澳大利亚 - 英文 - Department of Health (Therapeutic Goods Administration)

inova pharmaceuticals (australia) pty ltd - zinc oxide -

美国 - 英文 - NLM (National Library of Medicine)

sun pharmaceutical industries, inc. - topiramate (unii: 0h73wjj391) (topiramate - unii:0h73wjj391) - topiramate 25 mg - topiramate tablets are indicated as initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients 2 years of age and older. topiramate tablets are indicated as adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-clonic seizures, and seizures associated with lennox-gastaut syndrome in patients 2 years of age and older. topiramate tablets are indicated for the preventive treatment of migraine in patients 12 years of age and older. none. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to topiramate during pregnancy. patients should be encouraged to enroll in the north american antiepileptic drug (naaed) pregnancy registry if they become pregnant. this registry is collecting information about the safety of antiepileptic drugs during pregnancy. to enroll, patients can call the toll-free number 1-888-233-2334. information about the north american drug pregnancy registry can be found at http://www.aedpregnancyregistry.org/. risk summary topiramate can cause fetal harm when administered to a pregnant woman. data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk of major congenital malformations, including but not limited to  cleft lip and/or cleft palate (oral clefts), and of being small for gestational age (sga) [see human data] . sga has been observed at all doses and appears to be dose-dependent. the prevalence of sga is greater in infants of women who received higher doses of topiramate during pregnancy. in addition, the prevalence of sga in infants of women who continued topiramate use until later in pregnancy is higher compared to the prevalence in infants of women who stopped topiramate use before the third trimester.    in multiple animal species, topiramate produced developmental toxicity, including increased incidences of fetal malformations, in the absence of maternal toxicity at clinically relevant doses [see animal data] . all pregnancies have a background risk of birth defects, loss, or other adverse outcomes. the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. in the u.s. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively. clinical considerations fetal/neonatal adverse reactions consider the benefits and risks of topiramate when prescribing this drug to women of childbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death. because of the risk of oral clefts to the fetus, which occur in the first trimester of pregnancy, all women of childbearing potential should be informed of the potential risk to the fetus from exposure to topiramate. women who are planning a pregnancy should be counseled regarding the relative risks and benefits of topiramate use during pregnancy, and alternative therapeutic options should be considered for these patients. labor or delivery although the effect of topiramate on labor and delivery in humans has not been established, the development of topiramate-induced metabolic acidosis in the mother and/or in the fetus might affect the fetus’ ability to tolerate labor. topiramate treatment can cause metabolic acidosis [see warnings and precautions (5.4)]. the effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus’ ability to tolerate labor. pregnant patients should be monitored for metabolic acidosis and treated as in the nonpregnant state [see warnings and precautions (5.4)]. newborns of mothers treated with topiramate should be monitored for metabolic acidosis because of transfer of topiramate to the fetus and possible occurrence of transient metabolic acidosis following birth. based on limited information, topiramate has also been associated with pre-term labor and premature delivery. data human data data from pregnancy registries indicate an increased risk of major congenital malformations, including but not limited to oral clefts in infants exposed to topiramate during the first trimester of pregnancy. other than oral clefts, no specific pattern of major congenital malformations or grouping of major congenital malformation types were observed. in the naaed pregnancy registry, when topiramate-exposed infants with only oral clefts were excluded, the prevalence of major congenital malformations (4.1%) was higher than that in infants exposed to a reference aed (1.8%) or in infants with mothers without epilepsy and without exposure to aeds (1.1%). the prevalence of oral clefts among topiramate-exposed infants  (1.4%) was higher than the prevalence  in infants exposed to a reference aed (0.3%) or the prevalence in infants with mothers without epilepsy and without exposure to aeds(0.11%). it was also higher than the background prevalence in united states (0.17%) as estimated by the centers for disease control and prevention (cdc). the relative risk of oral clefts in topiramate-exposed pregnancies in the naaed pregnancy registry was 12.5 (95% confidence interval [ci]5.9 to 26.37) as compared to the risk in a background population of untreated women. the uk epilepsy and pregnancy register reported a prevalence of oral clefts among infants exposed to topiramate monotherapy (3.2%) that was 16 times higher than the background rate in the uk (0.2%). data from the naaed pregnancy registry and a population-based birth registry cohort indicate that exposure to topiramate in utero is associated with an increased risk of sga newborns (birth weight <10th percentile). in the naaed pregnancy registry, 19.7% of topiramate-exposed newborns were sga compared to 7.9% of newborns exposed to a reference aed and 5.4% of newborns of mothers without epilepsy and without aed exposure. in the medical birth registry of norway (mbrn), a population-based pregnancy registry, 25% of newborns in the topiramate monotherapy exposure group were sga compared to 9 % in the comparison group unexposed to aeds. the long-term consequences of the sga findings are not known. animal data when topiramate (0, 20, 100, or 500 mg/kg/day) was administered to pregnant mice during the period of organogenesis, incidences of fetal malformations (primarily craniofacial defects) were increased at all doses. fetal body weights and skeletal ossification were reduced at the highest dose tested in conjunction with decreased maternal body weight gain. a no-effect dose for embryofetal developmental toxicity in mice was not identified. the lowest dose tested, which was associated with increased malformations, is less than the maximum recommended human dose (mrhd) for epilepsy (400 mg/day) or migraine (100 mg/day) on a body surface area (mg/m2 ) basis. in pregnant rats administered topiramate (0, 20, 100, and 500 mg/kg/day or 0, 0.2, 2.5, 30, and 400 mg/kg/day) orally during the period of organogenesis, the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased in fetuses at 400 and 500 mg/kg/day. embryotoxicity (reduced fetal body weights, increased incidences of structural variations) was observed at doses as low as 20 mg/kg/day. clinical signs of maternal toxicity were seen at 400 mg/kg/day and above, and maternal body weight gain was reduced at doses of 100 mg/kg/day or greater. the no-effect dose (2.5 mg/kg/day) for embryofetal developmental toxicity in rats is less than the mrhd for epilepsy or migraine on a mg/m2 basis. in pregnant rabbits administered topiramate (0, 20, 60, and 180 mg/kg/day or 0, 10, 35, and 120 mg/kg/day) orally during organogenesis, embryofetal mortality was increased at 35 mg/kg/day, and increased incidences of fetal malformations (primarily rib and vertebral malformations) were observed at 120 mg/kg/day. evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35 mg/kg/day and above. the no-effect dose (20 mg/kg/day) for embryofetal developmental toxicity in rabbits is equivalent to the mrhd for epilepsy and approximately 4 times the mrhd for migraine on a mg/m2 basis. when topiramate (0, 0.2, 4, 20, and 100 mg/kg/day or 0, 2, 20, and 200 mg/kg/day) was administered orally to female rats during the latter part of gestation and throughout lactation, offspring exhibited decreased viability and delayed physical development at 200 mg/kg/day and reductions in pre- and/or postweaning body weight gain at 2 mg/kg/day and above. maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/kg/day or greater. in a rat embryofetal development study which included postnatal assessment of offspring, oral administration of topiramate (0, 0.2, 2.5, 30, and 400 mg/kg) to pregnant animals during the period of organogenesis resulted in delayed physical development in offspring at 400 mg/kg/day and persistent reductions in body weight gain in offspring at 30 mg/kg/day and higher. the no-effect dose (0.2 mg/kg/day) for pre- and postnatal developmental toxicity in rats is less than the mrhd for epilepsy or migraine on a mg/m2 basis. risk summary topiramate is excreted in human milk [see data]. the effects of topiramate on milk production are unknown. diarrhea and somnolence have been reported in breastfed infants whose mothers receive topiramate treatment. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for topiramate and any potential adverse effects on the breastfed infant from topiramate or from the underlying maternal condition. data human data limited data from 5 women with epilepsy treated with topiramate during lactation showed drug levels in milk similar to those in maternal plasma. contraception women of childbearing potential who are not planning a pregnancy should use effective contraception because of the risk of major congenital malformations, including oral clefts, and the risk of infants being  sga [see drug interactions (7.4) and use in specific populations 8.1] . adjunctive treatment for epilepsy pediatric patients 2 years of age and older the safety and effectiveness of topiramate as adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with lennox-gastaut syndrome have been established in pediatric patients 2 years of age and older [see adverse reactions (6.1) and clinical studies (14.2)] . pediatric patients below the age of 2 years safety and effectiveness in patients below the age of 2 years have not been established for the adjunctive therapy treatment of partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with lennox-gastaut syndrome. in a single randomized, double-blind, placebo-controlled investigational trial, the efficacy, safety, and tolerability of topiramate oral liquid and sprinkle formulations as an adjunct to concurrent antiepileptic drug therapy in pediatric patients 1 to 24 months of age with refractory partial-onset seizures were assessed. after 20 days of double-blind treatment, topiramate (at fixed doses of 5, 15, and 25 mg/kg/day) did not demonstrate efficacy compared with placebo in controlling seizures. in general, the adverse reaction profile for topiramate in this population was similar to that of older pediatric patients, although results from the above controlled study and an open-label, long-term extension study in these pediatric patients 1 to 24 months old suggested some adverse reactions/toxicities (not