Buprenorphine HCl and Naloxone HCl

5 WARNINGS AND PRECAUTIONS Addiction, Abuse, and Misuse : Buprenorphine can be abused in a similar manner to other opioids. Clinical monitoring appropriate to the patient’s level of stability is essential. 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 benzodiazepine or other CNS depressants while under treatment with Buprenorphine and Naloxone Sublingual Tablets. ( 5.2 , 5.3 ) Unintentional Pediatric Exposure : Store Buprenorphine and Naloxone Sublingual Tablets safely out of the sight and reach of children. Buprenorphine can cause severe, possibly 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 Buprenorphine and Naloxone Sublingual Tablets 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 : Buprenorphine and Naloxone Sublingual Tablets are not appropriate as an analgesic. There have been reported deaths of opioid naïve individuals who received a 2 mg sublingual dose. ( 5.11 ) 5.1 Addiction, Abuse, and Misuse Buprenorphine and Naloxone Sublingual Tablets contain 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 Life-Threatening Respiratory Depression 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 Buprenorphine and Naloxone Sublingual Tablets [see Warnings and Precautions (5.3) , Drug Interactions (7) ] . Use Buprenorphine and Naloxone Sublingual Tablets 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 (2.7) ] . 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 Buprenorphine and Naloxone Sublingual Tablets. 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 Buprenorphine and Naloxone Sublingual Tablets 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 Buprenorphine and Naloxone Sublingual Tablets and its affinity for the mu opioid 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 [see Patient Counseling Information (17) ]. 5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Concomitant use of buprenorphine and benzodiazepines and/or other CNS depressants (e.g., alcohol, non-benzodiazepines, 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 in buprenorphine treatment, benzodiazepines are not the treatment of choice for anxiety or insomnia. Before co-prescribing benzodiazepines, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments to address anxiety or insomnia. Ensure that other healthcare providers prescribing benzodiazepines or other CNS depressants are aware of the patient’s buprenorphine treatment and coordinate care to minimize the risks associated with concomitant use. 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 Dosage and Administration (2.2) , Warnings and Precautions (5.2) , Overdosage (10) ]. In addition, take measures to confirm that patients are taking their medications as prescribed and are not diverting or supplementing with illicit drugs. Toxicology screening should test for prescribed and illicit benzodiazepines [see Drug Interactions (7) ]. 5.4 Unintentional Pediatric Exposure Buprenorphine can cause severe, possibly 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 Neonatal Opioid Withdrawal Syndrome Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy, whether that use is medically-authorized or illicit. Unlike opioid withdrawal syndrome in adults, NOWS may be life-threatening if not recognized and treated in the neonate. Healthcare professionals should observe newborns for signs of NOWS and manage accordingly [see Use in Specific Populations (8.1) ] . Advise pregnant women receiving opioid addiction treatment with Buprenorphine and Naloxone Sublingual Tablets of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1) ] . This risk must be balanced against the risk of untreated opioid addiction which often results in continued or relapsing illicit opioid use and is associated with poor pregnancy outcomes. Therefore, prescribers should discuss the importance and benefits of management of opioid addiction throughout pregnancy. 5.6 Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. 5.7 Risk of Opioid Withdrawal with Abrupt Discontinuation 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 [see Drug Abuse and Dependence (9.3) ] . When discontinuing Buprenorphine and Naloxone Sublingual Tablets, gradually taper the dosage [see Dosage and Administration (2.7) ]. 5.8 Risk of 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, Buprenorphine and Naloxone Sublingual Tablets 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. 5.9 Hypersensitivity 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 Buprenorphine and Naloxone Sublingual Tablets. 5.10 Precipitation of Opioid Withdrawal Signs and Symptoms Because it contains naloxone, Buprenorphine and Naloxone Sublingual Tablets are highly likely to produce marked and intense withdrawal signs and symptoms if misused parenterally by individual dependent on full opioid agonists such as heroin, morphine, or methadone. Because of the partial agonist properties of buprenorphine, Buprenorphine and Naloxone Sublingual Tablets may precipitate opioid withdrawal signs and symptoms in such persons if administered sublingually before the agonist effects of the opioid have subsided. 5.11 Risk of Overdose 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. Buprenorphine and Naloxone Sublingual Tablets are not appropriate as an analgesic. 5.12 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 result in an increased risk of precipitated withdrawal at the beginning of treatment (induction) and 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. However, buprenorphine/naloxone products are not recommended for initiation of treatment (induction) in patients with moderate hepatic impairment due to the increased risk of precipitated withdrawal. 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) ] . 5.13 Dental Adverse Events Cases of dental caries, some severe (i.e., tooth fracture, tooth loss), have been reported following the use of transmucosal buprenorphine-containing products. Reported events include cavities, tooth decay, dental abscesses/infection, rampant caries, tooth erosion, fillings falling out, and, in some cases, total tooth loss. Treatment for these events included tooth extraction, root canal, dental surgery, as well as other restorative procedures (i.e., fillings, crowns, implants, dentures). Multiple cases were reported in individuals without any prior history of dental problems. Refer patients to dental care services and encourage them to have regular dental checkups while taking Buprenorphine and Naloxone Sublingual Tablets. Educate patients to seek dental care and strategies to maintain or improve oral health while being treated with transmucosal buprenorphine-containing products. Strategies include, but are not limited to, gently rinsing the teeth and gums with water and then swallowing after Buprenorphine and Naloxone Sublingual Tablets has been completely dissolved in the oral mucosa. Advise patients to wait for at least one hour after taking Buprenorphine and Naloxone Sublingual Tablets before brushing teeth [see Dosing and Administration (2.4) , Information for Patients (17) , and Medication Guide ]. 5.14 QTc Prolongation Thorough QT studies with buprenorphine products have demonstrated QT prolongation ≤15 msec. This QTc prolongation effect does not appear to be mediated by hERG channels. Based on these two findings, buprenorphine is unlikely to be pro-arrhythmic when used alone in patients without risk factors. The risk of combining buprenorphine with other QT prolonging agents is not known. Consider these observations in clinical decisions when prescribing Buprenorphine and Naloxone Sublingual Tablets to patients with risk factors such as hypokalemia, bradycardia, recent conversion from atrial fibrillation, congestive heart failure, digitalis therapy, baseline QT prolongation, subclinical long-QT syndrome, or severe hypomagnesemia. 5.15 Impairment of Ability to Drive or Operate Machinery Buprenorphine and Naloxone Sublingual Tablets 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. Caution patients about driving or operating hazardous machinery until they are reasonably certain that Buprenorphine and Naloxone Sublingual Tablets therapy does not adversely affect his or her ability to engage in such activities. 5.16 Orthostatic Hypotension Like other opioids, Buprenorphine and Naloxone Sublingual Tablets may produce orthostatic hypotension in ambulatory patients. 5.17 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. 5.18 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. 5.19 Effects in Acute Abdominal Conditions As with other opioids, buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions.