Australia - English - Department of Health (Therapeutic Goods Administration)

aa-med pty ltd - buprenorphine hydrochloride,naloxone hydrochloride dihydrate -

United States - English - NLM (National Library of Medicine)

orexo us, inc. - buprenorphine hydrochloride (unii: 56w8mw3en1) (buprenorphine - unii:40d3scr4gz), naloxone hydrochloride (unii: f850569pqr) (naloxone - unii:36b82amq7n) - buprenorphine 1.4 mg -       zubsolv is indicated for treatment of opioid dependence. zubsolv should be used as part of a complete treatment plan that includes counseling and psychosocial support.       zubsolv is contraindicated in patients with a history of hypersensitivity to buprenorphine or naloxone as serious adverse reactions, including anaphylactic shock, have been reported [see warnings and precautions ( 5.9 )]. risk summary       the data on use of buprenorphine, one of the active ingredients in zubsolv, in pregnancy, are limited; however, these data do not indicate an increased risk of major malformations specifically due to buprenorphine exposure. there are limited data from randomized clinical trials in women maintained on buprenorphine that were not designed appropriately to assess the risk of major malformations [see data] . observational studies have reported on congenital malformations among buprenorphine-exposed pregnancies, but were also not designed appropriately to assess the risk of congenital malformations specifically due to buprenorphine exposure [see data] . the extremely limited data on sublingual naloxone exposure in pregnancy are not sufficient to evaluate a drug-associated risk.       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 post-natal 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 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]. based on animal data, advise pregnant women of the potential risk to a fetus.       the estimated background risk of major birth defects and miscarriage for the indicated population are 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 2-4% and 15-20%, 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. dose adjustment during pregnancy and the postpartum period       dosage adjustments of buprenorphine may be required during pregnancy, even if the patient was maintained on a stable dose prior to pregnancy. withdrawal signs and symptoms should be monitored closely and the dose adjusted as necessary. fetal/neonatal adverse reactions       neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with zubsolv.       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       opioid-dependent women on buprenorphine maintenance therapy may require additional analgesia during labor. data human data       studies have been conducted to evaluate neonatal outcomes in women exposed to buprenorphine during pregnancy. limited data from trials, observational studies, case series, and case reports on buprenorphine use in pregnancy do not indicate an increased risk of major malformations specifically due to buprenorphine. several factors may complicate the interpretation of investigations of the children of women who take buprenorphine during pregnancy, including maternal use of illicit drugs, late presentation for prenatal care, infection, poor compliance, poor nutrition, and psychosocial circumstances. interpretation of data is complicated further by the lack of information on untreated opioid-dependent pregnant women, who would be the most appropriate group for comparison. rather, women on another form of opioid medication-assisted treatment, or women in the general population are generally used as the comparison group. however, women in these comparison groups may be different from women prescribed buprenorphine-containing products with respect to maternal factors that may lead to poor pregnancy outcomes.       in a multicenter, double-blind, randomized, controlled trial [maternal opioid treatment: human experimental research (mother)] designed primarily to assess neonatal opioid withdrawal effects, opioid-dependent pregnant women were randomized to buprenorphine (n=86) or methadone (n=89) treatment, with enrollment at an average gestational age of 18.7 weeks in both groups. a total of 28 of the 86 women in the buprenorphine group (33%) and 16 of the 89 women in the methadone group (18%) discontinued treatment before the end of pregnancy.       