Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adverse Events in Clinical Trials
The safety of SUBUTEX sublingual tablet was supported by clinical trials using SUBUTEX sublingual tablet, SUBOXONE (buprenorphine/naloxone sublingual tablet) and other trials using buprenorphine sublingual solutions. In total, safety data were available from 3214 opioid-dependent subjects exposed to buprenorphine at doses in the range used in treatment of opioid addiction.
Few differences in adverse event profile were noted between SUBUTEX or buprenorphine administered as a sublingual solution.
The following adverse events were reported to occur by at least 5% of patients in a 4-week study (Table 1).
Table 1: Adverse Events > 5% by Body System and Treatment
Group in a 4-week study
|Body System / Adverse Event (COSTART Terminology)||N (%)
SUBUTEX 16 mg/day
|Body as a Whole|
|Asthenia||5 (4.9%)||7 (6.5%)|
|Chills||8 (7.8%)||8 (7.5%)|
|Headache||30 (29.1%)||24 (22.4%)|
|Infection||12 (11.7%)||7 (6.5%)|
|Pain||19 (18.4%)||20 (18.7%)|
|Pain Abdomen||12 (11.7%)||7 (6.5%)|
|Pain Back||8 (7.8%)||12 (11.2%)|
|Withdrawal Syndrome||19 (18.4%)||40 (37.4%)|
|Vasodilation||4 (3.9%)||7 (6.5%)|
|Constipation||8 (7.8%)||3 (2.8%)|
|Diarrhea||5 (4.9%)||16 (15.0%)|
|Nausea||14 (13.6%)||12 (11.2%)|
|Vomiting||8 (7.8%)||5 (4.7%)|
|Insomnia||22 (21.4%)||17 (15.9%)|
|Rhinitis||10 (9.7%)||14 (13.1%)|
|Skin And Appendages|
|Sweating||13 (12.6%)||11 (10.3%)|
The adverse event profile of buprenorphine was also characterized in the dose-controlled study of buprenorphine solution, over a range of doses in four months of treatment. Table 2 shows adverse events reported by at least 5% of subjects in any dose group in the dose-controlled study.
Table 2: Adverse Events ( ≥ 5%) by Body System and
Treatment Group in a 16-week Study
|Body System /Adverse Event (COSTART Terminology)||Buprenorphine Dose*|
|Very Low* (N=184)
|*Sublingual solution. Doses in this table cannot necessarily
be delivered in tablet form, but for comparison purposes:
“Very low” dose (1 mg solution) would be less than a tablet dose of 2 mg
“Low” dose (4mg solution) approximates a 6 mg tablet dose
“Moderate” dose (8mg solution) approximates a 12 mg tablet dose
“High” dose (16mg solution) approximates a 24 mg tablet dose
|Body as a Whole|
|Abscess||9 (5%)||2 (1%)||3 (2%)||2 (1%)||16 (2%)|
|Asthenia||26 (14%)||28 (16%)||26 (14%)||24 (13%)||104 (14%)|
|Chills||11 (6%)||12 (7%)||9 (5%)||10 (6%)||42 (6%)|
|Fever||7 (4%)||2 (1%)||2 (1%)||10 (6%)||21 (3%)|
|Flu Syndrome||4 (2%)||13 (7%)||19 (10%)||8 (4%)||44 (6%)|
|Headache||51 (28%)||62 (34%)||54 (29%)||53 (29%)||220 (30%)|
|Infection||32 (17%)||39 (22%)||38 (20%)||40 (22%)||149 (20%)|
|Injury Accidental||5 (3%)||10 (6%)||5 (3%)||5 (3%)||25 (3%)|
|Pain||47 (26%)||37 (21%)||49 (26%)||44 (24%)||177 (24%)|
|Pain Back||18 (10%)||29 (16%)||28 (15%)||27 (15%)||102 (14%)|
|Withdrawal Syndrome||45 (24%)||40 (22%)||41 (22%)||36 (20%)||162 (22%)|
|Constipation||10 (5%)||23 (13%)||23 (12%)||26 (14%)||82 (11%)|
|Diarrhea||19 (10%)||8 (4%)||9 (5%)||4 (2%)||40 (5%)|
|Dyspepsia||6 (3%)||10 (6%)||4 (2%)||4 (2%)||24 (3%)|
|Nausea||12 (7%)||22 (12%)||23 (12%)||18 (10%)||75 (10%)|
|Vomiting||8 (4%)||6 (3%)||10 (5%)||14 (8%)||38 (5%)|
|Anxiety||22 (12%)||24 (13%)||20 (11%)||25 (14%)||91 (12%)|
|Depression||24 (13%)||16 (9%)||25 (13%)||18 (10%)||83 (11%)|
|Dizziness||4 (2%)||9 (5%)||7 (4%)||11 (6%)||31 (4%)|
|Insomnia||42 (23%)||50 (28%)||43 (23%)||51 (28%)||186 (25%)|
|Nervousness||12 (7%)||11 (6%)||10 (5%)||13 (7%)||46 (6%)|
|Somnolence||5 (3%)||13 (7%)||9 (5%)||11 (6%)||38 (5%)|
|Cough Increase||5 (3%)||11 (6%)||6 (3%)||4 (2%)||26 (4%)|
|Pharyngitis||6 (3%)||7 (4%)||6 (3%)||9 (5%)||28 (4%)|
|Rhinitis||27 (15%)||16 (9%)||15 (8%)||21 (12%)||79 (11%)|
|Skin And Appendages|
|Sweat||23 (13%)||21 (12%)||20 (11%)||23 (13%)||87 (12%)|
|Runny Eyes||13 (7%)||9 (5%)||6 (3%)||6 (3%)||34 (5%)|
Adverse Events - Post-marketing Experience with SUBUTEX Sublingual Tablets
The most frequently reported post-marketing adverse events with SUBUTEX not observed in clinical trials, excluding drug exposure during pregnancy, was drug misuse or abuse.
