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civica, inc. - ephedrine sulfate (unii: u6x61u5zeg) (ephedrine - unii:gn83c131xs) - ephedrine sulfate injection is indicated for the treatment of clinically important hypotension occurring in the setting of anesthesia. none risk summary available data from randomized studies, case series, and reports of ephedrine sulfate use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. however, there are clinical considerations due to underlying conditions (see clinical considerations ). in animal reproduction studies, decreased fetal survival and fetal body weights were observed in the presence of maternal toxicity after normotensive pregnant rats were administered 60 mg/kg intravenous ephedrine sulfate (12 times the maximum recommended human dose (mrhd) of 50 mg/day). no malformations or embryofetal adverse effects were observed when pregnant rats or rabbits were treated with intravenous bolus doses of ephedrine sulfate during organogenesis at doses 1.9 and 7.7 times the mrhd, respectively [see data ]. the estimated

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civica inc. - albuterol sulfate (unii: 021sef3731) (albuterol - unii:qf8svz843e) - albuterol sulfate inhalation aerosol is indicated in adults and children 4 years of age and older for the treatment or prevention of bronchospasm with reversible obstructive airway disease and for the prevention of exercise-induced bronchospasm. albuterol sulfate inhalation aerosol is contraindicated in patients with a history of hypersensitivity to albuterol or any other albuterol sulfate inhalation aerosol components.

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civica, inc. - ketamine hydrochloride (unii: o18yuo0i83) (ketamine - unii:690g0d6v8h) - ketamine hydrochloride injection is indicated: • as the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation. • for the induction of anesthesia prior to the administration of other general anesthetic agents. • as a supplement to other anesthetic agents. • ketamine hydrochloride injection is contraindicated in patients for whom a significant elevation of blood pressure would constitute a serious hazard [see warnings and precautions (5.1)] . • ketamine hydrochloride injection is contraindicated in patients with known hypersensitivity to ketamine or to any excipient [see adverse reactions (6)] . risk summary there are no adequate and well-controlled studies of ketamine hydrochloride injection in pregnant women. in animal reproduction studies in rats, developmental delays (hypoplasia of skeletal tissues) were noted at 0.3 times the human intramuscular dose of 10 mg/kg. in rabbits, developmental delays and increased fetal resorptions were noted at 0.6 times the human dose. published studies in pregnant primates demonstrate that the administration of anesthetic and sedation drugs that block nmda receptors and/or potentiate gaba activity during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring when used for longer than 3 hours. there are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans. 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 ketamine hydrochloride injection use in pregnancy, including obstetrics (either vaginal or abdominal delivery), is not recommended because safe use has not been established [see warnings and precautions (5.5), use in specific populations (8.4) and nonclinical toxicology (13.2)] . data animal data pregnant rats were treated intramuscularly with 20 mg/kg ketamine (0.3 times the human dose of 10 mg/kg im based on body surface area) on either gestation days 6 to 10 or gestation days 11 to 15. ketamine treatment produced an increased incidence of hypoplastic skull, phalanges, and sternebrae in the pups. pregnant rabbits were treated intramuscularly with 20 mg/kg ketamine (0.6 times the human dose of 10 mg/kg im based on body surface area) on either gestation days 6 to 10 or gestation days 11 to 15. an increase in resorptions and skeletal hypoplasia of the fetuses were noted. additional pregnant rabbits were treated intramuscularly with a single dose 60 mg/kg (1.9 times the human dose of 10 mg/kg im based on body surface area) on gestation day 6 only. skeletal hypoplasia was reported in the fetuses. in a study where pregnant rats were treated intramuscularly with 20 mg/kg ketamine (0.3 times the human dose of 10 mg/kg im based on body surface area) from gestation day 18 to 21. there was a slight increase in incidence of delayed parturition by one day in treated dams of this group. no adverse effects on the litters or pups were noted; however, learning and memory assessments were not completed. three pregnant beagle dogs were treated intramuscularly with 25 mg/kg ketamine (1.3 times the human dose of 10 mg/kg im based on body surface area) twice weekly for the three weeks of the first, second, and third trimesters of pregnancy, respectively, without the development of adverse effects in the pups. in a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on gestation day 122 increased neuronal apoptosis in the developing brain of the fetus. in other published studies, administration of either isoflurane or propofol for 5 hours on gestation day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring. with respect to brain development, this time period corresponds to the third trimester of gestation in the human. the clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits [see warnings and precautions (5.5), use