Yhdysvallat - englanti - NLM (National Library of Medicine)

remedyrepack inc. - acetaminophen (unii: 362o9itl9d) (acetaminophen - unii:362o9itl9d), tramadol hydrochloride (unii: 9n7r477wck) (tramadol - unii:39j1lgj30j) - tramadol hydrochloride and acetaminophen tablets are indicated for the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. limitations of use tramadol hydrochloride and acetaminophen tablets are indicated for short-term use of five days or less. because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses [see warnings and precautions ( 5.1)] , reserve tramadol hydrochloride and acetaminophen tablets for use in patients for whom alternative treatment options [e.g., non-opioid analgesics]: - have not been tolerated, or are not expected to be tolerated, - have not provided adequate analgesia, or are not expected to provide adequate analgesia. tramadol hydrochloride and acetaminophen tablets are contraindicated for: -   all children younger than 12 years of age [see warnings and precautions ( 5.4)] -   post-operative management

Yhdysvallat - englanti - NLM (National Library of Medicine)

lake erie medical dba quality care products llc - oxymorphone hydrochloride (unii: 5y2ei94nbc) (oxymorphone - unii:9vxa968e0c) - 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: - significant respiratory depression - acute or severe bronchial asthma or hypercarbia - known or suspe

Yhdysvallat - englanti - NLM (National Library of Medicine)

amneal pharmaceuticals llc - oxymorphone hydrochloride (unii: 5y2ei94nbc) (oxymorphone - unii:9vxa968e0c) - 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 [see warnings and precautions (5.1)] , 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: - 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)] - hypersensitivity (e.g., anaphylaxis) to oxymorphone, any other ingredients in oxymorphone hydrochloride extended-release tablets [see warnings and precautions (5.7) and adverse reactions (6)]. - moderate and severe hepatic impairment [see warnings and precautions (5.9) and clinical pharmacology (12.3)] - known or suspected gastrointestinal obstruction, including paralytic ileus [see warnings and precautions (5.12)] risk summary prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see warnings and precautions (5.4)] . available data with oxymorphone hydrochloride extended-release tablets in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. in animal reproduction studies, reduced postnatal survival of pups and an increased incidence of stillborn pups were observed following oral treatment of pregnant rats with oxymorphone during gestation and through lactation at doses 2.4 and 12 times the human daily dose of 20 mg/day (hdd), respectively. reduced fetal weights were observed with oral administration of oxymorphone to pregnant rats and rabbits during organogenesis at exposures up to 4.9 and 48.8 times the hdd, respectively [see data] . based on animal data, advise pregnant women of the potential risk to a fetus. the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinical recognized pregnancies is 2% to 4% and 14% to 20%, respectively. clinical considerations fetal/neonatal adverse reactions prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes may cause fetal-neonatal physical dependence and neonatal 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 pyscho-physiologic effects in neonates. an opioid antagonist, such as naloxone must be available for reversal of opioid-induced respiratory depression in the neonate. oxymorphone hydrochloride extended-release 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 oxymorphone hydrochloride 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 dilatation, which tends to shorten labor. monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. data animal data pregnant rats were treated with oxymorphone hydrochloride from gestation day 6 to 17 via oral gavage doses of 5, 10, or 25 mg/kg/day (2.4, 4.9, or 12.2 times the hdd based on body surface area, respectively). reduced mean fetal weights were observed at 4.9 times the hdd. maternal toxicity was noted in all treatment groups (reduced food consumption and body weights in all groups and mortality in the high dose group). pregnant rabbits were treated with oxymorphone hydrochloride from gestation day 7 to 20 via oral gavage doses of 10, 25, or 50 mg/kg/day (9.8, 24.4, or 48.8 times the hdd based on body surface area, respectively). decreased mean fetal weights were noted at 48.8 times the hdd. maternal toxicity was noted in all treatment groups (reduced food consumption and body weights). pregnant rats were treated with oxymorphone hydrochloride from gestation day 6 to lactation day 20 via oral gavage doses of 1, 5, 10, or 25 mg/kg/day (0.5, 2.4, 4.9, or 12.2 times the hdd based on body surface area, respectively). increased neonatal death (postnatal day 0 to 1) was noted at 2.4 times the hdd. decreased pup survival over the first week of life, reduced pup birth weight, and reduced postnatal weight gain were noted at 4.9 times the hdd. maternal toxicity was noted in all treatment groups (reduced food consumption and body weights in all groups and mortality in the 10 and 25 mg/kg/day groups). in a published study, neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of 153 mg/kg oxymorphone hydrochloride (62.2 times the hdd) on gestation day 8 to pregnant hamsters. this dose also produced significant maternal toxicity (20% maternal deaths). risk summary there is no information regarding the presence of oxymorphone in human milk, the effects on the breastfed infant, or the effects on milk production. because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with oxymorphone hydrochloride extended-release tablets. clinical considerations monitor infants exposed to oxymorphone 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 [clinical pharmacology (12.2) and nonclinical toxicology (13.1)] . the safety and effectiveness of oxymorphone hydrochloride extended-release tablets in patients below the age of 18 years have not been established. two open-label studies were conducted in a total of 42 pediatric patients between the ages of 7 to 17 years requiring continuous, around the clock opioid treatment. the available safety and efficacy data were inconclusive for chronic use of oxymorphone hydrochloride extended-release tablets. limited data from one of the studies suggested that oxymorphone hydrochloride extended-release tablets is not recommended for post-surgical pain. of the total number of subjects in clinical studies of oxymorphone hydrochloride extended-release tablets, 27% were 65 and over, while 9% were 75 and over. no overall differences in effectiveness were observed between these subjects and younger subjects. there were several adverse events that were more frequently observed in subjects 65 and over compared to younger subjects. these adverse events included dizziness, somnolence, confusion, and nausea. on average, age greater than 65 years was associated with an increase in oxymorphone auc and cmax . initiate dosing with oxymorphone hydrochloride extended-release tablets in patients 65 years of age and over using the 5 mg dose and monitor closely for signs of respiratory and central nervous system depression when initiating and titrating oxymorphone hydrochloride extended-release tablets. for patients on prior opioid therapy, start at 50% of the starting dose for a younger patient on prior opioids and titrate slowly. oxymorphone 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 the 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. patients with mild hepatic impairment have an increase in oxymorphone bioavailability compared to the subjects with normal hepatic function. in opioid-naïve patients with mild hepatic impairment, initiate oxymorphone hydrochloride extended-release tablets using the 5 mg dose and monitor closely for respiratory and central nervous system depression. oxymorphone hydrochloride extended-release tablets are contraindicated for patients with moderate and severe hepatic impairment [see dosage and administration (2.6), contraindications (4) , warnings and precautions (5.9), and clinical pharmacology (12.3)] . for patients on prior opioid therapy, start at the 50% of the dose for that a patient with normal hepatic function on prior opioids and titrate slowly. patients with moderate to severe renal impairment were shown to have an increase in oxymorphone bioavailability compared to the subjects with normal renal function [see clinical pharmacology (12.3)] . start opioid-naïve patients with the 5 mg dose of oxymorphone hydrochloride extended-release tablets and titrate slowly while closely monitoring for respiratory and central nervous system depression [see dosage and administration (2.6)] . for patients on prior opioid therapy, start at 50% of the dose for a patient with normal renal function on prior opioids and titrate slowly. oxymorphone hydrochloride extended-release tablets contain oxymorphone, a schedule ii controlled substance. oxymorphone hydrochloride extended-release tablets contains oxymorphone a substance with a high potential for abuse similar to other opioids fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, and tapentadol. oxymorphone hydrochloride 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, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. “drug seeking" behavior is very common in persons with substance use disorders. drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). "doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. abuse and addiction are separate and distinct from physical dependence and tolerance. healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. in addition, abuse of opioids can occur in the absence of true addiction. oxymorphone hydrochloride extended-release tablets, like other opioids, can be diverted for non-medical use into illicit channels of distribution. careful record-keeping of prescribing information, including quantity, frequency, and renewal requests as required by state and federal law, is strongly advised. proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to reduce abuse of opioid drugs. risks specific to abuse of oxymorphone hydrochloride extended-release tablets oxymorphone hydrochloride extended-release tablets are for oral use only. abuse of oxymorphone hydrochloride extended-release tablets poses a risk of overdose and death. this risk is increased with concurrent abuse of oxymorphone hydrochloride extended-release tablets with alcohol and other substances. taking cut, broken, chewed, crushed, or dissolved oxymorphone hydrochloride extended-release tablets enhances drug release and increases the risk of over dose and death. 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 oxymorphone hydrochloride extended-release tablets in a patient physically dependent on opioids. rapid tapering of oxymorphone hydrochloride 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 oxymorphone hydrochloride extended-release tablets, gradually taper the dosage using a patient-specific plan that considers the following: the dose of oxymorphone hydrochloride 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 (2.5) 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 (8.2)].

