USA - engelsk - NLM (National Library of Medicine)

hikma pharmaceuticals usa inc. - butalbital (unii: khs0az4jvk) (butalbital - unii:khs0az4jvk), acetaminophen (unii: 362o9itl9d) (acetaminophen - unii:362o9itl9d), caffeine (unii: 3g6a5w338e) (caffeine - unii:3g6a5w338e), codeine phosphate (unii: gsl05y1mn6) (codeine anhydrous - unii:ux6owy2v7j) - butalbital, acetaminophen, caffeine, and codeine phosphate capsules are indicated for the management of the symptom complex of tension (or muscle contraction) headache when non-opioid analgesic and alternative treatments are inadequate. limitations of use because of the risks of addiction, abuse, and misuse with opioids and butalbital, which can occur at any dosage or duration [see warnings and precautions ( 5.1)] , reserve butalbital, acetaminophen, caffeine, and codeine phosphate capsules for use in patients for whom alternative treatment options [e.g., non-opioid, non-barbiturate analgesics]: butalbital, acetaminophen, caffeine, and codeine phosphate capsules are contraindicated for: butalbital, acetaminophen, caffeine, and codeine phosphate capsules are also contraindicated in patients with: 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 butalbital, acetaminophen, caffeine, and codeine phosphate capsules in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. there are risks to the mother and infant associated with use of butalbital, acetaminophen, caffeine, and codeine phosphate capsules for an extended period of time during pregnancy (see clinical considerations) . animal reproduction studies have not been conducted with the combination of butalbital, acetaminophen, caffeine, and codeine phosphate capsules or with butalbital alone. in animal reproduction studies, codeine administration during organogenesis has been shown to produce delayed ossification in the offspring of mice at 2.8 times maximum recommended human dose (mrhd) of 180 mg/day, embryolethal and fetotoxic effects in the offspring of rats and hamsters at approximately 4 to 6 times the mrhd, and cranial malformations/cranioschisis in the offspring of hamsters between 2 and 8 times the mrhd. reproductive and developmental studies in rats and mice from the published literature identified adverse events at clinically relevant doses with acetaminophen. treatment of pregnant rats with doses of acetaminophen approximately 2 times the maximum human daily dose (mhdd) showed evidence of fetotoxicity and increases in bone variations in the fetuses. in another study, necrosis was observed in the liver and kidney of both pregnant rats and fetuses at doses approximately 2 times the mhdd. in mice treated with acetaminophen at doses within the clinical dosing range, cumulative adverse effects on reproduction were seen in a continuous breeding study. a reduction in number of litters of the parental mating pair was observed as well as retarded growth and abnormal sperm in their offspring and reduced birth weight in the next generation [see data ]. the background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations fetal/neonatal adverse reactions use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. the onset, 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 use of codeine during labor may lead to respiratory depression in the neonate. 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. butalbital, acetaminophen, caffeine, and codeine phosphate capsules are not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. opioid analgesics, including butalbital, acetaminophen, caffeine, and codeine phosphate capsules, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. however, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. data human data published data from a large population-based prospective cohort study and a population-based, case-control study do not clearly report an association with oral acetaminophen and major birth defects, miscarriage, or adverse maternal or fetal outcomes when acetaminophen is used during pregnancy. however, these studies cannot definitely establish the absence of any risk because of methodological limitations including recall bias. withdrawal seizures were reported in a two-day-old male infant whose mother had taken a butalbital containing drug during the last 2 months of pregnancy. butalbital was found in the infant's serum. the infant was given phenobarbital 5 mg/kg, which was tapered without further seizure or other withdrawal symptoms. animal data animal reproduction studies have not been conducted with butalbital, acetaminophen, caffeine, and codeine phosphate capsules or with butalbital alone. the following data are based on findings from studies performed with either codeine or acetaminophen alone. codeine in a study in which pregnant hamsters were administered 150 mg/kg twice daily of codeine (oral; approximately 14 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m2 basis) during organogenesis cranial malformations (i.e., meningoencephalocele) in several fetuses were reported; as well as the observation of increases in the percentage of resorptions per litter. doses of 50 and 150 mg/kg, bid resulted in fetotoxicity as demonstrated by decreased fetal body weight. in an earlier study in hamsters, single oral doses of 73 to 360 mg/kg level on gestation day 8 (oral; approximately 4 to 16 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m2 basis), reportedly produced cranioschisis in all of the fetuses examined. in studies in rats, doses at the 120 mg/kg level (oral; approximately 6 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m2 basis) during organogenesis, in the toxic range for the adult animal, were associated with an increase in embryo resorption at the time of implantation. in pregnant mice, a single 100 mg/kg dose (subcutaneous; approximately 2.8 times the recommended daily dose of 180 mg/day for adults on a mg/mg2 basis) administered between gestation day 7 and 12 reportedly resulted in delayed ossification in the offspring. no teratogenic effects were observed in rabbits administered up to 30 mg/kg (approximately 4 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m2 basis) of codeine during organogenesis. codeine (30 mg/kg) administered subcutaneously to pregnant rats during pregnancy and for 25 days after delivery increased neonatal mortality at birth. this dose is 1.6 times the maximum recommended human dose of 180 mg/day on a body surface area comparison. acetaminophen studies in pregnant rats that received oral acetaminophen during organogenesis at doses up to 1.7 the maximum human daily dose (mhdd) of 1950 mg/day based on a body surface area comparison showed evidence of fetotoxicity (reduced fetal weight and length) and a dose-related increase in bone variations (reduced ossification and rudimentary rib changes). offspring had no evidence of external, visceral, or skeletal malformations. when pregnant rats received oral acetaminophen throughout gestation at doses of 2.4 times the mhdd (based on a body surface area comparison), areas of necrosis occurred in both the liver and kidney of pregnant rats and fetuses. these effects did not occur in animals that received oral acetaminophen at doses 0.6 times the mhdd, based on a body surface area comparison. in a continuous breeding study, pregnant mice received 0.25, 0.5, or 1.0% acetaminophen via the diet (357, 715, or 1430 mg/kg/day). these doses are approximately 0.86, 1.7, and 3.4 times the mhdd, respectively, based on a body surface area comparison. a dose-related reduction in body weights of fourth and fifth litter offspring of the treated mating pair occurred during lactation and post-weaning at all doses. animals in the high dose group had a reduced number of litters per mating pair, male offspring with an increased percentage of abnormal sperm, and reduced birth weights in the next generation pups. caffeine in studies performed in adult animals, caffeine (as caffeine base) administered to pregnant mice as sustained release pellets at 50 mg/kg (less than the maximum recommended daily dose on a mg/m2 basis), during the period of organogenesis, caused a low incidence of cleft palate and exencephaly in the fetuses. risk summary 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 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. 