warnings and cautions
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 (IV) route in combination with benzodiazepines or other CNS depressants (including alcohol). ( 5.2 ) Consider dose reduction of CNS depressants, buprenorphine hydrochloride sublingual tablets, or both in situations of concomitant prescription. ( 5.3 ) Store buprenorphine hydrochloride sublingual tablets safely out of the sight and reach of children. Buprenorphine can cause severe, possibly 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 ) Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.6 ) Monitor liver function tests prior to initiation and during treatment and evaluate suspected hepatic events. ( 5.7 ) Do not administer buprenorphine hydrochloride sublingual tablets to patients with known hypersensitivity to buprenorphine. ( 5.8 ) Buprenorphine hydrochloride sublingual tablets may precipitate opioid withdrawal signs and symptoms in individuals physically dependent on full opioid agonists if administered sublingually or parenterally before the agonist effects of other opioids have subsided. ( 5.9 ) Neonatal withdrawal has been reported following use of buprenorphine by the mother during pregnancy. ( 5.10 ) Buprenorphine hydrochloride sublingual tablets are NOT appropriate as an analgesic. There have been reported deaths of opioid naïve individuals who received a 2 mg sublingual dose of buprenorphine. ( 5.11 ) Buprenorphine hydrochloride sublingual tablets should be used with caution in patients with moderate to severe hepatic impairment and a dose adjustment is recommended for patients with severe hepatic impairment. ( 5.12 ) Caution patients about the risk of driving or operating hazardous machinery. ( 5.13 ) 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 buprenorphine hydrochloride 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. Buprenorphine hydrochloride 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 preexisting 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, buprenorphine hydrochloride sublingual tablets, or both in situations of concomitant prescription [see Drug Interactions (7.3) ]. 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 (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 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 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 preexisting 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 hydrochloride 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. 5.8 Allergic Reactions Cases of hypersensitivity to buprenorphine 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 is a contraindication to the use of buprenorphine hydrochloride sublingual tablets. 5.9 Precipitation of Opioid Withdrawal Signs and Symptoms Because of the partial agonist properties of buprenorphine, buprenorphine hydrochloride sublingual tablets may precipitate opioid withdrawal signs and symptoms in individuals physically dependent on full opioid agonists if administered sublingually or parenterally before the agonist effects of other opioids have subsided. 5.10 Neonatal Withdrawal Neonatal withdrawal 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 and symptoms ranged from Day 1 to Day 8 of life with most cases occurring on Day 1. Adverse events associated with the neonatal withdrawal syndrome included hypertonia, neonatal tremor, neonatal agitation, and myoclonus and there have been reports of convulsions, apnea, respiratory depression and bradycardia. 5.11 Use in Opioid Naïve Patients There have been reported deaths of opioid naïve individuals who received a 2 mg dose of buprenorphine as a sublingual tablet for analgesia. Buprenorphine hydrochloride sublingual tablets are not appropriate as an analgesic. 5.12 Use in Patients with Impaired Hepatic Function In a pharmacokinetic study, buprenorphine plasma levels were found to be higher and the half-life was found to be longer in subjects with moderate and severe hepatic impairment, but not in subjects with mild hepatic impairment. For patients with severe hepatic impairment, a dose adjustment is recommended, and patients with moderate or severe hepatic impairment should be monitored for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine [see Dosage and Administration (2.5) and Use in Specific Populations (8.6) ] . 5.13 Impairment of Ability to Drive or Operate Machinery Buprenorphine hydrochloride 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. Patients should be cautioned about driving or operating hazardous machinery until they are reasonably certain that buprenorphine therapy does not adversely affect his or her ability to engage in such activities. 5.14 Orthostatic Hypotension Like other opioids, buprenorphine hydrochloride sublingual tablets may produce orthostatic hypotension in ambulatory patients. 5.15 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. 5.16 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. 5.17 Effects in Acute Abdominal Conditions As with other opioids, buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions. 5.18 General Precautions Buprenorphine hydrochloride sublingual tablets 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.