Buprenorphine

May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).

Hepatitis has been reported; hepatic events ranged from transient, asymptomatic transaminase elevations to hepatic failure; in many cases, patients had preexisting hepatic impairment. Monitor liver function tests in patients at increased risk for hepatotoxicity (eg, history of alcohol abuse, preexisting hepatic dysfunction, IV drug abusers) prior to and during therapy. Remove buprenorphine subdermal implant if signs and symptoms of buprenorphine toxicity develop concurrent with hepatic impairment. If signs and symptoms of toxicity or overdose occur within 2 weeks of extended-release injection, removal of the depot may be required.

Hypersensitivity, including bronchospasm, angioneurotic edema, and anaphylactic shock, have been reported. The most common symptoms include rash, hives, and pruritus.

May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), or drugs that may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Monitor for symptoms of hypotension following initiation or dose titration. Avoid use in patients with circulatory shock.

Subdermal implant: Infection may occur at site of insertion or removal, with excessive palpation shortly after insertion and improper removal increasing the risk. Examine the insertion site 1 week following insertion for signs of infection or problems with wound healing.

Buprenorphine has been observed to cause QTc prolongation. Do not exceed a dose of 900 mcg every 12 hours buccal film or one 20 mcg/hour transdermal patch. Avoid using in patients with a personal or family history of long QT syndrome or in patients taking concurrent class IA or III antiarrhythmics or other medications that prolong the QT interval. Use with caution in patients with hypokalemia, hypomagnesemia, or clinically unstable cardiac disease, including unstable heart failure, unstable atrial fibrillation, symptomatic bradycardia, or active MI.

Buccal film, extended-release and immediate-release injection, transdermal patch: [US Boxed Warning]: Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely for respiratory depression, especially during initiation or dose escalation. Misuse or abuse by chewing, swallowing, snorting, or injecting buprenorphine extracted from the buccal film or transdermal system will result in the uncontrolled delivery of buprenorphine and pose a significant risk of overdose and death. Misuse by self-injection of buprenorphine or the concomitant use of buprenorphine and benzodiazepines (or other CNS depressants, including alcohol) may result in coma or death. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. If the extended-release injection is discontinued due to respiratory depression, monitor the patient for ongoing respiratory depression for several months due to its extended-release characteristics. Use with caution in patients with compromised respiratory function (eg, chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression). Disease-related concerns:

May obscure diagnosis or clinical course of patients with acute abdominal conditions.

Use with caution in patients with adrenal insufficiency, including Addison disease. Long-term opioid use may cause adrenal insufficiency (nausea, vomiting, anorexia, fatigue, weakness, dizziness and low blood pressure) or secondary hypogonadism, which may lead to sexual dysfunction, infertility, mood disorders, and osteoporosis (Brennan 2013).

Use with caution in patients with biliary tract dysfunction, including acute pancreatitis; opioids may cause constriction of sphincter of Oddi.

Use with caution in patients with a history of ileus or bowel obstruction; buccal film, immediate-release injection, and transdermal patch are contraindicated in patients with known or suspected GI obstruction, including paralytic ileus.

Avoid use in patients with impaired consciousness or coma because these patients are susceptible to intracranial effects of CO2 retention.

Use with caution in patients with delirium tremens.

Subdermal implant: Use subdermal implants with caution in patients with a history of keloid formation, connective tissue disease (ie, scleroderma), or history of recurrent MRSA infections.

Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure (ICP); exaggerated elevation of ICP may occur. Buprenorphine can produce miosis and changes in the level of consciousness that may interfere with patient evaluation.

Use buccal film and sublingual tablet with caution in patients with moderate hepatic impairment; dosage adjustment recommended in severe hepatic impairment. Use immediate-release injection with caution in patients with severe impairment. Subdermal implants should not be used in patients with preexisting moderate to severe hepatic impairment. Transdermal patch should not be used in patients with severe hepatic impairment; consider alternative therapy with more flexibility for dosing adjustments. Patients with preexisting moderate or severe hepatic impairment are not candidates for the extended-release injection. If moderate or severe impairment develops during treatment with the extended-release injection, continue with caution and monitor for toxicity for several months.

Use with caution in patients who are morbidly obese.

Buccal film: Oral mucositis may lead to more rapid absorption and higher buprenorphine plasma levels; reduce dose in patients with oral mucositis and monitor closely for signs and symptoms of toxicity or overdose.

Use with caution in patients with prostatic hyperplasia and/or urinary stricture.

Use with caution in patients with toxic psychosis.

Use with caution in patients with renal impairment.

Use with caution and monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression, particularly when initiating and titrating therapy; critical respiratory depression may occur, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.

Use with caution in patients with a history of seizure disorders; may cause or exacerbate preexisting seizures.

