Buprenorphine Hydrochloride and Naloxone Hydrochloride

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 )

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 induced with either ZUBSOLV or with sublingual buprenorphine monotherapy. At treatment initiation, the first dose of ZUBSOLV should be administered when objective signs of moderate opioid withdrawal appear, not less than six hours after the patient last used opioids, to avoid precipitating an opioid withdrawal syndrome. 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 5.7 mg/1.4 mg ZUBSOLV is recommended. Clinicians should start with an initial dose of 1.4 mg/0.36 mg ZUBSOLV. The remainder of the Day 1 dose of up to 4.2 mg/1.08 mg should be divided into doses of 1 to 2 tablets of 1.4 mg/0.36 mg at 1.5 to 2 hour intervals. Some patients (e.g., those with recent exposure to buprenorphine) may tolerate up to 3 x 1.4 mg/0.36 mg ZUBSOLV as a single, second dose. On Day 2, a single daily dose of up to 11.4 mg/2.9 mg ZUBSOLV is recommended. Patients dependent on methadone or long-acting opioid products Patients dependent on 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/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 ZUBSOLV. 2.4 Maintenance The dosage of ZUBSOLV from Day 3 onwards should be progressively adjusted in increments/decrements of 2.9 mg/0.71 mg or lower of buprenorphine/naloxone to a level that holds the patient in treatment and suppresses opioid withdrawal signs and symptoms. After treatment induction to the recommended dose of 11.4 mg/2.9 mg buprenorphine/naloxone per day, dosing should be further adjusted based on the individual patient and clinical response. The maintenance dose of ZUBSOLV is generally in the range of 2.9 mg/0.71 mg buprenorphine/naloxone to 17.2 mg/4.2 mg buprenorphine/naloxone per day. Dosages higher than 17.2 mg/4.2 mg buprenorphine/naloxone daily have not been investigated in randomized clinical trials but may be appropriate for some patients. 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 ZUBSOLV contributes to the intended treatment goals. 2.5 Method of Administration ZUBSOLV must be administered whole. Do not cut, chew, or swallow ZUBSOLV. Advise patients not to eat or drink anything until the tablet is completely dissolved. ZUBSOLV should be placed under the tongue until dissolved. The dissolve time for ZUBSOLV varies between individuals, and the median dissolve time observed was 5 minutes. For dosages requiring more than one sublingual tablet, place all tablets in different places under the tongue at the same time. Patients should keep the tablets under the tongue until dissolved; swallowing the tablets reduces the bioavailability of the drug. To ensure consistency in bioavailability, patients should follow the same manner of dosing with continued use of the product. If a sequential mode of administration is prefe

