`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: 02/2018
`
`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 (2.2, 2.3, 2.5, 2.8)
`Warnings and Precautions (5.2, 5.3)
`
`
`09/2017
`02/2018
`
`
`
`
`----------------------------------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)
`• 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. (2.3)
`• 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. (2.3)
`• For patients dependent on methadone or long‐acting opioid products,
`induction onto sublingual buprenorphine monotherapy is recommended
`on Days 1 and 2 of treatment. (2.3)
`• For maintenance treatment, the target dosage of SUBOXONE sublingual
`film is usually 16 mg/4 mg as a single daily dose. (2.4)
`• 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. (2.5)
`• SUBOXONE sublingual film must be administered whole. Do not cut,
`chew, or swallow SUBOXONE sublingual film (2.5)
`• When discontinuing treatment, gradually taper to avoid signs and
`symptoms of withdrawal. (2.8)
`
`-----------------------------DOSAGE FORMS AND STRENGTHS----------------------------
`Sublingual film:
`•
`buprenorphine 2 mg/ naloxone 0.5 mg,
`•
`buprenorphine 4 mg/ naloxone 1 mg,
`•
`buprenorphine 8 mg/ naloxone 2 mgand
`•
`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
`or other CNS depressants while under treatment with SUBOXONE
`sublingual film. (5.2, 5.3)
`
`Reference ID: 4215179
`
`
`
`
`DRUG INTERACTIONS
`USE IN SPECIFIC POPULATIONS
` 8.1
`Pregnancy
` 8.2
`Lactation
` 8.3
`Females and Males of Reproductive Potential
` 8.4
`Pediatric Use
` 8.5 Geriatric Use
` 8.6 Hepatic Impairment
` 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
`
`Safe Use
`
`Disposal of Unused SUBOXONE Sublingual Films
`
`
`*
`
`Sections or subsections omitted from the full
`prescribing information are not listed.
`
`7
`8
`
`
`
`
`
`
`9
`
`
`
`10
`11
`12
`
`
`
`13
`
`16
`17
`
`
`
`
`
`
`
`
`
`
`3
`4
`5
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`2
`DOSAGE AND ADMINISTRATION
`
` 2.1 Drug Addiction Treatment Act
` 2.2
`Important Dosage and Administration
`Information
`Induction
`2.3
` 2.4 Maintenance
` 2.5 Method of Administration
` 2.6
`Clinical Supervision
` 2.7 Unstable Patients
` 2.8 Discontinuing Treatment
` 2.9
`Switching Between Buprenorphine or
`Buprenorphine and Naloxone Sublingual Tablets
`and SUBOXONE Sublingual Film
` 2.10 Switching Between SUBOXONE Sublingual Film
`Strengths
` 2.11 Switching Between Sublingual and Buccal Sites
`of Administration
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
` 5.1
`Addiction, Abuse, and Misuse
` 5.2
`Risk of 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
` 5.8
`Risk of Hepatitis, Hepatic Events
` 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
` 5.13
`Impairment of Ability to Drive or Operate
`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
`
`6
`
`Reference ID: 4215179
`
`
`
`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`1
`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.
`2.2
`Important Dosage and Administration Information
`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.
`2.3
`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.
`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
`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
`
`Reference ID: 4215179
`
`
`
`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.
`2.4
`Maintenance
`• 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
`2.5
`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
`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.
`2.6
`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.
`
`
`Reference ID: 4215179
`
`
`
`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.
`2.7
`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.
`2.8
`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
`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)].
`2.9
`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 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.
`2.10
`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.,
`
`Reference ID: 4215179
`
`
`
`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
`
`Switching Between Sublingual and Buccal Sites of Administration
`2.11
`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.
`3
`DOSAGE FORMS AND STRENGTHS
`SUBOXONE sublingual film is supplied as an orange rectangular film with a white printed logo in four dosage
`strengths:
`• 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
`
`Reference ID: 4215179
`
`
`
`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
`Risk of Respiratory and Central Nervous System (CNS) Depression
`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).
`5.3
`Managing Risks from Concomitant Use of Benzodiazepines or Other CNS Depressants
`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.
`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)].
`5.4
`Unintentional Pediatric Exposure
`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 medication appropriately [see Patient Counseling Information (17)].
`
`Reference ID: 4215179
`
`
`
`Neonatal Opioid Withdrawal Syndrome
`5.5
`Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of
`opioids during pregnancy, whether that use is medically‐authorized or illicit. Unlike opioid withdrawal
`syndrome in adults, NOWS may be life‐threatening if not recognized and treated in the neonate. Healthcare
`professionals should observe newborns for signs of NOWS and manage accordingly [see Use in Specific
`Populations (8.1)].
`Advise pregnant women receiving opioid addiction treatment with SUBOXONE sublingual film of the risk of
`neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in
`Specific Populations (8.1)]. This risk must be balanced against the risk of untreated opioid addiction which often
`results in continued or relapsing illicit opioid use and is associated with poor pregnancy outcomes. Therefore,
`prescribers should discuss the importance and benefits of management of opioid addiction throughout
`pregnancy.
`5.6
`Adrenal Insufficiency
`Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one
`month of use. Presentation of adrenal insufficiency may include non‐specific symptoms and signs including
`nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is
`suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is
`diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to
`allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other
`opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal
`insufficiency. The information available does not identify any particular opioids as being more likely to be
`associated with adrenal insufficiency.
`5.7
`Risk of Opioid Withdrawal with Abrupt Discontinuation
`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 [see Drug Abuse and Dependence (9.3)]. When discontinuing SUBOXONE sublingual film, gradually taper
`the dosage [see Dosage and Administration (2.8)].
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`Reference ID: 4215179
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`Risk of Hepatitis, Hepatic Events
`5.8
`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.
`5.9
`Hypersensitivity Reactions
`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.
`5.10
`Precipitation of Opioid Withdrawal Signs and Symptoms
`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 before the agonist effects of the opioid have
`subsided.
`5.11
`Risk of Overdose in Opioid Naïve Patients
`There have been reported deaths of opioid‐naïve individuals who received a 2 mg dose of buprenorphine as a
`sublingual tablet for analgesia. SUBOXONE sublingual film is not appropriate as an analgesic.
`5.12 Use in Patients With Impaired Hepatic Function
`Buprenorphine/naloxone product