previously observed in older pediatric patients and adults; i.e., growth/length retardation, certain clinical laboratory abnormalities, and other adverse reactions/toxicities that occurred with a greater frequency and/or greater severity than had been recognized previously from studies in older pediatric patients or adults for various indications). these very young pediatric patients appeared to experience an increased risk for infections (any topiramate dose 12%, placebo 0%) and  of  respiratory   disorders   (any   topiramate dose 40%, placebo 16%). the following adverse reactions were observed in at least 3% of patients on topiramate and were 3% to 7% more frequent than in patients on placebo: viral infection, bronchitis, pharyngitis, rhinitis, otitis media, upper respiratory infection, cough, and bronchospasm. a generally similar profile was observed in older pediatric patients [see adverse reactions (6)]. topiramate resulted in an increased incidence of patients with increased creatinine (any topiramate dose 5%, placebo 0%), bun (any topiramate dose 3%, placebo 0%), and protein (any topiramate dose 34%, placebo 6%), and an increased incidence of decreased potassium (any topiramate dose 7%, placebo 0%). this increased frequency of abnormal values was not dose-related. creatinine was the only analyte showing a noteworthy increased incidence (topiramate 25 mg/kg/day 5%, placebo 0%) of a markedly abnormal increase. the significance of these findings is uncertain. topiramate treatment also produced a dose-related increase in the percentage of patients who had a shift from normal at baseline to high/increased (above the normal reference range) in total eosinophil count at the end of treatment. the incidence of these abnormal shifts was 6 % for placebo, 10% for 5 mg/kg/day, 9% for 15 mg/kg/day, 14% for 25 mg/kg/day, and 11% for any topiramate dose. there was a mean dose-related increase in alkaline phosphatase. the significance of these findings is uncertain. topiramate produced a dose-related increased incidence of hyperammonemia [see warnings and precautions (5.12)]. treatment with topiramate for up to 1 year was associated with reductions in z scores for length, weight, and head circumference [see warnings and precautions (5.4), adverse reactions (6)]. in open-label, uncontrolled experience, increasing impairment of adaptive behavior was documented in behavioral testing over time in this population. there was a suggestion that this effect was dose-related. however, because of the absence of an appropriate control group, it is not known if this decrement in function was treatment-related or reflects the patient’s underlying disease (e.g., patients who received higher doses may have more severe underlying disease) [see warnings and precautions (5.6) ]. in this open-label, uncontrolled study, the mortality was 37 deaths/1000 patient years. it is not possible to know whether this mortality rate is related to topiramate treatment, because the background mortality rate for a similar, significantly refractory, young pediatric population (1 to 24 months) with partial epilepsy is not known. monotherapy treatment for epilepsy pediatric patients 2 years of age and older   the safety and effectiveness of topiramate as monotherapy for the treatment of  partial-onset seizures or primary generalized tonic-clonic seizures have been established in pediatric patients aged 2 years and older [see adverse reactions (6.1), clinical studies (14.1)] .   a one-year, active-controlled, open-label study with blinded assessments of bone mineral density (bmd) and growth in pediatric patients 4 to 15 years of age, including 63 patients with recent or new onset of epilepsy, was conducted to assess effects of topiramate (n=28, 6 to 15 years of age) versus levetiracetam (n=35, 4 to 15 years of age) monotherapy on bone mineralization and on height and weight, which reflect growth. effects on bone mineralization were evaluated via dual-energy x-ray absorptiometry and blood markers. table 10 summarizes effects of topiramate at 12 months for key safety outcomes including bmd, height, height velocity, and weight. all least square mean values for topiramate  and the comparator were positive. therefore, the least square mean treatment differences shown reflect a topiramate -induced attenuation of the key safety outcomes. statistically significant effects were observed for decreases in bmd (and bone mineral content) in lumbar spine and total body less head and in weight. subgroup analyses according to age demonstrated similar negative effects for all key safety outcomes (i.e., bmd, height, weight).   table 10 summary of topiramate treatment difference results at 12 months for key safety outcomes metabolic acidosis (serum bicarbonate < 20 meq/l) was observed in all topiramate-treated patients at some time in the study [see warnings and precautions (5.4)] . over the whole study, 76% more topiramate-treated patients experienced persistent metabolic acidosis (i.e. 2 consecutive visits with or final serum bicarbonate < 20 meq/l) compared to levetiracetam treated patients. over the whole study, 35% more topiramate-treated patients experienced a markedly abnormally low serum bicarbonate (i.e., absolute value < 17 meq/l and ≥ 5 meq/l decrease from pre-treatment), indicating the frequency of more severe metabolic acidosis, compared to levetiracetam-treated patients. the decrease in bmd at 12 months was correlated with decreased serum bicarbonate, suggesting that metabolic acidosis was at least a partial factor contributing to this adverse effect on bmd. topiramate-treated patients exhibited an increased risk for developing an increased serum creatinine and an increased serum glucose above the normal reference range compared to control patients. pediatric patients below the age of 2 years safety and effectiveness in patients below the age of 2 years have not been established for the monotherapy treatment of epilepsy. preventive treatment of migraine  pediatric patients 12 to 17 years of age safety and  effectiveness  of  topiramate  for the preventive treatment of migraine was studied in 5 double-blind, randomized, placebo-controlled, parallel-group trials in a total of 219 pediatric patients, at doses of 50 to 200 mg/day, or 2 to 3 mg/kg/day. these comprised a fixed dose study in 103 pediatric patients 12 to 17 years of age [see clinical studies (14.3) ], a flexible dose (2 to 3 mg/kg/day), placebo-controlled study in 157 pediatric patients 6 to 16 years of age (including 67 pediatric patients 12 to 16 years of age), and a total of 49 pediatric patients 12 to 17 years of age in 3 studies for the preventive treatment of migraine primarily in adults. open-label extension phases of 3 studies enabled evaluation of long-term safety for up to 6 months after the end of the double-blind phase. efficacy of topiramate for the preventive treatment of migraine in pediatric patients 12 to 17 years of age is demonstrated for a 100 mg daily dose in study 13 [see clinical studies (14.3)] . efficacy of topiramate (2 to 3 mg/kg/day) for the preventive treatment of migraine was not demonstrated in a placebo- controlled trial of 157 pediatric  patients  (6  to  16 years  of  age)  that  included  treatment  of 67 pediatric patients (12 to 16 years of age) for 20 weeks. in the pediatric trials (12 to 17 years of age) in which patients were randomized to placebo or a fixed daily dose of topiramate, the most common adverse reactions with topiramate that were seen at an incidence higher (≥5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain [see adverse reactions (6) ]. the most common cognitive adverse reaction in pooled double-blind studies in pediatric patients 12 to 17 years of age was difficulty with concentration/attention [see warnings and precautions (5.6) ]. markedly abnormally low serum bicarbonate values indicative of metabolic acidosis were reported in topiramate-treated pediatric migraine patients [see warnings and precautions (5.4) ]. in topiramate-treated pediatric patients (12 to 17 years of age) compared to placebo-treated patients, abnormally increased results were more frequent for creatinine, bun, uric acid, chloride, ammonia, total protein, and platelets. abnormally decreased results were observed with topiramate vs placebo treatment for phosphorus and bicarbonate [see adverse reactions   (6.1)]. notable changes (increases and decreases) from baseline in systolic blood pressure, diastolic blood pressure, and pulse were observed occurred more commonly in pediatric patients treated with topiramate compared to pediatric patients treated with placebo [see clinical pharmacology (12.2)] . pediatric patients  below the age of 12 years safety and effectiveness in pediatric patients below the age of 12 years have not been established for the preventive treatment of migraine. in  a  double-blind  study   in   90 pediatric   patients   6   to   11 years   of   age   (including 59 topiramate-treated and 31 placebo patients), the adverse reaction profile was generally similar to that seen in pooled double-blind studies of pediatric patients 12 to 17 years of age. the most common adverse reactions that occurred in topiramate-treated pediatric patients 6 to 11 years of age, and at least twice as frequently than placebo, were gastroenteritis (12% topiramate, 6% placebo), sinusitis (10% topiramate, 3% placebo), weight loss (8% topiramate, 3% placebo) and paresthesia (7% topiramate,  0% placebo).  difficulty with  concentration/attention  occurred  in 3 topiramate-treated patients (5%) and 0 placebo-treated patients. the risk for cognitive adverse reaction was greater in younger patients (6 to 11 years of age) than in older patients (12 to 17 years of age) [see warnings and precautions (5.6)]. juvenile animal studies when topiramate (0, 30, 90, and 300 mg/kg/day) was administered orally to rats during the juvenile period of development (postnatal days 12 to 50), bone growth plate thickness was reduced in males at the highest dose. the no-effect dose (90 mg/kg/day) for adverse developmental effects is approximately 2 times the maximum recommended pediatric dose (9 mg/kg/day) on a body surface area (mg/m2 ) basis. in clinical trials, 3% of patients were over age 60. no age-related differences in effectiveness or adverse effects were evident. however, clinical studies of topiramate did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently than younger subjects. dosage adjustment may be necessary for elderly with age-related renal impairment (creatinine clearance rate <70 ml/min/1.73 m2 ) resulting in reduced clearance [see dosage and administration (2.5), clinical pharmacology (12.3)]. the clearance of topiramate is reduced in patients with moderate (creatinine clearance 30 to 69 ml/min/1.73 m2 ) and severe (creatinine clearance <30 ml/min/1.73 m2 ) renal impairment. a dosage adjustment is recommended in patients with moderate or severe renal impairment [see dosage and administration (2.5), clinical pharmacology (12.3)]. topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than in a normal individual. a dosage adjustment may be required [see dosage and administration (2.6), clinical pharmacology (12.3)].

