BUPRENORPHINE: Package Insert and Label Information (Page 5 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity

Carcinogenicity studies of buprenorphine were conducted in Sprague-Dawley rats and CD-1 mice. Buprenorphine was administered in the diet to rats at doses of 0.6, 5.5, and 56 mg/kg/day (estimated exposure was approximately 0.4, 3, and 35 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis) for 27 months. As in the buprenorphine/naloxone carcinogenicity study in rat, statistically significant dose-related increases in Leydig cell tumors occurred. In an 86-week study in CD-1 mice, buprenorphine was not carcinogenic at dietary doses up to 100 mg/kg/day (estimated exposure was approximately 30 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis).

Mutagenicity

Buprenorphine was studied in a series of tests utilizing gene, chromosome, and DNA interactions in both prokaryotic and eukaryotic systems. Results were negative in yeast (S. cerevisiae) for recombinant, gene convertant, or forward mutations; negative in Bacillus subtilis “rec” assay, negative for clastogenicity in CHO cells, Chinese hamster bone marrow and spermatogonia cells, and negative in the mouse lymphoma L5178Y assay.

Results were equivocal in the Ames test, negative in studies in two laboratories, but positive for frame shift mutation at a high dose (5 mg/plate) in a third study. Results were positive in the Green-Tweets (E. coli) survival test, positive in a DNA synthesis inhibition (DSI) test with testicular tissue from mice, for both in vivo and in vitro incorporation of [3 H]thymidine, and positive in unscheduled DNA synthesis (UDS) test using testicular cells from mice.

Impairment of Fertility

Reproduction studies of buprenorphine in rats demonstrated no evidence of impaired fertility at daily oral doses up to 80 mg/kg/day (estimated exposure was approximately 50 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis) or up to 5 mg/kg/day IM or SC (estimated exposure was approximately 3 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis).

14 CLINICAL STUDIES

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.

16 HOW SUPPLIED/STORAGE AND HANDLING

NDC: 71335-0950-8: 120 Tablets in a BOTTLE

NDC: 71335-0950-1: 60 Tablets in a BOTTLE

NDC: 71335-0950-2: 90 Tablets in a BOTTLE

NDC: 71335-0950-3: 30 Tablets in a BOTTLE

NDC: 71335-0950-4: 7 Tablets in a BOTTLE

NDC: 71335-0950-5: 28 Tablets in a BOTTLE

NDC: 71335-0950-6: 1 Tablets in a BOTTLE

NDC: 71335-0950-7: 12 Tablets in a BOTTLE

17 PATIENT COUNSELING INFORMATION

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

Storage and Disposal

Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to 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 [see Warnings and Precautions (5.1, 5.4), Drug Abuse and Dependence (9.2)]. Inform patients that leaving buprenorphine sublingual tablets unsecured can pose a deadly risk to others in the home.

Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused buprenorphine sublingual tablets should be disposed of by flushing the unused medication down the toilet if a drug take-back option is not readily available. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines.

Safe Use

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

  • Inform patients and caregivers that potentially fatal additive effects may occur if buprenorphine sublingual tablets are used with benzodiazepines or other CNS depressants, including alcohol. Counsel patients that such medications should not be used concomitantly unless supervised by a health care provider [see Warnings and Precautions (5.2, 5.3), Drug Interactions (7)].
  • 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 Warnings and Precautions (5.2)].
  • Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose
    Because patients being treated for opioid use disorder are at risk for relapse, discuss the importance of having access to naloxone with the patient and caregiver. Also discuss the importance of having access to naloxone if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose.
    Inform patients and caregivers of the 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).
    Educate patients and caregivers on how to recognize the signs and symptoms of an opioid overdose.
    Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered. Repeat administration may be necessary, particularly for overdose involving buprenorphine and naloxone sublingual film, because naloxone is often not effective at the doses available for patient access [Dosage and Administration (2.3), Warnings and Precautions (5.2), Overdosage (10)].
    If naloxone is prescribed, also advise patients and caregivers:

