- Generic Name: buprenorphine
- Brand Name: Subutex
SUBUTEX (buprenorphine) sublingual tablet is an uncoated oval white flat bevelled edged tablet, debossed with an alphanumeric word identifying the product and strength on one side. It contains buprenorphine HCl, a partial agonist at the mu-opioid receptor, and is available in two dosage strengths, 2 mg buprenorphine and 8 mg buprenorphine (as the free base, equivalent to 2.16 mg buprenorphine hydrochloride USP and 8.64 mg buprenorphine hydrochloride USP). Each tablet also contains lactose, mannitol, cornstarch, povidone K30, citric acid, sodium citrate and magnesium stearate.
Chemically, buprenorphine HCl is (2S)-2-[17-Cyclopropylmethyl-4,5α-epoxy-3-hydroxy-6-methoxy6α,14-ethano-14α-morphinan-7α-yl]-3,3-dimethylbutan-2-ol hydrochloride. It has the following chemical structure:
Buprenorphine HCl has the molecular formula C29 H41 NO4 • HCl and the molecular weight is 504.10. It is a white or off-white crystalline powder, sparingly soluble in water, freely soluble in methanol, soluble in alcohol and practically insoluble in cyclohexane.
DOSAGE AND ADMINISTRATION
Drug Addiction Treatment 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 healthcare providers 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.
Important Dosage And Administration Instructions
SUBUTEX is administered sublingually as a single daily dose.
SUBUTEX does not contain naloxone and is preferred for use only during induction. Following induction, SUBOXONE sublingual film or SUBOXONE sublingual tablet is preferred due to the presence of naloxone when clinical use includes unsupervised administration. The use of SUBUTEX for unsupervised administration should be limited to those patients who cannot tolerate SUBOXONE sublingual film or SUBOXONE sublingual tablet; for example, those patients who have been shown to be hypersensitive to naloxone.
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.
Prior to induction, consideration should be given to the type of opioid dependence (i.e., 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 SUBUTEX 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 SUBUTEX on Day 1 and 16 mg SUBUTEX on Day 2. From Day 3 onward, patients received either SUBOXONE sublingual tablet or SUBUTEX at the same buprenorphine dose as Day 2 based on their assigned treatment. Induction in the studies of buprenorphine solution was accomplished over 3-4 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 SUBUTEX 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.
- SUBOXONE is preferred for maintenance treatment.
- Where SUBUTEX is used in maintenance in patients who cannot tolerate the presence of naloxone, the dosage of SUBUTEX 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 SUBUTEX is generally in the range of 4 mg to 24 mg buprenorphine per day depending on the individual patient. The recommended target dosage of SUBUTEX 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 patientâ€™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 SUBUTEX contributes to the intended treatment goals.
Method Of Administration
SUBUTEX must be administered whole. Do not cut, chew, or swallow SUBUTEX. Advise patients not to eat or drink anything until the tablet is completely dissolved.
SUBUTEX 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.
Treatment should be initiated with supervised administration, progressing to unsupervised administration as the patientâ€™s clinical stability permits. The use of SUBUTEX for unsupervised administration should be limited to those patients who cannot tolerate SUBOXONE, for example those patients with known hypersensitivity to naloxone. SUBOXONE and SUBUTEX are both subject to diversion and abuse. When determining the prescription quantity for unsupervised administration, consider the patientâ€™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.
Ideally, patients should be seen at reasonable intervals (e.g., 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.
Once a stable dosage has been achieved and patient assessment (e.g., 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 providerâ€™s evaluation of treatment outcomes and objectives such as:
- Absence of medication toxicity.
- Absence of medical or behavioral adverse effects.
- Responsible handling of medications by the patient.
- Patientâ€™s compliance with all elements of the treatment plan (including recovery-oriented activities, psychotherapy, and/or other psychosocial modalities).
- 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.
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.
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.
The decision to discontinue therapy with SUBOXONE or SUBUTEX 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].
Dosage Forms And Strengths
SUBUTEX sublingual tablet is supplied as an uncoated oval white tablet in two dosage strengths:
- buprenorphine 2 mg, and
- buprenorphine 8 mg
Storage And Handling
SUBUTEX sublingual tablet is an uncoated oval white flat bevelled edged tablet, debossed with an alphanumeric word identifying the product and strength on one side (“B2” and “B8” on 2 mg and 8 mg tablets respectively), supplied in desiccated high density polyethylene (HDPE) bottle:
NDC 12496-1278-2 (buprenorphine 2 mg/sublingual tablet; content expressed in terms of free base, equivalent to 2.16 mg buprenorphine hydrochloride USP) -30 tablets per bottle
NDC 12496-1310-2 (buprenorphine 8 mg/sublingual tablet; content expressed in terms of free base, equivalent to 8.64 mg buprenorphine hydrochloride USP) -30 tablets per bottle
Store at 25°C (77°F), excursions permitted to 15°-30°C (59°-86°F). [see USP Controlled Room Temperature].
Store SUBUTEX securely and dispose of properly [see Patient Counseling Information].
The following serious adverse reactions are described elsewhere in the labeling:
- Addiction, Abuse, and Misuse [see WARNINGS AND PRECAUTIONS]
- Respiratory and CNS Depression [see WARNINGS AND PRECAUTIONS]
- Neonatal Opioid Withdrawal Syndrome [see WARNINGS AND PRECAUTIONS]
- Adrenal Insufficiency [seeWARNINGS AND PRECAUTIONS]
- Opioid Withdrawal [see WARNINGS AND PRECAUTIONS]
- Hepatitis, Hepatic Events [seeWARNINGS AND PRECAUTIONS]
- Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
- Orthostatic Hypotension [seeWARNINGS AND PRECAUTIONS]
- Elevation of Cerebrospinal FluidPressure [see WARNINGS AND PRECAUTIONS]
- Elevation of Intracholedochal Pressure [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience
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.
The safety of SUBUTEX was supported by clinical trials using SUBUTEX, 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 (%)||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*|
|N (%)||N (%)||N (%)||N (%)||N (%)|
|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%)|
|*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 (4 mg solution) approximates a 6 mg tablet dose
”Moderate” dose (8 mg solution) approximates a 12 mg tablet dose
”High” dose (16 mg solution) approximates a 24 mg tablet dose
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 SUBUTEX 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 SUBUTEX.
Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see CLINICAL PHARMACOLOGY].
Local reactions: Glossodynia, glossitis, oral mucosal erythema, oral hypoesthesia, and stomatitis.
Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor’s approval.
The risk of serious side effects (such as slow/shallow breathing, severe drowsiness/dizziness) may be increased if this medication is used with other products that may also affect breathing or cause drowsiness. Tell your doctor or pharmacist if you are taking other products such as alcohol, marijuana (cannabis), antihistamines (such as cetirizine, diphenhydramine), drugs for sleep or anxiety (such as alprazolam, diazepam, zolpidem), muscle relaxants (such as carisoprodol, cyclobenzaprine), and other opioid pain relievers (such as codeine, hydrocodone).
Deaths have occurred when buprenorphine has been misused by injecting it (“shooting up”), especially when used in combination with benzodiazepines (such as diazepam) or other depressants such as alcohol or additional opioids.
If someone has overdosed and has serious symptoms such as passing out or trouble breathing, give them naloxone if available, then call 911. If the person is awake and has no symptoms, call a poison control center right away. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: slow breathing, slow heartbeat, loss of consciousness.
Do not share this medication with others. Sharing it is against the law.
Tell all of your doctors that you use this medication and have regularly used opioids, especially in cases of emergency treatment.
Laboratory and/or medical tests (such as liver function tests) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.
If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose. Take your next dose at the regular time. Do not double the dose to catch up.
Store at room temperature away from light and moisture. Do not store in the bathroom. Keep all medications away from children and pets.
Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. For more details, read the Medication Guide, or consult your pharmacist or local waste disposal company.Information last revised April 2020.