Buprenorphine And Naloxone
(Buprenorphine Hydrochloride And Naloxone Hydrochloride)Buprenorphine And Naloxone Prescribing Information
Dosage and Administration (Buprenorphine and naloxone sublingual tablets are administered sublingually as a single daily dose. Buprenorphine and naloxone sublingual tablets should be used in patients who have been initially inducted using buprenorphine sublingual tablets. 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. | 05/2023 |
Buprenorphine and naloxone sublingual tablets are indicated for the maintenance treatment of opioid dependence. Buprenorphine and naloxone sublingual tablets should be used as part of a complete treatment plan that includes counseling and psychosocial support.
- Administer buprenorphine and naloxone sublingual tablets sublingually as a single daily dose. ()
2.1 Important Dosage and Administration InformationBuprenorphine and naloxone sublingual tablets are administered sublingually as a single daily dose. Buprenorphine and naloxone sublingual tablets should be used in patients who have been initially inducted using buprenorphine sublingual tablets.
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.
- Strongly consider prescribing naloxone at the time buprenorphine and naloxone sublingual tablets is initiated or renewed because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose ().
2.2 Patient Access to Naloxone for the Emergency Treatment of Opioid OverdoseDiscuss 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 and naloxone sublingual tablets.
Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose[see Warnings and Precautions ]Advise patients and caregivers that naloxone 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 naloxone 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 ].Inform patients and caregivers of their options for obtaining naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program)
[see Patient Counseling Information ]. - To avoid precipitating withdrawal, induction with buprenorphine sublingual tablets should be undertaken when objective and clear signs of withdrawal are evident. After induction, doses of buprenorphine and naloxone sublingual tablets should be progressively adjusted to a level that holds the patient in treatment and suppresses opioid withdrawal signs and symptoms ().
2.3 Maintenance- The dosage of buprenorphine and naloxone sublingual tablets should be progressively adjusted in increments/decrements of 2 mg/0.5 mg or 4 mg/1 mg buprenorphine/naloxone to a level that holds the patient in treatment and suppresses opioid withdrawal signs and symptoms.
- The maintenance dose of buprenorphine and naloxone sublingual tablets are generally in the range of 4 mg/1 mg buprenorphine/naloxone to 24 mg/6 mg buprenorphine/naloxone per day depending on the individual patient. The recommended target dosage of buprenorphine and naloxone sublingual tablets is 16 mg/4 mg buprenorphine/naloxone/day as a single daily dose. Dosages higher than 24 mg/6 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 and naloxone sublingual tablets contributes to the intended treatment goals.
- The recommended target dosage of buprenorphine and naloxone sublingual tablets for maintenance is 16 mg/4 mg ().
2.3 Maintenance- The dosage of buprenorphine and naloxone sublingual tablets should be progressively adjusted in increments/decrements of 2 mg/0.5 mg or 4 mg/1 mg buprenorphine/naloxone to a level that holds the patient in treatment and suppresses opioid withdrawal signs and symptoms.
- The maintenance dose of buprenorphine and naloxone sublingual tablets are generally in the range of 4 mg/1 mg buprenorphine/naloxone to 24 mg/6 mg buprenorphine/naloxone per day depending on the individual patient. The recommended target dosage of buprenorphine and naloxone sublingual tablets is 16 mg/4 mg buprenorphine/naloxone/day as a single daily dose. Dosages higher than 24 mg/6 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 and naloxone sublingual tablets contributes to the intended treatment goals.
- Administer buprenorphine and naloxone sublingual tablets as directed in the Full Prescribing Information. (,
2.3 Maintenance- The dosage of buprenorphine and naloxone sublingual tablets should be progressively adjusted in increments/decrements of 2 mg/0.5 mg or 4 mg/1 mg buprenorphine/naloxone to a level that holds the patient in treatment and suppresses opioid withdrawal signs and symptoms.
