buprenorphine hydrochloride

Dosage and Administration ( 2.2 ) 10/2025 Warnings and Precautions ( 5.2 , 5.3 ) 10/2025

1 INDICATIONS AND USAGE Buprenorphine sublingual tablets is indicated for the treatment of opioid dependence and is preferred for induction. Buprenorphine sublingual tablets should be used as part of a complete treatment plan to include counseling and psychosocial support. Buprenorphine sublingual tablets contains buprenorphine, a partial opioid agonist, and is indicated for the treatment of opioid dependence and is preferred for induction. ( 1 ) Buprenorphine sublingual tablets should be used as part of a complete treatment plan that includes counseling and psychosocial support ( 1 ).

2 DOSAGE AND ADMINISTRATION Administer buprenorphine sublingual tablets sublingually as a single daily dose. ( 2.1 ) Strongly consider prescribing naloxone at the time buprenorphine sublingual tablets 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 buprenorphine sublingual tablets should be undertaken when objective and clear signs of withdrawal are evident. ( 2.3 ). Buprenorphine and naloxone sublingual film or buprenorphine and naloxone sublingual tablet is generally initiated after two days of buprenorphine sublingual tablets titration. ( 2.4 ) Administer buprenorphine sublingual tablets as directed in the Full Prescribing Information. ( 2.3 , 2.4 , 2.5 ) Buprenorphine sublingual tablets must be administered whole. Do not cut, chew, or swallow buprenorphine sublingual tablets. ( 2.5 ) When discontinuing treatment, gradually taper to avoid signs and symptoms of withdrawal. ( 2.9 ) 2.1 Important Dosage and Administration Instructions Buprenorphine sublingual tablets is administered sublingually as a single daily dose. Buprenorphine sublingual tablets does not contain naloxone and is preferred for use only during induction. Following induction, buprenorphine and naloxone sublingual film or buprenorphine and naloxone sublingual tablets is preferred due to the presence of naloxone when clinical use includes unsupervised administration. The use of buprenorphine sublingual tablets for unsupervised administration should be limited to those patients who cannot tolerate buprenorphine and naloxone sublingual film or buprenorphine and naloxone sublingual tablets; for example, those patients who have been shown to be hypersensitive to naloxone. 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 Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver. Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with buprenorphine sublingual tablets. Also consider prescribing naloxone 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 )]. Advise patients and caregivers that naloxone may also be administered for a known or suspected overdose with buprenorphine sublingual tablets itself. Higher than normal doses and repeated administration of naloxone may be necessary due to the long duration of action of buprenorphine and its affinity for the mu-opioid receptor [see Overdosage ( 10 )] . Inform patients and caregivers of their options for obtaining naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription directly from a pharmacist, or as part of a community-based program) [see Patient Counseling Information ( 17 )] . 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: At treatment initiation, the first dose of buprenorphine sublingual tablets should be administered only when objective and clear signs of moderate opioid withdrawal appear, and not less than 4 hours after the patient last used an opioid. It is recommended that an adequate treatment dose, titrated to clinical effectiveness, should be …

3 DOSAGE FORMS AND STRENGTHS Buprenorphine Sublingual Tablets are supplied as a white to off white round convex tablet in four dosage strengths: buprenorphine 2 mg, buprenorphine 4 mg, buprenorphine 8 mg, and buprenorphine 12 mg Sublingual tablet: buprenorphine 2 mg, buprenorphine 4 mg, buprenorphine 8 mg and buprenorphine 12 mg. ( 3 )

4 CONTRAINDICATIONS Buprenorphine Sublingual Tablets are contraindicated in patients with a history of hypersensitivity to buprenorphine, as serious adverse reactions, including anaphylactic shock, have been reported [see Warnings and Precautions ( 5.9 )] . Hypersensitivity to buprenorphine. ( 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 administration of buprenorphine 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 Advagen Pharma Ltd, at 866-488-0312 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 Sublingual Tablets was supported by clinical trials using buprenorphine sublingual tablets, buprenorphine and naloxone sublingual tablets and other trials using buprenorphine sublingual solutions. In total, safety data were available from 3214 opioid-dependent subjects exposed to buprenorphine at doses in the range used in treatment of opioid addiction. Few differences in adverse event profile were noted between buprenorphine sublingual tablets or buprenorphine administered as a sublingual solution. The following adverse events were reported to occur by at least 5% of patients in a 4-week study ( Table 1 ). Table 1. Adverse Events ≥5% by Body System and Treatment Group in a 4-week Study N(%) N(%) Body System / Adverse Event (COSTART Terminology) Buprenorphine Sublingual Tablets 16 mg/day N=103 Placebo N=107 Body as a Whole Asthenia 5 (4.9%) 7 (6.5%) Chills 8 (7.8%) 8 (7.5%) Headache 30 (29.1%) 24 (22.4%) Infection 12 (11.7%) 7 (6.5%) Pain 19 (18.4%) 20 (18.7%) Pain Abdomen 12 (11.7%) 7 (6.5%) Pain Back 8 (7.8%) 12 (11.2%) Withdrawal Syndrome 19 (18.4%) 40 (37.4%) Cardiovascular System Vasodilation 4 (3.9%) 7 (6.5%) Digestive System Constipation 8 (7.8%) 3 (2.8%) Diarrhea 5 (4.9%) 16 (15.0%) Nausea 14 (13.6%) 12 (11.2%) Vomiting 8 (7.8%) 5 (4.7%) Nervous System Insomnia 22 (21.4%) 17 (15.9%) Respiratory System Rhinitis 10 (9.7%) 14 (13.1%) Skin and Appendages Sweating 13 (12.6%) 11 (10.3%) The adverse event profile of buprenorphine was also characterized in the dose-controlled study of buprenorphine solution, over a range of doses in four months of treatment. Table 2 shows adverse events reported by at least 5% of subjects in any dose group in the dose-controlled study. Table 2. Adverse Events (≥5%) by Body System and Treatment Group in a 16-week Study Body System/ Adverse Event (COSTART Terminology) Buprenorphine Dose* Very Low* (N=184) Low* (N=180) Moderate* (N=186) High* (N=181) Total* (N=731) N (%) N (%) N (%) N (%) 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%) …

