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

nutrivital pty ltd - bacopa monnieri,centella asiatica,curcumin,ginkgo biloba -

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

living strength health services pty ltd -

Marekani - Kiingereza - NLM (National Library of Medicine)

teva pharmaceuticals usa, inc. - fentanyl citrate (unii: mun5lyg46h) (fentanyl - unii:uf599785jz) - fentanyl 200 ug - oral transmucosal fentanyl citrate (otfc) is indicated for the management of breakthrough pain in cancer patients 16 years of age and older who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. patients considered opioid tolerant are those who are taking, for one week or longer, around-the-clock medicine consisting of at least 60 mg of oral morphine per day, at least 25 mcg of transdermal fentanyl per hour, at least 30 mg of oral oxycodone per day, at least 8 mg of oral hydromorphone per day, at least 25 mg oral oxymorphone per day, at least 60 mg of oral hydrocodone per day, or an equianalgesic dose of another opioid. patients must remain on around-the-clock opioids when taking otfc. limitations of use: - not for use in opioid non-tolerant patients. - not for use in the management of acute or postoperative pain, including headache/migraine and dental pain [see contraindications (4)] . - as a part of the tirf rems, otfc may be dispensed by outpatient pharmacies only to outpatients enrolled in the program [see  warnings and precautions  (5.7)] . for inpatient administration of otfc, patient and prescriber enrollment are not required.  oral transmucosal fentanyl citrate (otfc) is contraindicated in: - opioid non-tolerant patients: life-threatening respiratory depression and death could occur at any dose in opioid non-tolerant patients [see indications and usage ( 1), warnings and precautions (5.2)]. - significant respiratory depression [see warnings and precautions (5.2 )]. - acute or postoperative pain including headache/migraine and dental pain, or acute pain in the emergency department [see indications and usage (1)] . - acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see warnings and precautions (5.11 )]. - known or suspected gastrointestinal obstruction, including paralytic ileus [see warnings and precautions (5.15 )]. - known hypersensitivity to fentanyl or components of otfc (e.g., anaphylaxis, hypersensitivity) [see adverse reactions (6.2)]. risk summary use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see warnings and precautions (5.8)] . available data with oral transmucosal fentanyl citrate (otfc) in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. there are risks to the mother and infant associated with use of otfc for an extended period of time during pregnancy (see clinical considerations). in animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing. when administered during gestation through lactation fentanyl administration to pregnant rats resulted in reduced pup survival at doses within the range of the human recommended dosing. no evidence of malformations were noted in animal studies completed to date [see data] . the 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 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 of neonatal withdrawal symptoms usually occurs in the first days after birth. the duration and severity of neonatal opioid withdrawal syndrome may vary. observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see warnings and precautions (5.8)] . 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. otfc is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. opioid analgesics, including otfc, 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. monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. data human data in women treated acutely with intravenous or epidural fentanyl during labor, symptoms of neonatal respiratory or neurological depression were no more frequent than would be expected in infants of untreated mothers. transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl. animal data fentanyl (25, 50, or 100 mcg/kg) citrate was administered subcutaneously to pregnant rats during the period of organogenesis (gestation day, gd 6 to 17). maternal toxicity and a decrease in fetal weights were observed at 100 mcg/kg but no teratogenicity was seen in the study (the no observed effect level of 50 mcg/kg is equivalent to 0.7 times the exposure of a single human dose of 1600 mcg per pain episode, based on an auc comparison). fentanyl (50, 100, or 250 mcg/kg) was also administered subcutaneously to pregnant rabbits during the period of organogenesis (gd 6-18). maternal toxicity was noted at doses >100 mcg/kg. no teratogenicity was seen in the study (250 mcg/kg dose is equivalent to 3.5 times the exposure of a single human dose of 1600 mcg per pain episode, based on an auc comparison). fentanyl has been shown to be embryocidal in pregnant rats at doses of 30 mcg/kg intravenously (0.2 times the 1600 mcg dose of otfc on a mg/m2 basis) from gd 6 to 18 and 160 mcg/kg subcutaneously (1 times the 1600 mcg dose of otfc based on a mg/m2 basis). no evidence of teratogenicity was reported. no evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered fentanyl continuously via subcutaneously implanted osmotic minipumps at doses of 10, 100, or 500 mcg/kg/day starting 2-weeks prior to breeding and throughout pregnancy. the high dose was approximately 3 times the human dose of 1600 mcg otfc per pain episode on a mg/m2 basis and produced mean steady-state plasma levels that are 3.4 times higher than the mean cmax observed following administration of 1600 mcg dose of otfc in humans. in a postnatal development study, pregnant rats were treated from gd 6 through lactation day (ld) 20 with subcutaneous doses of fentanyl (25, 50, 100, and 400 mcg/kg). maternal toxicity was noted at doses >100 mcg/kg. a reduction in pup growth and delayed attainment of developmental indices were observed at >100 mcg/kg. no difference in the number of live pups/litter was seen at birth, however, pup survival at ld 4 was reduced to 48% at 400 mcg/kg and by ld 21 pup survival was reduced to 30% and 26% at 100 and 400 mcg/kg, respectively. during lactation, fentanyl-related clinical signs (decreased activity, skin cold to touch, and moribund appearance) were noted in the f1 pups, most prominently in the 400 mcg/kg group. pups from this group also had significantly reduced body weights throughout the lactation period. the dose of fentanyl administered to rats at which no developmental toxicity in the f1 generation was seen was 50 mcg/kg which is 0.6 times the exposure of a single human dose of 1600 mcg per pain episode, based on an auc comparison. risk summary fentanyl is present in breast milk. one published lactation study reports a relative infant dose of fentanyl of 0.024%. however, there is insufficient information to determine the effects of fentanyl on the breastfed infant and the effects of fentanyl 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 otfc. clinical considerations monitor infants exposed to otfc through breast milk for excess sedation and respiratory depression. withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breastfeeding is stopped. 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)] . safety and effectiveness in pediatric patients below 16 years of age have not been established. in a clinical study, 15 opioid-tolerant pediatric patients with breakthrough pain, ranging in age from 5 to 15 years, were treated with otfc. the study was too small to allow conclusions on safety and efficacy in this patient population. twelve of the fifteen opioid-tolerant children and adolescents aged 5 to 15 years in this study received otfc at doses ranging from 200 mcg to 600 mcg. the mean (cv%; range) dose-normalized (to 200 mcg) cmax and auc0-8 values were 0.87 ng/ml (51%; 0.42-1.30) and 4.54 ng. h/ml (42%; 2.37-6.0), respectively, for children ages 5 to <11 years old (n = 3) and 0.68 ng/ml (72%; 0.15-1.44) and 8.38 (192%; 0.84-50.78), respectively, for children ages ≥11 to <16 y (n = 9). of the 257 patients in clinical studies of otfc in breakthrough cancer pain, 61 (24%) were 65 years of age and older, while 15 (6%) were 75 years of age and older. those patients over the age of 65 years were titrated to a mean dose that was about 200 mcg less than the mean dose titrated to by younger patients. no difference was noted in the safety profile of the group over 65 years of age as compared to younger patients in otfc clinical trials. elderly patients have been shown to be more sensitive to the effects of fentanyl when administered intravenously, compared with the younger population. therefore, exercise caution when individually titrating otfc in elderly patients to provide adequate efficacy while minimizing risk. 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 otfc slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see warnings and precautions (5.11)] . fentanyl 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. insufficient information exists to make recommendations regarding the use of otfc in patients with impaired renal or hepatic function. fentanyl is metabolized primarily via human cytochrome p450 3a4 isoenzyme system and mostly eliminated in urine. if the drug is used in these patients, it should be used with caution because of the hepatic metabolism and renal excretion of fentanyl. both male and female opioid-tolerant patients with cancer were studied for the treatment of breakthrough cancer pain. no clinically relevant sex differences were noted either in dosage requirement or in observed adverse reactions. oral transmucosal fentanyl citrate (otfc) contains fentanyl, a schedule ii controlled substance. otfc contains fentanyl, 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 otfc 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 otfc 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 otfc abuse include those with a history of prolonged use of any opioid, including products containing fentanyl, those with a history of drug or alcohol abuse, or those who use otfc 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. otfc, 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 otfc abuse of otfc poses a risk of overdose and death. the risk is increased with concurrent use of otfc with alcohol and/or other cns depressants. otfc is approved for oral transmucosal use only. 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. 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)].

