USA - engelsk - NLM (National Library of Medicine)

aidarex pharmaceuticals llc - buprenorphine hydrochloride (unii: 56w8mw3en1) (buprenorphine - unii:40d3scr4gz) - buprenorphine 8 mg - buprenorphine sublingual tablets is indicated for the treatment of opioid dependence and is preferred for induction. buprenorphine sublingual tablets should be used as part of a complete treatment plan to include counseling and psychosocial support. under the drug addiction treatment act (data) codified at 21 u.s.c. 823(g), prescription use of this product in the treatment of opioid dependence is limited to physicians who meet certain qualifying requirements, and who have notified the secretary of health and human services (hhs) of their intent to prescribe this product for the treatment of opioid dependence and have been assigned a unique identification number that must be included on every prescription. buprenorphine sublingual tablets should not be administered to patients who have been shown to be hypersensitive to buprenorphine, as serious adverse reactions, including anaphylactic shock, have been reported. [see warnings and precautions (5.8

USA - engelsk - NLM (National Library of Medicine)

mylan pharmaceuticals inc. - butorphanol tartrate (unii: 2l7i72ruhn) (butorphanol - unii:qv897jc36d) - butorphanol tartrate 10 mg in 1 ml - butorphanol tartrate nasal spray is indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. because of the risks of addiction, abuse, and misuse, with opioids, even at recommended doses (see warnings), reserve butorphanol tartrate nasal spray for use in patients for whom alternative treatment options (e.g., non-opioid analgesics) butorphanol tartrate nasal spray is contraindicated in: butorphanol tartrate nasal spray contains butorphanol, a schedule iv controlled substance. butorphanol tartrate nasal spray contains butorphanol, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. butorphanol tartrate nasal spray can be abused and is subject to misuse, addiction, and criminal diversion (see warnings). all patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of

USA - engelsk - NLM (National Library of Medicine)

