Buprenorphine Other names: Buprenorphine hydrochloride

Possible exacerbation of the opioids effects, based on experience with morphine.

Buprenorphine is also metabolised to buprenorphine-3-glucuronide by UGT1A1. UGT1A1 inhibitors may affect the systemic exposure of buprenorphine.

This combination may result in death due to respiratory depression. Therefore, dosages must be closely monitored and this combination must be avoided in cases where there is a risk of misuse. Patients should be cautioned to use gabapentinoids (such as pregabalin and gabapentin) concurrently with this product only as directed by their physician.

The concomitant use of opioid analgesics, including buprenorphine, and anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention or reduced gastric motility when BUTRANS is used concomitantly with anticholinergic drugs.

Buprenorphine is metabolised to norbuprenorphine primarily by CYP3A4. The effects on buprenorphine exposure in patients treated with buprenorphine have not been studied. Interaction with co-administered inducers or inhibitors have been established in studies using transmucosal and transdermal buprenorphine. Buprenorphine is also metabolised to buprenorphine-3-glucuronide by UGT1A1.

CYP3A4 inducers may induce the metabolism of buprenorphine resulting in decreased buprenorphine levels. Buprenorphine avoids first-pass effects and CYP3A4 inducers (e.g. phenobarbital, carbamazepine, phenytoin or rifampicin) are expected to have less effects on buprenorphine metabolism when co-administered with buprenorphine as compared to when co-administered with sublingual buprenorphine. When switching from sublingual buprenorphine to buprenorphine, patients may need to be monitored to ensure plasma buprenorphine levels are adequate. Patients already on buprenorphine who start treatment with CYP3A4 inducers should be treated with weekly buprenorphine and be monitored for signs and symptoms of withdrawal. Conversely, if a patient who is concomitantly treated with buprenorphine and a CYP3A4 inducer stops treatment with the CYP3A4 inducer, the patient should be monitored for symptoms of overtreatment.

Buprenorphine is metabolised to norbuprenorphine primarily by CYP3A4. The effects on buprenorphine exposure in patients treated with buprenorphine have not been studied. Interaction with co-administered inducers or inhibitors have been established in studies using transmucosal and transdermal buprenorphine. Buprenorphine is also metabolised to buprenorphine-3-glucuronide by UGT1A1.

CYP3A4 inhibitors may inhibit the metabolism of buprenorphine resulting in increased C_max and AUC of buprenorphine and norbuprenorphine. Buprenorphine avoids first-pass effects and CYP3A4 inhibitors (e.g. protease inhibitors like ritonavir, nelfinavir or indinavir, or azole antifungals such as ketoconazole or itraconazole, or macrolide antibiotics) are expected to have less effects on buprenorphine metabolism when co-administered with buprenorphine as compared to when co-administered with sublingual buprenorphine. When switching from sublingual buprenorphine to buprenorphine, patients may need to be monitored to ensure plasma buprenorphine levels are adequate. Patients already on buprenorphine who start treatment with CYP3A4 inhibitors should be treated with weekly buprenorphine and be monitored for signs and symptoms of overtreatment. Conversely, if a patient who is concomitantly treated with buprenorphine and a CYP3A4 inhibitor stops treatment with the CYP3A4 inhibitor, the patient should be monitored for symptoms of withdrawal.

Alcohol increases the sedative effect of buprenorphine.

Caution is recommended when dosing patients with severe renal impairment (creatinine clearance <30 ml/min).

Buprenorphine should be used with caution in patients with moderate hepatic impairment.

Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

Adequate analgesia may be difficult to achieve when administering a full opioid agonist in patients receiving buprenorphine. The potential for overdose also exists with a full agonist, especially when attempting to overcome buprenorphine partial agonist effects, or when buprenorphine plasma levels are declining.

Other opioid derivatives (e.g. methadone, analgesics and antitussives); certain antidepressants, sedative H₁-receptor antagonists, barbiturates, anxiolytics other than benzodiazepines, antipsychotics, clonidine and related substances. These combinations increase central nervous system depression. The reduced level of alertness can make driving and using machinery hazardous.

This combination may result in death due to respiratory depression of central origin. Therefore, dosages must be closely monitored and this combination must be avoided in cases where there is a risk of misuse. Patients should be warned that it is extremely dangerous to self-administer non-prescribed benzodiazepines whilst taking this product, and should also be cautioned to use benzodiazepines concurrently with this product only as directed by their physician.

These are opioid antagonists that can block the pharmacological effects of buprenorphine. For opioid-dependent patients currently receiving buprenorphine treatment, naltrexone may precipitate a sudden onset of prolonged and intense opioid withdrawal symptoms. For patients currently receiving naltrexone treatment, the intended therapeutic effects of buprenorphine administration may be blocked by naltrexone.

Caution should be exercised when co-administering buprenorphine with other medicinal products that prolong the QT interval and in patients with a history of long QT syndrome or other risk factors for QT prolongation.

Buprenorphine is a partial agonist at the mu-opiate receptor and chronic administration can produce opioid dependence.

A number of cases of death due to respiratory depression have been reported for patients being treated with buprenorphine, particularly when used in combination with benzodiazepines or when buprenorphine was not used according to prescribing information. Deaths have also been reported in association with concomitant administration of buprenorphine and other depressants such as alcohol, gabapentinoids (such as pregabalin and gabapentin) or other opioids. Buprenorphine should be used with care in patients with respiratory insufficiency (e.g. chronic obstructive pulmonary disease, asthma, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, pre-existing respiratory depression or kyphoscoliosis).

Buprenorphine may cause severe, possibly fatal, respiratory depression in children and non-opioid dependent persons who accidentally or deliberately use it.

There are no or limited data from the use of buprenorphine in pregnant women. Animal studies do not indicate reproductive toxicity. Buprenorphine should be used during pregnancy only if the potential benefit outweighs the potential risk to the foetus.

Towards the end of pregnancy, buprenorphine may induce respiratory depression in the newborn infant even after a short period of administration. Long-term administration during the last three months of pregnancy may cause a withdrawal syndrome in the neonate (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus or convulsions). The syndrome is generally delayed from several hours to several days after birth.

Due to the long half-life of buprenorphine, neonatal monitoring for several days after birth should be considered to prevent the risk of respiratory depression or withdrawal syndrome in neonates.

Due to the inflexibility with regard to dose increases and to the increased dose requirements during pregnancy, Sixmo is not considered to be an optimal treatment choice for pregnant women, therefore treatment with Sixmo should not be started in pregnant women. Sixmo is not recommended during pregnancy and in women of childbearing potential not using contraception. If pregnancy occurs during treatment with Sixmo the benefit to the patient should be weighed against the risk to the foetus. Generally, other buprenorphine treatments/formulations are considered more appropriate in this situation.

Buprenorphine and its metabolites are excreted in human breast milk. In rats, buprenorphine has the potential to inhibit lactation or milk production. Therefore buprenorphine should be used with caution during breast-feeding.

Fertility

There are no or limited data on effects of buprenorphine on human fertility. An effect of buprenorphine on fertility in animals has not been seen.

Buprenorphine can influence the ability to drive and use machines and may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery. This product may cause dizziness, somnolence or sedation especially at the start of treatment.

Plasma concentrations of buprenorphine after insertion of buprenorphine are highest during the first 24 to 48 hours. In particular, patients may experience somnolence for up to one week after subcutaneous insertion; therefore, they should be cautioned about driving or operating hazardous machinery especially during this time period. Before engaging driving or operating hazardous machinery patients should be reasonably certain that buprenorphine does not adversely affect their ability to engage in such activities.