Data from FDA - Curated by EPG Health - Last updated 05 July 2018

Indication(s)

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. Buprenorphine and naloxone sublingual film contains buprenorphine, a partial-opioid agonist, and naloxone, an opioid antagonist, and is indicated for treatment of opioid dependence. (1) Buprenorphine and naloxone sublingual film should be used as part of a complete treatment plan that includes counseling and psychosocial support. (1)

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Advisory information

contraindications
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) ]. Hypersensitivity to buprenorphine or naloxone. (4)
Adverse reactions
6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: •Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)] •Respiratory and CNS Depression [see Warnings and Precautions (5.2), (5.3)] •Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.5)] •Adrenal Insufficiency [see Warnings and Precautions (5.6)] •Opioid Withdrawal [see Warnings and Precautions (5.7, 5.10)] •Hepatitis, Hepatic Events [see Warnings and Precautions (5.8)] •Hypersensitivity Reactions [see Warnings and Precautions (5.9)] •Orthostatic Hypotension [see Warnings and Precautions (5.14)] •Elevation of Cerebrospinal Fluid Pressure [see Warnings and Precautions (5.15)] •Elevation of Intracholedochal Pressure [see Warnings and Precautions (5.16)] 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 Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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. The safety of buprenorphine and naloxone sublingual film is supported by clinical trials using buprenorphine sublingual tablets and buprenorphine and naloxone sublingual tablets, and other trials using buprenorphine sublingual solutions, as well as an open-label study in 194 patients treated with buprenorphine and naloxone sublingual film administered sublingually and 188 patients treated with the film administered buccally. 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 with regard to sublingually and buccally administered buprenorphine and naloxone sublingual film, buprenorphine and naloxone sublingual tablets, buprenorphine sublingual tablets and a buprenorphine ethanolic sublingual solution. The most common adverse event (> 1%) associated with the sublingual administration of the buprenorphine and naloxone 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. The most common adverse events associated with the buccal administration were similar to those observed with sublingual administration of the film. Other adverse event data were derived from larger, controlled studies of buprenorphine and naloxone sublingual tablets and buprenorphine sublingual tablets and of buprenorphine sublingual solution. In a comparative study of buprenorphine and naloxone sublingual tablets and buprenorphine sublingual tablets, adverse event profiles were similar for subjects treated with 16 mg/4 mg buprenorphine and naloxone sublingual tablets or 16 mg buprenorphine sublingual tablets. The following adverse events were reported to occur by at least 5% of patients in a 4 week study of buprenorphine and naloxone sublingual tablets and buprenorphine sublingual tablets. Table 2. Adverse Events (≥ 5%) by Body System and Treatment Group in a 4 Week Study Abbreviations: COSTART = Coding Symbols for Thesaurus of Adverse Reaction Terms. Body System/ Adverse Event (COSTART Terminology) Buprenorphine and Naloxone Sublingual Tablets 16 mg/4 mg/day N = 107 n (%) Buprenorphine Sublingual Tablets 16 mg/day N = 103 n (%) Placebo N = 107 n (%) Body as a Whole Asthenia 7 (6.5%) 5 (4.9%) 7 (6.5%) Chills 8 (7.5%) 8 (7.8%) 8 (7.5%) Headache 39 (36.4%) 30 (29.1%) 24 (22.4%) Infection 6 (5.6%) 12 (11.7%) 7 (6.5%) Pain 24 (22.4%) 19 (18.4%) 20 (18.7%) Pain abdomen 12 (11.2%) 12 (11.7%) 7 (6.5%) Pain back 4 (3.7%) 8 (7.8%) 12 (11.2%) Withdrawal syndrome 27 (25.2%) 19 (18.4%) 40 (37.4%) Cardiovascular System Vasodilation 10 (9.3%) 4 (3.9%) 7 (6.5%) Digestive System Constipation 13 (12.1%) 8 (7.8%) 3 (2.8%) Diarrhea 4 (3.7%) 5 (4.9%) 16 (15.0%) Nausea 16 (15.0%) 14 (13.6%) 12 (11.2%) Vomiting 8 (7.5%) 8 (7.8%) 5 (4.7%) Nervous System Insomnia 15 (14.0%) 22 (21.4%) 17 (15.9%) Respiratory System Rhinitis 5 (4.7%) 10 (9.7%) 14 (13.1%) Skin And Appendages Sweating 15 (14.0%) 13 (12.6%) 11 (10.3%) 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 System/ Adverse Event (COSTART Terminology) Buprenorphine Dose Very LowSublingual solution. Doses in this table cannot necessarily be delivered in tablet form, but for comparison purposes: “Very low” dose (1 mg solution) would be less than a tablet dose of 2 mg “Low” dose (4 mg solution) approximates a 6 mg tablet dose “Moderate” dose (8 mg solution) approximates a 12 mg tablet dose “High” dose (16 mg solution) approximates a 24 mg tablet dose N = 184 n (%) Low N = 180 n (%) Moderate N = 186 n (%) High N = 181 n (%) Total