in specific populations (8.4), and nonclinical toxicology (13.2)] . safety and effectiveness in pediatric patients below the age of 16 have not been established. published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as ketamine hydrochloride injection, that either block nmda receptors or potentiate the activity of gaba during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately 3 years of age in humans. in primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss. data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory. the clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in neonates and young children who require procedures with the potential risks suggested by the nonclinical data [see warnings and precautions (5.5), use in specific populations (8.1), and nonclinical toxicology (13.2)] . clinical studies of ketamine hydrochloride 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. ketamine hydrochloride injection contains ketamine, a schedule iii controlled substance under the controlled substance act. individuals with a history of drug abuse or dependence may be at greater risk for abuse and misuse of ketamine hydrochloride injection. abuse is the intentional, non-therapeutic use of a drug, even once, for its psychological or physiological effects. 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. in a context of drug abuse, ketamine hydrochloride injection may produce a variety of symptoms including anxiety, dysphoria, disorientation, insomnia, flashback, hallucinations, and feelings of floating, detachment and being “spaced out”. recurrent high-dose ketamine misuse or abuse may be associated with memory and/or attention impairment. physical dependence has been reported with prolonged use of ketamine. 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 significant dosage reduction of a drug. withdrawal symptoms have been reported after the discontinuation of frequently used (more than weekly), large doses of ketamine for long periods of time. reported symptoms of withdrawal associated with daily intake of large doses of ketamine include craving, fatigue, poor appetite, and anxiety. tolerance has been reported with prolonged use of ketamine. 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).

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civica, inc. - fentanyl citrate (unii: mun5lyg46h) (fentanyl - unii:uf599785jz) - fentanyl citrate injection is indicated for: - analgesic action of short duration during the anesthetic periods, premedication, induction and maintenance, and in the immediate postoperative period (recovery room) as the need arises. - use as a narcotic analgesic supplement in general or regional anesthesia. - administration with a neuroleptic as an anesthetic premedication, for the induction of anesthesia and as an adjunct in the maintenance of general and regional anesthesia. - use as an anesthetic agent with oxygen in selected high risk patients, such as those undergoing open heart surgery or certain complicated neurological or orthopedic procedures. fentanyl citrate injection is contraindicated in patients with: - hypersensitivity to fentanyl (e.g., anaphylaxis) [see adverse reactions (6)] risk summary prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. available data with fentanyl citrate injection in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. in animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing.  no evidence of malformations was noted in animal studies completed to date [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 prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. the onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly. labor or delivery there are insufficient data to support the use of fentanyl in labor or delivery. therefore, such use is not recommended. 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.  fentanyl citrate injection is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate.  opioid analgesics, including fentanyl citrate injection, 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 fentanyl has been shown to be embryocidal in pregnant rats at doses of 30 mcg/kg intravenously (0.05 times the human dose of 100 mcg/kg on a mg/m2 basis) and 160 mcg/kg subcutaneously (0.26 times the human dose of 100 mcg/kg on a mg/m2 basis).  there was no evidence of teratogenicity reported. no evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered fentanyl continuously via  subcutaneously implanted osmotic minipumps at doses of 10, 100, or 500 mcg/kg/day starting 2-weeks prior to breeding and throughout pregnancy.  the high dose was approximately 0.81 times the human dose of 100 mcg/kg on a mg/m2 basis.  risk summary fentanyl is present in breast milk. one published lactation study reports a relative infant dose of fentanyl of 0.38%. however, there is insufficient information to determine the effects of fentanyl on the breastfed infant and the effects of fentanyl on milk production.  