: Use caution in prescribing SUBOXONE sublingual film
`for patients receiving benzodiazepines or other CNS depressants and
`warn patients against concomitant self‐administration/misuse. (7)
`
` CYP3A4Inhibitors and Inducers: Monitor patients starting or ending
`
`CYP3A4 inhibitors or inducers for potential over‐ or under‐ dosing. (7)
`
` Antiretrovirals: Patients who are on chronic buprenorphine treatment
`
`should have their dose monitored if NNRTIs are added to their treatment
`
`regimen. Monitor patients taking buprenorphine and atazanavir with and
`without ritonavir. Dose reduction of buprenorphine may be warranted
`
`(7).
`
`
`Serotonergic Drugs: Concomitant use may result in serotonin syndrome.
`
`Discontinue SUBOXONE sublingual film if serotonin syndrome is
`
`suspected. (7)
`
`‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐USE IN SPECIFIC POPULATIONS‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
`
`Lactation: Buprenorphine passes into mother’s milk. (8.2)
`
`
`
`Geriatric Patients: Monitor for sedation and respiratory depression.
`
`
`(8.5)
`
` Moderate or Severe Hepatic Impairment: 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: 03/2021
`
`
`
`
` 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
`
`
`or buccal use, CIII
`
`Initial U.S. Approval: 2002
`‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐RECENT MAJOR CHANGES‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
`
`
`
`Dosage and Administration (2.3)
`03/2021
`
`
`
`
`
`Warnings and Precautions (5.2, 5.3)
`03/2021
`
`
`
`‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐INDICATIONS AND USAGE‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
`
`SUBOXONE® sublingual film contains buprenorphine, a partial‐opioid agonist,
`
`and naloxone, an opioid antagonist, and is indicated for treatment of opioid
`dependence. (1)
`SUBOXONE sublingual film should be used as part of a complete treatment
`plan that includes counseling and psychosocial support. (1)
`
`‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐DOSAGE AND ADMINISTRATION‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
`
`
` Prescription use of this product is limited under the Drug Addiction
`
`Treatment Act. (2.1)
`
`
` Administer SUBOXONE sublingual film as a single daily dose. (2.2)
`
` Strongly consider prescribing naloxone at the time SUBOXONE sublingual
`
`film is initiated or renewed because patients being treated for opioid use
`disorder have the potential for relapse, putting them at risk for opioid
`
`overdose. (2.3)
`
` To avoid precipitating withdrawal, induction with SUBOXONE sublingual
`film should be undertaken when objective and clear signs of withdrawal
`are evident and SUBOXONE sublingual film should be administered in
`
`divided doses when used as initial treatment. (2.4)
`
` 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. (2.4)
`
` For patients dependent on methadone or long‐acting opioid products,
`
`
`induction onto sublingual buprenorphine monotherapy is recommended
`
`on Days 1 and 2 of treatment. (2.4)
`
` For maintenance treatment, the target dosage of SUBOXONE sublingual
`
`
`film is usually 16 mg/4 mg as a single daily dose. (2.5)
`
`
` Sublingual Administration: Place one film under the tongue, close to the
`base on the left or right side, and allow to completely dissolve.
`
`
`Buccal Administration: Place one film on the inside of the left or right
`cheek and allow to completely dissolve. (2.6)
`
` SUBOXONE sublingual film must be administered whole. Do not cut,
`
`chew, or swallow SUBOXONE sublingual film (2.6)
`
` When discontinuing treatment, gradually taper to avoid signs and
`
`symptoms of withdrawal. (2.9)
`
`‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐DOSAGE FORMS AND STRENGTHS‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
`
`Sublingual film:
`
`
`
`buprenorphine 2 mg/ naloxone 0.5 mg,
`
`
`
`buprenorphine 4 mg/ naloxone 1 mg,
`
`
`
`buprenorphine 8 mg/ naloxone 2 mg and
`
`
`
`
`buprenorphine 12 mg/ naloxone 3 mg. (3)
`
`
`‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐CONTRAINDICATIONS‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
`Hypersensitivity to buprenorphine or naloxone. (4)
`
`‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐WARNINGS AND PRECAUTIONS‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
`
`
` Addiction, Abuse, and Misuse: Buprenorphine can be abused in a similar
`manner to other opioids. Monitor patients for conditions indicative of
`diversion or progression of opioid dependence and addictive behaviors.
