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 administration CIII.
`
`
`Initial U.S. Approval: 2002
`
`-------------------------INDICATIONS AND USAGE-----------------------
`SUBOXONE sublingual film is indicated for maintenance
`treatment of opioid dependence. Prescription use of this product
`is limited under the Drug Addiction Treatment Act. (1)
`--------------------DOSAGE AND ADMINISTRATION-------------------
`Administer SUBOXONE sublingual film sublingually as a single
`daily dose. (2)
`The recommended daily dose for maintenance treatment is 16
`mg/4mg buprenorphine and naloxone. Advise patients not to cut,
`chew, or swallow SUBOXONE sublingual film
`-----------------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)
` Chronic administration produces opioid-type physical
`
`dependence. Abrupt discontinuation or rapid dose taper may
`result in opioid withdrawal syndrome. (5.5)
` Monitor liver function tests prior to initiation and during
`
`treatment and evaluate suspected hepatic events. (5.6)
` Do not administer SUBOXONE sublingual film to patients with
`
`known hypersensitivity to buprenorphine or naloxone. (5.7)
`
` A marked and intense opioid withdrawal syndrome is highly
`
`
`likely to occur with parenteral misuse of SUBOXONE
`sublingual film by individuals physically dependent on full
`opioid agonists or by sublingual administration before the
`agonist effects of other opioids have subsided. (5.8)
` Neonatal withdrawal has been reported following use of
`
`buprenorphine by the mother during pregnancy. (5.9)
` SUBOXONE sublingual film is not appropriate as an
`
`
`analgesic. There have been reported deaths of opioid naïve
`individuals who received a 2 mg sublingual dose. (5.10)
` Caution patients about the risk of driving or operating
`
`hazardous machinery. (5.11)
`
`
`---------------------------ADVERSE REACTIONS--------------------------
`Adverse events commonly observed with the sublingual
`administration of the SUBOXONE sublingual film was oral
`hypoesthesia, glossodynia, oral mucosal erythema, headache,
`nausea, vomiting, hyperhidrosis, constipation, signs and
`symptoms of withdrawal, insomnia, pain, and peripheral edema.
`(6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact Reckitt
`Benckiser Pharmaceuticals Inc. at 1-877-782-6966,FDA at 1­
`800-FDA-1088, or www.fda.gov/medwatch.
`
`---------------------------DRUG INTERACTIONS--------------------------
` Monitor patients starting or ending CYP3A4 inhibitors or
`
`inducers for potential over or under dosing. (7.1)
`
` Use caution in prescribing SUBOXONE sublingual film for
`
`patients receiving benzodiazepines or other CNS depressants
`and warn patients against concomitant self­
`administration/misuse. (7.3)
`-------------------USE IN SPECIFIC POPULATIONS-------------------
` SUBOXONE sublingual film is not indicated for use during
`
`pregnancy unless potential benefit justifies potential risk. (8.1)
` Buprenorphine passes into the mother’s milk. Breast-feeding
`
`is not advised while taking SUBOXONE sublingual film. (8.3)
` Safety and effectiveness of SUBOXONE sublingual film in
`
`patients below the age of 16 has not been established. (8.4)
` Administer SUBOXONE sublingual film with caution to elderly
`
`
`or debilitated patients. (8.5)
`
` Administer SUBOXONE sublingual film with caution to
`
`patients with liver dysfunction. (8.6)
`See 17 for PATIENT COUNSELING
`INFORMATION and Medication Guide
`
`Revised August 2012
`
`Reference ID: 3172979
`
`

