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

indivior uk ltd - buprenorphine hydrochloride; naloxone hydrochloride dihydrate - sublingual tablet - 16mg ; 4mg

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

indivior inc. - buprenorphine hydrochloride (unii: 56w8mw3en1) (buprenorphine - unii:40d3scr4gz), naloxone hydrochloride (unii: f850569pqr) (naloxone - unii:36b82amq7n) - buprenorphine 2 mg - suboxone sublingual film is indicated for treatment of opioid dependence. suboxone sublingual film should be used as part of a complete treatment plan that includes counseling and psychosocial support. suboxone sublingual film 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 suboxone sublingual film, 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 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 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 suboxone sublingual film. 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 on malformations 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 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 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 daily 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 daily 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 daily 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 infant urine. 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 suboxone sublingual film and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition. clinical considerations advise 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), clinical pharmacology (12.2), nonclinical toxicology (13.1)]. the safety and effectiveness of suboxone sublingual film 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. clinical studies of suboxone sublingual film, suboxone sublingual tablets, or subutex 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. due to possible decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in geriatric patients, the decision to prescribe suboxone sublingual film 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 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), 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. suboxone sublingual film contains buprenorphine, a schedule iii controlled substance under the controlled substances act. buprenorphine, like morphine and other opioids, has the potential for being abused and is subject to criminal diversion. this should be considered when prescribing or dispensing buprenorphine in situations when the clinician is concerned about an increased risk of misuse, abuse, or diversion. healthcare professionals should contact their state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. patients who continue to misuse, abuse, or divert buprenorphine products or other opioids should be provided with or referred for more intensive and structured treatment. abuse of buprenorphine poses a risk of overdose and death. this risk is increased with the abuse of buprenorphine and alcohol and other substances, especially benzodiazepines. the healthcare provider may be able to more easily detect misuse or diversion by maintaining records of medication prescribed including date, dose, quantity, frequency of refills, and renewal requests of medication prescribed. proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper handling and storage of the medication are appropriate measures that help to limit abuse of opioid drugs. 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)] . instructions for use suboxone (sub-ox-own) (buprenorphine and naloxone) sublingual film, ciii this “instructions for use” contains information on how to correctly take suboxone sublingual film. important information you need to know before taking suboxone sublingual film: - your healthcare provider should show you how to take suboxone sublingual film the right way. - each suboxone sublingual film comes in a sealed child‐resistant foil pouch. do not open the foil pouch until you are ready to take it. preparing to take suboxone sublingual film: - to open your suboxone sublingual film foil pouch, fold along the dotted line (see figure 1). figure 1 to open your suboxone sublingual film foil pouch, fold along the dotted line (see figure 1). figure 1 - tear down at slit or cut with scissors along the arrow (see figure 2). figure 2 tear down at slit or cut with scissors along the arrow (see figure 2). figure 2 - before taking suboxone sublingual film, drink water to moisten your mouth. this helps the film dissolve more easily. to take suboxone sublingual film under your tongue (sublingual administration): - hold the film between two fingers by the outside edges. - place the suboxone sublingual film under your tongue , close to the base either to the left or right of the center (see figure 3). figure 3 place the suboxone sublingual film under your tongue , close to the base either to the left or right of the center (see figure 3). figure 3 - if your healthcare provider tells you to take 2 films at a time, place the second film under your tongue on the opposite side. avoid letting the films touch. - keep the films in place until they have completely dissolved. - if your healthcare provider tells you to take a third film, place it under your tongue on either side after the first 2 films have dissolved. to take suboxone sublingual film on the inside of your cheek (buccal administration): - hold the film between two fingers by the outside edges. - place one film on the inside of your right or left cheek (see figure 4). figure 4 if your healthcare provider tells you to take 2 films at a time, place the other film on the inside of the opposite cheek. keep the films in place until they have completely dissolved. if your healthcare provider tells you to take a third film, place it on the inside of your right or left cheek after the first 2 films have dissolved. place one film on the inside of your right or left cheek (see figure 4). figure 4 - if your healthcare provider tells you to take 2 films at a time, place the other film on the inside of the opposite cheek. - keep the films in place until they have completely dissolved. - if your healthcare provider tells you to take a third film, place it on the inside of your right or left cheek after the first 2 films have dissolved. - while suboxone sublingual film is dissolving, do not chew or swallow the film because the medicine will not work as well. - talking while the film is dissolving can affect how well the medicine in suboxone sublingual film is absorbed. - after suboxone is completely dissolved, rinse your mouth with water and swallow. wait for at least one hour before brushing teeth. - if you miss a dose of suboxone sublingual film, take your medicine when you remember. if it is almost time for your next dose, skip the missed dose and take the next dose at your regular time. do not take 2 doses at the same time unless your healthcare provider tells you to. if you are not sure about your dosing, call your healthcare provider. - do not stop taking suboxone sublingual film suddenly. you could become sick and have withdrawal symptoms because your body has become used to the medicine. physical dependence is not the same as drug addiction. your healthcare provider can tell you more about the differences between physical dependence and drug addiction. to have fewer withdrawal symptoms, ask your healthcare provider how to stop using suboxone sublingual film the right way. if you take too much suboxone sublingual film or overdose, call poison control or get emergency medical help right away. storing suboxone sublingual film: - store suboxone sublingual film at room temperature between 68°f to 77°f (20°c to 25°c). - keep suboxone sublingual film in a safe place, out of the sight and reach of children. disposing of suboxone sublingual film: - dispose of unused suboxone sublingual film as soon as you no longer need them. - dispose of expired, unwanted or unused suboxone sublingual film by removing the suboxone sublingual film from the foil packaging, and promptly flushing down the toilet (if a drug take-back option is not readily available). do not flush the suboxone sublingual film foil pouch down the toilet. visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. if you need help with disposal of suboxone sublingual film, call 1‐877‐782‐6966. suboxone® is a registered trademark of indivior uk limited. this “instructions for use” has been approved by the u.s. food and drug administration. revised 06/2022