美国 - 英文 - NLM (National Library of Medicine)

sun pharmaceutical industries, inc. - phenytoin sodium (unii: 4182431bjh) (phenytoin - unii:6158tkw0c5) - phenytoin sodium 200 mg - extended phenytoin sodium capsules are indicated for the treatment of tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures and prevention and treatment of seizures occurring during or following neurosurgery. extended phenytoin sodium capsules are contraindicated in patients with: - a history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins [see warnings and precautions (5.5)] . reactions have included angioedema. -  a history of prior acute hepatotoxicity attributable to phenytoin [see warnings and precautions (5.8)] . - coadministration with delavirdine because of the potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (aeds), such as extended phenytoin sodium capsules, during pregnancy. physicians are advised to recommend that pregn

美国 - 英文 - NLM (National Library of Medicine)

sun pharmaceutical industries, inc. - tramadol hydrochloride (unii: 9n7r477wck) (tramadol - unii:39j1lgj30j) - tramadol hydrochloride 50 mg - tramadol hydrochloride tablets are indicated in adults 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 tramadol hydrochloride tablets 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. tramadol hydrochloride tablets 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. tramadol hydrochloride tablets are contraindicated for: - all children younger than 12 years of age [see warnings and precautions (5.6)]. - postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see warnings and precautions (5.6)] . tramadol hydrochloride tablets are also contraindicated in patients with: - significant respiratory depression [see warnings and precautions (5.2)]. - acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see warnings and precautions (5.12)] . - known or suspected gastrointestinal obstruction, including paralytic ileus [see warnings and precautions (5.16)]. - hypersensitivity to tramadol, any other component of this product or opioids [see warnings and precautions (5.17)]. - concurrent use of monoamine oxidase inhibitors (maois) or use within the last 14 days [see drug interactions (7)]. risk summary use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [ see warnings and precautions (5.4) ]. available data with tramadol hydrochloride tablets in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. in animal reproduction studies, tramadol administration during organogenesis decreased fetal weights and reduced ossification in mice, rats, and rabbits at 1.4, 0.6, and 3.6 times the maximum recommended human daily dosage (mrhd). tramadol decreased pup body weight and increased pup mortality at 1.2 and 1.9 times the mrhd [see data] . based on animal data, advise pregnant women of the potential risk to a fetus. the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, 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 respiratory depression and physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. neonatal opioid withdrawal syndrome can present as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. the onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. observe newborns for symptoms and signs of neonatal opioid withdrawal syndrome and manage accordingly [see warnings and precautions (5.4)] . neonatal seizures, neonatal withdrawal syndrome, fetal death and still birth have been reported during postmarketing. labor or delivery opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. an opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. tramadol hydrochloride tablets are not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. opioid analgesics, including tramadol hydrochloride tablets, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. however, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. tramadol has been shown to cross the placenta. the mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labor. the effect of tramadol hydrochloride tablets, if any, on the later growth, development, and functional maturation of the child is unknown. data animal data tramadol has been shown to be embryotoxic and fetotoxic in mice, (120 mg/kg), rats (25 mg/kg) and rabbits (75 mg/kg) at maternally toxic dosages, but was not teratogenic at these dose levels. these doses on a mg/m 2 basis are 1.4, 0.6, and 3.6 times the maximum recommended human daily dosage (mrhd) for mouse, rat and rabbit, respectively. no drug-related teratogenic effects were observed in progeny of mice (up to 140 mg/kg), rats (up to 80 mg/kg) or rabbits (up to 300 mg/kg) treated with tramadol by various routes. embryo and fetal toxicity consisted primarily of decreased fetal weights, decreased skeletal ossification and increased supernumerary ribs at maternally toxic dose levels. transient delays in developmental or behavioral parameters were also seen in pups from rat dams allowed to deliver. embryo and fetal lethality were reported only in one rabbit study at 300 mg/kg, a dose that would cause extreme maternal toxicity in the rabbit. the dosages listed for mouse, rat and rabbit are 1.7, 1.9 and 14.6 times the mrhd, respectively. tramadol was evaluated in pre- and post-natal studies in rats. progeny of dams receiving oral (gavage) dose levels of 50 mg/kg 1.2 times the mrhd) or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (1.9 times the mrhd). risk summary tramadol hydrochloride tablets are not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied. tramadol and its metabolite, o-desmethyltramadol (m1), are present in human milk. there is no information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. the m1 metabolite is more potent than tramadol in mu opioid receptor binding [ see clinical pharmacology (12)] . published studies have reported tramadol and m1 in colostrum with administration of tramadol to nursing mothers in the early post-partum period. women who are ultra-rapid metabolizers of tramadol may have higher than expected serum levels of m1, potentially leading to higher levels of m1 in breast milk that can be dangerous in their breastfed infants. in women with normal tramadol metabolism, the amount of tramadol secreted into human milk is low and dose-dependent. because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with tramadol hydrochloride tablets [ see warnings and precautions (5.6)] . clinical considerations if infants are exposed to tramadol hydrochloride tablets through breast milk, they should be monitored for excess sedation and respiratory depression. withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. data following a single iv 100 mg dose of tramadol, the cumulative excretion in breast milk within 16 hours post dose was 100 mcg of tramadol (0.1% of the maternal dose) and 27 mcg of m1. infertility use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. it is not known whether these effects on fertility are reversible [see adverse reactions (6.2)] . the safety and effectiveness of tramadol hydrochloride tablets in pediatric patients have not been established. life-threatening respiratory depression and death have occurred in children who received tramadol [see warnings and precautions (5.6)] . in some of the reported cases, these events followed tonsillectomy and/or adenoidectomy, and one of the children had evidence of being an ultra-rapid metabolizer of tramadol (i.e., multiple copies of the gene for cytochrome p450 isoenzyme 2d6). children with sleep apnea may be particularly sensitive to the respiratory depressant effects of tramadol. because of the risk of life-threatening respiratory depression and death: - tramadol hydrochloride tablets are contraindicated for all children younger than 12 years of age [see contraindications (4)] . - tramadol hydrochloride tablets are contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see contraindications (4)]. avoid the use of tramadol hydrochloride tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol unless the benefits outweigh the risks. risk factors include conditions associated with hypoventilation such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression. a total of 455 elderly (65 years of age or older) subjects were exposed to tramadol hydrochloride tablets in controlled clinical trials. of those, 145 subjects were 75 years of age and older. in studies including geriatric patients, treatment-limiting adverse events were higher in subjects over 75 years of age compared to those under 65 years of age. specifically, 30% of those over 75 years of age had gastrointestinal treatment-limiting adverse events compared to 17% of those under 65 years of age. constipation resulted in discontinuation of treatment in 10% of