|Dosage and Administration, Induction || 08/2015 |
|Dosage and Administration, Patients With Hepatic Impairment (2.6) || 12/2014 |
|Warnings and Precautions, Use in Patients With Impaired Hepatic Function (5.11) || 12/2014 |
1 INDICATIONS AND USAGE ZUBSOLV sublingual tablet is indicated for treatment of opioid dependence and should be used as part of a complete treatment plan to include counseling and psychosocial support. Under the Drug Addiction Treatment Act (DATA) codified at 21 U.S.C. 823(g), prescription use of this product in the treatment of opioid dependence is limited to physicians who meet certain qualifying requirements, and who have notified the Secretary of Health and Human Services (HHS) of their intent to prescribe this product for the treatment of opioid dependence and have been assigned a unique identification number that must be included on every prescription. ZUBSOLV is a partial opioid agonist indicated for treatment of opioid dependence. Prescription use of this product is limited under the Drug Addiction Treatment Act. (1)
| SUBOXONE sublingual tablets, including generic equivalents || Corresponding dosage strength of ZUBSOLV sublingual tablets |
|One 2 mg/0.5 mg buprenorphine/naloxone sublingual tablet ||One 1.4 mg/0.36 mg ZUBSOLV sublingual tablet |
|4 mg/1 mg buprenorphine/naloxone taken as: • Two 2 mg/0.5 mg sublingual buprenorphine/naloxone tablets ||One 2.9 mg/0.71 mg ZUBSOLV sublingual tablet |
|One 8 mg/2 mg buprenorphine/naloxone sublingual tablet ||One 5.7 mg/1.4 mg ZUBSOLV sublingual tablet |
|12 mg/3 mg buprenorphine/naloxone, taken as: • One 8 mg/2 mg sublingual buprenorphine/naloxone tablet AND • Two 2 mg/0.5 mg sublingual buprenorphine/naloxone tablets ||One 8.6 mg/2.1 mg ZUBSOLV sublingual tablet |
|16 mg/4 mg buprenorphine/naloxone, taken as: • Two 8 mg/2 mg sublingual buprenorphine/naloxone tablets ||One 11.4 mg/2.9 mg ZUBSOLV sublingual tablet |
3 DOSAGE FORMS AND STRENGTHS ZUBSOLV sublingual tablet is supplied in five dosage strengths: buprenorphine/naloxone 1.4 mg/0.36 mg, white, triangular shape, tablets and buprenorphine/naloxone 2.9 mg/0.71 mg white, D shape tablets buprenorphine/naloxone 5.7 mg/1.4 mg, white, round shape tablets buprenorphine/naloxone 8.6 mg/2.1 mg, white, diamond shape tablets buprenorphine/naloxone 11.4 mg/2.9 mg, white, capsule shape tablets Sublingual tablet: 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. (3)
4 CONTRAINDICATIONS ZUBSOLV sublingual tablet should not be administered to patients who have been shown to be hypersensitive to buprenorphine or naloxone as serious adverse reactions, including anaphylactic shock, have been reported. [see Warnings and Precautions ( 5.7 ) ]. Hypersensitivity to buprenorphine or naloxone. (4)
5 WARNINGS AND PRECAUTIONS Buprenorphine can be abused in a similar manner to other opioids. 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. (5.1) Significant respiratory depression and death have occurred in association with buprenorphine, particularly when taken by the intravenous route in combination with benzodiazepines or other CNS depressants (including alcohol). (5.2) Consider dose reduction of CNS depressants, ZUBSOLV, or both, in situations of concomitant prescription. (5.3) Store safely out of the sight and reach of children. Buprenorphine can cause severe and fatal respiratory depression in children. (5.4) Chronic administration produces opioid-type physical dependence. Abrupt discontinuation or rapid dose taper may result in opioid withdrawal syndrome. (5.5) Monitor liver function tests prior to initiation and during treatment and evaluate suspected hepatic events. (5.6) 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. (5.8) Neonatal withdrawal has been reported following use of buprenorphine by the mother during pregnancy. (5.9) ZUBSOLV is not appropriate as an analgesic. There have been reported deaths of opioid naïve individuals who received a 2 mg sublingual dose of buprenorphine. (5.10) Buprenorphine/naloxone products are not recommended in patients with severe hepatic impairment and may not be appropriate for patients with moderate hepatic impairment. (5.11) Caution patients about the risk of driving or operating hazardous machinery. (5.12) 5.1 Abuse Potential Buprenorphine 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 Respiratory Depression Buprenorphine, particularly when taken by the IV route, in combination with benzodiazepines or other CNS depressants (including alcohol), has been associated with significant