Yhdysvallat - englanti - NLM (National Library of Medicine)

quality care products, llc - oxymorphone hydrochloride (unii: 5y2ei94nbc) (oxymorphone - unii:9vxa968e0c) - 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 [see warnings and precautions (5.1)] , 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: - significant respiratory depression [see warnings and precaution

Yhdysvallat - englanti - NLM (National Library of Medicine)

preferred pharmaceuticals, inc. - tramadol hydrochloride (unii: 9n7r477wck) (tramadol - unii:39j1lgj30j) - tramadol 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 use tramadol hydrochloride extended-release tablets are contraindicated for: tramadol hydrochloride extended-release tablets are also contraindicated in patients with: risk summary prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see warnings and precautions (5.5)] . available data with tramadol hydrochloride extended-release tablets in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage.   in animal reproduction studies, tramadol administration during organogenesis decreased fetal weights and reduced ossification in mice, rats, and rabbits at 1.4, 0.6, and 3.6 times the maximum recommended human daily dosage (mrhd). tramadol decreased pup body weight and increased pup

Yhdysvallat - englanti - NLM (National Library of Medicine)

remedyrepack inc. - tramadol hydrochloride (unii: 9n7r477wck) (tramadol - unii:39j1lgj30j) - tramadol hydrochloride extended-release tablet is indicated for the management of severe and persistent pain that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options are inadequate. limitations of use - because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosages or duration, and because of the greater risks of overdose and death with extended-release opioid formulations [see warnings and precautions ( 5.1)] , reserve tramadol 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. - tramadol hydrochloride extended-release tablet is not indicated as an as-needed (prn) analgesic. tramadol hydrochloride extended-release tablets are contraindicated for: - all children younger than 12 years of age [see warnings and precautions ( 5.4)] - post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see warnings and precautions ( 5.4)] . tramadol hydrochloride extended-release tablets are also 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 ( 5.12)] - known or suspected gastrointestinal obstruction, including paralytic ileus [see warnings and precautions ( 5.15)] - hypersensitivity to tramadol (e.g., anaphylaxis) [see warnings and precautions (5.16), adverse reactions ( 6.2)] - concurrent use of monoamine oxidase inhibitors (maois) or use within the last 14 days [see drug interactions ( 7)]. risk summary use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see warnings and precautions ( 5.4)] . available data with tramadol hydrochloride extended-release tablets in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. in animal reproduction studies, tramadol administration during organogenesis decreased fetal weights and reduced ossification in mice, rats, and rabbits at 1.4, 0.6, and 3.6 times the maximum recommended human daily dosage (mrhd). tramadol decreased pup body weight and increased pup mortality at 1.2 and 1.9 times the mrhd [see data] . based on animal data, advise pregnant women of the potential risk to a fetus. the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 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 and signs of neonatal opioid withdrawal syndrome and manage accordingly [see warnings and precautions ( 5.4)] . neonatal seizures, neonatal withdrawal syndrome, fetal death and stillbirth have been reported with tramadol during post-approval use of tramadol immediate-release products. labor or delivery opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. an opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. tramadol hydrochloride extended-release tablets 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 tramadol hydrochloride 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. tramadol has been shown to cross the placenta. the mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labor. the effect of tramadol hydrochloride extended-release tablets, if any, on the later growth, development, and functional maturation of the child is unknown. data animal data tramadol has been shown to be embryotoxic and fetotoxic in mice, (120 mg/kg), rats (25 mg/kg) and rabbits (75 mg/kg) at maternally toxic dosages, but was not teratogenic at these dose levels. these doses on a mg/m 2 basis are 1.9, 0.8, and 4.9 times the maximum recommended human daily dosage (mrhd) for mouse, rat and rabbit, respectively. no drug-related teratogenic effects were observed in progeny of mice (up to 140 mg/kg), rats (up to 80 mg/kg) or rabbits (up to 300 mg/kg) treated with tramadol by various routes. embryo and fetal toxicity consisted primarily of decreased fetal weights, decreased skeletal ossification, and increased supernumerary ribs at maternally toxic dose levels. transient delays in developmental or behavioral parameters were also seen in pups from rat dams allowed to deliver. embryo and fetal lethality were reported only in one rabbit study at 300 mg/kg, a dose that would cause extreme maternal toxicity in the rabbit. the dosages listed for mouse, rat, and rabbit are 2.3, 2.6, and 19 times the mrhd, respectively. tramadol was evaluated in pre- and post-natal studies in rats. progeny of dams receiving oral (gavage) dose levels of 50 mg/kg (1.6 times the mrhd) or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (2.6 times the mrhd). risk summary tramadol hydrochloride extended-release tablets are not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied. tramadol and its metabolite, o-desmethyl tramadol (m1), are present in human milk. there is no information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. the m1 metabolite is more potent than tramadol in mu opioid receptor binding [see clinical pharmacology ( 12.1)] . published studies have reported tramadol and m1 in colostrum with administration of tramadol to nursing mothers in the early post-partum period. women who are ultra-rapid metabolizers of tramadol may have higher than expected serum levels of m1, potentially leading to higher levels of m1 in breast milk that can be dangerous in their breastfed infants. in women with normal tramadol metabolism, the amount of tramadol secreted into human milk is low and dose-dependent. because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with tramadol hydrochloride extended-release tablets. clinical considerations if infants are exposed to tramadol hydrochloride through breast milk, they should be