N = 731 n (%) Body as a Whole Abscess 9 (5%) 2 (1%) 3 (2%) 2 (1%) 16 (2%) Asthenia 26 (14%) 28 (16%) 26 (14%) 24 (13%) 104 (14%) Chills 11 (6%) 12 (7%) 9 (5%) 10 (6%) 42 (6%) Fever 7 (4%) 2 (1%) 2 (1%) 10 (6%) 21 (3%) Flu syndrome 4 (2%) 13 (7%) 19 (10%) 8 (4%) 44 (6%) Headache 51 (28%) 62 (34%) 54 (29%) 53 (29%) 220 (30%) Infection 32 (17%) 39 (22%) 38 (20%) 40 (22%) 149 (20%) Injury accidental 5 (3%) 10 (6%) 5 (3%) 5 (3%) 25 (3%) Pain 47 (26%) 37 (21%) 49 (26%) 44 (24%) 177 (24%) Pain back 18 (10%) 29 (16%) 28 (15%) 27 (15%) 102 (14%) Withdrawal syndrome 45 (24%) 40 (22%) 41 (22%) 36 (20%) 162 (22%) Digestive System Constipation 10 (5%) 23 (13%) 23 (12%) 26 (14%) 82 (11%) Diarrhea 19 (10%) 8 (4%) 9 (5%) 4 (2%) 40 (5%) Dyspepsia 6 (3%) 10 (6%) 4 (2%) 4 (2%) 24 (3%) Nausea 12 (7%) 22 (12%) 23 (12%) 18 (10%) 75 (10%) Vomiting 8 (4%) 6 (3%) 10 (5%) 14 (8%) 38 (5%) Nervous System Anxiety 22 (12%) 24 (13%) 20 (11%) 25 (14%) 91 (12%) Depression 24 (13%) 16 (9%) 25 (13%) 18 (10%) 83 (11%) Dizziness 4 (2%) 9 (5%) 7 (4%) 11 (6%) 31 (4%) Insomnia 42 (23%) 50 (28%) 43 (23%) 51 (28%) 186 (25%) Nervousness 12 (7%) 11 (6%) 10 (5%) 13 (7%) 46 (6%) Somnolence 5 (3%) 13 (7%) 9 (5%) 11 (6%) 38 (5%) Respiratory System Cough increase 5 (3%) 11 (6%) 6 (3%) 4 (2%) 26 (4%) Pharyngitis 6 (3%) 7 (4%) 6 (3%) 9 (5%) 28 (4%) Rhinitis 27 (15%) 16 (9%) 15 (8%) 21 (12%) 79 (11%) Skin and Appendages Sweat 23 (13%) 21 (12%) 20 (11%) 23 (13%) 87 (12%) Special Senses Runny eyes 13 (7%) 9 (5%) 6 (3%) 6 (3%) 34 (5%) The safety of buprenorphine and naloxone sublingual film during treatment induction is supported by a clinical trial using 16 patients treated with buprenorphine and naloxone sublingual film and 18 treated with a buprenorphine-only sublingual film. Few differences in the adverse event profiles were noted between buprenorphine and naloxone sublingual film and the buprenorphine-only sublingual film. The most common adverse event occurring during treatment induction and the 3 days following induction using buprenorphine and naloxone sublingual film was restlessness. Other adverse events were anxiety, piloerection, stomach discomfort, irritability, headache, rhinorrhea, cold sweat, arthralgia, and lacrimation increased. Four subjects left the study early on the first day of sublingual film administration. However, there was no evidence to suggest that any of the four subjects experienced precipitated withdrawal secondary to the administration of buprenorphine or buprenorphine and naloxone sublingual films. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of buprenorphine and naloxone sublingual film. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The most frequently reported postmarketing adverse events were peripheral edema, stomatitis, glossitis, and blistering and ulceration of the mouth or tongue. Serotonin Syndrome Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis Anaphylaxis has been reported with ingredients contained in buprenorphine and naloxone sublingual film. Androgen Deficiency Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)]. Local Reactions glossodynia, glossitis, oral mucosal erythema, oral hypoesthesia, and stomatitis

Usage information

Dosing and administration
2 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) 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 film or 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 and 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 and 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 film is recommended. Because the exposure to naloxone is somewhat higher after buccal than after sublingual administration, it is recommended that the sublingual site of administration be used during induction to minimize exposure to naloxone, to reduce the risk of precipitated withdrawal. Patients Dependent on Methadone or Long-Acting Opioid Products Patients dependent upon methadone or long-acting opioid products may be more susceptible to precipitated and prolonged withdrawal during induction than those on short-acting opioid products. Buprenorphine and naloxone combination products have not been evaluated in adequate and well-controlled studies for induction in patients who are physically dependent on long-acting opioid products, and the naloxone in these combination products is absorbed in small amounts by the sublingual route and could cause worse precipitated and prolonged withdrawal. For this reason, buprenorphine monotherapy is recommended in patients taking long-acting opioids when used according to approved administration instructions. Following induction, the patient may then be transitioned to once-daily buprenorphine and naloxone sublingual film. 2.4 Maintenance •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 and 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 and naloxone to 24 mg/6 mg buprenorphine and 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 and 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 buprenorphine and naloxone 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 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 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 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. 2.10 Switching Between Buprenorphine and Naloxone Sublingual Film Strengths As indicated in Table 1, the sizes and the compositions of the two units of buprenorphine and naloxone sublingual films, i.e., 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 % (w/w) Naloxone Concentration % (w/w) 8 mg/2 mg 22.0 mm x 12.8 mm 17.2 4.88 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 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.