Marekani - Kiingereza - NLM (National Library of Medicine)

cephalon, llc - fentanyl citrate (unii: mun5lyg46h) (fentanyl - unii:uf599785jz) - fentanyl 200 ug - actiq is indicated for the management of breakthrough pain in cancer patients 16 years of age and older who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. patients considered opioid tolerant are those who are taking, for one week or longer, around-the-clock medicine consisting of at least 60 mg of oral morphine per day, at least 25 mcg of transdermal fentanyl per hour, at least 30 mg of oral oxycodone per day, at least 8 mg of oral hydromorphone per day, at least 25 mg oral oxymorphone per day, at least 60 mg of oral hydrocodone per day, or an equianalgesic dose of another opioid. patients must remain on around-the-clock opioids when taking actiq. limitations of use: - not for use in opioid non-tolerant patients. - not for use in the management of acute or postoperative pain, including headache/migraine and dental pain [see contraindications (4)] . - as a part of the tirf rems, actiq may be dispensed by outpatient pharmacies only to outpatients enrolled in the program [see  warnings and precautions  (5.7)] . for inpatient administration of actiq, patient and prescriber enrollment are not required. actiq is contraindicated in: - opioid non-tolerant patients: life-threatening respiratory depression and death could occur at any dose in opioid non-tolerant patients [see indications and usage (1), warnings and precautions (5.2)]. - significant respiratory depression [see warnings and precautions (5.2)]. - acute or postoperative pain including headache/migraine and dental pain, or acute pain in the emergency department [see indications and usage (1)] . - acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see warnings and precautions (5.11 )]. - known or suspected gastrointestinal obstruction, including paralytic ileus [see warnings and precautions (5.15 )]. - known hypersensitivity to fentanyl or components of actiq (e.g., anaphylaxis, hypersensitivity) [see adverse reactions (6.2)]. risk summary use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see warnings and precautions (5.8)] . available data with actiq in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. there are risks to the mother and infant associated with use of actiq for an extended period of time during pregnancy (see clinical considerations). in animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing. when administered during gestation through lactation fentanyl administration to pregnant rats resulted in reduced pup survival at doses within the range of the human recommended dosing. no evidence of malformations were noted in animal studies completed to date [see data] . the 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 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 of neonatal withdrawal symptoms usually occurs in the first days after birth. the duration and severity of neonatal opioid withdrawal syndrome may vary. observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see warnings and precautions (5.8)] . 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. actiq is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. opioid analgesics, including actiq, 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. monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. data human data in women treated acutely with intravenous or epidural fentanyl during labor, symptoms of neonatal respiratory or neurological depression were no more frequent than would be expected in infants of untreated mothers. transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl. animal data fentanyl (25, 50, or 100 mcg/kg) citrate was administered subcutaneously to pregnant rats during the period of organogenesis (gestation day, gd 6 to 17). maternal toxicity and a decrease in fetal weights were observed at 100 mcg/kg but no teratogenicity was seen in the study (the no observed effect level of 50 mcg/kg is equivalent to 0.7 times the exposure of a single human dose of 1600 mcg per pain episode, based on an auc comparison). fentanyl (50, 100, or 250 mcg/kg) was also administered subcutaneously to pregnant rabbits during the period of organogenesis (gd 6-18). maternal toxicity was noted at doses >100 mcg/kg. no teratogenicity was seen in the study (250 mcg/kg dose is equivalent to 3.5 times the exposure of a single human dose of 1600 mcg per pain episode, based on an auc comparison). fentanyl has been shown to be embryocidal in pregnant rats at doses of 30 mcg/kg intravenously (0.2 times the 1600 mcg dose of actiq on a mg/m2 basis) from gd 6 to 18 and 160 mcg/kg subcutaneously (1 times the 1600 mcg dose of actiq based on a mg/m2 basis). no evidence of teratogenicity was reported. no evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered fentanyl continuously via subcutaneously implanted osmotic minipumps at doses of 10, 100, or 500 mcg/kg/day starting 2-weeks prior to breeding and throughout pregnancy. the high dose was approximately 3 times the human dose of 1600 mcg actiq per pain episode on a mg/m2 basis and produced mean steady-state plasma levels that are 3.4 times higher than the mean cmax observed following administration of 1600 mcg dose of actiq in humans. in a postnatal development study, pregnant rats were treated from gd 6 through lactation day (ld) 20 with subcutaneous doses of fentanyl (25, 50, 100, and 400 mcg/kg). maternal toxicity was noted at doses >100 mcg/kg. a reduction in pup growth and delayed attainment of developmental indices were observed at >100 mcg/kg. no difference in the number of live pups/litter was seen at birth, however, pup survival at ld 4 was reduced to 48% at 400 mcg/kg and by ld 21 pup survival was reduced to 30% and 26% at 100 and 400 mcg/kg, respectively. during lactation, fentanyl-related clinical signs (decreased activity, skin cold to touch, and moribund appearance) were noted in the f1 pups, most prominently in the 400 mcg/kg group. pups from this group also had significantly reduced body weights throughout the lactation period. the dose of fentanyl administered to rats at which no developmental toxicity in the f1 generation was seen was 50 mcg/kg which is 0.6 times the exposure of a single human dose of 1600 mcg per pain episode, based on an auc comparison. risk summary fentanyl is present in breast milk. one published lactation study reports a relative infant dose of fentanyl of 0.024%. however, there is insufficient information to determine the effects of fentanyl on the breastfed infant and the effects of fentanyl 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 actiq. clinical considerations monitor infants exposed to actiq through breast milk for excess sedation and respiratory depression. withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breastfeeding is stopped. 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)] . safety and effectiveness in pediatric patients below 16 years of age have not been established. in a clinical study, 15 opioid-tolerant pediatric patients with breakthrough pain, ranging in age from 5 to 15 years, were treated with actiq. the study was too small to allow conclusions on safety and efficacy in this patient population. twelve of the fifteen opioid-tolerant children and adolescents aged 5 to 15 years in this study received actiq at doses ranging from 200 mcg to 600 mcg. the mean (cv%; range) dose-normalized (to 200 mcg) cmax and auc0-8 values were 0.87 ng/ml (51%; 0.42-1.30) and 4.54 ng. h/ml (42%; 2.37-6.0), respectively, for children ages 5 to <11 years old (n = 3) and 0.68 ng/ml (72%; 0.15-1.44) and 8.38 (192%; 0.84-50.78), respectively, for children ages ≥11 to <16 y (n = 9). of the 257 patients in clinical studies of actiq in breakthrough cancer pain, 61 (24%) were 65 years of age and older, while 15 (6%) were 75 years of age and older. those patients over the age of 65 years were titrated to a mean dose that was about 200 mcg less than the mean dose titrated to by younger patients. no difference was noted in the safety profile of the group over 65 years of age as compared to younger patients in actiq clinical trials. elderly patients have been shown to be more sensitive to the effects of fentanyl when administered intravenously, compared with the younger population. therefore, exercise caution when individually titrating actiq in elderly patients to provide adequate efficacy while minimizing risk. 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 actiq slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see warnings and precautions (5.11)] . fentanyl 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. insufficient information exists to make recommendations regarding the use of actiq in patients with impaired renal or hepatic function. fentanyl is metabolized primarily via human cytochrome p450 3a4 isoenzyme system and mostly eliminated in urine. if the drug is used in these patients, it should be used with caution because of the hepatic metabolism and renal excretion of fentanyl. both male and female opioid-tolerant patients with cancer were studied for the treatment of breakthrough cancer pain. no clinically relevant sex differences were noted either in dosage requirement or in observed adverse reactions. actiq contains fentanyl, a schedule ii controlled substance. actiq contains fentanyl, 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 actiq 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 actiq 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 actiq abuse include those with a history of prolonged use of any opioid, including products containing fentanyl, those with a history of drug or alcohol abuse, or those who use actiq 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. actiq, 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 actiq abuse of actiq poses a risk of overdose and death. the risk is increased with concurrent use of actiq with alcohol and/or other cns depressants. actiq is approved for oral transmucosal use only. 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. 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)].