those over 75. respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. titrate the dosage of tramadol hydrochloride tablets slowly in geriatric patients starting at the low end of the dosing range and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see warnings and precautions (5.12)] . tramadol is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function. impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, m1. in patients with creatinine clearances of less than 30 ml/min, dosing reduction is recommended [see dosage and administration ( 2.3)] . metabolism of tramadol and m1 is reduced in patients with severe hepatic impairment based on a study in patients with advanced cirrhosis of the liver. in patients with severe hepatic impairment, dosing reduction is recommended [see dosage and administratio n (2.3)] . with the prolonged half-life in these conditions, achievement of steady-state is delayed, so that it may take several days for elevated plasma concentrations to develop. tramadol hydrochloride tablets contain tramadol, a schedule iv controlled substance. tramadol hydrochloride tablets contain tramadol, a substance with 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 health care provider or for whom it was not prescribed. abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. misuse and abuse of tramadol hydrochloride tablets increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. the risk is increased with concurrent abuse of tramadol hydrochloride tablets with alcohol and other cns depressants. abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. in addition, abuse of opioids can occur in the absence of addiction. all patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. patients at high risk of tramadol hydrochloride tablets abuse include those with a history of prolonged use of any opioid, including products containing tramadol, those with a history of drug or alcohol abuse, or those who use tramadol hydrochloride tablets in combination with other abused drugs. “drug-seeking” behavior is very common in persons with substance use disorders. drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. tramadol hydrochloride tablets, like other opioids, can be diverted for non-medical use into illicit channels of distribution. careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. risks specific to abuse of tramadol hydrochloride tablets abuse of tramadol hydrochloride tablets poses a risk of overdose and death. the risk is increased with concurrent use of tramadol hydrochloride tablets with alcohol and/or other cns depressants. tramadol hydrochloride tablets are approved for oral use only. 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 tramadol hydrochloride tablets in a patient physically dependent on opioids. rapid tapering of tramadol hydrochloride tablets in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. when discontinuing tramadol hydrochloride tablets, gradually taper the dosage using a patient-specific plan that considers the following: the dose of tramadol hydrochloride tablets the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. to improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. in patients taking opioids for 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), and 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)].

美国 - 英文 - NLM (National Library of Medicine)

sun pharmaceutical industries, inc. - phenytoin sodium (unii: 4182431bjh) (phenytoin - unii:6158tkw0c5) - phenytoin sodium 100 mg - extended phenytoin sodium capsules, usp are indicated for the treatment of tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures and prevention and treatment of seizures occurring during or following neurosurgery. extended phenytoin sodium capsules are contraindicated in patients with: - a history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins [see warnings and precautions (5.5)] . reactions have included angioedema. - a history of prior acute hepatotoxicity attributable to phenytoin [see warnings and precautions (5.8)]. - coadministration with delavirdine because of the potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (aeds), such as extended phenytoin sodium capsules, during pregnancy. physicians are advised to recommend that pregnant patients taking extended phenytoin sodium capsules enroll in the north american antiepileptic drug (naaed) pregnancy registry. this can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. information on the registry can also be found at the website http://www.aedpregnancyregistry.org/ risk summary in humans, prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. prenatal phenytoin exposure is associated with an increased incidence of major malformations, including orofacial clefts and cardiac defects. in addition, the fetal hydantoin syndrome, a pattern of abnormalities including dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits has been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy [see data] . there have been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. administration of phenytoin to pregnant animals resulted in an increased incidence of fetal malformations and other manifestations of developmental toxicity (including embryofetal death, growth impairment, and behavioral abnormalities) in multiple species at clinically relevant doses [see data]. in the u.s. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. the background risk of major birth defects and miscarriage for the indicated population is unknown. clinical considerations disease-associated maternal risk an increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. periodic measurement of serum phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage [see dosage and administration (2.3, 2.7)] . however, postpartum restoration of the original dosage will probably be indicated [see clinical pharmacology (12.3)]. fetal/neonatal adverse reactions a potentially life-threatening bleeding disorder related to decreased levels of vitamin k-dependent clotting factors may occur in newborns exposed to phenytoin in utero . this drug-induced condition can be prevented with vitamin k administration to the mother before delivery and to the neonate after birth. data human data meta-analyses using data from published observational studies and registries have estimated an approximately 2.4-fold increased risk for any major malformation in children with prenatal phenytoin exposure compared to controls. an increased risk of heart defects, facial clefts, and digital hypoplasia has been reported. the fetal hydantoin syndrome is a pattern of congenital anomalies including craniofacial anomalies, nail and digital hypoplasia, prenatal-onset growth deficiency, and neurodevelopmental deficiencies. animal data administration of phenytoin to pregnant rats, rabbits, and mice during organogenesis resulted in embryofetal death, fetal malformations, and decreased fetal growth. malformations (including craniofacial, cardiovascular, neural, limb, and digit abnormalities) were observed in rats, rabbits, and mice at doses as low as 100 mg/kg, 75 mg/kg, and 12.5 mg/kg, respectively. risk summary phenytoin is secreted in human milk. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for extended phenytoin sodium capsules and any potential adverse effects on the breastfed infant from extended phenytoin sodium capsules or from the underlying maternal condition. initially, 5 mg/kg/day in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily. a recommended daily maintenance dosage is usually 4 mg/kg to 8 mg/kg. children over 6 years and adolescents may require the minimum adult dosage (300 mg/day) [see dosage and administration (2.2)] . phenytoin clearance tends to decrease with increasing age [see clinical pharmacology (12.3)] . lower or less frequent dosing may be required [see dosage and administration (2.6)] . the liver is the chief site of biotransformation of phenytoin; patients with impaired liver function, elderly patients, or those who are gravely ill may show early signs of toxicity. because the fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients. patients who are intermediate or poor metabolizers of cyp2c9 substrates (e.g., *1/*3, *2/*2, *3/*3) may exhibit increased phenytoin serum concentrations compared to patients who are normal metabolizers (e.g., *1/*1). thus, patients who are known to be intermediate or poor metabolizers may ultimately require lower doses of phenytoin to maintain similar steady-state concentrations compared to normal metabolizers. if early signs of dose-related central nervous system (cns) toxicity develop, serum concentrations should be checked immediately [see clinical pharmacology (12.5)].