Use opioids with caution for chronic pain and titrate dosage cautiously in patients with risk factors for sleep-disordered breathing, including HF and obesity. Avoid opioids in patients with moderate to severe sleep-disordered breathing (Dowell [CDC 2016]).

Use with caution in patients with thyroid dysfunction. Concurrent drug therapy issues:

Buccal film, extended-release and immediate-release injection, transdermal patch: Concomitant use of benzodiazepines or other CNS depressants, including alcohol and opioids, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of opioids and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation. Prohibiting medication-assisted treatment of opioid use disorder may increase the risk of morbidity and mortality, therefore patients should be educated on the risks of concomitant use with benzodiazepines, sedatives, opioid analgesics, and alcohol. Strategies should be developed to manage use of prescribed or illicit benzodiazepines or other CNS depressants at initiation of or during treatment with buprenorphine; adjustments to induction procedures and additional monitoring may be required. If appropriate, delay or omit buprenorphine dose if a patient is sedated at time of buprenorphine dosing. Discontinuation of benzodiazepines or other CNS depressants is preferred; gradual tapering of benzodiazepine or other CNS depressant, decreasing to lowest effective dose, or monitoring in a higher level of care for taper may be appropriate. Benzodiazepines are not the treatment of choice for anxiety or insomnia for patients in buprenorphine treatment;

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

Use with caution in cachectic or debilitated patients; there is a greater potential for life-threatening respiratory depression, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.

Use with caution in elderly patients; may be more sensitive to adverse effects (eg, life-threatening respiratory depression). In chronic pain, monitor opioid use closely in this age group due to an increased potential for risks, including certain risks such as falls/fracture, cognitive impairment, and constipation (Dowell [CDC 2016]). Consider the use of alternative nonopioid analgesics in these patients.

Neonatal withdrawal syndrome: Buccal film, extended-release and immediate-release injection, transdermal patch: [US Boxed Warning]: Prolonged use of opioids during pregnancy can cause neonatal withdrawal syndrome, which may be life-threatening if not recognized and treated according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal withdrawal syndrome and ensure that appropriate treatment will be available. Signs and symptoms include irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity depend on the drug used, duration of use, maternal dose, and rate of drug elimination by the newborn. Dosage form specific issues:

Serious harm or death could result if extended-release injection is administered IV. The injection forms a solid mass upon contact with body fluids and may cause occlusion, local tissue damage, and thromboembolic events, including life-threatening pulmonary emboli if administered IV. Because of the risk of serious harm or death that could result from IV self-administration, buprenorphine extended-release injection is only available through a restricted program called the Sublocade REMS Program. Health care settings and pharmacies that order and dispense buprenorphine extended-release injection must be certified in this program and comply with the REMS requirements. Administer via subcutaneous route only. Do not administer IM or IV.

Insertion and removal of implant are associated with the risk of implant migration, protrusion, and expulsion. Rare but serious complications including nerve damage and migration resulting in embolism and death may result from improper insertion in the upper arm. Additional complications may include local migration, protrusion, and expulsion. Incomplete insertions or infections may lead to protrusion or expulsion. Because of the risks associated with insertion and removal, buprenorphine implant is available only through a restricted program. All health care providers must successfully complete a live training program on the insertion and removal procedures and become certified, prior to performing insertions or prescribing buprenorphine implants. Patients must be monitored to ensure that the implant is removed by a health care provider certified to perform insertions.

To properly dispose of transdermal patch, fold it over on itself and flush down the toilet; alternatively, seal the used patch in the provided Patch-Disposal Unit and dispose of in the trash. Avoid exposure of application site and surrounding area to direct external heat sources (eg, heating pads, electric blankets, heat or tanning lamps, hot baths/saunas, hot water bottles, direct sunlight). Buprenorphine release from the patch is temperature-dependent and may result in overdose. Patients who experience fever or increase in core temperature should be monitored closely and adjust dose if signs of respiratory depression or CNS depression occur. Application-site reactions, including rare cases of severe reactions (eg, vesicles, discharge, "burns"), have been observed with use; onset varies from days to months after initiation; patients should be instructed to report severe reactions promptly and discontinue therapy. Special handling:

Extended-release injection and subdermal implant: Handle the removed depots or implants with adequate security, accountability, and proper disposal, per facility procedure for a Schedule III drug product, and per applicable federal, state, and local regulations. Other warnings/precautions:

Buccal film, extended-release and immediate-release injection, transdermal patch: [US Boxed Warning]: Use exposes patients and other users to the risks of addiction, abuse, and misuse, potentially leading to overdose and death. Assess each patient's risk prior to prescribing; monitor all patients regularly for development of these behaviors or conditions. Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Other factors associated with an increased risk for misuse include younger age and psychotropic medication use. Consider offering naloxone prescriptions in patients with factors associated with an increased risk for overdose, such as history of overdose or substance use disorder, higher opioid dosages (≥50 morphine milligram equivalents/day orally), and concomitant benzodiazepine use (Dowell [CDC 2016]). The misuse of buccal film by swallowing or of transdermal patch by placing it in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking, overdose, and death.