the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for fentanyl citrate injection and any potential adverse effects on the breastfed infant from fentanyl citrate injection or from the underlying maternal condition. clinical considerations monitor infants exposed to fentanyl through breast milk for excess sedation and respiratory depression. withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. infertility chronic use of opioids may cause reduced fertility in females and males of reproductive potential. it is not known whether these effects on fertility are reversible [see adverse reactions (6), clinical pharmacology (12.2), nonclinical toxicology (13.1)] . the safety and efficacy of fentanyl citrate injection in pediatric patients under two years of age has not been established. rare cases of unexplained clinically significant methemoglobinemia have been reported in premature neonates undergoing emergency anesthesia and surgery which included combined use of fentanyl, pancuronium and atropine. a direct cause and effect relationship between the combined use of these drugs and the reported cases of methemoglobinemia has not been established. elderly patients (aged 65 years or older) may have increased sensitivity to fentanyl. 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 fentanyl citrate injection slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see warnings and precautions (5.2)] . fentanyl 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. fentanyl citrate injection should be administered with caution to patients with liver dysfunction because of the extensive hepatic metabolism. reduce the dosage as needed and monitor closely for signs of respiratory depression, sedation, and hypotension. fentanyl citrate injection should be administered with caution to patients with kidney dysfunction because of the renal excretion of fentanyl citrate injection and its metabolites. reduce the dosage as needed and monitor closely for signs of respiratory depression, sedation, and hypotension. fentanyl citrate injection contains fentanyl, a schedule ii controlled drug substance. fentanyl citrate injection contains fentanyl, a substance with a high potential for abuse similar to other opioids including hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. fentanyl citrate injection can be abused and is subject to misuse, addiction, and criminal diversion [see warnings and precautions (5.1)] . prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. fentanyl citrate 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. risks specific to abuse of fentanyl citrate injection abuse of fentanyl citrate injection poses a risk of overdose and death.  the risk is increased with concurrent use of fentanyl citrate injection with alcohol and other central nervous system 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 chronic opioid therapy. tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors).  tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug.  withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

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civica, inc. - ondansetron hydrochloride (unii: nmh84ozk2b) (ondansetron - unii:4af302esos) - ondansetron injection is indicated for the prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including high-dose cisplatin. ondansetron injection is approved for patients aged 6 months and older. ondansetron injection is indicated for the prevention of postoperative nausea and/or vomiting. as with other antiemetics, routine prophylaxis is not recommended for patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively. in patients in whom nausea and/or vomiting must be avoided postoperatively, ondansetron injection is recommended even when the incidence of postoperative nausea and/or vomiting is low. for patients who do not receive prophylactic ondansetron injection and experience nausea and/or vomiting postoperatively, ondansetron injection may be given to prevent further episodes. ondansetron injection is approved for patients aged 1 month and older. ondansetron injection is contraindicated for patients know

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civica - sodium bicarbonate (unii: 8mdf5v39qo) (bicarbonate ion - unii:hn1zra3q20) - sodium bicarbonate injection, usp is indicated in the treatment of metabolic acidosis which may occur in severe renal disease, uncontrolled diabetes, circulatory insufficiency due to shock or severe dehydration, extracorporeal circulation of blood, cardiac arrest and severe primary lactic acidosis. sodium bicarbonate is further indicated in the treatment of certain drug intoxications, including barbiturates (where dissociation of the barbiturate-protein complex is desired), in poisoning by salicylates or methyl alcohol and in hemolytic reactions requiring alkalinization of the urine to diminish nephrotoxicity of hemoglobin and its breakdown products. sodium bicarbonate also is indicated in severe diarrhea which is often accompanied by a significant loss of bicarbonate. treatment of metabolic acidosis should, if possible, be superimposed on measures designed to control the basic cause of the acidosis - e.g., insulin in uncomplicated diabetes, blood volume restoration in shock. but since an appreciable time interval may elapse before all of the ancillary effects are brought about, bicarbonate therapy is indicated to minimize risks inherent to the acidosis itself. vigorous bicarbonate therapy is required in any form of metabolic acidosis where a rapid increase in plasma total co2 content is crucial - e.g., cardiac arrest, circulatory insufficiency due to shock or severe dehydration, and in severe primary lactic acidosis or severe diabetic acidosis. sodium bicarbonate injection, usp is contraindicated in patients who are losing chloride by vomiting or from continuous gastrointestinal suction, and in patients receiving diuretics known to produce a hypochloremic alkalosis.