Use in special populations
8 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 and naloxone products are not recommended in patients with severe hepatic impairment and may not be appropriate for patients with moderate hepatic impairment. (8.6) 8.1 Pregnancy Risk Summary The data on use of buprenorphine, one of the active ingredients in buprenorphine and naloxone sublingual film, in pregnancy, are limited; however, these data do not indicate an increased risk of major malformations specifically due to buprenorphine exposure. There are limited data from randomized clinical trials in women maintained on buprenorphine that were not designed appropriately to assess the risk of major malformations [see Data]. Observational studies have reported on congenital malformations among buprenorphine-exposed pregnancies, but were also not designed appropriately to assess the risk of congenital malformations specifically due to buprenorphine exposure [see Data]. The extremely limited data on sublingual naloxone exposure in pregnancy are not sufficient to evaluate a drug-associated risk. Reproductive and developmental studies in rats and rabbits identified adverse events at clinically relevant and higher doses. Embryofetal death was observed in both rats and rabbits administered buprenorphine during the period of organogenesis at doses approximately 6 and 0.3 times, respectively, the human sublingual dose of 16 mg/day of buprenorphine. Pre- and postnatal development studies in rats demonstrated increased neonatal deaths at 0.3 times and above and dystocia at approximately 3 times the human sublingual dose of 16 mg/day of buprenorphine. No clear teratogenic effects were seen when buprenorphine was administered during organogenesis with a range of doses equivalent to or greater than the human sublingual dose of 16 mg/day of buprenorphine. However, increases in skeletal abnormalities were noted in rats and rabbits administered buprenorphine daily during organogenesis at doses approximately 0.6 and approximately equal to the human sublingual dose of 16 mg/day of buprenorphine, respectively. In a few studies, some events such as acephalus and omphalocele were also observed but these findings were not clearly treatment-related [see Data]. Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and Embryo-Fetal Risk Untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes such as low birth weight, preterm birth, and fetal death. In addition, untreated opioid addiction often results in continued or relapsing illicit opioid use. Dose Adjustment during Pregnancy and the Postpartum Period Dosage adjustments of buprenorphine may be required during pregnancy, even if the patient was maintained on a stable dose prior to pregnancy. Withdrawal signs and symptoms should be monitored closely and the dose adjusted as necessary. Fetal/Neonatal Adverse Reactions Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with buprenorphine and naloxone sublingual film. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight. Signs of neonatal withdrawal usually occur in the first days after birth. The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.5)]. Labor or Delivery Opioid-dependent women on buprenorphine maintenance therapy may require additional analgesia during labor. Data Human Data Studies have been conducted to evaluate neonatal outcomes in women exposed to buprenorphine during pregnancy. Limited data on malformations from trials, observational studies, case series, and case reports on buprenorphine use in pregnancy do not indicate an increased risk of major malformations specifically due to buprenorphine. Several factors may complicate the interpretation of investigations of the children of women who take buprenorphine during pregnancy, including maternal use of illicit drugs, late presentation for prenatal care, infection, poor compliance, poor nutrition, and psychosocial circumstances. Interpretation of data is complicated further by the lack of information on untreated opioid-dependent pregnant women, who would be the most appropriate group for comparison. Rather, women on another form of opioid medication-assisted treatment, or women in the general population are generally used as the comparison