Ամերիկայի Միացյալ Նահանգներ - անգլերեն - 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)].

Ամերիկայի Միացյալ Նահանգներ - անգլերեն - NLM (National Library of Medicine)

hikma pharmaceuticals usa inc. - lisdexamfetamine dimesylate (unii: sjt761gegs) (lisdexamfetamine - unii:h645gul8kj) - lisdexamfetamine dimesylate capsules are indicated for the treatment of: lisdexamfetamine dimesylate capsules are contraindicated in patients with: pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to adhd medications during pregnancy. healthcare providers are encouraged to register patients by calling the national pregnancy registry for psychostimulants at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/clinical-and researchprograms/pregnancyregistry/adhd-medications/ . risk summary the limited available data from published literature and postmarketing reports on use of lisdexamfetamine dimesylate in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage. adverse pregnancy outcomes, including premature delivery and low birth weight, have been seen in infants born to mothers dependent on amphetamines [see clinical considerations] . in animal reproduction studies, lisdexamfetamine dimesylate (a prodrug of d-amphetamine) had no effects on embryo-fetal morphological development or survival when administered orally to pregnant rats and rabbits throughout the period of organogenesis. pre-and postnatal studies were not conducted with lisdexamfetamine dimesylate. however, amphetamine (d-to l-ratio of 3:1) administration to pregnant rats during gestation and lactation caused a decrease in pup survival and a decrease in pup body weight that correlated with a delay in developmental landmarks at clinically relevant doses of amphetamine. in addition, adverse effects on reproductive performance were observed in pups whose mothers were treated with amphetamine. long-term neurochemical and behavioral effects have also been reported in animal developmental studies using clinically relevant doses of amphetamine [see data] . the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. clinical considerations fetal/neonatal adverse reactions amphetamines, such as lisdexamfetamine dimesylate, cause vasoconstriction and thereby may decrease placental perfusion. in addition, amphetamines can stimulate uterine contractions increasing the risk of premature delivery. infants born to amphetamine-dependent mothers have an increased risk of premature delivery and low birth weight. monitor infants born to mothers taking amphetamines for symptoms of withdrawal such as feeding difficulties, irritability, agitation, and excessive drowsiness. data animal data lisdexamfetamine dimesylate had no apparent effects on embryo-fetal morphological development or survival when administered orally to pregnant rats and rabbits throughout the period of organogenesis at doses of up to 40 and 120 mg/kg/day, respectively. these doses are approximately 5.5 and 33 times, respectively, the maximum recommended human dose (mrhd) of 70 mg/day given to adults, on a mg/m2 body surface area basis. a study was conducted with amphetamine (d-to l-enantiomer ratio of 3:1) in which pregnant rats received daily oral doses of 2, 6, and 10 mg/kg from gestation day 6 to lactation day 20. all doses caused hyperactivity and decreased weight gain in the dams. a decrease in pup survival was seen at all doses. a decrease in pup body weight was seen at 6 and 10 mg/kg which correlated with delays in developmental landmarks, such as preputial separation and vaginal opening. increased pup locomotor activity was seen at 10 mg/kg on day 22 postpartum but not at 5 weeks postweaning. when pups were tested for reproductive performance at maturation, gestational weight gain, number of implantations, and number of delivered pups were decreased in the group whose mothers had been given 10 mg/kg. a number of studies from the literature in rodents indicate that prenatal or early postnatal exposure to amphetamine (d- or d, l-) at doses similar to those used clinically can result in long term neurochemical and behavioral alterations. reported behavioral effects include learning and memory deficits, altered locomotor activity, and changes in sexual function. risk summary lisdexamfetamine is a pro-drug of dextroamphetamine. based on limited case reports in published literature, amphetamine (d-or d, l-) is present in human milk, at relative infant doses of 2% to 13.8% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.9 and 7.5. there are no reports of adverse effects on the breastfed infant. long-term neurodevelopmental effects on infants from amphetamine exposure are unknown. it is possible that large dosages of dextroamphetamine might interfere with milk production, especially in women whose lactation is not well established. because of the potential for serious adverse reactions in nursing infants, including serious cardiovascular reactions, blood pressure and heart rate increase, suppression of growth, and peripheral vasculopathy, advise patients that breastfeeding is not recommended during treatment with lisdexamfetamine dimesylate. adhd safety and effectiveness of lisdexamfetamine dimesylate have been established in pediatric patients with adhd ages 6 to 17 years [see dosage and administration (2.3), adverse reactions (6.1), clinical pharmacology (12.3), and clinical studies (14.1)] . safety and effectiveness of lisdexamfetamine dimesylate have not been established in pediatric patients below the age of 6 years. safety and efficacy of lisdexamfetamine dimesylate were