• 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)
`• 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)
`• Buprenorphine/naloxone products are not recommended in patients
`with severe hepatic impairment and may not be appropriate for patients
`with moderate hepatic impairment (5.12)
`• Caution patients about the risk of driving or operating hazardous
`machinery. (5.13)
`-------------------------------------ADVERSE REACTIONS-------------------------------------
`Adverse events commonly observed with the sublingual/buccal
`administration of the SUBOXONE sublingual film were oral hypoesthesia,
`glossodynia, oral mucosal erythema, headache, nausea, vomiting,
`hyperhidrosis, constipation, signs and symptoms of withdrawal, insomnia,
`pain, and peripheral edema. (6)
`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-----------------------------------
`• Use caution in prescribing SUBOXONE sublingual film for patients
`receiving benzodiazepines or other CNS depressants and warn patients
`against concomitant self-administration/misuse. (7)
`• Monitor patients starting or ending CYP3A4 inhibitors or inducers for
`potential over or under dosing. (7)
`• 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,
`and reduce dose of buprenorphine if warranted (7).
`Serotonergic Drugs: Concomitant use may result in serotonin syndrome.
`Discontinue SUBOXONE if serotonin syndrome is suspected. (7)
`
`•
`
`•
`
`---------------------------------USE IN SPECIFIC POPULATIONS----------------------------
`•
`Nursing mothers: Caution should be exercised when administered to a
`nursing woman. (8.2)
`Safety and effectiveness of SUBOXONE sublingual film in patients below
`the age of 16 has not been established. (8.4)
`Administer SUBOXONE sublingual film with caution to elderly or
`debilitated patients. (8.5)
`Buprenorphine/naloxone products are not recommended in patients
`with severe hepatic impairment and may not be appropriate for
`patients with moderate hepatic impairment. (8.6)
`
`•
`
`•
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
`
`Revised: 12/2016
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`SUBOXONE safely and effectively. See full prescribing information for
`SUBOXONE.
`
`SUBOXONE® (buprenorphine and naloxone) sublingual film, for sublingual
`or buccal use CIII
`Initial U.S. Approval: 2002
`
`----------------------------------RECENT MAJOR CHANGES---------------------------------
`Warnings and Precautions (5.5, 5.6)
`
`
`12/2016
`
`----------------------------------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. Prescription use of this product is limited under the Drug
`Addiction Treatment Act. (1)
`
`------------------------------DOSAGE AND ADMINISTRATION-----------------------------
`• For patients dependent on short-acting opioid products who are in opioid
`withdrawal; on Day 1, administer up to 8 mg/2 mg SUBOXONE sublingual
`film (in divided doses). On Day 2, administer up to 16 mg/4 mg of
`SUBOXONE sublingual film as a single dose. (2.1)
`• For patients dependent on methadone or long-acting opioid products,
`induction onto sublingual buprenorphine monotherapy is recommended
`on Days 1 and 2 of treatment. (2.1)
`• For maintenance treatment, the target dosage of SUBOXONE sublingual
`film is usually 16 mg/4 mg as a single daily dose. (2.2)
`• 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.
`• SUBOXONE sublingual film must be administered whole. Do not cut,
`chew, or swallow SUBOXONE sublingual film (2.3)
`
`-----------------------------DOSAGE FORMS AND STRENGTHS----------------------------
`Sublingual film: 2 mg buprenorphine with 0.5 mg naloxone, 4 mg
`buprenorphine with 1 mg naloxone, 8 mg buprenorphine with 2 mg naloxone
`and 12 mg buprenorphine with 3 mg naloxone. (3)
`-------------------------------------CONTRAINDICATIONS------------------------------------
`Hypersensitivity to buprenorphine or naloxone. (4)
`
`-------------------------------WARNINGS AND PRECAUTIONS-----------------------------
`• Buprenorphine can be abused in a similar manner to other opioids.
`Clinical monitoring appropriate to the patient’s level of stability is
`essential. Multiple refills should not be prescribed early in treatment or
`without appropriate patient follow-up visits. (5.1)
`• Significant respiratory depression and death have occurred in association
`with buprenorphine, particularly when taken by the intravenous (IV)
`route in combination with benzodiazepines or other CNS depressants
`(including alcohol). (5.2)
`• Consider dose reduction of CNS depressants, SUBOXONE sublingual film,
`or both in situations of concomitant prescription. (5.3)
`• Store SUBOXONE sublingual film safely out of the sight and reach of
`children. Buprenorphine can cause severe, possibly fatal, respiratory
`depression in children. (5.4)
`• 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)
`• Chronic administration produces opioid-type physical dependence.
`Abrupt discontinuation or rapid dose taper may result in opioid
`withdrawal syndrome. (5.7)
`• Monitor liver function tests prior to initiation and during treatment and
`evaluate suspected hepatic events. (5.8)
`• Do not administer SUBOXONE sublingual film to patients with known
`hypersensitivity to buprenorphine or naloxone. (5.9)
`
`Reference ID: 4028529
`
`