`

`2.7
`
`7
`
`
`
`8
`
`
`
`
`9
`
`10
`11
`12
`
`
`
`13
`
`16
`
`17
`
`
`
`
`
`DRUG INTERACTIONS
`Cytochrome P-450 3A4 (CYP3A4)
`7.1
`Inhibitors and Inducers
`
`
` Antiretrovirals
`7.2
`7.3
` Benzodiazepines
`USE IN SPECIFIC POPULATIONS
`8.1
` Pregnancy
`8.3
` Nursing Mothers
` Pediatric Use
`8.4
`
` Geriatric Use
`8.5
`
` Hepatic Impairment
`8.6
`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
`
`* Sections and subsections omitted from
`the full prescribing information are not
`listed.
`
`FULL PRESCRIBING INFORMATION:
`CONTENTS*
`
`INDICATIONS AND USAGE
`1
`2
`DOSAGE AND ADMINISTRATION
`
` Maintenance
`2.1
`
`Method of Administration
`2.2
`
`2.3
` Clinical Supervision
`2.4
` Unstable Patients
`2.5
` Stopping Treatment
`2.6
`Switching between SUBOXONE
`(buprenorphine and naloxone)
`Sublingual Tablets and
`SUBOXONE Sublingual Film
`Switching between different
`
`strengths of SUBOXONE
`Sublingual Film
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`
`WARNINGS AND PRECAUTIONS
` Abuse Potential
`5.1
`5.2
`Respiratory Depression
`5.3
`CNS Depression
`5.4
` Unintentional Pediatric Exposure
`5.5
` Dependence
`5.6
`Hepatitis, Hepatic Events
`5.7
`Allergic Reactions
`5.8
`Precipitation of Opioid Withdrawal
`Signs and Symptoms
` Neonatal Withdrawal
`5.9
`5.10 Use in Opioid Naïve Patients
`
`5.11
`Impairment of Ability to Drive and
`
`Operate Machinery
`5.12 Orthostatic Hypotension
`5.13
`Elevation of Cerebrospinal Fluid
`
`Pressure
`Elevation of Intracholedochal
`Pressure
`Effects in Acute Abdominal
`Conditions
`5.16 General Precautions
`
` ADVERSE REACTIONS
`Adverse Events in Clinical Trials -
`6.1
`SUBOXONE Sublingual Film
`Adverse Events – Post-marketing
`Experience with SUBOXONE
`Sublingual Tablets
`
`3
`4
`5
`
`6
`
`5.14
`
`
`5.15
`
`
`6.2
`
`Reference ID: 3172979
`
`

`

`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`1
`SUBOXONE sublingual film is indicated for maintenance treatment of opioid dependence and should be used as
`part of a complete treatment plan to include counseling and psychosocial support.
`
`Under the Drug Addiction Treatment Act (DATA) codified at 21 U.S.C. 823(g), prescription use of this
`product in the treatment of opioid dependence is limited to physicians who meet certain qualifying
`
`requirements, and who have notified the Secretary of Health and Human Services (HHS) of their intent to
`prescribe this product for the treatment of opioid dependence and have been assigned a unique
`identification number that must be included on every prescription.
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`SUBOXONE sublingual film is administered sublingually as a single daily dose. SUBOXONE sublingual film
`should be used in patients who have been initially inducted using SUBUTEX® (buprenorphine) sublingual tablets.
`
`
`2.1
`Maintenance
`
`
`
`
` SUBOXONE sublingual film is indicated for maintenance treatment. The recommended target dosage of
`
`
`SUBOXONE sublingual film is 16 mg/4 mg buprenorphine/naloxone/day as a single daily dose.
`
`
`
` The dosage of SUBOXONE sublingual film 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.
`
`
` 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.
`Dosages higher than this have not been demonstrated to provide any clinical advantage.
`
`
`
`2.2
`Method of Administration
`
`
`Do not cut, chew, or swallow SUBOXONE sublingual film. Place a sublingual film under the tongue. If an
`
`
`additional sublingual film is necessary to achieve the prescribed dose, place an additional sublingual film
`
`
`sublingually on the opposite side from the first film. Place the sublingual film in a manner to minimize overlapping
`
`
`as much as possible. The sublingual film must be kept under the tongue until the film is completely dissolved.
`
`SUBOXONE sublingual film should NOT be moved after placement.
`
`
`Proper administration technique should be demonstrated to the patient.
`
`Clinical Supervision
`2.3
`Treatment should be initiated with supervised administration, progressing to unsupervised administration as the
`
`patient’s clinical stability permits. SUBOXONE sublingual film is subject to diversion and abuse. When
`determining the prescription quantity for unsupervised administration, consider the patient’s level of stability, the
`security of his or her home situation, and other factors likely to affect the ability to manage supplies of take-home
`medication.
`
`Ideally patients should be seen at reasonable intervals (e.g., at least weekly during the first month of treatment)
`based upon the individual circumstances of the patient. Medication should be prescribed in consideration of the
`frequency of visits. Provision of multiple refills is not advised early in treatment or without appropriate patient
`follow-up visits. Periodic assessment is necessary to determine compliance with the dosing regimen,
`effectiveness of the treatment plan, and overall patient progress.
`
`Once a stable dosage has been achieved and patient assessment (e.g., urine drug screening) does not indicate
`illicit drug use, less frequent follow-up visits may be appropriate. A once-monthly visit schedule may be
`reasonable for patients on a stable dosage of medication who are making progress toward their treatment
`objectives. Continuation or modification of pharmacotherapy should be based on the physician’s evaluation of
`treatment outcomes and objectives such as:
`
`1. Absence of medication toxicity.
`
`
`Reference ID: 3172979
`
`