evaluated in a double-blind, randomized, parallel-group, placebo-controlled, fixed-dose study in pediatric patients ages 4 to 5 years with adhd, followed by a 1-year open-label extension study. in these studies, patients experienced elevated rates of adverse reactions, including weight loss, decreased bmi, decreased appetite, insomnia, infections (upper respiratory and nasopharyngitis), irritability, and affect lability. with the same lisdexamfetamine dimesylate dose, mean steady state exposure of dextroamphetamine was approximately 44% higher in pediatric patients ages 4 to 5 years compared to the pediatric patients ages 6 to 11 years. bed safety and effectiveness of lisdexamfetamine dimesylate have not been established in pediatric patients with bed less than 18 years of age. growth suppression growth should be monitored during treatment with stimulants, including lisdexamfetamine dimesylate, and pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see warnings and precautions (5.5) and adverse reactions (6.1)] . juvenile animal data studies conducted in juvenile rats and dogs at clinically relevant doses showed growth suppression that partially or fully reversed in dogs and female rats but not in male rats after a four-week drug-free recovery period. a study was conducted in which juvenile rats received oral doses of 4, 10, or 40 mg/kg/day of lisdexamfetamine dimesylate from day 7 to day 63 of age. these doses are approximately 0.3, 0.7, and 3 times the maximum recommended human daily dose of 70 mg on a mg/m2 basis for a child. dose-related decreases in food consumption, bodyweight gain, and crown-rump length were seen; after a four-week drug-free recovery period, bodyweights and crown-rump lengths had significantly recovered in females but were still substantially reduced in males. time to vaginal opening was delayed in females at the highest dose, but there were no drug effects on fertility when the animals were mated beginning on day 85 of age. in a study in which juvenile dogs received lisdexamfetamine dimesylate for 6 months beginning at 10 weeks of age, decreased bodyweight gain was seen at all doses tested (2, 5, and 12 mg/kg/day, which are approximately 0.5, 1, and 3 times the maximum recommended human daily dose on a mg/m2 basis for a child). this effect partially or fully reversed during a four-week drug-free recovery period. clinical studies of lisdexamfetamine dimesylate 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 and pharmacokinetic data [see clinical pharmacology (12.3)] have not identified differences in responses between the elderly and younger patients. in general, dose selection for an elderly patient should start 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. due to reduced clearance in patients with severe renal impairment (gfr 15 to < 30 ml/min/1.73 m2 ), the maximum dose should not exceed 50 mg/day. the maximum recommended dose in esrd (gfr < 15 ml/min/1.73 m2 ) patients is 30 mg/day [see clinical pharmacology (12.3)] . lisdexamfetamine and d-amphetamine are not dialyzable. lisdexamfetamine dimesylate capsules contain lisdexamfetamine, a prodrug of amphetamine, a schedule ii controlled substance. lisdexamfetamine dimesylate capsules has a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction [see warnings and precautions (5.1)] . lisdexamfetamine dimesylate capsules can be diverted for non-medical use into illicit channels or distribution. abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. 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 lisdexamfetamine, a prodrug of amphetamine, may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with cns stimulants abuse and/or misuse. misuse and abuse of cns stimulants, including lisdexamfetamine dimesylate capsules, can result in overdose and death [see overdosage (10)] , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. studies of lisdexamfetamine dimesylate capsules in drug abusers a randomized, double-blind, placebo-control, cross-over, abuse liability study in 38 patients with a history of drug abuse was conducted with single-doses of 50, 100, or 150 mg of lisdexamfetamine dimesylate capsules, 40 mg of immediate-release d-amphetamine sulphate (a controlled ii substance), and 200 mg of diethylpropion hydrochloride (a controlled iv substance). lisdexamfetamine dimesylate capsules 100 mg produced significantly less “drug liking effects” as measured by the drug rating questionnaire-subject score, compared to d-amphetamine 40 mg; and 150 mg of lisdexamfetamine dimesylate capsules demonstrated similar “drug-liking effects” compared to 40 mg of d-amphetamine and 200 mg of diethylpropion. intravenous administration of 50 mg lisdexamfetamine dimesylate to individuals with a history of drug abuse produced positive subjective responses on scales measuring “drug liking”, “euphoria”, “amphetamine effects”, and “benzedrine effects” that were greater than placebo but less than those produced by an equivalent dose (20 mg) of intravenous d-amphetamine. physical dependence : lisdexamfetamine dimesylate capsules may produce physical dependence. physical dependence is a state that develops as a result of 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 signs and symptoms after abrupt discontinuation or dose reduction following prolonged use of cns stimulants including lisdexamfetamine dimesylate capsules include dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation. tolerance : lisdexamfetamine dimesylate capsules may produce tolerance. 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).