monitored for excess sedation and respiratory depression. withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. data following a single iv 100 mg dose of tramadol, the cumulative excretion in breast milk within 16 hours post dose was 100 mcg of tramadol (0.1% of the maternal dose) and 27 mcg of m1. infertility use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. it is not known whether these effects on fertility are reversible [see adverse reactions ( 6.2), clinical pharmacology ( 12.2), nonclinical toxicology ( 13.1)] . the safety and effectiveness of tramadol hydrochloride extended-release tablets in pediatric patients have not been established. life-threatening respiratory depression and death have occurred in children who received tramadol [see warnings and precautions ( 5.6)] . in some of the reported cases, these events followed tonsillectomy and/or adenoidectomy, and one of the children had evidence of being an ultra-rapid metabolizer of tramadol (i.e., multiple copies of the gene for cytochrome p450 isoenzyme 2d6). children with sleep apnea may be particularly sensitive to the respiratory depressant effects of tramadol. because of the risk of life-threatening respiratory depression and death: - tramadol hydrochloride extended-release tablets are contraindicated for all children younger than 12 years of age [see contraindications ( 4)] . - tramadol hydrochloride extended-release tablets are contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see contraindications ( 4)]. - avoid the use of tramadol hydrochloride extended-release tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol unless the benefits outweigh the risks. risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression. [see warnings and precautions ( 5.6)]. nine-hundred-one elderly (65 years of age or older) subjects were exposed to tramadol hydrochloride extended-release tablets in clinical trials. of those subjects, 156 were 75 years of age and older. in general, higher incidence rates of adverse events were observed for patients older than 65 years of age compared with patients 65 years and younger, particularly for the following adverse events: constipation, fatigue, weakness, postural hypotension and dyspepsia. for this reason, tramadol hydrochloride extended-release tablets should be used with caution in patients over 65 years of age, and with even greater caution in patients older than 75 years of age [see dosage and administration ( 2.5), clinical pharmacology ( 12.3)] . respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. titrate the dosage of tramadol hydrochloride extended-release tablets slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see warnings and precautions ( 5.12)] . tramadol is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function. metabolism of tramadol and m1 is reduced in patients with advanced cirrhosis of the liver. tramadol hydrochloride extended-release tablet has not been studied in patients with severe hepatic impairment. the limited availability of dose strengths and once daily dosing of tramadol hydrochloride extended-release tablets do not permit the dosing flexibility required for safe use in patients with severe hepatic impairment (child-pugh class c). therefore, tramadol hydrochloride extended-release tablets should not be used in patients with severe hepatic impairment [see clinical pharmacology ( 12.3)] . impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, m1. tramadol hydrochloride extended-release tablet has not been studied in patients with severe renal impairment (clcr < 30 ml/min). the limited availability of dose strengths and once daily dosing of tramadol hydrochloride extended-release tablets do not permit the dosing flexibility required for safe use in patients with severe renal impairment (child-pugh class c). therefore, tramadol hydrochloride extended-release tablets should not be used in patients with severe renal impairment [see clinical pharmacology ( 12.3)] . tramadol hydrochloride extended-release tablet contains tramadol, a scheduled iv controlled substance. tramadol hydrochloride extended-release tablet contains tramadol, 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 tramadol hydrochloride extended-release tablet increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. the risk is increased with concurrent abuse of tramadol hydrochloride extended-release tablet with alcohol and other cns depressants. abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. in addition, abuse of opioids can occur in the absence of addiction. all patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. patients at high risk of tramadol hydrochloride extended-release tablet abuse include those with a history of prolonged use of any opioid, including products containing tramadol, those with a history of drug or alcohol abuse, or those who use tramadol hydrochloride extended-release tablet in combination with other abused drugs. "drug-seeking" behavior is very common in persons with substance use disorders. drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated "loss" of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). "doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. tramadol hydrochloride 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 tramadol hydrochloride extended-release tablets abuse of tramadol hydrochloride extended-release tablets poses a risk of overdose and death. this is increased with concurrent use of tramadol hydrochloride extended-release tablets with alcohol and/or other cns depressants. tramadol hydrochloride extended-release tablets are approved for oral use only. inappropriate intravenous, intramuscular, or subcutaneous use of tramadol hydrochloride extended-release tablets can result in death, local tissue necrosis, infection, pulmonary granulomas, increased risk of endocarditis, and valvular heart injury, and embolism. with parenteral abuse the inactive ingredients can result in local tissue necrosis, infection, pulmonary granulomas, increased risk of endocarditis and valvular heart injury, embolism, and death. 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 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 tramadol hydrochloride extended-release tablets in a patient physically dependent on opioids. rapid tapering of tramadol hydrochloride 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 tramadol hydrochloride extended-release tablets, gradually taper the dosage using a patient specific plan that considers the following: the dose of tramadol hydrochloride 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 ( 2.1), warnings and precautions  ( 5.18)]. infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see use in specific populations ( 8.1)].

Yhdysvallat - englanti - NLM (National Library of Medicine)

precision dose, inc. - methadone hydrochloride (unii: 229809935b) (methadone - unii:uc6vbe7v1z) - methadone hydrochloride oral solution 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 long-acting opioids [see warnings and precautions (5.2)] , reserve methadone hydrochloride oral solution for use in patients for whom alternative analgesic treatment options (e.g., non-opioid analgesics or immediate-release opioid analgesics) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. - methadone hydrochloride oral solution is not indicated as an as-needed (prn) analgesic. - detoxification treatment of opioid addiction (heroin or other morphine-like drugs). - maintenance treatment of opioid addiction (heroin or other morphine-like drugs), in conjunction with appropriate social and medical services. limitations of use: - methadone products used for the treatment of opioid addiction in detoxification or maintenance programs are subject to the conditions for distribution and use required under 42 cfr 8.12 [see dosage and administration (2.1)] . methadone hydrochloride 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 resuscitative equipment [see warnings and precautions (5.9)] - known or suspected gastrointestinal obstruction, including paralytic ileus [see warnings and precautions (5.14)] - hypersensitivity (e.g., anaphylaxis) to methadone [see adverse reactions (6)] risk summary: neonatal opioid withdrawal syndrome (nows) is an expected and treatable outcome of prolonged use of opioids during pregnancy [see warnings and precautions (5.6)] . pregnant women in methadone maintenance programs may have reduced incidence of obstetric and fetal complications and neonatal morbidity and mortality when compared to women using illicit drugs. untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes and risk of continued or relapsing illicit opioid use. these risks should be considered in women treated with methadone hydrochloride oral solution for maintenance treatment of opioid addiction. for women treated with methadone hydrochloride oral solution for pain severe enough to require daily, around-the-clock, long-term opioid treatment, methadone hydrochloride oral solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. there are no adequate and well-controlled studies in pregnant women. in published animal reproduction studies, methadone administered subcutaneously during the early gestational period produced neural tube defects (i.e., exencephaly and cranioschisis) in the hamster at doses 2 times the human daily oral dose of 120 mg/day on a mg/m2 basis (hdd) and in mice at doses equivalent to the hdd. administration of methadone to pregnant animals during organogenesis and through lactation resulted decreased litter size, increased pup mortality, decreased pup body weights, developmental delays, 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. administration of methadone to male rodents prior to mating with untreated females resulted in increased neonatal mortality and significant differences in behavioral tests in the offspring at exposures comparable to and less than the hdd [see data]. based on animal data, advise pregnant women of the potential risk to a fetus. the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations: disease-associated maternal and embryo-fetal risk: untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes such as low birth weight, preterm birth, and fetal death. in addition, untreated opioid addiction often results in continued or relapsing illicit opioid use. dosage adjustment during pregnancy: the disposition of oral methadone has been studied in approximately 30 pregnant patients in second and third trimesters. total body clearance of methadone was increased in pregnant patients compared to the same patients postpartum or to non-pregnant opioid-dependent women. the terminal half-life of methadone is decreased during second and third trimesters. the decrease in plasma half-life and increased clearance of methadone resulting in lower methadone trough levels during pregnancy can lead to withdrawal symptoms in some pregnant patients. the dosage may need to be increased or the dosing interval decreased in pregnant patients receiving methadone to achieve therapeutic effect [see dosage and administration (2.12)] . fetal/neonatal adverse reactions: neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with methadone hydrochloride oral solution. 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 (5.6)] . 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. use of methadone hydrochloride oral solution as an analgesic is not recommended for pregnant women during or immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. opioid analgesics, including methadone hydrochloride oral solution 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: reported studies have generally compared the benefit of methadone to the risk of untreated addiction to illicit drugs; the relevance of these findings to pain patients prescribed methadone during pregnancy is unclear. pregnant women involved in methadone maintenance programs have been reported to have significantly improved prenatal care leading to significantly reduced incidence of obstetric and fetal complications and neonatal morbidity and mortality when compared to women using illicit drugs. several factors, including maternal use of illicit drugs, nutrition, infection and psychosocial circumstances, complicate the interpretation of investigations of the children of women who take methadone during pregnancy. information is limited regarding dose and duration of methadone use during pregnancy, and most maternal exposure appears to occur after the first trimester of pregnancy. a review of published data on experiences with methadone use during pregnancy by the teratogen information system (teris) concluded that maternal use of methadone during pregnancy as part of a supervised, therapeutic regimen is unlikely to pose a substantial teratogenic risk (quantity and quality of data assessed as "limited to fair"). however, the data are insufficient to state that there is no risk (teris, last reviewed october, 2002). a retrospective case series of 101 pregnant, opioid-dependent women who underwent inpatient opioid detoxification with methadone did not demonstrate any increased risk of miscarriage in the second trimester or premature delivery in the third trimester. recent studies suggest an increased risk of premature delivery in opioid-dependent women exposed to methadone during pregnancy, although the presence of confounding factors makes it difficult to determine a causal relationship. several studies have suggested that infants born to narcotic-addicted women treated with methadone during all or part of pregnancy have been found to have decreased fetal growth with reduced birth weight, length, and/or head circumference compared to controls. this growth deficit does not appear to persist into later childhood. children prenatally exposed to methadone have been reported to demonstrate mild but persistent deficits in performance on psychometric and behavioral tests. in addition, several studies suggest that children born to opioid-dependent women exposed to methadone during pregnancy may have an increased risk of visual development anomalies; however, a causal relationship has not been assigned. there are conflicting reports on whether sudden infant death syndrome occurs with an increased incidence in infants born to women treated with methadone during pregnancy. abnormal fetal non-stress tests have been reported to occur more frequently when the test is performed 1 to 2 hours after a maintenance dose of methadone in late pregnancy compared to controls. animal data: formal reproductive and developmental toxicology studies for methadone have not been conducted. exposure margins for the following published study reports are based on a human daily dose (hdd) of 120 mg methadone using a body surface area comparison. in a published study in pregnant hamsters, a single subcutaneous dose of methadone ranging from 31 mg/kg (2 times the hdd) to 185 mg/kg on gestation day 8 resulted in a decrease in the number of fetuses per litter and an increase in the percentage of fetuses exhibiting neural tube defects including exencephaly, cranioschisis, and "various other lesions." the majority of the doses tested also resulted in maternal death. in a study in pregnant mice, a single subcutaneous dose of 22 to 24 mg/kg methadone (approximately equivalent to the hdd) administered on gestation day 9 produced exencephaly in 11% of the embryos. in another study in pregnant mice, subcutaneous doses up to 28 mg/kg/day methadone (equivalent to the hdd) administered from gestation day 6 to 15 resulted in no malformations, but there were increased postimplantation loss and decreased live fetuses at 10 mg/kg/day or greater (0.4 times the hdd) and decreased ossification and fetal body weight at 20 mg/kg/day or greater (0.8 times the hdd). in a second study of pregnant mice dosed with subcutaneous doses up to 28 mg/kg/day methadone from gestation day 6 to 15, there was decreased pup viability, delayed onset of development of negative phototaxis and eye opening, increased righting reflexes at 5 mg/kg/day or greater (0.2 times the hdd), and decreased number of live pups at birth and decreased pup weight gain at 20 mg/kg/day or greater (0.8 times the hdd). no effects were reported in a study of pregnant rats and rabbits at oral doses up to 40 mg/kg (3 and 6 times, respectively, the hdd) administered from gestation days 6 to 15 and 6 to 18, respectively. when pregnant rats were treated with intraperitoneal doses of 2.5, 5, or 7.5 mg/kg methadone from one week prior to mating, through gestation until the end of lactation period, 5 mg/kg or greater (0.4 times the hdd) methadone resulted in decreases in litter size and live pups born and 7.5 mg/kg (0.6 times the hdd) resulted in decreased birth weights. furthermore, decreased pup viability and pup body weight gain at 2.5 mg/kg or greater (0.2 times the hdd) were noted during the preweaning period. additional animal data demonstrates evidence for neurochemical changes in the brains of offspring from methadone-treated pregnant rats, including changes to the cholinergic, dopaminergic, noradrenergic and serotonergic systems at doses below the hdd. other animal studies have reported that prenatal and/or postnatal exposure to opioids including methadone alters neuronal development and behavior in the offspring including alterations in learning ability, motor activity, thermal regulation, nociceptive responses, and sensitivity to drugs at doses below the hdd. treatment of pregnant rats subcutaneously with 5 mg/kg methadone from gestation day 14 to 19 (0.4 times the hdd) reduced fetal blood testosterone and androstenedione in males. published animal data have reported increased neonatal mortality in the offspring of male rodents that were treated with methadone at doses comparable to and less than the hdd for 1 to 12 days before and/or during mating (with more pronounced effects in the first 4 days). in these studies, the female rodents were not treated with methadone, indicating paternally-mediated developmental toxicity. specifically, methadone administered to the male rat prior to mating with methadone-naïve females resulted in decreased weight gain in progeny after weaning. the male progeny demonstrated reduced thymus weights, whereas the female progeny demonstrated increased adrenal weights. behavioral testing of these male and female progeny revealed significant differences in behavioral tests compared to control animals, suggesting that paternal methadone exposure can produce physiological and behavioral changes in progeny in this model. examination of uterine contents of methadone-naïve female mice bred to methadone-treated male mice (once a day for three consecutive days) indicated that methadone treatment produced an increase in the rate of preimplantation deaths in all post-meiotic states at 1 mg/kg/day or greater (0.04 times the hdd). chromosome analysis revealed a dose-dependent increase in the frequency of chromosomal abnormalities at 1 mg/kg/day or greater. studies demonstrated that methadone treatment of male rats for 21 to 32 days prior to mating with methadone-naïve females did not produce any adverse effects, suggesting that prolonged methadone treatment of the male rat resulted in tolerance to the developmental toxicities noted in the progeny. mechanistic studies in this rat model suggest that the developmental effects of "paternal" methadone on the progeny appear to be due to decreased testosterone production. these animal data mirror the reported clinical findings of decreased testosterone levels in human males on methadone maintenance therapy for opioid addiction and in males receiving chronic intraspinal opioids. risk summary: based on two studies in 22 breastfeeding women maintained on methadone treatment, methadone was present in low levels in human milk, and did not show adverse reactions in breastfed infants. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for methadone and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition. clinical considerations: advise breastfeeding women taking methadone to monitor the infant for increased drowsiness and breathing difficulties. data: in a study of ten breastfeeding women maintained on oral methadone doses of 10 to 80 mg/day, methadone concentrations from 50 to 570 mcg/l in milk were reported, which, in the majority of samples, were lower than maternal serum drug concentrations at steady state. in a study of twelve breastfeeding women maintained on oral methadone doses of 20 to 80 mg/day, methadone concentrations from 39 to 232 mcg/l in milk were reported. based on an average milk consumption of 150 ml/kg/day, an infant would consume approximately 17.4 mcg/kg/day which is approximately 2 to 3% of the oral maternal dose. methadone has been detected in very low plasma concentrations in some infants whose mothers were taking methadone. there have been rare cases of sedation and respiratory depression in infants exposed to methadone through breast milk. 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), clinical pharmacology (12.2), nonclinical pharmacology (13.1)] . reproductive function in human males may be decreased by methadone treatment. reductions in ejaculate volume and seminal vesicle and prostate secretions have been reported in methadone-treated individuals. in addition, reductions in serum testosterone levels and sperm motility, and abnormalities in sperm morphology have been reported. in published animal studies, methadone produces a significant regression of sex accessory organs and testes of male mice and rats and administration of methadone to pregnant rats reduced fetal blood testosterone and androstenedione in male offspring [see nonclinical toxicology (13)] . the safety, effectiveness, and pharmacokinetics of methadone in pediatric patients below the age of 18 years have not been established. clinical studies of methadone did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently compared to younger subjects. other reported clinical experience has not identified differences in responses between elderly and younger patients. elderly patients (aged 65 years or older) may have increased sensitivity to methadone. 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 methadone hydrochloride oral solution slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see warnings and precautions (5.9)] . methadone 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. methadone pharmacokinetics have not been extensively evaluated in patients with hepatic insufficiency. methadone is metabolized by hepatic pathways; therefore, patients with liver impairment may be at risk of increased systemic exposure to methadone after multiple dosing. start these patients on lower doses and titrate slowly while carefully monitoring for signs of respiratory and central nervous system depression. methadone pharmacokinetics have not been extensively evaluated in patients with renal insufficiency. since unmetabolized methadone and its metabolites are excreted in urine to a variable degree, start these patients on lower doses and with longer dosing intervals and titrate slowly while carefully monitoring for signs of respiratory and central nervous system depression. methadone hydrochloride oral solution contains methadone, a schedule ii controlled substance. methadone hydrochloride oral solution contains methadone, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, and tapentadol. methadone hydrochloride oral solution can be abused and is subject to misuse, addiction, and criminal diversion [see warnings and precautions (5.2)] . all patients treated with opioids for pain management require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and include: 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 addicts and drug abusers. drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of lost prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(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. methadone hydrochloride oral solution, like other opioids, can be diverted for non-medical use into illicit channels of distribution. careful record-keeping of prescribing information, including quantity, frequency, and renewal requests as required by state and federal law, is strongly advised. proper assessment and selection of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. risks specific to abuse of methadone hydrochloride oral solution: abuse of methadone hydrochloride oral solution poses a risk of overdose and death. this risk is increased with concurrent abuse of methadone and other substances. methadone hydrochloride oral solution is for oral use only and must not be injected. with intravenous abuse the inactive ingredients in methadone hydrochloride oral solution can result in local tissue necrosis, infection, pulmonary granulomas, embolism and death, and 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 methadone hydrochloride oral solution in a patient physically dependent on opioids. rapid tapering of methadone hydrochloride oral solution 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 methadone hydrochloride oral solution, gradually taper the dosage using a patient-specific plan that considers the following: the dose of methadone hydrochloride oral solution 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 (2.5) and warnings (5.16)] . 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)] .

