FDA Label for Buprenorphine Hydrochloride

1 Indications And Usage

Buprenorphine Sublingual Tablets is indicated for the treatment of opioid dependence and is preferred for induction. Buprenorphine Sublingual Tablets 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.

2 Dosage And Administration

Buprenorphine Sublingual Tablets is administered sublingually as a single daily dose. Buprenorphine Sublingual Tablets contain no naloxone HCL and is preferred for use only during induction. Following induction, Buprenorphine and Naloxone Sublingual Film or Buprenorphine and Naloxone Sublingual Tablets is preferred due to the presence of naloxone when clinical use includes unsupervised administration. The use of Buprenorphine Sublingual Tablets for unsupervised administration should be limited to those patients who cannot tolerate Buprenorphine and Naloxone Sublingual Film or Buprenorphine and Naloxone Sublingual Tablets; 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.

2.1 Induction

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 Buprenorphine Sublingual Tablets 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 Buprenorphine Sublingual Tablets on Day 1 and 16 mg Buprenorphine Sublingual Tablets on Day 2. From Day 3 onward, patients received either buprenorphine and naloxone sublingual tablet or Buprenorphine Sublingual Tablets at the same buprenorphine dose as Day 2 based on their assigned treatment. Induction in the studies of buprenorphine solution was accomplished over 3 to 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.

2.2 Maintenance

• Buprenorphine and naloxone is preferred for maintenance treatment.
• Where buprenorphine is used in maintenance in patients who cannot tolerate the presence of naloxone, the dosage of buprenorphine 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.

2.3 Method Of Administration

Buprenorphine Sublingual Tablets 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.

2.4 Clinical Supervision

Treatment should be initiated with supervised administration, progressing to unsupervised administration as the patient's clinical stability permits. The use of buprenorphine for unsupervised administration should be limited to those patients who cannot tolerate buprenorphine and naloxone, for example those patients with known hypersensitivity to naloxone. Buprenorphine and naloxone and buprenorphine 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:

• Absence of medication toxicity.
• Absence of medical or behavioral adverse effects.
• Responsible handling of medications by the patient.
• Patient'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 physician should re-evaluate the appropriateness of continuing the current treatment.

2.5 Patients With Hepatic Impairment

Severe hepatic impairment: Consider reducing the starting and titration incremental dose by half compared to patients with normal liver function, and monitor for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine.

Moderate hepatic impairment: Although no dose adjustment is necessary for patients with moderate hepatic impairment, Buprenorphine Sublingual Tablets should be used with caution in these patients and prescribers should monitor patients for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine.

Mild hepatic impairment: No clinically significant differences in pharmacokinetic parameters were observed in subjects with mild hepatic impairment. No dose adjustment is needed in patients with mild hepatic impairment. [see Warnings and Precautions ( 5.11)] .

2.6 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.

2.7 Stopping Treatment

The decision to discontinue therapy with buprenorphine and naloxone or buprenorphine 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.

3 Dosage Forms And Strengths

Buprenorphine Sublingual Tablets is supplied as white, sublingual tablets available in two dosage strengths:

• buprenorphine 2 mg, and
• buprenorphine 8 mg

4 Contraindications

Buprenorphine Sublingual Tablets 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. [see Warnings and Precautions ( 5.8)].

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 Buprenorphine 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.

Buprenorphine 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, Buprenorphine 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 Patient Counseling ( 17)].

5.5 Neonatal Opioid Withdrawal Syndrome

Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy, whether that use is medically-authorized or illicit. Unlike opioid withdrawal syndrome in adults, NOWS may be life-threatening if not recognized and treated in the neonate. Healthcare professionals should observe newborns for signs of NOWS and manage accordingly [ see Use in Specific Populations ( 8.1)].

Advise pregnant women receiving opioid addiction treatment with Buprenorphine Sublingual Tablets of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [ see Use in Specific Populations ( 8.1)]. This risk must be balanced against the risk of untreated opioid addiction which often results in continued or relapsing illicit opioid use and is associated with poor pregnancy outcomes. Therefore, prescribers should discuss the importance and benefits of management of opioid addiction throughout pregnancy.

5.6 Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

5.7 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)].

5.8 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, Buprenorphine Sublingual Tablets 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.

5.9 Allergic Reactions

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 Buprenorphine Sublingual Tablets.

5.10 Precipitation Of Opioid Withdrawal Signs And Symptoms

Because of the partial agonist properties of buprenorphine, Buprenorphine Sublingual Tablets 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.

5.11 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. Buprenorphine Sublingual Tablets are not appropriate as an analgesic.