`

` 2.9
`
`7
`8
`
`
`
`
`
`
`9
`
`
`
`10
`11
`12
`
`
`
`13
`
`16
`17
`
`
`
`
`DRUG INTERACTIONS
`USE IN SPECIFIC POPULATIONS
` 8.1
`Pregnancy
` 8.1
`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
` 17.1 Safe Use
` 17.2 Disposal of Unused SUBOXONE Sublingual Films
`
`
`*
`
`Sections or subsections omitted from the full
`prescribing information are not listed.
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`2
`DOSAGE AND ADMINISTRATION
`
` 2.1
`Induction
` 2.2 Maintenance
`
` 2.3 Method of Administration
`
` 2.4
`
`Clinical Supervision
` 2.5
`
`Patients With Hepatic Impairment
` 2.6 Unstable Patients
`
` 2.7
`Stopping Treatment
` 2.8
`Switching Between Buprenorphine or
`Buprenorphine and Naloxone Sublingual Tablets
`and SUBOXONE Sublingual Film
`Switching Between SUBOXONE Sublingual Film
`Strengths
` 2.10 Switching Between Sublingual and Buccal Sites
`of Administration
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
` 5.1
`Abuse Potential
` 5.2
`Respiratory Depression
` 5.3
`CNS Depression
` 5.4 Unintentional Pediatric Exposure
` 5.5 Neonatal Opioid Withdrawal Syndrome
` 5.6
`Adrenal Insufficiency
` 5.7 Dependence
` 5.8 Hepatitis, Hepatic Events
` 5.9
`Allergic Reactions
` 5.10 Precipitation of Opioid Withdrawal Signs and
`Symptoms
` 5.11 Use 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
` 5.18 General Precautions
`ADVERSE REACTIONS
` 6.1
`Clinical Trials Experience
` 6.2
`Postmarketing Experience
`
`3
`4
`5
`
`6
`
`Reference ID: 4028529
`
`

`

`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`1
`SUBOXONE sublingual film is indicated for treatment of opioid dependence and should be used as part of a
`complete treatment plan to include counseling and psychosocial support.
`Under the Drug Addiction Treatment Act (DATA) codified at 21 U.S.C. 823(g), prescription use of this product in
`the treatment of opioid dependence is limited to 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
`
`DOSAGE AND ADMINISTRATION
`
`Induction
`2.1
`Prior to induction, consideration should be given to the type of opioid dependence (i.e., long- or short-acting
`opioid products), the time since last opioid use, and the degree or level of opioid dependence. To avoid
`precipitating an opioid withdrawal syndrome, the first dose of buprenorphine/naloxone should be started only
`when objective signs of moderate withdrawal appear.
`
`On Day 1, an induction dosage of up to 8 mg/2 mg SUBOXONE sublingual film is recommended. Clinicians
`should start with an initial dose of 2 mg/0.5 mg or 4 mg/1 mg buprenorphine/naloxone and may titrate
`upwards in 2 or 4 mg increments of buprenorphine, at approximately 2-hour intervals, under supervision, to 8
`mg/2 mg buprenorphine/naloxone based on the control of acute withdrawal symptoms.
`On Day 2, a single daily dose of up to 16 mg/4 mg SUBOXONE sublingual film is recommended.
`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.
`
`Medication should be prescribed in consideration of the frequency of visits. Provision of multiple refills is not
`advised early in treatment or without appropriate patient follow-up visits.
`
`Patients dependent on methadone or long-acting opioid products
`
`Patients dependent upon methadone or long-acting opioid products may be more susceptible to precipitated
`and prolonged withdrawal during induction than those on short-acting opioid products.
`Buprenorphine/naloxone combination products have not been evaluated in adequate and well-controlled
`studies for induction in patients on long-acting opioid products, and contain naloxone, which is absorbed in
`small amounts by the sublingual route and could cause worse precipitated and prolonged withdrawal. For this
`reason, buprenorphine monotherapy is recommended in patients taking long-acting opioids when used
`according to approved administration instructions. Following induction, the patient may then be transitioned
`to once-daily SUBOXONE sublingual film.
`
`Patients dependent on heroin or other short-acting opioid products
`Patients dependent on heroin or short-acting opioid products may be inducted with either SUBOXONE sublingual
`film or with sublingual buprenorphine monotherapy. The first dose of SUBOXONE sublingual film or
`buprenorphine should be administered when objective signs of moderate opioid withdrawal appear, and not less
`than 6 hours after the patient last used an opioid.
`
`Reference ID: 4028529
`
`

