These Highlights Do Not Include All The Information Needed To Use Buprenorphine Sublingual Tablets Safely And Effectively. See Full Prescribing Information For Buprenorphine Sublingual Tablets.

Patients dependent on heroin or other short-acting opioid products:

At treatment initiation, the first dose of buprenorphine sublingual tablets 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 drop-out of buprenorphine patients during the induction period.

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 tablets 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.

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Store Buprenorphine Sublingual Tablets securely and dispose of properly [see Patient Counseling Information (17)].

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 healthcare provider 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.

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.

Buprenorphine Sublingual Tablets are supplied as white to off white, round flat-faced beveled edged tablets debossed with "RP" on one side and an alphanumeric word identifying product and strength on the other side. They contain buprenorphine HCl, a partial agonist at the mu-opioid receptor, and are 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, respectively). Each tablet also contains lactose monohydrate, povidone K29/32, anhydrous citric acid, trisodium citrate dihydrate, corn starch, mannitol, crospovidone, 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]-3,3-dimethylbutan-2-ol hydrochloride. It has the following chemical structure:

Buprenorphine HCl has the molecular formula C ₂₉ H 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.

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 (5.7) ].

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

• Buprenorphine and naloxone sublingual tablets are preferred for maintenance treatment.
• Where buprenorphine sublingual tablets are used in maintenance in patients who cannot tolerate the presence of naloxone, the dosage of buprenorphine sublingual tablets 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 buprenorphine sublingual tablets is generally in the range of 4 mg to 24 mg buprenorphine per day depending on the individual patient. The recommended target dosage of buprenorphine sublingual tablets 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 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.
• 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 buprenorphine sublingual tablets contributes to the intended treatment goals.

What is the most important information I should know about buprenorphine sublingual tablets?

• Buprenorphine sublingual tablets contain a medicine called buprenorphine. Buprenorphine is an opioid that can cause serious and life-threatening breathing problems, especially if you take or use certain other medicines or drugs.
• Talk to your healthcare provider about naloxone. Naloxone is a medicine that is available to patients for the emergency treatment of an opioid overdose, including accidental use of buprenorphine sublingual tablets by a child. If naloxone is given, you must call 911 or get emergency medical help right away to treat an overdose or accidental use of an opioid.
• Buprenorphine sublingual tablets may cause serious and life-threatening breathing problems. Get emergency help right away if you:

• Do not take buprenorphine sublingual tablets with certain medicines. Taking buprenorphine sublingual tablets with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.
• Do not inject ("shoot-up") buprenorphine sublingual tablets. Injecting buprenorphine sublingual tablets may cause life-threatening infections and other serious health problems.
• Do not switch from buprenorphine sublingual tablets to other medicines that contain buprenorphine without talking with your healthcare provider. The amount of buprenorphine in a dose of buprenorphine sublingual tablets is not the same as in other medicines that contain buprenorphine. Your healthcare provider will prescribe a starting dose of buprenorphine sublingual tablets that may be different than other buprenorphine containing medicines you may have been taking.
• Do not stop taking buprenorphine sublingual tablets suddenly. You could become sick and have withdrawal symptoms because your body has become used to the medicine (physical dependence). Physical dependence is not the same as drug addiction.
• In an emergency, have family members tell emergency department staff that you are physically dependent on an opioid and are being treated with buprenorphine sublingual tablets.
• Never give anyone else your buprenorphine sublingual tablets. They could die from taking it. Selling or giving away buprenorphine sublingual tablets is against the law.
• Store buprenorphine sublingual tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.

What are buprenorphine sublingual tablets?

• Buprenorphine sublingual tablets are a prescription medicine used to treat opioid addiction in adults and is part of a complete treatment program that also includes counseling and behavioral therapy.

Who should not take buprenorphine sublingual tablets?

Do not take buprenorphine sublingual tablets if you are allergic to buprenorphine.

Before taking buprenorphine sublingual tablets, tell your healthcare provider about all of your medical conditions, including if you have:

Tell your healthcare provider if you are:

• pregnant or plan to become pregnant. If you take buprenorphine sublingual tablets while pregnant, your baby may have symptoms of opioid withdrawal at birth that could be life-threatening if not recognized and treated. Talk to your healthcare provider if you are pregnant or plan to become pregnant.
• breastfeeding or plan to breastfeed. Buprenorphine can pass into your breast milk and harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take buprenorphine sublingual tablets. Monitor your baby for increased drowsiness and breathing problems if you breastfeed during treatment with buprenorphine sublingual tablets.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, or herbal supplements.

How should I take buprenorphine sublingual tablets?

• After buprenorphine sublingual tablets are completely dissolved, rinse your mouth with water and swallow. Wait for at least one hour before brushing teeth.
• Report any problems with your teeth immediately to your provider and schedule an appointment with a dentist. Tell your dentist that you have started taking buprenorphine sublingual tablets.

Read the Instructions for Use at the end of this Medication Guide for detailed instructions on how to take buprenorphine sublingual tablets.

• Take buprenorphine sublingual tablets exactly as prescribed by your healthcare provider. Your healthcare provider may change your dose after seeing how it affects you. Do not change your dose unless your healthcare provider tells you to change it.
• Do not take buprenorphine sublingual tablets more often than prescribed by your healthcare provider.
• Buprenorphine sublingual tablets are not for occasional or "as needed" use.
• If you are prescribed a dose of 2 or more buprenorphine sublingual tablets at the same time:
  • Ask your healthcare provider for instructions on the right way to take buprenorphine sublingual tablets
• Follow the same instructions every time you take a dose of buprenorphine sublingual tablets.
• Take the entire buprenorphine sublingual tablet. Do not cut, chew, or swallow buprenorphine sublingual tablet because the medicine will not work as well.
• If you miss a dose of buprenorphine sublingual tablets, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the next dose at your regular time. Do not take 2 doses at the same time unless your healthcare provider tells you to. If you are not sure about your dosing, call your healthcare provider.
• Dispose of expired, unwanted, or unused buprenorphine sublingual tablets by promptly flushing down the toilet (if a drug take-back option is not readily available). Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.
• If you take too much buprenorphine sublingual tablets or overdose, call Poison Control or get emergency medical help right away.