Ամերիկայի Միացյալ Նահանգներ - անգլերեն - NLM (National Library of Medicine)

hikma pharmaceuticals usa inc. - ciprofloxacin hydrochloride (unii: 4ba73m5e37) (ciprofloxacin - unii:5e8k9i0o4u) - ciprofloxacin 250 mg - ciprofloxacin tablets are indicated in adult patients for treatment of skin and skin structure infections caused by escherichia coli, klebsiella pneumoniae, enterobacter cloacae, proteus mirabilis, proteus vulgaris, providencia stuartii, morganella morganii, citrobacter freundii, pseudomonas aeruginosa, methicillin-susceptible staphylococcus aureus, methicillin-susceptible staphylococcus epidermidis, or streptococcus pyogenes. ciprofloxacin tablets are indicated in adult patients for treatment of bone and joint infections caused by enterobacter cloacae, serratia marcescens, or pseudomonas aeruginosa. ciprofloxacin tablets are indicated in adult patients for treatment of complicated intra-abdominal infections (used in combination with metronidazole) caused by escherichia coli, pseudomonas aeruginosa, proteus mirabilis, klebsiella pneumoniae, or bacteroides fragilis. ciprofloxacin tablets are indicated in adult patients for treatment of infectious diarrhea caused by escherichia coli ( enterotoxigenic isolates), campylobacter jejuni, shigella boydii †, shigella dysenteriae, shigella flexneri or shigella sonnei † when antibacterial therapy is indicated. † although treatment of infections due to this organism in this organ system demonstrated a clinically significant outcome, efficacy was studied in fewer than 10 patients. ciprofloxacin tablets are indicated in adult patients for treatment of typhoid fever (enteric fever) caused by salmonella typhi. the efficacy of ciprofloxacin in the eradication of the chronic typhoid carrier state has not been demonstrated. ciprofloxacin tablets are indicated in adult patients for treatment of uncomplicated cervical and urethral gonorrhea due to neisseria gonorrhoeae [see warnings and precautions (5.17)]. ciprofloxacin tablets are indicated in adults and pediatric patients from birth to 17 years of age for inhalational anthrax (post-exposure) to reduce the incidence or progression of disease following exposure to aerosolized bacillus anthracis. ciprofloxacin serum concentrations achieved in humans served as a surrogate endpoint reasonably likely to predict clinical benefit and provided the initial basis for approval of this indication.1 supportive clinical information for ciprofloxacin for anthrax post-exposure prophylaxis was obtained during the anthrax bioterror attacks of october 2001 [see clinical studies ( 14.2 )]. ciprofloxacin tablets are indicated for treatment of plague, including pneumonic and septicemic plague, due to yersinia pestis (y. pestis) and prophylaxis for plague in adults and pediatric patients from birth to 17 years of age. efficacy studies of ciprofloxacin could not be conducted in humans with plague for feasibility reasons. therefore this indication is based on an efficacy study conducted in animals only [see clinical studies ( 14.3 ) ]. ciprofloxacin tablets are indicated in adult patients for treatment of chronic bacterial prostatitis caused by escherichia coli or proteus mirabilis. ciprofloxacin tablets are indicated in adult patients for treatment of lower respiratory tract infections caused by escherichia coli, klebsiella pneumoniae, enterobacter cloacae, proteus mirabilis, pseudomonas aeruginosa, haemophilus influenzae, haemophilus parainfluenzae, or streptococcus pneumoniae. ciprofloxacin tablets are not a drug of first choice in the treatment of presumed or confirmed pneumonia secondary to streptococcus pneumoniae . ciprofloxacin tablets are indicated for the treatment of acute exacerbations of chronic bronchitis (aecb) caused by moraxella catarrhalis. because fluoroquinolones, including ciprofloxacin tablets, have been associated with serious adverse reactions [see warnings and precautions ( 5.1 – 5.16 )] and for some patients aecb is self-limiting, reserve ciprofloxacin tablets for treatment of aecb in patients who have no alternative treatment options. urinary tract infections in adults ciprofloxacin tablets are indicated in adult patients for treatment of urinary tract infections caused by escherichia coli , klebsiella pneumoniae , enterobacter cloacae , serratia marcescens , proteus mirabilis , providencia rettgeri , morganella morganii , citrobacter koseri , citrobacter freundii , pseudomonas aeruginosa , methicillin-susceptible staphylococcus epidermidis , staphylococcus saprophyticus , or enterococcus faecalis . acute uncomplicated cystitis ciprofloxacin tablets are indicated in adult female patients for treatment of acute uncomplicated cystitis caused by escherichia coli or staphylococcus saprophyticus. because fluoroquinolones, including