Yhdysvallat - englanti - NLM (National Library of Medicine)

pai holdings, llc - codeine phosphate (unii: gsl05y1mn6) (codeine anhydrous - unii:ux6owy2v7j), promethazine hydrochloride (unii: r61zeh7i1i) (promethazine - unii:ff28ejq494), phenylephrine hydrochloride (unii: 04ja59tnsj) (phenylephrine - unii:1ws297w6mv) - promethazine vc with codeine oral solution is indicated for the temporary relief of coughs and upper respiratory symptoms, including nasal congestion, associated with allergy or the common cold in patients 18 years of age and older. important limitations of use • not indicated for pediatric patients under 18 years of age [see use in specific populations (8.4)]. • contraindicated in pediatric patients under 12 years of age [see contraindications (4) and use in specific populations (8.4)]. • contraindicated in pediatric patients 12 to 18 years of age after tonsillectomy or adenoidectomy [see contraindications (4) and use in specific populations (8.4)]. • because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses [see warnings and precautions (5.1)], reserve promethazine vc with codeine oral solution for use in adult patients for whom the benefits of cough suppression are expected to outweigh the risks,and in whom an adequate assessment of the etiology of the cough has been made. promethazine vc with codeine oral solution is contraindicated for: • all children younger than 12 years of age [ see warnings and precautions ( 5.2, 5.3, 5.5 ), use in specific populations ( 8.4) ]. • postoperative pain management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [ see warnings and precautions ( 5.2, 5.3) ]. promethazine vc with codeine oral solution is also contraindicated in patients with: • significant respiratory depression [ see warnings and precautions ( 5.2) ]. • acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [ see warnings and precautions ( 5.6) ]. • known or suspected gastrointestinal obstruction, including paralytic ileus [ see warnings and precautions ( 5.11) ]. • narrow angle glaucoma, urinary retention, severe hypertension, severe coronary artery disease, or peripheral vascular insufficiency (ischemia    may result with risk of gangrene or thrombosis of compromised vascular beds) [ see warnings and precautions ( 5.13 )]. • a history of an idiosyncratic reaction to promethazine or to other phenothiazines [ see warnings and precautions ( 5.15) ]. • concurrent use of monoamine oxidase inhibitors (maois) or use of maois within 14 days [ see warnings and precautions ( 5.17 ) and drug    interactions ( 7.6) ]. • hypersensitivity to codeine, promethazine, phenylephrine, or any of the inactive ingredients in promethazine vc with codeine oral solution [ see    adverse reactions ( 6) ]. persons known to be hypersensitive to certain other opioids may exhibit cross-reactivity to codeine. risk summary promethazine vc with codeine oral solution is not recommended for use in pregnant women, including during or immediately prior to labor. prolonged use of opioids during pregnancy may cause neonatal opioid withdrawal syndrome [ see warnings and precautions ( 5.20 ), clinical considerations ]. there are no available data with promethazine vc with codeine oral solution use in pregnant women to inform a drug-associated risk for adverse developmental outcomes. published studies with codeine have reported inconsistent findings and have important methodological limitations ( see data ). there are reports of respiratory depression when codeine is used during labor and delivery ( see clinical considerations ). reproductive toxicity studies have not been conducted with promethazine vc with codeine oral solution; however, studies are available with individual active ingredients ( see data ). in animal reproduction studies, codeine administered by the oral route to pregnant rats during the period of organogenesis increased resorptions and decreased fetal weights at a dose approximately 26 times the maximum recommended human dose (mrhd) in the presence of maternal toxicity ( see data ). for pregnant mice and rats that received promethazine at doses 0.15 to 3 times the mrhd, during various periods of gestation, there were findings of increased fetal resorptions and skeletal fragility, decreased pup weight, and developmental delays of pups ( see data ). in studies with normotensive pregnant rabbits, which received phenylephrine during the period of organogenesis or later, there were findings of increased fetal lethality, adverse placental effects, and possible teratogenic effects at subcutaneous doses approximately 0.8 times the mrhd on a mg/m2 basis. premature labor was also observed when treatment was initiated during the second trimester or later ( see data ). based on the 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 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 ( 5.20 )]. maternal use of phenylephrine can cause fetal tachycardia. 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. opioids, including promethazine vc with codeine oral solution, 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 opioids during labor for signs of excess sedation and respiratory depression. data human data published data from case-control and observational studies on codeine use during pregnancy are inconsistent in their findings. some studies of codeine exposure showed an increased risk of overall congenital malformations while others did not. an increased risk of specific malformations with codeine exposure such as respiratory malformations, spina bifida and congenital heart defects were reported in some studies. the majority of studies examining the use of phenylephrine and promethazine in pregnancy did not find an association with an increased risk of congenital anomalies. in the few studies reporting an association, no consistent pattern of malformations was noted. most of the studies, both positive and negative, were limited by small sample size, recall bias and lack of information regarding dose and timing of exposure. animal data reproductive toxicity studies have not been conducted with promethazine vc with codeine oral solution; however, studies are available with individual active ingredients. codeine in an embryofetal development study in pregnant rats dosed throughout the period of organogenesis, codeine increased resorptions and decreased fetal weights at a dose approximately 26 times the mrhd (on a mg/m 2 basis with a maternal oral dose of 120 mg/kg/day); however, these effects occurred in the presence of maternal toxicity. in embryofetal development studies with pregnant rabbits and mice dosed throughout the period of organogenesis, codeine produced no adverse developmental effects at doses approximately 13 and 66 times, respectively, the mrhd (on a mg/m 2 basis with maternal oral doses of 30 mg/kg/day in rabbits and 600 mg/kg/day in mice). promethazine in pregnant mice dosed during the period of implantation from gestation days 1 to 5, promethazine increased resorption at doses approximately 0.2 times the mrhd (on a mg/m2 basis with maternal intraperitoneal and subcutaneous doses up to 1 mg/kg/day). in pregnant rats dosed during the period of organogenesis from gestation days 5 to 16, promethazine hydrochloride induced complete resorption at doses approximately 6 times the mrhd (on a mg/m 2 basis with maternal oral doses up to 20 mg/kg/day). in pregnant rats dosed during the period of organogenesis from gestation days 7 to 13, promethazine resulted in skeletal fragility of pups at doses approximately 3 times the mrhd (on a mg/m 2 basis with maternal oral doses up to 10 mg/kg/day). in pregnant rats dosed during the period of organogenesis from gestation days 10 to 12, promethazine resulted in decreased weight and delays in initial occurrence of behavioral/reflex of pups at doses approximately 3 times the mrhd (on a mg/m 2 basis with maternal oral doses up to 10 mg/kg/day). the relevance of these findings to humans is unclear. phenylephrine in studies with normotensive pregnant rabbits, which received phenylephrine during the period of organogenesis or later, there were findings of fetal deaths, adverse histopathology findings in the placenta (necrosis, calcification and thickened vascular walls with narrowed lumen), and possible teratogenic effects (one incidence of clubbed feet, partial development of the intestine) at doses approximately 0.8 times the mrhd (on a mg/m 2 basis with a maternal subcutaneous dose of 1 mg/kg/day). premature labor was also observed when treatment was initiated during the second trimester or later. mean percentage of implantations in rabbits was decreased