`Multiple refills should not be prescribed early in treatment or without
`
`appropriate patient follow‐up visits. (5.1)
`
` Respiratory Depression: Life‐threatening respiratory depression and
`
`death have occurred in association with buprenorphine use. Warn
`patients of the potential danger of self‐administration of benzodiazepines
`
`Reference ID: 4756504
`
`
`
`
`DRUG INTERACTIONS
`
`USE IN SPECIFIC POPULATIONS
`
`
`Pregnancy
`
`8.1
`
`
`8.2
`Lactation
`
`
`
`8.3
`Females and Males of Reproductive Potential
`
`
`Pediatric Use
`
`8.4
`
`
`
`8.5 Geriatric Use
`
`
`8.6 Hepatic Impairment
`
`
`
`
`Renal Impairment
`
`8.7
`
`DRUG ABUSE AND DEPENDENCE
`
`
`Controlled Substance
`
`9.1
`
`
`Abuse
`
`9.2
`
`
`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
`
`
`
`Storage and Disposal
`
`Safe Use
`
`
`
`
`
`*
`
`Sections or subsections omitted from the full
`
`prescribing information are not listed.
`
`7
`8
`
`
`
`
`
`
`9
`
`
`
`10
`
`11
`
`12
`
`
`
`
`13
`
`16
`
`17
`
`
`
`
`
`
`
`2.3
`
`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`1
` INDICATIONS AND USAGE
` DOSAGE AND ADMINISTRATION
`
`
` 2
`
`
`2.1 Drug Addiction Treatment Act
`
`
`2.2
`Important Dosage and Administration
`
`Information
`
`Patient Access to Naloxone for the Emergency
`
`
`Treatment of Opioid Overdose
`
`Induction
`
`2.4
`
`2.5 Maintenance
`
`
`2.6 Method of Administration
`
`
`2.7
`Clinical Supervision
`
`
`2.8 Unstable Patients
`
`
`2.9 Discontinuing Treatment
`
`
`2.10 Switching Between Buprenorphine or
`
`Buprenorphine and Naloxone Sublingual Tablets
`
`and SUBOXONE Sublingual Film
`
`
`2.11 Switching Between SUBOXONE Sublingual Film
`
`Strengths
`
`2.12 Switching Between Sublingual and Buccal Sites
`
`of Administration
`
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`
`WARNINGS AND PRECAUTIONS
`
`Addiction, Abuse, and Misuse
`
`5.1
`
`5.2
`Risk of Life‐Threatening Respiratory and Central
`
`
`Nervous System (CNS) Depression
`
`5.3 Managing Risks from Concomitant Use of
`
`Benzodiazepines or Other CNS Depressants
`
`
`5.4 Unintentional Pediatric Exposure
`
`
`5.5 Neonatal Opioid Withdrawal Syndrome
`
`
`
`
`5.6
`Adrenal Insufficiency
`
`5.7
`Risk of Opioid Withdrawal with Abrupt
`
`
`Discontinuation
`
`
`Risk of Hepatitis, Hepatic Events
`
`5.8
`5.9 Hypersensitivity Reactions
`
`5.10 Precipitation of Opioid Withdrawal Signs and
`
`
`Symptoms
`
`5.11 Risk of Overdose in Opioid Naïve Patients
`
`
`5.12 Use in Patients with Impaired Hepatic Function
`
`
`Impairment of Ability to Drive or Operate
`
`5.13
`
`Machinery
`
`
`
`5.14 Orthostatic Hypotension
`
`
`
`5.15 Elevation of Cerebrospinal Fluid Pressure
`
`
`
`5.16 Elevation of Intracholedochal Pressure
`
`
`
`5.17 Effects in Acute Abdominal Conditions
`
`ADVERSE REACTIONS
`
`
`6.1
`Clinical Trials Experience
`
`
`
`
`6.2
`Postmarketing Experience
`
`
`
`
`
`
`
`3
`
`4
`5
`
`6
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4756504
`
`
`
`FULL PRESCRIBING INFORMATION
`
`
`1
`INDICATIONS AND USAGE
`
`SUBOXONE sublingual film is indicated for treatment of opioid dependence. SUBOXONE sublingual film should
`
`be used as part of a complete treatment plan that includes counseling and psychosocial support.