among women who remained in treatment until delivery, there was no difference between buprenorphine-treated and methadone-treated groups in the number of neonates requiring nows treatment or in the peak severity of nows. buprenorphine-exposed neonates required less morphine (mean total dose, 1.1 mg vs. 10.4 mg), had shorter hospital stays (10.0 days vs. 17.5 days), and shorter duration of treatment for nows (4.1 days vs. 9.9 days) compared to the methadone-exposed group. there were no differences between groups in other primary outcomes (neonatal head circumference,) or secondary outcomes (weight and length at birth, preterm birth, gestational age at delivery, and 1-minute and 5-minute apgar scores), or in the rates of maternal or neonatal adverse events. the outcomes among mothers who discontinued treatment before delivery and may have relapsed to illicit opioid use are not known. because of the imbalance in discontinuation rates between the buprenorphine and methadone groups, the study findings are difficult to interpret. animal data       zubsolv has been shown to have differences in bioavailability compared to other buprenorphine/naloxone-containing sublingual products. the exposure margins listed below are based on body surface area comparisons (mg/m2 ) to the human sublingual dose of 16 mg buprenorphine via suboxone, which is equivalent to a human sublingual dose of 11.4 mg buprenorphine via zubsolv.       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 daily 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, 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). risk summary       based on two studies in 13 lactating women, maintained on buprenorphine treatment, buprenorphine and its metabolite norbuprenorphine were present in low levels in human milk 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 limited. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for zubsolv and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition. clinical considerations       advise the breastfeeding women taking buprenorphine products to monitor the infant for increased drowsiness and breathing difficulties. data       data were consistent from two studies (n=13) of breastfeeding infants whose mothers were maintained on sublingual doses of buprenorphine ranging from 2.4 to 24 mg/day, showing that the infants were exposed to less than 1% of the maternal daily dose.       in a study of six lactating women who were taking a median sublingual buprenorphine dose of 0.29 mg/kg/day 5 to 8 days after delivery, breast milk provided a median infant dose of 0.42 mcg/kg/day of buprenorphine and 0.33 mcg/kg/day of norbuprenorphine, equal to 0.2% and 0.12%, respectively, of the maternal weight-adjusted dose (relative dose/kg (%) of norbuprenorphine was calculated from the assumption that buprenorphine and norbuprenorphine are equipotent).       data from a study of seven lactating women who were taking a median sublingual buprenorphine dose of 7 mg/day an average of 1.12 months after delivery indicated that the mean milk concentrations (cavg ) of buprenorphine and norbuprenorphine were 3.65 mcg/l and 1.94 mcg/l respectively. based on the study data, and assuming milk consumption of 150 ml/kg/day, an exclusively breastfed infant would receive an estimated mean absolute infant dose (aid) of 0.55 mcg/kg/day of buprenorphine and 0.29 mcg/kg/day of norbuprenorphine, or a mean relative infant dose (rid) of 0.38% and 0.18%, respectively, of the maternal weight-adjusted dose. 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 ), nonclinical toxicology ( 13.1 )] .       the safety and effectiveness of zubsolv have not been established in pediatric patients. this product is not appropriate for the treatment of neonatal opioid withdrawal syndrome in neonates, because it contains naloxone, an opioid antagonist.       clinical studies of buprenorphine/naloxone 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 have 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 zubsolv 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.       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 is 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 ), clinical pharmacology ( 12.3 )].       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 [see clinical pharmacology ( 12.3 )].       zubsolv contains buprenorphine, a schedule iii substance under the controlled substances act.       buprenorphine, like morphine and other opioids, has the potential to be abused and is subject to criminal diversion. this should be considered when prescribing or dispensing buprenorphine in situations when the clinician is concerned about an increased risk of misuse, abuse, or diversion. healthcare professionals should contact their state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.       patients who continue to misuse, abuse, or divert buprenorphine products or other opioids should be provided with, or referred to, more intensive and structured treatment.       abuse of buprenorphine poses a risk of overdose and death. this risk is increased with the abuse of buprenorphine and alcohol and other substances, especially benzodiazepines.       the 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.       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 )].