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civica, inc. - levetiracetam (unii: 44yrr34555) (levetiracetam - unii:44yrr34555) - levetiracetam injection is indicated for the treatment of partial-onset seizures in patients 1 month of age and older. levetiracetam injection is indicated as adjunctive therapy for the treatment of myoclonic seizures in patients 12 years of age and older with juvenile myoclonic epilepsy. levetiracetam injection is indicated as adjunctive therapy for the treatment of primary generalized tonic-clonic seizures in patients 6 years of age and older with idiopathic generalized epilepsy. levetiracetam injection is for intravenous use only as an alternative for patients when oral administration is temporarily not feasible. levetiracetam injection is contraindicated in patients with a hypersensitivity to levetiracetam. reactions have included anaphylaxis and angioedema [see warnings and precautions  (5.3) ] . pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (aeds), including levetiracetam injection, during pregnancy. encourage women who are taking levetiracetam injection during pregnancy to enroll in the north american antiepileptic drug (naaed) pregnancy registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/. risk summary prolonged experience with levetiracetam injection in pregnant women has not identified a drug-associated risk of major birth defects or miscarriage, based on published literature, which includes data from pregnancy registries, and reflects experience over two decades [see human data ] . in animal studies, levetiracetam produced developmental toxicity (increased embryofetal and offspring mortality, increased incidences of fetal structural abnormalities, decreased embryofetal and offspring growth, neurobehavioral alterations in offspring) at doses similar to human therapeutic doses [see animal data ] . 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. the background risk of major birth defects and miscarriage for the indicated population is unknown. clinical considerations levetiracetam blood levels may decrease during pregnancy [see warnings and precautions (5.9) ] . physiological changes during pregnancy may affect levetiracetam concentration. decrease in levetiracetam plasma concentrations has been observed during pregnancy. this decrease is more pronounced during the third trimester. dose adjustments may be necessary to maintain clinical response. data human data while available studies cannot definitively establish the absence of risk, data from the published literature and pregnancy registries have not established an association with levetiracetam use during pregnancy and major birth defects or miscarriage. animal data when levetiracetam (0, 400, 1200, or 3600 mg/kg/day) was administered orally to pregnant rats during the period of organogenesis, reduced fetal weights and increased incidence of fetal skeletal variations were observed at the highest dose tested. there was no evidence of maternal toxicity. the no-effect dose for adverse effects on embryofetal developmental in rats (1200 mg/kg/day) is approximately 4 times the maximum recommended human dose (mrhd) of 3000 mg on a body surface area (mg/m2 ) basis. oral administration of levetiracetam (0, 200, 600, or 1800 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in increased embryofetal mortality and incidence of fetal skeletal variations at the mid and high dose and decreased fetal weights and increased incidence of fetal malformations at the high dose, which was associated with maternal toxicity. the no-effect dose for adverse effects on embryofetal development in rabbits (200 mg/kg/day) is approximately equivalent to the mrhd on a mg/m2 basis. oral administration of levetiracetam (0, 70, 350, or 1800 mg/kg/day) to female rats throughout pregnancy and lactation led to an increased incidence of fetal skeletal variations, reduced fetal body weight, and decreased growth in offspring at the mid and high doses and increased pup mortality and neurobehavioral alterations in offspring at the highest dose tested. there was no evidence of maternal toxicity. the no-effect dose for adverse effects on pre-and postnatal development in rats (70 mg/kg/day) is less than the mrhd on a mg/m2 basis. oral administration of levetiracetam to rats during the latter part of gestation and throughout lactation produced no adverse developmental or maternal effects at doses of up to 1800 mg/kg/day (6 times the mrhd on a mg/m2 basis).   risk summary levetiracetam is excreted in human milk. there are no data on the effects of levetiracetam injection on the breastfed infant, or the effects on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for levetiracetam injection and any potential adverse effects on the breastfed infant from levetiracetam injection or from the underlying maternal condition. the safety and effectiveness of levetiracetam injection for the treatment of partial onset seizures in patients 1 month to 16 years of age have been established [see clinical pharmacology (12.3) and clinical studies (14.1) ] . the dosing recommendation in these pediatric patients varies according to age group and is weight-based [see dosage and administration (2.6) ] . the safety and effectiveness of levetiracetam injection as adjunctive therapy for the treatment of myoclonic seizures in adolescents 12 years of age and older with juvenile myoclonic epilepsy have been established [see clinical studies (14.2) ] . the safety and effectiveness of levetiracetam injection as adjunctive therapy for the treatment of primary generalized tonic-clonic seizures in pediatric patients 6 years of age and older with idiopathic generalized epilepsy have been established [see clinical studies (14.3) ] . safety and effectiveness for the treatment of partial-onset seizures in pediatric patients below the age of 1 month; adjunctive therapy for the treatment of myoclonic seizures in pediatric patients below the age of 12 years; and adjunctive therapy for the treatment of primary generalized tonic-clonic seizures in pediatric patients below the age of 6 years have not been established. a 3-month, randomized, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of levetiracetam injection as adjunctive therapy in 98 (levetiracetam injection n=64, placebo n=34) pediatric patients, ages 4 years to 16 years, with partial seizures that were inadequately controlled. the target dose was 60 mg/kg/day. neurocognitive effects were measured by the leiter-r attention and memory (am) battery, which measures various aspects of a child's memory and attention. although no substantive differences were observed between the placebo and drug treated groups in the median change from baseline in this battery, the study was not adequate to assess formal statistical non-inferiority of the drug and placebo. the achenbach child behavior checklist (cbcl/6-18), a standardized validated tool used to assess a child’s competencies and behavioral/emotional problems, was also assessed in this study. an analysis of the cbcl/6-18 indicated, on average, a worsening in levetiracetam injection-treated patients in aggressive behavior, one of the eight syndrome scores [see warnings and precautions (5.1) ]. juvenile animal toxicity data studies of levetiracetam in juvenile rats (dosed on postnatal days 4 through 52) and dogs (dosed from postnatal weeks 3 through 7) at doses of up to 1800 mg/kg/day (approximately 7 and 24 times, respectively, the maximum recommended pediatric dose of 60 mg/kg/day on a mg/m2 basis) did not demonstrate adverse effects on postnatal development. there were 347 subjects in clinical studies of levetiracetam that were 65 years old and over. no overall differences in safety were observed between these subjects and younger subjects. there were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the effectiveness of levetiracetam injection in these patients. levetiracetam 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 [see clinical pharmacology (12.3) ] . clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance [see clinical pharmacology (12.3) ] . dosage adjustment is recommended for patients with impaired renal function and supplemental doses should be given to patients after dialysis [see dosage and administration ( 2.7 ) ] .