hikma pharmaceuticals usa inc. - morphine sulfate (unii: x3p646a2j0) (morphine - unii:76i7g6d29c) - morphine sulfate 15 mg - morphine sulfate tablets are indicated for the management of: 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 morphine sulfate tablets for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or opioid combination products): morphine sulfate 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 inadeq uate. morphine sulfate tablets are contraindicated in patients with: risk summary: use of opioid analgesics for an extended period of time during pregnancy can cause neonatal opioid withdrawal syndrome [see warnings and precautions (5.4)]. there are no available data with morphine sulfate tablets in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. published studies with morphine use during pregnancy have not reported a clear association with morphine and major birth defects [see human data]. in published animal reproduction studies, morphine administered subcutaneously during the early gestational period produced neural tube defects (i.e., exencephaly and cranioschisis) at 5 and 16 times the human daily dose of 60 mg based on body surface area (hdd) in hamsters and mice, respectively, lower fetal body weight and increased incidence of abortion at 0.4 times the hdd in the rabbit, growth retardation at 6 times the hdd in the rat, and axial skeletal fusion and cryptorchidism at 16 times the hdd in the mouse. administration of morphine sulfate to pregnant rats during organogenesis and through lactation resulted in cyanosis, hypothermia, decreased brain weights, pup mortality, decreased pup body weights, and adverse effects on reproductive tissues at 3 to 4 times the hdd; and long-term neurochemical changes in the brain of offspring which correlate with altered behavioral responses that persist through adulthood at exposures comparable to and less than the hdd [see animal 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 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 signs of neonatal opioid withdrawal syndrome and manage accordingly [see warnings and precautions (5.4)] . labor or delivery: opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. an opioid antagonist, such as naloxone, must be available for reversal of opioid induced respiratory depression in the neonate. morphine sulfate tablets are not recommended for use in women during and immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. opioid analgesics, including morphine sulfate tablets, 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. monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. data: human data: the results from a population-based prospective cohort, including 70 women exposed to morphine during the first trimester of pregnancy and 448 women exposed to morphine at any time during pregnancy, indicate no increased risk for congenital malformations. however, these studies cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and non-randomized study design. animal data: formal reproductive and developmental toxicology studies for morphine have not been conducted. exposure margins for the following published study reports are based on human daily dose of 60 mg morphine using a body surface area comparison (hdd). neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of morphine sulfate (35 to 322 mg/kg) on gestation day 8 to pregnant hamsters (4.7 to 43.5 times the hdd). a no adverse effect level was not defined in this study and the findings cannot be clearly attributed to maternal toxicity. neural tube defects (exencephaly), axial skeletal fusions, and cryptorchidism were reported following a single subcutaneous (sc) injection of morphine sulfate to pregnant mice (100 to 500 mg/kg) on gestation day 8 or 9 at 200 mg/kg or greater (16 times the hdd) and fetal resorption at 400 mg/kg or higher (32 times the hdd). no adverse effects were noted following 100 mg/kg morphine in this model (8 times the hdd). in one study, following continuous subcutaneous infusion of doses greater than or equal to 2.72 mg/kg to mice (0.2 times the hdd), exencephaly, hydronephrosis, intestinal hemorrhage, split supraoccipital, malformed sternebrae, and malformed xiphoid were noted. the effects were reduced with increasing daily dose; possibly due to rapid induction of tolerance under these infusion conditions. the clinical significance of this report is not clear. decreased fetal weights were observed in pregnant rats treated with 20 mg/kg/day morphine sulfate (3.2 times the hdd) from gestation day 7 to 9. there was no evidence of malformations despite maternal toxicity (10% mortality). in a second rat study, decreased fetal weight and increased incidences of growth retardation were noted at 35 mg/kg/day (5.7 times the hdd) and there was a reduced number of fetuses at 70 mg/kg/day (11.4 times the hdd) when pregnant rats were treated with 10, 35, or 70 mg/kg/day morphine sulfate via continuous infusion from gestation day 5 to 20. there was no evidence of fetal malformations or maternal toxicity. an increased incidence of abortion was noted in a study in which pregnant rabbits were treated with 2.5 (0.8 times the hdd) to 10 mg/kg morphine sulfate via subcutaneous injection from gestation day 6 to 10. in a second study, decreased fetal body weights were reported following treatment of pregnant rabbits with increasing doses of morphine (10 to 50 mg/kg/day) during the pre-mating period and 50 mg/kg/day (16 times the hdd) throughout the gestation period. no overt malformations were reported in either publication; although only limited endpoints were evaluated. in published studies in rats, exposure to morphine during gestation and/or lactation periods is associated with: decreased pup viability at 12.5 mg/kg/day or greater (2 times the hdd); decreased pup body weights at 15 mg/kg/day or greater (2.4 times the hdd); decreased litter size, decreased absolute brain and cerebellar weights, cyanosis, and hypothermia at 20 mg/kg/day (3.2 times the hdd); alteration of behavioral responses (play, social-interaction) at 1 mg/kg/day or greater (0.2 times the hdd); alteration of maternal behaviors (e.g., decreased nursing and pup retrievals) in mice at 1 mg/kg or higher (0.08 times the hdd) and rats at 1.5 mg/kg/day or higher (0.2 times the hdd); and a host of behavioral abnormalities in the offspring of rats, including altered responsiveness to opioids at 4 mg/kg/day (0.7 times the hdd) or greater. fetal and/or postnatal exposure to morphine in mice and rats has been shown to result in morphological changes in fetal and neonatal brain and neuronal cell loss, alteration of a number of neurotransmitter and neuromodulator systems, including opioid and non-opioid systems, and impairment in various learning and memory tests that appear to persist into adulthood. these studies were conducted with morphine treatment usually in the range of 4 to 20 mg/kg/day (0.7 to 3.2 times the hdd). additionally, delayed sexual maturation and decreased sexual behaviors in female offspring at 20 mg/kg/day (3.2 times the hdd), and decreased plasma and testicular levels of luteinizing hormone and testosterone, decreased testes weights, seminiferous tubule shrinkage, germinal cell aplasia, and decreased spermatogenesis in male offspring were also observed at 20 mg/kg/day (3.2 times the hdd). decreased litter size and viability were observed in the offspring of male rats that were intraperitoneally administered morphine sulfate for 1 day prior to mating at 25 mg/kg/day (4.1 times the hdd) and mated to untreated females. decreased viability and body weight and/or movement deficits in both first and second generation offspring were reported when male mice were treated for 5 days with escalating doses of 120 to 240 mg/kg/day morphine sulfate (9.7 to 19.5 times the hdd) or when female mice treated with escalating doses of 60 to 240 mg/kg/day (4.9 to 19.5 times the hdd) followed by a 5-day treatment-free recovery period prior to mating. similar multigenerational findings were also seen in female rats pre-gestationally treated with escalating doses of 10 to 22 mg/kg/day morphine (1.6 to 3.6 times the hdd). risk summary: morphine is present in breast milk. published lactation studies report variable concentrations of morphine in breast milk with administration of immediate-release morphine to nursing mothers in the early postpartum period with a milk-to-plasma morphine auc ratio of 2.5:1 measured in one lactation study. however, there is insufficient information to determine the effects of morphine on the breastfed infant and the effects of morphine on milk production. lactation studies have not been conducted with morphine sulfate tablets and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for morphine sulfate tablets and any potential adverse effects on the breastfed infant from morphine sulfate tablets or from the underlying maternal condition. clinical considerations: monitor infants exposed to morphine sulfate tablets through breast milk for excess sedation and respiratory depression. withdrawal symptoms can occur in breastfed infants when maternal administration of morphine 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) and clinical pharmacology (12.2)] . in published animal studies, morphine administration adversely effected fertility and reproductive endpoints in male rats and prolonged estrus cycle in female rats [see nonclinical toxicology (13)]. the safety and effectiveness of morphine sulfate tablets have been established for the management of pediatric patients weighing at least 50 kg with acute pain severe enough to require an opioid analgesic when alternative treatments are inadequate. use of morphine sulfate tablets in this age group is supported by clinical evidence in adults and supportive data from an open-label, safety and pharmacokinetic study in pediatric patients 2 through 17 years of age with post-operative acute pain. patients were excluded if they had used opioids for more than 7 days within the previous 30 days prior to surgery or had received opioids in any form in the previous 7 days prior to surgery.  initial dosing was approximately 0.15 mg/kg to 0.3 mg/kg.  pharmacokinetic modeling and simulation indicate that an initial dose of 15 mg morphine sulfate tablets to pediatric patients weighing at least 50 kg is expected to produce a maximum systemic exposure (cmax ) similar to that achieved after single dose administration of 10 mg morphine sulfate oral solution to adults [see clinical pharmacology (12.3)] . safety data were available in 81 patients who received single and multiple doses (63 patients aged 2 to 17 years received the oral solution; 18 patients aged 12 years to 17 years received the tablets). the median duration of treatment was 20 hours (range 4 hours to 36 hours). opioid and non-opioid rescue analgesics were allowed. the safety profile in pediatric patients consisted primarily of opioid-related adverse reactions and is similar to that observed in adults [see adverse reactions (6)]. the safety and effectiveness of morphine sulfate tablets have not been established for the management of pediatric patients weighing less than 50 kg with acute pain severe enough to require an opioid analgesic when alternative treatments are inadequate because the recommended dosage cannot be achieved with available tablet strengths. consider use of another morphine sulfate product in patients who cannot swallow oral tablets or who weigh less than 50 kg [see dosage and administration (2.3)] . the safety and effectiveness of morphine sulfate tablets have not been established for the management of pediatric patients with chronic pain severe enough to require an opioid analgesic when alternative treatments are inadequate. elderly patients (aged 65 years or older) may have increased sensitivity to morphine. in general, use caution when selecting a dose for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. 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 morphine sulfate tablets slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see warnings and precautions (5.7)] . morphine 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. morphine pharmacokinetics have been reported to be significantly altered in patients with cirrhosis. start these patients with a lower than usual dosage of morphine sulfate tablets and titrate slowly while regularly evaluating for signs of respiratory depression, sedation, and hypotension [see clinical pharmacology (12.3)]. morphine sulfate pharmacokinetics are altered in patients with renal failure. start these patients with a lower than usual dosage of morphine sulfate tablets and titrate slowly while regularly evaluating for signs of respiratory depression, sedation, and hypotension [see clinical pharmacology (12.3)]. morphine sulfate tablets contain morphine, a schedule ii controlled substance. morphine sulfate tablets contains morphine, 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 morphine sulfate 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 morphine sulfate 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 re-evaluation 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 morphine sulfate tablets abuse include those with a history of prolonged use of any opioid, including products containing morphine, those with a history of drug or alcohol abuse, or those who use morphine sulfate 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. morphine sulfate 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 morphine sulfate tablets abuse of morphine sulfate tablets poses a risk of overdose and death. the risk is increased with concurrent use of morphine sulfate tablets with alcohol and/or other cns depressants. morphine sulfate 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 morphine sulfate tablets in a patient physically dependent on opioids. rapid tapering of morphine sulfate 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 morphine sulfate tablets gradually taper the dosage using a patient-specific plan that considers the following: the dose of morphine sulfate 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), and warnings and precautions (5.14)]. 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)].

