Buprenorphine Hydrochloride

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF BUPRENORPHINE HYDROCHLORIDE INJECTION Addiction, Abuse, and Misuse Because the use of buprenorphine hydrochloride injection exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient's risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see WARNINGS] . Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of buprenorphine hydrochloride injection, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of buprenorphine hydrochloride injection are essential [see WARNINGS]. Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of buprenorphine hydrochloride injection and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see WARNINGS, PRECAUTIONS] . Neonatal Opioid Withdrawal Syndrome (NOWS) If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see WARNINGS] .

WARNINGS Addiction, Abuse, and Misuse Buprenorphine hydrochloride injection contains buprenorphine, a Schedule III controlled substance. As an opioid, buprenorphine hydrochloride injection exposes users to the risks of addiction, abuse, and misuse. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed buprenorphine hydrochloride injection. Addiction can occur at recommended doses and if the drug is misused or abused. Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing buprenorphine hydrochloride injection, and reassess all patients receiving buprenorphine hydrochloride injection for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of buprenorphine hydrochloride injection for the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as buprenorphine hydrochloride injection but use in such patients necessitates intensive counseling about the risks and proper use of buprenorphine hydrochloride injection along with frequent reevaluation for signs of addiction, abuse, and misuse. Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing buprenorphine hydrochloride injection. Strategies to reduce these risks include proper product storage and control practices for a C-III drug. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory depression and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of buprenorphine hydrochloride injection, the risk is greatest during the initiation of therapy or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of buprenorphine hydrochloride injection are essential. Overestimating the buprenorphine hydrochloride injection dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. 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] . Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of buprenorphine hydrochloride injection with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions]. If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Monitor patients closely for signs and symptoms of respiratory depression and sedation. Neonatal Opioid Withdrawal Syndrome Use of buprenorphine hydrochloride injection for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that management by neonatology experts will be available at delivery [see WARNINGS, PRECAUTIONS: Information for Patients, Pregnancy]. Opioid-Induced Hyperalgesia and Allodynia Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [ see DEPENDENCE ]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see DOSAGE and ADMINISTRATION, WARNINGS] . Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of buprenorphine hydrochloride injection in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease : Buprenorphine hydrochloride injection -treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive, including apnea, even at recommended dosages of buprenorphine hydrochloride injection [see WARNINGS]. Elderly, Cachectic, or Debilitated Patients : Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Monitor such patients closely, particularly when initiating and titrating buprenorphine hydrochloride injection and when buprenorphine hydrochloride injection is given concomitantly with other drugs that depress respiration [see WARNINGS]. Alternatively, consider the use of non-opioid analgesics in these patients. 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. Severe Hypotension Buprenorphine hydrochloride injection may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume, or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dosage of buprenorphine hydrochloride injection. In patients with circulatory shock, buprenorphine hydrochloride injection may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of buprenorphine hydrochloride injection in patients with circulatory shock. Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), buprenorphine hydrochloride injection may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with buprenorphine hydrochloride injection. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of buprenorphine hydrochloride injection in patients with impaired consciousness or coma. 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 hydrochloride injection 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. Anaphylactic/Allergic Reactions Cases of acute and chronic hypersensitivity to buprenorphine have been reported both in clinical trials and in post-marketing experience. The most common signs and symptoms include rashes, hives, and pruritus. Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. Buprenorphine hydrochloride injection is contraindicated in patients with a history of hypersensitivity to buprenorphine. Risks of Use in Patients with Gastrointestinal Conditions Buprenorphine hydrochloride injection is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The buprenorphine in buprenorphine hydrochloride injection may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Increased Risk of Seizures in Patients with Seizure Disorders The buprenorphine in buprenorphine hydrochloride injection may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during buprenorphine hydrochloride injection therapy. Risks Driving and Operating Machinery Buprenorphine hydrochloride injection may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of buprenorphine hydrochloride injection and know how they will react to the medication [see PRECAUTIONS: Information for Patients].

ADVERSE REACTIONS The most frequent side effect in clinical studies involving 1,133 patients was sedation which occurred in approximately two-thirds of the patients. Although sedated, these patients could easily be aroused to an alert state. Other less frequent adverse reactions occurring in 5-10% of the patients were: Nausea Dizziness/Vertigo Occurring in 1-5% of the patients: Sweating Headache Hypotension Nausea/Vomiting Vomiting Hypoventilation Miosis The following adverse reactions were reported to have occurred in less than 1% of the patients: CNS Effect: confusion, blurred vision, euphoria, weakness/fatigue, dry mouth, nervousness, depression, slurred speech, paresthesia. Cardiovascular: hypertension, tachycardia, bradycardia. Gastrointestinal: constipation. Respiratory: dyspnea, cyanosis. Dermatological: pruritus. Ophthalmological: diplopia, visual abnormalities. Miscellaneous: injection site reaction, urinary retention, dreaming, flushing/warmth, chills/cold, tinnitus, conjunctivitis, Wenckebach block, and psychosis. Other effects observed infrequently include malaise, hallucinations, depersonalization, coma, dyspepsia, flatulence, apnea, rash, amblyopia, tremor, and pallor. The following reactions have been reported to occur rarely: loss of appetite, dysphoria/agitation, diarrhea, urticaria, and convulsions/lack of muscle coordination. Allergic Reactions: Cases of acute and chronic hypersensitivity to buprenorphine have been reported both in clinical trials and in the postmarketing experience of buprenorphine hydrochloride injection and other buprenorphine- containing products. The most common signs and symptoms include rashes, hives, and pruritus. Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. A history of hypersensitivity to buprenorphine is a contraindication to buprenorphine hydrochloride injection. In the United Kingdom, buprenorphine hydrochloride was made available under monitored release regulation during the first year of sale, and yielded data from 1,736 physicians on 9,123 patients (17,120 administrations). Data on 240 children under the age of 18 years were included in this monitored release program. No important new adverse effects attributable to buprenorphine hydrochloride were observed. To report SUSPECTED ADVERSE REACTIONS, contact Somerset Therapeutics, LLC at 1-800-417-9175 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . Postmarketing Experience 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. Androgen deficiency : Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see CLINICAL PHARMACOLOGY: Pharmacodynamics]. Hyperalgesia and Allodynia : Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see WARNINGS] . 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).