United States - English - NLM (National Library of Medicine)

braeburn pharmaceuticals - buprenorphine hydrochloride (unii: 56w8mw3en1) (buprenorphine - unii:40d3scr4gz) - buprenorphine 80 mg - probuphine is indicated for the maintenance treatment of opioid dependence in patients who have achieved and sustained prolonged clinical stability on low-to-moderate doses of a transmucosal buprenorphine-containing product (i.e., doses of no more than 8 mg per day of subutex or suboxone sublingual tablet or generic equivalent). probuphine should be used as part of a complete treatment program to include counseling and psychosocial support. probuphine is not appropriate for new entrants to treatment and patients who have not achieved and sustained prolonged clinical stability, while being maintained on buprenorphine 8 mg per day or less of a subutex or suboxone sublingual tablet equivalent or generic equivalent. probuphine is contraindicated in patients with a history of hypersensitivity to buprenorphine or any other ingredients in probuphine (e.g., eva). [see warnings and precautions (5.11)]. risk summary the data on use of buprenorphine, the active ingredient in probuphine implant, in pregnancy, are limited

United States - English - NLM (National Library of Medicine)

biodelivery sciences international inc - buprenorphine hydrochloride (unii: 56w8mw3en1) (buprenorphine - unii:40d3scr4gz) - buprenorphine 75 ug - belbuca is indicated for the management of severe and persistent pain that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options are inadequate. limitations of use - because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration, and because of the greater risks of overdose and death with extended-release/long-acting opioid formulations [see warnings and precautions (5.1)] , reserve belbuca for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. - belbuca is not indicated as an as-needed (prn) analgesic. belbuca is contraindicated in patients with: - significant respiratory depression [see warnings and precautions (5.2)] - acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see warnings and precautions (5.7)] - known or suspected gastrointestinal obstruction, including paralytic ileus [see warnings and precautions (5.12)] - hypersensitivity (e.g., anaphylaxis) to buprenorphine [see warnings and precautions (5.16), adverse reactions (6)] risk summary use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see warnings and precautions (5.4)] . there are no adequate and well-controlled studies of belbuca or buprenorphine in pregnant women. limited published data on use of buprenorphine, the active ingredient in belbuca, in pregnancy, have not shown an increased risk of major malformations. reproductive and developmental studies in rats and rabbits identified adverse events at approximately 2 times the maximum recommended human dose (mrhd) of 1.8 mg/day of belbuca. embryofetal death was observed in both rats and rabbits administered buprenorphine during the period of organogenesis at doses approximately 54 and 2.2 times, respectively, the mrhd of 1.8 mg/day of buprenorphine. pre-and postnatal development studies in rats demonstrated increased neonatal deaths at 2.7 times and above and dystocia at approximately 27 times the mrhd of 1.8 mg/day of buprenorphine. no clear teratogenic effects were seen when buprenorphine was administered during organogenesis with a range of doses 5 times or greater than the mrhd of 1.8 mg/day of buprenorphine. however, increases in skeletal abnormalities were noted in rats and rabbits administered buprenorphine daily during organogenesis at doses approximately 5.4 and 10.8 times the mrhd of 1.8 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 background risk of major birth defects and miscarriage for the indicated population is unknown. adverse outcomes in pregnancy can occur regardless of the health of the mother or the use of medications. 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 fetal/neonatal adverse reactions use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. the onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see warnings and precautions (5.4)] . labor or delivery opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. an opioid antagonist such as naloxone must be available for reversal of opioid-induced respiratory depression in the neonate. belbuca is not recommended for use in women immediately prior to labor, when shorter-acting analgesics or other analgesic techniques are more appropriate. opioid analgesics, including belbuca, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. however, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. data animal data the exposure margins listed below are based on body surface area comparisons (mg/m2 ) to mrhd of 1.8 mg buprenorphine via belbuca. following oral administration to rats no teratogenic effects were observed at buprenorphine doses up to 250 mg/kg/day (estimated exposure approximately 1351 times the mrhd of 1.8 mg). following oral administration to rabbits, no teratogenic effects were observed at buprenorphine doses up to 40 mg/kg/day (estimated exposure approximately 432 times the mrhd of 1.8 mg). no definitive drug-related teratogenic effects were observed in rats and rabbits at im doses up to 30 mg/kg/day (estimated exposure approximately 161 times and 324 times, respectively, the mrhd of 1.8 mg). 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. 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 54 times the mrhd of 1.8 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 27 and 54 times, respectively, the mrhd of 1.8 mg), after iv doses up to 0.8 mg/kg/day (estimated exposure was approximately 4.3 and 8.7 times, respectively, the mrhd of 1.8 mg), or after oral doses up to 160 mg/kg/day in rats (estimated exposure was approximately 865 times the mrhd of 1.8 mg) and 25 mg/kg/day in rabbits (estimated exposure was approximately 270 times the mrhd of 1.8 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 5.4 times the mrhd of 1.8 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 54 times the mrhd of 1.8 mg) or oral administration of 1 mg/kg/day or greater (estimated exposure was approximately 10.8 times the mrhd of 1.8 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 2.2 times the mrhd of 1.8 mg). dystocia was noted in pregnant rats treated intramuscularly with buprenorphine during gestation and lactation at 5 mg/kg/day (approximately 27 times the mrhd of 1.8 mg). fertility, 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 4.3 times the mrhd of 1.8 mg), after im doses of 0.5 mg/kg/day and up (approximately 2.7 times the mrhd of 1.8 mg), and after sc doses of 0.1 mg/kg/day and up (approximately 0.5 times the mrhd of 1.8 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 432 times the mrhd of 1.8 mg). risk summary based on two studies in 13 lactating women being treated for opioid dependence and their breastfed infants, 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 [see data] . there are no data on the effects of belbuca on milk production. because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with belbuca. clinical considerations monitor infants exposed to belbuca through breast milk for excess sedation and respiratory depression. withdrawal symptoms can occur in breastfed infants when maternal administration of buprenorphine is stopped or when breastfeeding is stopped. data based on limited data from a study of six lactating women being treated for opioid dependence who were taking a median oral dose of buprenorphine of 0.29 mg/kg/day 5-8 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. the median concentrations of