`

`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 physician should re-evaluate the appropriateness of continuing the
`current treatment.
`
`Unstable Patients
`2.4
`Physicians will need to decide when they cannot appropriately provide further management for particular
`
`patients. For example, some patients may be abusing or dependent on various drugs, or unresponsive to
`psychosocial intervention such that the physician does not feel that he/she has the expertise to manage the
`patient. In such cases, the physician may want to assess whether to refer the patient to a specialist or more
`intensive behavioral treatment environment. Decisions should be based on a treatment plan established and
`agreed upon with the patient at the beginning of treatment.
`
`Patients who continue to misuse, abuse, or divert buprenorphine products or other opioids should be provided
`with, or referred to, more intensive and structured treatment.
`
`
`2.5
`Stopping 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. Both gradual and abrupt discontinuation of buprenorphine has
`been used, but the data are insufficient to determine the best method of dose taper at the end of treatment.
`
`Switching between SUBOXONE Sublingual Tablets and SUBOXONE Sublingual Film
`2.6
`
`Patients being switched between SUBOXONE sublingual tablets and SUBOXONE sublingual film should be
`
`started on the same dosage as the previously administered product. However, dosage adjustments may be
`necessary when switching between products. Not all strengths and combinations of the SUBOXONE sublingual
`films are bioequivalent to the SUBOXONE 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 strips or vice-versa. Patients should be monitored for symptoms
`
`related to over-dosing or under-dosing.
`
`Switching between SUBOXONE Sublingual Film strengths
`
`2.7
`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/2 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 film strengths by dimensions and drug concentrations.
`
`Suboxone film unit strength
`(buprenorphine/naloxone)
`
`Suboxone film unit
`
`dimensions
`
`
`
`Buprenorphine Naloxone
`Concentration
`Concentration
`% (w/w)
`% (w/w)
`
`2 mg/0.5 mg
`
`22.0 mm x 12.8 mm 5.4
`
`1.53
`
`Reference ID: 3172979
`
`

`

`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
`
`1.53
`
`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 mm X 19.2 mm
`
`17.2
`
`4.88
`
`4.88
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`SUBOXONE sublingual film is supplied as an orange rectangular sublingual film with a white printed logo in four
`
`dosage strengths:
` buprenorphine/naloxone 2 mg/0.5 mg,
`
` buprenorphine/naloxone 4 mg/1 mg,
`
` buprenorphine/naloxone 8 mg/2 mg, and
`
`
` buprenorphine/naloxone 12 mg/3 mg
`
`
`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 (5.7)].
`
`5
`
`WARNINGS AND PRECAUTIONS
`
`
`Abuse Potential
`5.1
`Buprenorphine can be abused in a manner similar to other opioids, legal or illicit. Prescribe and dispense
`buprenorphine with appropriate precautions to minimize risk of misuse, abuse, or diversion, and ensure
`appropriate protection from theft, including in the home. Clinical monitoring appropriate to the patient’s level of
`stability is essential. Multiple refills should not be prescribed early in treatment or without appropriate patient
`
`follow-up visits. [see Drug Abuse and Dependence (9.2)].
`
`
`
`5.2
`Respiratory Depression
`Buprenorphine, particularly when taken by the IV route, in combination with benzodiazepines or other CNS
`depressants (including alcohol), has been associated with significant respiratory depression and death. Many,
`
`but not all, post-marketing reports regarding coma and death associated with the concomitant use of
`buprenorphine and benzodiazepines involved misuse by self-injection. Deaths have also been reported in
`association with concomitant administration of buprenorphine with other depressants such as alcohol or other
`
`CNS depressant drugs. Patients should be warned of the potential danger of self-administration of
`benzodiazepines or other depressants while under treatment with SUBOXONE sublingual film. [see Drug
`Interactions (7.3)].
`
`
`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).
`
`Reference ID: 3172979
`
`