7 DRUG INTERACTIONS Table 3 includes clinically significant drug interactions with Buprenorphine Sublingual Tablets. Table 3. Clinically Significant Drug Interactions with Buprenorphine Sublingual Tablets Benzodiazepines or 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 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 : Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), other opioids, alcohol. 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 sublingual tablets 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 sublingual tablets 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 sublingual tablets 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 sublingual tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider buprenorphine sublingual tablets 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. Si …

8 USE IN SPECIFIC POPULATIONS Lactation: Buprenorphine passes into mother’s milk. ( 8.2 ) Geriatric Patients: Monitor for sedation or respiratory depression. ( 8.5 ) Severe Hepatic Impairment: Consider reducing the starting and titration incremental dose by half and monitor for signs and symptoms of toxicity or overdose. ( 8.6 ) 8.1 Pregnancy Risk Summary The data on use of buprenorphine, the active ingredient in buprenorphine sublingual tablets, 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 ] . 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 post-natal 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 times 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, advice pregnant women of the potential risk to a fetus. The estimated background risks 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 a 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 buprenorphine sublingual tablets. 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 De …

12.1 Mechanism of Action Buprenorphine sublingual tablets contain buprenorphine, a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor.

11 DESCRIPTION Buprenorphine Sublingual Tablets are a white to off white round convex, tablet debossed with ˄ on 2 mg, ˄ on 8 mg on one side and plain on the B9 B10 other side, debossed with 24 on one side and ˄ on other side of 4 mg, debossed with L52 on one side and ˄ on other side of 12 mg. It contains buprenorphine HCl, a partial agonist at the mu-opioid receptor, and is available in four dosage strengths, buprenorphine 2 mg, buprenorphine 4 mg, buprenorphine 8 mg and buprenorphine 12 mg (as the free base, equivalent to 2.16 mg buprenorphine hydrochloride USP, 4.3 mg buprenorphine hydrochloride USP, 8.64 mg buprenorphine hydrochloride USP and 12.96 mg buprenorphine hydrochloride USP). Each tablet also contains lactose monohydrate, mannitol, corn starch, citric acid anhydrous, sodium citrate dihydrate and magnesium stearate. 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. "Image Description"

10 OVERDOSAGE Clinical Presentation The manifestations of acute 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 buprenorphine sublingual tablets 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 Buprenorphine sublingual tablets containing 2 mg buprenorphine (as the free base, equivalent to 2.16 mg buprenorphine hydrochloride, USP) are white to off white round convex, tablet debossed with ‘˄’ on one side and plain on the other side and are supplied as: B9 Bottles of 30 with child resistant cap.................NDC 72888-182-30 Bottles of 90 with child resistant cap.................NDC 72888-182-90 Buprenorphine sublingual tablets containing 4 mg buprenorphine (as the free base, equivalent to 4.32 mg buprenorphine hydrochloride, USP) are white to off white round convex, tablet debossed with ‘24’ on one side and ‘˄’ on other side and are supplied as: Bottles of 30 with child resistant cap.................NDC 72888-509-01 Bottles of 90 with child resistant cap.................NDC 72888-509-02 Buprenorphine sublingual tablets containing 8 mg buprenorphine (as the free base, equivalent to 8.64 mg buprenorphine hydrochloride, USP) are white to off white round convex, tablet debossed with ‘˄’ on one side and plain on the other side and are supplied as: B10 Bottles of 30 with child resistant cap.................NDC 72888-183-30 Bottles of 90 with child resistant cap.................NDC 72888-183-90 Buprenorphine sublingual tablets containing 12 mg buprenorphine (as the free base, equivalent to 12.96 mg buprenorphine hydrochloride, USP) are white to off white round convex, tablet debossed with ‘L52’ on one side and ‘˄’ on other side and are supplied as: Bottles of 30 with child resistant cap.................NDC 72888-510-01 Bottles of 90 with child resistant cap.................NDC 72888-510-02 Store at 20°C to 25°C (68°F to 77°F); excursion permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature.]. Protect from moisture. Dispense in a tight, light-resistant container as defined in USP. Store Buprenorphine Sublingual Tablets securely and dispose of properly [see Patient Counseling Information ( 17 )].