respiratory depression and death. Many, but not all, post-marketing reports regarding coma and death associated with the concomitant use of buprenorphine and benzodiazepines involved misuse by self-injection. Deaths have also been reported in association with concomitant administration of buprenorphine with other depressants such as alcohol or other CNS depressant drugs. Patients should be warned of the potential danger of self-administration of benzodiazepines or other depressants while under treatment with ZUBSOLV sublingual tablets. [see Drug Interactions (7.3)] In the case of overdose, the primary management should be the re-establishment of adequate ventilation with mechanical assistance of respiration, if required. Naloxone may be of value for the management of buprenorphine overdose. Higher than normal doses and repeated administration may be necessary. ZUBSOLV sublingual tablets should be used 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). 5.3 CNS Depression Patients receiving buprenorphine in the presence of opioid analgesics, general anesthetics, benzodiazepines, phenothiazines, other tranquilizers, sedative/hypnotics, or other CNS depressants (including alcohol) may exhibit increased CNS depression. Consider dose reduction of CNS depressants, ZUBSOLV sublingual tablets, or both in situations of concomitant prescription. [see Drug Interactions ( 7.3 ) ] 5.4 Unintentional Pediatric Exposure Buprenorphine can cause fatal respiratory depression in children who are accidentally exposed to it. Store buprenorphine containing medications safely out of the sight and reach of children and destroy any unused medication appropriately. [see Patient Counseling Information ( 17 ) ] 5.5 Dependence Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by withdrawal signs and symptoms upon abrupt discontinuation or rapid taper. The withdrawal syndrome is typically milder than seen with full agonists and may be delayed in onset. Buprenorphine can be abused in a manner similar to other opioids. This should be considered when prescribing or dispensing buprenorphine in situations when the clinician is concerned about an increased risk of misuse, abuse, or diversion. [see Drug Abuse and Dependence ( 9.3 ) ] 5.6 Hepatitis, Hepatic Events Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving buprenorphine in clinical trials and through post-marketing adverse event reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of death, hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy. In many cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injecting drug use may have played a causative or contributory role. In other cases, insufficient data were available to determine the etiology of the abnormality. Withdrawal of buprenorphine has resulted in amelioration of acute hepatitis in some cases; however, in other cases no dose reduction was necessary. The possibility exists that buprenorphine had a causative or contributory role in the development of the hepatic abnormality in some cases. Liver function tests, prior to initiation of treatment is recommended to establish a baseline. Periodic monitoring of liver function during treatment is also recommended. A biological and etiological evaluation is recommended when a hepatic event is suspected. Depending on the case, ZUBSOLV sublingual tablet may need to be carefully discontinued to prevent withdrawal signs and symptoms and a return by the patient to illicit drug use, and strict monitoring of the patient should be initiated. 5.7 Allergic Reactions Cases of hypersensitivity to buprenorphine and naloxone containing products have been reported both in clinical trials and in the post-marketing experience. Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. The most common signs and symptoms include rashes, hives, and pruritus. A history of hypersensitivity to buprenorphine or naloxone is a contraindication to the use of ZUBSOLV sublingual tablet. 5.8 Precipitation of Opioid Withdrawal Signs and Symptoms Because it contains naloxone, ZUBSOLV sublingual tablet is likely to produce withdrawal signs and symptoms if misused parenterally by individuals dependent on full opioid agonists such as heroin, morphine, or methadone. Because of the partial agonist properties of buprenorphine, ZUBSOLV sublingual tablet may precipitate opioid withdrawal signs and symptoms in such persons if administered sublingually before the agonist effects of the opioid have subsided. 