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 butalbital, acetaminophen, caffeine, and codeine phosphate capsules [see warnings and precautions (5.6)] . acetaminophen is present in human milk in small quantities after oral administration. based on data from more than 15 nursing mothers, the calculated infant daily dose of acetaminophen is approximately 1 to 2% of the maternal dose. there is one well-documented report of a rash in a breastfed infant that resolved when the mother stopped acetaminophen use and recurred when she resumed acetaminophen use. barbiturates and caffeine are also excreted in breast milk in small amounts. because of potential for serious adverse reactions in nursing infants from butalbital, acetaminophen, caffeine, and codeine phosphate capsules, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. clinical considerations if infants are exposed to butalbital, acetaminophen, caffeine, and codeine phosphate capsules 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. 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), clinical pharmacology (12.2), nonclinical toxicology (13.1)]. published literature indicates that acetaminophen affects sperm development in mice with consequent reduction in litter size in a multigeneration study [see nonclinical toxicology (13.1)] . the safety and effectiveness of butalbital, acetaminophen, caffeine, and codeine phosphate capsules in pediatric patients have not been established. life-threatening respiratory depression and deaths have occurred in children who received codeine [see warnings and precautions (5.6)] . 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 (i.e., 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. because of the risk of life-threatening respiratory depression and death: clinical studies of butalbital, acetaminophen, caffeine, and codeine phosphate capsules did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. other reported clinical experience has not identified differences in responses between the elderly and younger patients. in general, dose selection for an elderly patient should be cautious, 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. butalbital is known to be substantially excreted by the kidney, and the risk of toxic 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. elderly patients (aged 65 years or older) may have increased sensitivity to butalbital, acetaminophen, caffeine, and codeine phosphate capsules. 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 butalbital, acetaminophen, caffeine, and codeine phosphate capsules slowly in geriatric patients and frequently reevaluate the patient for signs of respiratory depression [see warnings and precautions (5.10)]. components of this product are 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. no formal studies have been conducted in patients with hepatic impairment so the pharmacokinetics of butalbital, codeine, and acetaminophen in this patient population are unknown. start these patients cautiously with lower doses of codeine sulfate or with longer dosing intervals and titrate slowly while regularly evaluating for side effects. 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. start these patients cautiously with lower doses of codeine sulfate or with longer dosing intervals and titrate slowly while carefully regularly evaluating for side effects. in patients with renal disease, regularly evaluate effects of therapy with serial renal function tests. butalbital, acetaminophen, caffeine, and codeine phosphate capsules contain codeine. codeine in combination with butalbital, acetaminophen, and caffeine is a schedule iii controlled substance. butalbital, acetaminophen, caffeine, and codeine phosphate capsules contain codeine, 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 butalbital, acetaminophen, caffeine, and codeine phosphate capsules increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. the risk is increased with concurrent abuse of butalbital, acetaminophen, caffeine, and codeine phosphate capsules with alcohol and/or other cns depressants. abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. in addition, abuse of opioids can occur in the absence of addiction. all patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. patients at high risk of butalbital, acetaminophen, caffeine, and codeine phosphate capsules abuse include those with a history of prolonged use of any opioid, including products containing codeine, those with a history of drug or alcohol abuse, or those who use butalbital, acetaminophen, caffeine, and codeine phosphate capsules in combination with other abused drugs. “drug-seeking” behavior is very common in persons with substance use disorders. drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. butalbital, acetaminophen, caffeine, and codeine phosphate capsules, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. careful record keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. risks specific to abuse of butalbital, acetaminophen, caffeine, and codeine phosphate capsules abuse of butalbital, acetaminophen, caffeine, and codeine phosphate capsules poses a risk of overdose and death. the risk is increased with concurrent use of butalbital, acetaminophen, caffeine, and codeine phosphate capsules with alcohol and/or other cns depressants. butalbital, acetaminophen, caffeine, and codeine phosphate capsules are approved for oral use only. parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and hiv. butalbital barbiturates may be habit-forming: tolerance, psychological dependence, and physical dependence may occur especially following prolonged use of high doses of barbiturates. the average daily dose for the barbiturate addict is usually about 1,500 mg. as tolerance to barbiturates develops, the amount needed to maintain the same level of intoxication increases; tolerance to a fatal dosage, however, does not increase more than twofold. as this occurs, the margin between an intoxication dosage and fatal dosage becomes smaller. the lethal dose of a barbiturate is far less if alcohol is also ingested. major withdrawal symptoms (convulsions and delirium) may occur within 16 hours and last up to 5 days after abrupt cessation of these drugs. intensity of withdrawal symptoms gradually declines over a period of approximately 15 days. treatment of barbiturate dependence consists of cautious and gradual withdrawal of the drug. barbiturate-dependent patients can be withdrawn by using a number of different withdrawal regimens. one method involves initiating treatment at the patient's regular dosage level and gradually decreasing the daily dosage as tolerated by the patient. both tolerance and physical dependence can develop during use of opioid therapy. tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. do not abruptly discontinue butalbital, acetaminophen, caffeine, and codeine phosphate capsules in a patient physically dependent on opioids. rapid tapering of butalbital, acetaminophen, caffeine, and codeine phosphate capsules in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. when discontinuing butalbital, acetaminophen, caffeine, and codeine phosphate capsules gradually taper the dosage using a patient-specific plan that considers the following: the dose of butalbital, acetaminophen, caffeine, and codeine phosphate capsules the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. to improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. in patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see dosage and administration (2.5), 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)] .