ciprofloxacin tablets, have been associated with serious adverse reactions [see warnings and precautions (5.1-5.16)] and for some patients acute uncomplicated cystitis is self-limiting, reserve ciprofloxacin tablets for treatment of acute uncomplicated cystitis in patients who have no alternative treatment options. complicated urinary tract infection and pyelonephritis in pediatric patients ciprofloxacin tablets are indicated in pediatric patients aged one to 17 years of age for treatment of complicated urinary tract infections (cuti) and pyelonephritis due to escherichia coli [see use in specific populations (8.4)] . although effective in clinical trials, ciprofloxacin tablets are not a drug of first choice in the pediatric population due to an increased incidence of adverse reactions compared to controls, including reactions related to joints and/or surrounding tissues. ciprofloxacin tablets, like other fluoroquinolones, is associated with arthropathy and histopathological changes in weight-bearing joints of juvenile animals [see warnings and precautions (5.13), adverse reactions (6.1), usein specific populations (8.4) and nonclinical toxicology (13.2)]. ciprofloxacin tablets are indicated in adult patients for treatment of acute sinusitis caused by haemophilus influenzae, streptococcus pneumoniae, or moraxella catarrhalis. because fluoroquinolones, including ciprofloxacin tablets, have been associated with serious adverse reactions [see warnings and precautions ( 5.1 - 5.16 )] and for some patients acute sinusitis is self-limiting, reserve ciprofloxacin tablets for treatment of acute sinusitis in patients who have no alternative treatment options. to reduce the development of drug-resistant bacteria and maintain the effectiveness of ciprofloxacin tablets and other antibacterial drugs, ciprofloxacin tablets 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. if anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be administered. appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing infection and to determine their susceptibility to ciprofloxacin. therapy with ciprofloxacin tablets may be initiated before results of these tests are known; once results become available appropriate therapy should be continued. as with other drugs, some isolates of pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with ciprofloxacin. culture and susceptibility testing performed periodically during therapy will provide information not only on the therapeutic effect of the antimicrobial agent but also on the possible emergence of bacterial resistance.  ciprofloxacin tablets are contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any member of the quinolone class of antibacterials, or any of the product components [see warnings and precautions ( 5.7 ) ]. concomitant administration with tizanidine is contraindicated [see drug interactions ( 7 ) ]. risk summary prolonged experience with ciprofloxacin in pregnant women over several decades, based on available published information from case reports, case control studies and observational studies on ciprofloxacin administered during pregnancy, have not identified any drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes (see data). oral administration of ciprofloxacin during organogenesis at doses up to 100 mg/kg to pregnant mice and rats, and up to 30 mg/kg to pregnant rabbits did not cause fetal malformations (see data). these doses were up to 0.3, 0.6, and 0.4 times the maximum recommended clinical oral dose in mice, rats, and rabbits, respectively, based on body surface area. the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. data human data while available studies cannot definitively establish the absence of risk, published data from prospective observational studies over several decades have not established an association with ciprofloxacin use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes. available studies have methodological limitations including small sample size and some of them are not specific for ciprofloxacin. a controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5% exposed to ciprofloxacin and 68% first trimester exposures) during gestation. in utero exposure to fluoroquinolones during embryogenesis was not associated with increased risk of major malformations. the reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for the control group (background incidence of major malformations is 1–5%). rates of spontaneous abortions, prematurity and low birth weight did not differ between the groups and there were no clinically significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed children. another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93% first trimester exposures). there were 70 ciprofloxacin