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civica, inc. - rocuronium bromide (unii: i65mw4ofhz) (rocuronium - unii:wre554rfez) - rocuronium bromide injection is indicated for inpatients and outpatients as an adjunct to general anesthesia to facilitate both rapid sequence and routine tracheal intubation, and to provide skeletal muscle relaxation during surgery or mechanical ventilation. rocuronium bromide is contraindicated in patients known to have hypersensitivity (e.g., anaphylaxis) to rocuronium bromide or other neuromuscular blocking agents [see warnings and precautions (5.2)] . developmental toxicology studies have been performed with rocuronium bromide in pregnant, conscious, nonventilated rabbits and rats. inhibition of neuromuscular function was the endpoint for high-dose selection. the maximum tolerated dose served as the high dose and was administered intravenously 3 times a day to rats (0.3 mg/kg, 15%–30% of human intubation dose of 0.6–1.2 mg/kg based on the body surface unit of mg/m2) from day 6 to 17 and to rabbits (0.02 mg/kg, 25% human dose) from day 6 to 18 of pregnancy. high-dose treatment caused acute symptoms of respiratory dysfunction due to the pharmacological activity of the drug. teratogenicity was not observed in these animal species. the incidence of late embryonic death was increased at the high dose in rats, most likely due to oxygen deficiency. therefore, this finding probably has no relevance for humans because immediate mechanical ventilation of the intubated patient will effectively prevent embryo-fetal hypoxia. however, there are no adequate and well-controlled studies in pregnant women. rocuronium bromide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. the use of rocuronium bromide in cesarean section has been studied in a limited number of patients [see clinical studies (14.1)] . rocuronium bromide is not recommended for rapid sequence induction in cesarean section patients. the use of rocuronium bromide has been studied in pediatric patients 3 months to 14 years of age under halothane anesthesia. of the pediatric patients anesthetized with halothane who did not receive atropine for induction, about 80% experienced a transient increase (30% or greater) in heart rate after intubation. one of the 19 infants anesthetized with halothane and fentanyl who received atropine for induction experienced this magnitude of change [see dosage and administration (2.6) and clinical studies (14.3)] . rocuronium bromide was also studied in pediatric patients up to 17 years of age, including neonates, under sevoflurane (induction) and isoflurane/nitrous oxide (maintenance) anesthesia. onset time and clinical duration varied with dose, the age of the patient, and anesthetic technique. the overall analysis of ecg data in pediatric patients indicates that the concomitant use of rocuronium bromide with general anesthetic agents can prolong the qtc interval. the data also suggest that rocuronium bromide may increase heart rate. however, it was not possible to conclusively identify an effect of rocuronium bromide independent of that of anesthesia and other factors. additionally, when examining plasma levels of rocuronium bromide in correlation to qtc interval prolongation, no relationship was observed [see dosage and administration (2.6), warnings and precautions (5.9), and clinical studies (14.3)] . rocuronium bromide is not recommended for rapid sequence intubation in pediatric patients. recommendations for use in pediatric patients are discussed in other sections [see dosage and administration (2.6) and clinical pharmacology (12.2)] . rocuronium bromide was administered to 140 geriatric patients (65 years or greater) in us clinical trials and 128 geriatric patients in european clinical trials. the observed pharmacokinetic profile for geriatric patients (n=20) was similar to that for other adult surgical patients [see clinical pharmacology (12.3)] . onset time and duration of action were slightly longer for geriatric patients (n=43) in clinical trials. clinical experiences and recommendations for use in geriatric patients are discussed in other sections [see dosage and administration (2.6), warnings and precautions (5.5), clinical pharmacology (12.2), and clinical studies (14.2)] . since rocuronium bromide is primarily excreted by the liver, it should be used with caution in patients with clinically significant hepatic impairment. rocuronium bromide 0.6 mg/kg has been studied in a limited number of patients (n=9) with clinically significant hepatic impairment under steady-state isoflurane anesthesia. after rocuronium bromide 0.6 mg/kg, the median (range) clinical duration of 60 (35–166) minutes was moderately prolonged compared to 42 minutes in patients with normal hepatic function. the median recovery time of 53 minutes was also prolonged in patients with cirrhosis compared to 20 minutes in patients with normal hepatic function. four of 8 patients with cirrhosis, who received rocuronium bromide 0.6 mg/kg under opioid/nitrous oxide/oxygen