Marekani - Kiingereza - NLM (National Library of Medicine)

specgx llc - fentanyl citrate (unii: mun5lyg46h) (fentanyl - unii:uf599785jz) - fentanyl 200 ug - oral transmucosal fentanyl citrate is indicated for the management of breakthrough pain in cancer patients 16 years of age and older who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. patients considered opioid tolerant are those who are taking, for one week or longer, around-the-clock medicine consisting of at least 60 mg of oral morphine per day, at least 25 mcg of transdermal fentanyl per hour, at least 30 mg of oral oxycodone per day, at least 8 mg of oral hydromorphone per day, at least 25 mg oral oxymorphone per day, at least 60 mg of oral hydrocodone per day, or an equianalgesic dose of another opioid. patients must remain on around-the-clock opioids when taking oral transmucosal fentanyl citrate. limitations of use : - not for use in opioid non-tolerant patients. not for use in opioid non-tolerant patients. - not for use in the management of acute or postoperative pain, including headache/migraine and dental pain [see contraindications (4)] . not for use in the management of acute or postoperative pain, including headache/migraine and dental pain [see contraindications (4)] . - as a part of the tirf rems, oral transmucosal fentanyl citrate may be dispensed by outpatient pharmacies only to outpatients enrolled in the program [see warnings and precautions (5.7)] . for inpatient administration of oral transmucosal fentanyl citrate, patient and prescriber enrollment are not required. as a part of the tirf rems, oral transmucosal fentanyl citrate may be dispensed by outpatient pharmacies only to outpatients enrolled in the program [see warnings and precautions (5.7)] . for inpatient administration of oral transmucosal fentanyl citrate, patient and prescriber enrollment are not required. oral transmucosal fentanyl citrate is contraindicated in: - opioid non-tolerant patients: life-threatening respiratory depression and death could occur at any dose in opioid non-tolerant patients [see indications and usage (1)]; warnings and precautions (5.1) [see indications and usage (1)] . - significant respiratory depression [see warnings and precautions (5.1)] . significant respiratory depression [see warnings and precautions (5.1)] . - acute or postoperative pain including headache/migraine and dental pain, or acute pain in the emergency department. acute or postoperative pain including headache/migraine and dental pain, or acute pain in the emergency department. - acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see warnings and precautions (5.9)] . acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see warnings and precautions (5.9)] . - known or suspected gastrointestinal obstruction, including paralytic ileus [see warnings and precautions (5.14)] . known or suspected gastrointestinal obstruction, including paralytic ileus [see warnings and precautions (5.14)] . - known hypersensitivity to fentanyl or components of oral transmucosal fentanyl citrate (e.g., anaphylaxis, hypersensitivity) [see adverse reactions (6.2)] . known hypersensitivity to fentanyl or components of oral transmucosal fentanyl citrate (e.g., anaphylaxis, hypersensitivity) [see adverse reactions (6.2)] . risk summary prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see warnings and precautions (5.8)] . available data with oral transmucosal fentanyl citrate in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. in animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing. when administered during gestation through lactation fentanyl administration to pregnant rats resulted in reduced pup survival at doses within the range of the human recommended dosing. no evidence of malformations were noted in animal studies completed to date [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 fetal/neonatal adverse reactions prolonged use of opioid analgesics 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 of neonatal withdrawal symptoms usually occurs in the first days after birth. the duration and severity of neonatal opioid withdrawal syndrome may vary. observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see warnings and precautions (5.8)] . 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. oral transmucosal fentanyl citrate is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. opioid analgesics, including oral transmucosal fentanyl citrate, 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. monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. data human data in women treated acutely with intravenous or epidural fentanyl during labor, symptoms of neonatal respiratory or neurological depression were no more frequent than would be expected in infants of untreated mothers. transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl. animal data fentanyl (25, 50, or 100 mcg/kg) citrate was administered subcutaneously to pregnant rats during the period of organogenesis (gestation day, gd 6 to 17). maternal toxicity and a decrease in fetal weights were observed at 100 mcg/kg but no teratogenicity was seen in the study (the no observed effect level of 50 mcg/kg is equivalent to 0.7 times the exposure of a single human dose of 1600 mcg per pain episode, based on an auc comparison). fentanyl (50, 100, or 250 mcg/kg) was also administered subcutaneously to pregnant rabbits during the period of organogenesis (gd 6 to 18). maternal toxicity was noted at doses >100 mcg/kg. no teratogenicity was seen in the study (250 mcg/kg dose is equivalent to 3.5 times the exposure of a single human dose of 1600 mcg per pain episode, based on an auc comparison). fentanyl has been shown to embryocidal in pregnant rats at doses of 30 mcg/kg intravenously (0.2 times the 1600 mcg dose of oral transmucosal fentanyl citrate on a mg/m2 basis) from gd 6 to 18 and 160 mcg/kg subcutaneously (1 times the 1600 mcg dose of oral transmucosal fentanyl citrate based on a mg/m2 basis). no evidence of teratogenicity was reported. no evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered fentanyl continuously via subcutaneously implanted osmotic minipumps at doses of 10, 100, or 500 mcg/kg/day starting 2-weeks prior to breeding and throughout pregnancy. the high dose was approximately 3 times the human dose of 1600 mcg oral transmucosal fentanyl citrate per pain episode on a mg/m2 basis and produced mean steady-state plasma levels that are 3.4 times higher than the mean cmax observed following administration of 1600 mcg dose of oral transmucosal fentanyl citrate in humans. in a postnatal development study, pregnant rats were treated from gd 6 through lactation day (ld) 20 with subcutaneous doses of fentanyl (25, 50, 100, and 400 mcg/kg). maternal toxicity was noted at doses >100 mcg/kg. a reduction in pup growth and delayed attainment of developmental indices were observed at >100 mcg/kg. no difference in the number of live pups/litter was seen at birth, however, pup survival at ld 4 was reduced to 48% at 400 mcg/kg and by ld 21 pup survival was reduced to 30% and 26% at 100 and 400 mcg/kg, respectively. during lactation, fentanyl-related clinical signs (decreased activity, skin cold to touch, and moribund appearance) were noted in the f1 pups, most prominently in the 400 mcg/kg group. pups from this group also had significantly reduced body weights throughout the lactation period. the dose of fentanyl administered to rats at which no developmental toxicity in the f1 generation was seen was 50 mcg/kg which is 0.6 times the exposure of a single human dose of 1600 mcg per pain episode, based on an auc comparison. risk summary fentanyl is present in breast milk. one published lactation study reports a relative infant dose of fentanyl of 0.024%. however, there is insufficient information to determine the effects of fentanyl on the breastfed infant and the effects of fentanyl 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 oral transmucosal fentanyl citrate. clinical considerations monitor infants exposed to oral transmucosal fentanyl citrate through breast milk for excess sedation and respiratory depression. withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. 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)] . safety and effectiveness in pediatric patients below 16 years of age have not been established. in a clinical study, 15 opioid-tolerant pediatric patients with breakthrough pain, ranging in age from 5 to 15 years, were treated with oral transmucosal fentanyl citrate. the study was too small to allow conclusions on safety and efficacy in this patient population. twelve of the fifteen opioid-tolerant children and adolescents aged 5 to 15 years in this study received oral transmucosal fentanyl citrate at doses ranging from 200 mcg to 600 mcg. the mean (cv%; range) dose-normalized (to 200 mcg) cmax and auc0-8 values were 0.87 ng/ml (51%; 0.42-1.30) and 4.54 ng•h/ml (42%; 2.37-6.0), respectively, for children ages 5 to <11 years old (n = 3) and 0.68 ng/ml (72%; 0.15-1.44) and 8.38 (192%; 0.84-50.78), respectively, for children ages ≥11 to <16 y (n = 9). of the 257 patients in clinical studies of oral transmucosal fentanyl citrate in breakthrough cancer pain, 61 (24%) were 65 years of age and older, while 15 (6%) were 75 years of age and older. those patients over the age of 65 years were titrated to a mean dose that was about 200 mcg less than the mean dose titrated to by younger patients. no difference was noted in the safety profile of the group over 65 years of age as compared to younger patients in oral transmucosal fentanyl citrate clinical trials. elderly patients have been shown to be more sensitive to the effects of fentanyl when administered intravenously, compared with the younger population. therefore, exercise caution when individually titrating oral transmucosal fentanyl citrate in elderly patients to provide adequate efficacy while minimizing risk. 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 oral transmucosal fentanyl citrate slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see warnings and precautions (5.9)] . fentanyl 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 monitor renal function. insufficient information exists to make recommendations regarding the use of oral transmucosal fentanyl citrate in patients with impaired renal or hepatic function. fentanyl is metabolized primarily via human cytochrome p450 3a4 isoenzyme system and mostly eliminated in urine. if the drug is used in these patients, it should be used with caution because of the hepatic metabolism and renal excretion of fentanyl. both male and female opioid-tolerant cancer patients were studied for the treatment of breakthrough cancer pain. no clinically relevant sex differences were noted either in dosage requirement or in observed adverse reactions. oral transmucosal fentanyl citrate contains fentanyl, a schedule ii controlled substance. oral transmucosal fentanyl citrate contains fentanyl, a substance with a high potential for abuse similar to other opioids including hydrocodone, hydromorphone, methadone, morphine oxycodone, oxymorphone, and tapentadol. oral transmucosal fentanyl citrate can be abused and is subject to misuse, addiction, and criminal diversion [see warnings and precautions (5.6)] . all patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. “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 drug abusers and people suffering from untreated addiction. preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. abuse and addiction are separate and distinct from physical dependence and tolerance. healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. in addition, abuse of opioids can occur in the absence of true addiction. oral transmucosal fentanyl citrate, like other opioids, can be diverted for non-medical 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 re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. risks specific to the abuse of oral transmucosal fentanyl citrate oral transmucosal fentanyl citrate is for oral transmucosal use only. abuse of oral transmucosal fentanyl citrate poses a risk of overdose and death. the risk is increased with concurrent abuse of oral transmucosal fentanyl citrate with alcohol and other central nervous system depressants. both tolerance and physical dependence can develop during chronic opioid therapy. tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), 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 opioid usage. 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)] .