exposures, all within the first trimester. the malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall were both within background incidence ranges. no specific patterns of congenital abnormalities were found. the study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin. no differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women exposed to ciprofloxacin during pregnancy. however, these small postmarketing epidemiology studies, of which most experience is from short term, first trimester exposure, are insufficient to evaluate the risk for less common defects or to permit reliable and definitive conclusions regarding the safety of ciprofloxacin in pregnant women and their developing fetuses. animal data developmental toxicology studies have been performed with ciprofloxacin in rats, mice, and rabbits. in rats and mice, oral doses up to 100 mg/kg administered during organogenesis (gestation days, gd, 6-17) were not associated with adverse developmental outcomes, including embryofetal toxicity or malformations. in rats and mice, a 100 mg/kg dose is approximately 0.6 and 0.3 times the maximum daily human oral dose (1500 mg/day) based upon body surface area, respectively. in a series of rabbit developmental toxicology studies, does received oral or intravenous ciprofloxacin for one of the following 5 day periods: gd 6 to 10, gd 10 to 14, or gd 14 to 18, intended to cover the period of organogenesis. this was an attempt to mitigate the gastrointestinal intolerance observed in rabbits that receive antibacterials manifested by reduced maternal food consumption and weight loss, that can lead to embryofetal resorption or spontaneous abortion. an oral ciprofloxacin dose of 100 mg/kg (approximately 1.3 times the highest recommended clinical oral dose based on body surface area) caused excessive maternal toxicity confounding evaluation of the fetuses. a 30 mg/kg oral dose (approximately 0.4 times the highest recommended clinical oral dose) was associated with suppression of maternal and fetal body weight gain, but fetal malformations were not observed. intravenous administration of doses up to 20 mg/kg (approximately 0.3 times the highest recommended clinical oral dose based upon body surface area) to pregnant rabbits was not maternally toxic and neither embryofetal toxicity nor fetal malformations were observed. in peri-and post-natal studies, rats received ciprofloxacin doses up to 200 mg/kg/day (oral) or up to 30 mg/kg/day (subcutaneous) from gd 16 to 22 days postpartum. the 200 mg/kg dose is approximately 1.3-times the maximum recommended clinical oral dose based on body surface area. neither maternal toxicity nor adverse effects on growth and development of the pups were observed, including no sign of arthropathy on the rear leg joints of the pups. ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested when administered directly [see warnings and precautions (5.13) and nonclinical toxicology 13.2]. risk summary published literature reports that ciprofloxacin is present in human milk following intravenous and oral administration. there is no information regarding effects of ciprofloxacin tablets on milk production or the breastfed infant. because of the potential risk of serious adverse reactions in breastfed infants, including arthropathy shown in juvenile animal studies [see use in specific populations (8.4),  (clinical considerations)], for most indications a lactating woman may consider pumping and discarding breast milk during treatment with ciprofloxacin tablets and an additional two days (five half-lives) after the last dose. alternatively, advise a woman that breastfeeding is not recommended during treatment with ciprofloxacin tablets and for an additional two days (five half-lives) after the last dose. however, for inhalation anthrax (post exposure), during an incident resulting in exposure to anthrax, the risk-benefit assessment of continuing breastfeeding while the mother (and potentially the infant) is (are) on ciprofloxacin tablets may be acceptable [see dosage and administration (2.2) , pediatric use (8.4), and clinical studies (14.2)] . the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ciprofloxacin tablets and any potential adverse effects on the breastfed child from ciprofloxacin tablets or from the underlying maternal condition. clinical considerations ciprofloxacin may cause intestinal flora alteration of the breastfeeding infant. advise a woman to monitor the breastfed infant for loose or bloody stools and candidiasis (thrush, diaper rash). although effective in clinical trials, ciprofloxacin tablets are not a drug of first choice in the pediatric population due to an increased incidence of adverse reactions compared to controls. quinolones, including ciprofloxacin tablets, cause