`

`It is recommended that an adequate maintenance dose, titrated to clinical effectiveness, be achieved as rapidly
`as possible. In some studies, a too-gradual induction over several days led to a high rate of drop-out of
`buprenorphine patients during the induction period.
`
`Maintenance
`2.2
`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.
`
`Method of Administration
`2.3
`SUBOXONE sublingual film must be administered whole. Do not cut, chew, or swallow SUBOXONE sublingual
`film.
`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. Proper administration technique should be
`demonstrated to the patient.
`
`Clinical Supervision
`2.4
`Treatment should be initiated with supervised administration, progressing to unsupervised administration as
`the patient’s clinical stability permits. SUBOXONE sublingual film is subject to diversion and abuse. When
`determining the prescription quantity for unsupervised administration, consider the patient’s level of stability,
`the security of his or her home situation, and other factors likely to affect the ability to manage supplies of
`take-home medication.
`
`Ideally patients should be seen at reasonable intervals (e.g., at least weekly during the first month of
`treatment) based upon the individual circumstances of the patient. Medication should be prescribed in
`consideration of the frequency of visits. Provision of multiple refills is not advised early in treatment or without
`appropriate patient follow-up visits. Periodic assessment is necessary to determine compliance with the dosing
`regimen, effectiveness of the treatment plan, and overall patient progress.
`
`
`Reference ID: 4028529
`
`

`

`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.
`
`
`Patients With Hepatic Impairment
`2.5
`Severe hepatic impairment results in a reduced clearance of naloxone to a much greater extent than
`buprenorphine, and moderate hepatic impairment also results in a reduced clearance of naloxone to a greater
`extent than buprenorphine. Because the doses of this fixed combination product cannot be individually
`titrated, the combination product should generally be avoided in patients with severe hepatic impairment and
`may not be appropriate for patients with moderate hepatic impairment [see Warnings and Precautions (5.12)].
`
`Unstable Patients
`2.6
`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.
`
`Stopping Treatment
`2.7
`The decision to discontinue therapy with SUBOXONE sublingual film after a period of maintenance should be
`made as part of a comprehensive treatment plan. Taper patients to avoid opioid withdrawal signs and
`symptoms.
`
`Switching Between Buprenorphine or Buprenorphine and Naloxone Sublingual Tablets and
`2.8
`SUBOXONE Sublingual Film
`Patients being switched between buprenorphine and naloxone or buprenorphine only sublingual tablets and
`SUBOXONE sublingual film should be started on the corresponding dosage of the previously administered
`product. However, dosage adjustments may be necessary when switching between buprenorphine products.
`Not all strengths and combinations of the SUBOXONE sublingual films are bioequivalent to the SUBOXONE
`
`Reference ID: 4028529
`
`

`

`(buprenorphine and naloxone) sublingual tablets as observed in pharmacokinetic studies [see Clinical
`Pharmacology (12.3)]. Therefore, systemic exposures of buprenorphine and naloxone may be different when
`patients are switched from tablets to film or vice-versa. Patients should be monitored for symptoms related to
`over-dosing or under-dosing.
`
`Switching Between SUBOXONE Sublingual Film Strengths
`2.9
`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)
`
`Buprenorphine
`Concentration
`% (w/w)
`5.4
`
`Naloxone
`Concentration
`% (w/w)
`1.53
`
`SUBOXONE sublingual
`film unit dimensions
`
`2 mg/0.5 mg
`
`22.0 mm x 12.8 mm
`
`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
`
`4.88
`
`4.88
`
`Switching Between Sublingual and Buccal Sites of Administration
`2.10
`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:
`• 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: 4028529
`
`