USA - engelsk - NLM (National Library of Medicine)

hikma pharmaceuticals usa inc. - lithium carbonate (unii: 2bmd2gna4v) (lithium cation - unii:8h8z5uer66) - lithium carbonate 450 mg - lithium carbonate extended-release tablets are indicated in the treatment of manic episodes of manic-depressive illness. maintenance therapy prevents or diminishes the intensity of subsequent episodes in those manic-depressive patients with a history of mania. typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, elation, poor judgment, aggressiveness and possibly hostility. when given to a patient experiencing a manic episode, lithium carbonate extended-release tablets may produce a normalization of symptomatology within 1 to 3 weeks.

USA - engelsk - NLM (National Library of Medicine)

hikma pharmaceuticals usa inc. - meperidine hydrochloride (unii: n8e7f7q170) (meperidine - unii:9e338qe28f) - meperidine hydrochloride 50 mg - meperidine hydrochloride tablets and oral solution 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 because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [see warnings and precautions (5.2)] , reserve meperidine hydrochloride tablets and oral solution for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products] : meperidine hydrochloride tablets or oral solution should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate. meperidine hydrochloride tablets or oral solution should not be used for the treatment of chronic pain. use of meperidine hydrochloride tablets or oral solution for an extended period of time may increase the risk of toxicity (e.g. seizures) from the accumulation of the meperidine metabolite, normeperidine . meperidine hydrochloride tablets and oral solution are contraindicated in patients with: risk summary use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see warnings and precautions (5.5)]. available data with meperidine is insufficient to inform a drug-associated risk for major birth defects and miscarriage. formal animal reproduction studies have not been conducted with meperidine. neural tube defects (exencephaly and cranioschisis) have been reported in hamsters administered a single bolus dose of meperidine during a critical period of organogenesis at 0.85 and 1.5 times the total human daily dose of 1,200 mg [see data]. adverse outcomes in pregnancy can occur regardless of the health of the mother or the use of medications. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. clinical considerations fetal/neonatal adverse reactions : use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. the onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see warnings and precautions (5.5)]. labor and delivery : opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. resuscitation may be required [see overdose (10)]. an opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. meperidine is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. opioid analgesics, including meperidine, 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 animal data : formal reproductive and developmental toxicology studies for meperidine have not been completed. in a published study, neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of meperidine hydrochloride (127 and 218 mg/kg, respectively) on gestation day 8 to pregnant hamsters (0.85 and 1.5 times the total daily dose of 1,200 mg/day based on body surface area). the findings cannot be clearly attributed to maternal toxicity. risk summary meperidine appears in the milk of nursing mothers receiving the drug. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for meperidine and any potential adverse effects on the breastfed infant from meperidine hydrochloride tablets or oral solution or from the underlying maternal condition. clinical considerations monitor infants exposed to meperidine 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 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), clinical pharmacology (12.2)], nonclinical toxicology (13.1)]. the safety and effectiveness of meperidine in pediatric patients has not been established. literature reports indicate that meperidine has a slower elimination rate in neonates and young infants compared to older children and adults. neonates and young infants may also be more susceptible to the effects, especially the respiratory depressant effects. if meperidine use is contemplated in neonates or young infants, any potential benefits of the drug need to be weighed against the relative risk of the patient. clinical studies of meperidine during product development did not include sufficient numbers of subjects aged 65 and over to evaluate age-related differences in safety or efficacy. literature reports indicate that geriatric patients have a slower elimination rate compared to young patients and they may be more susceptible to the effects of meperidine. reducing the total daily dose of meperidine is recommended in elderly patients, and the potential benefits of the drug should be weighed against the relative risk to a geriatric patient. 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 meperidine hydrochloride tablets or oral solution slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see warnings and precautions (5.4, 5.11)]. meperidine 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. accumulation of meperidine and/or its active metabolite, normeperidine, can occur in patients with hepatic impairment. elevated serum levels have been reported to cause central nervous system excitatory effects. meperidine should therefore be used with caution in patients with hepatic impairment. titrate the dosage of meperidine hydrochloride tablets or oral solution slowly in patients with hepatic impairment and regularly evaluate for signs of central nervous system and respiratory depression. accumulation of meperidine and/or its active metabolite, normeperidine, can also occur in patients with renal impairment. meperidine should therefore be used with caution in patients with renal impairment. titrate the dosage of meperidine hydrochloride tablets or oral solution slowly in patients with renal impairment and regularly evaluate for signs of central nervous system and respiratory depression. meperidine hydrochloride tablets and oral solution contain meperidine, a schedule ii controlled substance. meperidine hydrochloride tablets and oral solution contain meperidine, 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 (5.2)]. 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 meperidine hydrochloride tablets and oral solution 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 meperidine hydrochloride tablets and/or oral solution 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 meperidine hydrochloride tablets and oral solution abuse include those with a history of prolonged use of any opioid, including products containing meperidine, those with a history of drug or alcohol abuse, or those who use meperidine hydrochloride tablets and oral solution 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. meperidine hydrochloride tablets and oral solution, 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 meperidine hydrochloride tablets and oral solution abuse of meperidine hydrochloride tablets and oral solution poses a risk of overdose and death. the risk is increased with concurrent use of meperidine hydrochloride tablets and oral solution with alcohol and/or other cns depressants. meperidine hydrochloride tablets and oral solution are approved for oral use only. meperidine hydrochloride tablets have been reported as being abused by crushing, chewing, snorting, or injecting the dissolved product. inappropriate intravenous, intramuscular, or subcutaneous use of meperidine hydrochloride tablets and oral solution can result in death, local tissue necrosis, infection, pulmonary granulomas, increased risk of endocarditis, and valvular heart injury, and embolism. parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and hiv. both tolerance and physical dependence can develop during use of opioid therapy. tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. do not abruptly discontinue meperidine hydrochloride tablets and oral solution in a patient physically dependent on opioids. rapid tapering of meperidine hydrochloride tablets and 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, gradually taper the dosage using a patient-specific plan that considers the following: the dose of meperidine hydrochloride tablets and 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 an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see dosage and administration (2.6), and warnings and precautions (5.17)]. infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see use in specific populations (8.1)].

USA - engelsk - NLM (National Library of Medicine)

hikma pharmaceuticals usa inc. - milrinone lactate (unii: 9k8xr81mo8) (milrinone - unii:ju9yax04c7) - milrinone lactate 10 mg in 10 ml - milrinone lactate injection, usp and milrinone lactate in 5% dextrose injection are indicated for the short-term intravenous treatment of patients with acute decompensated heart failure. patients receiving milrinone should be observed closely with appropriate electrocardiographic equipment. the facility for immediate treatment of potential cardiac events, which may include life threatening ventricular arrhythmias, must be available. the majority of experience with intravenous milrinone has been in patients receiving digoxin and diuretics. there is no experience in controlled trials with infusions of milrinone for periods exceeding 48 hours. milrinone lactate injection, usp and milrinone lactate in 5% dextrose injection are contraindicated in patients who are hypersensitive to it.

USA - engelsk - NLM (National Library of Medicine)

hikma pharmaceuticals usa inc. - octreotide acetate (unii: 75r0u2568i) (octreotide - unii:rwm8ccw8gp) - octreotide 50 ug in 1 ml - octreotide acetate injection is indicated to reduce blood levels of growth hormone (gh) and insulin growth factor-1 (igf-1; somatomedin c) in acromegaly patients who have had inadequate response to or cannot be treated with surgical resection, pituitary irradiation, and bromocriptine mesylate at maximally tolerated doses. the goal is to achieve normalization of gh and igf-1 (somatomedin c) levels (see dosage and administration ). in patients with acromegaly, octreotide acetate injection reduces gh to within normal ranges in 50% of patients and reduces igf-1 (somatomedin c) to within normal ranges in 50% to 60% of patients. since the effects of pituitary irradiation may not become maximal for several years, adjunctive therapy with octreotide acetate injection to reduce blood levels of gh and igf-1 (somatomedin c) offers potential benefit before the effects of irradiation are manifested. improvement in clinical signs and symptoms, or reduction in tumor size or rate of growth, were not shown in clinical trials p

USA - engelsk - NLM (National Library of Medicine)