buprenorphine and norbuprenorphine in infant urine were 1.0 nmol/l and 2.3 nmol/l, respectively. based on limited data from a study of seven lactating women being treated for opioid dependence 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. infertility use of opioids for an extended period of time 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)] . the safety and efficacy of belbuca have not been established in pediatric patients. of the total number of patients that were treated with belbuca in controlled and open-label chronic pain trials (2,127), 340 patients were 65 years and older. of those, 49 patients were aged 75 years and older. the incidences of selected belbuca-related adverse effects were higher in older subjects. no notable differences in pharmacokinetics were observed from population pharmacokinetic analysis in subjects aged 65 and older compared to younger subjects. other reported clinical experience with buprenorphine has not identified differences in responses between the elderly and younger patients. although specific dose adjustments on the basis of advanced age are not required for pharmacokinetic reasons, use caution in the elderly population to ensure safe use. respiratory depression is the chief risk for elderly patients treated with opioids and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. titrate the dosage of belbuca slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see warnings and precautions (5.7), clinical pharmacology (12.3)] . buprenorphine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function. belbuca has not been evaluated in patients with severe hepatic impairment. the effects of hepatic impairment on the pharmacokinetics of buprenorphine were evaluated in a pharmacokinetic study. buprenorphine is extensively metabolized in the liver and buprenorphine plasma levels were found to be higher and the half-life was found to be longer in subjects with moderate and severe hepatic impairment, but not in subjects with mild hepatic impairment. given that increased buprenorphine plasma levels are associated with a greater risk of toxicity and overdose, a dosage reduction in patients with severe hepatic impairment (i.e., child-pugh c) is recommended [see dosage and administration (2.6)] . regularly evaluate patients with severe hepatic impairment for signs and symptoms of overdose. a dosage reduction in patients with moderate hepatic impairment (child-pugh b) is not needed; however, regularly evaluate these patients for signs and symptoms of toxicity or overdose. a dosage reduction in patients with mild hepatic impairment (child-pugh a) is not needed [see dosage and administration (2.6), warnings and precautions (5.19), clinical pharmacology (12.3)] . belbuca contains buprenorphine hydrochloride, a schedule iii controlled substance. belbuca contains buprenorphine, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see warnings and precautions (5.1)] . misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. misuse and abuse of belbuca increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. the risk is increased with concurrent abuse of belbuca with alcohol and/or other cns depressants. abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. in addition, abuse of opioids can occur in the absence of addiction. all patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. patients at high risk of belbuca abuse include those with a history of prolonged use of any opioid, including products containing buprenorphine, those with a history of drug or alcohol abuse, or those who use belbuca in combination with other abused drugs. "drug-seeking" behavior is very common in persons with substance use disorders. drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated "loss" of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). "doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. belbuca, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. risks specific to abuse of belbuca abuse of belbuca poses a risk of overdose and death. this risk is increased with concurrent use of belbuca with alcohol and/or other substances, including other opioids and benzodiazepines [see warnings and precautions (5.1, 5.3), drug interactions (7)] . belbuca is approved for buccal use only. intentional compromise of the buccal film might result in the uncontrolled delivery of buprenorphine and pose a significant risk to the abuser that could result in overdose and death [see warnings and precautions (5.1)] . abuse may occur by applying the buccal film in the absence of legitimate purpose, or by chewing, swallowing, snorting, or injecting buprenorphine extracted from the buccal film. parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and hiv. both tolerance and physical dependence can develop during use of opioid therapy. tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. do not abruptly discontinue belbuca in a patient physically dependent on opioids. rapid tapering of belbuca in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. when discontinuing belbuca, gradually taper the dosage using a patient-specific plan that considers the following: the dose of belbuca the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. to improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. in patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see dosage and administration (2.5), warnings and precautions (5.17)] . infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see use in specific populations (8.1)] . belbuca (bel-bue-kuh) (buprenorphine buccal film), ciii before you use belbuca buccal film, it is important that you read the medication guide and these patient instructions for use so that you use belbuca the right way. ask your healthcare provider or pharmacist if you have any questions about the right way to use belbuca. important: - belbuca buccal film is sealed in a foil package. do not open the package until ready to use. after opening, use the entire belbuca buccal film right away. - do not apply belbuca buccal film if the package seal is broken or the film is cut, damaged, or changed in any way. - belbuca buccal film is available in different strengths. make sure you have the strength that has been prescribed for you. - avoid placing belbuca buccal film to areas of the mouth with any open sores or lesions. open the belbuca package: - hold the foil package as shown below (see figure a) . fold along the dotted line at the top of the foil package. figure a figure a - keep folded and tear down or cut with scissors at the notch in the direction of the scissors on the dotted line (see figure b) . tear all the way to the bottom. be careful to avoid cutting and damaging the belbuca buccal film when using scissors. figure b figure b - remove belbuca film from the foil package (see figure c) . figure c figure c use belbuca buccal film as follows: figure d figure e figure f - avoid eating food or drinking liquids until belbuca buccal film has dissolved. - avoid touching or moving belbuca buccal film with your tongue or finger after it is in place. - do not chew or swallow belbuca. - after belbuca is completely dissolved, rinse your mouth with water and swallow. wait at least one hour before brushing your teeth. these instructions for use have been approved by the u.s. food and drug administration. for more information call collegium pharmaceutical, inc. at 855-331-5615. manufactured for: collegium pharmaceutical, inc., stoughton, ma 02072 belbuca is a trademark of biodelivery sciences international, inc., a wholly owned subsidiary of collegium pharmaceutical, inc. ©2023 biodelivery sciences international, inc. all rights reserved. bel-001-mg-dec2023