Read the Subutex (buprenorphine) Side Effects Center for a complete guide to possible side effects »
Cytochrome P-450 3A4 (CYP3A4) Inhibitors and Inducers
Buprenorphine is metabolized to norbuprenorphine primarily by cytochrome CYP3A4; therefore, potential interactions may occur when SUBUTEX sublingual tablet is given concurrently with agents that affect CYP3A4 activity. The concomitant use of SUBUTEX sublingual tablet with CYP3A4 inhibitors (e.g., azole antifungals such as ketoconazole, macrolide antibiotics such as erythromycin, and HIV protease inhibitors) should be monitored and may require dose-reduction of one or both agents.
The interaction of buprenorphine with many CYP3A4 inducers has not been studied; therefore, it is recommended that patients receiving SUBUTEX sublingual tablet be monitored for signs and symptoms of opioid withdrawal if inducers of CYP3A4 (e.g., phenobarbital, carbamazepine, phenytoin, rifampicin) are co-administered. [see CLINICAL PHARMACOLOGY]
Three classes of antiretroviral agents have been evaluated for CYP3A4 interactions with buprenorphine. Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine and etravirine are known CYP3A inducers whereas delaviridine 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. It is recommended that patients who are on chronic buprenorphine treatment have their dose monitored if NNRTIs are added to their treatment regimen. 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. Monitoring of patients taking buprenorphine and atazanavir with and without ritonavir is recommended, and dose reduction of buprenorphine may be warranted.
There have been a number of post-marketing reports regarding coma and death associated with the concomitant use of buprenorphine and benzodiazepines. In many, but not all, of these cases, buprenorphine was misused by self-injection. Preclinical studies have shown that the combination of benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists. SUBUTEX sublingual tablet should be prescribed with caution to patients taking benzodiazepines or other drugs that act on the CNS, regardless of whether these drugs are taken on the advice of a physician or are being abused/misused. Patients should be warned that it is extremely dangerous to self-administer non-prescribed benzodiazepines while taking SUBUTEX sublingual tablet, and should also be cautioned to use benzodiazepines concurrently with SUBUTEX sublingual tablet only as directed by their physician.
Drug Abuse And Dependence
Buprenorphine is a Schedule III narcotic under the Controlled Substances Act.
Under the Drug Addiction Treatment Act (DATA) codified at 21 U.S.C. 823(g), prescription use of this product in the treatment of opioid dependence is limited to physicians who meet certain qualifying requirements, and who have notified the Secretary of Health and Human Services (HHS) of their intent to prescribe this product for the treatment of opioid dependence and have been assigned a unique identification number that must be included on every prescription.
Buprenorphine, like morphine and other opioids, has the potential for being abused and is subject to criminal diversion. This should be considered when prescribing or dispensing buprenorphine in situations when the clinician is concerned about an increased risk of misuse, abuse, or diversion. Healthcare professionals should contact their state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
Patients who continue to misuse, abuse, or divert, buprenorphine products or other opioids should be provided or referred for more intensive and structured treatment.
Abuse of buprenorphine poses a risk of overdose and death. This risk is increased with the abuse of buprenorphine and alcohol and other substances, especially benzodiazepines.
The physician may be able to more easily detect misuse or diversion by maintaining records of medication prescribed including date, dose, quantity, frequency of refills, and renewal requests of medication prescribed.
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper handling and storage of the medication are appropriate measures that help to limit abuse of opioid drugs.
Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by moderate 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 WARNINGS AND PRECAUTIONS]
Last reviewed on RxList: 1/10/2012
This monograph has been modified to include the generic and brand name in many instances.
Additional Subutex Information
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