Marekani - Kiingereza - NLM (National Library of Medicine)

golden state medical supply, inc. - tramadol hydrochloride (unii: 9n7r477wck) (tramadol - unii:39j1lgj30j) - tramadol hydrochloride 50 mg - tramadol hydrochloride tablets are indicated in adults for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. limitations of use because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [see warnings and precautions ( 5.1)] , reserve tramadol hydrochloride tablets 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. tramadol hydrochloride tablets should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate. tramadol hydrochloride tablets are contraindicated for: - all children younger than 12 years of age [see warnings and precautions ( 5.6)] . - postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see warnings and precautions ( 5.6)] . tramadol hydrochloride tablets are also 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 ( 5.12)] . - known or suspected gastrointestinal obstruction, including paralytic ileus [see warnings and precautions ( 5.16)] . - hypersensitivity to tramadol, any other component of this product or opioids [see warnings and precautions ( 5.17)] . - concurrent use of monoamine oxidase inhibitors (maois) or use within the last 14 days [see drug interactions ( 7)] . 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)] . available data with tramadol hydrochloride tablets in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. in animal reproduction studies, tramadol administration during organogenesis decreased fetal weights and reduced ossification in mice, rats, and rabbits at 1.4, 0.6, and 3.6 times the maximum recommended human daily dosage (mrhd). tramadol decreased pup body weight and increased pup mortality at 1.2 and 1.9 times the mrhd [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 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 2-4% and 15-20%, 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 respiratory depression and physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. neonatal opioid withdrawal syndrome can present 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 and signs of neonatal opioid withdrawal syndrome and manage accordingly [see warnings and precautions ( 5.4)] . neonatal seizures, neonatal withdrawal syndrome, fetal death and still birth have been reported during postmarketing. 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. tramadol hydrochloride tablets are not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. opioid analgesics, including tramadol hydrochloride tablets, 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. monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. tramadol has been shown to cross the placenta. the mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labor. the effect of tramadol hydrochloride tablets, if any, on the later growth, development, and functional maturation of the child is unknown. data animal data tramadol has been shown to be embryotoxic and fetotoxic in mice, (120 mg/kg), rats (25 mg/kg) and rabbits (75 mg/kg) at maternally toxic dosages, but was not teratogenic at these dose levels. these doses on a mg/m 2 basis are 1.4, 0.6, and 3.6 times the maximum recommended human daily dosage (mrhd) for mouse, rat and rabbit, respectively. no drug-related teratogenic effects were observed in progeny of mice (up to 140 mg/kg), rats (up to 80 mg/kg) or rabbits (up to 300 mg/kg) treated with tramadol by various routes. embryo and fetal toxicity consisted primarily of decreased fetal weights, decreased skeletal ossification and increased supernumerary ribs at maternally toxic dose levels. transient delays in developmental or behavioral parameters were also seen in pups from rat dams allowed to deliver. embryo and fetal lethality were reported only in one rabbit study at 300 mg/kg, a dose that would cause extreme maternal toxicity in the rabbit. the dosages listed for mouse, rat and rabbit are 1.7, 1.9 and 14.6 times the mrhd, respectively. tramadol was evaluated in pre- and post-natal studies in rats. progeny of dams receiving oral (gavage) dose levels of 50 mg/kg (1.2 times the mrhd) or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (1.9 times the mrhd). risk summary tramadol hydrochloride tablets are not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied. tramadol and its metabolite, o -desmethyltramadol (m1), are present in human milk. there is no information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. the m1 metabolite is more potent than tramadol in mu opioid receptor binding [see clinical pharmacology ( 12)] . published studies have reported tramadol and m1 in colostrum with administration of tramadol to nursing mothers in the early post-partum period. women who are ultra-rapid metabolizers of tramadol may have higher than expected serum levels of m1, potentially leading to higher levels of m1 in breast milk that can be dangerous in their breastfed infants. in women with normal tramadol metabolism, the amount of tramadol secreted into human milk is low and dose-dependent. 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 tramadol hydrochloride tablets  [see warnings and precautions ( 5.6)] . clinical considerations if infants are exposed to tramadol hydrochloride through breast milk, they should be monitored for excess sedation and respiratory depression. withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. data following a single iv 100 mg dose of tramadol, the cumulative excretion in breast milk within 16 hours post dose was 100 mcg of tramadol (0.1% of the maternal dose) and 27 mcg of m1. 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)] . the safety and effectiveness of tramadol hydrochloride tablets in pediatric patients have not been established. life-threatening respiratory depression and death have occurred in children who received tramadol [see warnings and precautions ( 5.6)] . in some of the reported cases, these events followed tonsillectomy and/or adenoidectomy, and one of the children had evidence of being an ultra-rapid metabolizer of tramadol (i.e., multiple copies of the gene for cytochrome p450 isoenzyme 2d6). children with sleep apnea may be particularly sensitive to the respiratory depressant effects of tramadol. because of the risk of life-threatening respiratory depression and death: - tramadol hydrochloride tablets are contraindicated for all children younger than 12 years of age [see contraindications ( 4)] . - tramadol hydrochloride tablets are contraindicated for postoperative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see contraindications ( 4)] . avoid the use of tramadol hydrochloride tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol unless the benefits outweigh the risks. risk factors include conditions associated with hypoventilation such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression. a total of 455 elderly (65 years of age or older) subjects were exposed to tramadol hydrochloride tablets in controlled clinical trials. of those, 145 subjects were 75 years of age and older. in studies including geriatric patients, treatment-limiting adverse events were higher in subjects over 75 years of age compared to those under 65 years of age. specifically, 30% of those over 75 years of age had gastrointestinal treatment-limiting adverse events compared to 17% of those under 65 years of age. constipation resulted in discontinuation of treatment in 10% of those over 75. 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 tramadol hydrochloride tablets slowly in geriatric patients starting at the low end of the dosing range and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see warnings and precautions ( 5.12)] . tramadol 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 monitor renal function. impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, m1. in patients with creatinine clearances of less than 30 ml/min, dosing reduction is recommended [see dosage and administration ( 2.3)] . metabolism of tramadol and m1 is reduced in patients with severe hepatic impairment based on a study in patients with advanced cirrhosis of the liver. in patients with severe hepatic impairment, dosing reduction is recommended [see dosage and administration ( 2.3)] . with the prolonged half-life in these conditions, achievement of steady-state is delayed, so that it may take several days for elevated plasma concentrations to develop. tramadol hydrochloride tablets contain tramadol, a schedule iv controlled substance. tramadol hydrochloride tablets contain tramadol, a substance with 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 tramadol hydrochloride tablets 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 tramadol hydrochloride tablets with alcohol and 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 tramadol hydrochloride tablets abuse include those with a history of prolonged use of any opioid, including products containing tramadol, those with a history of drug or alcohol abuse, or those who use tramadol hydrochloride tablets 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. tramadol hydrochloride tablets, 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 tramadol hydrochloride tablets abuse of tramadol hydrochloride tablets poses a risk of overdose and death. the risk is increased with concurrent use of tramadol hydrochloride tablets with alcohol and/or other cns depressants. tramadol hydrochloride tablets are approved for oral use only. 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 tramadol hydrochloride tablets in a patient physically dependent on opioids. rapid tapering of tramadol hydrochloride tablets 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 tramadol hydrochloride tablets, gradually taper the dosage using a patient-specific plan that considers the following: the dose of tramadol hydrochloride tablets 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 ( 5.18)] . 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)] .