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

indivior inc. - buprenorphine (unii: 40d3scr4gz) (buprenorphine - unii:40d3scr4gz) - buprenorphine 100 mg - sublocade is indicated for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a buprenorphine-containing product, followed by dose adjustment for a minimum of 7 days. sublocade should be used as part of a complete treatment plan that includes counseling and psychosocial support. sublocade should not be administered to patients who have been shown to be hypersensitive to buprenorphine or any component of the atrigel® delivery system [see warnings and precautions (5.11)] . risk summary the data on use of buprenorphine, the active ingredient in sublocade, 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 human data] . observational studies have reported 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 human data] . in animal reproduction studies with sublocade, sublocade administered subcutaneously to pregnant rats and rabbits during the period of organogenesis at a buprenorphine dose equivalent to 38 and 15 times, respectively, the maximum recommended human dose (mrhd) of 300 mg caused embryolethality, which appeared to be attributable primarily to the sublocade vehicle (atrigel® delivery system). in addition, reduced fetal body weights, increased visceral malformations and skeletal malformations were observed in rats and rabbits at buprenorphine doses equivalent to 38 and 15 times, respectively, the mrhd. these effects were also observed with the atrigel® delivery system alone, but the skeletal and visceral malformations in rat appear at least partially attributable to buprenorphine [see animal 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 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. sublocade should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 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 sublocade. 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 (5.7)] . labor or delivery opioid-dependent women on buprenorphine maintenance therapy may require additional analgesia during labor. 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 data on malformations 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. pregnancy in an opioid dependent woman poses challenges to treating physicians and potential hazards for the fetus including control of illicit drug, nicotine and alcohol use, infections, premature birth, abortion, low birth weight, toxaemia, third trimester bleeding, malpresentation, puerperal morbidity, fetal distress, meconium aspiration, narcotic withdrawal, postnatal growth deficiency, microcephaly, (neuro-) developmental disorders and increased neonatal mortality. a multicenter, double-blind, double-dummy, flexible-dose study in 175 pregnant women [maternal opioid treatment: human experimental research (mother)] was conducted to study outcomes in neonates born to mothers using methadone or buprenorphine, including the number of neonates requiring treatment for nows, the peak nows score, the total amount of morphine needed to treat nows, the length of hospital stay for neonates, and neonatal head circumference. the authors found that 18% of pregnant women in the methadone group and 33% in the buprenorphine group discontinued treatment over the course of the pregnancy. they reported no significant difference in the incidence of nows, but in the prenatally buprenorphine-exposed condition, the duration of treatment for nows was shorter, duration of hospital stays were shorter and the amount of morphine required was significantly less; however, methodological concerns limit the conclusions that may be made. animal data in an embryofetal development study in rats, sublocade administered subcutaneously to pregnant animals before mating and again on gestation day (gd) 7 during the period of organogenesis resulted in increased post-implantation loss, which correlated with higher mean number of resorptions and decreased number of viable fetuses per litter, and decreased mean fetal body weights at 900 mg/kg (approximately 38 times the maximum recommended human dose [mrhd] of 300 mg of sublocade on an auc basis); however, similar effects were observed with an equivalent level of atrigel® delivery system alone, indicating they may be attributable to the vehicle. dose-related increases in incidences of skeletal malformations of the head and visceral malformations were observed with sublocade with significant changes at 900 mg/kg (approximately 38 times the mrhd on an auc basis). although similar effects were observed with equivalent levels of atrigel® delivery system, the incidence of skeletal malformations, primarily skull malformations, was higher in the sublocade groups suggesting that buprenorphine contributed to the increased incidence. based on these results, the noael for developmental toxicity was approximately 15 times the mrhd on an auc basis. in an embryofetal development study in rabbits, administration of a single subcutaneous injection of sublocade to pregnant animals on gd 7 during the period of organogenesis resulted an increased litter incidence of skeletal malformations at 155 mg/kg (approximately 7 times the mrhd on an auc basis), which appear to be buprenorphine-related adverse effects. there was also an increased litter incidence of external malformations, visceral, and skeletal malformations and variations at 390 mg/kg sublocade (approximately 15 times the mrhd on an auc basis); however, similar effects were observed with an equivalent level of the atrigel® delivery system, indicating