5.12 Use In Patients With Impaired Hepatic Function

In a pharmacokinetic study, buprenorphine plasma levels were found to be higher and the half-life was found to be longer in subjects with moderate and severe hepatic impairment, but not in subjects with mild hepatic impairment.

For patients with severe hepatic impairment, a dose adjustment is recommended, and patients with moderate or severe hepatic impairment should be monitored for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine [see Dosage and Administration ( 2.5) and Use in Specific Populations ( 8.6)].

5.13 Impairment Of Ability To Drive Or Operate Machinery

Buprenorphine Sublingual Tablets 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.

5.14 Orthostatic Hypotension

Like other opioids, Buprenorphine Sublingual Tablets may produce orthostatic hypotension in ambulatory patients.

5.15 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.

5.16 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.

5.17 Effects In Acute Abdominal Conditions

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

5.18 General Precautions

Buprenorphine Sublingual Tablets 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 Adverse Reactions

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.

6.1 Adverse Events In Clinical Trials

The safety of Buprenorphine Sublingual Tablets was supported by clinical trials using Buprenorphine Sublingual Tablets, buprenorphine and naloxone sublingual tablets 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 Buprenorphine Sublingual Tablets 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 - Postmarketing Experience With Buprenorphine Sublingual Tablets

The most frequently reported postmarketing 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)] .

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 Buprenorphine Sublingual Tablets is given concurrently with agents that affect CYP3A4 activity. The concomitant use of Buprenorphine Sublingual Tablets 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 Buprenorphine Sublingual Tablets 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 ( 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. Buprenorphine 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 Buprenorphine Sublingual Tablets, and should also be cautioned to use benzodiazepines concurrently with Buprenorphine Sublingual Tablets only as directed by their physician.

7.4 Serotonergic Drugs

The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system, such as selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue), has resulted in serotonin syndrome.

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.

8.3 Nursing Mothers

Risk Summary
Based on two studies in 13 lactating women, buprenorphine and its metabolite norbuprenorphine are present in low levels in human milk and infant urine, and available data have not shown adverse reactions in breastfed infants. There are no data on the combination product buprenorphine/naloxone in breastfeeding, however oral absorption of naloxone is minimal. Caution should be exercised when buprenorphine is administered to a nursing woman. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for buprenorphine and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

Clinical Considerations
Advise the nursing mother taking buprenorphine to monitor the infant for increased drowsiness and breathing difficulties.

Data
Based on limited data from a study of 6 lactating women who were taking a median oral dose of buprenorphine of 0.29 mg/kg/day 5 to 8 days after delivery, breast milk contained a median infant dose of 0.42 mcg/kg/day of buprenorphine and 0.33 mcg/kg/day of norbuprenorphine, which are equal to 0.2% and 0.12% of the maternal weight-adjusted dose.

Based on limited data from a study of 7 lactating women who were taking a median oral dose of buprenorphine of 7 mg/day an average of 1.12 months after delivery, the mean milk concentrations of buprenorphine and norbuprenorphine were 3.65 mcg/L and 1.94 mcg/L respectively. Based on the limited data from this study, and assuming milk consumption of 150 mL/kg/day, an exclusively breastfed infant would receive an estimated mean of 0.55 mcg/kg/day of buprenorphine and 0.29 mcg/kg/day of norbuprenorphine, which are 0.38% and 0.18% of the maternal weight-adjusted dose.

No adverse reactions were observed in the infants in these two studies.

Females and Males of Reproductive Potential

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions ( 6.2)].

8.4 Pediatric Use

The safety and effectiveness of Buprenorphine Sublingual Tablet has not been established in pediatric patients.

8.5 Geriatric Use

Clinical studies of Buprenorphine Sublingual Tablets, buprenorphine and naloxone sublingual film, or buprenorphine and naloxone sublingual tablet 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 effects of hepatic impairment on the pharmacokinetics of buprenorphine were evaluated in a pharmacokinetic study.  Buprenorphine is extensively metabolized in the liver and buprenorphine plasma levels were found to be higher and the half-life was found to be longer in subjects with moderate and severe hepatic impairment, but not in subjects with mild hepatic impairment.

For patients with severe hepatic impairment, a dose adjustment is recommended, and patients with moderate or severe hepatic impairment should be monitored for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine. [see Dosage and Administration ( 2.5), Warnings and Precautions ( 5.12) and Clinical Pharmacology ( 12.3)] .

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.

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 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.

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)].

Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy [ see Warnings and Precautions ( 5.5) ]

10 Overdosage

The manifestations of acute overdose include pinpoint pupils, sedation, hypotension, respiratory depression, and death.

In the event of overdose, the respiratory and cardiac status of the patient should be monitored carefully. When respiratory or cardiac functions are depressed, primary attention should be given to the re-establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. Oxygen, IV fluids, vasopressors, and other supportive measures should be employed as indicated.

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. The long duration of action of buprenorphine should be taken into consideration when determining the length of treatment and medical surveillance needed to reverse the effects of an overdose. Insufficient duration of monitoring may put patients at risk.

11 Descriptions

Buprenorphine Sublingual Tablets are uncoated round white tablets intended for sublingual administration. The tablets contain buprenorphine HCL and are available in two dosage strengths, 2 mg buprenorphine and 8 mg buprenorphine (as free base). Each tablet also contains citric acid, cornstarch, lactose monohydrate, mannitol, povidone K30, sodium citrate anhydrous and sodium stearyl fumerate. The 2 mg buprenorphine tablet is debossed with a "2" on one side and an "→" on the other. The 8 mg buprenorphine tablet is debossed with a "8" on one side and an "→" on the other.

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.

It has the following chemical structure:

Chemical Structure - buprenorphine hydrochloride 1

Buprenorphine HCl has the molecular formula C ₂₉H ₄₁ NO ₄ ∙ 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.

12.1 Mechanism Of Action

Buprenorphine Sublingual Tablets contain buprenorphine. Buprenorphine is a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor.

14 Clinical Studies

Clinical data on the safety and efficacy of buprenorphine were derived from studies of Buprenorphine Sublingual Tablet formulations, with and without naloxone, and from studies of sublingual administration of a more bioavailable ethanolic solution of buprenorphine.

Buprenorphine Sublingual Tablets were studied in 1834 patients; buprenorphine and naloxone tablets in 575 patients, and buprenorphine sublingual solutions in 2470 patients. A total of 1270 women received buprenorphine in those clinical trials. Dosing recommendations are based on data from one trial of both tablet formulations and two trials of the ethanolic solution. All trials used buprenorphine in conjunction with psychosocial counseling as part of a comprehensive addiction treatment program. There were no clinical studies conducted to assess the efficacy of buprenorphine as the only component of treatment.

In a double-blind placebo- and active-controlled study, 326 heroin-addicted subjects were randomly assigned to either buprenorphine and naloxone sublingual tablets, 16/4 mg per day; Buprenorphine Sublingual Tablets, 16 mg per day; or placebo sublingual tablets. For subjects randomized to either active treatment, dosing began with one 8 mg Buprenorphine on Day 1, followed by 16 mg (two 8 mg tablets) of buprenorphine on Day 2. On Day 3, those randomized to receive buprenorphine and naloxone sublingual tablets were switched to the combination tablet. Subjects randomized to placebo received one placebo tablet on Day 1 and two placebo tablets per day thereafter for four weeks. Subjects were seen daily in the clinic (Monday through Friday) for dosing and efficacy assessments. Take-home doses were provided for weekends. Subjects were instructed to hold the medication under the tongue for approximately 5 to 10 minutes until completely dissolved. Subjects received counseling regarding HIV infection and up to one hour of individualized counseling per week. The primary study comparison was to assess the efficacy of buprenorphine and naloxone sublingual tablets and Buprenorphine Sublingual Tablets individually against placebo sublingual tablet. The percentage of thrice-weekly urine samples that were negative for non-study opioids was statistically higher for both buprenorphine and naloxone sublingual tablets and Buprenorphine Sublingual Tablets than for placebo sublingual tablets.

In a double-blind, double-dummy, parallel-group study comparing buprenorphine ethanolic solution to a full agonist active control, 162 subjects were randomized to receive the ethanolic sublingual solution of buprenorphine at 8 mg/day (a dose which is roughly comparable to a dose of 12 mg per day of Buprenorphine Sublingual Tablets), or two relatively low doses of active control, one of which was low enough to serve as an alternative to placebo, during a 3 to 10 day induction phase, a 16-week maintenance phase and a 7-week detoxification phase. Buprenorphine was titrated to maintenance dose by Day 3; active control doses were titrated more gradually.

Maintenance dosing continued through Week 17, and then medications were tapered by approximately 20% to 30% per week over Weeks 18 to 24, with placebo dosing for the last two weeks. Subjects received individual and/or group counseling weekly.

Based on retention in treatment and the percentage of thrice-weekly urine samples negative for non-study opioids, buprenorphine was more effective than the low dose of the control, in keeping heroin addicts in treatment and in reducing their use of opioids while in treatment. The effectiveness of buprenorphine, 8 mg per day was similar to that of the moderate active control dose, but equivalence was not demonstrated.