Marekani - Kiingereza - NLM (National Library of Medicine)

purdue pharma lp - buprenorphine (unii: 40d3scr4gz) (buprenorphine - unii:40d3scr4gz) - buprenorphine 10 ug in 1 h - butrans 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 risk of overdose and death with extended-release/long-acting opioid formulations [see warnings and precautions (5.1)] , reserve butrans 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. - butrans is not indicated as an as-needed (prn) analgesic butrans 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 (5.10)] - known or suspected gastrointestinal obstruction, including paralytic ileus [see warnings and precautions (5.15)] - hypersensitivity (e.g., anaphylaxis) to buprenorphine [see warnings and precautions (5.18), 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)]. available data with butrans in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. in animal reproduction studies, buprenorphine caused an increase in the number of stillborn offspring, reduced litter size, and reduced offspring growth in rats at maternal exposure levels that were approximately 10 times that of human subjects who received one butrans 20 mcg/hour, the maximum recommended human dose (mrhd) [see data]. based on animal data, advise pregnant women of the potential risk to a fetus. the 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 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 and delivery opioids cross the placenta and may produce respiratory depression in neonates. an opioid antagonist such as naloxone must be available for reversal of opioid-induced respiratory depression in the neonate. butrans 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 butrans, can prolong labor through actions that 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 dilatation, which tends to shorten labor. data animal data studies in rats and rabbits demonstrated no evidence of teratogenicity following butrans or subcutaneous (sc) administration of buprenorphine during the period of organogenesis. rats were administered up to one butrans 20 mcg/hour every 3 days (gestation days 6, 9, 12, & 15) or received daily sc buprenorphine up to 5 mg/kg (gestation days 6 to 17). rabbits were administered four butrans 20 mcg/hour every 3 days (gestation days 6, 9, 12, 15, 18, and 19) or received daily sc buprenorphine up to 5 mg/kg (gestation days 6-19). no teratogenicity was observed at any dose. auc values for buprenorphine with butrans application and sc injection were approximately 110 and 140 times, respectively, that of human subjects who received the mrhd of one butrans 20 mcg/hour. in a pre- and post-natal study conducted in pregnant and lactating rats, administration of buprenorphine either as butrans or sc buprenorphine was associated with toxicity to offspring. buprenorphine was present in maternal milk. pregnant rats were administered 1/4 of one butrans 5 mcg/hour every 3 days or received daily sc buprenorphine at doses of 0.05, 0.5, or 5 mg/kg from gestation day 6 to lactation day 21 (weaning). administration of butrans or sc buprenorphine at 0.5 or 5 mg/kg caused maternal toxicity and an increase in the number of stillborns, reduced litter size, and reduced offspring growth at maternal exposure levels that were approximately 10 times that of human subjects who received the mrhd of one butrans 20 mcg/hour. maternal toxicity was also observed at the no observed adverse effect level (noael) for offspring. risk summary 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 butrans. clinical considerations monitor infants exposed to butrans 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 breast-feeding is stopped. 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), preclinical pharmacology (12.2), nonclinical toxicology (13.1)] . the safety and efficacy of butrans in patients under 18 years of age has not been established. butrans has been evaluated in an open-label clinical trial in pediatric patients. however, definitive conclusions are not possible because of the small sample size. of the total number of subjects in the clinical trials (5,415), butrans was administered to 1,377 patients aged 65 years and older. of those, 457 patients were 75 years of age and older. in the clinical program, the incidences of selected butrans-related aes were higher in older subjects. the incidences of application site aes were slightly higher among subjects < 65 years of age than those ≥ 65 years of age for both butrans and placebo treatment groups. in a single-dose study of healthy elderly and healthy young subjects treated with butrans 10 mcg/hour, the pharmacokinetics were similar. in a separate dose-escalation safety study, the pharmacokinetics in the healthy elderly and hypertensive elderly subjects taking thiazide diuretics were similar to those in the healthy young adults. in the elderly groups evaluated, adverse event rates were similar to or lower than rates in healthy young adult subjects, except for constipation and urinary retention, which were more common in the elderly. 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 [see clinical pharmacology (12.3)] . 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 butrans slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see warnings and precautions (5.10)] . in a study utilizing intravenous buprenorphine, peak plasma levels (cmax ) and exposure (auc) of buprenorphine in patients with mild and moderate hepatic impairment did not increase as compared to those observed in subjects with normal hepatic function. butrans has not been evaluated in patients with severe hepatic impairment. as butrans is intended for 7-day dosing, consider the use of alternate analgesic therapy in patients with severe hepatic impairment [see dosage and administration (2.6) and clinical pharmacology (12.3)]. butrans contains buprenorphine, a schedule iii controlled substance. butrans 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 butrans 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 butrans 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 butrans 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 butrans 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. butrans, 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 the abuse of butrans abuse of butrans poses a risk of overdose and death. this risk is increased with the concurrent use of butrans with alcohol and/or other substances including other opioids and benzodiazepines [see warnings and precautions (5.1, 5.3), drug interactions (7)] . butrans is approved for transdermal use only. intentional compromise of the transdermal delivery system will 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 transdermal system in the absence of legitimate purpose, or by chewing, swallowing, snorting, or injecting buprenorphine extracted from the transdermal system. 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 butrans in a patient physically dependent on opioids. rapid tapering of butrans 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 butrans, gradually taper the dosage using a patient-specific plan that considers the following: the dose of butrans 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 (2.1), warnings and precautions (5.19)] . 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)] .