美国 - 英文 - NLM (National Library of Medicine)

sun pharmaceutical industries, inc. - methadone hydrochloride (unii: 229809935b) (methadone - unii:uc6vbe7v1z) - methadone hydrochloride tablets are indicated for the: limitations of use methadone products used for the treatment of opioid addiction in detoxification or maintenance programs are subject to the conditions for distribution and use required under 42 cfr 8.12 [see dosage and administration (2.1)] . methadone hydrochloride tablets are contraindicated in patients with: risk summary neonatal opioid withdrawal syndrome (nows) is an expected and treatable outcome of prolonged use of opioids during pregnancy [see warnings and precautions (5.4)]. pregnant women in methadone maintenance programs may have reduced incidence of obstetric and fetal complications and neonatal morbidity and mortality when compared to women using illicit drugs. untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes and risk of continued or relapsing illicit opioid use. these risks should be considered in women treated with methadone hydrochloride tablets for maintenance treatment of opioid addiction. for wom

美国 - 英文 - NLM (National Library of Medicine)

sun pharmaceutical industries, inc. - sumatriptan succinate (unii: j8bdz68989) (sumatriptan - unii:8r78f6l9vo), naproxen sodium (unii: 9tn87s3a3c) (naproxen - unii:57y76r9atq) - sumatriptan and naproxen sodium tablets are indicated for the acute treatment of migraine with or without aura in adults and pediatric patients 12 years of age and older. limitations of use: - use only if a clear diagnosis of migraine headache has been established. if a patient has no response to the first migraine attack treated with sumatriptan and naproxen sodium tablets, reconsider the diagnosis of migraine before sumatriptan and naproxen sodium tablets are administered to treat any subsequent attacks. - sumatriptan and naproxen sodium tablets are not indicated for the prevention of migraine attacks. - safety and effectiveness of sumatriptan and naproxen sodium tablets have not been established for cluster headache. sumatriptan and naproxen sodium tablets are contraindicated in the following patients: - ischemic coronary artery disease (cad) (angina pectoris, history of myocardial infarction, or documented silent ischemia) or coronary artery vasospasm, including prinzmetal’s angina [see warnings and precautions (5.1)]. - in the setting of coronary artery bypass graft (cabg) surgery [see warnings and precautions (5.1)] . - wolff-parkinson-white syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders [see warnings and precautions (5.3)]. - history of stroke or transient ischemic attack (tia) or history of hemiplegic or basilar migraine because these patients are at a higher risk of stroke [see warnings and precautions (5.5)]. - peripheral vascular disease [see warnings and precautions (5.6)]. - ischemic bowel disease [see warnings and precautions (5.6)]. - uncontrolled hypertension [see warnings and precautions (5.8)]. - recent use (i.e., within 24 hours) of ergotamine-containing medication, ergot-type medication (such as dihydroergotamine or methysergide), or another 5-hydroxytryptamine1 (5-ht1) agonist [see drug interactions (7)]. - concurrent administration of a monoamine oxidase (mao)-a inhibitor or recent (within 2 weeks) use of an mao-a inhibitor [see drug interactions (7), clinical pharmacology (12.3)]. - history of asthma, urticaria, or allergic-type reactions after taking aspirin or other nsaids. severe, sometimes fatal, anaphylactic reactions to nsaids have been reported in such patients [see warnings and precautions (5.13, 5.14, 5.18)]. - known hypersensitivity (e.g., anaphylactic reactions, angioedema, and serious skin reactions) to sumatriptan, naproxen, or any components of sumatriptan and naproxen sodium tablets [see warnings and precautions (5.14)]. - severe hepatic impairment [see warnings and precautions (5.7), use in specific populations (8.7), clinical pharmacology (12.3)]. risk summary use of nsaids, including sumatriptan and naproxen sodium tablets, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. because of these risks, limit dose and duration of sumatriptan and naproxen sodium tablets use between about 20 and 30 weeks of gestation, and avoid sumatriptan and naproxen sodium tablets use at about 30 weeks of gestation and later in pregnancy (see clinical considerations, data ). premature closure of fetal ductus arteriosus use of nsaids, including sumatriptan and naproxen sodium tablets, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. oligohydramnios/neonatal renal impairment use of nsaids at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. data from observational studies regarding other potential embryofetal risks of nsaid use in women in the first or second trimesters of pregnancy are inconclusive. data from a prospective pregnancy exposure registry and epidemiological studies of pregnant women have not detected an increased frequency of birth defects or a consistent pattern of birth defects among women exposed to sumatriptan compared with the general population (see human data ). in animal studies, administration of sumatriptan and naproxen, alone or in combination, during pregnancy resulted in developmental toxicity (increased incidences of fetal malformations, embryofetal and pup mortality, decreased embryofetal growth) at clinically relevant doses (see animal data ). based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. in animal studies, administration of prostaglandin synthesis inhibitors such as naproxen sodium resulted in increased pre- and post-implantation loss. prostaglandins also have been shown to have an important role in fetal kidney development. in published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. all pregnancies have a background risk of birth defects, 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. the reported rate of major birth defects among deliveries to women with migraine ranged from 2.2% to 2.9% and the reported rate of miscarriage was 17%, which were similar to rates reported in women without migraine. clinical considerations disease-associated maternal and/or embryo/fetal risk several studies have suggested that women with migraine may be at increased risk of preeclampsia and gestational hypertension during pregnancy. fetal/neonatal adverse reactions premature closure of fetal ductus arteriosus: avoid use of nsaids in women at about 30 weeks gestation and later in pregnancy, because nsaids, including sumatriptan and naproxen sodium tablets, can cause premature closure of the fetal ductus arteriosus (see data ). oligohydramnios/neonatal renal impairment: if an nsaid is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. if sumatriptan and naproxen sodium tablets treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. if oligohydramnios occurs, discontinue sumatriptan and naproxen sodium tablets and follow up according to clinical practice (see data ). labor or delivery there are no studies on the effects of naproxen tablets during labor or delivery. in animal studies, nsaids, including naproxen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. data human data there is some evidence to suggest that when inhibitors of prostaglandin synthesis are used to delay preterm labor, there is an increased risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus, and intracranial hemorrhage. naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction, and abnormal prostaglandin e levels in preterm infants. the sumatriptan/naratriptan/sumatriptan and naproxen sodium tablets (sumatriptan and naproxen sodium) pregnancy registry, a population-based international prospective study, collected data for sumatriptan from january 1996 to september 2012. the registry included only 6 pregnancy exposures to sumatriptan and naproxen sodium tablets, with no major birth defects reported. the registry documented outcomes of 626 infants and fetuses exposed to sumatriptan during pregnancy (528 with earliest exposure during the first trimester, 78 during the second trimester, 16 during the third trimester, and 4 unknown). the occurrence of major birth defects (excluding fetal deaths and induced abortions without reported defects and all spontaneous pregnancy losses) during first-trimester exposure to sumatriptan was 4.2% (20/478 [95% ci: 2.6% to 6.5%]) and during any trimester of exposure was 4.2% (24/576 [95% ci: 2.7% to 6.2%]). the sample size in this study had 80% power to detect at least a 1.73- to 1.91-fold increase in the rate of major malformations. the number of exposed pregnancy