SUBUTEX (buprenorphine) sublingual tablet is an uncoated oval white tablet, imprinted with a sword logo on one side and an alphanumeric imprint identifying the product and strength. It contains buprenorphine HCl and is available in two dosage strengths, 2 mg buprenorphine and 8 mg buprenorphine (as free base).
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-methoxy-6α,14-ethano-14α-morphinan-7α-yl]-3,3dimethylbutan-2-ol hydrochloride.
SUBUTEX sublingual tablet is indicated for the treatment of opioid dependence and is preferred for induction. SUBUTEX sublingual tablet should be used as part of a complete treatment plan to include counseling and psychosocial support. 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.
Dosage and administration
SUBUTEX sublingual tablet is supplied as an uncoated oval white tablet in two dosage strengths:
• Buprenorphine 2 mg, and
• Buprenorphine 8 mg.
SUBUTEX sublingual tablet is administered sublingually as a single daily dose. SUBUTEX sublingual tablet contains no 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 sublingual tablet 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), the time since last opioid use, and the degree or level of opioid dependence. To avoid precipitating withdrawal, induction with SUBUTEX sublingual tablet should be undertaken when objective and clear signs of withdrawal are evident. It is recommended that an adequate treatment dose, titrated to clinical effectiveness, should be achieved as rapidly as possible.
In a one-month study, patients received 8 mg of SUBUTEX sublingual tablet on Day 1 and 16 mg SUBUTEX sublingual tablet on Day 2. From Day 3 onward, patients received either SUBOXONE sublingual tablet or SUBUTEX sublingual tablet 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. In some studies, gradual induction over several days led to a high rate of drop-out of buprenorphine patients during the induction period.
Patients taking heroin or other short-acting opioids: At treatment initiation, the dose of SUBUTEX sublingual tablet should be administered at least 4 hours after the patient last used opioids or preferably when moderate objective signs of opioid withdrawal appear.
Patients on methadone or other long-acting opioids:
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. SUBUTEX sublingual tablet dosing should be initiated preferably when moderate objective signs of opioid withdrawal appear.
• 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.
• The maintenance dose is generally in the range of 4 mg to 24 mg buprenorphine per day depending on the individual patient. Doses higher than this have not been demonstrated to provide any clinical advantage.
Method of Administration
SUBUTEX sublingual tablet 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 patient’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 size of 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 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 physician’s evaluation of treatment outcomes and objectives such as:
1. Absence of medication toxicity.
2. Absence of medical or behavioral adverse effects.
3. Responsible handling of medications by the patient.
4. Patient’s compliance with all elements of the treatment plan (including recovery-oriented activities, psychotherapy, and/or other psychosocial modalities).
5. Abstinence from illicit drug use (including problematic alcohol and/or benzodiazepine use).
If treatment goals are not being achieved, the physician should re-evaluate the appropriateness of continuing the current 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. Both gradual and abrupt discontinuation of buprenorphine has been used, but the data are insufficient to determine the best method of dose taper at the end of treatment.
SUBUTEX sublingual tablet should not be administered to patients who have been shown to be hypersensitive to buprenorphine, as serious adverse reactions, including anaphylactic shock, have been reported.
Buprenorphine 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
Buprenorphine, particularly when taken by the IV route, in combination with benzodiazepines or other CNS depressants (including alcohol), has been associated with significant respiratory depression and death. Many, but not all post-marketing reports regarding coma and death associated with the concomitant use of buprenorphine and benzodiazepines involved misuse by self-injection. Deaths have also been reported in association with concomitant administration of buprenorphine with other depressants such as alcohol or other CNS depressant drugs. Patients should be warned of the potential danger of self-administration of benzodiazepines or other depressants while under treatment with SUBUTEX sublingual tablet.
In the case of overdose, the primary management should be the re-establishment of adequate ventilation with mechanical assistance of respiration, if required. Naloxone may be of value for the management of buprenorphine overdose. Higher than normal doses and repeated administration may be necessary. SUBUTEX sublingual tablet should be used 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).
Patients receiving buprenorphine in the presence of opioid analgesics, general anesthetics, benzodiazepines, phenothiazines, other tranquilizers, sedative/hypnotics or other CNS depressants (including alcohol) may exhibit increased CNS depression. Consider dose reduction of CNS depressants, SUBUTEX sublingual tablet, or both in situations of concomitant prescription.
Buprenorphine 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. Buprenorphine can be abused in a manner similar to other opioids. 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.
Cases of hypersensitivity to buprenorphine products have been reported both in clinical trials and in the post-marketing experience. Cases of bronchospasm, angioneutrotic edema, and anaphylactic shock have been reported. The most common signs and symptoms include rashes, hives, and pruritus. A history of hypersensitivity to buprenorphine is a contraindication to the use of SUBUTEX sublingual tablet.
Precipitation of Opioid Withdrawal Signs and Symptoms
Because of the partial agonist properties of buprenorphine, SUBUTEX sublingual tablet may precipitate opioid withdrawal signs and symptoms in individuals physically dependent on full opioid agonists if administered sublingually or parenterally before the agonist effects of other opioids have subsided.
Neonatal withdrawal has been reported in the infants of women treated with buprenorphine during pregnancy. From post-marketing reports, the time to onset of neonatal withdrawal signs and symptoms ranged from Day 1 to Day 8 of life with most cases occurring on Day 1. Adverse events associated with the neonatal withdrawal syndrome included hypertonia, neonatal tremor, neonatal agitation, and myoclonus and there have been reports of convulsions, apnea, respiratory depression and bradycardia.
Use in Opioid Naïve Patients
There have been reported deaths of opioid naïve individuals who received a 2 mg dose of buprenorphine as a sublingual tablet for analgesia. SUBUTEX sublingual tablet is not appropriate as an analgesic.
Impairment of Ability to Drive or Operate Machinery
SUBUTEX sublingual tablet may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery, especially during treatment induction and dose adjustment. Patients should be cautioned about driving or operating hazardous machinery until they are reasonably certain that buprenorphine therapy does not adversely affect his or her ability to engage in such activities.
Pregnancy: Pregnancy Category C. There are no adequate and well-controlled studies SUBUTEX sublingual tablet in pregnant women. SUBUTEX sublingual tablet should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing: Mothers Buprenorphine passes into breast milk. Breast-feeding is not advised in mothers treated with buprenorphine products. An apparent lack of milk production during general reproduction studies with buprenorphine in rats caused decreased viability and lactation indices.
Pediatric Use: The safety and effectiveness of SUBUTEX sublingual tablet has not been established in pediatric patients.