`

`CNS Depression
`5.3
`Patients receiving buprenorphine in the presence of opioid analgesics, general anesthetics, benzodiazepines,
`phenothiazines, other tranquilizers, sedative/hypnotics, or other CNS depressants (including alcohol) may exhibit
`increased CNS depression. Consider dose reduction of CNS depressants, SUBOXONE sublingual film, or both
`in situations of concomitant prescription. [see Drug Interactions (7.3)].
`
`Unintentional Pediatric Exposure
`5.4
`
`Buprenorphine can cause severe, possibly fatal, respiratory depression in children who are accidentally exposed
`
`to it. Store buprenorphine-containing medications safely out of the sight and reach of children.
`
`
`5.5
`Dependence
`Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical
`dependence of the opioid type, characterized by withdrawal signs and symptoms upon abrupt discontinuation or
`
`rapid taper. The withdrawal syndrome is typically milder than seen with full agonists and may be delayed in
`
`onset. Buprenorphine can be abused in a manner similar to other opioids. This should be considered when
`prescribing or dispensing buprenorphine in situations when the clinician is concerned about an increased risk of
`
`misuse, abuse, or diversion. [see Drug Abuse and Dependence (9.3)]
`
`Hepatitis, Hepatic Events
`5.6
`Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving
`buprenorphine in clinical trials and through post-marketing adverse event reports. The spectrum of
`abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of death,
`
`hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy. In many cases, the
`presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant
`
`usage of other potentially hepatotoxic drugs, and ongoing injecting drug use may have played a causative or
`contributory role. In other cases, insufficient data were available to determine the etiology of the abnormality.
`Withdrawal of buprenorphine has resulted in amelioration of acute hepatitis in some cases; however, in other
`cases no dose reduction was necessary. The possibility exists that buprenorphine had a causative or
`
`contributory role in the development of the hepatic abnormality in some cases. Liver function tests, prior to
`initiation of treatment is recommended to establish a baseline. Periodic monitoring of liver function during
`treatment is also recommended. A biological and etiological evaluation is recommended when a hepatic event
`is suspected. Depending on the case, SUBOXONE sublingual film may need to be carefully discontinued to
`
`prevent withdrawal signs and symptoms and a return by the patient to illicit drug use, and strict monitoring of the
`
`patient should be initiated.
`
`
`
`Allergic Reactions
`5.7
`Cases of hypersensitivity to buprenorphine and naloxone containing products have been reported both in clinical
`trials and in the post-marketing experience. Cases of bronchospasm, angioneurotic edema, and anaphylactic
`shock have been reported. The most common signs and symptoms include rashes, hives, and pruritus. A
`history of hypersensitivity to buprenorphine or naloxone is a contraindication to the use of SUBOXONE
`sublingual film.
`
`5.8
`Precipitation of Opioid Withdrawal Signs and Symptoms
`
`Because it contains naloxone, SUBOXONE sublingual film is highly likely to produce marked and intense
`
`withdrawal signs and symptoms if misused parenterally by individuals dependent on full opioid agonists such as
`heroin, morphine, or methadone. Because of the partial agonist properties of buprenorphine, SUBOXONE
`sublingual film may precipitate opioid withdrawal signs and symptoms in such persons if administered
`sublingually before the agonist effects of the opioid have subsided.
`
`Reference ID: 3172979
`
`