hikma pharmaceuticals usa inc. - morphine sulfate (unii: x3p646a2j0) (morphine - unii:76i7g6d29c) - morphine sulfate 0.5 mg in 1 ml - duramorph is indicated for: - the management of pain severe enough to require use of an opioid analgesic by intravenous administration, and for which alternative treatments are not expected to be adequate. - the epidural or intrathecal management of pain without attendant loss of motor, sensory, or sympathetic function. limitation of use duramorph is not for use in continuous microinfusion devices. because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [see warnings and precautions (5.2)] , reserve duramorph for use in patients for whom alternative treatment options (e.g., nonopioid analgesics or opioid combination products): -  have not been tolerated, or are not expected to be tolerated, -  have not provided adequate analgesia, or are not expected to provide adequate analgesia. duramorph should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate. duramorph is 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 (5.9)] - concurrent use of monoamine oxidase inhibitors (maois) or use of maois within the last 14 days [see warnings and precautions (5.10), drug interactions (7)] - known or suspected gastrointestinal obstruction, including paralytic ileus [see warnings and precautions (5.14)] - hypersensitivity to morphine (e.g., anaphylaxis) [see adverse reactions (6)]  neuraxial administration of duramorph is contraindicated in patients with: - infection at the injection microinfusion site [see warnings and precautions (5.1)] - concomitant anticoagulant therapy [see warnings and precautions (5.1)] - uncontrolled bleeding diathesis [see warnings and precautions (5.1)] - the presence of any other concomitant therapy or medical condition which would render epidural or intrathecal administration of medication especially hazardous. risk summary use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see warnings and precautions (5.5)] . available data with duramorph in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. there are adverse outcomes reported with fetal exposure to opioid analgesics (see clinical considerations) . published studies with morphine use during pregnancy have not reported a clear association with morphine and major birth defects [see human data] . in published animal reproduction studies, morphine administered subcutaneously during the early gestational period produced neural tube defects (i.e., exencephaly and cranioschisis) at 5 and 16 times the human daily dose of 60 mg based on body surface area (hdd) in hamsters and mice, respectively, lower fetal body weight and increased incidence of abortion at 0.4 times the hdd in the rabbit, growth retardation at 6 times the hdd in the rat, and axial skeletal fusion and cryptorchidism at 16 times the hdd in the mouse. administration of morphine sulfate to pregnant rats during organogenesis and through lactation resulted in cyanosis, hypothermia, decreased brain weights, pup mortality, decreased pup body weights, and adverse effects on reproductive tissues at 3-4 times the hdd; and long-term neurochemical changes in the brain of offspring which correlate with altered behavioral responses that persist through adulthood at exposures comparable to and less than the hdd [see animal data] . based on animal data, advise pregnant women of the potential risk to a fetus. the background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s.general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations fetal/neonatal adverse reactions use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. the onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see warnings and precautions (5.5)] . labor or delivery opioids cross the placenta and may produce respiratory depression and psychophysiologic effects in neonates. an opioid antagonist, such as naloxone, must be available for reversal of opioid induced respiratory depression in the neonate. duramorph is 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 duramorph, can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. however, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. data human data the results from a population-based prospective cohort, including 70 women exposed to morphine during the first trimester of pregnancy and 448 women exposed to morphine at any time during pregnancy, indicate no increased risk for congenital malformations. however, these studies cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and nonrandomized study design. animal data formal reproductive and developmental toxicology studies for morphine have not been conducted. exposure margins for the following published study reports are based on human daily dose of 60 mg morphine using a body surface area comparison (hdd). neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of morphine sulfate (35-322 mg/kg) on gestation day 8 to pregnant hamsters (4.7 to 43.5 times the hdd). a no adverse effect level was not defined in this study and the findings cannot be clearly attributed to maternal toxicity. neural tube defects (exencephaly), axial skeletal fusions, and cryptorchidism were reported following a single subcutaneous (sc) injection of morphine sulfate to pregnant mice (100-500 mg/kg) on gestation day 8 or 9 at 200 mg/kg or greater (16 times the hdd) and fetal resorption at 400 mg/kg or higher (32 times the hdd). no adverse effects were noted following 100 mg/kg morphine in this model (8 times the hdd). in one study, following continuous subcutaneous infusion of doses greater than or equal to 2.72 mg/kg to mice (0.2 times the hdd), exencephaly, hydronephrosis, intestinal hemorrhage, split supraoccipital, malformed sternebrae, and malformed xiphoid were noted. the effects were reduced with increasing daily dose; possibly due to rapid induction of tolerance under these infusion conditions. the clinical significance of this report is not clear. decreased fetal weights were observed in pregnant rats treated with 20 mg/kg/day morphine sulfate (3.2 times the hdd) from gestation day 7 to 9. there was no evidence of malformations despite maternal toxicity (10% mortality). in a second rat study, decreased fetal weight and increased incidences of growth retardation were noted at 35 mg/kg/day (5.7 times the hdd) and there was a reduced number of fetuses at 70 mg/kg/day (11.4 times the hdd) when pregnant rats were treated with 10, 35, or 70 mg/kg/day morphine sulfate via continuous infusion from gestation day 5 to 20. there was no evidence of fetal malformations or maternal toxicity. an increased incidence of abortion was noted in a study in which pregnant rabbits were treated with 2.5 (0.8 times the hdd) to 10 mg/kg morphine sulfate via subcutaneous injection from gestation day 6 to 10. in a second study, decreased fetal body weights were reported following treatment of pregnant rabbits with increasing doses of morphine (10-50 mg/kg/day) during the pre-mating period and 50 mg/kg/day (16 times the hdd) throughout the gestation period. no overt malformations were reported in either publication; although only limited endpoints were evaluated. in published studies in rats, exposure to morphine during gestation and/or lactation periods is associated with: decreased pup viability at 12.5 mg/kg/day or greater (2 times the hdd); decreased pup body weights at 15 mg/kg/day or greater (2.4 times the hdd); decreased litter size, decreased absolute brain and cerebellar weights, cyanosis, and hypothermia at 20 mg/kg/day (3.2 times the hdd); alteration of behavioral responses (play, social-interaction) at 1 mg/kg/day or greater (0.2 times the hdd); alteration of maternal behaviors (e.g., decreased nursing and pup retrievals) in mice at 1 mg/kg or higher (0.08 times the hdd) and rats at 1.5 mg/kg/day or higher (0.2 times the hdd); and a host of behavioral abnormalities in the offspring of rats, including altered responsiveness to opioids at 4 mg/kg/day (0.7 times the hdd) or greater. fetal and/or postnatal exposure to morphine in mice and rats has been shown to result in morphological changes in fetal and neonatal brain and neuronal cell loss, alteration of a number of neurotransmitter and neuromodulator systems, including opioid and nonopioid systems, and impairment in various learning and memory tests that appear to persist into adulthood. these studies were conducted with morphine treatment usually in the range of 4 to 20 mg/kg/day (0.7 to 3.2 times the hdd). additionally, delayed sexual maturation and decreased sexual behaviors in female offspring at 20 mg/kg/day (3.2 times the hdd), and decreased plasma and testicular levels of luteinizing hormone and testosterone, decreased testes weights, seminiferous tubule shrinkage, germinal cell aplasia, and decreased spermatogenesis in male offspring were also observed at 20 mg/kg/day (3.2 times the hdd). decreased litter size and viability were observed in the offspring of male rats that were intraperitoneally administered morphine sulfate for 1 day prior to mating at 25 mg/kg/day (4.1 times the hdd) and mated to untreated females. decreased viability and body weight and/or movement deficits in both first and second generation offspring were reported when male mice were treated for 5 days with escalating doses of 120 to 240 mg/kg/day morphine sulfate (9.7 to 19.5 times the hdd) or when female mice treated with escalating doses of 60 to 240 mg/kg/day (4.9 to 19.5 times the hdd) followed by a 5- day treatment-free recovery period prior to mating. similar multigenerational findings were also seen in female rats pre-gestationally treated with escalating doses of 10 to 22 mg/kg/day morphine (1.6 to 3.6 times the hdd). risk summary morphine is present in breast milk. published lactation studies report variable concentrations of morphine in breast milk with administration of immediate-release morphine to nursing mothers in the early postpartum period with a milk-to-plasma morphine auc ratio of 2.5:1 measured in one lactation study. however, there is insufficient information to determine the effects of morphine on the breastfed infant and the effects of morphine on milk production. lactation studies have not been conducted with duramorph, and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for duramorph and any potential adverse effects on the breastfed infant from duramorph or from the underlying maternal condition. clinical considerations monitor infants exposed to duramorph through breast milk for excess sedation and respiratory depression. withdrawal symptoms can occur in breastfed infants when maternal administration of morphine is stopped, or when breastfeeding is stopped. infertility use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. it is not known whether these effects on fertility are reversible [see adverse reactions (6), clinical pharmacology (12.2)] . in published animal studies, morphine administration adversely effected fertility and reproductive endpoints in male rats and prolonged estrus cycle in female rats [see nonclinical toxicology (13)] . adequate studies to establish the safety and effectiveness of spinal morphine in pediatric patients have not been performed, and usage in this population is not recommended. elderly patients (aged 65 years or older) may have increased sensitivity to duramorph. 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 duramorph slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see warnings and precautions (5.9)] . the pharmacodynamic effects of neuraxial morphine in the elderly are more variable than in the younger population. patients will vary widely in the effective initial dose, rate of development of tolerance and the frequency and magnitude of associated adverse effects as the dose is increased. initial doses should be based on careful clinical observation following “test doses”, after making due allowances for the effects of the patient’s age and infirmity on his/her ability to clear the drug, particularly in patients receiving epidural morphine. morphine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. the elimination half-life of morphine may be prolonged in patients with reduced metabolic rates and with hepatic and/or renal dysfunction. hence, care should be exercised in administering duramorph epidurally to patients with these conditions. high blood morphine levels, due to reduced clearance, may take several days to develop. duramorph contains morphine, a schedule ii controlled drug substance. duramorph contains morphine, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see warnings and precautions (5.2)] . 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, nontherapeutic 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 duramorph 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 duramorph with alcohol and/or other cns depressants. abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. in addition, abuse of opioids can occur in the absence of addiction. all patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. patients at high risk of duramorph abuse include those with a history of prolonged use of any opioid, including products containing morphine, those with a history of drug or alcohol abuse, or those who use duramorph 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. duramorph, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. careful recordkeeping 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 duramorph abuse of duramorph poses a risk of overdose and death. the risk is increased with concurrent use of duramorph with alcohol and/or other cns depressants. parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and hiv. both tolerance and physical dependence can develop during use of opioid therapy. tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. duramorph should not be abruptly discontinued in a physically dependent patient [see dosage and administration (2.6)] . if duramorph is abruptly discontinued in a physically dependent patient, a withdrawal syndrome may occur, typically characterized by restlessness, lacrimation, rhinorrhea, 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)] .

USA - engelsk - NLM (National Library of Medicine)

hikma pharmaceuticals usa inc. - morphine sulfate (unii: x3p646a2j0) (morphine - unii:76i7g6d29c) - morphine sulfate 10 mg in 1 ml - infumorph is for use in continuous microinfusion devices and indicated only for intrathecal or epidural infusion in the management of intractable chronic pain severe enough to require an opioid analgesic and for which less invasive means of controlling pain are inadequate. limitations of use not for single-dose intravenous, intramuscular, or subcutaneous administration due to the risk of overdose. not for single-dose neuraxial injection because infumorph is too concentrated for accurate delivery of the smaller doses used in this setting. infumorph should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate. infumorph is contraindicated in patients with: - significant respiratory depression [see warnings and precautions (5.2)] - acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see warnings and precautions (5.9)] - concurrent use of monoamine oxidase inhibitors (maois) or use of maois within the last 14 days [see warnings and precautions (5.10), drug interactions (7)] - known or suspected gastrointestinal obstruction, including paralytic ileus [see warnings and precautions (5.14)] - hypersensitivity to morphine (e.g., anaphylaxis) [see adverse reactions (6)] neuraxial administration of infumorph is contraindicated in patients with: - infection at the injection microinfusion site [see warnings and precautions (5.1)] - concomitant anticoagulant therapy [see warnings and precautions (5.1)] - uncontrolled bleeding diathesis [see warnings and precautions (5.1)] - the presence of any other concomitant therapy or medical condition which would render epidural or intrathecal administration of medication especially hazardous. risk summary use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see warnings and precautions (5.5)] . available data with infumorph in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. there are adverse outcomes reported with fetal exposure to opioid analgesics (see clinical considerations) . published studies with morphine use during pregnancy have not reported a clear association with morphine and major birth defects [see human data] . in published animal reproduction studies, morphine administered subcutaneously during the early gestational period produced neural tube defects (i.e., exencephaly and cranioschisis) at 5 and 16 times the human daily dose of 60 mg based on body surface area (hdd) in hamsters and mice, respectively, lower fetal body weight and increased incidence of abortion at 0.4 times the hdd in the rabbit, growth retardation at 6 times the hdd in the rat, and axial skeletal fusion and cryptorchidism at 16 times the hdd in the mouse. administration of morphine sulfate to pregnant rats during organogenesis and through lactation resulted in cyanosis, hypothermia, decreased brain weights, pup mortality, decreased pup body weights, and adverse effects on reproductive tissues at 3-4 times the hdd; and long-term neurochemical changes in the brain of offspring which correlate with altered behavioral responses that persist through adulthood at exposures comparable to and less than the hdd [see animal data] . based on animal data, advise pregnant women of the potential risk to a fetus. the background risk of major birth defects and miscarriage for the indicated population is unknown.  all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations fetal/neonatal adverse reactions use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. the onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see warnings and precautions (5.5)] . labor or delivery infumorph 200 and 500 (10 and 25 mg/ml, respectively) are too highly concentrated for routine use in obstetric neuraxial analgesia. opioids, including intravenously, epidurally, and intrathecally administered morphine, readily cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. an opioid antagonist, such as naloxone, and resuscitative equipment must be available for reversal of opioid-induced respiratory depression in the neonate.  infumorph is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. opioid analgesics, including infumorph, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. however, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. data human data the results from a population-based prospective cohort, including 70 women exposed to morphine during the first trimester of pregnancy and 448 women exposed to morphine at any time during pregnancy, indicate no increased risk for congenital malformations. however, these studies cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and nonrandomized study design. animal data formal reproductive and developmental toxicology studies for morphine have not been conducted. exposure margins for the following published study reports are based on human daily dose of 60 mg morphine using a body surface area comparison (hdd). neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of morphine sulfate (35-322 mg/kg) on gestation day 8 to pregnant hamsters (4.7 to 43.5 times the hdd). a no adverse effect level was not defined in this study and the findings cannot be clearly attributed to maternal toxicity. neural tube defects (exencephaly), axial skeletal fusions, and cryptorchidism were reported following a single subcutaneous (sc) injection of morphine sulfate to pregnant mice (100-500 mg/kg) on gestation day 8 or 9 at 200 mg/kg or greater (16 times the hdd) and fetal resorption at 400 mg/kg or higher (32 times the hdd). no adverse effects were noted following 100 mg/kg morphine in this model (8 times the hdd). in one study, following continuous subcutaneous infusion of doses greater than or equal to 2.72 mg/kg to mice (0.2 times the hdd), exencephaly, hydronephrosis, intestinal hemorrhage, split supraoccipital, malformed sternebrae, and malformed xiphoid were noted. the effects were reduced with increasing daily dose; possibly due to rapid induction of tolerance under these infusion conditions. the clinical significance of this report is not clear. decreased fetal weights were observed in pregnant rats treated with 20 mg/kg/day morphine sulfate (3.2 times the hdd) from gestation day 7 to 9. there was no evidence of malformations despite maternal toxicity (10% mortality). in a second rat study, decreased fetal weight and increased incidences of growth retardation were noted at 35 mg/kg/day (5.7 times the hdd) and there was a reduced number of fetuses at 70 mg/kg/day (11.4 times the hdd) when pregnant rats were treated with 10, 35, or 70 mg/kg/day morphine sulfate via continuous infusion from gestation day 5 to 20. there was no evidence of fetal malformations or maternal toxicity. an increased incidence of abortion was noted in a study in which pregnant rabbits were treated with 2.5 (0.8 times the hdd) to 10 mg/kg morphine sulfate via subcutaneous injection from gestation day 6 to 10. in a second study, decreased fetal body weights were reported following treatment of pregnant rabbits with increasing doses of morphine (10-50 mg/kg/day) during the pre-mating period and 50 mg/kg/day (16 times the hdd) throughout the gestation period. no overt malformations were reported in either publication; although only limited endpoints were evaluated. in published studies in rats, exposure to morphine during gestation and/or lactation periods is associated with: decreased pup viability at 12.5 mg/kg/day or greater (2 times the hdd); decreased pup body weights at 15 mg/kg/day or greater (2.4 times the hdd); decreased litter size, decreased absolute brain and cerebellar weights, cyanosis, and hypothermia at 20 mg/kg/day (3.2 times the hdd); alteration of behavioral responses (play, social-interaction) at 1 mg/kg/day or greater (0.2 times the hdd); alteration of maternal behaviors (e.g., decreased nursing and pup retrievals) in mice at 1 mg/kg or higher (0.08 times the hdd) and rats at 1.5 mg/kg/day or higher (0.2 times the hdd); and a host of behavioral abnormalities in the offspring of rats, including altered responsiveness to opioids at 4 mg/kg/day (0.7 times the hdd) or greater. fetal and/or postnatal exposure to morphine in mice and rats has been shown to result in morphological changes in fetal and neonatal brain and neuronal cell loss, alteration of a number of neurotransmitter and neuromodulator systems, including opioid and nonopioid systems, and impairment in various learning and memory tests that appear to persist into adulthood. these studies were conducted with morphine treatment usually in the range of 4 to 20 mg/kg/day (0.7 to 3.2 times the hdd). additionally, delayed sexual maturation and decreased sexual behaviors in female offspring at 20 mg/kg/day (3.2 times the hdd), and decreased plasma and testicular levels of luteinizing hormone and testosterone, decreased testes weights, seminiferous tubule shrinkage, germinal cell aplasia, and decreased spermatogenesis in male offspring were also observed at 20 mg/kg/day (3.2 times the hdd). decreased litter size and viability were observed in the offspring of male rats that were intraperitoneally administered morphine sulfate for 1 day prior to mating at 25 mg/kg/day (4.1 times the hdd) and mated to untreated females. decreased viability and body weight and/or movement deficits in both first and second generation offspring were reported when male mice were treated for 5 days with escalating doses of 120 to 240 mg/kg/day morphine sulfate (9.7 to 19.5 times the hdd) or when female mice treated with escalating doses of 60 to 240 mg/kg/day (4.9 to 19.5 times the hdd) followed by a 5-day treatment-free recovery period prior to mating. similar multigenerational findings were also seen in female rats pre-gestationally treated with escalating doses of 10 to 22 mg/kg/day morphine (1.6 to 3.6 times the hdd). risk summary morphine is present in breast milk. published lactation studies report variable concentrations of morphine in breast milk with administration of immediate-release morphine to nursing mothers in the early postpartum period with a milk-to-plasma morphine auc ratio of 2.5:1 measured in one lactation study. however, there is insufficient information to determine the effects of morphine on the breastfed infant and the effects of morphine on milk production. lactation studies have not been conducted with infumorph, and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for infumorph and any potential adverse effects on the breastfed infant from infumorph or from the underlying maternal condition. clinical considerations monitor infants exposed to infumorph through breast milk for excess sedation and respiratory depression. withdrawal symptoms can occur in breastfed infants when maternal administration of morphine is stopped, or when breastfeeding is stopped. infertility   use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. it is not known whether these effects on fertility are reversible [see adverse reactions (6), clinical pharmacology (12.2)] . in published animal studies, morphine administration adversely effected fertility and reproductive endpoints in male rats and prolonged estrus cycle in female rats [see nonclinical toxicology (13) ]. adequate studies to establish the safety and effectiveness of spinal morphine in pediatric patients have not been performed, and usage in this population is not recommended. elderly patients (aged 65 years or older) may have increased sensitivity to infumorph. 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 infumorph slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see warnings and precautions (5.8)] . the pharmacodynamic effects of neuraxial morphine in the elderly are more variable than in the younger population. patients will vary widely in the effective initial dose, rate of development of tolerance and the frequency and magnitude of associated adverse effects as the dose is increased.  initial doses should be based on careful clinical observation following “test doses”, after making due allowances for the effects of the patient’s age and infirmity on his/her ability to clear the drug, particularly in patients receiving epidural morphine. morphine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. the elimination half-life of morphine may be prolonged in patients with reduced metabolic rates and with hepatic and/or renal dysfunction. hence, care should be exercised in administering infumorph epidurally to patients with these conditions. high blood morphine levels, due to reduced clearance, may take several days to develop. infumorph contains morphine, a schedule ii controlled drug substance. infumorph contains morphine, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see warnings and precautions (5.2)] . 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 infumorph 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 infumorph with alcohol and/or other cns depressants. abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. in addition, abuse of opioids can occur in the absence of addiction. all patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. patients at high risk of infumorph abuse include those with a history of prolonged use of any opioid, including products containing morphine, those with a history of drug or alcohol abuse, or those who use infumorph 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. infumorph, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. careful recordkeeping 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 infumorph abuse of infumorph poses a risk of overdose and death. the risk is increased with concurrent use of infumorph with alcohol and/or other cns depressants. parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and hiv. both tolerance and physical dependence can develop during use of opioid therapy. tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. infumorph should not be abruptly discontinued in a physically-dependent patient [see dosage and administration (2.6)]. if infumorph is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur, typically characterized by restlessness, lacrimation, rhinorrhea, 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) ].

USA - engelsk - NLM (National Library of Medicine)

