Suboxone

Dosage and Administration ( 2.2 ) 12/2025 Dosage and Administration ( 2.4 ) 05/2025 Warnings and Precautions ( 5.2 , 5.3 ) 12/2025

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

2 DOSAGE AND ADMINISTRATION Administer SUBOXONE sublingual film as a single daily dose. ( 2.1 ) Strongly consider recommending or prescribing an opioid overdose reversal agent (e.g., naloxone, nalmefene) at the time SUBOXONE sublingual film is initiated or renewed because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose. ( 2.2 ) To avoid precipitating withdrawal, induction with SUBOXONE sublingual film should be undertaken when objective and clear signs of withdrawal are evident and SUBOXONE sublingual film should be administered in divided doses when used as initial treatment. ( 2.3 ) For patients dependent on short‐acting opioid products who are in opioid withdrawal; on Day 1, administer up to 8 mg/2 mg SUBOXONE sublingual film (in divided doses). On Day 2, administer up to 16 mg/4 mg of SUBOXONE sublingual film as a single dose. ( 2.3 ) For patients dependent on methadone or long‐acting opioid products, induction onto sublingual buprenorphine monotherapy is recommended on Days 1 and 2 of treatment. ( 2.3 ) The maintenance dose of SUBOXONE sublingual film is generally in the range of 4 mg/1 mg to 24 mg/6 mg per day and should be based on clinical response. ( 2.4 ) Sublingual Administration: Place one film under the tongue, close to the base on the left or right side, and allow to completely dissolve. Buccal Administration: Place one film on the inside of the left or right cheek and allow to completely dissolve. ( 2.5 ) SUBOXONE sublingual film must be administered whole. Do not cut, chew, or swallow SUBOXONE sublingual film ( 2.5 ) When discontinuing treatment, gradually taper to avoid signs and symptoms of withdrawal. ( 2.8 ) 2.1 Important Dosage and Administration Information SUBOXONE sublingual film is administered sublingually or buccally as a single daily dose. Medication should be prescribed in consideration of the frequency of visits. Provision of multiple refills is not advised early in treatment or without appropriate patient follow‐up visits. 2.2 Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene) and discuss the importance of having access to an opioid overdose reversal agent. Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, strongly consider recommending or prescribing an overdose reversal agent for the emergency treatment of opioid overdose, both when initiating and renewing treatment with SUBOXONE sublingual film. Also consider recommending or prescribing such an agent if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose [see Warnings and Precautions ( 5.2 )] . Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) [see Warnings and Precautions ( 5.2 )] . There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. Advise patients and caregivers that opioid overdose reversal agents, such as naloxone or nalmefene, may also be administered for a known or suspected overdose with buprenorphine itself. Higher than normal doses and repeated administration of an opioid overdose reversal agent may be necessary due to the long duration of action of buprenorphineand its affinity for the mu-opioid receptor [see Overdosage ( 10 )] . 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, an …

3 DOSAGE FORMS AND STRENGTHS SUBOXONE sublingual film is supplied as an orange rectangular film with a white printed logo in four dosage strengths: Buprenorphine 2 mg/naloxone 0.5 mg, Buprenorphine 4 mg/naloxone 1 mg, Buprenorphine 8 mg/naloxone 2 mg and Buprenorphine 12 mg/naloxone 3 mg Sublingual film: buprenorphine 2 mg/ naloxone 0.5 mg, buprenorphine 4 mg/ naloxone 1 mg, buprenorphine 8 mg/ naloxone 2 mg and buprenorphine 12 mg/ naloxone 3 mg. ( 3 )

4 CONTRAINDICATIONS SUBOXONE sublingual film is contraindicated in patients with a history of hypersensitivity to buprenorphine or naloxone as serious adverse reactions, including anaphylactic shock, have been reported [see Warnings and Precautions ( 5.9 )] . Hypersensitivity to buprenorphine or naloxone. ( 4 )

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 ( 5.16 )] Elevation of Cerebrospinal Fluid Pressure [see Warnings and Precautions ( 5.17 )] Elevation of Intracholedochal Pressure [see Warnings and Precautions ( 5.18 )] Adverse events commonly observed with the sublingual/buccal administration of the SUBOXONE sublingual film are oral hypoesthesia, glossodynia, oral mucosal erythema, headache, nausea, vomiting, hyperhidrosis, constipation, signs and symptoms of withdrawal, insomnia, pain, and peripheral edema. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Indivior Inc. at 1-877-782-6966 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 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 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 bucally administered SUBOXONE sublingual film, SUBOXONE sublingual tablets, SUBUTEX sublingual tablets and a buprenorphine ethanolic sublingual solution. 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. 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 SUBOXONE sublingual tablets and SUBUTEX sublingual tablets and of buprenorphine sublingual solution. In a comparative study of SUBOXONE sublingual tablets and SUBUTEX sublingual tablets, adverse event profiles were similar for subjects treated with 16 mg/4 mg SUBOXONE sublingual tablets or 16 mg SUBUTEX sublingual tablets. The following adverse events were reported to occur by at least 5% of patients in a 4 week study of SUBOXONE sublingual tablets and SUBUTEX 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) SUBOXONE sublingual tablets 16 mg/4 mg/day N = 107 n (%) SUBUTEX 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%) …