`2
`DOSAGE AND ADMINISTRATION
`2.1
`Drug Addiction and Treatment Act
`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 healthcare providers 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.
`
`Important Dosage and Administration Information
`2.2
`
`SUBOXONE sublingual film is administered sublingually or buccally as a single daily dose.
`
`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.
`Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose
`2.3
`
`Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and
`
`
`
`caregiver. Because patients being treated for opioid use disorder have the potential for relapse, putting them
`at risk for opioid overdose, strongly consider prescribing naloxone for the emergency treatment of opioid
`
`overdose, both when initiating and renewing treatment with SUBOXONE sublingual film. Also consider
`
`
`prescribing naloxone if the patient has household members (including children) or other close contacts at risk
`
`for accidental ingestion or opioid overdose [see Warnings and Precautions (5.2)].
`Advise patients and caregivers that naloxone may also be administered for a known or suspected overdose with
`
`
`
`
`
`SUBOXONE sublingual film itself. Higher than normal doses and repeated administration of naloxone may be
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`necessary due to the long duration of action of SUBOXONE sublingual film and its affinity for the mu‐opioid receptor
`
`
`
`[see Overdosage (10)].
`Inform patients and caregivers of their options for obtaining naloxone as permitted by individual state naloxone
`
`
`
`dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part
`
`
`
`
`
`
`
`
`
`of a community‐based program) [see Patient Counseling Information (17)].
`
`Induction
`2.4
`
`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.
`
`
`Patients dependent on heroin or other short‐acting opioid products
`
`Patients dependent on heroin or other short‐acting opioid products may be inducted with either SUBOXONE
`
`
`
`sublingual film or with sublingual buprenorphine monotherapy. At treatment initiation, the first dose of
`
`SUBOXONE sublingual film should be administered when objective signs of moderate opioid withdrawal appear,
`
`
`
`
`not less than six hours after the patient last used opioids.
`
`
`
`It is recommended that an adequate treatment 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.
`
`
`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
`
`
`
`Reference ID: 4756504
`
`
`
` 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.
`
`
`
`Because the exposure to naloxone is somewhat higher after buccal than after sublingual administration, it is
`recommended that the sublingual site of administration be used during induction to minimize exposure to
`
`
`
`naloxone, to reduce the risk of precipitated withdrawal.
`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 who are physically dependent on long‐acting opioid products, and the
`
`
`naloxone in these combination products 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.
`
`
`Maintenance
`2.5
`
`For maintenance, SUBOXONE sublingual film may be administered buccally or sublingually.
`
`
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
` 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.
`
`
` There is no maximum recommended duration of maintenance treatment. Patients may require treatment
`
` indefinitely and should continue for as long as patients are benefiting and the use of SUBOXONE sublingual
`
`
`
`
`
`
`
` film contributes to the intended treatment goals.
`
`Method of Administration
`2.6
`
`
`
`
`
`SUBOXONE sublingual film must be administered whole. Do not cut, chew, or swallow SUBOXONE sublingual film.
`
`
`
`Advise patients not to eat or drink anything until the film is completely dissolved.
`Sublingual Administration
`
`
`Place one film under the tongue, close to the base on the left or right side. If an additional film is necessary to
`
`
`
`achieve the prescribed dose, place an additional film sublingually on the opposite side from the first film. Place
`
`
`
`
`the film in a manner to minimize overlapping as much as possible. The film must be kept under the tongue until
`
`
`
`
`
`
`
`the film is completely dissolved. If a third film is necessary to achieve the prescribed dose, place it under the
`
`
`
`
`
`
`tongue on either side after the first 2 films have dissolved.
`
`Buccal Administration
`Place one film on the inside of the right or left cheek. If an additional film is necessary to achieve the prescribed
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4756504
`
`
`
`dose, place an additional film on the inside of the opposite cheek. The film must be kept on the inside of the
`
`
`
`
`
`
`cheek until the film is completely dissolved. If a third film is necessary to achieve the prescribed dose, place it on
`
`
`
`the inside of the right or left cheek after the first two films have dissolved.
`
`
`
`
`SUBOXONE sublingual film should NOT be moved after placement.
`
`
`
`To ensure consistency in bioavailability, patients should follow the same manner of dosing with continued use of
`
`the product. Proper administration technique should be demonstrated to the patient.
`2.7
`Clinical Supervision
`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 healthcare provider’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).
`
`If treatment goals are not being achieved, the healthcare provider should re‐evaluate the appropriateness of
`
`
`continuing the current treatment.
`2.8
`Unstable Patients
`Healthcare providers 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 healthcare provider does not feel that he/she has the
`
`
`
`expertise to manage the patient. In such cases, the healthcare provider 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.
`
`2.9
`Discontinuing 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. Advise patients of the potential to relapse to illicit drug use
`
`
`
`Reference ID: 4756504
`
`
`
`following discontinuation of opioid agonist/partial agonist medication‐assisted treatment. Taper patients to
`
`
`reduce the occurrence of opioid withdrawal signs and symptoms [See Warnings and Precautions (5.7)].
`
`
`Switching Between Buprenorphine or Buprenorphine and Naloxone Sublingual Tablets and
`2.10
`SUBOXONE Sublingual Film
`Patients being switched between buprenorphine and naloxone or buprenorphine only sublingual tablets and
`
`
`
`SUBOXONE sublingual film should be started on the same dosage of the previously administered product.
`
`However, dosage adjustments may be necessary when switching between buprenorphine products. Not all
`
`
`strengths and combinations of the SUBOXONE sublingual films are bioequivalent to 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 film or
`
`
`
`vice‐versa. Patients should be monitored for symptoms related to over‐dosing or under‐dosing.
`
`Switching Between SUBOXONE Sublingual Film Strengths
`2.11
`
`
`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.
`
`
`SUBOXONE sublingual film unit strength
`(buprenorphine/naloxone)
`
`SUBOXONE sublingual
`film unit dimensions
`
`
`Buprenorphine
`Concentration
`% (w/w)
`
`
`Naloxone
`Concentration
`% (w/w)
`
`
`2 mg/0.5 mg
`
`22.0 mm x 12.8 mm
`
`5.4
`
`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
`
`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)
`
`
`
`
`22.0 mm X 19.2 mm
`
`17.2
`
`1.53
`
`1.53
`
`4.88
`
`4.88
`
`2.12
`Switching Between Sublingual and Buccal Sites of Administration
`
`The systemic exposure of buprenorphine between buccal and sublingual administration of SUBOXONE
`sublingual film is similar. Therefore, once induction is complete, patients can switch between buccal and
`
`
`
`
`
`sublingual administration without significant risk of under or overdosing.
`
`DOSAGE FORMS AND STRENGTHS
`3
`SUBOXONE sublingual film is supplied as an orange rectangular film with a white printed logo in four dosage
`
`strengths:
`
`Reference ID: 4756504
`
`
`
`
`
` Buprenorphine 2 mg/naloxone 0.5 mg,
`
` Buprenorphine 4 mg/naloxone 1 mg,
`
`
` Buprenorphine 8 mg/naloxone 2 mg and
`
`
` Buprenorphine 12 mg/naloxone 3 mg
`
`4
`CONTRAINDICATIONS
`SUBOXONE sublingual film is contraindicated in patients with a history of hypersensitivity to buprenorphine or
`
`naloxone as serious adverse reactions, including anaphylactic shock, have been reported [see Warnings and
`Precautions (5.9)].
`5
`WARNINGS AND PRECAUTIONS
`5.1
`Addiction, Abuse, and Misuse
`SUBOXONE sublingual film contains buprenorphine, a schedule III controlled substance that 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)].
`Risk of Life‐Threatening Respiratory and Central Nervous System (CNS) Depression
`5.2
`
`
`Buprenorphine has been associated with life‐threatening respiratory depression and death. Many, but not all,
`
`
`post‐marketing reports regarding coma and death involved misuse by self‐injection or were associated with the
`
`
`
`concomitant use of buprenorphine and benzodiazepines or other CNS depressants, including alcohol. Warn
`
`
`patients of the potential danger of self‐administration of benzodiazepines or other CNS depressants while
`under treatment with SUBOXONE sublingual film [see Warnings and Precautions (5.3), Drug Interactions (7)].