Buccal film, transdermal patch: [US Boxed Warning]: Accidental ingestion of even one dose, especially in children, can result in a fatal overdose of buprenorphine.

When using buprenorphine for treatment of opioid dependence, treat acute pain with nonopioid analgesics whenever possible. If treatment with a high-affinity full opioid analgesic is required, monitor closely for respiratory depression because high doses may be necessary to achieve pain relief.

Buccal film, transdermal patch: Indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment; should not be used for as-needed pain relief. Therapy with the buccal film or transdermal patch is not appropriate for use in the management of addictions. When used for chronic pain (outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-assisted treatment for opioid use disorder) in outpatient setting in adults, opioids should not be used as first-line therapy for chronic pain management (pain >3-month duration or beyond time of normal tissue healing) due to limited short-term benefits, undetermined long-term benefits, and association with serious risks (eg, overdose, MI, auto accidents, risk of developing opioid use disorder). Preferred management includes nonpharmacologic therapy and nonopioid therapy (eg, NSAIDs, acetaminophen, certain anticonvulsants and antidepressants). If opioid therapy is initiated, it should be combined with nonpharmacologic and nonopioid therapy, as appropriate. Prior to initiation, known risks of opioid therapy should be discussed and realistic treatment goals for pain/function should be established, including consideration for discontinuation if benefits do not outweigh risks. Therapy should be continued only if clinically meaningful improvement in pain/function outweighs risks. Therapy should be initiated at the lowest effective dosage using immediate-r

Subdermal implant: Not appropriate for patients who are new to treatment or have not sustained prolonged clinical stability on buprenorphine ≤8 mg/day.

Extended-release injection and sublingual tablet: There is no maximum recommended duration for maintenance treatment of opioid addiction; patients may require treatment indefinitely. Advise patients of the potential to relapse to illicit drug use following discontinuation of opioid agonist/partial agonist medication-assisted treatment. If the extended-release injection is discontinued or the depot is removed, monitor the patient for several months for signs and symptoms of withdrawal. After steady-state has been achieved (4 to 6 months), patients discontinuing extended-release injections may have detectable plasma levels of buprenorphine for 12 months or longer.

An opioid-containing analgesic regimen should be tailored to each patient's needs and based upon the type of pain being treated (acute versus chronic), the route of administration, degree of tolerance for opioids (naive versus chronic user), age, weight, and medical condition. The optimal analgesic dose varies widely among patients; doses should be titrated to pain relief/prevention. When switching patients from buprenorphine to naltrexone, do not initiate naltrexone until 7 to 14 days after buprenorphine discontinuation. No time delay is required when switching patients from buprenorphine to methadone (Kampman [ASAM 2015]).

Reversal of partial opioid agonists or mixed opioid agonist/antagonists (eg, buprenorphine, pentazocine) may be incomplete and large doses of naloxone may be required.

In patients undergoing elective surgery (excluding caesarean section), discontinuation of buprenorphine 24 to 36 hours before anticipated need for surgical anesthesia may be considered. Short-acting opioids may be given during and/or after surgery. In patients unable to abruptly discontinue buprenorphine prior to surgery, full opioid agonists may be added to the buprenorphine to maintain proper anesthesia; however, increased doses may be required to overcome buprenorphine receptor blockade. If opioid therapy is required as part of anesthesia, patients should be continuously monitored in an anesthesia care setting by persons not involved in in the conduct of the surgical or diagnostic procedure. This guidance applies to anyone who has been treated with extended release buprenorphine injection within the past 6 months. The decision whether to discontinue buprenorphine prior to elective surgery should be made in consultation with the surgeon and anesthesiologist (Kampman [ASAM 2015]).

Concurrent use of opioid agonist/antagonist analgesics may precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists. Abrupt discontinuation following prolonged use may also lead to withdrawal symptoms and is not recommended; taper dose gradually when discontinuing. Withdrawal signs and symptoms will be delayed in patients who discontinue the extended-release injection or have it removed; transmucosal buprenorphine may be needed to treat withdrawal in these patients. Tablets, which are used for induction treatment of opioid dependence, should not be started until objective and clear signs of moderate withdrawal are evident. If subdermal implants are not immediately replaced in contralateral arm after removal, maintain patients on their previous dosage of sublingual buprenorphine.