5.9 Neonatal Abstinence Syndrome Neonatal abstinence syndrome has been reported in the infants of women treated with buprenorphine during pregnancy. From post-marketing reports, the time to onset of neonatal withdrawal signs ranged from Day 1 to Day 8 of life with most cases occurring on Day 1. Adverse events associated with the neonatal abstinence syndrome included hypertonia, neonatal tremor, neonatal agitation, and myoclonus, and there have been reports of convulsions, apnea, respiratory depression, and bradycardia. 5.10 Use in Opioid Naïve Patients There have been reported deaths of opioid naive individuals who received a 2 mg dose of buprenorphine as a sublingual tablet for analgesia. ZUBSOLV sublingual tablet is not appropriate as an analgesic. 5.11 Use in Patients With Impaired Hepatic Function Buprenorphine/naloxone products are not recommended in patients with severe hepatic impairment and may not be appropriate for patients with moderate hepatic impairment. The doses of buprenorphine and naloxone in this fixed-dose combination product cannot be individually titrated, and hepatic impairment results in a reduced clearance of naloxone to a much greater extent than buprenorphine. Therefore, patients with severe hepatic impairment will be exposed to substantially higher levels of naloxone than patients with normal hepatic function. This may interfere with buprenorphine’s efficacy throughout treatment. In patients with moderate hepatic impairment, the differential reduction of naloxone clearance compared to buprenorphine clearance is not as great as in subjects with severe hepatic impairment. Therefore, buprenorphine/naloxone products may be used with caution for maintenance treatment in patients with moderate hepatic impairment who have initiated treatment on a buprenorphine product without naloxone. However, patients should be carefully monitored and consideration given to the possibility of naloxone interfering with buprenorphine’s efficacy [see Use in Specific Populations ( 8.6 ) ]. 5.12 Impairment of Ability to Drive or Operate Machinery ZUBSOLV sublingual tablet may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery, especially during treatment induction and dose adjustment. Patients should be cautioned about driving or operating hazardous machinery until they are reasonably certain that ZUBSOLV sublingual tablet therapy does not adversely affect his or her ability to engage in such activities. 5. 13 Orthostatic Hypotension Like other opioids, ZUBSOLV sublingual tablets may produce orthostatic hypotension in ambulatory patients. 5.14 Elevation of Cerebrospinal Fluid Pressure Buprenorphine, like other opioids, may elevate cerebrospinal fluid pressure and should be used with caution in patients with head injury, intracranial lesions, and other circumstances when cerebrospinal pressure may be increased. Buprenorphine can produce miosis and changes in the level of consciousness that may interfere with patient evaluation. 5.15 Elevation of Intracholedochal Pressure Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus should be administered with caution to patients with dysfunction of the biliary tract. 5.16 Effects in Acute Abdominal Conditions As with other opioids, buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions. 5.17 General Precautions ZUBSOLV sublingual tablet should be administered with caution in debilitated patients and those with myxedema or hypothyroidism, adrenal cortical insufficiency (e.g., Addison's disease); CNS depression or coma; toxic psychoses; prostatic hypertrophy or urethral stricture; acute alcoholism; delirium tremens; or kyphoscoliosis.
6 ADVERSE REACTIONS 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. Adverse events commonly observed with administration of buprenorphine/naloxone sublingual tablets during clinical trials and post-marketing experience 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 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 1.4mg/0.36 mg or generic buprenorphine 2 mg, followed by ZUBSOLV 4.2mg/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 16mg/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 (%) *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 Suboxone tablet dose of 2 mg "Low" dose (4 mg solution) approximates a 6 mg Suboxone tablet dose "Moderate" dose (8 mg solution) approximates a 12 mg Suboxone tablet dose "High" dose (16 mg solution) approximates a 24 mg Suboxone tablet dose 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%) 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.