Marekani - Kiingereza - NLM (National Library of Medicine)

rhodes pharmaceuticals l.p. - buprenorphine (unii: 40d3scr4gz) (buprenorphine - unii:40d3scr4gz) - buprenorphine 5 ug in 1 h - buprenorphine transdermal system 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 risk of overdose and death with extended-release/long-acting opioid formulations [see warnings and precautions (5.1)] , reserve buprenorphine transdermal system 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. - buprenorphine transdermal system is not indicated as an as-needed (prn) analgesic. buprenorphine transdermal system 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 (5.10)] - known or suspected gastrointestinal obstruction, including paralytic ileus [see warnings and precautions (5.15)] - hypersensitivity (e.g., anaphylaxis) to buprenorphine [see warnings and precautions (5.18), 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)]. available data with buprenorphine transdermal system in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. in animal reproduction studies, buprenorphine caused an increase in the number of stillborn offspring, reduced litter size, and reduced offspring growth in rats at maternal exposure levels that were approximately 10 times that of human subjects who received one buprenorphine transdermal system 20 mcg/hour, the maximum recommended human dose (mrhd) [see data]. based on animal data, advise pregnant women of the potential risk to a fetus. the 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 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 and delivery opioids cross the placenta and may produce respiratory depression in neonates. an opioid antagonist such as naloxone must be available for reversal of opioid-induced respiratory depression in the neonate. buprenorphine transdermal system 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 buprenorphine transdermal system, can prolong labor through actions that 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 dilatation, which tends to shorten labor. data animal data studies in rats and rabbits demonstrated no evidence of teratogenicity following buprenorphine transdermal system or subcutaneous (sc) administration of buprenorphine during the period of organogenesis. rats were administered up to one buprenorphine transdermal system 20 mcg/hour every 3 days (gestation days 6, 9, 12, & 15) or received daily sc buprenorphine up to 5 mg/kg (gestation days 6 to 17). rabbits were administered four buprenorphine transdermal system 20 mcg/hour every 3 days (gestation days 6, 9, 12, 15, 18, and 19) or received daily sc buprenorphine up to 5 mg/kg (gestation days 6 to 19). no teratogenicity was observed at any dose. auc values for buprenorphine with buprenorphine transdermal system application and sc injection were approximately 110 and 140 times, respectively, that of human subjects who received the mrhd of one buprenorphine transdermal system 20 mcg/hour. in a pre- and post-natal study conducted in pregnant and lactating rats, administration of buprenorphine either as buprenorphine transdermal system or sc buprenorphine was associated with toxicity to offspring. buprenorphine was present in maternal milk. pregnant rats were administered 1/4 of one buprenorphine transdermal system 5 mcg/hour every 3 days or received daily sc buprenorphine at doses of 0.05, 0.5, or 5 mg/kg from gestation day 6 to lactation day 21 (weaning). administration of buprenorphine transdermal system or sc buprenorphine at 0.5 or 5 mg/kg caused maternal toxicity and an increase in the number of stillborns, reduced litter size, and reduced offspring growth at maternal exposure levels that were approximately 10 times that of human subjects who received the mrhd of one buprenorphine transdermal system 20 mcg/hour. maternal toxicity was also observed at the no observed adverse effect level (noael) for offspring. risk summary 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 buprenorphine transdermal system. clinical considerations monitor infants exposed to buprenorphine transdermal system 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 breast-feeding is stopped. 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), preclinical pharmacology (12.2), nonclinical toxicology (13.1)] . the safety and efficacy of buprenorphine transdermal system in patients under 18 years of age has not been established. buprenorphine transdermal system has been evaluated in an open-label clinical trial in pediatric patients. however, definitive conclusions are not possible because of the small sample size. of the total number of subjects in the clinical trials (5,415), buprenorphine transdermal system was administered to 1,377 patients aged 65 years and older. of those, 457 patients were 75 years of age and older. in the clinical program, the incidences of selected buprenorphine transdermal system-related aes were higher in older subjects. the incidences of application site aes were slightly higher among subjects < 65 years of age than those ≥ 65 years of age for both buprenorphine transdermal system and placebo treatment groups. in a single-dose study of healthy elderly and healthy young subjects treated with buprenorphine transdermal system 10 mcg/hour, the pharmacokinetics were similar. in a separate dose-escalation safety study, the pharmacokinetics in the healthy elderly and hypertensive elderly subjects taking thiazide diuretics were similar to those in the healthy young adults. in the elderly groups evaluated, adverse event rates were similar to or lower than rates in healthy young adult subjects, except for constipation and urinary retention, which were more common in the elderly. 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 [see clinical pharmacology (12.3)] . 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 buprenorphine transdermal system slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see warnings and precautions (5.10)] . in a study utilizing intravenous buprenorphine, peak plasma levels (cmax ) and exposure (auc) of buprenorphine in patients with mild and moderate hepatic impairment did not increase as compared to those observed in subjects with normal hepatic function. buprenorphine transdermal system has not been evaluated in patients with severe hepatic impairment. as buprenorphine transdermal system is intended for 7-day dosing, consider the use of alternate analgesic therapy in patients with severe hepatic impairment [see dosage and administration (2.6), clinical pharmacology (12.3)]. buprenorphine transdermal system contains buprenorphine, a schedule iii controlled substance. buprenorphine transdermal system 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 buprenorphine transdermal system 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 buprenorphine transdermal system 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 buprenorphine transdermal system 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 buprenorphine transdermal system 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. buprenorphine transdermal system, 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 buprenorphine transdermal system abuse of buprenorphine transdermal system poses a risk of overdose and death. this risk is increased with the concurrent use of buprenorphine transdermal system with alcohol and/or other substances including other opioids and benzodiazepines [see warnings and precautions (5.1, 5.3), drug interactions (7)] . buprenorphine transdermal system is approved for transdermal use only. intentional compromise of the transdermal delivery system will 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 transdermal system in the absence of legitimate purpose, or by chewing, swallowing, snorting, or injecting buprenorphine extracted from the transdermal system. 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 buprenorphine transdermal system in a patient physically dependent on opioids. rapid tapering of buprenorphine transdermal system 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 buprenorphine transdermal system, gradually taper the dosage using a patient-specific plan that considers the following: the dose of buprenorphine transdermal system 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 (2.1), warnings and precautions (5.19)] . 