Buprenorphine

2)]. Advise patients and caregivers that naloxone may also be administered for a known or suspected overdose with buprenorphine sublingual tablet itself. Higher than normal doses and repeated administration of naloxone may be necessary due to the long duration of action of buprenorphine sublingual tablet and its affinity for the mu-opioid receptor [see Overdosage (10)].

, by prescription, directly from a pharmacist, or as part of a community-based program) [see Patient Counseling Information (17)]. , long- or short-acting opioid products), the time since last opioid use, and the degree or level of opioid dependence.

Patients dependent on heroin or other short-acting opioid products:

At treatment initiation, the first dose of buprenorphine sublingual tablet should be administered only when objective and clear signs of moderate opioid withdrawal appear, and not less than 4 hours after the patient last used an opioid.

It is recommended that an adequate treatment dose, titrated to clinical effectiveness, should be achieved as rapidly as possible. The dosing on the initial day of treatment may be given in 2 mg to 4 mg increments if preferred. In some studies, gradual induction over several days led to a high rate of dropout of buprenorphine patients during the induction period.

In a one-month study, patients received 8 mg of buprenorphine sublingual tablet on Day 1 and 16 mg buprenorphine sublingual tablet on Day 2. From Day 3 onward, patients received either buprenorphine and naloxone sublingual tablet or buprenorphine sublingual tablet at the same buprenorphine dose as Day 2 based on their assigned treatment.

Induction in the studies of buprenorphine solution was accomplished over 3 to 4 days, depending on the target dose.

Patients dependent on methadone or other long-acting opioid products:

Patients dependent upon methadone or other long-acting opioid products may be more susceptible to precipitated and prolonged withdrawal during induction than those on short-acting opioid products; therefore, the first dose of buprenorphine sublingual tablet should only be administered when objective and clear signs of moderate opioid withdrawal appear, and generally not less than 24 hours after the patient last used a long-acting opioid product.

There is little controlled experience with the transfer of methadone-maintained patients to buprenorphine. Available evidence suggests that withdrawal signs and symptoms are possible during induction onto buprenorphine. Withdrawal appears more likely in patients maintained on higher doses of methadone (>30 mg) and when the first buprenorphine dose is administered shortly after the last methadone dose.

4 Maintenance Buprenorphine and naloxone sublingual tablet is preferred for maintenance treatment. Where buprenorphine sublingual tablet is used in maintenance in patients who cannot tolerate the presence of naloxone, the dosage of buprenorphine sublingual tablets should be progressively adjusted in increments/decrements of 2 mg or 4 mg buprenorphine to a level that holds the patient in treatment and suppresses opioid withdrawal signs and symptoms.

After treatment induction and stabilization, the maintenance dose of buprenorphine sublingual tablet is generally in the range of 4 mg to 24 mg buprenorphine per day depending on the individual patient. The recommended target dosage of buprenorphine sublingual tablet is 16 mg as a single daily dose.

Dosages higher than 24 mg have not been demonstrated to provide any clinical advantage. When determining the prescription quantity for unsupervised administration, consider the patient’s level of stability, the security of his or her home situation, and other factors likely to affect the ability to manage supplies of take-home medication.

There is no maximum recommended duration of maintenance treatment. Patients may require treatment indefinitely and should continue for as long as patients are benefiting and the use of buprenorphine sublingual tablet contributes to the intended treatment goals.

5 Method of Administration Buprenorphine sublingual tablet must be administered whole. Do not cut, chew, or swallow buprenorphine sublingual tablet. Advise patients not to eat or drink anything until the tablet is completely dissolved.

Buprenorphine sublingual tablet should be placed under the tongue until it is dissolved. For doses requiring the use of more than two tablets, patients are advised to either place all the tablets at once or alternatively (if they cannot fit in more than two tablets comfortably), place two tablets at a time under the tongue.

Either way, the patients should continue to hold the tablets under the tongue until they dissolve; swallowing the tablets reduces the bioavailability of the drug. To ensure consistency in bioavailability, patients should follow the same manner of dosing with continued use of the product.

Proper administration technique should be demonstrated to the patient. Advise patients to do the following after the product has completely dissolved in the oral mucosa: take a sip of water, swish gently around the teeth and gums, and swallow.

2), Information for Patients (17), and the Medication Guide] . 6 Clinical Supervision Treatment should be initiated with supervised administration, progressing to unsupervised administration as the patient’s clinical stability permits.

The use of buprenorphine sublingual tablets for unsupervised administration should be limited to those patients who cannot tolerate buprenorphine and naloxone sublingual tablet, for example those patients with known hypersensitivity to naloxone.

Buprenorphine and naloxone sublingual tablets and buprenorphine sublingual tablets are both subject to diversion and abuse. When determining the prescription quantity for unsupervised administration, consider the patient’s level of stability, the security of his or her home situation, and other factors likely to affect the ability of the patient to manage supplies of take-home medication.