they may be attributable to the vehicle. in addition, increased post-implantation loss, which correlated with increased mean number of resorptions and decreased mean number of viable fetuses, and decreased fetal body weights were observed at 390 mg/kg (approximately 15 times the mrhd on an auc basis); however, similar findings were also observed with an equivalent level of the atrigel® delivery system alone. based on these results, the noael for developmental toxicity for sublocade was 78 mg/kg (approximately 2 times the mrhd on an auc basis). in a pre- and postnatal development study in rats, sublocade was administered subcutaneously to pregnant animals once during implantation (on gd 7) and once during weaning (on lactation day 7). there were no adverse effects on offspring survival, sexual maturation, behavioral assessment, or reproductive performance at up to 300 mg/kg (approximately 15 times the mrhd on an auc basis). risk summary based on two studies in 13 lactating women maintained on buprenorphine treatment, buprenorphine and its metabolite norbuprenorphine are present in low levels in human milk and infant urine. available data have not shown adverse reactions in breastfed infants. caution should be exercised when sublocade is administered to a nursing woman. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for sublocade and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition. clinical considerations advise 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. human data 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)] . animal data infertility male male fertility may be reduced based on animal data demonstrating adverse effects of sublocade on sperm parameters [see nonclinical toxicology (13.1)]. the safety and effectiveness of sublocade have not been established in pediatric patients. clinical studies of sublocade did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently than younger subjects. other reported clinical experience with buprenorphine has not identified differences in responses between geriatric 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 sublocade 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 sublocade has not been studied. the effect of hepatic impairment on the pharmacokinetics of sublingual buprenorphine has been evaluated in a pharmacokinetic study. 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 buprenorphine in subjects with moderate and severe hepatic impairment. because of the long-acting nature of the product, adjustments to dosages of sublocade are not rapidly reflected in plasma buprenorphine levels. because buprenorphine levels cannot be rapidly adjusted, patients with pre-existing moderate to severe hepatic impairment are not candidates for treatment with sublocade. patients who develop moderate to severe hepatic impairment while being treated with sublocade should be monitored for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine. if signs and symptoms of toxicity or overdose occur within 2 weeks of sublocade administration, removal of the depot may be required [see dosage and administration (2.7), warnings and precautions (5.10), clinical pharmacology (12.3)] . clinical studies of sublocade did not include subjects with 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. sublocade contains buprenorphine, a schedule iii substance under the controlled substances act. sublocade contains buprenorphine, a schedule iii controlled substance that can be abused similar to other opioids. patients who continue to misuse, abuse, or divert buprenorphine products or other opioids should be provided with or referred for more intensive and structured treatment. abuse of buprenorphine poses a risk of overdose and death. this risk is increased with the abuse of buprenorphine and alcohol and other substances, especially benzodiazepines. sublocade is distributed through a restricted distribution system, which is intended to prevent the direct distribution to a patient. sublocade should only be dispensed directly to a healthcare provider for administration by a healthcare provider. it is supplied in prefilled syringes and is intended for administration only by subcutaneous injection by a healthcare provider. the entire contents of the prefilled syringe should be administered. after administration, a small amount (approximately 0.1 ml) of sublocade will remain in the needle and syringe and should be properly disposed of [see how supplied/storage and handling (16)] . sublocade is injected as a liquid, and the subsequent precipitation of the poly (dl-lactide-co-glycolide) polymer creates a solid depot which contains buprenorphine. after initial formation of the depot, buprenorphine is released via diffusion from, and the biodegradation of, the depot. clinical monitoring for evidence at the injection site of tampering or attempting to remove the depot should be ongoing throughout treatment. no accounts of subjects removing or attempting to remove the depot after administration of sublocade were reported in premarketing studies. 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. the withdrawal syndrome is typically milder than seen with full agonists and may be delayed in onset [see warnings and precautions (5.12)] . due to the long-acting nature of sublocade, withdrawal signs and symptoms may not be evident immediately following the discontinuation of treatment. neonatal opioid withdrawal syndrome (nows) is an expected and treatable outcome of prolonged use of opioids during pregnancy [see warnings and precautions (5.7)] .