- The maintenance dose of buprenorphine and naloxone sublingual tablets are generally in the range of 4 mg/1 mg buprenorphine/naloxone to 24 mg/6 mg buprenorphine/naloxone per day depending on the individual patient. The recommended target dosage of buprenorphine and naloxone sublingual tablets is 16 mg/4 mg buprenorphine/naloxone/day as a single daily dose. Dosages higher than 24 mg/6 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 and naloxone sublingual tablets contributes to the intended treatment goals.
)2.4 Method of AdministrationBuprenorphine and naloxone sublingual tablets must be administered whole. Do not cut, chew, or swallow buprenorphine and naloxone sublingual tablets. Advise patients not to eat or drink anything until the tablet is completely dissolved.
Buprenorphine and naloxone sublingual tablets should be placed under the tongue until they are 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. Advise patients to wait for at least one hour after taking buprenorphine and naloxone sublingual tablets before brushing teeth
[see Warnings and Precautions , Postmarketing Experience , Information for Patients , and the Medication Guide]. - When discontinuing treatment, gradually taper to avoid signs and symptoms of withdrawal. ()
2.7 Discontinuing TreatmentThe decision to discontinue therapy with buprenorphine and naloxone 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. Taper patients to reduce the occurrence of withdrawal signs and symptoms
[See Warnings and Precautions ].
Buprenorphine and naloxone sublingual tablets are supplied as an uncoated, round, white, biconvex tablet in two dosage strengths:
- buprenorphine 2 mg/naloxone 0.5 mg, and
- buprenorphine 8 mg/naloxone 2 mg
Buprenorphine and naloxone sublingual tablets are contraindicated in patients with a history of hypersensitivity to buprenorphine or naloxone as serious adverse reactions, including anaphylactic shock, have been reported
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.
- Addiction, Abuse, and Misuse[see Warnings and Precautions ()]
5.1 Addiction, Abuse, and MisuseBuprenorphine 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 ]. - Respiratory and CNS Depression[see Warnings and Precautions (,
5.2 Risk of Life-Threatening Respiratory and Central Nervous System (CNS) DepressionBuprenorphine 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 depressant, 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 , Drug Interactions].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 ].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 ].Patient Access to Naloxone for the Emergency Treatment of Opioid OverdoseDiscuss 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 and naloxone sublingual tablets.
Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose
[see Dosage and Administration ].Advise patients and caregivers that naloxone 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 naloxone 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 ].Inform patients and caregivers of their options for obtaining naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., 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 ].)]5.3 Managing Risks from Concomitant Use of Benzodiazepines or Other CNS DepressantsConcomitant 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.
If concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in buprenorphine treatment for opioid use disorder
[see Warnings and Precautions ]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 ]. - Neonatal Opioid Withdrawal Syndrome[see Warnings and Precautions ()]
5.5 Neonatal Opioid Withdrawal SyndromeNeonatal 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 ].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 ]. 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. - Adrenal Insufficiency[see Warnings and Precautions ()]
5.6 Adrenal InsufficiencyCases 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.
- Opioid Withdrawal[see Warnings and Precautions (,
5.7 Risk of Opioid Withdrawal with Abrupt DiscontinuationBuprenorphine 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 ].When discontinuing buprenorphine and naloxone sublingual tablet, gradually taper the dosage[see Dosage and Administration ].)]5.10 Precipitation of Opioid Withdrawal Signs and SymptomsBecause 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.
- Hepatitis, Hepatic Events[see Warnings and Precautions ()]
5.8 Risk of Hepatitis, Hepatic EventsCases 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.
- Hypersensitivity Reactions[see Warnings and Precautions ()]
5.9 Hypersensitivity ReactionsCases 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.
- Orthostatic Hypotension[see Warnings and Precautions ()]
5.16 Orthostatic HypotensionLike other opioids, buprenorphine and naloxone sublingual tablets may produce orthostatic hypotension in ambulatory patients.
- Elevation of Cerebrospinal Fluid Pressure[see Warnings and Precautions ()]
5.17 Elevation of Cerebrospinal Fluid PressureBuprenorphine, 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.
- Elevation of Intracholedochal Pressure[see Warnings and Precautions ()]
5.18 Elevation of Intracholedochal PressureBuprenorphine 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.