7 DRUG INTERACTIONS Monitor patients starting or ending CYP3A4 inhibitors or inducers for potential over or under dosing. (7.1) Use caution in prescribing ZUBSOLV for patients receiving benzodiazepines or other CNS depressants and warn patients against concomitant self-administration/misuse. (7.3) 7.1 Cytochrome P-450 3A4 (CYP3A4) Inhibitors and Inducers Buprenorphine is metabolized to norbuprenorphine primarily by cytochrome CYP3A4; therefore, potential interactions may occur when ZUBSOLV sublingual tablets is given concurrently with agents that affect CYP3A4 activity. The concomitant use of ZUBSOLV sublingual tablet with CYP3A4 inhibitors (e.g., azole antifungals such as ketoconazole, macrolide antibiotics such as erythromycin, and HIV protease inhibitors) should be monitored and may require dose-reduction of one or both agents. The interaction of buprenorphine with CYP3A4 inducers has not been studied; therefore, it is recommended that patients receiving ZUBSOLV sublingual tablets be monitored for signs and symptoms of opioid withdrawal if inducers of CYP3A4 (e.g., efavirenz, phenobarbital, carbamazepine, phenytoin, rifampicin) are co-administered [see Clinical Pharmacology ( 12.3 ) ] 7.2 Antiretrovirals Three classes of antiretroviral agents have been evaluated for CYP3A4 interactions with buprenorphine. Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine and etravirine are known CYP3A inducers whereas delaviridine 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. It is recommended that patients who are on chronic buprenorphine treatment have their dose monitored if NNRTIs are added to their treatment regimen. 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. Monitoring of patients taking buprenorphine and atazanavir with and without ritonavir is recommended, and dose reduction of buprenorphine may be warranted. 7.3 Benzodiazepines There have been a number of post-marketing reports regarding coma and death associated with the concomitant use of buprenorphine and benzodiazepines. In many, but not all of these cases, buprenorphine was misused by self-injection. Preclinical studies have shown that the combination of benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists. ZUBSOLV sublingual tablets should be prescribed with caution to patients taking benzodiazepines or other drugs that act on the CNS, regardless of whether these drugs are taken on the advice of a physician or are being abused/misused. Patients should be warned that it is extremely dangerous to self-administer non-prescribed benzodiazepines while taking ZUBSOLV sublingual tablets, and should also be cautioned to use benzodiazepines concurrently with ZUBSOLV sublingual tablets only as directed by their physician.
8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm. (8.1) Nursing mothers: Caution should be exercised when administered to a nursing woman. (8.3) Safety and effectiveness in patients below the age of 16 has not been established. (8.4) Administer with caution to elderly or debilitated patients. (8.5) 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 Pregnancy Category C. Risk Summary There are no adequate and well-controlled studies of ZUBSOLV sublingual tablets or buprenorphine/naloxone in pregnant women. . Limited published data on use of buprenorphine, the active ingredient in Zubsolv, in pregnancy, have not shown an increased risk of major malformations. All pregnancies, regardless of drug exposure, have a background risk of 2-4% for major birth defects, and 15-20% for pregnancy loss. Reproductive and developmental studies in rats and rabbits identified adverse events at clinically relevant doses. Pre- and postnatal development studies in rats demonstrated dystocia, increased neonatal deaths, and developmental delays. No clear teratogenic effects were seen with a range of doses equivalent to or greater than the human dose. However, in a few studies, some events such as acephalus, omphalocele, and skeletal abnormalities were observed but these findings were not clearly treatment-related. Embryofetal death was also observed in both rats and rabbits. ZUBSOLV sublingual tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations Disease-associated maternal and embryo-fetal risk Opioid dependence in pregnancy is associated with adverse obstetrical outcomes such as low birth weight, preterm birth, and fetal death. Fetal/neonatal adverse reactions Neonatal abstinence syndrome may occur in newborn infants of mothers who were on buprenorphine maintenance treatment. Observe newborns for poor feeding, diarrhea, irritability, tremor, rigidity, and seizures, and manage accordingly. [See Warnings and Precautions ( 5.9 ) ] Labor or Delivery As with all opioids, use of buprenorphine prior to delivery may result in respiratory depression in the newborn. Closely monitor neonates for signs of respiratory depression. An opioid antagonist such as naloxone should be available for reversal of opioid induced respiratory depression in the neonate. Data Human Data Studies have been conducted to evaluate neonatal outcomes in women exposed to buprenorphine during pregnancy. Limited published data on malformations from trials, observational studies, case series, and case reports on buprenorphine use in pregnancy have not shown an increased risk of major malformations. Based on these studies the incidence of neonatal abstinence syndrome is not clear and there does not appear to be a dose-response relationship. Animal Data ZUBSOLV has been shown to have differences in bioavailability compared to other buprenorphine/naloxone-containing sublingual products. The exposure margins listed below are based on body surface area comparisons (mg/m2) to the recommended human sublingual dose of 16 mg buprenorphine via Suboxone, which is equivalent to a human sublingual dose of 11.4 mg buprenorphine via ZUBSOLV. Effects on embryo-fetal development were studied in Sprague-Dawley rats and Russian white rabbits following oral (1:1) and intramuscular (IM) (3:2) administration of mixtures of buprenorphine and naloxone. Following oral administration to rats and rabbits, no teratogenic effects were observed at buprenorphine doses up to 250 mg/kg/day and 40 mg/kg/day, respectively (estimated exposure approximately 150 times and 50 times, respectively, the recommended human sublingual dose). No definitive drug-related teratogenic effects were observed in rats and rabbits at IM doses up to 30 mg/kg/day (estimated exposure approximately 20 times and 35 times, respectively, the recommended human sublingual dose). Acephalus was observed in one rabbit fetus from the low-dose group and omphalocele was observed in two rabbit fetuses from the same litter in the mid-dose group; no findings were observed in fetuses from the high-dose group. Following oral administration of buprenorphine to rats, dose-related post-implantation losses, evidenced by increases in the numbers of early resorptions with consequent reductions in the numbers of fetuses, were observed at doses of 10 mg/kg/day or greater (estimated exposure approximately 6 times the recommended human sublingual dose). In the rabbit, increased post-implantation losses occurred at an oral dose of 40 mg/kg/day. Following IM administration in the rat and the rabbit, post-implantation losses, as evidenced by decreases in live fetuses and increases in resorptions, occurred at 30 mg/kg/day. Buprenorphine was not teratogenic in rats or rabbits after IM or subcutaneous (SC) doses up to 5 mg/kg/day (estimated exposure was approximately 3 and 6 times, respectively, the recommended human sublingual dose), after IV doses up to 0.8 mg/kg/day (estimated exposure was approximately 0.5 times and equal to, respectively, the recommended human sublingual dose), or after oral doses up to 160 mg/kg/day in rats (estimated exposure was approximately 95 times the recommended human sublingual dose) and 25 mg/kg/day in rabbits (estimated exposure was approximately 30 times the recommended human sublingual dose). Significant increases in skeletal abnormalities (e.g., extra thoracic vertebra or thoraco-lumbar ribs) were noted in rats after SC administration of 1 mg/kg/day and up (estimated exposure was approximately 0.6 times the recommended human sublingual dose), but were not observed at oral doses up to 160 mg/kg/day. Increases in skeletal abnormalities in rabbits after IM administration of 5 mg/kg/day (estimated exposure was approximately 6 times the recommended human sublingual dose) or oral administration of 1 mg/kg/day or greater (estimated exposure was approximately equal to the recommended human sublingual dose) were not statistically significant. In rabbits, buprenorphine produced statistically significant pre-implantation losses at oral doses of 1 mg/kg/day or greater and post-implantation losses that were statistically significant at IV doses of 0.2 mg/kg/day or greater (estimated