What should I avoid while taking buprenorphine sublingual tablets?

• Do not drive, operate heavy machinery, or perform any other dangerous activities until you know how buprenorphine sublingual tablets affect you. Buprenorphine can cause drowsiness and slow reaction times. Buprenorphine sublingual tablets can make you sleepy, dizzy, or lightheaded.
• You should not drink alcohol or take prescription or over-the-counter medicines that contain alcohol while taking buprenorphine sublingual tablets, because this can lead to loss of consciousness or even death.

What are the possible side effects of buprenorphine sublingual tablets?

Buprenorphine sublingual tablets can cause serious side effects including:

• Trouble breathing. Taking buprenorphine sublingual tablets with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants can cause breathing problems that can lead to coma and death.
• Sleepiness, dizziness, and problems with coordination
• Physical dependence or abuse
• Liver problems. Call your healthcare provider right away if you notice any of these symptoms:

• Your healthcare provider should do blood tests to check your liver before you start taking and while you take buprenorphine sublingual tablets.
• Allergic reaction. You may have a rash, hives, swelling of your face, wheezing, low blood pressure, or loss of consciousness. Call your healthcare provider or get emergency help right away.
• Opioid withdrawal. Call your healthcare provider right away if you get any of these symptoms:

• Decrease in blood pressure. You may feel dizzy if you get up too fast from sitting or lying down.
• The most common side effects of buprenorphine sublingual tablets include:

• Buprenorphine sublingual tablets may affect fertility in males and females. Talk to your healthcare provider if this is a concern for you.

These are not all the possible side effects of buprenorphine sublingual tablets

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of buprenorphine sublingual tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not take buprenorphine sublingual tablets for a condition for which it was not prescribed. Do not give buprenorphine sublingual tablets to other people, even if they have the same symptoms you have. It may harm them and it is against the law.

You can ask your doctor or pharmacist for information that is written for healthcare professionals.

What are the ingredients in buprenorphine sublingual tablets?

Active Ingredients: buprenorphine

Inactive Ingredients: lactose monohydrate, povidone K29/32, anhydrous citric acid, trisodium citrate dihydrate, corn starch, mannitol, crospovidone, and magnesium stearate.

Marketed by: Rhodes Pharmaceuticals L.P., Coventry, RI 02816

Manufactured by: Purdue Pharma L.P., Stamford, CT 06901

Repackaged by: Clinical Solutions Wholesale, Franklin, TN 37067

For more information, call Rhodes Pharmaceuticals L.P. at 1-888-827-0616.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Revised: 06/2022

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

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.

Due to possible decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in geriatric patients, the decision to prescribe buprenorphine sublingual tablets should be made cautiously in individuals 65 years of age or older and these patients should be monitored for signs and symptoms of toxicity or overdose.

Clinical data on the safety and efficacy of buprenorphine sublingual tablets 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 sublingual 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 sublingual tablets on Day 1, followed by 16 mg (two 8 mg tablets) of buprenorphine sublingual tablets 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 through 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.

Buprenorphine sublingual tablets are contraindicated in patients with a history of hypersensitivity to buprenorphine, as serious adverse reactions, including anaphylactic shock, have been reported [see Warnings and Precautions (5.9)].

The following serious adverse reactions are described elsewhere in the labeling:

• Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]
• Respiratory and CNS Depression [see Warnings and Precautions (5.2, 5.3)]
• Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.5)]
• Adrenal Insufficiency [see Warnings and Precautions (5.6)]
• Opioid Withdrawal [see Warnings and Precautions (5.7, 5.10)]
• Hepatitis, Hepatic Events [see Warnings and Precautions (5.8)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.9)]
• Orthostatic Hypotension [see Warnings and Precautions (5.16)]
• Elevation of Cerebrospinal Fluid Pressure [see Warnings and Precautions (5.17)]
• Elevation of Intracholedochal Pressure [see Warnings and Precautions (5.18)]

Table 3 includes clinically significant drug interactions with buprenorphine sublingual tablets.

No differences in buprenorphine pharmacokinetics were observed between 9 dialysis-dependent and 6 normal patients following IV administration of 0.3 mg buprenorphine.

This "Instructions for Use" contains information on how to correctly take buprenorphine sublingual tablets.

Important Information You Need to Know Before Taking Buprenorphine Sublingual Tablets:

• Your healthcare provider should show you how to take buprenorphine sublingual tablets the right way.

Preparing to take Buprenorphine sublingual tablets:

• Put the tablets under your tongue. Let them dissolve completely.

• While buprenorphine sublingual tablets are dissolving, do not chew or swallow the tablet because the medicine will not work as well.
• Talking while the tablet is dissolving can affect how well the medicine in buprenorphine sublingual tablets is absorbed.
• After buprenorphine sublingual tablet is completely dissolved, rinse your mouth with water and swallow. Wait for at least one hour before brushing teeth.
• If you miss a dose of buprenorphine sublingual tablets, take your medicine when you remember. If it is almost time for your next dose, skip the missed dose and take the next dose at your regular time. Do not take 2 doses at the same time unless your healthcare provider tells you to. If you are not sure about your dosing, call your healthcare provider.
• Do not stop taking buprenorphine sublingual tablets suddenly. You could become sick and have withdrawal symptoms because your body has become used to the medicine. Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction. To have fewer withdrawal symptoms, ask your healthcare provider how to stop using buprenorphine sublingual tablets the right way.

