HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`BUPRENORPHINE AND NALOXONE SUBLINGUAL FIILM safely and
`effectively. See full prescribing information for buprenorphine and
`naloxone sublingual film.
`
`BUPRENORPHINE AND NALOXONE SUBLINGUAL FIILM , 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
`01/2018
`
`----------------------------------INDICATIONS AND USAGE---------------------------------
`
`Buprenorphine and naloxone sublingual filmcontains buprenorphine, a
`partial‐opioid agonist, and naloxone, an opioid antagonist, and is indicated
`for treatment of opioid dependence. (1)
`
`buprenorphine and naloxone sublingual filmshould 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 buprenorphine and naloxone sublingual film as a single daily
`dose. (2.2)
` To avoid precipitating withdrawal, induction with buprenorphine and
`naloxone sublingual film should be undertaken when objective and clear
`signs of withdrawal are evident and buprenorphine and naloxone
`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 buprenorphine and
`naloxone sublingual film(in divided doses). On Day 2, administer up to 16
`mg/4 mg of buprenorphine and naloxone 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 buprenorphine and
`naloxone 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)
` buprenorphine and naloxone sublingual film must be administered
`whole. Do not cut, chew, or swallow buprenorphine and naloxone
`sublingual film (2.5)
` When discontinuing treatment, gradually taper to avoid signs and
`symptoms of withdrawal. (2.8)
`
`-----------------------------DOSAGE FORMS AND STRENGTHS----------------------------
`
`Sublingual film:
`
`
`
`
`-------------------------------------CONTRAINDICATIONS------------------------------------
`
`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)
`
`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)
`
`Reference ID: 4276171
`
` 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 buprenorphine and
`naloxone sublingual film. (5.2, 5.3)
` Unintentional Pediatric Exposure: Store buprenorphine and naloxone
`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 E
`buprenorphine and naloxone sublingual filmby 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: buprenorphine and naloxone
`sublingual film i s 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 buprenorphine and naloxone 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 buprenorphine and naloxone
`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 buprenorphine and naloxone 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: 06/2018
`
`

`

`
`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 buprenorphine and naloxone
`Sublingual Films
`
`
`
`*
`
`Sections or subsections omitted from the full
`prescribing information are not listed.
`
`7
`8
`
`
`
`
`
`
`9
`
`
`
`10
`11
`12
`
`
`
`13
`
`16
`17
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1
`2
`
`
`
`
`
`
`
`3
`4
`5
`
`6
`
`INDICATIONS AND USAGE
`DOSAGE AND ADMINISTRATION
` 2.1 Drug Addiction and 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 Sublingual Film
` 2.10 Switching Between Buprenorphine and naloxone
`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
`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
` 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
`
`Reference ID: 4276171
`
`

`

`FULL PRESCRIBING INFORMATION
`
`1
`
`INDICATIONS AND USAGE
`
`Buprenorphine and naloxone sublingual film is indicated for treatment of opioid dependence. buprenorphine
`and naloxone 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
`
`Buprenorphine and naloxone 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 buprenorphine
`and naloxone sublingual filmor with sublingual buprenorphine monotherapy. At treatment initiation, the first
`dose of buprenorphine and naloxone 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 buprenorphine and naloxone 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 buprenorphine and naloxone sublingual filmis
`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
`
`Reference ID: 4276171
`
`

`

`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 sublingual film.
`
`Maintenance
`2.4
` For maintenance, buprenorphine and naloxone sublingual film may be administered buccally or sublingually.
` The dosage of buprenorphine and naloxone 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 buprenorphine and naloxone 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
`buprenorphine and naloxone 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 buprenorphine and
`naloxone sublingual film contributes to the intended treatment goals.
`
`2.5
`
`Method of Administration
`
`Buprenorphine and naloxone sublingual film must be administered whole. Do not cut, chew, or swallow
`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.
`
` Buprenorphine and naloxone 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. buprenorphine and naloxone sublingual film is subject to diversion and
`
`Reference ID: 4276171
`
`

`

`
`
`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.
`
`2.7
`
`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 buprenorphine and naloxone 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
`Buprenorphine and naloxone Sublingual Film
`
`Patients being switched between buprenorphine and naloxone or buprenorphine only sublingual tablets and
`buprenorphine and naloxone sublingual film should be started on the same dosage of the previously
`
`Reference ID: 4276171
`
`

`

`administered product. However, dosage adjustments may be necessary when switching between
`buprenorphine products. Not all strengths and combinations of the buprenorphine and naloxone 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 Buprenorphine and naloxone sublingual film Strengths
`
`As indicated in Table 1, the sizes and the compositions of the four units of 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 buprenorphine and naloxone
`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 Buprenorphine and naloxone sublingual film Strengths by Dimensions and
`Drug Concentrations.
`
`buprenorphine and naloxone sublingual
`film unit strength
`(buprenorphine/naloxone)
`
` buprenorphine and
`naloxone sublingual
`film unit dimensions
`
`Buprenorphine
`Concentration
`
`Naloxone
`Concentration
`
`% (w/w)
`
`% (w/w)
`
`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
`
`12 mg/3 mg
`
`(1.5 times the length of the 8 mg/2 mg unit)
`
`22.0 mm x 12.8 mm
`
`5.4
`
`22.0 mm x 25.6 mm
`
`5.4
`
`22.0 mm x 12.8 mm
`
`17.2
`
`22.0 mm X 19.2 mm
`
`17.2
`
`1.53
`
`1.53
`
`4.88
`
`4.88
`
`2.11
`
`Switching Between Sublingual and Buccal Sites of Administration
`
`The systemic exposure of buprenorphine between buccal and sublingual administration of buprenorphine and
`naloxone 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
`
`Buprenorphine and naloxone sublingual film is supplied as an orange rectangular 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
`
`Reference ID: 4276171
`
`

`

`4
`
`CONTRAINDICATIONS
`
`Buprenorphine and naloxone 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
`
`Buprenorphine and naloxone 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)].
`
`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 buprenorphine and naloxone sublingual film [see Warnings and Precautions (5.3), Drug
`Interactions (7)].
`
`Use buprenorphine and naloxone 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.
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`Reference ID: 4276171
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`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)].
`
`5.5
`
`Neonatal Opioid Withdrawal Syndrome
`
`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 buprenorphine and naloxone 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 buprenorphine and naloxone sublingual
`film, gradually taper the dosage [see Dosage and Administration (2.8)].
`
`5.8
`
`Risk of Hepatitis, Hepatic Events
`
`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
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`Reference ID: 4276171
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`

`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, buprenorphine and naloxone 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
`anaph