, at least weekly during the first month of treatment) based upon the individual circumstances of the patient. Medication should be prescribed in consideration of the frequency of visits. Provision of multiple refills is not advised early in treatment or without appropriate patient follow-up visits.

Periodic assessment is necessary to determine compliance with the dosing regimen, effectiveness of the treatment plan, and overall patient progress. , urine drug screening) does not indicate illicit drug use, less frequent follow-up visits may be appropriate.

A once-monthly visit schedule may be reasonable for patients on a stable dosage of medication who are making progress toward their treatment objectives. Continuation or modification of pharmacotherapy should be based on the healthcare provider’s evaluation of treatment outcomes and objectives such as: 1.

Absence of medication toxicity. 2. Absence of medical or behavioral adverse effects. 3. Responsible handling of medications by the patient. 4. Patient’s compliance with all elements of the treatment plan (including recovery-oriented activities, psychotherapy, and/or other psychosocial modalities).

5. Abstinence from illicit drug use (including problematic alcohol and/or benzodiazepine use). If treatment goals are not being achieved, the healthcare provider should re-evaluate the appropriateness of continuing the current treatment.

7 Patients With Severe Hepatic Impairment Consider reducing the starting and titration incremental dose by half and monitor for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine. 8 Unstable Patients Healthcare providers will need to decide when they cannot appropriately provide further management for particular patients.

For example, some patients may be abusing or dependent on various drugs, or unresponsive to psychosocial intervention such that the healthcare provider does not feel that he/she has the expertise to manage the patient. In such cases, the healthcare provider may want to assess whether to refer the patient to a specialist or more intensive behavioral treatment environment.

Decisions should be based on a treatment plan established and agreed upon with the patient at the beginning of treatment. Patients who continue to misuse, abuse, or divert buprenorphine products or other opioids should be provided with, or referred to, more intensive and structured treatment.

9 Discontinuing Treatment The decision to discontinue therapy with buprenorphine and naloxone sublingual tablets or buprenorphine sublingual tablets after a period of maintenance should be made as part of a comprehensive treatment plan.

Advise patients of the potential to relapse to illicit drug use following discontinuation of opioid agonist/partial agonist medication-assisted treatment. 7)].

2 Postmarketing Experience The following adverse reactions have been identified during post approval use of buprenorphine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The most frequently reported postmarketing adverse events with buprenorphine not observed in clinical trials, excluding drug exposure during pregnancy, was drug misuse or abuse.

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.

Anaphylaxis :

Anaphylaxis has been reported with ingredients contained in buprenorphine. 2)].

Local reactions :

Dental decay (including caries, tooth fracture, and tooth loss), glossodynia, glossitis, oral mucosal erythema, oral hypoesthesia, and stomatitis.

Hypoglycemia:

Cases of hypoglycemia have been reported in patients taking opioids. , diabetes).

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.

2)]. 2 Risk of Life-Threatening Respiratory and Central Nervous System (CNS) Depression Buprenorphine has been associated with life-threating respiratory depression and death. Many, but not all, postmarketing reports regarding coma and death involved misuses by self-injection or were associated with the concomitant use of benzodiazepines or other CNS depressants, including alcohol.

3), Drug Interactions (7)]. , chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, or preexisting 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. 9)]. Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver.

Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with buprenorphine sublingual tablets.

2)]. Advise patients and caregivers that naloxone may also be administered for a known or suspected overdose with buprenorphine sublingual tablets itself. Higher than normal doses and repeated administration of naloxone may be necessary due to the long duration of action of buprenorphine sublingual tablets and its affinity for the mu-opioid receptor [see Overdosage (10)].

, by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and, if naloxone is prescribed, how to treat with naloxone. Emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see Patient Counseling Information (17)].

3 Managing Risks from Concomitant Use of Benzodiazepines or Other CNS Depressants Concomitant use of buprenorphine and benzodiazepines or other CNS depressants increases the risk of adverse reactions including overdose 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. 2)]. 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)]. 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 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. 1)]. 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. 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.

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.

3)]. 9)]. 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 postmarketing 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 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.

9 Hypersensitivity Reactions Cases of hypersensitivity to buprenorphine products have been reported both in clinical trials and in the postmarketing 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 sublingual tablet. 10 Precipitation of Opioid Withdrawal Signs and Symptoms Because of the partial agonist properties of buprenorphine, buprenorphine sublingual tablet 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.

11 Risk of Overdose 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 sublingual tablet is not appropriate as an analgesic.

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.

6)]. , 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.

, 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 sublingual tablet.

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 sublingual tablet has been completely dissolved in the oral mucosa.

5), Information for Patients (17), Medication Guide] . 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 sublingual tablet 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.

15 Impairment of Ability to Drive or Operate Machinery Buprenorphine 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.

Caution patients 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. 16 Orthostatic Hypotension Like other opioids, buprenorphine sublingual tablet may produce orthostatic hypotension in ambulatory patients.

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. 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.

19 Effects in Acute Abdominal Conditions As with other opioids, buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions.