2.1 Maintenance

• SUBOXONE sublingual tablet is indicated for maintenance treatment. The recommended target dosage of SUBOXONE sublingual tablet is 16/4 mg buprenorphine/naloxone/day as a single daily dose
• The dosage of SUBOXONE sublingual tablet should be progressively adjusted in increments/decrements of 2/0.5 mg or 4/1 mg buprenorphine/naloxone to a level that holds the patient in treatment and suppresses opioid withdrawal signs and symptoms
• The maintenance dose of SUBOXONE sublingual tablet is generally in the range of 4/1 mg buprenorphine/naloxone to 24/6 mg buprenorphine/naloxone per day depending on the individual patient. Dosages higher than this have not been demonstrated to provide any clinical advantage

2.2 Method of Administration

SUBOXONE 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.

2.3 Clinical Supervision

Treatment should be initiated with supervised administration, progressing to unsupervised administration as the patient's clinical stability permits. SUBOXONE sublingual tablet is subject to diversion and abuse. When determining 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 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.

2.4 Unstable Patients

Physicians 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 physician does not feel that he/she has the expertise to manage the patient. In such cases, the physician 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.

2.5 Stopping Treatment

The decision to discontinue therapy with SUBOXONE sublingual tablets 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.

2.6 Switching between SUBOXONE (buprenorphine and naloxone) Sublingual Film and SUBOXONE Sublingual Tablets

Patients being switched between SUBOXONE (buprenorphine and naloxone) sublingual tablets and SUBOXONE sublingual film should be started on the same dosage as the previously administered product. However, dosage adjustments may be necessary when switching between products. Because of the potentially greater relative bioavailability of SUBOXONE sublingual film compared to SUBOXONE (buprenorphine and naloxone) sublingual tablets, patients switching from SUBOXONE (buprenorphine and naloxone) sublingual tablets to SUBOXONE sublingual film should be monitored for over-medication. Those switching from SUBOXONE sublingual film to SUBOXONE (buprenorphine and naloxone) sublingual tablets should be monitored for withdrawal or other indications of under-dosing. In clinical studies, pharmacokinetics of SUBOXONE sublingual film was similar to the respective dosage strengths of SUBOXONE (buprenorphine and naloxone) sublingual tablets, although not all doses and dose combinations met bioequivalence criteria.

5.1 Abuse Potential

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. [see Drug Abuse and Dependence ( 9.2)] .

5.2 Respiratory Depression

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 SUBOXONE sublingual tablets. [see Drug Interactions ( 7.3)]

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.

SUBOXONE sublingual tablets 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).

5.3 CNS 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, SUBOXONE sublingual tablets, or both in situations of concomitant prescription. [see Drug Interactions ( 7.3)]

5.4 Unintentional Pediatric Exposure

Buprenorphine can cause severe, possibly fatal, respiratory depression in children who are accidentally exposed to it. Store buprenorphine-containing medications safely out of the sight and reach of children and destroy any unused medication appropriately. [see Disposal of Unused SUBOXONE Sublingual Tablets ( 17.2)]

5.5 Dependence

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. [see Drug Abuse and Dependence ( 9.3)]

5.6 Hepatitis, Hepatic Events

Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving buprenorphine in clinical trials and through post-marketing adverse event reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of death, hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy. In many cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injecting drug use may have played a causative or contributory role. In other cases, insufficient data were available to determine the etiology of the abnormality. Withdrawal of buprenorphine has resulted in amelioration of acute hepatitis in some cases; however, in other cases no dose reduction was necessary. The possibility exists that buprenorphine had a causative or contributory role in the development of the hepatic abnormality in some cases. Liver function tests, prior to initiation of treatment is recommended to establish a baseline. Periodic monitoring of liver function during treatment is also recommended. A biological and etiological evaluation is recommended when a hepatic event is suspected. Depending on the case, SUBOXONE sublingual tablet may need to be carefully discontinued to prevent withdrawal signs and symptoms and a return by the patient to illicit drug use, and strict monitoring of the patient should be initiated.

5.7 Allergic Reactions

Cases of hypersensitivity to buprenorphine and naloxone containing products have been reported both in clinical trials and in the post-marketing experience. Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. The most common signs and symptoms include rashes, hives, and pruritus. A history of hypersensitivity to buprenorphine or naloxone is a contraindication to the use of SUBOXONE sublingual tablet.

5.8 Precipitation of Opioid Withdrawal Signs and Symptoms

Because it contains naloxone, SUBOXONE sublingual tablet is highly likely to produce marked and intense withdrawal signs and symptoms if misused parenterally by individuals dependent on full opioid agonists such as heroin, morphine, or methadone. Because of the partial agonist properties of buprenorphine, SUBOXONE sublingual tablet may precipitate opioid withdrawal signs and symptoms in such persons if administered sublingually before the agonist effects of the opioid have subsided.

5.9 Neonatal Withdrawal

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 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.

5.10 Use in Opioid Naïve Patients

There have been reported deaths of opioid naive individuals who received a 2 mg dose of buprenorphine as a sublingual tablet for analgesia. SUBOXONE sublingual tablet is not appropriate as an analgesic.

5.11 Impairment of Ability to Drive or Operate Machinery

SUBOXONE 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 SUBOXONE sublingual tablet therapy does not adversely affect his or her ability to engage in such activities.

5.12 Orthostatic Hypotension

Like other opioids, SUBOXONE sublingual tablets may produce orthostatic hypotension in ambulatory patients.

5.13 Elevation of Cerebrospinal Fluid Pressure

Buprenorphine, like other opioids, may elevate cerebrospinal fluid pressure and should be used with caution in patients with head injury, intracranial lesions, and other circumstances when cerebrospinal pressure may be increased. Buprenorphine can produce miosis and changes in the level of consciousness that may interfere with patient evaluation.

5.14 Elevation of Intracholedochal Pressure

Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus should be administered with caution to patients with dysfunction of the biliary tract.

5.15 Effects in Acute Abdominal Conditions

As with other opioids, buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

5.16 General Precautions

SUBOXONE sublingual tablet should be administered with caution in debilitated patients and those with myxedema or hypothyroidism, adrenal cortical insufficiency (e.g., Addison's disease); CNS depression or coma; toxic psychoses; prostatic hypertrophy or urethral stricture; acute alcoholism; delirium tremens; or kyphoscoliosis.

6.1 Adverse Events in Clinical Trials - SUBOXONE Sublingual Tablets

The safety of SUBOXONE was evaluated in 497 opioid-dependent subjects. The prospective evaluation of SUBOXONE was supported by clinical trials using SUBUTEX (buprenorphine tablets without naloxone) 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 SUBOXONE and 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).

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.

6.2 Adverse Events – Post-marketing Experience with SUBOXONE Sublingual Tablets

The most frequently reported post-marketing adverse event not observed in clinical trials was peripheral edema.

7.1 Cytochrome P-450 3A4 (CYP3A4) Inhibitors and Inducers

Buprenorphine is metabolized to norbuprenorphine primarily by cytochrome CYP3A4; therefore, potential interactions may occur when SUBOXONE sublingual tablets is given concurrently with agents that affect CYP3A4 activity. The concomitant use of SUBOXONE 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 CYP3A4 inducers has not been studied; therefore, it is recommended that patients receiving SUBOXONE sublingual tablets be monitored for signs and symptoms of opioid withdrawal if inducers of CYP3A4 (e.g., efavirenz, phenobarbital, carbamazepine, phenytoin, rifampicin) are co-administered [see Clinical Pharmacology ( 12.3)]

7.2 Antiretrovirals

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.

7.3 Benzodiazepines

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. SUBOXONE sublingual tablets 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 SUBOXONE sublingual tablets, and should also be cautioned to use benzodiazepines concurrently with SUBOXONE sublingual tablets only as directed by their physician.

8.1 Pregnancy

Pregnancy Category C.

There are no adequate and well-controlled studies of SUBOXONE sublingual tablets or buprenorphine/naloxone in pregnant women. SUBOXONE sublingual tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

8.3 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.

8.4 Pediatric Use

The safety and effectiveness of SUBOXONE sublingual tablets have not been established in pediatric patients.

8.5 Geriatric Use

Clinical studies of SUBOXONE sublingual tablets, SUBOXONE (buprenorphine and naloxone) sublingual film, or SUBUTEX (buprenorphine) sublingual tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone is unknown. Since both drugs are extensively metabolized, the plasma levels will be expected to be higher in patients with moderate and severe hepatic impairment. However, it is not known whether both drugs are affected to the same degree. Therefore, dosage should be adjusted and patients should be watched for signs and symptoms of precipitated opioid withdrawal.

8.7 Renal Impairment

No differences in buprenorphine pharmacokinetics were observed between 9 dialysis-dependent and 6 normal patients following IV administration of 0.3 mg buprenorphine. The effects of renal failure on naloxone pharmacokinetics are unknown.

9.1 Controlled Substance

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.

9.2 Abuse

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 with, or referred to, 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.

9.3 Dependence

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 ( 5.5)]

A neonatal withdrawal syndrome has been reported in the infants of women treated with buprenorphine during pregnancy. [see Warnings and Precautions ( 5.9)]

12.1 Mechanism of Action

SUBOXONE sublingual tablet contains buprenorphine and naloxone. Buprenorphine is a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor. Naloxone is a potent antagonist at mu-opioid receptors and produces opioid withdrawal signs and symptoms in individuals physically dependent on full opioid agonists when administered parenterally.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

17.1 Safe Use

Before initiating treatment with SUBOXONE sublingual tablets, explain the points listed below to caregivers and patients. Instruct patients to read the Medication Guide each time SUBOXONE is dispensed because new information may be available.

• Patients should be warned that it is extremely dangerous to self-administer non-prescribed benzodiazepines or other CNS depressants (including alcohol) while taking SUBOXONE sublingual tablets. Patients prescribed benzodiazepines or other CNS depressants should be cautioned to use them only as directed by their physician. [ see Warnings and Precautions ( 5.2), Drug Interactions ( 7.3)]
• Patients should be advised that SUBOXONE sublingual tablets contain an opioid that can be a target for people who abuse prescription medications or street drugs. Patients should be cautioned to keep their tablets in a safe place, and to protect them from theft.
• Patients should be instructed to keep SUBOXONE sublingual tablets in a secure place, out of the sight and reach of children. Accidental or deliberate ingestion by a child may cause respiratory depression that can result in death. Patients should be advised that if a child is exposed to SUBOXONE sublingual tablets, medical attention should be sought immediately.
• Patients should be advised never to give SUBOXONE sublingual tablets to anyone else, even if he or she has the same signs and symptoms. It may cause harm or death.
• Patients should be advised that selling or giving away this medication is against the law.
• Patients should be cautioned that SUBOXONE sublingual tablets may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving or operating machinery. Caution should be taken especially during drug induction and dose adjustment and until individuals are reasonably certain that buprenorphine therapy does not adversely affect their ability to engage in such activities. [see Warnings and Precautions ( 5.11)]
• Patients should be advised not to change the dosage of SUBOXONE sublingual tablets without consulting their physician.
• Patients should be advised to take SUBOXONE sublingual tablets once a day.
• Patients should be informed that SUBOXONE sublingual tablets can cause drug dependence and that withdrawal signs and symptoms may occur when the medication is discontinued.
• Patients seeking to discontinue treatment with buprenorphine for opioid dependence should be advised to work closely with their physician on a tapering schedule and should be apprised of the potential to relapse to illicit drug use associated with discontinuation of opioid agonist/partial agonist medication-assisted treatment.
• Patients should be cautioned that, like other opioids, SUBOXONE sublingual tablets may produce orthostatic hypotension in ambulatory individuals. [see Warnings and Precautions. ( 5.12)]
• Patients should inform their physician if any other prescription medications, over-the-counter medications, or herbal preparations are prescribed or currently being used. [see Drug Interactions ( 7.1, 7.2 and 7.3)]
• Women of childbearing potential, who become pregnant or are planning to become pregnant, should be advised to consult their physician regarding the possible effects of using SUBOXONE sublingual tablets during pregnancy. [see Use in Specific Populations ( 8.1)]
• Patients should be warned that buprenorphine passes into breast milk. Breast-feeding is not advised in mothers treated with buprenorphine products. [see Use in Specific Populations ( 8.3)]
• Patients should inform their family members that, in the event of emergency, the treating physician or emergency room staff should be informed that the patient is physically dependent on an opioid and that the patient is being treated with SUBOXONE sublingual tablets.
• Refer to the Medication Guide for additional information regarding the counseling information.

17.2 Disposal of Unused SUBOXONE Sublingual Tablets

Unused SUBOXONE sublingual tablets should be disposed of as soon as they are no longer needed. Unused tablets should be flushed down the toilet.

Manufactured by:
Reckitt Benckiser Healthcare (UK) Ltd.
Hull, UK, HU8 7DS

Distributed by:
Reckitt Benckiser Pharmaceuticals Inc.
Richmond, VA 23235

1-1283-001-US-0112