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

indivior inc. - buprenorphine hydrochloride (unii: 56w8mw3en1) (buprenorphine - unii:40d3scr4gz), naloxone hydrochloride (unii: f850569pqr) (naloxone - unii:36b82amq7n) - buprenorphine and naloxone sublingual film is indicated for treatment of opioid dependence. buprenorphine and naloxone sublingual film should be used as part of a complete treatment plan that includes counseling and psychosocial support. buprenorphine and naloxone sublingual film 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 buprenorphine and naloxone sublingual film, 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 bu

Malta - English - Medicines Authority

indivior uk limited - buprenorphine - sublingual tablet - buprenorphine 2 mg - other nervous system drugs

Malta - English - Medicines Authority

indivior uk limited - buprenorphine - sublingual tablet - buprenorphine 8 mg - other nervous system drugs

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

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

indivior pty ltd - naloxone hydrochloride dihydrate, quantity: 2.44 mg (equivalent: naloxone, qty 2 mg); buprenorphine hydrochloride, quantity: 8.64 mg (equivalent: buprenorphine, qty 8 mg) - soluble film - excipient ingredients: acesulfame potassium; maltitol; polyethylene oxide; citric acid; sunset yellow fcf; hypromellose; sodium citrate; titanium dioxide; propylene glycol; purified water; industrial methylated spirit; flavour - for the treatment of opiate dependence within a framework of medical, social, and psychological treatment.

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

indivior pty ltd - buprenorphine hydrochloride, quantity: 2.16 mg (equivalent: buprenorphine, qty 2 mg); naloxone hydrochloride dihydrate, quantity: 0.61 mg (equivalent: naloxone, qty 0.5 mg) - soluble film - excipient ingredients: sunset yellow fcf; polyethylene oxide; hypromellose; maltitol; citric acid; acesulfame potassium; sodium citrate; titanium dioxide; propylene glycol; purified water; industrial methylated spirit; flavour - for the treatment of opiate dependence within a framework of medical, social, and psychological treatment.

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

indivior pty ltd - buprenorphine hydrochloride, quantity: 8.64 mg (equivalent: buprenorphine, qty 8 mg) - tablet - excipient ingredients: lactose monohydrate; mannitol; maize starch; povidone; citric acid; sodium citrate dihydrate; magnesium stearate - treatment of opiate dependence, including maintenance and detoxification, within a framework of medical, social and psychological treatment.