7 DRUG INTERACTIONS Table 4 includes clinically significant drug interactions with SUBOXONE. 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 )] . If concomitant use is warranted, strongly consider recommending or prescribing an opioid overdose reversal agent, as is recommended for all patients on buprenorphine treatment for opioid use disorder [see Warnings and Precautions ( 5.2 )] . Examples: Alcohol, benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), 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 SUBOXONE 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 SUBOXONE 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 SUBOXONE 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 SUBOXONE sublingual film dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider SUBOXONE 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 bupre …

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/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 SUBOXONE 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 2-4% and 15-20%, 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, such as using higher doses, may be required during pregnancy, even if the patient was maintained on a stable dose prior to pregnancy. Dosing should be based on individual response, and 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 SUBOXONE 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 wit …

12.1 Mechanism of Action SUBOXONE sublingual film contains buprenorphine and naloxone. Buprenorphine is a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor. Naloxone is a potent antagonist at mu opioid receptors and produces opioid withdrawal signs and symptoms in individuals physically dependent on full opioid agonists when administered parenterally.

11 DESCRIPTION SUBOXONE® (buprenorphine and naloxone) sublingual film is an orange film, imprinted with a logo identifying the product and strength in white ink. It contains buprenorphine HCl, a mu-opioid receptor partial agonist, and a kappa-opioid receptor antagonist, and naloxone HCl dihydrate, an opioid antagonist, at a ratio of 4:1 (ratio of free bases). It is intended for sublingual or buccal administration and is available in four dosage strengths, 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. Each film also contains polyethylene oxide, hydroxypropyl methylcellulose, maltitol, acesulfame potassium, lime flavor, citric acid, sodium citrate, FD&C yellow #6, and white ink. Chemically, buprenorphine HCl is (2S)-2-[17-Cyclopropylmethyl-4,5α-epoxy-3-hydroxy-6-methoxy-6α,14- ethano-14α-morphinan-7α-yl]-3,3-dimethylbutan-2-ol hydrochloride. It has the following chemical structure: Buprenorphine HCl has the molecular formula C 29 H 41 NO 4 • HCl and the molecular weight is 504.10. It is a white or off-white crystalline powder, sparingly soluble in water, freely soluble in methanol, soluble in alcohol, and practically insoluble in cyclohexane. Chemically, naloxone HCl dihydrate is 17-Allyl-4,5 α -epoxy-3, 14-dihydroxymorphinan-6-one hydrochloride dihydrate. It has the following chemical structure: Naloxone hydrochloride dihydrate has the molecular formula C 19 H 21 NO 4 • HCl • 2H 2 O and the molecular weight is 399.87. It is a white to slightly off-white powder and is freely soluble in water, soluble in alcohol, and practically insoluble in toluene and ether. Figure Figure

10 OVERDOSAGE Clinical Presentation The manifestations of acute buprenorphine overdose include pinpoint pupils, sedation, hypotension, hypoglycemia, respiratory depression, and death. Toxic leukoencephalopathy has been reported after opioid overdose and can present hours, days, or weeks after apparent recovery from the initial intoxication. Treatment of Overdose In the event of overdose, the respiratory and cardiac status of the patient should be monitored carefully. When respiratory or cardiac functions are depressed, primary attention should be given to the re-establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. Oxygen, IV fluids, vasopressors, and other supportive measures should be employed as indicated. In the case of overdose, the primary management should be the re-establishment of adequate ventilation with mechanical assistance of respiration, if required. An opioid overdose reversal agent may be of value for the management of buprenorphine overdose. Higher than normal doses and repeated administration may be necessary. The long duration of action of SUBOXONE sublingual film should be taken into consideration when determining the length of treatment and medical surveillance needed to reverse the effects of an overdose. Insufficient duration of monitoring may put patients at risk.

16 HOW SUPPLIED / STORAGE AND HANDLING SUBOXONE sublingual film is supplied as an orange rectangular film with a white printed logo in child-resistant polyester/foil laminated pouches: NDC 12496-1202-3 (buprenorphine 2 mg/naloxone 0.5 mg/film; content expressed in terms of free base, equivalent to 2.16 mg buprenorphine hydrochloride USP and 0.61 mg naloxone hydrochloride dihydrate USP) - 30 films per carton NDC 12496-1204-3 (buprenorphine 4 mg/naloxone 1 mg/film; content expressed in terms of free base, equivalent to 4.32 mg buprenorphine hydrochloride USP and 1.22 mg naloxone hydrochloride dihydrate USP) - 30 films per carton NDC 12496-1208-3 (buprenorphine 8 mg/naloxone 2 mg/film; content expressed in terms of free base, equivalent to 8.64 mg buprenorphine hydrochloride USP and 2.44 mg naloxone hydrochloride dihydrate USP) - 30 films per carton NDC 12496-1212-3 (buprenorphine 12 mg/naloxone 3 mg/film; content expressed in terms of free base, equivalent to 12.96 mg buprenorphine hydrochloride USP and 3.66 mg naloxone hydrochloride dihydrate USP) - 30 films per carton Store at 25°C (77°F), excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Store SUBOXONE sublingual film securely and dispose of properly [see Patient Counseling Information ( 17 )] .