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)] . be sure that you read, understand, and follow these instructions for use before you use buprenorphine transdermal system. talk to your healthcare provider or pharmacist if you have any questions. before applying buprenorphine transdermal system: - do not use soap, alcohol, lotions, oils, or other products to remove any leftover adhesive from a patch because this may cause more buprenorphine transdermal system to pass through the skin. - each patch is sealed in its own protective pouch. do not remove a patch from the pouch until you are ready to use it. - do not use a patch if the seal on the protective pouch is broken or if the patch is cut, damaged, or changed in any way. - buprenorphine transdermal system patches are available in different strengths and patch sizes. make sure you have the right strength patch that has been prescribed for you. where to apply buprenorphine transdermal system: - buprenorphine transdermal system should be applied to the upper outer arm, upper chest, upper back, or the side of the chest (see figure a ). these 4 sites (located on both sides of the body) provide 8 possible buprenorphine transdermal system application sites. - do not apply more than 1 patch at the same time unless your doctor tells you to. however, if your healthcare provider tells you to do so, you may use 2 patches as prescribed, applied at the same site (see figure a for application sites) right next to each other (see figure b for an example of patch position when applying 2 patches). always apply and remove the two patches together at the same time. - you should change the skin site where you apply buprenorphine transdermal system each week, making sure that at least 3 weeks (21 days) pass before you re-use the same skin site. - apply buprenorphine transdermal system to a hairless or nearly hairless skin site . if needed, you can clip the hair at the skin site (see figure c ). do not shave the area. the skin site should not be irritated. use only water to clean the application site. you should not use soaps, alcohol, oils, lotions, or abrasive devices. allow the skin to dry before you apply the patch. - the skin site should be free of cuts and irritation (rashes, swelling, redness, or other skin problems). when to apply a new patch: - when you apply a new patch, write down the date and time that the patch is applied. use this to remember when the patch should be removed. - change the patch at the same time of day, one week (exactly 7 days) after you apply it. - after removing and disposing of the patch, write down the time it was removed and how it was disposed. how to apply buprenorphine transdermal system: - if you are wearing a patch, remember to remove it before applying a new one. - each patch is sealed in its own protective pouch. - if you are using two patches, remember to apply them at the same site right next to each other. always apply and remove the two patches together at the same time. - use scissors to cut open the pouch along the dotted line (see figure d ) and remove the patch. do not remove the patch from the pouch until you are ready to use it. do not use patches that have been cut or damaged in any way. - hold the patch with the protective liner facing you. - gently bend the patch (see figures e and f ) along the faint line and slowly peel the larger portion of the liner, which covers the sticky surface of the patch. - do not touch the sticky side of the patch with your fingers. - using the smaller portion of the protective liner as a handle (see figure g ), apply the sticky side of the patch to one of the 8 body locations described above (see "where to apply buprenorphine transdermal system" ). - while still holding the sticky side down, gently fold back the smaller portion of the patch. grasp an edge of the remaining protective liner and slowly peel it off (see figure h ). - press the entire patch firmly into place with the palm (see figure i ) of your hand over the patch, for about 15 seconds. do not rub the patch. - make sure that the patch firmly sticks to the skin. - go over the edges with your fingers to assure good contact around the patch. - if you are using two patches, follow the steps in this section to apply them right next to each other. - always wash your hands after applying or handling a patch. - after the patch is applied, write down the date and time that the patch is applied. use this to remember when the patch should be removed. if the patch falls off right away after applying, throw it away and put a new one on at a different skin site (see "disposing of buprenorphine transdermal system patch") . if a patch falls off, do not touch the sticky side of the patch with your fingers. a new patch should be applied to a different site. patches that fall off should not be re-applied . they must be thrown away correctly. short-term exposure of the buprenorphine transdermal system patch to water, such as when bathing or showering, is permitted. if the edges of the buprenorphine transdermal system patch start to loosen: - apply first aid tape only to the edges of the patch. - if problems with the patch not sticking continue, cover the patch with special see-through adhesive dressings (for example bioclusive or tegaderm). remove the backing from the transparent adhesive dressing and place it carefully and completely over the buprenorphine transdermal system patch, smoothing it over the patch and your skin. - remove the backing from the transparent adhesive dressing and place it carefully and completely over the buprenorphine transdermal system patch, smoothing it over the patch and your skin. - never cover a buprenorphine transdermal system patch with any other bandage or tape. it should only be covered with a special see-through adhesive dressing. talk to your healthcare provider or pharmacist about the kinds of dressing that should be used. if your patch falls off later, but before 1 week (7 days) of use, throw it away properly (see "disposing of a buprenorphine transdermal system patch") and apply a new patch at a different skin site. be sure to let your healthcare provider know that this has happened. do not replace the new patch until 1 week (7 days) after you put it on (or as directed by your healthcare provider). disposing of buprenorphine transdermal system patch: buprenorphine transdermal system patches should be disposed of by using the patch-disposal unit. alternatively, the patches can be flushed down the toilet if a drug take-back option is not readily available. to dispose of buprenorphine transdermal system patches in household trash using the patch-disposal unit: remove your patch and follow the directions printed on the patch-disposal unit (see figure j ) or see complete instructions below. use one patch-disposal unit for each patch. 1. peel back the disposal unit liner to show the sticky surface (see figure k ). 2. place the sticky side of the used or unused patch to the indicated area on the disposal unit (see figure l ). 3. close the disposal unit by folding the sticky sides together (see figure m ). press firmly and smoothly over the entire disposal unit so that the patch is sealed within. 4. the closed disposal unit, with the patch sealed inside may be thrown away in the trash (see figure n ). do not put expired, unwanted, or unused patches in household trash without first sealing them in the patch-disposal unit. always remove the leftover patches from their protective pouch and remove the protective liner. the pouch and liner can be disposed of separately in the trash and should not be sealed in the patch-disposal unit. to flush your buprenorphine transdermal system patches down the toilet: remove your buprenorphine transdermal system patch, fold the sticky sides of a used patch together and flush it down the toilet right away (see figure o ). when disposing of unused buprenorphine transdermal system patches you no longer need, remove the leftover patches from their protective pouch and remove the protective liner. fold the patches in half with the sticky sides together, and flush the patches down the toilet. do not flush the pouch or the protective liner down the toilet. these items can be thrown away in the trash. if you prefer not to flush the used patch down the toilet , and if there is not a drug take-back option readily available, you must use the patch-disposal unit provided to you to discard the patch. never put used buprenorphine transdermal system patches in the trash without first sealing them in the patch-disposal unit. this "instructions for use" has been approved by the u.s. food and drug administration. marketed by: rhodes pharmaceuticals, wilson, nc 27893 revised: 2/2023 bioclusive is a trademark of systagenix wound management (us), inc. tegaderm is a trademark of 3m.