`

`CONTRAINDICATIONS
`4
`SUBOXONE sublingual film should not be administered to patients who have been shown to be hypersensitive
`to buprenorphine or naloxone as serious adverse reactions, including anaphylactic shock, have been reported
`[see Warnings and Precautions (5.9)].
`
`5
`
`WARNINGS AND PRECAUTIONS
`
`Abuse Potential
`5.1
`Buprenorphine can be abused in a manner similar to other opioids, legal or illicit. Prescribe and dispense
`buprenorphine with appropriate precautions to minimize risk of misuse, abuse, or diversion, and ensure
`appropriate protection from theft, including in the home. Clinical monitoring appropriate to the patient’s level
`of stability is essential. Multiple refills should not be prescribed early in treatment or without appropriate
`patient follow-up visits [see Drug Abuse and Dependence (9.2)].
`
`Respiratory Depression
`5.2
`Buprenorphine, particularly when taken by the IV route, in combination with benzodiazepines or other CNS
`depressants (including alcohol), has been associated with significant respiratory depression and death. Many,
`but not all, post-marketing reports regarding coma and death associated with the concomitant use of
`buprenorphine and benzodiazepines involved misuse by self-injection. Deaths have also been reported in
`association with concomitant administration of buprenorphine with other depressants such as alcohol or other
`CNS depressant drugs. Patients should be warned of the potential danger of self-administration of
`benzodiazepines or other depressants while under treatment with SUBOXONE sublingual film [see Drug
`Interactions (7)].
`In the case of overdose, the primary management should be the re-establishment of adequate ventilation with
`mechanical assistance of respiration, if required. Naloxone may be of value for the management of
`buprenorphine overdose. Higher than normal doses and repeated administration may be necessary.
`SUBOXONE sublingual film should be used with caution in patients with compromised respiratory function
`(e.g., chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia,
`hypercapnia, or pre-existing respiratory depression).
`
`CNS Depression
`5.3
`Patients receiving buprenorphine in the presence of opioid analgesics, general anesthetics, benzodiazepines,
`phenothiazines, other tranquilizers, sedative/hypnotics, or other CNS depressants (including alcohol) may
`exhibit increased CNS depression. Consider dose reduction of CNS depressants, SUBOXONE sublingual film, or
`both in situations of concomitant prescribing [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.
`
`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 Specific Populations
`(8.1)].
`Advise pregnant women receiving opioid addiction treatment with SUBOXONE of the risk of neonatal opioid
`withdrawal syndrome and ensure that appropriate treatment will be available [see Specific Populations (8.1)].
`
`Reference ID: 4028529
`
`

`

`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.
`
`Dependence
`5.7
`Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical
`dependence of the opioid type, characterized by withdrawal signs and symptoms upon abrupt discontinuation
`or rapid taper. The withdrawal syndrome is typically milder than seen with full agonists and may be delayed in
`onset. Buprenorphine can be abused in a manner similar to other opioids. This should be considered when
`prescribing or dispensing buprenorphine in situations when the clinician is concerned about an increased risk
`of misuse, abuse, or diversion [see Drug Abuse and Dependence (9.3)].
`
`Hepatitis, Hepatic Events
`5.8
`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.
`
`Allergic Reactions
`5.9
`Cases of hypersensitivity to buprenorphine and naloxone containing products have been reported both in
`clinical trials and in the post-marketing experience. Cases of bronchospasm, angioneurotic edema, and
`anaphylactic shock have been reported. The most common signs and symptoms include rashes, hives, and
`pruritus. A history of hypersensitivity to buprenorphine or naloxone is a contraindication to the use of
`SUBOXONE sublingual film.
`
`Reference ID: 4028529
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`

`

`Precipitation of Opioid Withdrawal Signs and Symptoms
`5.10
`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 Use 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 products are not recommended in patients with severe hepatic impairment and may
`not be appropriate for patients with moderate hepatic impairment. Because hepatic impairment results in a
`reduced clearance of naloxone to a much greater extent than buprenorphine, the doses of buprenorphine and
`naloxone in this fixed-dose combination product cannot be individually titrated. Therefore, patients with
`severe hepatic impairment will be exposed to substantially higher levels of naloxone than patients with normal
`hepatic function. This may result in an increased risk of precipitated withdrawal at the beginning of treatment
`(induction) and may interfere with buprenorphine’s efficacy throughout treatment. In patients with moderate
`hepatic impairment, the differential reduction of naloxone clearance compared to buprenorphine clearance is
`not as great as in subjects with severe hepatic impairment. Therefore, buprenorphine/naloxone products are
`not recommended for initiation of treatment (induction) in patients with moderate hepatic impairment due to
`the increased risk of precipitated withdrawal. However, buprenorphine/naloxone products may be used with
`caution for maintenance treatment in patients with moderate hepatic impairment who have initiated
`treatment on a buprenorphine product without naloxone. However, patients should be carefully monitored
`and consideration given to the possibility of naloxone interfering with buprenorphine’s efficacy [see Use in
`Specific Populations (8.6)].
`
`Impairment of Ability to Drive or Operate Machinery
`5.13
`SUBOXONE sublingual film may impair the mental or physical abilities required for the performance of
`potentially dangerous tasks such as driving a car or operating machinery, especially during treatment induction
`and dose adjustment. Patients should be cautioned about driving or operating hazardous machinery until they
`are reasonably certain that SUBOXONE sublingual film therapy does not adversely affect his or her ability to
`engage in such activities.
`
`5.14 Orthostatic Hypotension
`Like other opioids, SUBOXONE sublingual film may produce orthostatic hypotension in ambulatory patients.
`
`Elevation of Cerebrospinal Fluid Pressure
`5.15
`Buprenorphine, like other opioids, may elevate cerebrospinal fluid pressure and should be used with caution in
`patients with head injury, intracranial lesions, and other circumstances when cerebrospinal pressure