group. However, women in these comparison groups may be different from women prescribed buprenorphine-containing products with respect to maternal factors that may lead to poor pregnancy outcomes. In a multicenter, double-blind, randomized, controlled trial [Maternal Opioid Treatment: Human Experimental Research (MOTHER)] designed primarily to assess neonatal opioid withdrawal effects, opioid-dependent pregnant women were randomized to buprenorphine (n = 86) or methadone (n = 89) treatment, with enrollment at an average gestational age of 18.7 weeks in both groups. A total of 28 of the 86 women in the buprenorphine group (33%) and 16 of the 89 women in the methadone group (18%) discontinued treatment before the end of pregnancy. Among women who remained in treatment until delivery, there was no difference between buprenorphine-treated and methadone-treated groups in the number of neonates requiring NOWS treatment or in the peak severity of NOWS. Buprenorphine-exposed neonates required less morphine (mean total dose, 1.1 mg vs. 10.4 mg), had shorter hospital stays (10.0 days vs. 17.5 days), and shorter duration of treatment for NOWS (4.1 days vs. 9.9 days) compared to the methadone-exposed group. There were no differences between groups in other primary outcomes (neonatal head circumference,) or secondary outcomes (weight and length at birth, preterm birth, gestational age at delivery, and 1-minute and 5-minute Apgar scores), or in the rates of maternal or neonatal adverse events. The outcomes among mothers who discontinued treatment before delivery and may have relapsed to illicit opioid use are not known. Because of the imbalance in discontinuation rates between the buprenorphine and methadone groups, the study findings are difficult to interpret. Animal Data The exposure margins listed below are based on body surface area comparisons (mg/m2) to the human sublingual dose of 16 mg buprenorphine via buprenorphine and naloxone sublingual tablets. Effects on embryo-fetal development were studied in Sprague-Dawley rats and Russian white rabbits following oral (1:1) and intramuscular (IM) (3:2) administration of mixtures of buprenorphine and naloxone during the period of organogenesis. Following oral administration to rats no teratogenic effects were observed at buprenorphine doses up to 250 mg/kg/day (estimated exposure approximately 150 times the human sublingual dose of 16 mg) in the presence of maternal toxicity (mortality). Following oral administration to rabbits, no teratogenic effects were observed at buprenorphine doses up to 40 mg/kg/day (estimated exposure approximately 50 times, the human sublingual dose of 16 mg) in the absence of clear maternal toxicity. No definitive drug-related teratogenic effects were observed in rats and rabbits at IM doses up to 30 mg/kg/day (estimated exposure approximately 20 times and 35 times, respectively, the human sublingual dose of 16 mg). Maternal toxicity resulting in mortality was noted in these studies in both rats and rabbits. Acephalus was observed in one rabbit fetus from the low-dose group and omphalocele was observed in two rabbit fetuses from the same litter in the mid-dose group; no findings were observed in fetuses from the high-dose group. Maternal toxicity was seen in the high-dose group but not at the lower doses where the findings were observed. Following oral administration of buprenorphine to rats, dose-related post-implantation losses, evidenced by increases in the numbers of early resorptions with consequent reductions in the numbers of fetuses, were observed at doses of 10 mg/kg/day or greater (estimated exposure approximately 6 times the human sublingual dose of 16 mg). In the rabbit, increased post-implantation losses occurred at an oral dose of 40 mg/kg/day. Following IM administration in the rat and the rabbit, post-implantation losses, as evidenced by decreases in live fetuses and increases in resorptions, occurred at 30 mg/kg/day. Buprenorphine was not teratogenic in rats or rabbits after IM or subcutaneous (SC) doses up to 5 mg/kg/day (estimated exposure was approximately 3 and 6 times, respectively, the human sublingual dose of 16 mg), after IV doses up to 0.8 mg/kg/day (estimated exposure was approximately 0.5 times and equal to, respectively, the human sublingual dose of 16 mg), or after oral doses up to 160 mg/kg/day in rats (estimated exposure was approximately 95 times the human sublingual dose of 16 mg) and 25 mg/kg/day in rabbits (estimated exposure was approximately 30 times the human daily sublingual dose of 16 mg). Significant increases in skeletal abnormalities (e.g., extra thoracic vertebra or thoraco-lumbar ribs) were noted in rats after SC administration of 1 mg/kg/day and up (estimated exposure was approximately 0.6 times the human sublingual dose of 16 mg), but were not observed at oral doses up to 160 mg/kg/day. Increases in skeletal abnormalities in rabbits after IM administration of 5 