by injection of phenylephrine. risk summary because of the potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with promethazine vc with codeine oral solution [see warnings and precautions ( 5.3) ]. there are no data on the presence of promethazine vc with codeine oral solution in human milk, the effects of promethazine vc with codeine oral solution on the breastfed infant, or the effects of promethazine vc with codeine oral solution on milk production; however, data are available with codeine and promethazine. codeine codeine and its active metabolite, morphine, are present in human milk. there are published studies and cases that have reported excessive sedation, respiratory depression and death (in one infant) in infants exposed to codeine via breast milk. women who are ultra-rapid metabolizers of codeine achieve higher than expected serum levels of morphine, potentially leading to higher levels of morphine in breast milk that can be dangerous in their breastfed infants. in women with normal codeine metabolism (normal cyp2d6 activity), the amount of codeine secreted into human milk is low and dose-dependent. there is no information on the effects of the codeine on milk production. promethazine there are no data on the presence of promethazine in human milk. however, direct oral administration of promethazine has been associated with respiratory depression, including fatalities, in pediatric patients [ see warnings and precautions ( 5.4) ]. promethazine has been shown to decrease basal prolactin levels in non-nursing women, and therefore may affect milk production. phenylephrine there are no data on the presence of phenylephrine in human milk or on its effects on the breastfed infant. phenylephrine is known to be poorly absorbed orally. animal data indicate that phenylephrine can decrease milk production and pharmacologically similar vasoconstrictors, such as pseudoephedrine, decrease milk production in lactating women after oral use. clinical considerations infants exposed to promethazine vc with codeine oral solution through breast milk should be monitored for excess sedation and respiratory depression. withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid is stopped, or when breastfeeding is stopped. infertility chronic use of opioids, such as codeine, a component of promethazine vc with codeine oral solution, 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) ]. promethazine vc with codeine oral solution is not indicated for use in patients younger than 18 years of age because the benefits of symptomatic treatment of cough associated with allergies or the common cold do not outweigh the risks for use of codeine in these patients [ see indications ( 1) and warnings and precautions ( 5.5) ]. life-threatening respiratory depression and death have occurred in children who received codeine [see warnings and precautions ( 5.2) ]. in most of the reported cases, these events followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine (ie, multiple copies of the gene for cytochrome p450 isoenzyme 2d6 or high morphine concentrations). children with sleep apnea may be particularly sensitive to the respiratory depressant effects of codeine. life-threatening respiratory depression and death have also occurred in children who received promethazine [see warnings and precautions ( 5.4) ]. because of the risk of life-threatening respiratory depression and death: - promethazine vc with codeine oral solution is contraindicated for all children younger than 12 years of age [see contraindications ( 4) ]. - promethazine vc with codeine oral solution is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see contraindications ( 4) ]. - avoid the use of promethazine vc with codeine oral solution in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine unless the benefits outweigh the risks. risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression [see warnings and precautions ( 5.3, 5.6) ]. clinical studies have not been conducted with promethazine vc with codeine oral solution in geriatric populations. use caution when considering the use of promethazine vc with codeine oral solution in patients 65 years of age or older. elderly patients may have increased sensitivity to codeine; greater frequency of decreased hepatic, renal, or cardiac function; or concomitant disease or other drug therapy [see warnings and precautions ( 5.6) ]. respiratory depression is the chief risk for elderly patients treated with opioids, including promethazine vc with codeine oral solution.  respiratory depression has occurred after large initial doses of opioids were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration [see warnings and precautions ( 5.6, 5.10) ]. codeine 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, monitor these patients closely for respiratory depression, sedation, and hypotension. the pharmacokinetics of promethazine vc with codeine oral solution has not been characterized in patients with renal impairment.  codeine pharmacokinetics may be altered in patients with renal failure. clearance may be decreased and the metabolites may accumulate to much higher plasma levels in patients with renal failure as compared to patients with normal renal function. promethazine vc with codeine oral solution should be used with caution in patients with severe impairment of renal function, and patients should be monitored closely for respiratory depression, sedation, and hypotension. no formal studies have been conducted in patients with hepatic impairment so the pharmacokinetics of promethazine vc with codeine oral solution in this patient population are unknown. promethazine vc with codeine oral solution should be used with caution in patients with impairment of hepatic function, and patients should be monitored closely for respiratory depression, sedation, and hypotension. promethazine vc with codeine oral solution contains codeine, a schedule v controlled substance. codeine promethazine vc with codeine oral solution contains codeine, a substance with a high potential for abuse similar to other opioids including morphine and codeine. promethazine vc with codeine oral solution can be abused and is subject to misuse, addiction, and criminal diversion [see warnings and precautions ( 5.1) ]. all patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic and antitussive products carries the risk of addiction even under appropriate medical use. prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. “drug-seeking” behavior is very common in persons with substance use disorders. drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating health care 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. health care 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. promethazine vc with codeine oral solution, like other opioids, can be diverted for non-medical use into illicit channels of distribution.  careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. risks specific to abuse of promethazine vc with codeine oral solution promethazine vc with codeine oral solution is for oral use only. abuse of promethazine vc with codeine oral solution poses a risk of overdose and death. the risk is increased with concurrent use of promethazine vc with codeine oral solution with alcohol and other central nervous system depressants [see warnings and precautions ( 5.10 )]. parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and hiv. psychological dependence, physical dependence, and tolerance may develop upon repeated administration of opioids; therefore, promethazine vc with codeine oral solution should be prescribed and administered for the shortest duration that is consistent with individual patient treatment goals and patients should be reevaluated prior to refills [see dosage and administration ( 2.3) and warnings and precautions ( 5.1) ]. physical dependence, the condition in which continued administration of the drug is required to prevent the appearance of a withdrawal syndrome, assumes clinically significant proportions only after several weeks of continued oral opioid use, although some mild degree of physical dependence may develop after a few days of opioid therapy. if promethazine vc with codeine oral solution is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur. withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (eg, naloxone, nalmefene), mixed agonist/antagonist analgesics (eg, pentazocine, butorphanol, nalbuphine), or partial agonists (eg, buprenorphine). some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. 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) ].