WARNINGS AND PRECAUTIONS Addiction, Abuse, and Misuse : Buprenorphine can be abused in a similar manner to other opioids. Monitor patients for conditions indicative of diversion or progression of opioid dependence and addictive behaviors. Multiple refills should not be prescribed early in treatment or without appropriate patient follow-up visits. ( 5.1 ) Respiratory Depression : Life-threatening respiratory depression and death have occurred in association with buprenorphine use. Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with ZUBSOLV. ( 5.2 , 5.3 ) Unintentional Pediatric Exposure : Store ZUBSOLV safely out of the sight and reach of children. Buprenorphine can cause severe and fatal respiratory depression in children. ( 5.4 ) Neonatal Opioid Withdrawal Syndrome : Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy. ( 5.5 ) Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.6 ) Risk of Opioid Withdrawal with Abrupt Discontinuation: If treatment is temporarily interrupted or discontinued, monitor patients for withdrawal and treat appropriately. ( 5.7 ) Risk of Hepatitis; Hepatic Events : Monitor liver function tests prior to initiation and during treatment and evaluate suspected hepatic events. ( 5.8 ) Precipitation of Opioid Withdrawal Signs and Symptoms : An opioid withdrawal syndrome is likely to occur with parenteral misuse of ZUBSOLV by individuals physically dependent on full opioid agonists or by sublingual administration before the agonist effects of other opioids have subsided. ( 5.10 ) Risk of Overdose in Opioid-Naïve Patients: ZUBSOLV is not appropriate as an analgesic. There have been reported deaths of opioid naïve individuals who received a 2 mg equivalent sublingual dose of buprenorphine. ( 5.11 ) 5.1 Addiction, Abuse and Misuse ZUBSOLV contains buprenorphine, a schedule III controlled substance that can be abused in a manner similar to other opioids, legal or illicit. Prescribe and dispense buprenorphine with appropriate precautions to minimize risk of misuse, abuse, or diversion, and ensure appropriate protection from theft, including in the home. Clinical monitoring appropriate to the patient’s level of stability is essential. Multiple refills should not be prescribed early in treatment or without appropriate patient follow-up visits [see Drug Abuse and Dependence ( 9.2 )]. 5.2 Risk of Life-Threatening Respiratory and Central Nervous System (CNS) Depression Buprenorphine has been associated with life-threatening respiratory depression and death. Many, but not all, post-marketing reports regarding coma and death involved misuse by self-injection or were associated with the concomitant use of buprenorphine and benzodiazepines or other CNS depressants, including alcohol. Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with ZUBSOLV [see Warnings and Precautions ( 5.3 ), Drug Interactions ( 7 )]. Use ZUBSOLV with caution in patients with compromised respiratory function (e.g., chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Patient Counseling Information ( 17 )] . Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration ( 2.8 )]. 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 opioid overdose reversal agent for the emergency treatment of an 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 Dosage and Administration ( 2.2 )] . Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program). 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 an opioid overdose reversal agent, 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 reversal agent may be necessary due to the long duration of action of ZUBSOLV and its affinity for the mu receptor [see Overdosage ( 10 )] . Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered. 5.3 Managing Risks from Concomitant Use of Benzodiazepines or Other CNS Depressants Concomitant use of buprenorphine and benzodiazepines and/or other CNS depressants (e.g., alcohol, non-benzodiazepine sedative/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids) increases the risk of adverse reactions including overdose, respiratory depression, and death. Medication-assisted treatment of opioid use disorder, however, should not be categorically denied to patients taking these drugs. Prohibiting or creating barriers to treatment can pose an even greater risk of morbidity and mortality due to the opioid use disorder alone. As a routine part of orientation to buprenorphine treatment, educate patients about the risks of concomitant use of benzodiazepines, sedatives, opioid analgesics, and alcohol. Develop strategies to manage use of prescribed or illicit benzodiazepines or other CNS depressants at initiation of buprenorphine treatment, or if it emerges as a concern during treatment. Adjustments to induction procedures and additional monitoring may be required. There is no evidence to support dose limitations or arbitrary caps of buprenorphine as a strategy to address benzodiazepine use in buprenorphine-treated patients. However, if a patient is sedated at the time of buprenorphine dosing, delay or omit the buprenorphine dose if appropriate. 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. For patients on buprenorphine treatment, benzodiazepines are not the treatment of choice for anxiety or insomnia. Before co-prescribing benzodiazepines, ensure that patients are appropriately diagnosed

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 )

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 pharmacokinetic interactions did not result in any significant pharmacodynamic effects. Intervention: Patients who are on chronic ZUBSOLV 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 ZUBSOLV and atazanavir with and without ritonavir, and reduce dose of ZUBSOLV 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 ZUBSOLV 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 effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), 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) [see Warnings and Precautions ( 5.2 )] Intervention: The use of ZUBSOLV 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 ZUBSOLV for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of ZUBSOLV and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, strongly consider recommending or prescribing an opioid overdose reversal agent, as is recommended for all patients on buprenorphine treatment for opioid use disorder. [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 , 5.3 )] . Examples: cyclobenzaprine, metaxalone 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 ZUBSOLV is used co

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 any dose group in the dose-controlled study. 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 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%) 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%) *Sublingual 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 6.2 Post-marketing Experience The following adverse reactions have been identified during post-approval use of buprenorphine and naloxone sublingual tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate a causal relationship to drug exposure. The most frequently reported post-marketing adverse event not observed in clinical trials was peripheral edema. 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 ZUBSOLV. Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology ( 12.2 )]. Local reactions : Dental decay (including caries, tooth fracture, and tooth loss),glossodynia, glossitis, oral mucosal erythema, oral hypoesthesia, and stomatitis. Hypoglycemia : Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes). Opioid-induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking opioids, and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term.

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.