United States - English - NLM (National Library of Medicine)

physicians total care, inc. - buprenorphine hydrochloride (unii: 56w8mw3en1) (buprenorphine - unii:40d3scr4gz), naloxone hydrochloride (unii: f850569pqr) (naloxone - unii:36b82amq7n) - buprenorphine hydrochloride 2 mg - suboxone and subutex are indicated for the treatment of opioid dependence. suboxone and subutex should not be administered to patients who have been shown to be hypersensitive to buprenorphine, and suboxone should not be administered to patients who have been shown to be hypersensitive to naloxone. suboxone and subutex are controlled as schedule iii narcotics under the controlled substances act. buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces dependence of the opioid type, characterized by moderate withdrawal upon abrupt discontinuation or rapid taper. the withdrawal syndrome is milder than seen with full agonists, and may be delayed in onset (see warnings) neonatal withdrawal has been reported in the infants of women treated with subutex during pregnancy (see precautions) suboxone contains naloxone and if misused parenterally, is highly likely to produce marked and intense withdrawal symptoms in subjects dependent on other opioid agonists.

United States - English - NLM (National Library of Medicine)

indivior inc. - buprenorphine hydrochloride (unii: 56w8mw3en1) (buprenorphine - unii:40d3scr4gz) - buprenorphine 0.3 mg in 1 ml - buprenex is indicated for the management of pain severe enough to require an opioid analgesic and for which alternate treatments are inadequate. because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses [see warnings: addiction, abuse, and misuse] reserve buprenex for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]: - have not been tolerated, or are not expected to be tolerated, - have not provided adequate analgesia, or are not expected to provide adequate analgesia. buprenex is contraindicated in patients with: - significant respiratory depression [see warnings]. - acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see warnings]. - known or suspected gastrointestinal obstruction, including paralytic ileus [see warnings]. - hypersensitivity to buprenorphine (e.g. anaphylaxis) or any other ingredient in buprenex [see warnings]. buprenex contains buprenor

United States - English - NLM (National Library of Medicine)

animalgesic laboratories, inc. - buprenorphine hydrochloride (unii: 56w8mw3en1) (buprenorphine - unii:40d3scr4gz) - buprenorphine 1 mg in 1 ml - abuse potential animalgesics for mice contains buprenorphine, a high concentration (1.3 mg/ml) opioid agonist and schedule iii controlled substance with an abuse potential similar to other schedule iii opioids. the high concentration of animalgesics for mice may be a particular target for human abuse. buprenorphine has opioid properties that in humans may lead to dependence of the morphine type. abuse of buprenorphine may lead to low or moderate physical dependence or high psychological dependence. the risk of abuse by humans should be considered when storing, administering, and disposing of animalgesics for mice. persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (suicidal depression). because of human safety risks, this drug should be used only with veterinary supervision. do not dispense animalgesics for mice. life-threatening respiratory depression the concentration of buprenorph

United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)

accord-uk ltd - buprenorphine hydrochloride - sublingual tablet - 2mg

United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)

accord-uk ltd - buprenorphine hydrochloride - sublingual tablet - 8mg

United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)

sun pharmaceutical industries europe b.v. - buprenorphine hydrochloride - sublingual tablet - 2mg