Yhdysvallat - englanti - NLM (National Library of Medicine)

indivior inc. - nalmefene hydrochloride (unii: k7k69qc05x) (nalmefene - unii:tov02tdp9i) - opvee nasal spray is indicated for the emergency treatment of known or suspected overdose induced by natural or synthetic opioids in adults and pediatric patients aged 12 years and older, as manifested by respiratory and/or central nervous system depression. opvee nasal spray is intended for immediate administration as emergency therapy in settings where opioids may be present. opvee nasal spray is not a substitute for emergency medical care. opvee nasal spray is contraindicated in patients known to be hypersensitive to nalmefene or to any of the other ingredients. risk summary life-sustaining therapy for opioid overdose should not be withheld (see clinical considerations). there are no available data on nalmefene use in pregnant women to evaluate for a drug-associated risk of major birth defects or miscarriage. in animal reproduction studies, no embryotoxic effects on embryo-fetal development were observed in rats and rabbits treated with nalmefene at exposures at least 6 times (rats) and up to 20 times (rabbits) the exposure at two human nasal doses of 5.4 mg (see data) . the background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk an opioid overdose is a medical emergency and can be fatal for the pregnant woman and fetus if left untreated. treatment with opvee for opioid overdose should not be withheld because of potential concerns regarding the effects of opvee on the fetus. data animal data reproduction studies have been performed in rats (up to 1200 mg/m2 /day) and rabbits (up to 2400 mg/m2 /day) by oral administration of nalmefene and in rabbits by intravenous administration up to 96 mg/m2 /day. no effects on embryo-fetal development were observed at exposures at least 6 times (rats) and up to 20 times (rabbits) the exposure corresponding to a human dose of 5.4 mg (two nalmefene nasal sprays) on an auc basis. the treatment in rats did not affect offspring survival. risk summary there are no data on the presence of nalmefene and its metabolites in human milk, the effects of nalmefene on the breastfed child, or the effects on milk production. nalmefene and its metabolites are present in rat milk (see data). when a drug is present in animal milk, it is likely that the drug will be present in human milk. data nalmefene and its metabolites were secreted into rat milk, reaching concentrations approximately three times those in plasma at one hour and decreasing to about half the corresponding plasma concentrations by 24 hours following bolus administration. the concentration of nalmefene in animal milk does not necessarily predict the concentration of drug in human milk. the safety and effectiveness of opvee nasal spray for the emergency treatment of known or suspected opioid overdose in adults and pediatric patients aged 12 years and older, as manifested by respiratory and/or central nervous system depression, have been established. use for this indication in this age group is supported by adult studies and pharmacokinetic simulation [see clinical pharmacology (12.3)] . there have been no studies conducted to evaluate the use of opvee nasal spray in pediatric patients. the safety and effectiveness of opvee nasal spray for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression have not been established in pediatric patients younger than 12 years of age. clinical studies of opvee nasal spray did not include subjects aged 65 and over. other reported clinical experience has not identified differences in responses between the elderly and younger patients. geriatric patients have a greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. therefore, the systemic exposure of nalmefene can be higher in these patients. hepatic impairment substantially reduces the clearance of nalmefene [see clinical pharmacology (12.3)]. for single episodes of opioid antagonism, adjustment of opvee nasal spray dosage is not required. renal impairment substantially reduces the clearance of nalmefene [see clinical pharmacology (12.3)]. for single episodes of opioid antagonisms, adjustment of opvee nasal spray dosage is not required. the instructions for use contains information on how to give opvee nasal spray in response to a known or suspected opioid overdose in adults and children 12 years of age and older. you and your family members or caregivers should read the instructions for use that comes with opvee nasal spray before using it. talk to your healthcare provider if you and your family members or caregivers have any questions about the use of opvee nasal spray. - for use in the nose only . - do not remove or test the opvee nasal spray before use. - each opvee nasal spray has 1 dose and cannot be reused. - you do not need to prime opvee nasal spray. - hand is supporting their head. - bend their knee. - turn their face to the side. - get a new opvee nasal spray from the box. - repeat steps 1 through 7 to give another dose of opvee in the other nostril. - if more opvee nasal sprays are available, repeat steps 1 through 7 every 2 to 5 minutes, alternating nostrils, until the person wakes up or medical help arrives. - store opvee nasal spray at room temperature between 59°f to 77°f (15°c to 25°c). - do not freeze opvee nasal spray. - keep opvee nasal spray in its box until ready to use. - protect from light. - replace opvee nasal spray before the expiration date on the box. for more information about opvee nasal spray, go to www.opvee.com or call 1-877-782-6966. opvee® is a registered trademark of indivior inc. ©2023 indivior inc. all rights reserved. manufactured for: indivior inc., north chesterfield, va, 23235, usa this instructions for use has been approved by the u.s. food and drug administration. issued: 06/2023

Yhdistynyt kuningaskunta - englanti - MHRA (Medicines & Healthcare Products Regulatory Agency)

lundbeck ltd - nalmefene hydrochloride - tablet - 18mg