exposure approximately 0.3 times the recommended human sublingual dose). Dystocia was noted in pregnant rats treated intramuscularly with buprenorphine 5 mg/kg/day (approximately 3 times the recommended human sublingual dose). Fertility, peri-, and post-natal development studies with buprenorphine in rats indicated increases in neonatal mortality after oral doses of 0.8 mg/kg/day and up (approximately 0.5 times the recommended human sublingual dose), after IM doses of 0.5 mg/kg/day and up (approximately 0.3 times the recommended human sublingual dose), and after SC doses of 0.1 mg/kg/day and up (approximately 0.06 times the recommended human sublingual dose). An apparent lack of milk production during these studies likely contributed to the decreased pup viability and lactation indices. Delays in the occurrence of righting reflex and startle response were noted in rat pups at an oral dose of 80 mg/kg/day (approximately 50 times the recommended human sublingual dose). 8.3 Nursing Mothers Risk Summary Based on two studies in 13 lactating women, buprenorphine and its metabolite norbuprenorphine are present in low levels in human milk and infant urine, and available data have not shown adverse reactions in breastfed infants. There are no data on the combination product buprenorphine/naloxone in breastfeeding, however oral absorption of naloxone is minimal. Caution should be exercised when ZUBSOLV is administered to a nursing woman. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZUBSOLV and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition. Clinical Considerations Advise the nursing mother taking ZUBSOLV to monitor the infant for increased drowsiness and breathing difficulties. Data Based on limited data from a study of 6 lactating women who were taking a median oral dose of buprenorphine of 0.29 mg/kg/day 5-8 days after delivery, breast milk contained a median infant dose of 0.42 mcg/kg/day of buprenorphine and 0.33 mg/kg/day of norbuprenorphine, which are equal to 0.2% and 0.12% of the maternal weight-adjusted dose. Based on limited data from a study of 7 lactating women who were taking a median oral dose of buprenorphine of 7 mg/day an average of 1.12 months after delivery, the mean milk concentrations of buprenorphine and norbuprenorphine were 3.65 mcg/L and 1.94 mcg/L respectively. Based on the limited data from this study, and assuming milk consumption of 150 mL/kg/day, an exclusively breastfed infant would receive an estimated mean of 0.55 mcg/kg/day of buprenorphine and 0.29 mcg/kg/day of norbuprenorphine, which are 0.38% and 0.18% of the maternal weight-adjusted dose. No adverse reactions were observed in the infants in these two studies. 8.4 Pediatric Use The safety and effectiveness of ZUBSOLV sublingual tablets have not been established in pediatric patients. This product is not appropriate for the treatment of neonatal abstinence syndrome in neonates, because it contains naloxone, an opioid antagonist. 8.5 Geriatric Use Clinical studies of buprenorphine/naloxone sublingual tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone has been evaluated in a pharmacokinetic study. Both drugs are extensively metabolized in the liver. While no clinically significant changes have been observed in subjects with mild hepatic impairment; the plasma levels have been shown to be higher and half-life values have been shown to be longer for both buprenorphine and naloxone in subjects with moderate and severe hepatic impairment. The magnitude of the effects on naloxone is greater than that on buprenorphine in both moderately and severely impaired subjects. The difference in magnitude of the effects on naloxone and buprenorphine are greater in subjects with severe hepatic impairment than in subjects with moderate hepatic impairment, and therefore the clinical impact of these effects is likely to be greater in patients with severe hepatic impairment than in patients with moderate hepatic impairment. Buprenorphine/naloxone products should be avoided in patients with severe hepatic impairment and may not be appropriate for patients with moderate hepatic impairment [see Warnings and Precautions (5.11) and Clinical Pharmacology (12.3)]. 8.7 Renal Impairment No differences in buprenorphine pharmacokinetics were observed between 9 dialysis-dependent and 6 normal patients following IV administration of 0.3 mg buprenorphine. The effects of renal failure on naloxone pharmacokinetics are unknown.