    • How to treat with naloxone in the event of an opioid overdose
    • To tell family and friends about their naloxone and to keep it in a place where family and friends can easily access it in an emergency
    • To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do.
  • Advise patients that buprenorphine sublingual tablets contain an opioid that can be a target for people who abuse prescription medications or street drugs, to keep their tablets in a safe place, and to protect them from theft.
  • Instruct patients to keep buprenorphine sublingual tablets in a secure place, out of the sight and reach of children. Accidental or deliberate ingestion by a child may cause respiratory depression that can result in death. Advise patients to seek medical attention immediately if a child is exposed to buprenorphine sublingual tablets.
  • Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take, serotonergic medications [see Drug Interactions (7)].
  • Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.6)] .
  • Advise patients to never give buprenorphine sublingual tablets to anyone else, even if he or she has the same signs and symptoms. It may cause harm or death.
  • Advise patients that selling or giving away this medication is against the law.
  • Advise patients that, after buprenorphine sublingual tablets have completely dissolved in the oral mucosa, to take a sip of water, swish it gently around their 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)].
  • Refer patients to dental care services and encourage them to have regular dental checkups while taking buprenorphine sublingual tablets. Instruct patients to inform their dentist that they have started therapy on buprenorphine sublingual tablets [see Warnings and Precautions (5.13)].
  • Caution patients that buprenorphine sublingual tablets may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving or operating hazardous machinery. Caution should be taken especially during drug induction and dose adjustment and until individuals are reasonably certain that buprenorphine therapy does not adversely affect their ability to engage in such activities [see Warnings and Precautions (5.15)] .
  • Advise patients not to change the dosage of buprenorphine sublingual tablets without consulting their healthcare providers.
  • Advise patients that if they miss a dose of buprenorphine sublingual tablets they should take it as soon as they remember. If it is almost time for the next dose, they should skip the missed dose and take the next dose at the regular time.
  • Advise patients to take buprenorphine sublingual tablets once a day.
  • Inform patients that buprenorphine sublingual tablets can cause drug dependence and that withdrawal signs and symptoms may occur when the medication is discontinued.
  • Advise patients seeking to discontinue treatment with buprenorphine for opioid dependence to work closely with their healthcare providers on a tapering schedule and inform them of the potential to relapse to illicit drug use associated with discontinuation of opioid agonist/partial agonist medication-assisted treatment.
  • Advise patients that, like other opioids, buprenorphine sublingual tablets may produce orthostatic hypotension in ambulatory individuals [see Warnings and Precautions (5.16)].
  • Advise patients to inform their healthcare providers if any other prescription medications, over-the-counter medications, or herbal preparations are prescribed or currently being used [see Drug Interactions (7)].
  • Advise women that if they are pregnant while being treated with buprenorphine sublingual tablets, the baby may have signs of withdrawal at birth and that withdrawal is treatable [see Warnings and Precautions (5.5), Use in Specific Populations (8.1)].
  • Advise women who are breastfeeding to monitor the infant for drowsiness and difficulty breathing [see Use in Specific Populations (8.2)].
  • Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations (8.3)].
  • Advise patients to inform their family members that, in the event of emergency, the treating healthcare providers or emergency room staff should be informed that the patient is physically dependent on an opioid and that the patient is being treated with buprenorphine sublingual tablets.

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

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

304679-0E

Rev: 06/2022

MEDICATION GUIDE Buprenorphine (byoo-pre-NOR-feen) Sublingual Tablets, CIII

IMPORTANT: Keep buprenorphine sublingual tablets in a secure place away from children. Accidental use by a child is a medical emergency and can result in death. If a child accidentally takes buprenorphine sublingual tablets, get emergency help or call 911 right away. Tell your healthcare provider if you are living in a household where there are small children.

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:
    • feel faint
    • have blurred vision
    • feel dizzy
    • have slurred speech
    • are confused
    • are breathing slower than normal
    • feel sleepy or uncoordinated
    • cannot think well or clearly
  • 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:

  • trouble breathing or lung problems
  • an enlarged prostate (men)
  • a head injury or brain problem
  • a curve in your spine that affects your breathing
  • problems urinating
  • mental health problems
  • Addison’s disease
  • liver, kidney, or gallbladder problems
  • adrenal gland or thyroid gland problems
  • alcoholism
  • tooth problems, including a history of cavities

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 skin or the white part of your eyes turns yellow (jaundice)
  • loss of appetite
  • dark or “tea-colored” urine
  • pain, aching, or tenderness on the right side of your stomach area
  • light colored stools (bowel movements)
  • nausea
  • 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:
  • shaking
  • goose bumps
  • sweating more than normal
  • diarrhea
  • feeling hot or cold more than normal
  • vomiting
  • runny nose
  • muscle aches
  • watery eyes
  • 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:
  • headache
  • pain
  • nausea
  • increased sweating
  • vomiting
  • decrease in sleep
  • constipation
  • 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

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

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