`

`Neonatal Withdrawal
`5.9
`Neonatal withdrawal has been reported in the infants of women treated with buprenorphine during pregnancy.
`From post-marketing reports, the time to onset of neonatal withdrawal signs ranged from Day 1 to Day 8 of life
`with most cases occurring on Day 1. Adverse events associated with the neonatal withdrawal syndrome
`included hypertonia, neonatal tremor, neonatal agitation, and myoclonus, and there have been reports of
`convulsions, apnea, respiratory depression, and bradycardia.
`
`
`5.10 Use in Opioid Naïve Patients
`There have been reported deaths of opioid naive individuals who received a 2 mg dose of buprenorphine as a
`sublingual tablet for analgesia. SUBOXONE sublingual film is not appropriate as an analgesic.
`
`
`5.11
`Impairment of Ability to Drive or Operate Machinery
`SUBOXONE sublingual film may impair the mental or physical abilities required for the performance of
`potentially dangerous tasks such as driving a car or operating machinery, especially during treatment induction
`and dose adjustment. Patients should be cautioned about driving or operating hazardous machinery until they
`are reasonably certain that SUBOXONE sublingual film therapy does not adversely affect his or her ability to
`engage in such activities.
`
`
`5.12 Orthostatic Hypotension
`
`Like other opioids, SUBOXONE sublingual film may produce orthostatic hypotension in ambulatory patients.
`
`
`Elevation of Cerebrospinal Fluid Pressure
`5.13
`Buprenorphine, like other opioids, may elevate cerebrospinal fluid pressure and should be used with caution in
`
`patients with head injury, intracranial lesions, and other circumstances when cerebrospinal pressure may be
`increased. Buprenorphine can produce miosis and changes in the level of consciousness that may interfere with
`patient evaluation.
`
`
`
`Elevation of Intracholedochal Pressure
`5.14
`Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus should be
`administered with caution to patients with dysfunction of the biliary tract.
`
`
`Effects in Acute Abdominal Conditions
`5.15
`As with other opioids, buprenorphine may obscure the diagnosis or clinical course of patients with acute
`abdominal conditions.
`
`5.16 General Precautions
`SUBOXONE sublingual film should be administered with caution in debilitated patients and those with
`myxedema or hypothyroidism, adrenal cortical insufficiency (e.g., Addison's disease); CNS depression or coma;
`toxic psychoses; prostatic hypertrophy or urethral stricture; acute alcoholism; delirium tremens; or
`
`kyphoscoliosis.
`
`ADVERSE REACTIONS
`6
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the
`
`
`clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect
`
`the rates observed in practice.
`
`Adverse Events in Clinical Trials - SUBOXONE sublingual film
`6.1
`The safety of SUBOXONE sublingual film is supported by clinical trials using SUBUTEX (buprenorphine)
`sublingual tablets and SUBOXONE (buprenorphine and naloxone) sublingual tablets, and other trials using
`
`buprenorphine sublingual solutions, as well as an open-label study in 194 patients treated with SUBOXONE
`
`sublingual film. In total, safety data from clinical studies are available from over 3000 opioid-dependent subjects
`exposed to buprenorphine at doses in the range used in the treatment of opioid dependence. Few differences in
`the adverse event profile were noted among SUBOXONE sublingual film, SUBOXONE (buprenorphine and
`naloxone) sublingual tablets, SUBUTEX (buprenorphine) sublingual tablets and a buprenorphine ethanolic
`sublingual solution.
`
`Reference ID: 3172979
`
`

`

`
`
`
`4 (3.7%)
`27 (25.2%)
`
`
`8 (7.8%)
`19 (18.4%)
`
`
`
`Placebo
`N=107
`n (%)
`
`
`
`7 (6.5%)
`
`8 (7.5%)
`24 (22.4%)
`
`7 (6.5%)
`20 (18.7%)
`
`7 (6.5%)
`
`12 (11.2%)
`40 (37.4%)
`
` The most common adverse event (>1%) associated with the sublingual administration of the SUBOXONE
`
`sublingual film was oral hypoesthesia. Other adverse events were constipation, glossodynia, oral mucosal
`erythema, vomiting, intoxication, disturbance in attention, palpitations, insomnia, withdrawal syndrome,
`hyperhidrosis, and blurred vision.
`Other adverse event data were derived from larger, controlled studies of SUBOXONE (buprenorphine and
`naloxone) and SUBUTEX (buprenorphine) tablets and of buprenorphine sublingual solution. In a comparative
`study of SUBOXONE (buprenorphine and naloxone) and SUBUTEX (buprenorphine) sublingual tablets, adverse
`event profiles were similar for subjects treated with 16 mg/4 mg SUBOXONE (buprenorphine and naloxone)
`sublingual tablets or 16 mg SUBUTEX (buprenorphine) sublingual tablets. The following adverse events were
`reported to occur by at least 5% of patients in a 4-week study of SUBOXONE (buprenorphine and naloxone)
`sublingual tablets and SUBUTEX (buprenorphine) sublingual tablets.
`
`
`Table 2. Adverse Events (5%) by Body System and Treatment Group in a 4-week Study
`SUBOXONE
`SUBUTEX
`Body
`(buprenorphine and
`(buprenorphine)
`System/
`naloxone) sublingual
`sublingual
`Adverse
`tablets
`tablets
`Event
`16 mg/4 mg/day
`16 mg/day
`(COSTART
`N=107
`N=103
`Terminology)
`
`n (%)
`n (%)
`
`
`Body as a Whole
`
`Asthenia
`7 (6.5%)
`
`8 (7.5%)
`Chills
`39 (36.4%)
`Headache
`
`6 (5.6%)
`Infection
`24 (22.4%)
`Pain
`Pain
`12 (11.2%)
`abdomen
`Pain back
`Withdrawal
`syndrome
`Cardiovascular System
`
`Vasodilation
`10 (9.3%)
`
`Digestive System
`13 (12.1%)
`Constipation
`
`4 (3.7%)
`Diarrhea
`16 (15.0%)
`Nausea
`
`8 (7.5%)
`Vomiting
`
`Nervous System
`15 (14.0%)
`Insomnia
`Respiratory System
`
`Rhinitis
`5 (4.7%)
`Skin And Appendages
`Sweating
`15 (14.0%)
`
`
`5 (4.9%)
`
`8 (7.8%)
`30 (29.1%)
`12 (11.7%)
`19 (18.4%)
`12 (11.7%)
`
`
`4 (3.9%)
`
`
`7 (6.5%)
`
`
`8 (7.8%)
`
`5 (4.9%)
`14 (13.6%)
`
`8 (7.8%)
`
`
`3 (2.8%)
`16 (15.0%)
`12 (11.2%)
`
`5 (4.7%)
`
`22 (21.4%)
`
`17 (15.9%)
`
`
`10 (9.7%)
`
`14 (13.1%)
`
`13 (12.6%)
`
`11 (10.3%)
`
`Reference ID: 3172979
`
`