mg/kg/day (estimated exposure was approximately 6 times the human daily sublingual dose of 16 mg) in the absence of maternal toxicity or oral administration of 1 mg/kg/day or greater (estimated exposure was approximately equal to the human sublingual dose of 16 mg) were not statistically significant. In rabbits, buprenorphine produced statistically significant pre-implantation losses at oral doses of 1 mg/kg/day or greater and post-implantation losses that were statistically significant at IV doses of 0.2 mg/kg/day or greater (estimated exposure approximately 0.3 times the human daily sublingual dose of 16 mg). No maternal toxicity was noted at doses causing post-implantation loss in this study. Dystocia was noted in pregnant rats treated intramuscularly with buprenorphine from Gestation Day 14 through Lactation Day 21 at 5 mg/kg/day (approximately 3 times the human sublingual dose of 16 mg). Fertility, pre- and post-natal development studies with buprenorphine in rats indicated increases in neonatal mortality after oral doses of 0.8 mg/kg/day and up (approximately 0.5 times the human daily sublingual dose of 16 mg), after IM doses of 0.5 mg/kg/day and up (approximately 0.3 times the human sublingual dose of 16 mg), and after SC doses of 0.1 mg/kg/day and up (approximately 0.06 times the human sublingual dose of 16 mg). An apparent lack of milk production during these studies likely contributed to the decreased pup viability and lactation indices. Delays in the occurrence of righting reflex and startle response were noted in rat pups at an oral dose of 80 mg/kg/day (approximately 50 times the human sublingual dose of 16 mg). 8.2 Lactation Risk Summary Based on two studies in 13 lactating women maintained on buprenorphine treatment, buprenorphine and its metabolite norbuprenorphine were present in low levels in human milk and infant urine. Available data have not shown adverse reactions in breastfed infants. There are no data on the combination product buprenorphine and naloxone in breastfeeding, however oral absorption of naloxone is limited. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for buprenorphine and naloxone sublingual film and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition. Clinical Considerations Advise breastfeeding women taking buprenorphine products to monitor the infant for increased drowsiness and breathing difficulties. Data Data were consistent from two studies (N = 13) of breastfeeding infants whose mothers were maintained on sublingual doses of buprenorphine ranging from 2.4 to 24 mg/day, showing that the infants were exposed to less than 1% of the maternal daily dose. In a study of six lactating women who were taking a median sublingual buprenorphine dose of 0.29 mg/kg/day 5 to 8 days after delivery, breast milk provided a median infant dose of 0.42 mcg/kg/day of buprenorphine and 0.33 mcg/kg/day of norbuprenorphine, equal to 0.2% and 0.12%, respectively, of the maternal weight-adjusted dose (relative dose/kg (%) of norbuprenorphine was calculated from the assumption that buprenorphine and norbuprenorphine are equipotent). Data from a study of seven lactating women who were taking a median sublingual buprenorphine dose of 7 mg/day an average of 1.12 months after delivery indicated that the mean milk concentrations (Cavg) of buprenorphine and norbuprenorphine were 3.65 mcg/L and 1.94 mcg/L respectively. Based on the study data, and assuming milk consumption of 150 mL/kg/day, an exclusively breastfed infant would receive an estimated mean absolute infant dose (AID) of 0.55 mcg/kg/day of buprenorphine and 0.29 mcg/kg/day of norbuprenorphine, or a mean relative infant dose (RID) of 0.38% and 0.18%, respectively, of the maternal weight-adjusted dose. 8.3 Females and Males of Reproductive Potential Infertility Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2), Clinical Pharmacology (12.2), Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of buprenorphine and naloxone sublingual film have not been established in pediatric patients. This product is not appropriate for the treatment of neonatal abstinence syndrome in neonates, because it contains naloxone, an opioid antagonist. 8.5 Geriatric Use Clinical studies of buprenorphine and naloxone sublingual film, buprenorphine and naloxone sublingual tablets, or buprenorphine sublingual tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Due to possible decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in geriatric patients, the decision to prescribe buprenorphine and naloxone sublingual film should be made cautiously in individuals 65 years of age or older and these patients should be monitored for signs and symptoms of toxicity or overdose. 