arthropathy (arthralgia, arthritis), in juvenile animals [see warnings and precautions ( 5.13 )   and nonclinical toxicology ( 13.2 ) ] . complicated urinary tract infection and pyelonephritis ciprofloxacin tablets are indicated for the treatment of cuti and pyelonephritis due to escherichia coli in pediatric patients 1 to 17 years of age. although effective in clinical trials, ciprofloxacin tablets are not a drug of first choice in the pediatric population due to an increased incidence of adverse reactions compared to the controls, including events related to joints and/or surrounding tissues [see adverse reactions (6.1) and clinical studies (14.1)]. inhalational anthrax (post-exposure) ciprofloxacin tablets are indicated in pediatric patients from birth to 17 years of age, for inhalational anthrax (post-exposure). the risk-benefit assessment indicates that administration of ciprofloxacin to pediatric patients is appropriate [see dosage and administration ( 2.2 )  and clinical studies ( 14.2 ) ]. plague ciprofloxacin tablets are indicated in pediatric patients from birth to 17 years of age, for treatment of plague, including pneumonic and septicemic plague due to yersinia pestis (y. pestis) and prophylaxis for plague. efficacy studies of ciprofloxacin tablets could not be conducted in humans with pneumonic plague for feasibility reasons. therefore, approval of this indication was based on an efficacy study conducted in animals. the risk-benefit assessment indicates that administration of ciprofloxacin tablets to pediatric patients is appropriate [s ee indications and usage ( 1.8 ), dosage and administration ( 2.2 ) and clinical studies ( 14.3 ) ] . geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as ciprofloxacin tablets. this risk is further increased in patients receiving concomitant corticosteroid therapy. tendinitis or tendon rupture can involve the achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. caution should be used when prescribing ciprofloxacin tablets to elderly patients especially those on corticosteroids. patients should be informed of this potential adverse reaction and advised to discontinue ciprofloxacin tablets and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur [s ee boxed warning , warnings and precautions ( 5.2 ),  and adverse reactions ( 6.2 ) ] . epidemiologic studies report an increased rate of aortic aneurysm and dissection within two months following use of fluoroquinolones, particularly in elderly patients [see warnings and precautions (5 .9 ) ]. in a retrospective analysis of 23 multiple-dose controlled clinical trials of ciprofloxacin tablets encompassing over 3500 ciprofloxacin-treated patients, 25% of patients were greater than or equal to 65 years of age and 10% were greater than or equal to 75 years of age. no overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals on any drug therapy cannot be ruled out. ciprofloxacin is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. no alteration of dosage is necessary for patients greater than 65 years of age with normal renal function. however, since some older individuals experience reduced renal function by virtue of their advanced age, care should be taken in dose selection for elderly patients, and renal function monitoring may be useful in these patients [s ee dosage and administration ( 2.3 )  a nd clinical pharmacology ( 12.3 ) ] . in general, elderly patients may be more susceptible to drug-associated effects on the qt interval. therefore, precaution should be taken when using ciprofloxacin tablets with concomitant drugs that can result in prolongation of the qt interval (for example, class ia or class iii antiarrhythmics) or in patients with risk factors for torsade de pointes (for example, known qt prolongation, uncorrected hypokalemia) [s ee warnings and precautions ( 5.12 ) ] . ciprofloxacin is eliminated primarily by renal excretion; however, the drug is also metabolized and partially cleared through the biliary system of the liver and through the intestine. these alternative pathways of drug elimination appear to compensate for the reduced renal excretion in patients with renal impairment. nonetheless, some modification of dosage is recommended, particularly for patients with severe renal dysfunction [s ee dosage and administration ( 2.3 )     and cli nical pharmacology ( 12.3 ) ] .   in preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in ciprofloxacin pharmacokinetics have been observed. the pharmacokinetics of ciprofloxacin in patients with acute hepatic insufficiency, have not been studied.

Ամերիկայի Միացյալ Նահանգներ - անգլերեն - 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.

Ամերիկայի Միացյալ Նահանգներ - անգլերեն - 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.

Ամերիկայի Միացյալ Նահանգներ - անգլերեն - NLM (National Library of Medicine)

hikma pharmaceuticals usa inc. - morphine sulfate (unii: x3p646a2j0) (morphine - unii:76i7g6d29c) - morphine sulfate 4 mg in 1 ml - morphine sulfate injection is indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.  limitations of use : because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [see warnings and precautions (5.1)] , reserve morphine sulfate injection for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]: - have not been tolerated, or are not expected to be tolerated, - have not provided adequate analgesia or are not expected to provide adequate analgesia. morphine sulfate injection 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. - significant respiratory depression [see warnings and precautions (5.2)] - acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see warnings and precautions (5.7)] - concurrent use of monoamine oxidase inhibitors (maois) or use of maois within the last 14 days [see warnings and precautions (5.8)]. - known or suspected gastrointestinal obstruction, including paralytic ileus [see warnings and precautions (5.12)] - hypersensitivity to morphine (e.g., anaphylaxis) [see adverse reactions (6)] risk summary use of opioid analgesics for an extended period of time during pregnancy can cause neonatal opioid withdrawal syndrome [see warnings and precautions (5.4)]. there are no available data with morphine sulfate injection in pregnant women to inform a drug-associated risk for major birth defects and miscarriage or adverse maternal outcomes. 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 estimated background risk of major birth defects and miscarriage for the indicated population is unknown. allpregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations   fetal/neonatal adverse reactions use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. the onset, duration, and severity of neonatal withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly [see warnings and precautions (5.4)] . labor or delivery opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. an opioid antagonist, such as naloxone, must be available for reversal of opioid induced respiratory depression in the neonate. morphine sulfate injection 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 morphine sulfate injection, can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. however, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. data human data the results from a population-based prospective cohort, including 70 women exposed to morphine during the first trimester of pregnancy and 448 women exposed to morphine at any time during pregnancy, indicate no increased risk for congenital malformations. however, these studies cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and non- randomized study design. animal data formal reproductive and developmental toxicology studies for morphine have not been conducted. exposure margins for the following published study reports are based on human daily dose of 60 mg morphine using a body surface area comparison (hdd). neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of morphine sulfate (35–322 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 cellloss, alteration of a number of neurotransmitter and neuromodulator systems, including opioid and non- opioid systems, and impairment in various learning and memory tests that appear to persist into adulthood. these studies were conducted with morphine treatment usually in the range of 4 to 20 mg/kg/day (0.7 to 3.2 times the hdd). additionally, delayed sexual maturation and decreased sexual behaviors in female offspring at 20 mg/kg/day (3.2 times the hdd), and decreased plasma and testicular levels of luteinizing hormone and testosterone, decreased testes weights, seminiferous tubule shrinkage, germinal cell aplasia, and decreased spermatogenesis in male offspring were also observed at 20 mg/kg/day (3.2 times the hdd). decreased litter size and viability were observed in the offspring of male rats that were intraperitoneally administered morphine sulfate for 1 day prior to mating at 25 mg/kg/day (4.1 times the hdd) and mated to untreated females. decreased viability and body weight and/or movement deficits in both first and second generation offspring were reported when male mice were treated for 5 days with escalating doses of 120 to 240 mg/kg/day morphine sulfate (9.7 to 19.5 times the hdd) or when female mice treated with escalating doses of 60 to 240 mg/kg/day (4.9 to 19.5 times the hdd) followed by a 5- day treatment-free recovery period prior to mating. similar multigenerational findings were also seen in female rats pre-gestationally treated with escalating doses of 10 to 22 mg/kg/day morphine (1.6 to 3.6 times the hdd). risk summary morphine is present in breast milk. published lactation studies report variable concentrations of morphine in breast milk with administration of immediate-release morphine to nursing mothers in the early postpartum period with a milk-to-plasma morphine auc ratio of 2.5:1 measured in one lactation study. however, there is insufficient information to determine the effects of morphine on the breastfed infant and the effects of morphine on milk production. lactation studies have not been conducted with morphine sulfate injection, and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for morphine sulfate injection, and any potential adverse effects on the breastfed infant from morphine sulfate injection, or from the underlying maternal condition. clinical considerations monitor infants exposed to morphine sulfate injection, 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 clinical pharmacology (12.2)]. in published animal studies, morphine administration adversely