In a dose-controlled, double-blind, parallel-group, 16-week study, 731 subjects were randomized to receive one of four doses of buprenorphine ethanolic solution: 1 mg, 4 mg, 8 mg, and 16 mg. Buprenorphine was titrated to maintenance doses over 1 to 4 days and continued for 16 weeks. Subjects received at least one session of AIDS education and additional counseling ranging from one hour per month to one hour per week, depending on site.

Based on retention in treatment and the percentage of thrice-weekly urine samples negative for non-study opioids, the three highest tested doses were superior to the 1 mg dose. Therefore, this study showed that a range of buprenorphine doses may be effective. The 1 mg dose of buprenorphine sublingual solution can be considered to be somewhat lower than a 2 mg tablet dose. The other doses used in the study encompass a range of tablet doses from approximately 6 mg to approximately 24 mg.

16 How Supplied/Storage And Handling

Buprenorphine Sublingual Tablets are supplied in white HDPE bottles.

2 mg - White, round, biconvex uncoated tablets with "2" debossed on one side and a dart "→" debossed on the other side

8 mg - White, round, biconvex uncoated tablets with "8" debossed on one side and a dart "→" debossed on the other side

17 Patient Counseling Information

See FDA-approved patient labeling (Medication Guide)

Safe Use
Before initiating treatment with Buprenorphine Sublingual Tablets, explain the points listed below to caregivers and patients. Instruct patients to read the Medication Guide each time Buprenorphine Sublingual Tablets are 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 Buprenorphine Sublingual Tablets. Patients prescribed benzodiazepines or other CNS depressants should be cautioned to use them only as directed by their physicians. [see Warnings and Precautions ( 5.2), Drug Interactions ( 7.3)].
• Patients should be advised that Buprenorphine Sublingual Tablets contains 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 Buprenorphine 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 Buprenorphine Sublingual Tablets, medical attention should be sought immediately.
• Inform patients that Buprenorphine Sublingual Tablets could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications [ see Drug Interactions ( 7.4].
• Inform patients that Buprenorphine Sublingual Tablets could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [ see Warnings and Precautions ( 5.6)].
• Patients should be advised never to give Buprenorphine 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 Buprenorphine Sublingual Tablets may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving or operating hazardous 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 ( 5.13)].
• Patients should be advised not to change the dosage of Buprenorphine Sublingual Tablets without consulting their physicians.
• Patients should be advised to take Buprenorphine Sublingual Tablets once a day.
• Patients should be informed that Buprenorphine 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 physicians 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, Buprenorphine Sublingual Tablets may produce orthostatic hypotension in ambulatory individuals. [see Warnings and Precautions ( 5.12)].
• Patients should inform their physicians 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)].
• Advise women that if they are pregnant while being treated with Buprenorphine Sublingual Tablets, the baby may have signs of withdrawal at birth and that withdrawal is treatable [ see Warnings and Precautions ( 5.5), Specific Populations ( 8.1) ].
• Patients should be warned that buprenorphine passes into breast milk. Breast-feeding is therefore not advised in mothers treated with buprenorphine products. [see 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 Buprenorphine Sublingual Tablets.
• Refer to the Medication Guide for additional information regarding the counseling information.

Disposal of Unused Buprenorphine Sublingual Tablets
Unused Buprenorphine Sublingual Tablets should be disposed of as soon as they are no longer needed. Flush unused tablets down the toilet.

Other

Manufactured by:

Ethypharm S.A.

76121 Le Grand Quevilly Cedex

France

Made in France

Distributed by:

Hi-Tech Pharmacal Co., Inc.

Amityville, NY 11701

Tel.:1-888-775-1770

www.hitechpharm.com/drugsafety

Rev. 924/930:04 11/16

Repackaged by:

Contract Pharmacy Services-PA
125 Titus Ave Suite 200
Warrington, PA 18976 USA

Principal Display Panel - 2 Mg Tablet Bottle Label

NDC 67046-990-30

Hi•Tech

PHARMACAL

30 Tablets

CIII

PHARMACIST: Dispense the accompanying

Medication Guide to each patient.

Buprenorphine HCl

Sublingual Tablets

2 mg*

LOT

EXP.

Rx only

PRINCIPAL DISPLAY PANEL - 2 mg Tablet Bottle Label - buprenorphine hydrochloride 3

Principal Display Panel - 8 Mg Tablet Bottle Label

NDC 67046-991-30

Hi•Tech

PHARMACAL

30 Tablets

CIII

PHARMACIST: Dispense the accompanying

Medication Guide to each patient.

Buprenorphine HCl

Sublingual Tablets

8 mg*

LOT

EXP.

Rx only

PRINCIPAL DISPLAY PANEL - 8 mg Tablet Bottle Label - buprenorphine hydrochloride 4