hikma pharmaceuticals usa inc. - phenobarbital sodium (unii: sw9m9bb5k3) (phenobarbital - unii:yqe403bp4d) - phenobarbital sodium 65 mg in 1 ml - - sedative. sedation is obtainable within an hour, and in adequate dosage, the duration of action is more than six hours. included in the more common conditions in which the sedative action of this class of drugs is desired are anxiety-tension states, hyperthyroidism, essential hypertension, nausea and vomiting of functional origin, motion sickness, acute labyrinthitis, pylorospasm in infants, chorea and cardiac failure. phenobarbital is also a useful adjunct in treatment of hemorrhage from the respiratory or gastrointestinal tract. phenobarbital controls anxiety, decreases muscular activity and lessens nervous excitability in hyperthyroid patients. however, thyrotoxic individuals occasionally react poorly to barbiturates. - hypnotic, for the short-term treatment of insomnia, since it appears to lose its effectiveness for sleep induction and sleep maintenance after 2 weeks (see clinical pharmacology ). -  preanesthetic. - long-term anticonvulsant, (phenobarbital, mephobarbital and metharbital) for the treatment of generalized tonic-clonic and cortical focal seizures. and, in the emergency control of certain acute convulsive episodes, e.g., those associated with status epilepticus, cholera, eclampsia, cerebral hemorrhage, meningitis, tetanus, and toxic reactions to strychnine or local anesthetics. phenobarbital sodium may be administered intramuscularly or intravenously as an anticonvulsant for emergency use. when administered intravenously, it may require 15 or more minutes before reaching peak concentrations in the brain. therefore, injecting phenobarbital sodium until the convulsions stop may cause the brain level to exceed that required to control the convulsions and lead to severe barbiturate-induced depression. - phenobarbital is indicated in pediatric patients as an anticonvulsant and as a sedative, including its preoperative and postoperative use. barbiturates are contraindicated in patients with known barbiturate sensitivity. barbiturates are also contraindicated in patients with a history of manifest or latent porphyria, marked impairment of liver functions or with severe respiratory distress where dyspnea or obstruction is evident. large doses are contraindicated in nephritic subjects. barbiturates should not be administered to persons with known previous addiction to the sedative-hypnotic group since ordinary doses may be ineffectual and may contribute to further addiction. intraarterial administration is contraindicated. its consequences vary from transient pain to gangrene. subcutaneous administration produces tissue irritation, ranging from tenderness and redness to necrosis and is not recommended. (see dosage and administration, treatment of adverse effects due to inadvertent error in administration .) phenobarbital sodium injection is a schedule iv controlled substance. barbiturates may be habit forming. tolerance and psychological dependence and physical dependence may occur especially following prolonged use of high doses of barbiturates. as tolerance to barbiturates develops, the amount needed to maintain the same level of intoxication increases; tolerance to a fatal dosage, however, does not increase more than two-fold. as this occurs, the margin between an intoxicating dosage and fatal dosage becomes smaller. symptoms of acute intoxication with barbiturates include unsteady gait, slurred speech and sustained nystagmus. mental signs of chronic intoxication include confusion, poor judgment, irritability, insomnia and somatic complaints. symptoms of barbiturate dependence are similar to those of chronic alcoholism. if an individual appears to be intoxicated with alcohol to a degree that is radically disproportionate to the amount of alcohol in his or her blood, the use of barbiturates should be suspected. the lethal dose of a barbiturate is far less if alcohol is also ingested. the symptoms of barbiturate withdrawal can be severe and may cause death. minor withdrawal symptoms may appear 8 to 12 hours after the last dose of a barbiturate. these symptoms usually appear in the following order: anxiety, muscle twitching, tremor of hands and fingers, progressive weakness, dizziness, distortion in visual perception, nausea, vomiting, insomnia and orthostatic hypotension. major withdrawal symptoms (convulsions and delirium) may occur within 16 hours and last up to 5 days after abrupt cessation of these drugs. intensity of withdrawal symptoms gradually declines over a period of approximately 15 days. individuals susceptible to barbiturate abuse and dependence include alcoholics and opiate abusers, as well as other sedative-hypnotic and amphetamine abusers. drug dependence to barbiturates arises from repeated administration of a barbiturate or agent with barbiturate-like effect on a continuous basis, generally in amounts exceeding therapeutic dose levels. the characteristics of drug dependence to barbiturates include: (a) a strong desire or need to continue taking the drug, (b) a tendency to increase the dose, (c) a psychic dependence on the effects of the drug related to subjective and individual appreciation of those effects and (d) a physical dependence on the effects of the drug requiring its presence for maintenance of homeostasis and resulting in a definite, characteristic and self-limited abstinence syndrome when the drug is withdrawn. individuals subject to barbiturate abuse and dependence include alcoholics and opiate abusers as well as other sedative-hypnotics and amphetamine abusers. treatment of barbiturate dependence consists of cautious and gradual withdrawal of the drug. barbiturate-dependent patients can be withdrawn by using a number of different withdrawal regimens. in all cases, withdrawal takes an extended period of time. one method involves substituting a 30 mg dose of phenobarbital for each 100 to 200 mg dose of barbiturate that the patient has been taking. the total daily amount of phenobarbital is then administered in 3 to 4 divided doses, not to exceed 600 mg daily. should signs of withdrawal occur on the first day of treatment, a loading dose of 100 to 200 mg of phenobarbital may be administered im in addition to the oral dose. after stabilization on phenobarbital, the total daily dose is decreased by 30 mg a day as long as withdrawal is proceeding smoothly. if withdrawal symptoms appear, dosage is maintained at that level or increased slightly until symptoms disappear. a modification of this regimen involves initiating treatment at the patient’s regular dosage level and decreasing the daily dosage by 10 percent if tolerated by the patient. the symptoms of withdrawal can be severe and may cause death. minor withdrawal symptoms (e.g., anxiety, muscle twitching, tremors, nausea, etc.) may appear 8-12 hours after the last dose of a barbiturate. major withdrawal symptoms (convulsions and delirium) may occur within 16 hours and last up to five days after abrupt cessation of the barbiturate. the intensity of withdrawal symptoms gradually declines over a period of two weeks. infants physically dependent on barbiturates may be given phenobarbital 3 to 10 mg/kg/day. after withdrawal symptoms (hyperactivity, disturbed sleep, tremors, hyperreflexia) are relieved, the dosage of phenobarbital should be gradually decreased and completely withdrawn over a 2-week period.

USA - engelsk - NLM (National Library of Medicine)

hikma pharmaceuticals usa inc. - cefazolin sodium (unii: p380m0454z) (cefazolin - unii:ihs69l0y4t) - cefazolin for injection, usp is indicated in the treatment of the following serious infections due to susceptible organisms: respiratory tract infections: due to s. penumoniae, klebsiella species, h. influenzae, s. aureus (penicillin-sensitive and penicillin-resistant) and group a beta-hemolytic streptococci. injectable benzathine penicillin is considered to be the drug of choice in treatment and prevention of streptococcal infections, including the prophylaxis of rheumatic fever. cefazolin for injection, usp is effective in the eradication of streptococci from the nasopharynx; however, data establishing the efficacy of cefazolin for injection, usp in the subsequent prevention of rheumatic fever are not available. urinary tract infections: due to e. coli, p. mirabilis, klebsiella species, and some strains of enterobacter and enterococci. skin and skin structure infections: due to s. aureus (penicillin-sensitive and penicillin-resistant), group a beta-hemolytic streptococci, and other strains of streptococci. biliary tract infections: due to e. coli , various strains of streptococci, p. mirabilis, klebsiella species and s. aureus . bone and joint infections: due to s. aureus . genital infections: (i.e., prostatitis, epididymitis) due to e. coli, p. mirabilis, klebsiella species, and some strains of enterococci. septicemia: due to s. pneumoniae , s. aureus (penicillin-sensitive and penicillin-resistant), p. mirabilis , e. coli, and klebsiella species. endocarditis: due to s. aureus (penicillin-sensitive and penicillin-resistant) and group a beta-hemolytic streptococci. perioperative prophylaxis: the prophylactic administration of cefazolin for injection, usp preoperatively, intraoperatively and postoperatively may reduce the incidence of certain postoperative infections in patients undergoing surgical procedures which are classified as contaminated or potentially contaminated (e.g., vaginal hysterectomy, and cholecystectomy in high‑risk patients such as those older than 70 years, with acute cholecystitis, obstructive jaundice or common duct bile stones). the perioperative use of cefazolin for injection, usp may also be effective in surgical patients in whom infection at the operative site would present a serious risk (e.g., during open-heart surgery and prosthetic arthroplasty). the prophylactic administration of cefazolin for injection, usp should usually be discontinued within a 24 hour period after the surgical procedure. in surgery where the occurrence of infection may be particularly devastating (e.g., open-heart surgery and prosthetic arthroplasty), the prophylactic administration of cefazolin for injection, usp may be continued for 3 to 5 days following the completion of surgery. if there are signs of infection, specimens for cultures should be obtained for the identification of the causative organism so that appropriate therapy may be instituted (see dosage and administration ). to reduce the development of drug-resistant bacteria and maintain the effectiveness of cefazolin for injection, usp and other antibacterial drugs, cefazolin for injection, usp should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. when culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. in the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. cefazolin for injection is contraindicated in patients with known allergy to the cephalosporin group of antibiotics.