effected fertility and reproductive endpoints in male rats and prolonged estrus cycle in female rats [see nonclinical toxicology (13)] . the safety and effectiveness of morphine sulfate injection in pediatric patients below the age of 18 have not been established. the pharmacodynamic effects of morphine in the elderly are more variable than in the younger population. older 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 elderly patients (aged 65 years or older) may have increased sensitivity to morphine. in general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid- tolerant or when opioids were co-administered with other agents that depress respiration. titrate the dosage of morphine sulfate injection slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see warnings and precautions (5.7)] . morphine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. morphine pharmacokinetics have been reported to be significantly altered in patients with cirrhosis. start these patients with a lower than normal dosage of morphine sulfate injection and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension [see clinical pharmacology (12.3)]. morphine pharmacokinetics are altered in patients with renal failure. start these patients with a lower than normal dosage of morphine sulfate injection and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension [see clinical pharmacology (12.3)]. morphine sulfate injection contains morphine., a schedule ii controlled substance. morphine sulfate injection contains morphine, a substance with a 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 to other activities and obligations), and possible tolerance or physical dependence. misuse and abuse of morphine sulfate injection increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. the risk is increased with concurrent abuse of morphine sulfate injection 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 morphine sulfate injection abuse include those with a history of prolonged use of any opioid, including products containing morphine, those with a history of drug or alcohol abuse, or those who use morphine sulfate injection in combination with other abused drugs. “drug-seeking” behavior is very common in persons with substance use disorders. drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. morphine sulfate injection, like other opioids, can be diverted for non-medical use into illicit channels of distribution. careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. risks specific to abuse of morphine sulfate injection abuse of morphine sulfate injection poses a risk of overdose and death. the risk is increased with concurrent use of morphine sulfate injection 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. morphine sulfate injection should not be abruptly discontinued in a physically-dependent patient [see dosage and administration 2.4]. if morphine sulfate injection is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur. some or allof the following can characterize this syndrome: 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)].

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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)] .

Ամերիկայի Միացյալ Նահանգներ - անգլերեն - NLM (National Library of Medicine)

hikma pharmaceuticals usa inc. - levofloxacin (unii: 6gnt3y5lmf) (levofloxacin anhydrous - unii:rix4e89y14) - levofloxacin anhydrous 250 mg in 50 ml - levofloxacin injection is indicated for the treatment of adults (≥ 18 years of age) with mild, moderate, and severe infections caused by susceptible isolates of the designated microorganisms in the conditions listed in this section. levofloxacin injection is indicated when intravenous administration offers a route of administration advantageous to the patient (e.g., patient cannot tolerate an oral dosage form). levofloxacin is indicated for the treatment of nosocomial pneumonia due to methicillin-susceptible staphylococcus aureus , pseudomonas aeruginosa , serratia marcescens , escherichia coli , klebsiella pneumoniae , haemophilus influenzae , or streptococcus pneumoniae . adjunctive therapy should be used as clinically indicated. where pseudomonas aeruginosa is a documented or presumptive pathogen, combination therapy with an anti-pseudomonal β-lactam is recommended [see clinical studies (14.1) ]. levofloxacin is indicated for the treatment of community-acquired pneumonia due to methicillin-susceptible sta

Ամերիկայի Միացյալ Նահանգներ - անգլերեն - NLM (National Library of Medicine)

hikma pharmaceuticals usa inc. - clonidine hydrochloride (unii: w76i6xxf06) (clonidine - unii:mn3l5rmn02) - clonidine hydrochloride 100 ug in 1 ml - clonidine hydrochloride injection, usp is indicated in combination with opiates for the treatment of severe pain in cancer patients that is not adequately relieved by opioid analgesics alone. epidural clonidine is more likely to be effective in patients with neuropathic pain than somatic or visceral pain (see clinical pharmacology: clinical trials). the safety of this drug product has only been established in a highly selected group of cancer patients, and only after an adequate trial of opioid analgesia. other use is of unproven safety and is not recommended. in a rare patient, the potential benefits may outweigh the known risks (see warnings). clonidine hydrochloride injection is contraindicated in patients with a history of sensitization or allergic reactions to clonidine. epidural administration is contraindicated in the presence of an injection site infection, in patients on anticoagulant therapy, and in those with a bleeding diathesis. administration of clonidine hydrochloride injection above the c4 der

Ամերիկայի Միացյալ Նահանգներ - անգլերեն - 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)] .