USA - engelsk - NLM (National Library of Medicine)

lupin pharmaceuticals,inc. - morphine sulfate (unii: x3p646a2j0) (morphine - unii:76i7g6d29c) - morphine sulfate 15 mg - morphine sulfate extended-release tablets is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. limitations of use - because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations [see warnings and precautions (5.1)] , reserve morphine sulfate extended-release tablets 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. - morphine sulfate extended-release tablets is not indicated as an as-needed (prn) analgesic. morphine sulfate extended-release tablets are contraindicated in patients with: - significant respiratory depression [see warnings and precautions (5.3)] - acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see warnings and precautions (5.6)] - concurrent use of monoamine oxidase inhibitors (maois) or use of maois within the last 14 days [see warnings and precautions (5.7), drug interactions (7)] . - known or suspected gastrointestinal obstruction, including paralytic ileus [see warnings and precautions (5.11)] - hypersensitivity (e.g., anaphylaxis) to morphine [see adverse reactions (6.2)] risk summary prolonged use of opioid analgesics during pregnancy may cause neonatal withdrawal syndrome [see warnings and precautions (5.4)]. there are no available data with morphine sulfate extended-release tablets in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. published studies with morphine use during pregnancy have not reported a clear association with morphine and major birth defects [see human data]. in published animal reproduction studies, morphine administered subcutaneously during the early gestational period produced neural tube defects (i.e., exencephaly and cranioschisis) at 5 and 16 times the human daily dose of 60 mg based on body surface area (hdd) in hamsters and mice, respectively, lower fetal body weight and increased incidence of abortion at 0.4 times the hdd in the rabbit, growth retardation at 6 times the hdd in the rat, and axial skeletal fusion and cryptorchidism at 16 times the hdd in the mouse. administration of morphine sulfate to pregnant rats during organogenesis and through lactation resulted in cyanosis, hypothermia, decreased brain weights, pup mortality, decreased pup body weights, and adverse effects on reproductive tissues at 3-4 times the hdd; and long-term neurochemical changes in the brain of offspring which correlate with altered behavioral responses that persist through adulthood at exposures comparable to and less than the hdd [see animal data ]. based on animal data, advise pregnant women of the potential risk to a fetus. the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, 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, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see warnings and precautions (5.4)] . labor or delivery opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. an opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate.  morphine sulfate extended-release tablets is not recommended for use in pregnant women during or immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. opioid analgesics, including morphine sulfate extended-release 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. data human data the results from a population-based prospective cohort, including 70 women exposed to morphine during the first trimester of pregnancy and 448 women exposed to morphine at any time during pregnancy, indicate no increased risk for congenital malformations. however, these studies cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and non-randomized study design. animal data formal reproductive and developmental toxicology studies for morphine have not been conducted. exposure margins for the following published study reports are based on human daily dose of 60 mg morphine using a body surface area comparison (hdd). neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of morphine sulfate (35to322 mg/kg) on gestation day 8 to pregnant hamsters (4.7 to 43.5 times the hdd). a no adverse effect level was not defined in this study and the findings cannot be clearly attributed to maternal toxicity. neural tube defects (exencephaly), axial skeletal fusions, and cryptorchidism were reported following a single subcutaneous (sc) injection of morphine sulfate to pregnant mice (100-500 mg/kg) on gestation day 8 or 9 at 200 mg/kg or greater (16 times the hdd) and fetal resorption at 400 mg/kg or higher (32 times the hdd).  no adverse effects were noted following 100 mg/kg morphine in this model (8 times the hdd). in one study, following continuous subcutaneous infusion of doses greater than or equal to 2.72 mg/kg to mice (0.2 times the hdd), exencephaly, hydronephrosis, intestinal hemorrhage, split supraoccipital, malformed sternebrae, and malformed xiphoid were noted. the effects were reduced with increasing daily dose; possibly due to rapid induction of tolerance under these infusion conditions. the clinical significance of this report is not clear. decreased fetal weights were observed in pregnant rats treated with 20 mg/kg/day morphine sulfate (3.2 times the hdd) from gestation day 7 to 9. there was no evidence of malformations despite maternal toxicity (10% mortality). in a second rat study, decreased fetal weight and increased incidences of growth retardation were noted at 35 mg/kg/day (5.7 times the hdd) and there was a reduced number of fetuses at 70 mg/kg/day (11.4 times the hdd) when pregnant rats were treated with 10, 35, or 70 mg/kg/day morphine sulfate via continuous infusion from gestation day 5 to 20. there was no evidence of fetal malformations or maternal toxicity. an increased incidence of abortion was noted in a study in which pregnant rabbits were treated with 2.5 (0.8 times the hdd) to 10 mg/kg morphine sulfate via subcutaneous injection from gestation day 6 to 10. in a second study, decreased fetal body weights were reported following treatment of pregnant rabbits with increasing doses of morphine (10-50 mg/kg/day) during the pre-mating period and 50 mg/kg/day (16 times the hdd) throughout the gestation period. no overt malformations were reported in either publication; although only limited endpoints were evaluated. in published studies in rats, exposure to morphine during gestation and/or lactation periods is associated with: decreased pup viability at 12.5 mg/kg/day or greater (2 times the hdd); decreased pup body weights at 15 mg/kg/day or greater (2.4 times the hdd); decreased litter size, decreased absolute brain and cerebellar weights, cyanosis, and hypothermia at 20 mg/kg/day (3.2 times the hdd); alteration of behavioral responses (play, social- interaction) at 1 mg/kg/day or greater (0.2 times the hdd); alteration of maternal behaviors (e.g., decreased nursing and pup retrievals) in mice at 1 mg/kg or higher (0.08 times the hdd) and rats at 1.5 mg/kg/day or higher (0.2 times the hdd); and a host of behavioral abnormalities in the offspring of rats, including altered responsiveness to opioids at 4 mg/kg/day (0.7 times the hdd) or greater. fetal and/or postnatal exposure to morphine in mice and rats has been shown to result in morphological changes in fetal and neonatal brain and neuronal cell loss, alteration of a number of neurotransmitter and neuromodulator systems, including opioid and non-opioid systems, and impairment in various learning and memory tests that appear to persist into adulthood. these studies were conducted with morphine treatment usually in the range of 4 to 20 mg/kg/day (0.7 to 3.2 times the hdd). additionally, delayed sexual maturation and decreased sexual behaviors in female offspring at 20 mg/kg/day (3.2 times the hdd), and decreased plasma and testicular levels of luteinizing hormone and testosterone, decreased testes weights, seminiferous tubule shrinkage, germinal cell aplasia, and decreased spermatogenesis in male offspring were also observed at 20 mg/kg/day (3.2 times the hdd).  decreased litter size and viability were observed in the offspring of male rats that were intraperitoneally administered morphine sulfate for 1 day prior to mating at 25 mg/kg/day (4.1 times the hdd) and mated to untreated females. decreased viability and body weight and/or movement deficits in both first and second generation offspring were reported when male mice were treated for 5 days with escalating doses of 120 to 240 mg/kg/day morphine sulfate (9.7 to 19.5 times the hdd) or when female mice treated with escalating doses of 60 to 240 mg/kg/day (4.9 to 19.5 times the hdd) followed by a 5-day treatment-free recovery period prior to mating. similar multigenerational findings were also seen in female rats pre- gestationally treated with escalating doses of 10 to 22 mg/kg/day morphine (1.6 to 3.6 times the hdd). risk summary morphine is present in breast milk. published lactation studies report variable concentrations of morphine in breast milk with administration of immediate-release morphine to nursing mothers in the early postpartum period with a milk-to-plasma morphine auc ratio of 2.5:1 measured in one lactation study. however, there is insufficient information to determine the effects of morphine on the breastfed infant and the effects of morphine on milk production. lactation studies have not been conducted with extended –release morphine, including morphine sulfate extended-release tablets. 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 morphine sulfate extended-release tablets. clinical considerations monitor infants exposed to morphine sulfate extended-release tablets 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)] . in published animal studies, morphine administration adversely effected fertility and reproductive endpoints in male rats and prolonged estrus cycle in female rats [see nonclinical toxicology (13) ]. the safety and effectiveness in pediatric patients below the age of 18 have not been established. the pharmacokinetics of morphine sulfate extended-release tablets have not been studied in elderly patients. clinical studies of morphine sulfate extended-release tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. elderly patients (aged 65 years or older) may have increased sensitivity to morphine. in general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. 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 morphine sulfate extended-release tablets slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see warnings and precautions (5.6)] . morphine 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. morphine pharmacokinetics have been reported to be significantly altered in patients with cirrhosis. start these patients with a lower than usual dosage of morphine sulfate extended-release tablets and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension [see clinical pharmacology (12.3)]. morphine pharmacokinetics are altered in patients with renal failure. start these patients with a lower than usual dosage of morphine sulfate extended-release tablets and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension [see clinical pharmacology (12.3)]. morphine sulfate extended-release tablets contains morphine, a schedule ii controlled substance. morphine sulfate extended-release tablets contains morphine, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, oxycodone, oxymorphone, and tapentadol. morphine sulfate extended-release tablets can be abused and is subject to misuse, addiction, and criminal diversion [see warnings and precautions (5.1)] . the high drug content in extended-release formulations adds to the risk of adverse outcomes from abuse and misuse. all patients treated with opioids require careful monitoring for signs of abuse and addiction, because 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 an over-the-counter or 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 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. morphine sulfate extended-release 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 morphine sulfate extended-release tablets morphine sulfate extended-release tablets is for oral use only. abuse of morphine sulfate extended-release tablets poses a risk of overdose and death. this risk is increased with concurrent use of morphine sulfate extended-release tablets with alcohol and/or other cns depressants. taking cut, broken, chewed, crushed, or dissolved morphine sulfate extended-release tablets enhances drug release and increases the risk of overdose and death. due to the presence of talc as one of the excipients in morphine sulfate extended-release tablets, parenteral abuse can be expected to result in local tissue necrosis, infection, pulmonary granulomas, increased risk of endocarditis and valvular heart injury. parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and hiv. 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 is a physiological state in which the body adapts to the drug after a period of regular exposure, resulting   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. do not abruptly discontinue morphine sulfate extended-release tablets in a patient physically dependent on opioids. rapid tapering of morphine sulfate extended-release 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 morphine sulfate extended-release tablets, gradually taper the dosage using a patient-specific plan that considers the following: the dose of morphine sulfate extended-release 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 a long duration 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 (2.6),warnings and precautions (5.13)]. 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)] .