If you take too much buprenorphine sublingual tablets or overdose, call Poison Control or get emergency medical help right away.

Storing buprenorphine sublingual tablets:

• Store buprenorphine sublingual tablets at room temperature between 68°F to 77°F (20°C to 25°C).
• Keep buprenorphine sublingual tablets in a safe place, out of the sight and reach of children.

Disposing of buprenorphine sublingual tablets:

• Dispose of unused buprenorphine sublingual tablets as soon as you no longer need them.
• Dispose of expired, unwanted or unused buprenorphine sublingual tablets by promptly flushing down the toilet (if a drug take-back option is not readily available). Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.

If you need help with disposal of buprenorphine sublingual tablets, call Rhodes Pharmaceuticals L.P. at 1-888-827-0616.

This "Instructions for Use" has been approved by the U.S. Food and Drug Administration.

Revised 06/2022

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.

Thorough QT studies with buprenorphine products have demonstrated QTc prolongation ≤15 msec. This QTc prolongation effect does not appear to be mediated by hERG channels. Based on these two findings, buprenorphine is unlikely to be pro-arrhythmic when used alone in patients without risk factors. The risk of combining buprenorphine with other QT-prolonging agents is not known.

Consider these observations in clinical decisions when prescribing buprenorphine sublingual tablets to patients with risk factors such as hypokalemia, bradycardia, recent conversion from atrial fibrillation, congestive heart failure, digitalis therapy, baseline QT prolongation, subclinical long-QT syndrome, or severe hypomagnesemia.

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 (2.8), Warnings and Precautions (5.12), Clinical Pharmacology (12.3)] .

Buprenorphine Sublingual Tablets are indicated for the treatment of opioid dependence and are preferred for induction. Buprenorphine sublingual tablets should be used as part of a complete treatment plan to include counseling and psychosocial support.

Buprenorphine sublingual tablets contain buprenorphine, a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor.

Treatment should be initiated with supervised administration, progressing to unsupervised administration as the patient's clinical stability permits. The use of buprenorphine sublingual tablets for unsupervised administration should be limited to those patients who cannot tolerate buprenorphine and naloxone sublingual tablets, for example those patients with known hypersensitivity to naloxone. Buprenorphine and naloxone sublingual tablets, and buprenorphine sublingual tablets are both 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 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 provider'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 healthcare provider should re-evaluate the appropriateness of continuing the current treatment.

Buprenorphine sublingual tablets contain buprenorphine, a Schedule III controlled substance 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 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.

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.

• Addiction, Abuse, and Misuse: Buprenorphine can be abused in a similar manner to other opioids. Monitor patients for conditions indicative of diversion or progression of opioid dependence and addictive behaviors. Multiple refills should not be prescribed early in treatment or without appropriate patient follow-up visits. ( 5.1)
• Respiratory Depression: Life-threatening respiratory depression and death have occurred in association with buprenorphine use. Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with buprenorphine sublingual tablets ( 5.2, 5.3)
• Unintentional Pediatric Exposure: Store buprenorphine sublingual tablets safely out of the sight and reach of children. Buprenorphine can cause severe, possibly fatal, respiratory depression in children. ( 5.4)
• Neonatal Opioid Withdrawal Syndrome: Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy. ( 5.5)
• Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.6)
• Risk of Opioid Withdrawal with Abrupt Discontinuation: If treatment is temporarily interrupted or discontinued, monitor patients for withdrawal and treat appropriately. ( 5.7)
• Risk of Hepatitis, Hepatic Events: Monitor liver function tests prior to initiation and during treatment and evaluate suspected hepatic events. ( 5.8)
• Precipitation of Opioid Withdrawal Signs and Symptoms: An opioid withdrawal syndrome is likely to occur with parenteral misuse of buprenorphine sublingual tablets by individuals physically dependent on full opioid agonists, or by sublingual administration before the agonist effects of other opioids have subsided. ( 5.10)
• Risk of Overdose in Opioid-Naïve Patients: Buprenorphine sublingual tablets are NOT appropriate as an analgesic. There have been reported deaths of opioid naïve individuals who received a 2 mg sublingual dose of buprenorphine. ( 5.11)

Cases of dental caries, some severe (i.e., tooth fracture, tooth loss), have been reported following the use of transmucosal buprenorphine-containing products. Reported events include cavities, tooth decay, dental abscesses/infection, rampant caries, tooth erosion, fillings falling out, and, in some cases, total tooth loss. Treatment for these events included tooth extraction, root canal, dental surgery, as well as other restorative procedures (i.e., fillings, crowns, implants, dentures). Multiple cases were reported in individuals without any prior history of dental problems.

Refer patients to dental care services and encourage them to have regular dental checkups while taking buprenorphine sublingual tablets. Educate patients to seek dental care and strategies to maintain or improve oral health while being treated with transmucosal buprenorphine-containing products. Strategies include, but are not limited to, gently rinsing the teeth and gums with water and then swallowing after buprenorphine sublingual tablets have been completely dissolved in the oral mucosa. Advise patients to wait for at least one hour after taking buprenorphine sublingual tablets before brushing teeth [see Dosing and Administration (2.6), Information for Patients (17), Medication Guide].