outcomes accumulated during the registry was insufficient to support definitive conclusions about overall malformation risk or to support making comparisons of the frequencies of specific birth defects. of the 20 infants with reported birth defects after exposure to sumatriptan in the first trimester, 4 infants had ventricular septal defects, including one infant who was exposed to both sumatriptan and naratriptan, and 3 infants had pyloric stenosis. no other birth defect was reported for more than 2 infants in this group. in a study using data from the swedish medical birth register, live births to women who reported using triptans or ergots during pregnancy were compared with those of women who did not. of the 2,257 births with first-trimester exposure to sumatriptan, 107 infants were born with malformations (relative risk 0.99 [95% ci: 0.91 to 1.21]). a study using linked data from the medical birth registry of norway to the norwegian prescription database compared pregnancy outcomes in women who redeemed prescriptions for triptans during pregnancy, as well as a migraine disease comparison group who redeemed prescriptions for sumatriptan before pregnancy only, compared with a population control group. of the 415 women who redeemed prescriptions for sumatriptan during the first trimester, 15 had infants with major congenital malformations (or 1.16 [95% ci: 0.69 to 1.94]) while for the 364 women who redeemed prescriptions for sumatriptan before, but not during, pregnancy, 20 had infants with major congenital malformations (or 1.83 [95% ci: 1.17 to 2.88]), each compared with the population comparison group. additional smaller observational studies evaluating use of sumatriptan during pregnancy have not suggested an increased risk of teratogenicity. premature closure of fetal ductus arteriosus: published literature reports that the use of nsaids at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. oligohydramnios/neonatal renal impairment: published studies and postmarketing reports describe maternal nsaid use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. these adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after nsaid initiation. in many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. there have been a limited number of case reports of maternal nsaid use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. these limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal nsaid use. because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to nsaids through maternal use is uncertain. animal data oral administration of sumatriptan alone to pregnant rats during the period of organogenesis resulted in an increased incidence of fetal blood vessel (cervicothoracic and umbilical) abnormalities. the highest no-effect dose for embryofetal developmental toxicity in rats was 60 mg/kg/day, or approximately 3 times the maximum recommended human dose (mrhd) of 170 mg/day on a mg/m2 basis. oral administration of sumatriptan alone to pregnant rabbits during the period of organogenesis resulted in increased incidences of embryolethality and fetal cervicothoracic vascular and skeletal abnormalities. intravenous administration of sumatriptan to pregnant rabbits during the period of organogenesis resulted in an increased incidence of embryolethality. the highest oral and intravenous no-effect doses for developmental toxicity in rabbits were 15 (approximately 2 times the mrhd on a mg/m2 basis) and 0.75 mg/kg/day, respectively. oral administration of sumatriptan combined with naproxen sodium (5/9 mg/kg/day, 25/45 mg/kg/day, or 50/90 mg/kg/day sumatriptan/naproxen sodium) or each drug alone (50/0 mg/kg/day, 0/90 mg/kg/day sumatriptan/naproxen sodium) to pregnant rabbits during the period of organogenesis resulted in increased total incidences of fetal abnormalities at all doses and increased incidences of specific malformations (cardiac interventricular septal defect in the 50/90 mg/kg/day group, fused caudal vertebrae in the 50/0 mg/kg/day and 0/90 mg/kg/day groups) and variations (absent intermediate lobe of the lung, irregular ossification of the skull, incompletely ossified sternal centra) at the highest dose of sumatriptan and naproxen alone and in combination. a no-effect dose for developmental toxicity in rabbit was not established. the lowest effect dose of 5/9 mg/kg/day sumatriptan/naproxen sodium was associated with plasma exposures (auc) to sumatriptan and naproxen that were less than those attained at the mrhd of 170 mg sumatriptan and 1,000 mg naproxen sodium (two tablets of sumatriptan and naproxen sodium tablets 85/500 mg in a 24-hour period). oral administration of sumatriptan alone to rats prior to and throughout gestation resulted in embryofetal toxicity (decreased body weight, decreased ossification, increased incidence of skeletal abnormalities). the highest no-effect dose was 50 mg/kg/day, or approximately 3 times the mrhd on a mg/m2 basis. in offspring of pregnant rats treated orally with sumatriptan during organogenesis, there was a decrease in pup survival. the highest no-effect dose for this effect was 60 mg/kg/day, or approximately 3 times the mrhd on a mg/m2 basis. oral treatment of pregnant rats with sumatriptan during the latter part of gestation and throughout lactation resulted in a decrease in pup survival. the highest no-effect dose for this finding was 100 mg/kg/day, or approximately 6 times the mrhd on a mg/m2 basis. in reproduction studies of naproxen in rats (20 mg/kg/day), rabbits (20 mg/kg/day, and mice (170 mg/kg/day, no evidence of impaired fertility or harm to the fetus was observed. the doses tested in rats, rabbits, and mice were less (≤0.8 times) the mrhd, based on body surface area (mg/m2 ) comparisons. risk summary the naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma. sumatriptan is excreted in human milk following subcutaneous administration (see data ). there is no information regarding sumatriptan concentrations in milk from lactating women following administration of sumatriptan tablets. there are no data on the effects of naproxen or sumatriptan on the breastfed infant or the effects of naproxen or sumatriptan on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for sumatriptan and naproxen sodium tablets and any potential adverse effects on the breastfed infant from sumatriptan and naproxen sodium tablets or from the underlying maternal condition. clinical considerations infant exposure to sumatriptan can be minimized by avoiding breastfeeding for 12 hours after treatment with sumatriptan tablets. data following subcutaneous administration of a 6-mg dose of sumatriptan injection in 5 lactating volunteers, sumatriptan was present in milk. infertility females based on the mechanism of action, the use of prostaglandin-mediated nsaids, including naproxen tablets, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. small studies in women treated with nsaids have also shown a reversible delay in ovulation. consider withdrawal of nsaids, including naproxen tablets, in women who have difficulties conceiving or who are undergoing investigation of infertility. safety and effectiveness of sumatriptan and naproxen sodium tablets in pediatric patients under 12 years of age have not been established. the safety and efficacy of sumatriptan and naproxen sodium tablets for the acute treatment of migraine in pediatric patients 12 to 17 years of age was established in a double-blind, placebo-controlled trial [see adverse reactions (6.1) and clinical studies (14.2)] . elderly patients, compared to younger patients, are at greater risk for nsaid-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. sumatriptan and naproxen sodium tablets are not recommended for use in elderly patients who have decreased renal function, higher risk for unrecognized cad, and increases in blood pressure that may be more pronounced in the elderly [see warnings and precautions (5.1, 5.2, 5.3, 5.8,5.12) and clinical pharmacology (12.3)] . a cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of cad) prior to receiving sumatriptan and naproxen sodium tablets [see warnings and precautions (5.1)] . sumatriptan and naproxen sodium tablets are not recommended for use in patients with creatinine clearance less than 30 ml/min. monitor the serum creatinine or creatinine clearance in patients with mild (crcl = 60 to 89 ml/min) or moderate (crcl = 30 to 59 ml/min) renal impairment, preexisting kidney disease, or dehydration [see warnings and precautions (5.12)and clinical pharmacology (12.3)] . sumatriptan and naproxen sodium tablets are contraindicated in patients with severe hepatic impairment.

美国 - 英文 - NLM (National Library of Medicine)

sun pharmaceutical industries, inc. - ambrisentan (unii: hw6nv07qec) (ambrisentan - unii:hw6nv07qec) - ambrisentan is indicated for the treatment of pulmonary arterial hypertension (pah) (who group 1): • to improve exercise ability and delay clinical worsening. studies establishing effectiveness included predominantly patients with who functional class ii–iii symptoms and etiologies of idiopathic or heritable pah (60%) or pah associated with connective tissue diseases (34%). ambrisentan may cause fetal harm when administered to a pregnant female. ambrisentan is contraindicated in females who are pregnant. ambrisentan was consistently shown to have teratogenic effects when administered to animals. if this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see warnings and precautions (5.1, 5.2) and use in specific populations (8.1)] . ambrisentan is contraindicated in patients with idiopathic pulmonary fibrosis (ipf), including ipf patients with pulmonary hypertension (who group 3) [see clinical studies (14.4)]. risk summary based on data from animal reproduction studies, ambrisentan may cause fetal harm when administered to a pregnant woman and is contraindicated during pregnancy. there are limited data on ambrisentan use in pregnant women. in animal reproduction studies, ambrisentan was teratogenic in rats and rabbits at doses which resulted in exposures of 3.5 and 1.7 times, respectively, the human dose of 10 mg per day [see animal data] . if this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential hazard to a fetus [see contraindications (4.1), warnings and precautions (5.1)] . the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. data animal data ambrisentan was teratogenic at oral dosages of ≥15 mg/kg/day (auc 51.7 h•mcg/ml) in rats and ≥7 mg/kg/day (24.7 h•mcg/ml) in rabbits; it was not studied at lower dosages. these dosages are of 3.5 and 1.7 times, respectively, the human dose of 10 mg per day (14.8 h•mcg/ml) based on auc. in both species, there were abnormalities of the lower jaw and hard and soft palate, malformation of the heart and great vessels, and failure of formation of the thymus and thyroid. a preclinical study in rats has shown decreased survival of newborn pups (mid and high dosages) and effects on testicle size and fertility of pups (high dosage) following maternal treatment with ambrisentan from late gestation through weaning. the mid and high dosages were 51 x, and 170 x (on a mg/m2 body surface area basis) the maximum oral human dose of 10 mg and an average adult body weight of 70 kg. these effects were absent at a maternal dosage 17 x the human dose based on mg/m2 . risk summary it is not known whether ambrisentan is present in human milk. because many drugs are present in human milk and because of the potential for serious adverse reactions in breastfed infants from ambrisentan, a decision should be made whether to discontinue breastfeeding or discontinue ambrisentan, taking into account the importance of the drug to the mother. pregnancy testing female patients of reproductive potential must have a negative pregnancy test prior to initiation of treatment, monthly pregnancy test during treatment, and pregnancy test 1 month after stopping treatment with ambrisentan. advise patients to contact their healthcare provider if they become pregnant or suspect they may be pregnant. perform a pregnancy test if pregnancy is suspected for any reason. for positive pregnancy tests, counsel patient on the potential risk to the fetus and patient options [see boxed warning and dosage and administration (2.2)].  contraception female patients of reproductive potential must use acceptable methods of contraception during treatment with ambrisentan and for 1 month after stopping treatment with ambrisentan. patients may choose one highly effective form of contraception (intrauterine device (iud), contraceptive implant, or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods). if a partner’s vasectomy is the chosen method of contraception, a hormone or barrier method must be used along with this method. counsel patients on pregnancy planning and prevention, including emergency contraception, or designate counseling by another healthcare provider trained in contraceptive counseling [see boxed warning]. infertility males in a 6-month study of another endothelin receptor antagonist, bosentan, 25 male patients with who functional class iii and iv pah and normal baseline sperm count were evaluated for effects on testicular function. there was a decline in sperm count of at least 50% in 25% of the patients after 3 or 6 months of treatment with bosentan. one patient developed marked oligospermia at 3 months, and the sperm count remained low with 2 follow-up measurements over the subsequent 6 weeks. bosentan was discontinued and after 2 months the sperm count had returned to baseline levels. in 22 patients who completed 6 months of treatment, sperm count remained within the normal range and no changes in sperm morphology, sperm motility, or hormone levels were observed. based on these findings and preclinical data [see nonclinical toxicology (13.1)] from endothelin receptor antagonists, it cannot be excluded that endothelin receptor antagonists such as ambrisentan have an adverse effect on spermatogenesis. counsel patients about the potential effects on fertility [see warnings and precautions (5.5)] . safety and effectiveness of ambrisentan in pediatric patients have not been established. juvenile animal data in juvenile rats administered ambrisentan orally once daily during postnatal day 7 to 26, 36, or 62, a decrease in brain weight (−3% to −8%) with no morphologic or neurobehavioral changes occurred after breathing sounds, apnea, and hypoxia were observed, at exposures approximately 1.8 to 7.0 times human pediatric exposures at 10 mg, based on auc. in the two placebo-controlled clinical studies of ambrisentan, 21% of patients were ≥65 years old and 5% were ≥75 years old. the elderly (age ≥65 years) showed less improvement in walk distances with ambrisentan than younger patients did, but the results of such subgroup analyses must be interpreted cautiously. peripheral edema was more common in the elderly than in younger patients. the impact of renal impairment on the pharmacokinetics of ambrisentan has been examined using a population pharmacokinetic approach in pah patients with creatinine clearances ranging between 20 and 150 ml/min. there was no significant impact of mild or moderate renal impairment on exposure to ambrisentan [see clinical pharmacology (12.3)] . dose adjustment of ambrisentan in patients with mild or moderate renal impairment is therefore not required. there is no information on the exposure to ambrisentan in patients with severe renal impairment. the impact of hemodialysis on the disposition of ambrisentan has not been investigated. preexisting hepatic impairment the influence of preexisting hepatic impairment on the pharmacokinetics of ambrisentan has not been evaluated. because there is in vitro and in vivo evidence of significant metabolic and biliary contribution to the elimination of ambrisentan, hepatic impairment might be expected to have significant effects on the pharmacokinetics of ambrisentan [see clinical pharmacology (12.3)] . ambrisentan is not recommended in patients with moderate or severe hepatic impairment. there is no information on the use of ambrisentan in patients with mild preexisting impaired liver function; however, exposure to ambrisentan may be increased in these patients. elevation of liver transaminases other endothelin receptor antagonists (eras) have been associated with aminotransferase (ast, alt) elevations, hepatotoxicity, and cases of liver failure [see adverse reactions (6.1, 6.2)]. in patients who develop hepatic impairment after ambrisentan initiation, the cause of liver injury should be fully investigated. discontinue ambrisentan if elevations of liver aminotransferases are >5 x uln or if elevations are accompanied by bilirubin >2 x uln, or by signs or symptoms of liver dysfunction and other causes are excluded.