8.6 Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone has been evaluated in a pharmacokinetic study. Both drugs are extensively metabolized in the liver. While no clinically significant changes have been observed in subjects with mild hepatic impairment; the plasma levels have been shown to be higher and half-life values have been shown to be longer for both buprenorphine and naloxone in subjects with moderate and severe hepatic impairment. The magnitude of the effects on naloxone are greater than that on buprenorphine in both moderately and severely impaired subjects. The difference in magnitude of the effects on naloxone and buprenorphine are greater in subjects with severe hepatic impairment than in subjects with moderate hepatic impairment, and therefore the clinical impact of these effects is likely to be greater in patients with severe hepatic impairment than in patients with moderate hepatic impairment. Buprenorphine and naloxone products should 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) , Clinical Pharmacology (12.3)]. 8.7 Renal Impairment No differences in buprenorphine pharmacokinetics were observed between 9 dialysis-dependent and 6 normal patients following IV administration of 0.3 mg buprenorphine. The effects of renal failure on naloxone pharmacokinetics are unknown.

Interactions

7 DRUG INTERACTIONS Table 4 Includes clinically significant drug interactions with buprenorphine and naloxone sublingual film. Table 4. Clinically Significant Drug Interactions Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effects, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death. Intervention: 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. Before co-prescribing benzodiazepines for anxiety or insomnia, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments [see Warnings and Precautions (5.2, 5.3)]. Examples: Alcohol, non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids. Inhibitors of CYP3A4 Clinical Impact: The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of buprenorphine and naloxone sublingual film is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease [see Clinical Pharmacology (12.3)], potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine. Intervention: If concomitant use is necessary, consider dosage reduction of buprenorphine and naloxone sublingual film until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the buprenorphine and naloxone sublingual film dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine [see Clinical Pharmacology (12.3)], potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression. Intervention: If concomitant use is necessary, consider increasing the buprenorphine and naloxone sublingual film dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider buprenorphine and naloxone sublingual film dosage reduction and monitor for signs of respiratory depression. Examples: Rifampin, carbamazepine, phenytoin Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Clinical Impact: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delavirdine 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. Intervention: Patients who are on chronic buprenorphine and naloxone sublingual film treatment should have their dose monitored if NNRTIs are added to their treatment regimen. Examples: efavirenz, nevirapine, etravirine, delavirdine Antiretrovirals: Protease inhibitors (PIs) Clinical Impact: 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 atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in post-marketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly. Intervention: Monitor patients taking buprenorphine and naloxone sublingual film and atazanavir with and without ritonavir, and reduce dose of buprenorphine and naloxone sublingual film if warranted. Examples: atazanavir, ritonavir Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs) Clinical Impact: Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected. Intervention: None Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue buprenorphine and naloxone sublingual film if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma). Intervention: The use of buprenorphine and naloxone sublingual film is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. Examples: phenelzine, tranylcypromine, linezolid Muscle Relaxants Clinical Impact: Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Monitor patients receiving muscle relaxants and buprenorphine and naloxone sublingual film for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of buprenorphine and naloxone sublingual film and/or the muscle relaxant as necessary. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when buprenorphine and naloxone sublingual film is used concomitantly with anticholinergic drugs. • 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) • CYP3A4 Inhibitors 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)

More information

Category Value
Authorisation number ANDA207607
Agency product number 5Q187997EE
Orphan designation No
Product NDC 0378-8767,0378-8768
Date Last Revised 03-05-2018
Type HUMAN PRESCRIPTION DRUG
RXCUI 1010604
Marketing authorisation holder Mylan Pharmaceuticals Inc.