• Prescription use of this product is limited under the Drug Addiction Treatment Act. ( 2.1)
• Administer buprenorphine sublingual tablets sublingually as a single daily dose. ( 2.2)
• Strongly consider prescribing naloxone at the time buprenorphine sublingual tablets are initiated or renewed because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose. ( 2.3)
• To avoid precipitating withdrawal, induction with buprenorphine sublingual tablets should be undertaken when objective and clear signs of withdrawal are evident. ( 2.4)
• Buprenorphine and naloxone sublingual film or buprenorphine and naloxone sublingual tablets are generally initiated after two days of buprenorphine sublingual tablet titration. ( 2.5)
• Administer buprenorphine sublingual tablets as directed in the Full Prescribing Information. ( 2.4, 2.5, 2.6)
• Buprenorphine sublingual tablets must be administered whole. Do not cut, chew, or swallow buprenorphine sublingual tablets ( 2.6).
• When discontinuing treatment, gradually taper to avoid signs and symptoms of withdrawal. ( 2.10)

The decision to discontinue therapy with buprenorphine and naloxone sublingual tablets or buprenorphine sublingual tablets 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 (5.7)].

Buprenorphine sublingual tablets must be administered whole. Do not cut, chew, or swallow buprenorphine sublingual tablets. Advise patients not to eat or drink anything until the tablet is completely dissolved.

Buprenorphine 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.

Advise patients to do the following after the product has completely dissolved in the oral mucosa: take a sip of water, swish gently around the teeth and gums, and swallow. Advise patients to wait for at least one hour after taking buprenorphine sublingual tablets before brushing teeth [see Warnings and Precautions (5.13), Postmarketing Experience (6.2), Information for Patients (17), and the Medication Guide].

Buprenorphine sublingual tablets are supplied as white to off-white, round, flat-faced, beveled edged tablets in two dosage strengths:

• buprenorphine 2 mg, and
• buprenorphine 8 mg

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

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 buprenorphine sublingual tablets 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)] .

Local reactions: dental decay (including caries, tooth fracture, and tooth loss), glossodynia, glossitis, oral mucosal erythema, oral hypoesthesia, and stomatitis.

• Lactation: Buprenorphine passes into mother's milk. ( 8.2)
• Geriatric Patients: Monitor for sedation or respiratory depression. ( 8.5)
• Severe Hepatic Impairment: Consider reducing the starting and titration incremental dose by half and monitor for signs and symptoms of toxicity or overdose. ( 8.6)

Cases of hypersensitivity to buprenorphine 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 is a contraindication to the use of buprenorphine sublingual tablets.

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 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.

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.

Buprenorphine sublingual tablets contain buprenorphine, a Schedule III controlled substance that 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)].

Advise patients to read the FDA-approved patient labeling (Medication Guide).

Buprenorphine Sublingual Tablets are available in the following strengths:

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)].

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.

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.

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

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.

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.

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.

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.

NDC 58118-0502-8

Buprenorphine

Sublingual

Tablets

CIII

8mg

R _x only

PHARMACIST : Dispense the accompanying

Medication Guide to each patient.

Children who accidently take

buprenorphine will need emergency

medical care. Keep out of the reach of

children.

30 Tablets

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 (2.8), Use in Specific Populations (8.6)] .

• Buprenorphine sublingual tablets are administered sublingually as a single daily dose.

Buprenorphine sublingual tablets do not contain naloxone and are preferred for use only during induction. Following induction, buprenorphine and naloxone sublingual film or buprenorphine and naloxone sublingual tablets are 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 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.

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. Caution patients 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.

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 [see Drug Abuse and Dependence (9.3)] . When discontinuing buprenorphine sublingual tablets, gradually taper the dosage [see Dosage and Administration (2.10)].

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.

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver. Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with buprenorphine sublingual tablets. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose [see Warnings and Precautions (5.2)].

Advise patients and caregivers that naloxone may also be administered for a known or suspected overdose with buprenorphine sublingual tablets itself. Higher than normal doses and repeated administration of naloxone may be necessary due to the long duration of action of buprenorphine sublingual tablets and its affinity for the mu-opioid receptor [see Overdosage (10)] .

Inform patients and caregivers of their options for obtaining naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Patient Counseling Information (17)].

Concomitant use of buprenorphine and benzodiazepines or other CNS depressants increases the risk of adverse reactions including overdose and death. Medication-assisted treatment of opioid use disorder, however, should not be categorically denied to patients taking these drugs. Prohibiting or creating barriers to treatment can pose an even greater risk of morbidity and mortality due to the opioid use disorder alone.

As a routine part of orientation to buprenorphine treatment, educate patients about the risks of concomitant use of benzodiazepines, sedatives, opioid analgesics, and alcohol.

Develop strategies to manage use of prescribed or illicit benzodiazepines or other CNS depressants at initiation of buprenorphine treatment, or if it emerges as a concern during treatment. Adjustments to induction procedures and additional monitoring may be required. There is no evidence to support dose limitations or arbitrary caps of buprenorphine as a strategy to address benzodiazepine use in buprenorphine-treated patients. However, if a patient is sedated at the time of buprenorphine dosing, delay or omit the buprenorphine dose if appropriate.

Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use. In some cases, monitoring in a higher level of care for taper may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate.

For patients in buprenorphine treatment, benzodiazepines are not the treatment of choice for anxiety or insomnia. Before co-prescribing benzodiazepines, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments to address anxiety or insomnia. Ensure that other healthcare providers prescribing benzodiazepines or other CNS depressants are aware of the patient's buprenorphine treatment and coordinate care to minimize the risks associated with concomitant use.

If concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in buprenorphine treatment for opioid use disorder [see Warnings and Precautions (5.2)].

In addition, take measures to confirm that patients are taking their medications as prescribed and are not diverting or supplementing with illicit drugs. Toxicology screening should test for prescribed and illicit benzodiazepines [see Drug Interactions (7)].

Buprenorphine has been associated with life-threating respiratory depression and death. Many, but not all, post-marketing reports regarding coma and death involved misuses by self-injection or were associated with the concomitant use of benzodiazepines or other CNS depressants, including alcohol. Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with buprenorphine sublingual tablets [see Warning and Precautions (5.3), Drug Interactions (7)].

