Buprenorphine and Naloxone Sublingual Tablets

Name: Buprenorphine and Naloxone Sublingual Tablets

Patient information

No information provided. Please refer to the WARNINGS AND PRECAUTIONS sections.

How is this medicine (Buprenorphine and Naloxone Sublingual Tablets) best taken?

Use this medicine (buprenorphine and naloxone sublingual tablets) as ordered by your doctor. Read all information given to you. Follow all instructions closely.

  • To gain the most benefit, do not miss doses.
  • Take this medicine at the same time of day.
  • Do not chew or swallow.
  • Do not eat, drink, smoke, or talk while this medicine (buprenorphine and naloxone sublingual tablets) is melting.
  • Take by mouth only. Very bad and sometimes deadly side effects may happen if this medicine is injected.
  • Place tablet under the tongue and let melt.
  • If your doctor tells you to use more than 1 tablet at a time, ask your doctor how to take them.

What do I do if I miss a dose?

  • Take a missed dose as soon as you think about it.
  • If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
  • Do not take 2 doses at the same time or extra doses.
  • If you are not sure what to do if you miss a dose, call your doctor.

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Very bad dizziness or passing out.
  • Trouble breathing, slow breathing, or shallow breathing.
  • Feeling very sleepy.
  • Feeling confused.
  • Very hard stools (constipation).
  • Change in eyesight.
  • Feeling very tired or weak.
  • Feeling nervous and excitable.
  • Change in balance.
  • Mood changes.
  • Anxiety.
  • Extra muscle action or slow movement.
  • Slurred speech.
  • Very bad and sometimes deadly liver problems have happened with this medicine (buprenorphine and naloxone sublingual tablets). Call your doctor right away if you have signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
  • Taking an opioid drug like this medicine may lead to a rare but very bad adrenal gland problem. Call your doctor right away if you have very bad dizziness or passing out, very bad upset stomach or throwing up, or if you feel less hungry, very tired, or very weak.
  • A very bad and sometimes deadly health problem called serotonin syndrome may happen if you take this medicine (buprenorphine and naloxone sublingual tablets) with drugs for depression, migraines, or certain other drugs. Call your doctor right away if you have agitation; change in balance; confusion; hallucinations; fever; fast or abnormal heartbeat; flushing; muscle twitching or stiffness; seizures; shivering or shaking; sweating a lot; very bad diarrhea, upset stomach, or throwing up; or very bad headache.

Indications and Usage for Buprenorphine and Naloxone Sublingual Tablets


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

Under the Drug Addiction Treatment Act (DATA) codified at 21 U.S.C. 823(g), prescription use of this product in the treatment of opioid dependence is limited to 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.

Drug Interactions

Table 3 Includes clinically significant drug interactions with Buprenorphine and Naloxone Sublingual Tablets
Benzodiazepines
Clinical Impact:
There have been a number of reports regarding coma and death associated with the misuse and abuse of the combination of buprenorphine and benzodiazepines. In many, but not all of these cases, buprenorphine was misused by self-injection of crushed buprenorphine tablets. Preclinical studies have shown that the combination of benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists.
Intervention:
Closely monitor patients with concurrent use of Buprenorphine and Naloxone Sublingual Tablets and benzodiazepines. Warn patients that it is extremely dangerous to self-administer benzodiazepines while taking Buprenorphine and Naloxone Sublingual Tablets, and warn patients to use benzodiazepines concurrently with Buprenorphine and Naloxone Sublingual Tablets only as directed by their healthcare provider.
Non-Benzodiazepine Central Nervous System (CNS) Depressants
Clinical Impact:
Due to additive pharmacologic effects, the concomitant use of non-benzodiazepine CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:
Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.2, 5.3)].
Examples:
Alcohol, non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids.
Inhibitors of CYP3A4
Clinical Impact:
The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of Buprenorphine and Naloxone Sublingual Tablets is achieved.
 
After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease [see Clinical Pharmacology (12.3)], potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine.
Intervention:
If concomitant use is necessary, consider dosage reduction of Buprenorphine and Naloxone Sublingual Tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.
 
If a CYP3A4 inhibitor is discontinued, consider increasing the Buprenorphine and Naloxone Sublingual Tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples:
Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:
The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine [see Clinical Pharmacology (12.3)], potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine.
 
After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression.
Intervention:
If concomitant use is necessary, consider increasing the Buprenorphine and Naloxone Sublingual Tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
 
If a CYP3A4 inducer is discontinued, consider Buprenorphine and Naloxone Sublingual Tablets dosage reduction and monitor for signs of respiratory depression.
Examples:
Rifampin, carbamazepine, phenytoin
Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Clinical Impact:
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delaviridine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects.
Intervention:
Patients who are on chronic Buprenorphine and Naloxone Sublingual Tablets treatment should have their dose monitored if NNRTIs are added to their treatment regimen.
Examples:
efavirenz, nevirapine, etravirine, delavirdine
Antiretrovirals: Protease inhibitors (PIs)
Clinical Impact:
Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in postmarketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly.
Intervention:
Monitor patients taking Buprenorphine and Naloxone Sublingual Tablets and atazanavir with and without ritonavir, and reduce dose of Buprenorphine and Naloxone Sublingual Tablets if warranted.
Examples:
atazanavir, ritonavir
Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs)
Clinical Impact:
Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected.
Intervention:
None
Serotonergic Drugs
Clinical Impact:
The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:
If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Buprenorphine and Naloxone Sublingual Tablets if serotonin syndrome is suspected.
Examples:
Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:
MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).
Intervention:
The use of Buprenorphine and Naloxone Sublingual Tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:
phenelzine, tranylcypromine, linezolid
Muscle Relaxants
Clinical Impact:
Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:
Monitor patients receiving muscle relaxants and Buprenorphine and Naloxone Sublingual Tablets for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Buprenorphine and Naloxone Sublingual Tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:
Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:
Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:
The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:
Monitor patients for signs of urinary retention or reduced gastric motility when Buprenorphine and Naloxone Sublingual Tablets are used concomitantly with anticholinergic drugs.

Use in specific populations

Pregnancy

Risk Summary

There are no adequate and well-controlled studies of Buprenorphine and Naloxone Sublingual Tablets or buprenorphine/naloxone in pregnant women. Limited published data on use of buprenorphine, the active ingredient in Buprenorphine and Naloxone Sublingual Tablets, in pregnancy, have not shown an increased risk of major malformations.

Reproductive and developmental studies in rats and rabbits identified adverse events at clinically relevant and higher doses. Embryofetal death was observed in both rats and rabbits administered buprenorphine during the period of organogenesis at doses approximately 6 and 0.3 times, respectively, the human sublingual dose of 16 mg/day of buprenorphine. Pre-and postnatal development studies in rats demonstrated increased neonatal deaths at 0.3 times and above and dystocia at approximately 3 times the human sublingual dose of 16 mg/day of buprenorphine. No clear teratogenic effects were seen when buprenorphine was administered during organogenesis with a range of doses equivalent to or greater than the human sublingual dose of 16 mg/day of buprenorphine. However, increases in skeletal abnormalities were noted in rats and rabbits administered buprenorphine daily during organogenesis at doses approximately 0.6 times and approximately equal to the human sublingual dose of 16 mg/day of buprenorphine, respectively. In a few studies, some events such as acephalus and omphalocele were also observed but these findings were not clearly treatment-related [see Data].


The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.


Clinical Considerations

Disease-associated maternal and embryo-fetal risk

Untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes such as low birth weight, preterm birth, and fetal death. In addition, untreated opioid addiction often results in continued or relapsing illicit opioid use.


Fetal/neonatal adverse reactions

Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with Buprenorphine and Naloxone Sublingual Tablets.


Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight. Signs of neonatal withdrawal usually occur in the first days after birth. The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.5)].


Labor or Delivery

As with all opioids, use of buprenorphine prior to delivery may result in respiratory depression in the newborn. Closely monitor neonates for signs of respiratory depression. An opioid antagonist such as naloxone should be available for reversal of opioid induced respiratory depression in the neonate.

Data

Human Data

Studies have been conducted to evaluate neonatal outcomes in women exposed to buprenorphine during pregnancy. Limited published data on malformations from trials, observational studies, case series, and case reports on buprenorphine use in pregnancy have not shown an increased risk of major malformations. Based on these studies the incidence of neonatal abstinence syndrome is not clear and there does not appear to be a dose-response relationship.


Animal Data

The exposure margins listed below are based on body surface area comparisons (mg/m2) to the human sublingual dose of 16 mg buprenorphine via Buprenorphine and Naloxone Sublingual Tablets.


Effects on embryo-fetal development were studied in Sprague-Dawley rats and Russian white rabbits following oral (1:1) and intramuscular (IM) (3:2) administration of mixtures of buprenorphine and naloxone during the period of organogenesis. Following oral administration to rats no teratogenic effects were observed at buprenorphine doses up to 250 mg/kg/day (estimated exposure approximately 150 times the human sublingual dose of 16 mg) in the presence of maternal toxicity (mortality). Following oral administration to rabbits, no teratogenic effects were observed at buprenorphine doses up to 40 mg/kg/day (estimated exposure approximately 50 times, the human sublingual dose of 16 mg) in the absence of clear maternal toxicity.


No definitive drug-related teratogenic effects were observed in rats and rabbits at IM doses up to 30 mg/kg/day (estimated exposure approximately 20 times and 35 times, respectively, the human sublingual dose of 16 mg). Maternal toxicity resulting in mortality was noted in these studies in both rats and rabbits. Acephalus was observed in one rabbit fetus from the low-dose group and omphalocele was observed in two rabbit fetuses from the same litter in the mid-dose group; no findings were observed in fetuses from the high dose group. Maternal toxicity was seen in the high-dose group but not at the lower doses where the findings were observed. Following oral administration of buprenorphine to rats, dose-related post-implantation losses, evidenced by increases in the numbers of early resorptions with consequent reductions in the numbers of fetuses, were observed at doses of 10 mg/kg/day or greater (estimated exposure approximately 6 times the human sublingual dose of 16 mg). In the rabbit, increased post-implantation losses occurred at an oral dose of 40 mg/kg/day. Following IM administration in the rat and the rabbit, post-implantation losses, as evidenced by decreases in live fetuses and increases in resorptions, occurred at 30 mg/kg/day.


Buprenorphine was not teratogenic in rats or rabbits after IM or subcutaneous (SC) doses up to 5 mg/kg/day (estimated exposure was approximately 3 and 6 times, respectively, the human sublingual dose of 16 mg), after IV doses up to 0.8 mg/kg/day (estimated exposure was approximately 0.5 times and equal to, respectively, the human sublingual dose of 16 mg), or after oral doses up to 160 mg/kg/day in rats (estimated exposure was approximately 95 times the human sublingual dose of 16 mg) and 25 mg/kg/day in rabbits (estimated exposure was approximately 30 times the human sublingual dose of 16 mg). Significant increases in skeletal abnormalities (e.g., extra thoracic vertebra or thoraco-lumbar ribs) were noted in rats after SC administration of 1 mg/kg/day and up (estimated exposure was approximately 0.6 times the human sublingual dose of 16 mg), but were not observed at oral doses up to 160 mg/kg/day. Increases in skeletal abnormalities in rabbits after IM administration of 5 mg/kg/day (estimated exposure was approximately 6 times the human sublingual dose of 16 mg) in the absence of maternal toxicity or oral administration of 1 mg/kg/day or greater (estimated exposure was approximately equal to the human sublingual dose of 16 mg) were not statistically significant.


In rabbits, buprenorphine produced statistically significant pre-implantation losses at oral doses of 1 mg/kg/day or greater and post-implantation losses that were statistically significant at IV doses of 0.2 mg/kg/day or greater (estimated exposure approximately 0.3 times the human sublingual dose of 16 mg). No maternal toxicity was noted at doses causing post-implantation loss in this study.

Dystocia was noted in pregnant rats treated intramuscularly with buprenorphine from Gestation Day 14 through Lactation Day 21 at 5 mg/kg/day (approximately 3 times the human sublingual dose of 16 mg).


Fertility, and pre- and post-natal development studies with buprenorphine in rats indicated increases in neonatal mortality after oral doses of 0.8 mg/kg/day and up (approximately 0.5 times the human sublingual dose of 16 mg), after IM doses of 0.5 mg/kg/day and up (approximately 0.3 times the human sublingual dose of 16 mg), and after SC doses of 0.1 mg/kg/day and up (approximately 0.06 times the human sublingual dose of 16 mg). An apparent lack of milk production during these studies likely contributed to the decreased pup viability and lactation indices.


Delays in the occurrence of righting reflex and startle response were noted in rat pups at an oral dose of 80 mg/kg/day (approximately 50 times the human sublingual dose of 16 mg).

Lactation

Risk Summary

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


Clinical Considerations

Advise the nursing mother taking Buprenorphine and Naloxone Sublingual Tablets to monitor the infant for increased drowsiness and breathing difficulties.


Data

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


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


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

Females and Males of Reproductive Potential

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2), Clinical Pharmacology (12.2). Nonclinical Toxicology (13.1)].

Pediatric Use

The safety and effectiveness of Buprenorphine and Naloxone Sublingual Tablets have not been established in pediatric patients. This product is not appropriate for the treatment of neonatal abstinence syndrome in neonates, because it contains naloxone, an opioid antagonist.

Geriatric Use

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

Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone has been evaluated in a pharmacokinetic study. Both drugs are extensively metabolized in the liver. While no clinically significant changes have been observed in subjects with mild hepatic impairment; the plasma levels have been shown to be higher and half-life values have been shown to be longer for both buprenorphine and naloxone in subjects with moderate and severe hepatic impairment. The magnitude of the effects on naloxone are greater than that on buprenorphine in both moderately and severely impaired subjects. The difference in magnitude of the effects on naloxone and buprenorphine are greater in subjects with severe hepatic impairment than in subjects with moderate hepatic impairment, and therefore the clinical impact of these effects is likely to be greater in patients with severe hepatic impairment than in patients with moderate hepatic impairment. Buprenorphine/naloxone products should be avoided in patients with severe hepatic impairment and may not be appropriate for patients with moderate hepatic impairment [see Warnings and Precautions (5.12), and Clinical Pharmacology (12.3)].

Renal Impairment

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

Clinical Studies

Clinical data on the safety and efficacy of Buprenorphine and Naloxone 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 and Naloxone Sublingual Tablets were studied in 575 patients, buprenorphine sublingual tablets (buprenorphine without naloxone) tablets in 1834 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 mg/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 tablet 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/3 mg per day of Buprenorphine and Naloxone Sublingual Tablets or 12 mg per day of buprenorphine sublingual tablets), or two relatively low doses of active control, one of which was low enough to serve as an alternative to placebo, during a 3 to 10 day induction phase, a 16-week maintenance phase and a 7-week detoxification phase. Buprenorphine was titrated to maintenance dose by Day 3; active control doses were titrated more gradually.

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

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

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

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

How supplied / storage and handling

Buprenorphine and Naloxone Sublingual Tablets containing 2 mg buprenorphine with 0.5 mg naloxone (in terms of free base, equivalent to 2.16 mg buprenorphine hydrochloride USP and 0.61 mg naloxone hydrochloride dihydrate USP)are uncoated, round, biconvex, orange, sublingual tablets, debossed with ‘969’ on one side and plain on other side and are supplied as:

Bottles of 30’s with Child Resistant Cap……………..NDC 62756-969-83

Unit-Doseblister pack of 30 (3 × 10) tablets ……..... NDC 62756-969-64


Buprenorphine and Naloxone Sublingual Tablets containing 8 mg buprenorphine with 2 mg naloxone (in terms of free base, equivalent to 8.64 mg buprenorphine hydrochloride USP and 2.44 mg naloxone hydrochloride dihydrate USP) are uncoated, round, biconvex, orange, sublingual tablets, debossed with ‘970’ on one side and plain on other side and are supplied as:


Bottles of 30’s with Child Resistant Cap……………..NDC 62756-970-83

Unit-Doseblister pack of 30 (3 × 10) tablets ……..... NDC 62756-970-64


Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature].


Patients should be advised to store buprenorphine-containing medications safely and out of sight and reach of children. Destroy any unused medication appropriately [see Disposal of Unused Buprenorphine and Naloxone Sublingual Tablets (17.2)]

Rx Only

PRINCIPAL DISPLAY PANEL - Label - 2 mg/0.5 mg


NDC 62756-969-83
Buprenorphine and Naloxone Sublingual Tablets CIII
(2 mg/0.5 mg)
Children who accidentally take this drug product will need emergency medical care.
Keep this and all medications out of reach of children.
Rx only
30 Tablets
SUN PHARMA
PHARMACIST: Please dispense with medication guide provided separately to each patient.

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