anesthesia, did not achieve complete block. these findings are consistent with the increase in volume of distribution at steady state observed in patients with significant hepatic impairment [see clinical pharmacology (12.3)] . if used for rapid sequence induction in patients with ascites, an increased initial dosage may be necessary to assure complete block. duration will be prolonged in these cases. the use of doses higher than 0.6 mg/kg has not been studied [see dosage and administration (2.6)] . due to the limited role of the kidney in the excretion of rocuronium bromide, usual dosing guidelines should be followed. in patients with renal dysfunction, the duration of neuromuscular blockade was not prolonged; however, there was substantial individual variability (range: 22-90 minutes) [see clinical pharmacology (12.3)] .

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civica, inc. - micafungin sodium (unii: is1up79r56) (micafungin - unii:r10h71bswg) - micafungin for injection is indicated for: - treatment of candidemia, acute disseminated candidiasis, candida peritonitis and abscesses in adult and pediatric patients 4 months of age and older [see clinical studies (14.1) and use in specific populations (8.4)]. - treatment of esophageal candidiasis in adult and pediatric patients 4 months of age and older [see clinical studies (14.2)]. - prophylaxis of candida infections in adult and pediatric patients 4 months of age and older undergoing hematopoietic stem cell transplantation [see clinical studies (14.3)]. limitations of use - micafungin for injection has not been adequately studied in patients with endocarditis, osteomyelitis and meningoencephalitis due to candida . - the efficacy of micafungin for injection against infections caused by fungi other than candida has not been established. additional pediatric use information is approved for astellas pharma us, inc.`s mycamine® (micafungin for injection). however, due to astellas pharma us, inc.`s marketing exclusivity rights, this drug product is not labeled with that information. micafungin for injection is contraindicated in persons with known hypersensitivity to micafungin, any component of micafungin for injection, or other echinocandins. risk summary based on findings from animal studies, micafungin for injection may cause fetal harm when administered to a pregnant woman (see data). there is insufficient human data on the use of micafungin for injection in pregnant women to inform a drug-associated risk of adverse developmental outcomes. in animal reproduction studies, intravenous administration of micafungin sodium to pregnant rabbits during organogenesis at doses four times the maximum recommended human dose resulted in visceral abnormalities and increased abortion (see data) . advise pregnant women of the risk to the fetus. the estimated background risk of major birth defects and miscarriage for the indicated populations 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. data animal data in an embryo-fetal toxicity study in pregnant rabbits, intravenous administration of micafungin sodium during organogenesis (days 6 to 18 of gestation) resulted in fetal visceral abnormalities and abortion at 32 mg/kg, a dose equivalent to four times the recommended human dose based on body surface area comparisons. visceral abnormalities included abnormal lobation of the lung, levocardia, retrocaval ureter, anomalous right subclavian artery, and dilatation of the ureter. risk summary there are no data on the presence of micafungin in human milk, the effects on the breast-fed infant or the effects on milk production. micafungin was present in the milk of lactating rats following intravenous administration. when a drug is present in animal milk, it is likely that the drug will be present in human milk. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for micafungin for injection, and any potential adverse effects on the breast-fed child from micafungin for injection, or from the underlying maternal condition. pediatric patients 4 months of age and older the safety and effectiveness of micafungin for injection for the treatment of esophageal candidiasis, candidemia, acute disseminated candidiasis, candida peritonitis and abscesses, esophageal candidiasis, and for prophylaxis of candida infections in patients undergoing hsct have been established in pediatric patients 4 months of age and older. use of micafungin for injection for these indications and in this age group is supported by evidence from adequate and well-controlled studies in adult and pediatric patients with additional pharmacokinetic and safety data in pediatric patients 4 months of age and older [see indications and usage (1), adverse reactions (6.1), clinical pharmacology (12.3), and clinical studies (14)] . pediatric patients younger than 4 months of age treatment of candidemia, acute disseminated candidiasis, candida peritonitis and abscesses with meningoencephalitis and/or ocular dissemination in pediatric patients younger than 4 months of age the safety and effectiveness of micafungin for injection have not been established for the treatment of candidemia with meningoencephalitis and/or ocular dissemination in pediatric patients younger than 4 months of age. in a rabbit model of hematogenous candida meningoencephalitis (hcme) with candida albicans (minimum inhibitory concentration of 0.125 mcg/ml), a decrease in mean fungal burden in central nervous system (cns) compartments assessed as the average of combined fungal burden in the cerebrum, cerebellum, and spinal cord relative to untreated controls, was observed with increasing micafungin dosages administered once daily for 7 days. in this rabbit model, micafungin concentrations could not be reliably detected in cerebrospinal fluid (csf). due to limitations of the study design, the clinical significance of a decreased cns fungal burden in the rabbit hcme model is uncertain. treatment of esophageal candidiasis and prophylaxis of candida infections in patients undergoing hematopoietic stem cell transplantation in pediatric patients younger than 4 months of age the safety and effectiveness of micafungin for injection in pediatric patients younger than 4 months of age have not been established for the: - treatment of esophageal candidiasis - prophylaxis of candida infections in patients undergoing hematopoietic stem cell transplantation additional pediatric use information is approved for astellas pharma us, inc.`s mycamine® (micafungin for injection). however, due to astellas pharma us, inc.`s marketing exclusivity rights, this drug product is not labeled with that information. a total of 418 subjects in clinical studies of micafungin for injection were 65 years of age and older, and 124 subjects were 75 years of age and older. no overall differences in safety and effectiveness were observed between these subjects and younger subjects. other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. the exposure and disposition of a 50 mg micafungin for injection dose administered as a single 1-hour infusion to 10 healthy subjects aged 66 to 78 years were not significantly different from those in 10 healthy subjects aged 20 to 24 years. no dose adjustment is necessary for the elderly. micafungin for injection does not require dose adjustment in patients with renal impairment. supplementary dosing should not be required following hemodialysis [see clinical pharmacology (12.3)] . dose adjustment of micafungin for injection is not required in patients with mild, moderate, or severe hepatic impairment [see clinical pharmacology (12.3)] . no dose adjustment of micafungin for injection is required based on gender or race. after 14 daily doses of 150 mg to healthy subjects, micafungin auc in women was greater by approximately 23% compared with men, due to smaller body weight. no notable differences among white, black, and hispanic subjects were seen. the micafungin auc was greater by 19% in japanese subjects compared to blacks, due to smaller body weight. there has been no evidence of either psychological or physical dependence or withdrawal or rebound effects with micafungin for injection.

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

civica, inc. - ceftriaxone sodium (unii: 023z5br09k) (ceftriaxone - unii:75j73v1629) - before instituting treatment with ceftriaxone for injection, usp, appropriate specimens should be obtained for isolation of the causative organism and for determination of its susceptibility to the drug. therapy may be instituted prior to obtaining results of susceptibility testing. to reduce the development of drug-resistant bacteria and maintain the effectiveness of ceftriaxone for injection, usp and other antibacterial drugs, ceftriaxone for injection, usp should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. when culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. in the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. ceftriaxone for injection, usp is indicated for the treatment of the following infections when caused by susceptible organisms: lower respiratory tract infections caused by streptococcus pneumoniae, staphylococcus aureus, haemophilus influenzae, haemophilus parainfluenzae, klebsiella pneumoniae, escherichia coli, enterobacter aerogenes, proteus mirabilis or serratia marcescens. acute bacterial otitis media caused by streptococcus pneumoniae, haemophilus influenzae (including beta‑lactamase producing strains) or moraxella catarrhalis (including beta-lactamase producing strains). note: in one study lower clinical cure rates were observed with a single dose of ceftriaxone for injection, usp compared to 10 days of oral therapy. in a second study comparable cure rates were observed between single dose of ceftriaxone for injection, usp and the comparator. the potentially lower clinical cure rate of ceftriaxone for injection, usp should be balanced against the potential advantages of parenteral therapy (see clinical studies ). skin and skin structure infections caused by staphylococcus aureus, staphylococcus epidermidis, streptococcus pyogenes , viridans group streptococci, escherichia coli, enterobacter cloacae, klebsiella oxytoca, klebsiella pneumoniae, proteus mirabilis, morganella morganii1 , pseudomonas aeruginosa, serratia marcescens, acinetobacter calcoaceticus, bacteroides fragilis1 or peptostreptococcus species. urinary tract infections (complicated and uncomplicated) caused by escherichia coli, proteus mirabilis, proteus vulgaris, morganella morganii or klebsiella pneumoniae. uncomplicated gonorrhea (cervical/urethral and rectal) caused by neisseria gonorrhoeae, including both penicillinase- and nonpenicillinase-producing strains, and pharyngeal gonorrhea caused by nonpenicillinase‑producing strains of neisseria gonorrhoeae. pelvic inflammatory disease caused by neisseria gonorrhoeae. ceftriaxone for injection, usp, like other cephalosporins, has no activity against chlamydia trachomatis . therefore, when cephalosporins are used in the treatment of patients with pelvic inflammatory disease and chlamydia trachomatis is one of the suspected pathogens, appropriate antichlamydial coverage should be added. bacterial septicemia caused by staphylococcus aureus, streptococcus pneumoniae, escherichia coli, haemophilus influenzae or klebsiella pneumoniae. bone and joint infections caused by staphylococcus aureus, streptococcus pneumoniae, escherichia coli, proteus mirabilis, klebsiella pneumoniae or enterobacter species. intra-abdominal infections caused by escherichia coli, klebsiella pneumoniae, bacteroides fragilis, clostridium species (note: most strains of clostridium difficile are resistant) or peptostreptococcus species. meningitis caused by haemophilus influenzae, neisseria meningitidis or streptococcus pneumoniae. ceftriaxone for injection, usp has also been used successfully in a limited number of cases of meningitis and shunt infection caused by staphylococcus epidermidis1 and escherichia coli.1 1 efficacy for this organism in this organ system was studied in fewer than ten infections. the preoperative administration of a single 1 gm dose of ceftriaxone for injection, usp may reduce the incidence of postoperative infections in patients undergoing surgical procedures classified as contaminated or potentially contaminated (e.g., vaginal or abdominal hysterectomy or cholecystectomy for chronic calculous cholecystitis in high-risk patients, such as those over 70 years of age, with acute cholecystitis not requiring therapeutic antimicrobials, obstructive jaundice or common duct bile stones) and in surgical patients for whom infection at the operative site would present serious risk (e.g., during coronary artery bypass surgery). although ceftriaxone for injection, usp has been shown to have been as effective as cefazolin in the prevention of infection following coronary artery bypass surgery, no placebo-controlled trials have been conducted to evaluate any cephalosporin antibiotic in the prevention of infection following coronary artery bypass surgery. when administered prior to surgical procedures for which it is indicated, a single 1 gm dose of ceftriaxone for injection, usp provides protection from most infections due to susceptible organisms throughout the course of the procedure. ceftriaxone is contraindicated in patients with known hypersensitivity to ceftriaxone, any of its excipients or to any other cephalosporin. patients with previous hypersensitivity reactions to penicillin and other beta lactam antibacterial agents may be at greater risk of hypersensitivity to ceftriaxone (see warnings – hypersensitivity ). premature neonates: ceftriaxone is contraindicated in premature neonates up to a postmenstrual age of 41 weeks (gestational age + chronological age). hyperbilirubinemic neonates: hyperbilirubinemic neonates should not be treated with ceftriaxone. ceftriaxone can displace bilirubin from its binding to serum albumin, leading to a risk of bilirubin encephalopathy in these patients. ceftriaxone is contraindicated in neonates (≤ 28 days) if they require (or are expected to require) treatment with calcium‑containing iv solutions, including continuous calcium-containing infusions such as parenteral nutrition because of the risk of precipitation of ceftriaxone‑calcium (see clinical pharmacology , warnings and dosage and administration ). cases of fatal outcomes in which a crystalline material was observed in the lungs and kidneys at autopsy have been reported in neonates receiving ceftriaxone and calcium-containing fluids. in some of these cases, the same intravenous infusion line was used for both ceftriaxone and calcium-containing fluids and in some a precipitate was observed in the intravenous infusion line. there have been no similar reports in patients other than neonates. intravenous administration of ceftriaxone solutions containing lidocaine is contraindicated. when lidocaine solution is used as a solvent with ceftriaxone for intramuscular injection, exclude all contraindications to lidocaine. refer to the prescribing information of lidocaine.