USA - engelsk - NLM (National Library of Medicine)

ranbaxy pharmaceuticals inc. - oxymorphone hydrochloride (unii: 5y2ei94nbc) (oxymorphone - unii:9vxa968e0c) - oxymorphone hydrochloride 5 mg - oxymorphone hydrochloride extended-release tablets are indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. limitations of usage because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve oxymorphone hydrochloride extended-release tablets 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. oxymorphone hydrochloride extended-release tablets are not indicated as an as-needed (prn) analgesic. oxymorphone hydrochloride extended-release tablets are contraindicated in patients with: clinical considerations fetal/neonatal adverse reactions prolonged use of opioid analgesics during pregnanc

USA - engelsk - NLM (National Library of Medicine)

hikma pharmaceuticals usa inc. - butorphanol tartrate (unii: 2l7i72ruhn) (butorphanol - unii:qv897jc36d) - butorphanol tartrate 10 mg in 1 ml - butorphanol tartrate nasal spray is indicated 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] reserve butorphanol tartrate nasal spray for use in patients for whom alternative treatment options (e.g., non-opioid analgesics): butorphanol tartrate nasal spray 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. butorphanol tartrate nasal spray is contraindicated in: butorphanol tartrate nasal spray contains butorphanol, a schedule iv controlled substance. butorphanol tartrate nasal spray contains butorphanol, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see warnings] . 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 butorphanol tartrate nasal spray 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 butorphanol tartrate nasal spray 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 butorphanol tartrate nasal spray abuse include those with a history of prolonged use of any opioid, including products containing butorphanol, those with a history of drug or alcohol abuse, or those who use butorphanol tartrate nasal spray 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. butorphanol tartrate nasal spray, 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 butorphanol tartrate nasal spray abuse of butorphanol tartrate nasal spray poses a risk of overdose and death. the risk is increased with concurrent use of butorphanol tartrate nasal spray with alcohol and/or other cns depressants. 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 butorphanol tartrate nasal spray in a patient physically dependent on opioids. rapid tapering of butorphanol tartrate nasal spray 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 butorphanol tartrate nasal spray, gradually taper the dosage using a patient-specific plan that considers the following: the dose of butorphanol tartrate nasal spray 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, and warnings] . infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see pregnancy] .