Use buprenorphine sublingual tablets 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).

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Patient Counseling Information (17)] .

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.10)].

Patients dependent on heroin or other short-acting opioid products:

At treatment initiation, the first dose of buprenorphine sublingual tablets 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 drop-out of buprenorphine patients during the induction period.

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 tablets 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.

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Store Buprenorphine Sublingual Tablets securely and dispose of properly [see Patient Counseling Information (17)].

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 healthcare provider 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.

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.

Buprenorphine Sublingual Tablets are supplied as white to off white, round flat-faced beveled edged tablets debossed with "RP" on one side and an alphanumeric word identifying product and strength on the other side. They contain buprenorphine HCl, a partial agonist at the mu-opioid receptor, and are 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, respectively). Each tablet also contains lactose monohydrate, povidone K29/32, anhydrous citric acid, trisodium citrate dihydrate, corn starch, mannitol, crospovidone, 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]-3,3-dimethylbutan-2-ol hydrochloride. It has the following chemical structure:

Buprenorphine HCl has the molecular formula C ₂₉ H 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.

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 (5.7) ].

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

• Buprenorphine and naloxone sublingual tablets are preferred for maintenance treatment.
• Where buprenorphine sublingual tablets are used in maintenance in patients who cannot tolerate the presence of naloxone, the dosage of buprenorphine sublingual tablets 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 buprenorphine sublingual tablets is generally in the range of 4 mg to 24 mg buprenorphine per day depending on the individual patient. The recommended target dosage of buprenorphine sublingual tablets 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 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.
• 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 buprenorphine sublingual tablets contributes to the intended treatment goals.

What is the most important information I should know about buprenorphine sublingual tablets?

• Buprenorphine sublingual tablets contain a medicine called buprenorphine. Buprenorphine is an opioid that can cause serious and life-threatening breathing problems, especially if you take or use certain other medicines or drugs.
• Talk to your healthcare provider about naloxone. Naloxone is a medicine that is available to patients for the emergency treatment of an opioid overdose, including accidental use of buprenorphine sublingual tablets by a child. If naloxone is given, you must call 911 or get emergency medical help right away to treat an overdose or accidental use of an opioid.
• Buprenorphine sublingual tablets may cause serious and life-threatening breathing problems. Get emergency help right away if you:

• Do not take buprenorphine sublingual tablets with certain medicines. Taking buprenorphine sublingual tablets with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.
• Do not inject ("shoot-up") buprenorphine sublingual tablets. Injecting buprenorphine sublingual tablets may cause life-threatening infections and other serious health problems.
• Do not switch from buprenorphine sublingual tablets to other medicines that contain buprenorphine without talking with your healthcare provider. The amount of buprenorphine in a dose of buprenorphine sublingual tablets is not the same as in other medicines that contain buprenorphine. Your healthcare provider will prescribe a starting dose of buprenorphine sublingual tablets that may be different than other buprenorphine containing medicines you may have been taking.
• Do not stop taking buprenorphine sublingual tablets suddenly. You could become sick and have withdrawal symptoms because your body has become used to the medicine (physical dependence). Physical dependence is not the same as drug addiction.
• In an emergency, have family members tell emergency department staff that you are physically dependent on an opioid and are being treated with buprenorphine sublingual tablets.
• Never give anyone else your buprenorphine sublingual tablets. They could die from taking it. Selling or giving away buprenorphine sublingual tablets is against the law.
• Store buprenorphine sublingual tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.

What are buprenorphine sublingual tablets?

• Buprenorphine sublingual tablets are a prescription medicine used to treat opioid addiction in adults and is part of a complete treatment program that also includes counseling and behavioral therapy.

Who should not take buprenorphine sublingual tablets?

Do not take buprenorphine sublingual tablets if you are allergic to buprenorphine.

Before taking buprenorphine sublingual tablets, tell your healthcare provider about all of your medical conditions, including if you have:

Tell your healthcare provider if you are:

• pregnant or plan to become pregnant. If you take buprenorphine sublingual tablets while pregnant, your baby may have symptoms of opioid withdrawal at birth that could be life-threatening if not recognized and treated. Talk to your healthcare provider if you are pregnant or plan to become pregnant.
• breastfeeding or plan to breastfeed. Buprenorphine can pass into your breast milk and harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take buprenorphine sublingual tablets. Monitor your baby for increased drowsiness and breathing problems if you breastfeed during treatment with buprenorphine sublingual tablets.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, or herbal supplements.

How should I take buprenorphine sublingual tablets?

• After buprenorphine sublingual tablets are completely dissolved, rinse your mouth with water and swallow. Wait for at least one hour before brushing teeth.
• Report any problems with your teeth immediately to your provider and schedule an appointment with a dentist. Tell your dentist that you have started taking buprenorphine sublingual tablets.

Read the Instructions for Use at the end of this Medication Guide for detailed instructions on how to take buprenorphine sublingual tablets.

• Take buprenorphine sublingual tablets exactly as prescribed by your healthcare provider. Your healthcare provider may change your dose after seeing how it affects you. Do not change your dose unless your healthcare provider tells you to change it.
• Do not take buprenorphine sublingual tablets more often than prescribed by your healthcare provider.
• Buprenorphine sublingual tablets are not for occasional or "as needed" use.
• If you are prescribed a dose of 2 or more buprenorphine sublingual tablets at the same time:
  • Ask your healthcare provider for instructions on the right way to take buprenorphine sublingual tablets
• Follow the same instructions every time you take a dose of buprenorphine sublingual tablets.
• Take the entire buprenorphine sublingual tablet. Do not cut, chew, or swallow buprenorphine sublingual tablet because the medicine will not work as well.
• If you miss a dose of buprenorphine sublingual tablets, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the next dose at your regular time. Do not take 2 doses at the same time unless your healthcare provider tells you to. If you are not sure about your dosing, call your healthcare provider.
• Dispose of expired, unwanted, or unused buprenorphine sublingual tablets by promptly flushing down the toilet (if a drug take-back option is not readily available). Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.
• If you take too much buprenorphine sublingual tablets or overdose, call Poison Control or get emergency medical help right away.