Marekani - Kiingereza - NLM (National Library of Medicine)

cephalon, llc - fentanyl citrate (unii: mun5lyg46h) (fentanyl - unii:uf599785jz) - fentanyl 100 ug - fentora is indicated for the management of breakthrough pain in cancer patients 18 years of age and older who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. patients considered opioid tolerant are those who are taking, for one week or longer, around-the-clock medicine consisting of at least 60 mg of oral morphine per day, at least 25 mcg of transdermal fentanyl per hour, at least 30 mg of oral oxycodone per day, at least 8 mg of oral hydromorphone per day, at least 25 mg oral oxymorphone per day, at least 60 mg of oral hydrocodone per day, or an equianalgesic dose of another opioid. patients must remain on around-the-clock opioids while taking fentora. limitations of use: - not for use in opioid non-tolerant patients. - not for use in the management of acute or postoperative pain, including headache/migraine and dental pain [see contraindications (4)] . - as a part of the tirf rems, fentora may be dispensed by outpatient pharmacies only to outpatients enrolled in the program [see  warnings and precautions  (5.7)] . for inpatient administration of fentora, patient and prescriber enrollment are not required. fentora is contraindicated in: - opioid non-tolerant patients: life-threatening respiratory depression and death could occur at any dose in opioid non-tolerant patients [see indications and usage (1), warnings and precautions (5.2)]. - significant respiratory depression [see warnings and precautions (5.2)]. - acute or postoperative pain including headache/migraine and dental pain, or acute pain in the emergency department [see indications and usage (1)] . - acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see warnings and precautions (5.11)]. - known or suspected gastrointestinal obstruction, including paralytic ileus [see warnings and precautions (5.15)]. - known hypersensitivity to fentanyl or components of fentora (e.g., anaphylaxis, hypersensitivity) [see adverse reactions (6.2)] . risk summary use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see warnings and precautions (5.8)] . available data with fentora in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. there are risks to the mother and infant associated with use of fentora for an extended period of time during pregnancy (see clinical considerations). in animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing. when administered during gestation through lactation fentanyl administration to pregnant rats resulted in reduced pup survival at doses within the range of the human recommended dosing. no evidence of malformations were noted in animal studies completed to date [see data] . the 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 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 of neonatal withdrawal symptoms usually occurs in the first days after birth. the duration and severity of neonatal opioid withdrawal syndrome may vary. observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see warnings and precautions (5.8)] . 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. fentora is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. opioid analgesics, including fentora, 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. monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. data human data in women treated acutely with intravenous or epidural fentanyl during labor, symptoms of neonatal respiratory or neurological depression were no more frequent than would be expected in infants of untreated mothers. transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl. animal data fentanyl (25, 50, or 100 mcg/kg) was administered subcutaneously to pregnant rats during the period of organogenesis (gestation day, gd 6-17). maternal toxicity and a decrease in fetal weights were observed at 100 mcg/kg but no teratogenicity was seen in the study (100 mcg/kg dose is equivalent to 1.4-times the exposure of a single human dose of 800 mcg per pain episode, based on an auc comparison). fentanyl (50, 100, or 250 mcg/kg) was also administered subcutaneously to pregnant rabbits during the period of organogenesis (gd 6-18). maternal toxicity was noted at doses >100 mcg/kg. no teratogenicity was seen in the study (250 mcg/kg dose is equivalent to 7.5-times the exposure of a single human dose of 800 mcg per pain episode, based on an auc comparison). fentanyl has been shown to be embryocidal in pregnant rats at doses of 30 mcg/kg intravenously (0.4 times the 800 mcg dose of fentora on a mg/m2 basis) from gd 6 to 18 and 160 mcg/kg subcutaneously (2 times the 800 mcg dose of fentora based on a mg/m2 basis). no evidence of teratogenicity was reported. no evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered fentanyl continuously via subcutaneously implanted osmotic minipumps at doses of 10, 100, or 500 mcg/kg/day starting 2-weeks prior to breeding and throughout pregnancy. the high dose was approximately 6 times the human dose of 800 mcg fentora per pain episode on a mg/m2 basis and produced mean steady-state plasma levels that are approximately 5 times higher than the mean cmax observed following administration of 800 mcg dose of fentora in humans. in a postnatal development study, pregnant rats were treated from gd 6 through lactation day (ld) 20 with subcutaneous doses of fentanyl (25, 50, 100, and 400 mcg/kg). maternal toxicity was noted at doses >100 mcg/kg. a reduction in pup growth and delayed attainment of developmental indices were observed at >100 mcg/kg. no difference in the number of live pups/litter was seen at birth, however, pup survival at ld 4 was reduced to 48% at 400 mcg/kg and by ld 21 pup survival was reduced to 30% and 26% at 100 and 400 mcg/kg, respectively. during lactation, fentanyl-related clinical signs (decreased activity, skin cold to touch, and moribund appearance) were noted in the f1 pups, most prominently in the 400 mcg/kg group. pups from this group also had significantly reduced body weights throughout the lactation period. the dose of fentanyl administered to rats at which no developmental toxicity in the f1 generation was seen was 50 mcg/kg which is approximately equal the exposure of a single human dose of 800 mcg per pain episode, based on an auc comparison. risk summary fentanyl is present in breast milk. one published lactation study reports a relative infant dose of fentanyl of 0.024%. however, there is insufficient information to determine the effects of fentanyl on the breastfed infant and the effects of fentanyl 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 fentora. clinical considerations monitor infants exposed to fentora through breast milk for excess sedation and respiratory depression. withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breastfeeding is stopped. 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 fentora have not been established in pediatric patients below the age of 18 years. of the 304 patients with cancer in clinical studies of fentora, 69 (23%) were 65 years of age and older. patients over the age of 65 years tended to titrate to slightly lower doses than younger patients. patients over the age of 65 years reported a slightly higher frequency for some adverse events specifically vomiting, constipation, and abdominal pain. therefore, caution should be exercised in individually titrating fentora in elderly patients to provide adequate efficacy while minimizing risk. 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 fentora slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see warnings and precautions (5.11)] . fentanyl 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. insufficient information exists to make recommendations regarding the use of fentora in patients with impaired renal or hepatic function. fentanyl is metabolized primarily via human cytochrome p450 3a4 isoenzyme system and mostly eliminated in urine. if the drug is used in these patients, it should be used with caution because of the hepatic metabolism and renal excretion of fentanyl. both male and female opioid-tolerant patients with cancer were studied for the treatment of breakthrough cancer pain. no clinically relevant sex differences were noted either in dosage requirement or in observed adverse reactions. the pharmacokinetic effects of race with the use of fentora have not been systematically evaluated. in studies conducted in healthy japanese subjects, systemic exposure was generally higher than that observed in u.s. subjects. fentora contains fentanyl, a schedule ii controlled substance. fentora contains fentanyl, 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 fentora 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 fentora 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 fentora abuse include those with a history of prolonged use of any opioid, including products containing fentanyl, those with a history of drug or alcohol abuse, or those who use fentora 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. fentora, 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 fentora abuse of fentora poses a risk of overdose and death. the risk is increased with concurrent use of fentora with alcohol and/or other cns depressants. fentora is approved for oral transmucosal use only. 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. 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)]. before you use fentora, it is important that you read the medication guide and these instructions for use. be sure that you read, understand, and follow these instructions for use so that you use fentora the right way. ask your healthcare provider or pharmacist if you have any questions about the right way to use fentora. when you get an episode of breakthrough cancer pain, use the dose of fentora prescribed by your healthcare provider as follows: - fentora comes packaged as a blister card containing 4 blister units. each blister unit contains 1 fentora tablet. do not open a blister until ready to use. - separate one of the blister units from the blister card by tearing apart at the perforations. bend the blister unit along the line where indicated. the product strength of your fentora tablets will be printed in the boxed area shown as (see figure 1). figure 1 - peel back foil on blister unit to expose tablet (see figure 2). figure 2 - do not push the tablet through the foil on the blister unit because this could damage the tablet. - when removed from the blister unit, fentora tablet must be used right away. - use fentora tablets whole. - do not crush, split, suck, or chew fentora tablets, or swallow the tablets whole. you will get less relief for your breakthrough cancer pain. - you can place a fentora tablet: in your mouth above a rear molar tooth between the upper cheek and gum (see figure 3). switch (alternate) sides of your mouth for each dose. - in your mouth above a rear molar tooth between the upper cheek and gum (see figure 3). switch (alternate) sides of your mouth for each dose. figure 3 or, - on the floor of your mouth, under your tongue (see figures 4a, 4b, 4c, 4d). -   when placing the tablet under your tongue, first lift your tongue (4b), then place the tablet under your tongue (4c), and lower your tongue over the tablet (4d). figure 4a figure 4b figure 4c figure 4d - leave the tablet in place until it dissolves. a fentora tablet generally takes between 14 to 25 minutes to dissolve. - after 30 minutes, if there is any fentora left in your mouth, you may drink a glass of water to help you swallow the left over medicine. - if you cannot use fentora in this manner, tell your healthcare provider. your healthcare provider will tell you what to do.  distributed by:  teva pharmaceuticals usa, inc.                 call 1-888-483-8279  parsippany, nj 07054  fentmg-012  ©2023 cephalon, llc.  printed in usa this medication guide has been approved by the u.s. food and drug administration.                                                       revised: 12/2023

Marekani - Kiingereza - 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 )].