USA - engelsk - NLM (National Library of Medicine)

rhodes pharmaceuticals l.p. - morphine sulfate (unii: x3p646a2j0) (morphine - unii:76i7g6d29c) - morphine sulfate 10 mg in 5 ml - morphine sulfate oral solution is indicated for the management of acute and chronic pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. morphine sulfate oral solution 100 mg per 5 ml (20 mg/ml) is indicated for the relief of acute and chronic pain in opioid-tolerant patients. limitations of use because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses [see warnings and precautions (5.2)] , reserve morphine sulfate oral solution 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 morphine sulfate oral solution is contraindicated in patients with: - significant respiratory depression [see warnings and precautions (5.4) ] - acute or severe bronchial asthma in an unmonitored setting or in the absence of resus

Irland - engelsk - HPRA (Health Products Regulatory Authority)

pharmaceuticals sales & development sweden ab (pharmswed) - apomorphine hydrochloride hemihydrate - solution for infusion - 5 milligram(s)/millilitre - dopamine agonists; apomorphine

USA - engelsk - NLM (National Library of Medicine)

actavis pharma, inc. - buprenorphine hydrochloride (unii: 56w8mw3en1) (buprenorphine - unii:40d3scr4gz) - buprenorphine 2 mg - buprenorphine sublingual tablets are indicated for the treatment of opioid dependence and is preferred for induction. buprenorphine sublingual tablets should be used as part of a complete treatment plan to include counseling and psychosocial support. buprenorphine sublingual tablets are contraindicated in patients with a history of hypersensitivity to buprenorphine, as serious adverse reactions, including anaphylactic shock, have been reported [see warnings and precautions  ( 5.9 ) ] . risk summary the data on use of buprenorphine, the active ingredient in buprenorphine sublingual tablets, 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] . 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 times and approximately equal to the human sublingual dose of 16 mg/day of buprenorphine, respectively. in a few studies, some events such as acephalus and omphalocele were also observed but these findings were not clearly treatment-related [see data] . based on animal data, advice pregnant women of the potential risk to a fetus. the estimated background risks 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. c linical 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 buprenorphine sublingual tablets. neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight. signs of neonatal withdrawal usually occur in the first days after birth. the duration and severity of neonatal opioid withdrawal syndrome may vary. observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly [see warnings and precautions (5.5)] . l abor 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. an i m al data the exposure margins listed below are based on body surface area comparisons (mg/m2 ) to the human sublingual dose of 16 mg buprenorphine via buprenorphine sublingual tablets. no definitive drug-related teratogenic effects were observed in rats and rabbits at im doses up to 30 mg/kg/day (estimated exposure approximately 20 times and 35 times, respectively, the human sublingual dose of 16 mg). maternal toxicity resulting in mortality was noted in these studies in both rats and rabbits. acephalus was observed in one rabbit fetus from the low-dose group and omphalocele was observed in two rabbit fetuses from the same litter in the mid-dose group; no findings were observed in fetuses from the high-dose group. maternal toxicity was seen in the high-dose group but not at the lower doses where the findings were observed. following oral administration of buprenorphine to rats, dose-related post-implantation losses, evidenced by increases in the numbers of early resorptions with consequent reductions in the numbers of fetuses, were observed at doses of 10 mg/kg/day or greater (estimated exposure approximately 6 times the human sublingual dose of 16 mg). in the rabbit, increased post-implantation losses occurred at an oral dose of 40 mg/kg/day. following im administration in the rat and the rabbit, post-implantation losses, as evidenced by decreases in live fetuses and increases in resorptions, occurred at 30 mg/kg/day. buprenorphine was not teratogenic in rats or rabbits after im or subcutaneous (sc) doses up to 5 mg/kg/day (estimated exposure was approximately 3 and 6 times, respectively, the human sublingual dose of 16 mg), after iv doses up to 0.8 mg/kg/day (estimated exposure was approximately 0.5 times and equal to, respectively, the human sublingual dose of 16 mg), or after oral doses up to 160 mg/kg/day in rats (estimated exposure was approximately 95 times the human sublingual dose of 16 mg) and 25 mg/kg/day in rabbits (estimated exposure was approximately 30 times the human sublingual dose of 16 mg). significant increases in skeletal abnormalities (e.g., extra thoracic vertebra or thoraco-lumbar ribs) were noted in rats after sc administration of 1 mg/kg/day and up (estimated exposure was approximately 0.6 times the human sublingual dose of 16 mg), but were not observed at oral doses up to 160 mg/kg/day. increases in skeletal abnormalities in rabbits after im administration of 5 mg/kg/day (estimated exposure was approximately 6 times the human sublingual dose of 16 mg) in the absence of maternal toxicity or oral administration of 1 mg/kg/day or greater (estimated exposure was approximately equal to the human sublingual dose of 16 mg) were not statistically significant. in rabbits, buprenorphine produced statistically significant pre-implantation losses at oral doses of 1 mg/kg/day or greater and post-implantation losses that were statistically significant at iv doses of 0.2 mg/kg/day or greater (estimated exposure approximately 0.3 times the human sublingual dose of 16 mg). no maternal toxicity was noted at doses causing post-implantation loss in this study. dystocia was noted in pregnant rats treated intramuscularly with buprenorphine from gestation day 14 through lactation day 21 at 5 mg/kg/day (approximately 3 times the human sublingual dose of 16 mg). fertility, and pre- and post-natal development studies with buprenorphine in rats indicated increases in neonatal mortality after oral doses of 0.8 mg/kg/day and up (approximately 0.5 times the human sublingual dose of 16 mg), after im doses of 0.5 mg/kg/day and up (approximately 0.3 times the human sublingual dose of 16 mg), and after sc doses of 0.1 mg/kg/day and up (approximately 0.06 times the human sublingual dose of 16 mg). an apparent lack of milk production during these studies likely contributed to the decreased pup viability and lactation indices. delays in the occurrence of righting reflex and startle response were noted in rat pups at an oral dose of 80 mg/kg/day (approximately 50 times the human sublingual dose of 16 mg). 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. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for buprenorphine sublingual tablets and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition. clinical considerations advise breastfeeding women taking buprenorphine products to monitor the infant for increased drowsiness and breathing difficulties. data data were consistent from two studies (n=13) of breastfeeding infants whose mothers were maintained on sublingual doses of buprenorphine ranging from 2.4 to 24 mg/day, showing that the infants were exposed to less than 1% of the maternal daily dose. in a study of six lactating women who were taking a median sublingual buprenorphine dose of 0.29 mg/kg/day 5 to 8 days after delivery, breast milk provided a median infant dose of 0.42 mcg/kg/day of buprenorphine and 0.33 mcg/kg/day of norbuprenorphine, equal to 0.2% and 0.12%, respectively, of the maternal weight-adjusted dose (relative dose/kg (%) of norbuprenorphine was calculated from the assumption that buprenorphine and norbuprenorphine are equipotent). data from a study of seven lactating women who were taking a median sublingual buprenorphine dose of 7 mg/day an average of 1.12 months after delivery indicated that the mean milk concentrations (cavg ) of buprenorphine and norbuprenorphine were 3.65 mcg/l and 1.94 mcg/l respectively. based on the study data, and assuming milk consumption of 150 ml/kg/day, an exclusively breastfed infant would receive an estimated mean absolute infant dose (aid) of 0.55 mcg/kg/day of buprenorphine and 0.29 mcg/kg/day of norbuprenorphine, or a mean relative infant dose (rid) of 0.38% and 0.18%, respectively, of the maternal weight-adjusted dose. infertility chronic use of opioids may cause reduced fertility in females and males of reproductive potential. it is not known whether these effects on fertility are reversible [see adverse reactions (6.2), clinical pharmacology (12.2), nonclinical toxicology (13.1)] . the safety and effectiveness of buprenorphine sublingual tablets has not been established in pediatric patients. clinical studies of buprenorphine sublingual tablets, buprenorphine and naloxone sublingual film, or buprenorphine and naloxone sublingual tablet did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently than younger subjects. other reported clinical experience has not identified differences in responses between the elderly and younger patients. due to possible decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in geriatric patients, the decision to prescribe buprenorphine sublingual tablets 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 effects of hepatic impairment on the pharmacokinetics of buprenorphine were evaluated in a pharmacokinetic study. buprenorphine is extensively metabolized in the liver and buprenorphine plasma levels were found to be higher and the half-life was found to be longer in subjects with moderate and severe hepatic impairment, but not in subjects with mild hepatic impairment. for patients with severe hepatic impairment, a dose adjustment is recommended, and patients with moderate or severe hepatic impairment should be monitored for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine [see dosage and administration (2.8), 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. buprenorphine sublingual tablets contain buprenorphine, a schedule iii controlled substance under the controlled substances act. buprenorphine, like morphine and other opioids, has the potential for being abused and is subject to criminal diversion. this should be considered when prescribing or dispensing buprenorphine in situations when the clinician is concerned about an increased risk of misuse, abuse, or diversion. healthcare professionals should contact their state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product. patients who continue to misuse, abuse, or divert, buprenorphine products or other opioids should be provided or referred for more intensive and structured treatment. abuse of buprenorphine poses a risk of overdose and death. this risk is increased with the abuse of buprenorphine and alcohol and other substances, especially benzodiazepines. the healthcare provider may be able to more easily detect misuse or diversion by maintaining records of medication prescribed including date, dose, quantity, frequency of refills, and renewal requests of medication prescribed. proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper handling and storage of the medication are appropriate measures that help to limit abuse of opioid drugs. buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by moderate withdrawal signs and symptoms upon abrupt discontinuation or rapid taper. the withdrawal syndrome is typically milder than seen with full agonists and may be delayed in onset [s e e   w arnings and pr ec autions ( 5. 7 ) ] . neonatal opioid withdrawal syndrome (nows) is an expected and treatable outcome of prolonged use of opioids during pregnancy [s e e w arnings and pr ec autions ( 5.5 ) ] . buprenorphine ( bue" pre nor' feen) sublingual tablets, ciii this “instructions for use” contains information on how to correctly take buprenorphine sublingual tablets. important information you need to know before taking buprenorphine sublingual tablets: - your healthcare provider should show you how to take buprenorphine sublingual tablets the right way. preparing to take buprenorphine sublingual tablets: - put the tablets under your tongue. let them dissolve completely. - while buprenorphine sublingual tablets are dissolving, do not chew or swallow the tablet because the medicine will not work as well. - talking while the tablet is dissolving can affect how well the medicine in buprenorphine sublingual tablets are absorbed. - after buprenorphine sublingual tablets are completely dissolved, rinse your mouth with water and swallow. wait for at least one hour before brushing teeth. - if you miss a dose of buprenorphine sublingual tablets, take your medicine when you remember. if it is almost time for your next dose, skip the missed dose and take the next dose at your regular time. do not take 2 doses at the same time unless your healthcare provider tells you to. if you are not sure about your dosing, call your healthcare provider. - do not stop taking buprenorphine sublingual tablets suddenly. you could become sick and have withdrawal symptoms because your body has become used to the medicine. physical dependence is not the same as drug addiction. your healthcare provider can tell you more about the differences between physical dependence and drug addiction. to have fewer withdrawal symptoms, ask your healthcare provider how to stop using buprenorphine sublingual tablets the right way. if you take too many buprenorphine sublingual tablets or overdose, call poison control or get emergency medical help right away. storing buprenorphine sublingual tablets: - store buprenorphine sublingual tablets at room temperature between 68°f to 77°f (20°c to 25°c). store buprenorphine sublingual tablets at room temperature between 68°f to 77°f (20°c to 25°c). - keep buprenorphine sublingual tablets in a safe place, out of the sight and reach of children . keep buprenorphine sublingual tablets in a safe place, out of the sight and reach of children . disposing of buprenorphine sublingual tablets: - dispose of unused buprenorphine sublingual tablets as soon as you no longer need them. dispose of unused buprenorphine sublingual tablets as soon as you no longer need them. - dispose of expired, unwanted or unused buprenorphine sublingual tablets by promptly flushing down the toilet (if a drug take‐back option is not readily available). visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. dispose of expired, unwanted or unused buprenorphine sublingual tablets by promptly flushing down the toilet (if a drug take‐back option is not readily available). visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. if you need help with disposal of buprenorphine sublingual tablets, call 1-888-838-2872. this “instructions for use” has been approved by the u.s. food and drug administration. manufactured for: teva pharmaceuticals parsippany, nj 07054 rev. e 1/2024