`
`
`
`
`Use SUBOXONE sublingual film 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).
`Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of
`
`
`
`
`calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see
`
`
`Patient Counseling Information (17)].
`
`Opioids can cause sleep‐related breathing disorders including central sleep apnea (CSA) and sleep‐related
`
`
`hypoxemia. Opioid use increases the risk of CSA in a dose‐dependent fashion. In patients who present with
`
`CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and
`
`
`
`Administration (2.9)].
`Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose
`
`
`
`Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and
`
`
`
`caregiver.
`Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for
`opioid overdose, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, both
`
`when initiating and renewing treatment with SUBOXONE sublingual film. Also consider prescribing naloxone if
`
`the patient has household members (including children) or other close contacts at risk for accidental ingestion
`
`or opioid overdose [see Dosage and Administration (2.3)].
`
`
`
`Advise patients and caregivers that naloxone may also be administered for a known or suspected overdose
`with SUBOXONE sublingual film itself. Higher than normal doses and repeated administration of naloxone may
`
`
`Reference ID: 4756504
`
`
`
`be necessary due to the long duration of action of SUBOXONE sublingual film and its affinity for the mu‐opioid
`receptor [see Overdosage (10)].
`
`Inform patients and caregivers of their options for obtaining naloxone as permitted by individual state
`
`
`
`
`
`naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a
`pharmacist, or as part of a community‐based program).
`Educate patients and caregivers on how to recognize respiratory depression and, if naloxone is prescribed, how
`
`
`
`
`to treat with naloxone. Emphasize the importance of calling 911 or getting emergency medical help, even if
`
`
`naloxone is administered [see Patient Counseling Information (17)].
`
`
`Managing Risks from Concomitant Use of Benzodiazepines or Other CNS Depressants
`5.3
`
`
`
`
`Concomitant use of buprenorphine and benzodiazepines or other CNS depressants increases the risk of adverse
`reactions including overdose and death. Medication‐assisted treatment of opioid use disorder, however,
`
`
`
`should not be categorically denied to patients taking these drugs. Prohibiting or creating barriers to treatment
`
`
`can pose an even greater risk of morbidity and mortality due to the opioid use disorder alone.
`As a routine part of orientation to buprenorphine treatment, educate patients about the risks of concomitant
`use of benzodiazepines, sedatives, opioid analgesics, and alcohol.
`
`Develop strategies to manage use of prescribed or illicit benzodiazepines or other CNS depressants at initiation
`
`of buprenorphine treatment, or if it emerges as a concern during treatment. Adjustments to induction
`
`procedures and additional monitoring may be required. There is no evidence to support dose limitations or
`
`arbitrary caps of buprenorphine as a strategy to address benzodiazepine use in buprenorphine‐treated
`
`patients. However, if a patient is sedated at the time of buprenorphine dosing, delay or omit the
`
`
`buprenorphine dose if appropriate.
`
`Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use. In some
`
`cases, monitoring in a higher level of care for taper may be appropriate. In others, gradually tapering a patient
`
`off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be
`
`appropriate.
`
`For patients in buprenorphine treatment, benzodiazepines are not the treatment of choice for anxiety or
`
`insomnia. Before co‐prescribing benzodiazepines, ensure that patients are appropriately diagnosed and
`
`consider alternative medications and non‐pharmacologic treatments to address anxiety or insomnia. Ensure
`
`that other healthcare providers prescribing benzodiazepines or other CNS depressants are aware of the
`
`
`patient’s buprenorphine treatment and coordinate care to minimize the risks associated with concomitant use.
`
`If concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid
`
`
`overdose, as is recommended for all patients in buprenorphine treatment for opioid use disorder [see
`Warnings and Precautions (5.2)].
`In addition, take measures to confirm that patients are taking their medications as prescribed and are not
`
`
`diverting or supplementing with illicit drugs. Toxicology screening should test for prescribed and illicit
`
`benzodiazepines [see Drug Interactions (7)].
`
`
`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 and
`
`destroy any unused medicatio