What should I avoid while taking buprenorphine sublingual tablets?

• Do not drive, operate heavy machinery, or perform any other dangerous activities until you know how buprenorphine sublingual tablets affect you. Buprenorphine can cause drowsiness and slow reaction times. Buprenorphine sublingual tablets can make you sleepy, dizzy, or lightheaded.
• You should not drink alcohol or take prescription or over-the-counter medicines that contain alcohol while taking buprenorphine sublingual tablets, because this can lead to loss of consciousness or even death.

What are the possible side effects of buprenorphine sublingual tablets?

Buprenorphine sublingual tablets can cause serious side effects including:

• Trouble breathing. Taking buprenorphine sublingual tablets with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants can cause breathing problems that can lead to coma and death.
• Sleepiness, dizziness, and problems with coordination
• Physical dependence or abuse
• Liver problems. Call your healthcare provider right away if you notice any of these symptoms:

• Your healthcare provider should do blood tests to check your liver before you start taking and while you take buprenorphine sublingual tablets.
• Allergic reaction. You may have a rash, hives, swelling of your face, wheezing, low blood pressure, or loss of consciousness. Call your healthcare provider or get emergency help right away.
• Opioid withdrawal. Call your healthcare provider right away if you get any of these symptoms:

• Decrease in blood pressure. You may feel dizzy if you get up too fast from sitting or lying down.
• The most common side effects of buprenorphine sublingual tablets include:

• Buprenorphine sublingual tablets may affect fertility in males and females. Talk to your healthcare provider if this is a concern for you.

These are not all the possible side effects of buprenorphine sublingual tablets

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of buprenorphine sublingual tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not take buprenorphine sublingual tablets for a condition for which it was not prescribed. Do not give buprenorphine sublingual tablets to other people, even if they have the same symptoms you have. It may harm them and it is against the law.

You can ask your doctor or pharmacist for information that is written for healthcare professionals.

What are the ingredients in buprenorphine sublingual tablets?

Active Ingredients: buprenorphine

Inactive Ingredients: lactose monohydrate, povidone K29/32, anhydrous citric acid, trisodium citrate dihydrate, corn starch, mannitol, crospovidone, and magnesium stearate.

Marketed by: Rhodes Pharmaceuticals L.P., Coventry, RI 02816

Manufactured by: Purdue Pharma L.P., Stamford, CT 06901

Repackaged by: Clinical Solutions Wholesale, Franklin, TN 37067

For more information, call Rhodes Pharmaceuticals L.P. at 1-888-827-0616.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Revised: 06/2022

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

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.

Due to possible decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in geriatric patients, the decision to prescribe buprenorphine sublingual tablets should be made cautiously in individuals 65 years of age or older and these patients should be monitored for signs and symptoms of toxicity or overdose.

Clinical data on the safety and efficacy of buprenorphine sublingual tablets 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 sublingual 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 sublingual tablets on Day 1, followed by 16 mg (two 8 mg tablets) of buprenorphine sublingual tablets 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 through 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.

Buprenorphine sublingual tablets are contraindicated in patients with a history of hypersensitivity to buprenorphine, as serious adverse reactions, including anaphylactic shock, have been reported [see Warnings and Precautions (5.9)].

The following serious adverse reactions are described elsewhere in the labeling:

• Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]
• Respiratory and CNS Depression [see Warnings and Precautions (5.2, 5.3)]
• Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.5)]
• Adrenal Insufficiency [see Warnings and Precautions (5.6)]
• Opioid Withdrawal [see Warnings and Precautions (5.7, 5.10)]
• Hepatitis, Hepatic Events [see Warnings and Precautions (5.8)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.9)]
• Orthostatic Hypotension [see Warnings and Precautions (5.16)]
• Elevation of Cerebrospinal Fluid Pressure [see Warnings and Precautions (5.17)]
• Elevation of Intracholedochal Pressure [see Warnings and Precautions (5.18)]

Table 3 includes clinically significant drug interactions with buprenorphine sublingual tablets.

No differences in buprenorphine pharmacokinetics were observed between 9 dialysis-dependent and 6 normal patients following IV administration of 0.3 mg buprenorphine.

This "Instructions for Use" contains information on how to correctly take buprenorphine sublingual tablets.

Important Information You Need to Know Before Taking Buprenorphine Sublingual Tablets:

• Your healthcare provider should show you how to take buprenorphine sublingual tablets the right way.

Preparing to take Buprenorphine sublingual tablets:

• Put the tablets under your tongue. Let them dissolve completely.

• While buprenorphine sublingual tablets are dissolving, do not chew or swallow the tablet because the medicine will not work as well.
• Talking while the tablet is dissolving can affect how well the medicine in buprenorphine sublingual tablets is absorbed.
• After buprenorphine sublingual tablet is completely dissolved, rinse your mouth with water and swallow. Wait for at least one hour before brushing teeth.
• If you miss a dose of buprenorphine sublingual tablets, take your medicine when you remember. If it is almost time for your next dose, skip the missed dose and take the next dose at your regular time. Do not take 2 doses at the same time unless your healthcare provider tells you to. If you are not sure about your dosing, call your healthcare provider.
• Do not stop taking buprenorphine sublingual tablets suddenly. You could become sick and have withdrawal symptoms because your body has become used to the medicine. Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction. To have fewer withdrawal symptoms, ask your healthcare provider how to stop using buprenorphine sublingual tablets the right way.