USA - engelsk - NLM (National Library of Medicine)

amneal pharmaceuticals of new york llc - morphine sulfate (unii: x3p646a2j0) (morphine - unii:76i7g6d29c) - morphine sulfate 20 mg - morphine sulfate extended-release capsules are indicated for the management of severe and persistent pain, that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options are inadequate. limitations of use: - because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration, and because of the greater risks of overdose and death with extended-release opioid formulations/long-acting opioid formulations, [see warnings and precautions (5.1)], reserve morphine sulfate extended-release capsules 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. - morphine sulfate extended-release capsules are not indicated as an as-needed (prn) analgesic. morphine sulfate extended-release capsules are contraindicated in patients with: - significant respiratory depression [see warnings and precautions (5.2)] -   acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see warnings and precautions (5.7)] -   concurrent use of monoamine oxidase inhibitors (maois) or use of maois within the last 14 days [see warnings and precautions (5.8),  drug interactions (7)] -   known or suspected gastrointestinal obstruction, including paralytic ileus [see warnings and precautions (5.12)] -   hypersensitivity (e.g., anaphylaxis) to morphine [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 (5.4)]. there are no available data with morphine sulfate extended-release capsules in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. published studies with morphine use during pregnancy have not reported a clear association with morphine and major birth defects [see human data] . in published animal reproduction studies, morphine administered subcutaneously during the early gestational period produced neural tube defects (i.e., exencephaly and cranioschisis) at 5 and 16 times the human daily dose of 60 mg based on body surface area (hdd) in hamsters and mice, respectively, lower fetal body weight and increased incidence of abortion at 0.4 times the hdd in the rabbit, growth retardation at 6 times the hdd in the rat, and axial skeletal fusion and cryptorchidism at 16 times the hdd in the mouse. administration of morphine sulfate to pregnant rats during organogenesis and through lactation resulted in cyanosis, hypothermia, decreased brain weights, pup mortality, decreased pup body weights, and adverse effects on reproductive tissues at 3 to 4 times the hdd; and long-term neurochemical changes in the brain of offspring which correlate with altered behavioral responses that persist through adulthood at exposures comparable to and less than the hdd [see animal data] . based on animal data, advise pregnant women of the potential risk to a fetus. the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. clinical considerations fetal/neonatal adverse reactions use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. the onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see warnings and precautions (5.4)]. labor or delivery opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. an opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. morphine sulfate extended-release capsules are not recommended for use in pregnant women during or immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. opioid analgesics, including morphine sulfate extended-release capsules, 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 the results from a population-based prospective cohort, including 70 women exposed to morphine during the first trimester of pregnancy and 448 women exposed to morphine at any time during pregnancy, indicate no increased risk for congenital malformations. however, these studies cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and non-randomized study design. animal data formal reproductive and developmental toxicology studies for morphine have not been conducted. exposure margins for the following published study reports are based on human daily dose of 60 mg morphine using a body surface area comparison (hdd). neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of morphine sulfate (35 to 322 mg/kg) on gestation day 8 to pregnant hamsters (4.7 to 43.5 times the hdd). a no adverse effect level was not defined in this study and the findings cannot be clearly attributed to maternal toxicity. neural tube defects (exencephaly), axial skeletal fusions, and cryptorchidism were reported following a single subcutaneous (sc) injection of morphine sulfate to pregnant mice (100 to 500 mg/kg) on gestation day 8 or 9 at 200 mg/kg or greater (16 times the hdd) and fetal resorption at 400 mg/kg or higher (32 times the hdd). no adverse effects were noted following 100 mg/kg morphine in this model (8 times the hdd). in one study, following continuous subcutaneous infusion of doses greater than or equal to 2.72 mg/kg to mice (0.2 times the hdd), exencephaly, hydronephrosis, intestinal hemorrhage, split supraoccipital, malformed sternebrae, and malformed xiphoid were noted. the effects were reduced with increasing daily dose; possibly due to rapid induction of tolerance under these infusion conditions. the clinical significance of this report is not clear. decreased fetal weights were observed in pregnant rats treated with 20 mg/kg/day morphine sulfate (3.2 times the hdd) from gestation day 7 to 9. there was no evidence of malformations despite maternal toxicity (10% mortality). in a second rat study, decreased fetal weight and increased incidences of growth retardation were noted at 35 mg/kg/day (5.7 times the hdd) and there was a reduced number of fetuses at 70 mg/kg/day (11.4 times the hdd) when pregnant rats were treated with 10, 35, or 70 mg/kg/day morphine sulfate via continuous infusion from gestation day 5 to 20. there was no evidence of fetal malformations or maternal toxicity. an increased incidence of abortion was noted in a study in which pregnant rabbits were treated with 2.5 (0.8 times the hdd) to 10 mg/kg morphine sulfate via subcutaneous injection from gestation day 6 to 10. in a second study, decreased fetal body weights were reported following treatment of pregnant rabbits with increasing doses of morphine (10 to 50 mg/kg/day) during the pre-mating period and 50 mg/kg/day (16 times the hdd) throughout the gestation period. no overt malformations were reported in either publication; although only limited endpoints were evaluated. in published studies in rats, exposure to morphine during gestation and/or lactation periods is associated with: decreased pup viability at 12.5 mg/kg/day or greater (2 times the hdd); decreased pup body weights at 15 mg/kg/day or greater (2.4 times the hdd); decreased litter size, decreased absolute brain and cerebellar weights, cyanosis, and hypothermia at 20 mg/kg/day (3.2 times the hdd); alteration of behavioral responses (play, social-interaction) at 1 mg/kg/day or greater (0.2 times the hdd); alteration of maternal behaviors (e.g., decreased nursing and pup retrievals) in mice at 1 mg/kg or higher (0.08 times the hdd) and rats at 1.5 mg/kg/day or higher (0.2 times the hdd); and a host of behavioral abnormalities in the offspring of rats, including altered responsiveness to opioids at 4 mg/kg/day (0.7 times the hdd) or greater. fetal and/or postnatal exposure to morphine in mice and rats has been shown to result in morphological changes in fetal and neonatal brain and neuronal cell loss, alteration of a number of neurotransmitter and neuromodulator systems, including opioid