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aphena pharma solutions - tennessee, llc - acetaminophen (unii: 362o9itl9d) (acetaminophen - unii:362o9itl9d), codeine phosphate (unii: gsl05y1mn6) (codeine anhydrous - unii:ux6owy2v7j) - acetaminophen and codeine phosphate tablets are indicated for the management of mild to moderate pain, where treatment with an opioid is appropriate and for which alternative treatments are inadequate. limitations of use because of the risks of addiction, abuse, and misuse, with opioids, even at recommended doses (see warnings ), reserve acetaminophen and codeine phosphate tablets for use in patients for whom alternative treatment options (e.g., non-opioid analgesics) - have not provided adequate analgesia, or are not expected to provide adequate analgesia, have not provided adequate analgesia, or are not expected to provide adequate analgesia, - have not been tolerated, or are not expected to be tolerated. acetaminophen and codeine phosphate tablets are contraindicated for: - all children younger than 12 years of age (see  warnings ). - post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy (see  warnings ). acetaminophen and codeine phosphate table

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

clinical solutions wholesale, llc - acetaminophen (unii: 362o9itl9d) (acetaminophen - unii:362o9itl9d), codeine phosphate (unii: gsl05y1mn6) (codeine anhydrous - unii:ux6owy2v7j) - acetaminophen and codeine phosphate tablets are indicated for the management of mild to moderate pain, where treatment with an opioid is appropriate and for which alternative treatments are inadequate. limitations of use because of the risks of addiction, abuse, and misuse, with opioids, even at recommended doses ( see warnings ), reserve acetaminophen and codeine phosphate tablets for use in patients for whom alternative treatment options (e.g., non-opioid analgesics) - have not provided adequate analgesia, or are not expected to provide adequate analgesia, - have not been tolerated, or are not expected to be tolerated. acetaminophen and codeine phosphate tablets are contraindicated for: - all children younger than 12 years of age ( see  warnings ). - postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy ( see  warnings ). acetaminophen and codeine phosphate tablets are contraindicated in patients with: - significant respiratory depression ( see  warnings ). - acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment ( see  warnings ). - concurrent use of monoamine oxidase inhibitors (maois) or use of maois within the last 14 days ( see  warnings ). - known or suspected gastrointestinal obstruction, including paralytic ileus ( see  warnings ). - hypersensitivity to codeine, acetaminophen, or any of the formulation excipients (e.g., anaphylaxis) ( see  warnings ). controlled substance acetaminophen and codeine phosphate tablets contain codeine. codeine in combination with acetaminophen, is a schedule iii controlled substance. abuse acetaminophen and codeine phosphate tablets contain codeine, a substance with a high potential for abuse similar to other opioids, including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. acetaminophen and codeine phosphate tablets can be abused and are subject to misuse, addiction, and criminal diversion ( see  warnings ). all patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of 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, or potentially 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 providers. “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. acetaminophen and codeine phosphate 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 limit abuse of opioid drugs. risks specific to abuse of acetaminophen and codeine phosphate tablets acetaminophen and codeine phosphate tablets are for oral use only. abuse of acetaminophen and codeine phosphate tablets poses a risk of overdose and death. the risk is increased with concurrent use of acetaminophen and codeine phosphate tablets with alcohol and other central nervous system depressants. parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and hiv. dependence both tolerance and physical dependence can develop during chronic opioid therapy. tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. acetaminophen and codeine phosphate tablets should not be abruptly discontinued ( see  dosage and administration ). if acetaminophen and codeine phosphate tablets are abruptly discontinued in a physically dependent patient, a withdrawal syndrome may occur. 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  precautions, pregnancy ).

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

clinical solutions wholesale, llc - acetaminophen (unii: 362o9itl9d) (acetaminophen - unii:362o9itl9d), codeine phosphate (unii: gsl05y1mn6) (codeine anhydrous - unii:ux6owy2v7j) - acetaminophen and codeine phosphate tablets are indicated for the management of mild to moderate pain, where treatment with an opioid is appropriate and for which alternative treatments are inadequate. limitations of use because of the risks of addiction, abuse, and misuse, with opioids, even at recommended doses ( see warnings ), reserve acetaminophen and codeine phosphate tablets for use in patients for whom alternative treatment options (e.g., non-opioid analgesics) - have not provided adequate analgesia, or are not expected to provide adequate analgesia, - have not been tolerated, or are not expected to be tolerated. acetaminophen and codeine phosphate tablets are contraindicated for: - all children younger than 12 years of age ( see  warnings ). - postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy ( see  warnings ). acetaminophen and codeine phosphate tablets are contraindicated in patients with: - significant respiratory depression ( see  warnings ). - acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment ( see  warnings ). - concurrent use of monoamine oxidase inhibitors (maois) or use of maois within the last 14 days ( see  warnings ). - known or suspected gastrointestinal obstruction, including paralytic ileus ( see  warnings ). - hypersensitivity to codeine, acetaminophen, or any of the formulation excipients (e.g., anaphylaxis) ( see  warnings ). controlled substance acetaminophen and codeine phosphate tablets contain codeine. codeine in combination with acetaminophen, is a schedule iii controlled substance. abuse acetaminophen and codeine phosphate tablets contain codeine, a substance with a high potential for abuse similar to other opioids, including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. acetaminophen and codeine phosphate tablets can be abused and are subject to misuse, addiction, and criminal diversion ( see  warnings ). all patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of 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, or potentially 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 providers. “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. acetaminophen and codeine phosphate 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 limit abuse of opioid drugs. risks specific to abuse of acetaminophen and codeine phosphate tablets acetaminophen and codeine phosphate tablets are for oral use only. abuse of acetaminophen and codeine phosphate tablets poses a risk of overdose and death. the risk is increased with concurrent use of acetaminophen and codeine phosphate tablets with alcohol and other central nervous system depressants. parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and hiv. dependence 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 acetaminophen and codeine phosphate tablets in a patient physically dependent on opioids. rapid tapering of acetaminophen and codeine phosphate 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 acetaminophen and codeine phosphate tablets, gradually taper the dosage using a patient-specific plan that considers the following: the dose of acetaminophen and codeine phosphate 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  and warnings ). infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs ( see  precautions, pregnancy ).

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

quality care products, llc - oxycodone hydrochloride (unii: c1enj2te6c) (oxycodone - unii:cd35pmg570), acetaminophen (unii: 362o9itl9d) (acetaminophen - unii:362o9itl9d) - oxycodone and acetaminophen tablets are indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. limitations of use because of the risks of addiction, abuse, and misuse, with opioids, even at recommended doses (see warnings ), reserve oxycodone 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. oxycodone and acetaminophen tablets are contraindicated in patients with: - significant respiratory depression (see warnings ) - acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment (see warnings ) - known or suspected gastrointestinal obstruction, including paralytic ileus (see warnings ) - hypersensitivity to oxycodone, acetaminophen, or any other component of the prod

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

quality care products, llc - oxycodone hydrochloride (unii: c1enj2te6c) (oxycodone - unii:cd35pmg570), acetaminophen (unii: 362o9itl9d) (acetaminophen - unii:362o9itl9d) - oxycodone and acetaminophen tablets are indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. limitations of use because of the risks of addiction, abuse, and misuse, with opioids, even at recommended doses (see warnings ), reserve oxycodone 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. oxycodone and acetaminophen tablets are contraindicated in patients with: - significant respiratory depression (see warnings ) - acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment (see warnings ) - known or suspected gastrointestinal obstruction, including paralytic ileus (see warnings ) - hypersensitivity to oxycodone, acetaminophen, or any other component of the prod

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

quality care products, llc - hydrocodone bitartrate (unii: no70w886kk) (hydrocodone - unii:6yks4y3wq7), acetaminophen (unii: 362o9itl9d) (acetaminophen - unii:362o9itl9d) - hydrocodone bitartrate and acetaminophen tablets are indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. limitations of use because of the risks of addiction, abuse, and misuse, with opioids, even at recommended doses (see warnings ), reserve hydrocodone bitartrate 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 been tolerated, or are not expected to be tolerated, - have not provided adequate analgesia, or are not expected to provide adequate analgesia have not provided adequate analgesia, or are not expected to provide adequate analgesia hydrocodone bitartrate and acetaminophen tablets are contraindicated in patients with: - significant respiratory depression (see warnings ) significant respiratory depression (see warnings ) - acute or severe bronchial asthma in an unmonitor

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

quality care products, llc - hydrocodone bitartrate (unii: no70w886kk) (hydrocodone - unii:6yks4y3wq7), acetaminophen (unii: 362o9itl9d) (acetaminophen - unii:362o9itl9d) - hydrocodone bitartrate and acetaminophen tablets are indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. limitations of use because of the risks of addiction, abuse, and misuse, with opioids, even at recommended doses (see warnings ), reserve hydrocodone bitartrate 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 been tolerated, or are not expected to be tolerated, - have not provided adequate analgesia, or are not expected to provide adequate analgesia have not provided adequate analgesia, or are not expected to provide adequate analgesia hydrocodone bitartrate and acetaminophen tablets are contraindicated in patients with: - significant respiratory depression (see warnings ) significant respiratory depression (see warnings ) - acute or severe bronchial asthma in an unmonitor

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

quality care products, llc - hydrocodone bitartrate (unii: no70w886kk) (hydrocodone - unii:6yks4y3wq7), acetaminophen (unii: 362o9itl9d) (acetaminophen - unii:362o9itl9d) - hydrocodone bitartrate and acetaminophen tablets are indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. limitations of use because of the risks of addiction, abuse, and misuse, with opioids, even at recommended doses (see warnings ), reserve hydrocodone bitartrate 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 been tolerated, or are not expected to be tolerated, - have not provided adequate analgesia, or are not expected to provide adequate analgesia have not provided adequate analgesia, or are not expected to provide adequate analgesia hydrocodone bitartrate and acetaminophen tablets are contraindicated in patients with: - significant respiratory depression (see warnings ) significant respiratory depression (see warnings ) - acute or severe bronchial asthma in an unmonitor

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

specgx llc - methadone hydrochloride (unii: 229809935b) (methadone - unii:uc6vbe7v1z) - methadone hydrochloride 10 mg in 1 ml - methadose contains methadone, an opioid agonist indicated for the: - 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 21 cfr, title 42, sec 8 [see dosage and administration (2.1)] . methadose is contraindicated in patients with: - significant respiratory depression [see warnings and precautions (5.1)] significant respiratory depression [see warnings and precautions (5.1)] - acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see warnings and precautions (5.8)] acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see warnings and precautions (5.8)] - known or suspected gastrointestinal obstruction, including paralytic ileus [see warnings and precautions (5.13)] known or suspected gastrointestinal obstruction, including paralytic ileus [see warnings and precautions (5.13)] - hypersensitivity (e.g., anaphylaxis) to methadone or any other ingredient in methadose [see adverse reactions (6)] hypersensitivity (e.g., anaphylaxis) to methadone or any other ingredient in methadose [see adverse reactions (6)] risk summary the majority of available data from clinical trials, observational studies, case series, and case reports on methadone use in pregnancy do not indicate an increased risk of major malformations specifically due to methadone. pregnant women involved in methadone maintenance programs have been reported to have improved prenatal care leading to 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 in these studies appears to occur after the first trimester of pregnancy (see data ). neonatal opioid withdrawal syndrome (nows) is an expected and treatable outcome of prolonged use of opioids during pregnancy [see warnings and precautions (5.6)] . 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 dosage adjustment using higher doses or administering the daily dose in divided doses may be necessary in pregnant women treated with methadose. pregnant women appear to have significantly lower trough plasma methadone concentrations, increased plasma methadone clearance, and shorter methadone half-life than after delivery [see dosage and administration (2.9), clinical pharmacology (12.3)] . withdrawal signs and symptoms should be closely monitored and the dose adjusted as necessary. fetal/neonatal adverse reactions neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with methadose. 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 opioid-dependent women on methadone maintenance therapy may require additional analgesia during labor. monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. data human data the majority of available data from clinical trials, observational studies, case series, and case reports on methadone use in pregnancy do not indicate an increased risk of major malformations specifically due to methadone. findings regarding specific major malformations, decreased fetal growth, premature birth and sudden infant death syndrome have been inconsistent. children prenatally exposed to methadone have been reported to demonstrate mild but persistent deficits in performance on psychometric and behavioral tests and visual abnormalities. in a multicenter, double-blind, randomized, controlled trial [maternal opioid treatment: human experimental research (mother)] designed primarily to assess neonatal opioid withdrawal effects, opioid-dependent pregnant women were randomized to buprenorphine (n=86) or methadone (n=89) treatment, with enrollment at an average gestational age of 18.7 weeks in both groups. a total of 28 of the 86 women in the buprenorphine group (33%) and 16 of the 89 women in the methadone group (18%) discontinued treatment before the end of pregnancy. among women who remained in treatment until delivery, there was no difference between methadone-treated and buprenorphine-treated groups in the number of neonates requiring nows treatment or in the peak severity of nows. buprenorphine-exposed neonates required less morphine (mean total dose, 1.1 mg vs. 10.4 mg), had shorter hospital stays (10.0 days vs. 17.5 days), and shorter duration of treatment for nows (4.1 days vs. 9.9 days) compared to the methadone-exposed group. there were no differences between groups in other primary outcomes (neonatal head circumference,) or secondary outcomes (weight and length at birth, preterm birth, gestational age at delivery, and 1-minute and 5-minute apgar scores), or in the rates of maternal or neonatal adverse events. the outcomes among mothers who discontinued treatment before delivery and may have relapsed to illicit opioid use are not known. because of the imbalance in discontinuation rates between the methadone and buprenorphine groups, the study findings are difficult to interpret. 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 jbt/jd 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 demonstrate 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 small clinical studies, methadone was present in low levels in human milk, but the exposed infants in these studies did not show adverse reactions. 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. there have been rare case reports of sedation and respiratory depression in infants exposed to methadone through breast milk (see data ). monitor infants exposed to methadose through breast milk for excess sedation and respiratory depression. 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. 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. peak methadone levels in milk occur approximately 4 to 5 hours after an oral dose. 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. infertility the effect of methadose on fertility is unknown. 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 toxicology (13)] . 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. in general, start elderly patients at the low end of the dosing range, taking into account the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. closely monitor elderly patients for signs of respiratory and central nervous system depression. 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. methadose contains methadone, a schedule ii opioid agonist. methadose contains methadone, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, and tapentadol. methadose can be abused and is subject to misuse, addiction, and criminal diversion [see warnings and precautions (5.5)] . 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 people who abuse opioids and people suffering from untreated addiction. 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 people with substance use disorders. in addition, abuse of opioids can occur in the absence of true addiction. methadose, like other opioids, can be diverted for non-medical use into illicit channels of distribution. careful record-keeping of prescribing information, including quantity and frequency 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 methadose abuse of methadone poses a risk of overdose and death. this risk is increased with concurrent abuse of methadone with alcohol and other substances. methadose is intended for oral use only and must not be injected. parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and hiv. methadose, when used for the treatment of opioid addiction in detoxification or maintenance programs, may be dispensed only by opioid treatment programs certified by the substance abuse and mental health services administration (and agencies, practitioners, and institutions by formal agreements with the program sponsor). 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 (in the absence of disease progression or other external factors). tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. physical dependence results in withdrawal symptoms after abrupt discontinuation or significant dose reduction of a drug. withdrawal is also precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone) or 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. physical dependence is expected during opioid agonist therapy of opioid addiction. methadose should not be abruptly discontinued [see dosage and administration (2.6, 2.7)] . if methadose is abruptly discontinued in a physically dependent patient, a withdrawal syndrome may occur. some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. other 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 [see dosage and administration (2.6)] . neonatal opioid withdrawal syndrome (nows) is an expected and treatable outcome of prolonged use of opioids during pregnancy [see warnings and precautions (5.6)] .

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

specgx llc - methadone hydrochloride (unii: 229809935b) (methadone - unii:uc6vbe7v1z) - methadone hydrochloride oral concentrate contains methadone, an opioid agonist indicated for the: - 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 21 cfr, title 42, sec 8 [see dosage and administration (2.1)] . methadone hydrochloride oral concentrate is contraindicated in patients with: - significant respiratory depression [see warnings and precautions (5.1)] significant respiratory depression [see warnings and precautions (5.1)] - acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see warnings and precautions (5.8)] acute or severe bronchial asthma in an unmonitored setting or in