美国 - 英文 - NLM (National Library of Medicine)

sun pharmaceutical industries, inc. - bosentan (unii: q326023r30) (bosentan anhydrous - unii:xul93r30k2) - bosentan is indicated for the treatment of pulmonary arterial hypertension (pah) (who group 1): - in adults to improve exercise ability and to decrease clinical worsening. studies establishing effectiveness included predominantly patients with who functional class ii-iv symptoms and etiologies of idiopathic or heritable pah (60%), pah associated with connective tissue diseases (21%), and pah associated with congenital heart disease with left-to-right shunts (18%) [see clinical studies (14.1)] . use of bosentan is contraindicated in females who are or may become pregnant. to prevent pregnancy, females of reproductive potential must use two reliable forms of contraception during treatment and for one month after stopping bosentan [see boxed warning, warnings and precautions (5.2), drug interactions (7.2), use in specific populations (8.1)] . coadministration of cyclosporine a and bosentan resulted in markedly increased plasma concentrations of bosentan. therefore, concomitant use of bosentan and cyclosporine a is contraindicated [see cytochrome p450 drug interactions (7.1)]. an increased risk of liver enzyme elevations was observed in patients receiving glyburide concomitantly with bosentan. therefore coadministration of glyburide and bosentan is contraindicated [see cytochrome p450 drug interactions (7.1)] . bosentan is contraindicated in patients who are hypersensitive to bosentan or any component of the product. observed reactions include drug reaction with eosinophilia and systemic symptoms (dress), anaphylaxis, rash, and angioedema [see adverse reactions (6.2), description (11)] . risk summary based on data from animal reproduction studies, bosentan may cause fetal harm, including birth defects and fetal death, when administered to a pregnant female and is contraindicated during pregnancy [see contraindications (4.1)]. there are limited data on bosentan use in pregnant women. in animal reproduction studies, oral administration of bosentan to pregnant rats at 2-times the maximum recommended human dose (mrhd) on a mg/m2 basis caused teratogenic effects in rats, including malformations of the head, mouth, face, and large blood vessels [see animal data] . advise pregnant women of the potential risk to a fetus. the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. data animal data bosentan was teratogenic in rats given oral doses two times the mrhd (on a mg/m2 basis). in an embryo-fetal toxicity study in rats, bosentan showed dose-dependent teratogenic effects, including malformations of the head, mouth, face and large blood vessels. bosentan increased stillbirths and pup mortality at oral doses 2 and 10 times the mrhd (on a mg/m2 basis). although birth defects were not observed in rabbits given oral doses of up to the equivalent of 10.5 g/day in a 70 kg person, plasma concentrations of bosentan in rabbits were lower than those reached in the rat. the similarity of malformations induced by bosentan and those observed in endothelin-1 knockout mice and in animals treated with other endothelin receptor antagonists indicates that embryo-fetal toxicity is a class effect of these drugs. risk summary data from a case report describe the presence of bosentan in human milk. there is insufficient information about the effects of bosentan on the breastfed infant and no information on the effects of bosentan on milk production. because of the potential for serious adverse reactions, such as fluid retention and hepatotoxicity, in breastfed infants from bosentan, advise women not to breastfeed during treatment with bosentan. pregnancy testing verify the pregnancy status of females of reproductive potential prior to initiating bosentan, monthly during treatment and one month after stopping treatment with bosentan. the patient should contact her physician immediately for pregnancy testing if onset of menses is delayed or pregnancy is suspected. if the pregnancy test is positive, the physician and patient must discuss the risks to her, the pregnancy, and the fetus. contraception drug interaction studies show that bosentan reduces serum levels of the estrogen and progestin in oral contraceptives. based on these findings, hormonal contraceptives (including oral, injectable, transdermal, and implantable contraceptives) may be less effective for preventing pregnancy in patients using bosentan and should not be used as a patient’s only contraceptive method [see drug interactions (7.2)] . females of reproductive potential using bosentan must use two acceptable methods of contraception during treatment and for 1 month after treatment with bosentan. patients may choose one highly effective form of contraception (intrauterine devices (iud) or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods). if a partner’s vasectomy is the chosen method of contraception, a hormone or barrier method must be used along with this method. counsel patients on pregnancy planning and prevention, including emergency contraception, or designate counseling by another healthcare provider trained in contraceptive counseling [see boxed warning]. infertility males decreased sperm counts have been observed in patients receiving bosentan. based on these findings and findings in animals, bosentan may impair fertility in males of reproductive potential. it is not known whether effects on fertility would be reversible [see warnings and precautions (5.6), adverse reactions (6.1), nonclinical toxicology (13.1)]. juvenile animal toxicity data in a juvenile rat toxicity study, rats were treated from day 4 postpartum to adulthood (day 69 postpartum). decreased body weights, absolute weights of testes and epididymides, and reduced number of sperm in epididymides were observed after weaning. no effect on testis histology or sperm morphology and function was seen. the noael was 4 times (at day 4 postpartum) and 2 times (day 69 postpartum) the human therapeutic exposure, respectively. no effects on general development, sensory, cognitive function and reproductive performance were detected at the highest dose tested in juvenile rats, 7 times the therapeutic exposure in children with pah. clinical studies of bosentan did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. because there is in vitro and in vivo evidence that the main route of excretion of bosentan is biliary, liver impairment could be expected to increase exposure (cmax and auc) of bosentan. the pharmacokinetics of bosentan have not been evaluated in patients with severe liver impairment (child-pugh class c). in patients with moderate hepatic impairment (child-pugh class b), the systemic exposures to bosentan and its active metabolite increased significantly. bosentan should generally be avoided in patients with moderate or severe liver impairment. pharmacokinetics of bosentan were not altered in patients with mild impairment of hepatic function (child-pugh class a) [see dosage and administration (2.6), warnings and precautions (5.1), pharmacokinetics (12.3)] . the effect of renal impairment on the pharmacokinetics of bosentan is small and does not require dosing adjustment [see pharmacokinetics (12.3)] .

美国 - 英文 - NLM (National Library of Medicine)

sun pharmaceutical industries, inc. - dalfampridine (unii: bh3b64okl9) (dalfampridine - unii:bh3b64okl9) - dalfampridine extended-release tablets are indicated as a treatment to improve walking in adult patients with multiple sclerosis (ms). this was demonstrated by an increase in walking speed [see clinical studies (14)]. the use of dalfampridine extended-release tablets are contraindicated in the following conditions: - history of seizure [see warnings and precautions (5.1)] - moderate or severe renal impairment (crcl ≤ 50 ml/min) [see warnings and precautions (5.2)] - history of hypersensitivity to dalfampridine or 4-aminopyridine; reactions have included anaphylaxis [see warnings and precautions (5.4)] risk summary there are no adequate data on the developmental risk associated with use of dalfampridine in pregnant women. administration of dalfampridine to animals during pregnancy and lactation resulted in decreased offspring viability and growth at clinically relevant doses [see data] . in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognize