Zubsolv

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

2 DOSAGE AND ADMINISTRATION Following induction, ZUBSOLV is administered sublingually as a single daily dose. ( 2.1 ) Strongly consider recommending or prescribing an opioid overdose reversal agent (e.g., naloxone, nalmefene) at the time ZUBSOLV 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 ZUBSOLV should be undertaken when objective and clear signs of withdrawal are evident and Zubsolv 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 5.7 mg/1.4 mg of Zubsolv (in divided doses). On Day 2, administer up to a total dose of 11.4 mg/2.9 mg of Zubsolv 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 ZUBSOLV is generally in the range of 2.9 mg/0.71 mg to 17.2 mg/4.2 mg per day and should be based on clinical response. ( 2.4 ) Administer Zubsolv as directed in the Full Prescribing Information. ( 2.5 ) When discontinuing treatment, gradually taper to avoid signs and symptoms of withdrawal. ( 2.8 ) 2.1 Important Dosage and Administration Information The difference in bioavailability of ZUBSOLV compared to Suboxone® sublingual tablet requires a different tablet strength to be given to the patient. One ZUBSOLV 5.7 mg/1.4 mg sublingual tablet provides equivalent buprenorphine exposure to one Suboxone 8 mg/2 mg sublingual tablet. 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 ZUBSOLV. 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 ZUBSOLV 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 ZUBSOLV and its affinity for the mu 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, 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 in …

3 DOSAGE FORMS AND STRENGTHS ZUBSOLV sublingual tablet is supplied in six dosage strengths: Buprenorphine 0.7 mg /naloxone 0.18 mg, white, oval shape tablets imprinted with “.7” Buprenorphine 1.4 mg /naloxone 0.36 mg, white, triangular shape tablets imprinted with “1.4” Buprenorphine 2.9 mg /naloxone 0.71 mg, white, D shape tablets imprinted with “2.9” Buprenorphine 5.7 mg /naloxone 1.4 mg, white, round shape tablets imprinted with “5.7” Buprenorphine 8.6 mg /naloxone 2.1 mg, white, diamond shape tablets imprinted with “8.6” Buprenorphine 11.4 mg /naloxone 2.9 mg, white, capsule shape tablets imprinted with “11.4” Sublingual tablet: Buprenorphine 0.7 mg /naloxone 0.18 mg, Buprenorphine 1.4 mg /naloxone 0.36 mg, Buprenorphine 2.9 mg /naloxone 0.71 mg, Buprenorphine 5.7 mg /naloxone 1.4 mg, Buprenorphine 8.6 mg /naloxone 2.1 mg and Buprenorphine 11.4 mg /naloxone 2.9 mg. ( 3 )

4 CONTRAINDICATIONS ZUBSOLV 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 sublingual administration of ZUBSOLV are headache, nausea, vomiting, hyperhidrosis, constipation, signs and symptoms of withdrawal, insomnia, pain, and peripheral edema. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Orexo at 1-888-982-7658, 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. ZUBSOLV for use as initial treatment was evaluated in two clinical trials that had identical, blinded, two-day induction phases, comparing ZUBSOLV to generic buprenorphine. On the first day, subjects received an initial dose of ZUBSOLV 1.4 mg/0.36 mg or generic buprenorphine 2 mg, followed by ZUBSOLV 4.2 mg/1.08 mg or generic buprenorphine 6 mg 1.5 hours later. In total, safety data were available for 538 opioid-dependent subjects exposed to ZUBSOLV (buprenorphine/naloxone) sublingual tablets when used for initial treatment. Table 1. Adverse Reactions in ≥ 5% of Patients During the Induction Phase by System Organ Class and Preferred Term (Safety Population) System Organ Class Preferred Term ZUBSOLV (N=538) Generic BUP (N=530) Overall (N=1068) N (%) Patients with any Adverse Reactions 139 (26%) 136 (26%) 275 (26%) Gastrointestinal Disorders 64 (12%) 60 (11%) 124 (12%) Nausea 29 (5%) 36 (7%) 65 (6%) Vomiting 25 (5%) 26 (5%) 51 (5%) Nervous System Disorders 48 (9%) 44 (8%) 92 (9%) Headache 36 (7%) 35 (7%) 71 (7%) BUP = buprenorphine ZUBSOLV = buprenorphine/naloxone The safety of buprenorphine/naloxone for longer-term use (up to 16 weeks of treatment) was evaluated in previous studies in 497 opioid-dependent subjects. The prospective evaluation of buprenorphine/naloxone was supported by clinical trials using buprenorphine tablets without naloxone 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. See Table 2. Table 2. Adverse Events > 5% by Body System and Treatment Group in a 4-week Study N (%) N (%) Body System / Adverse Event (COSTART Terminology) Buprenorphine/ naloxone 16/4 mg/day N=107 Placebo N=107 Body as a Whole Asthenia 7 (7%) 7 (7%) Chills 8 (8%) 8 (8%) Headache 39 (37%) 24 (22%) Infection 6 (6%) 7 (7%) Pain 24 (22%) 20 (19%) Pain Abdomen 12 (11%) 7 (7%) Pain Back 4 (4%) 12 (11%) Withdrawal Syndrome 27 (25%) 40 (37%) Cardiovascular System Vasodilation 10 (9%) 7 (7%) Digestive System Constipation 13 (12%) 3 (3%) Diarrhea 4 (4%) 16 (15%) Nausea 16 (15%) 12 (11%) Vomiting 8 (8%) 5 (5%) Nervous System Insomnia 15 (14%) 17 (16%) Respiratory System Rhinitis 5 (5%) 14 (13%) Skin and Appendages Sweating 15 (14%) 11 (10%) 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 3 shows adverse events reported by at least 5% of subjects in a …

7 DRUG INTERACTION S Table 4 includes clinically significant drug interactions with ZUBSOLV. Table 4. Clinically Significant Drug Interactions with ZUBSOLV Benzodiazepines and other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effects, the concomitant use of benzodiazepines and 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: 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 ZUBSOLV 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 ZUBSOLV 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 ZUBSOLV 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 ZUBSOLV dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider ZUBSOLV 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 pharmacokin …

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 and 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 ZUBSOLV, 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 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 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 ZUBSOLV. 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 …

12.1 Mechanism of Action ZUBSOLV 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, if administered parenterally, in individuals physically dependent on full opioid agonists.

11 DESCRIPTION ZUBSOLV (buprenorphine and naloxone) sublingual tablets are white menthol-flavored tablets in an oval shape for the dosage strength 0.7 mg/0.18 mg, a triangular shape for the dosage strength 1.4 mg /0.36 mg, a D shape for the dosage strength 2.9 mg/0.71 mg, a round shape for the dosage strength 5.7 mg/1.4 mg, a diamond shape for the dosage strength 8.6 mg/2.1 mg and a capsule shape for the dosage strength 11.4 mg/2.9 mg. They are debossed with the respective dosage strength of buprenorphine. They contain buprenorphine HCl, an opioid partial agonist and naloxone HCl dihydrate, an opioid antagonist, at a ratio of 4:1 (ratio of free bases). ZUBSOLV is intended for sublingual administration and is available in six dosage strengths, 0.7 mg buprenorphine with 0.18 mg naloxone, 1.4 mg buprenorphine with 0.36 mg naloxone, 2.9 mg buprenorphine with 0.71 mg naloxone, 5.7 mg buprenorphine with 1.4 mg naloxone, 8.6 mg buprenorphine with 2.1 mg naloxone and 11.4 mg buprenorphine with 2.9 mg naloxone. Each sublingual tablet also contains mannitol, citric acid, sodium citrate, microcrystalline cellulose, croscarmellose sodium, sucralose, menthol, silicon dioxide and sodium stearyl fumarate and menthol flavor. 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-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride dihydrate. It has the following chemical structure: Naloxone HCl dihydrate has the molecular formula C 19 H 21 NO 4 • HCl • 2H 2 0 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. It has the following chemical structure: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:Chemically, naloxone HCl dihydrate is 17-Allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride dihydrate.

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 ZUBSOLV 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 ZUBSOLV sublingual tablets are menthol-flavored white tablets supplied in aluminum/aluminum child resistant unit dose blister packages. ZUBSOLV is available in six dosage strengths imprinted in their respective buprenorphine strength Buprenorphine 0.7 mg /naloxone 0.18 mg, oval shape, imprinted with “.7” Buprenorphine 1.4 mg /naloxone 0.36 mg, triangular shape, imprinted with “1.4” Buprenorphine 2.9 mg /naloxone 0.71mg, D shape, imprinted with “2.9” Buprenorphine 5.7 mg /naloxone 1.4 mg, round shape, imprinted with “5.7” Buprenorphine 8.6 mg /naloxone 2.1 mg, diamond shape, imprinted with “8.6” Buprenorphine 11.4 mg /naloxone 2.9 mg, capsule shape, imprinted with “11.4” NDC 54123-907-30 (buprenorphine 0.7 mg /naloxone 0.18 mg) sublingual tablet – 3x10 tablets per carton NDC 54123-914-30 (buprenorphine 1.4 mg /naloxone 0.36 mg) sublingual tablet – 3x10 tablets per carton NDC 54123-929-30 (buprenorphine 2.9 mg /naloxone 0.71 mg) sublingual tablet – 3x10 tablets per carton NDC 54123-957-30 (buprenorphine 5.7 mg /naloxone 1.4 mg) sublingual tablet – 3x10 tablets per carton NDC 54123-986-30 (buprenorphine 8.6 mg /naloxone 2.1 mg) sublingual tablet – 3x10 tablets per carton NDC 54123-114-30 (buprenorphine 11.4 mg /naloxone 2.9 mg) sublingual tablet – 3x10 tablets per carton Store at 20-25°C (68-77°F), excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature] Store ZUBSOLV securely and dispose of properly [see Patient Counseling Information ( 17 )].