Buprenorphine (Page 5 of 11)

6.2 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 post-marketing 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 sublingual tablets.

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)].

Local reactions: Glossodynia, glossitis, oral mucosal erythema, oral hypoesthesia, and stomatitis.

7 DRUG INTERACTIONS

Table 3 includes clinically significant drug interactions with buprenorphine sublingual tablets.

Table 3: Clinically Significant Drug Interactions

Benzodiazepines or other Central Nervous System (CNS) Depressants

Clinical Impact:

Due to additive pharmacologic effects, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.

Intervention:

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 CNS depressant or decreasing to the lowest effective dose may be appropriate.

Before co-prescribing benzodiazepines for anxiety or insomnia, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments [see Warnings and Precautions (5.2, 5.3)].

If concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in treatment for opioid use disorder [see Warnings and Precautions (5.2)].

Examples:

Alcohol, benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids.

Inhibitors of CYP3A4

Clinical Impact:

The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of buprenorphine sublingual tablets is achieved.

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease [see Clinical Pharmacology (12.3)] , potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine.

Intervention:

If concomitant use is necessary, consider dosage reduction of buprenorphine sublingual tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.

If a CYP3A4 inhibitor is discontinued, consider increasing the buprenorphine sublingual tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.

Examples:

Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)

CYP3A4 Inducers

Clinical Impact:

The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine [see Clinical Pharmacology (12.3)] , potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine.

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase [see Clinical Pharmacology (12.3)] , which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression.

Intervention:

If concomitant use is necessary, consider increasing the buprenorphine sublingual tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.

If a CYP3A4 inducer is discontinued, consider buprenorphine sublingual tablets dosage reduction and monitor for signs of respiratory depression.

Examples:

Rifampin, carbamazepine, phenytoin

Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Clinical Impact:

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delavirdine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects.

Intervention:

Patients who are on chronic buprenorphine sublingual tablets treatment should have their dose monitored if NNRTIs are added to their treatment regimen.

Examples:

efavirenz, nevirapine, etravirine, delavirdine

Antiretrovirals: Protease inhibitors (PIs)

Clinical Impact:

Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in post-marketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly.

Intervention:

Monitor patients taking buprenorphine sublingual tablets and atazanavir with and without ritonavir, and reduce dose of buprenorphine sublingual tablets if warranted.

Examples:

atazanavir, ritonavir

Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs)

Clinical Impact:

Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected.

Intervention:

None

Serotonergic Drugs

Clinical Impact:

The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.

Intervention:

If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue buprenorphine sublingual tablets if serotonin syndrome is suspected.

Examples:

Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Monoamine Oxidase Inhibitors (MAOIs)

Clinical Impact:

MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).

Intervention:

The use of buprenorphine sublingual tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.

Examples:

phenelzine, tranylcypromine, linezolid

Muscle Relaxants

Clinical Impact:

Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

Intervention:

Monitor patients receiving muscle relaxants and buprenorphine sublingual tablets for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of buprenorphine sublingual tablets and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, strongly consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.3), Warnings and Precautions (5.2, 5.3)].

Diuretics

Clinical Impact:

Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.

Intervention:

Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

Anticholinergic Drugs

Clinical Impact:

The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Intervention:

Monitor patients for signs of urinary retention or reduced gastric motility when buprenorphine sublingual tablets are used concomitantly with anticholinergic drugs.

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