USA - engelsk - NLM (National Library of Medicine)

hikma pharmaceuticals usa inc. - neostigmine methylsulfate (unii: 98imh7m386) (neostigmine - unii:3982twq96g) - neostigmine methylsulfate injection, usp is a cholinesterase inhibitor indicated for the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery. neostigmine methylsulfate injection, usp is contraindicated in patients with: - known hypersensitivity to neostigmine methylsulfate (known hypersensitivity reactions have included urticaria, angioedema, erythema multiforme, generalized rash, facial swelling, peripheral edema, pyrexia, flushing, hypotension, bronchospasm, bradycardia and anaphylaxis). - peritonitis or mechanical obstruction of the intestinal or urinary tract. risk summary there are no adequate or well-controlled studies of neostigmine methylsulfate injection, usp in pregnant women.  it is not known whether neostigmine methylsulfate injection, usp can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity.  the incidence of malformations in human pregnancies has not been established for neostigmine as the data are limited.  all pregnancies, regardless of drug exposure, have a background risk of 2 to 4% for major birth defects and 15 to 20% for pregnancy loss. no adverse effects were noted in rats or rabbits treated with human equivalent doses of neostigmine methylsulfate doses up to 8.1 and 13 mcg/kg/day, respectively, during organogenesis (0.1 to 0.2 times the maximum recommended human dose of 5 mg/60 kg person/day based on body surface area comparisons). anticholinesterase drugs, including neostigmine, may cause uterine irritability and induce premature labor when administered to pregnant women near term. neostigmine methylsulfate injection, usp should be given to a pregnant woman only if clearly needed. data animal data in embryofetal development studies, rats and rabbits were administered neostigmine methylsulfate at human equivalent doses (hed, on a mg/m2 basis) of 1.6, 4 and 8.1 mcg/kg/day and 3.2, 8.1, and 13 mcg/kg/day, respectively, during the period of organogenesis (gestation days 6 through 17 for rats and gestation days 6 through 18 for rabbits).  there was no evidence for a teratogenic effect in rats and rabbits up to hed 8.1 and 13 mcg/kg/day, which are approximately 0.097 times and 0.16 times the mrhd of 5 mg/60 kg, respectively, in the presence of minimal maternal toxicity (tremors, ataxia, and prostration).  the studies resulted in exposures in the animals well below predicted exposures in humans. in a prenatal and postnatal development study in rats, neostigmine methylsulfate was administered to pregnant female rats at human equivalent doses (hed) of 1.6, 4 and 8.1 mcg/kg/day from day 6 of gestation through day 20 of lactation, with weaning on day 21.  there were no adverse effects on physical development, behavior, learning ability, or fertility in the offspring at hed doses up to 8.1 mcg/kg/day which is 0.097 times the mrhd of 5 mg/60 kg on a mg/m2 basis in the presence of minimal maternal toxicity (tremors, ataxia, and prostration). the studies resulted in exposures in the animals well below predicted exposures in humans. risk summary neostigmine methylsulfate has not been studied in lactating women. it is not known whether neostigmine methylsulfate is present in human milk, or if neostigmine methylsulfate has effects on milk production or the breastfed child. therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s need for neostigmine methylsulfate and any potential adverse effects on the breastfed child from neostigmine methylsulfate or from the underlying maternal condition. neostigmine methylsulfate injection, usp is approved for the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery in pediatric patients of all ages. recovery of neuromuscular activity occurs more rapidly with smaller doses of cholinesterase inhibitors in infants and children than in adults. however, infants and small children may be at greater risk of complications from incomplete reversal of neuromuscular blockade due to decreased respiratory reserve. the risks associated with incomplete reversal outweigh any risk from giving higher doses of neostigmine methylsulfate injection, usp (up to 0.07 mg/kg or up to a total of 5 mg, whichever is less). the dose of neostigmine methylsulfate injection, usp required to reverse neuromuscular blockade in children varies between 0.03 mg - 0.07 mg/kg, the same dose range shown to be effective in adults, and should be selected using the same criteria as used for adult patients [see clinical pharmacology (12.3)]. since the blood pressure in pediatric patients, particularly infants and neonates, is sensitive to changes in heart rate, the effects of an anticholinergic agent (e.g., atropine) should be observed prior to administration of neostigmine to lessen the probability of bradycardia and hypotension. because elderly patients are more likely to have decreased renal function, neostigmine methylsulfate injection, usp should be used with caution and monitored for a longer period in elderly patients. the duration of action of neostigmine methylsulfate is prolonged in the elderly; however, elderly patients also experience slower spontaneous recovery from neuromuscular blocking agents. therefore, dosage adjustments are not generally needed in geriatric patients; however, they should be monitored for longer periods than younger adults to assure additional doses of neostigmine methylsulfate injection, usp are not required. the duration of monitoring should be predicated on the anticipated duration of action for the nmba used on the patient [see dosage and administration (2.3)] . elimination half-life of neostigmine methylsulfate was prolonged in anephric patients compared to normal subjects. although no adjustments to neostigmine methylsulfate injection, usp dosing appear to be warranted in patients with impaired renal function, they should be closely monitored to assure the effects of the neuromuscular blocking agent, particularly one cleared by the kidneys, do not persist beyond those of neostigmine methylsulfate injection, usp.  in this regard, the interval for re-dosing the neuromuscular blocking agent during the surgical procedure may be useful in determining whether, and to what extent, post-operative monitoring needs to be extended. the pharmacokinetics of neostigmine methylsulfate in patients with hepatic impairment have not been studied. neostigmine methylsulfate is metabolized by microsomal enzymes in the liver. no adjustments to the dosing of neostigmine methylsulfate injection, usp appear to be warranted in patients with hepatic insufficiency. however, patients should be carefully monitored if hepatically cleared neuromuscular blocking agents were used during their surgical procedure as their duration of action may be prolonged by hepatic insufficiency whereas neostigmine methylsulfate injection, usp, which undergoes renal elimination, will not likely be affected. this could result in the effects of the neuromuscular blocking agent outlasting those of neostigmine methylsulfate injection, usp. this same situation may arise if the neuromuscular blocking agent has active metabolites. in this regard, the interval for re-dosing the neuromuscular blocking agent during the surgical procedure may be useful in determining whether, and to what extent, post-operative monitoring needs to be extended.