`

`
`16 (2%)
`104 (14%)
`
`42 (6%)
`
`21 (3%)
`
`44 (6%)
`220 (30%)
`149 (20%)
`25 (3%)
`
`
`The adverse event profile of buprenorphine was also characterized in the dose-controlled study of a
`buprenorphine ethanolic solution, over a range of doses in four months of treatment. Table 3 shows adverse
`events reported by at least 5% of subjects in any dose group in the dose-controlled trial.
`
`
`Table 3. Adverse Events (5%) by Body System and Treatment Group in a 16-week Study
`Body
`Buphrenorphine Dose
`
`System/
`Adverse
`Event
`(COSTART
`Terminology)
`
`Body as a Whole
`
`
`9 (5%)
`Abscess
`26 (14%)
`Asthenia
`
`11 (6%)
`Chills
`
`7 (4%)
`Fever
`
`4 (2%)
`Flu syndrome
`51 (28%)
`Headache
`Infection
`32 (17%)
`5 (3%)
`Injury
`
`accidental
`Pain
`Pain back
`Withdrawal
`syndrome
`Digestive System
`
`10 (5%)
`Constipation
`
`19 (10%)
`Diarrhea
`6 (3%)
`Dyspepsia
`
`12 (7%)
`Nausea
`
`8 (4%)
`Vomiting
`
`Nervous System
`
`22 (12%)
`Anxiety
`
`Depression
`24 (13%)
`4 (2%)
`Dizziness
`
`42 (23%)
`Insomnia
`Nervousness
`
` 12 (7%)
`5 (3%)
`Somnolence
`
`Respiratory System
`
`
`
`2 (1%)
`28 (16%)
`
`12 (7%)
`
`2 (1%)
`
`13 (7%)
`62 (34%)
`39 (22%)
`10 (6%)
`
`
`37 (21%)
`29 (16%)
`40 (22%)
`
`23 (13%)
`8 (4%)
`
`10 (6%)
`
`22 (12%)
`6 (3%)
`
`
`24 (13%)
`16 (9%)
`
`9 (5%)
`
`50 (28%)
`
` 11 (6%)
`13 (7%)
`
`
`
`3 (2%)
`26 (14%)
`
`9 (5%)
`
`2 (1%)
`19 (10%)
`54 (29%)
`38 (20%)
`5 (3%)
`
`
`49 (26%)
`28 (15%)
`41 (22%)
`
`23 (12%)
`9 (5%)
`
`4 (2%)
`
`23 (12%)
`10 (5%)
`
`
`20 (11%)
`25 (13%)
`7 (4%)
`
`43 (23%)
`
` 10 (5%)
`9 (5%)
`
`
`
`2 (1%)
`24 (13%)
`
`10 (6%)
`
`10 (6%)
`
`8 (4%)
`53 (29%)
`40 (22%)
`5 (3%)
`
`
`44 (24%)
`27 (15%)
`36 (20%)
`
`26 (14%)
`4 (2%)
`
`4 (2%)
`
`18 (10%)
`14 (8%)
`
`
`25 (14%)
`18 (10%)
`11 (6%)
`
`51 (28%)
`
` 13 (7%)
`11 (6%)
`
`
`177 (24%)
`102 (14%)
`162 (22%)
`
`82 (11%)
`40 (5%)
`
`24 (3%)
`
`75 (10%)
`38 (5%)
`
`
`91 (12%)
`83 (11%)
`31 (4%)
`
`186 (25%)
`
` 46 (6%)
`38 (5%)
`
`
`Abbreviations: COSTART = Coding Symbols for Thesaurus of Adverse Reaction
`Terms.
`
`
`Very Low*
`N=184
`n (%)
`
`
`Low*
`N=180
`n (%)
`
`
`Moderate*
`N=186
`n (%)
`
`
`High*
`N=181
`n (%)
`
`
`Total*
`N=731
`n (%)
`
`
`47 (26%)
`18 (10%)
`45 (24%)
`
`Reference ID: 3172979
`
`