and non-opioid systems, and impairment in various learning and memory tests that appear to persist into adulthood. these studies were conducted with morphine treatment usually in the range of 4 to 20 mg/kg/day (0.7 to 3.2 times the hdd). additionally, delayed sexual maturation and decreased sexual behaviors in female offspring at 20 mg/kg/day (3.2 times the hdd), and decreased plasma and testicular levels of luteinizing hormone and testosterone, decreased testes weights, seminiferous tubule shrinkage, germinal cell aplasia, and decreased spermatogenesis in male offspring were also observed at 20 mg/kg/day (3.2 times the hdd). decreased litter size and viability were observed in the offspring of male rats that were intraperitoneally administered morphine sulfate for 1 day prior to mating at 25 mg/kg/day (4.1 times the hdd) and mated to untreated females. decreased viability and body weight and/or movement deficits in both first and second generation offspring were reported when male mice were treated for 5 days with escalating doses of 120 to 240 mg/kg/day morphine sulfate (9.7 to 19.5 times the hdd) or when female mice treated with escalating doses of 60 to 240 mg/kg/day (4.9 to 19.5 times the hdd) followed by a 5-day treatment-free recovery period prior to mating. similar multigenerational findings were also seen in female rats pre-gestationally treated with escalating doses of 10 to 22 mg/kg/day morphine (1.6 to 3.6 times the hdd). risk summary morphine is present in breast milk. published lactation studies report variable concentrations of morphine in breast milk with administration of immediate-release morphine to nursing mothers in the early postpartum period with a milk-to-plasma morphine auc ratio of 2.5:1 measured in one lactation study. however, there is insufficient information to determine the effects of morphine on the breastfed infant and the effects of morphine on milk production. lactation studies have not been conducted with extended–release morphine, including morphine sulfate extended-release capsules. 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 morphine sulfate extended-release capsules. clinical considerations monitor infants exposed to morphine sulfate extended-release capsules through breast milk for excess sedation and respiratory depression. withdrawal symptoms can occur in breastfed infants when maternal administration of morphine 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)]. in published animal studies, morphine administration adversely effected fertility and reproductive endpoints in male rats and prolonged estrus cycle in female rats [see nonclinical toxicology (13)] . the safety and efficacy of morphine sulfate extended-release capsules in patients less than 18 years have not been established. clinical studies of morphine sulfate extended-release capsules did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. elderly patients (aged 65 years or older) may have increased sensitivity to morphine. in general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. 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 morphine sulfate extended-release capsules slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see warnings and precautions (5.7)] . this drug 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. morphine pharmacokinetics have been reported to be significantly altered in patients with cirrhosis. start these patients with a lower than usual dosage of morphine sulfate extended-release capsules and titrate slowly while regularly evaluate for signs of respiratory depression, sedation, and hypotension [see clinical pharmacology (12.3)]. morphine pharmacokinetics are altered in patients with renal failure. start these patients with a lower than usual dosage of morphine sulfate extended-release capsules and titrate slowly while regularly evaluate for signs of respiratory depression, sedation, and hypotension [see clinical pharmacology (12.3)]. morphine sulfate extended-release capsules contain morphine, a schedule ii controlled substance. morphine sulfate extended-release capsules contains morphine, 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 morphine sulfate extended-release capsules 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 morphine sulfate extended-release capsules 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 morphine sulfate extended-release capsules abuse include those with a history of prolonged use of any opioid, including products containing morphine, those with a history of drug or alcohol abuse, or those who use morphine sulfate extended-release capsules 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. morphine sulfate extended-release capsules, 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 morphine sulfate extended-release capsules abuse of morphine sulfate extended-release capsules poses a risk of overdose and death. this risk is increased with concurrent use of morphine sulfate extended-release capsules with alcohol and/or other cns depressants. taking cut, broken chewed, crushed, or dissolved morphine sulfate extended-release capsules enhances drug release and increases the risk of overdose and death. morphine sulfate extended-release capsules are approved for oral use only. inappropriate intravenous, intramuscular, or subcutaneous use of morphine sulfate extended-release capsules can result in death, local tissue necrosis, infection, pulmonary granulomas, increased risk of endocarditis, and valvular heart injury, and embolism. 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 morphine sulfate extended-release capsules in a patient physically dependent on opioids. rapid tapering of morphine sulfate extended-release capsules 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 morphine sulfate extended-release capsules, gradually taper the dosage using a patient-specific plan that considers the following: the dose of morphine sulfate extended-release capsules 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), and warnings and precautions (5.15)] . 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)] . morphine sulfate (mor’ feen sul’ fate) extended-release capsules, usp, cii if you cannot swallow morphine sulfate extended-release capsules, tell your healthcare provider. there may be another way to take morphine sulfate extended-release capsules that may be right for you. if your healthcare provider tells you that you can take morphine sulfate extended-release capsules using this other way, follow these steps: morphine sulfate extended-release capsules can be opened and the pellets inside the capsule can be sprinkled over applesauce, as follows: figure 1 - open the morphine sulfate extended-release capsule and sprinkle the pellets over about one tablespoon of applesauce. (see figure 1) figure 2 - swallow all of the applesauce and pellets right away. do not save any of the applesauce and pellets for another dose. (see figure 2) figure 3 - rinse your mouth to make sure you have swallowed all of the pellets. do not chew the pellets. (see figure 3) figure 4 - flush the empty capsule down the toilet right away. (see figure 4) you should not receive morphine sulfate extended-release capsules through a nasogastric tube. this instructions for use has been approved by the u.s. food and drug administration. manufactured by: amneal pharmaceuticals of ny, llc brookhaven, ny 11719 distributed by: amneal pharmaceuticals llc bridgewater, nj 08807 rev. 12-2021-03 dispense with medication guide available at: documents.amneal.com/mg/morphine-sulfate-er-cap.pdf