If you take too much buprenorphine sublingual tablets or overdose, call Poison Control or get emergency medical help right away.

Storing buprenorphine sublingual tablets:

• Store buprenorphine sublingual tablets at room temperature between 68°F to 77°F (20°C to 25°C).
• Keep buprenorphine sublingual tablets in a safe place, out of the sight and reach of children.

Disposing of buprenorphine sublingual tablets:

• Dispose of unused buprenorphine sublingual tablets as soon as you no longer need them.
• Dispose of expired, unwanted or unused buprenorphine sublingual tablets by promptly flushing down the toilet (if a drug take-back option is not readily available). Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.

If you need help with disposal of buprenorphine sublingual tablets, call Rhodes Pharmaceuticals L.P. at 1-888-827-0616.

This "Instructions for Use" has been approved by the U.S. Food and Drug Administration.

Revised 06/2022

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.

Thorough QT studies with buprenorphine products have demonstrated QTc prolongation ≤15 msec. This QTc prolongation effect does not appear to be mediated by hERG channels. Based on these two findings, buprenorphine is unlikely to be pro-arrhythmic when used alone in patients without risk factors. The risk of combining buprenorphine with other QT-prolonging agents is not known.

Consider these observations in clinical decisions when prescribing buprenorphine sublingual tablets to patients with risk factors such as hypokalemia, bradycardia, recent conversion from atrial fibrillation, congestive heart failure, digitalis therapy, baseline QT prolongation, subclinical long-QT syndrome, or severe hypomagnesemia.

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 (2.8), Warnings and Precautions (5.12), Clinical Pharmacology (12.3)] .

Buprenorphine Sublingual Tablets are indicated for the treatment of opioid dependence and are preferred for induction. Buprenorphine sublingual tablets should be used as part of a complete treatment plan to include counseling and psychosocial support.

Buprenorphine sublingual tablets contain buprenorphine, a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor.

Treatment should be initiated with supervised administration, progressing to unsupervised administration as the patient's clinical stability permits. The use of buprenorphine sublingual tablets for unsupervised administration should be limited to those patients who cannot tolerate buprenorphine and naloxone sublingual tablets, for example those patients with known hypersensitivity to naloxone. Buprenorphine and naloxone sublingual tablets, and buprenorphine sublingual tablets are both 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 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 provider'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 healthcare provider should re-evaluate the appropriateness of continuing the current treatment.

Buprenorphine sublingual tablets contain buprenorphine, a Schedule III controlled substance 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 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.

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.

• Addiction, Abuse, and Misuse: Buprenorphine can be abused in a similar manner to other opioids. Monitor patients for conditions indicative of diversion or progression of opioid dependence and addictive behaviors. Multiple refills should not be prescribed early in treatment or without appropriate patient follow-up visits. ( 5.1)
• Respiratory Depression: Life-threatening respiratory depression and death have occurred in association with buprenorphine use. Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with buprenorphine sublingual tablets ( 5.2, 5.3)
• Unintentional Pediatric Exposure: Store buprenorphine sublingual tablets safely out of the sight and reach of children. Buprenorphine can cause severe, possibly fatal, respiratory depression in children. ( 5.4)
• Neonatal Opioid Withdrawal Syndrome: Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy. ( 5.5)
• Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.6)
• Risk of Opioid Withdrawal with Abrupt Discontinuation: If treatment is temporarily interrupted or discontinued, monitor patients for withdrawal and treat appropriately. ( 5.7)
• Risk of Hepatitis, Hepatic Events: Monitor liver function tests prior to initiation and during treatment and evaluate suspected hepatic events. ( 5.8)
• Precipitation of Opioid Withdrawal Signs and Symptoms: An opioid withdrawal syndrome is likely to occur with parenteral misuse of buprenorphine sublingual tablets by individuals physically dependent on full opioid agonists, or by sublingual administration before the agonist effects of other opioids have subsided. ( 5.10)
• Risk of Overdose in Opioid-Naïve Patients: Buprenorphine sublingual tablets are NOT appropriate as an analgesic. There have been reported deaths of opioid naïve individuals who received a 2 mg sublingual dose of buprenorphine. ( 5.11)

Cases of dental caries, some severe (i.e., tooth fracture, tooth loss), have been reported following the use of transmucosal buprenorphine-containing products. Reported events include cavities, tooth decay, dental abscesses/infection, rampant caries, tooth erosion, fillings falling out, and, in some cases, total tooth loss. Treatment for these events included tooth extraction, root canal, dental surgery, as well as other restorative procedures (i.e., fillings, crowns, implants, dentures). Multiple cases were reported in individuals without any prior history of dental problems.

Refer patients to dental care services and encourage them to have regular dental checkups while taking buprenorphine sublingual tablets. Educate patients to seek dental care and strategies to maintain or improve oral health while being treated with transmucosal buprenorphine-containing products. Strategies include, but are not limited to, gently rinsing the teeth and gums with water and then swallowing after buprenorphine sublingual tablets have been completely dissolved in the oral mucosa. Advise patients to wait for at least one hour after taking buprenorphine sublingual tablets before brushing teeth [see Dosing and Administration (2.6), Information for Patients (17), Medication Guide].

• Prescription use of this product is limited under the Drug Addiction Treatment Act. ( 2.1)
• Administer buprenorphine sublingual tablets sublingually as a single daily dose. ( 2.2)
• Strongly consider prescribing naloxone at the time buprenorphine sublingual tablets are initiated or renewed because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose. ( 2.3)
• To avoid precipitating withdrawal, induction with buprenorphine sublingual tablets should be undertaken when objective and clear signs of withdrawal are evident. ( 2.4)
• Buprenorphine and naloxone sublingual film or buprenorphine and naloxone sublingual tablets are generally initiated after two days of buprenorphine sublingual tablet titration. ( 2.5)
• Administer buprenorphine sublingual tablets as directed in the Full Prescribing Information. ( 2.4, 2.5, 2.6)
• Buprenorphine sublingual tablets must be administered whole. Do not cut, chew, or swallow buprenorphine sublingual tablets ( 2.6).
• When discontinuing treatment, gradually taper to avoid signs and symptoms of withdrawal. ( 2.10)

The decision to discontinue therapy with buprenorphine and naloxone sublingual tablets or buprenorphine sublingual tablets 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 (5.7)].

Buprenorphine sublingual tablets must be administered whole. Do not cut, chew, or swallow buprenorphine sublingual tablets. Advise patients not to eat or drink anything until the tablet is completely dissolved.

Buprenorphine 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.

Advise patients to do the following after the product has completely dissolved in the oral mucosa: take a sip of water, swish gently around the teeth and gums, and swallow. Advise patients to wait for at least one hour after taking buprenorphine sublingual tablets before brushing teeth [see Warnings and Precautions (5.13), Postmarketing Experience (6.2), Information for Patients (17), and the Medication Guide].

Buprenorphine sublingual tablets are supplied as white to off-white, round, flat-faced, beveled edged tablets in two dosage strengths:

• buprenorphine 2 mg, and
• buprenorphine 8 mg

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

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 buprenorphine sublingual tablets 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)] .

Local reactions: dental decay (including caries, tooth fracture, and tooth loss), glossodynia, glossitis, oral mucosal erythema, oral hypoesthesia, and stomatitis.

• Lactation: Buprenorphine passes into mother's milk. ( 8.2)
• Geriatric Patients: Monitor for sedation or respiratory depression. ( 8.5)
• Severe Hepatic Impairment: Consider reducing the starting and titration incremental dose by half and monitor for signs and symptoms of toxicity or overdose. ( 8.6)

Cases of hypersensitivity to buprenorphine 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 is a contraindication to the use of buprenorphine sublingual tablets.

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 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.

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.

Buprenorphine sublingual tablets contain buprenorphine, a Schedule III controlled substance that 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)].

Advise patients to read the FDA-approved patient labeling (Medication Guide).

Buprenorphine Sublingual Tablets are available in the following strengths:

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)].

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.

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.

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

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.

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.

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.

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.

NDC 58118-0502-8

Buprenorphine

Sublingual

Tablets

CIII

8mg

R _x only

PHARMACIST : Dispense the accompanying

Medication Guide to each patient.

Children who accidently take

buprenorphine will need emergency

medical care. Keep out of the reach of

children.

30 Tablets

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 (2.8), Use in Specific Populations (8.6)] .

• Buprenorphine sublingual tablets are administered sublingually as a single daily dose.

Buprenorphine sublingual tablets do not contain naloxone and are preferred for use only during induction. Following induction, buprenorphine and naloxone sublingual film or buprenorphine and naloxone sublingual tablets are 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 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.

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. Caution patients 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.

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 [see Drug Abuse and Dependence (9.3)] . When discontinuing buprenorphine sublingual tablets, gradually taper the dosage [see Dosage and Administration (2.10)].

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.

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver. Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with buprenorphine sublingual tablets. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose [see Warnings and Precautions (5.2)].

Advise patients and caregivers that naloxone may also be administered for a known or suspected overdose with buprenorphine sublingual tablets itself. Higher than normal doses and repeated administration of naloxone may be necessary due to the long duration of action of buprenorphine sublingual tablets and its affinity for the mu-opioid receptor [see Overdosage (10)] .

Inform patients and caregivers of their options for obtaining naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Patient Counseling Information (17)].

Concomitant use of buprenorphine and benzodiazepines or other CNS depressants increases the risk of adverse reactions including overdose and death. Medication-assisted treatment of opioid use disorder, however, should not be categorically denied to patients taking these drugs. Prohibiting or creating barriers to treatment can pose an even greater risk of morbidity and mortality due to the opioid use disorder alone.

As a routine part of orientation to buprenorphine treatment, educate patients about the risks of concomitant use of benzodiazepines, sedatives, opioid analgesics, and alcohol.

Develop strategies to manage use of prescribed or illicit benzodiazepines or other CNS depressants at initiation of buprenorphine treatment, or if it emerges as a concern during treatment. Adjustments to induction procedures and additional monitoring may be required. There is no evidence to support dose limitations or arbitrary caps of buprenorphine as a strategy to address benzodiazepine use in buprenorphine-treated patients. However, if a patient is sedated at the time of buprenorphine dosing, delay or omit the buprenorphine dose if appropriate.

Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use. In some cases, monitoring in a higher level of care for taper may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate.

For patients in buprenorphine treatment, benzodiazepines are not the treatment of choice for anxiety or insomnia. Before co-prescribing benzodiazepines, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments to address anxiety or insomnia. Ensure that other healthcare providers prescribing benzodiazepines or other CNS depressants are aware of the patient's buprenorphine treatment and coordinate care to minimize the risks associated with concomitant use.

If concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in buprenorphine treatment for opioid use disorder [see Warnings and Precautions (5.2)].

In addition, take measures to confirm that patients are taking their medications as prescribed and are not diverting or supplementing with illicit drugs. Toxicology screening should test for prescribed and illicit benzodiazepines [see Drug Interactions (7)].

Buprenorphine has been associated with life-threating respiratory depression and death. Many, but not all, post-marketing reports regarding coma and death involved misuses by self-injection or were associated with the concomitant use of benzodiazepines or other CNS depressants, including alcohol. Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with buprenorphine sublingual tablets [see Warning and Precautions (5.3), Drug Interactions (7)].

Use buprenorphine sublingual tablets 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).

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Patient Counseling Information (17)] .

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.10)].