`

`
`
` 5 (3%)
`
`
`
` 11 (6%)
`
`
`
` 6 (3%)
`
`
`
` 4 (2%)
`
`
`
` 26 (4%)
`
`7 (4%)
`
`16 (9%)
`
`
`6 (3%)
`
`15 (8%)
`
`
`9 (5%)
`
`21 (12%)
`
`28 (4%)
`
`79 (11%)
`
`Cough
`increase
`6 (3%)
`Pharyngitis
`
`27 (15%)
`Rhinitis
`
`Skin and Appendages
`
`23 (13%)
`Sweat
`Special Senses
`
`Runny eyes
`34 (5%)
`6 (3%)
`6 (3%)
`9 (5%)
`13 (7%)
`
`
`
`
`
`*Sublingual solution. Doses in this table cannot necessarily be delivered in tablet form, but for comparison purposes:
`1 mg solution would be less than a tablet dose of 2 mg
`4 mg solution approximates a 6 mg tablet dose
`8 mg solution approximates a 12 mg tablet dose
`16 mg solution approximates a 24 mg tablet dose
`
`
`21 (12%)
`
`20 (11%)
`
`23 (13%)
`
`87 (12%)
`
`6.2
`
`Adverse Events – Post-marketing Experience with Suboxone Sublingual Tablets
`
`The most frequently reported post-marketing adverse event not observed in clinical trials was peripheral edema.
`
`
`
`7
`
`DRUG INTERACTIONS
`
`Cytochrome P-450 3A4 (CYP3A4) Inhibitors and Inducers
`7.1
`Buprenorphine is metabolized to norbuprenorphine primarily by cytochrome CYP3A4; therefore, potential
`interactions may occur when SUBOXONE sublingual film is given concurrently with agents that affect CYP3A4
`activity. The concomitant use of SUBOXONE sublingual film with CYP3A4 inhibitors (e.g., azole antifungals
`such as ketoconazole, macrolide antibiotics such as erythromycin, and HIV protease inhibitors) should be
`
`monitored and may require dose-reduction of one or both agents.
`The interaction of buprenorphine with CYP3A4 inducers has not been studied; therefore, it is recommended that
`patients receiving SUBOXONE sublingual film be monitored for signs and symptoms of opioid withdrawal if
`inducers of CYP3A4 (e.g., efavirenz, phenobarbital, carbamazepine, phenytoin, rifampicin) are co-administered
`[see Clinical Pharmacology (12.3)].
`
`Antiretrovirals
`7.2
`Three classes of antiretroviral agents have been evaluated for CYP3A4 interactions with buprenorphine.
`Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway,
`thus no interactions with buprenorphine are expected. Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
`
`are metabolized principally by CYP3A4. Efavirenz, nevirapine and etravirine are known CYP3A inducers
`
`whereas delaviridine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g.,
`efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic
`interactions did not result in any significant pharmacodynamic effects. It is recommended that patients who are
`on chronic buprenorphine treatment have their dose monitored if NNRTIs are added to their treatment regimen.
`
`Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir,
`lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant
`pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and a