Ηνωμένες Πολιτείες - Αγγλικά - NLM (National Library of Medicine)

zydus pharmaceuticals (usa) inc. - ketorolac tromethamine (unii: 4eve5946bq) (ketorolac - unii:yzi5105v0l) - carefully consider the potential benefits and risks of ketorolac tromethamine tablets and other treatment options before deciding to use ketorolac tromethamine tablets. use the lowest effective dose for the shortest duration consistent with individual patient treatment goals. ketorolac tromethamine tablets are indicated for the short-term (≤ 5 days) management of moderately severe acute pain that requires analgesia at the opioid level, usually in a postoperative setting. therapy should always be initiated with iv or im dosing of ketorolac tromethamine and ketorolac tromethamine tablets are to be used only as continuation treatment, if necessary. the total combined duration of use of ketorolac tromethamine tablets and ketorolac tromethamine is not to exceed 5 days of use because of the potential of increasing the frequency and severity of adverse reactions associated with the recommended doses (see warnings , precautions , dosage and administration , and adverse reactions ). patients should be switched to alternative analgesics as soon as possible, but ketorolac tromethamine tablet therapy is not to exceed 5 days. (see also boxed warning) ketorolac tromethamine tablets are contraindicated in patients with previously demonstrated hypersensitivity to ketorolac tromethamine. ketorolac tromethamine tablets are contraindicated in patients with active peptic ulcer disease, in patients with recent gastrointestinal bleeding or perforation and in patients with a history of peptic ulcer disease or gastrointestinal bleeding. ketorolac tromethamine tablets should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other nsaids. severe, rarely fatal, anaphylactic-like reactions to nsaids have been reported in such patients (see warnings, anaphylactoid reactions and precautions, preexisting asthma ). ketorolac tromethamine tablets are contraindicated as prophylactic analgesic before any major surgery. ketorolac tromethamine tablets are contraindicated in the setting of coronary artery bypass graft (cabg) surgery (see warnings ). ketorolac tromethamine tablets are contraindicated in patients with advanced renal impairment or in patients at risk for renal failure due to volume depletion (see warnings for correction of volume depletion). ketorolac tromethamine tablets are contraindicated in labor and delivery because, through its prostaglandin synthesis inhibitory effect, it may adversely affect fetal circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage. ketorolac tromethamine inhibits platelet function and is, therefore, contraindicated in patients with suspected or confirmed cerebrovascular bleeding, hemorrhagic diathesis, incomplete hemostasis and those at high risk of bleeding (see warnings and precautions ). ketorolac tromethamine tablets are contraindicated in patients currently receiving aspirin or nsaids because of the cumulative risks of inducing serious nsaid-related adverse events. the concomitant use of ketorolac tromethamine and probenecid is contraindicated. the concomitant use of ketorolac tromethamine and pentoxifylline is contraindicated.

Ηνωμένες Πολιτείες - Αγγλικά - NLM (National Library of Medicine)

zydus pharmaceuticals usa inc. - topiramate (unii: 0h73wjj391) (topiramate - unii:0h73wjj391) - topiramate extended-release capsules 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 extended-release capsules 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 extended-release capsules 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 antiepileptic drugs (aeds), such as topiramate extended-release capsules, 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 extended-release capsules can cause fetal harm when administered to a pregnant woman. data from pregnancy registries indicate that infants exposed to topiramate in utero have 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 demonstrated 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 before many women know they are pregnant, 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 extended-release capsules 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 extended-release capsules 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 the 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 who were unexposed to aeds. the long-term consequences of the sga findings are not known. animal data when topiramate (0 mg/kg/day, 20 mg/kg/day, 100 mg/kg/day, or 500 mg/kg/day) was administered orally to pregnant mice during the period of organogenesis, the incidence 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 an increased incidence of 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 mg/kg/day, 20 mg/kg/day, 100 mg/kg/day, and 500 mg/kg/day or 0 mg/kg/day, 0.2 mg/kg/day, 2.5 mg/kg/day, 30 mg/kg/day, 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 mg/kg/day 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 mg/kg/day, 20 mg/kg/day, 60 mg/kg/day, and 180 mg/kg/day or 0 mg/kg/day, 10 mg/kg/day, 35 mg/kg/day, and 120 mg/kg/day) orally during organogenesis, embryofetal mortality was increased at 35 mg/kg/day and an increased incidence of fetal malformations (primarily rib and vertebral malformations) was 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 mg/kg/day, 0.2 mg/kg/day, 4 mg/kg/day, 20 mg/kg/day, and 100 mg/kg/day or 0 mg/kg/day, 2 mg/kg/day, 20 mg/kg/day, 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 mg/kg/day, 0.2 mg/kg/day, 2.5 mg/kg/day, 30 mg/kg/day, and 400 mg/kg/day) 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 extended-release capsules and any potential adverse effects on the breastfed infant from topiramate extended-release capsules 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 extended-release capsules 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 and is based on controlled trials with immediate-release topiramate [see adverse reactions (6.1) and clinical studies (14.3, 14.4)] . the adverse reactions (both common and serious) in pediatric patients are similar to those seen in adults [see warnings and precautions (5) and adverse reactions (6)] . these include, but are not limited to: - oligohydrosis and hyperthermia [see warnings and precautions (5.3)] - dose-related increased incidence of metabolic acidosis [see warnings and precautions (5.4)] - dose-related increased incidence of hyperammonemia [see warnings and precautions (5.12)] pediatric patients below the age of 2 years   the following pediatric use information is based on studies conducted with immediate-release topiramate. 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 immediate-release topiramate oral liquid and sprinkle formulations as an adjunct to concurrent antiepileptic drug therapy in pediatric patients 1 month to 24 months of age with refractory partial-onset seizures were assessed. after 20 days of double-blind treatment, immediate-release topiramate (at fixed doses of 5 mg/kg/day, 15 mg/kg/day, and 25 mg/kg/day) did not demonstrate efficacy compared with placebo in controlling seizures. in general, the adverse reaction profile for immediate-release 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 month 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 immediate-release 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 (6.1)] . immediate-release 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 [see adverse  reactions (6.1)] . the significance of these findings is uncertain. immediate-release 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 [see adverse reactions (6.1)] . 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 immediate-release 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 (6.1)] . 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/1,000 patient years. it is not possible to know whether this mortality rate is related to immediate-release topiramate treatment, because the background mortality rate for a similar, significantly refractory, young pediatric population (1 month 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 extended-release capsules 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 and is based on controlled trials with immediate-release topiramate [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 immediate-release 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 11 summarizes effects of immediate-release topiramate at 12 months for key safety outcomes including bmd, height, height velocity, and weight. all least square mean values for immediate-release 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). * tblh = total body less head ** whereas no patients were randomized to 2 to 5 year of age subgroup for immediate-release topiramate, 5 patients (4 to 5 years) were randomized to the active control group. metabolic acidosis (serum bicarbonate < 20 meq/l) was observed in all immediate-release topiramate-treated patients at some time in the study [see warnings and precautions (5.4)]. over the whole study, 76% more immediate-release 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 immediate-release 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. immediate-release 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 mg/day to 200 mg/day, or 2 mg/kg/day to 3 mg/kg/day. these comprised a fixed dose study in 103 pediatric patients 12 years to 17 years of age [see clinical studies (14.5)] , a flexible dose (2 mg/kg/day to 3 mg/kg/day), placebo-controlled study in 157 pediatric patients 6 years to 16 years of age (including 67 pediatric patients 12 years to 16 years of age), and a total of 49 pediatric patients 12 years 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 years to 17 years of age is demonstrated for a 100 mg daily dose in study 13 [see clinical studies (14.5)] . efficacy of topiramate (2 mg/kg/day to 3 mg/kg/day) for the preventive treatment of migraine was not demonstrated in a placebo-controlled trial of 157 pediatric patients (6 years to 16 years of age) that included treatment of 67 pediatric patients (12 years to 16 years of age) for 20 weeks. in the pediatric trials (12 years to 17 years of age) in which patients were randomized to placebo or a fixed daily dose of immediate-release topiramate, the most common adverse reactions with immediate-release 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 (6.1)] . the most common cognitive adverse reaction in pooled double-blind studies in pediatric patients 12 years 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 years 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 warnings and precautions (5.4) and 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 years 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 years to 17 years of age. the most common adverse reactions that occurred in immediate-release topiramate-treated pediatric patients 6 years 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 years to 11 years of age) than in older patients (12 years to 17 years of age) [see warnings and precautions (5.6)] . juvenile animal studies when topiramate (0 mg/kg/day, 30 mg/kg/day, 90 mg/kg/day or 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, which is approximately 5 times to 8 times the maximum recommended pediatric dose (9 mg/kg/day) on a body surface area (mg/m2 ) basis. clinical studies of immediate-release 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 creatinine clearance less than 70 ml/min/1.73 m2 . estimate gfr should be measured prior to dosing [see dosage and administration (2.3) and clinical pharmacology (12.3)] . the clearance of topiramate is reduced in patients with moderate (creatinine clearance 30 ml/min/1.73 m2 to 69 ml/min/1.73 m2 ) and severe (creatinine clearance less than 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 (2.4) and clinical pharmacology (12.3)] . topiramate is cleared by hemodialysis at a rate that is 4 times to 6 times greater than in a normal individual. a dosage adjustment may be required [see dosage and administration (2.5) and clinical pharmacology (12.3)] .

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zydus pharmaceuticals usa inc. - varenicline tartrate (unii: 82269asb48) (varenicline - unii:w6hs99o8zo) - varenicline tablets are indicated for use as an aid to smoking cessation treatment. varenicline is contraindicated in patients with a known history of serious hypersensitivity reactions or skin reactions to varenicline. risk summary available data have not suggested an increased risk for major birth defects following exposure to varenicline in pregnancy, compared with women who smoke [see data]. smoking during pregnancy is associated with maternal, fetal and neonatal risks (see clinical considerations). in animal studies, varenicline did not result in major malformations but caused decreased fetal weights in rabbits when dosed during organogenesis at exposures equivalent to 50 times the exposure at the maximum recommended human dose (mrhd). additionally, administration of varenicline to pregnant rats during organogenesis through lactation produced developmental toxicity in offspring at maternal exposures equivalent to 36 times human exposure at the mrhd [see data]. the estimated background risk of oral clefts is increased by approximately 30% in infants of women who smoke during pregnancy, compared to pregnant women who do not smoke. the background risk of other major birth defects and miscarriage for the indicated population are unknown. in the us general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk smoking during pregnancy causes increased risks of orofacial clefts, premature rupture of membranes, placenta previa, placental abruption, ectopic pregnancy, fetal growth restriction and low birth weight, stillbirth, preterm delivery and shortened gestation, neonatal death, sudden infant death syndrome and reduction of lung function in infants. it is not known whether quitting smoking with varenicline during pregnancy reduces these risks. data human data a population-based observational cohort study using the national registers of denmark and sweden compared pregnancy and birth outcomes among women exposed to varenicline (n=335, includes 317 first trimester exposed) with women who smoked during pregnancy (n=78,412) and with non-smoking pregnant women   (n=806,438). the prevalence of major malformations, the primary outcome, was similar in all groups, including between smoking and non-smoking groups. the prevalence of adverse perinatal outcomes in the varenicline-exposed cohort was not greater than in the cohort of women who smoked and differed somewhat between the three cohorts. the prevalences of the primary and secondary outcomes are shown in table 6. * included only live births in the cohorts. prevalence among first trimester varenicline-exposed pregnancies (11/317 [3.5%]). ** there was a lag in death data in denmark, so the cohorts were smaller. the study limitations include the inability to capture malformations in pregnancies that do not result in a live birth and possible misclassification of outcome and of exposure to varenicline or to smoking. other small epidemiological studies of pregnant women exposed to varenicline did not identify an association with major malformations, consistent with the danish and swedish observational cohort study. methodological limitations of these studies include small samples and lack of adequate controls. overall, available studies cannot definitely establish or exclude any varenicline-associated risk during pregnancy. animal data pregnant rats and rabbits received varenicline succinate during organogenesis at oral doses up to 15 mg/kg/day and 30 mg/kg/day, respectively. while no fetal structural abnormalities occurred in either species, maternal toxicity, characterized by reduced body weight gain and reduced fetal weights occurred in rabbits at the highest dose (exposures 50 times the human exposure at the mrhd of 1 mg twice daily based on auc). fetal weight reduction did not occur in rabbits at exposures 23 times the human exposure at the mrhd based on auc. in a pre- and postnatal development study, pregnant rats received up to 15 mg/kg/day of oral varenicline succinate from organogenesis through lactation. maternal toxicity, characterized by a decrease in body weight gain was observed at 15 mg/kg/day (36 times the human exposure at the mrhd based on auc). however, decreased fertility and increased auditory startle response occurred in offspring at the highest maternal dose of 15 mg/kg/day. risk summary there are no data on the presence of varenicline in human milk, the effects on the breastfed infant or the effects on milk production. in animal studies varenicline was present in milk of lactating rats [see data]. however, due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk. the lack of clinical data during lactation precludes a clear determination of the risk of varenicline to an infant during lactation; however the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for varenicline and any potential adverse effects on the breastfed child from varenicline or from the underlying maternal condition. clinical considerations because there are no data on the presence of varenicline in human milk and the effects on the breastfed infant, breastfeeding women should monitor their infant for seizures and excessive vomiting, which are adverse reactions that have occurred in adults that may be clinically relevant in breastfeeding infants. data in a pre- and postnatal development study, pregnant rats received up to 15 mg/kg/day of oral varenicline succinate through gestation and lactation mean serum concentrations of varenicline in the nursing pups were 5% to 22% of maternal serum concentrations. varenicline is not recommended for use in pediatric patients 16 years of age or younger because its efficacy in this population was not demonstrated. single and multiple-dose pharmacokinetics of varenicline have been investigated in pediatric patients aged 12 years to 17 years old (inclusive) and were approximately dose-proportional over the 0.5 mg to 2 mg daily dose range studied. steady-state systemic exposure in adolescent patients of bodyweight > 55 kg, as assessed by auc (0 to 24), was comparable to that noted for the same doses in the adult population. when 0.5 mg bid was given, steady-state daily exposure of varenicline was, on average, higher (by approximately 40%) in adolescent patients with bodyweight ≤ 55 kg compared to that noted in the adult population. the efficacy and safety of varenicline was evaluated in a randomized, double-blind, placebo-controlled study of 312 patients aged 12 years to 19 years, who smoked an average of at least 5 cigarettes per day during the 30 days prior to recruitment, had a score of at least 4 on the fagerstrom test for nicotine dependence scale, and at least one previous failed quit attempt. patients were stratified by age (12 years to 16 years of age, n = 216 and 17 years to 19 years of age, n = 96) and by body weight (≤55 kg and >55 kg). patients were randomized to one of two doses of varenicline, adjusted by weight to provide plasma levels in the efficacious range (based on adult studies) and placebo. patients received treatment for 12 weeks, followed by a non-treatment period of 40 weeks, along with age-appropriate counseling throughout the study. results from this study showed that varenicline, at either dose studied, did not improve continuous abstinence rates at weeks 9 through 12 of treatment compared with placebo in subjects 12 years to 19 years of age. the varenicline safety profile in this study was consistent with that observed in adult studies. a combined single- and multiple-dose pharmacokinetic study demonstrated that the pharmacokinetics of 1 mg varenicline given once daily or twice daily to 16 healthy elderly male and female smokers (aged 65 years to 75 years) for 7 consecutive days was similar to that of younger subjects. no overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. varenicline is known to be substantially excreted by the kidney and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function [see dosage and administration (2.2)]. no dosage adjustment is recommended for elderly patients. varenicline is substantially eliminated by renal glomerular filtration along with active tubular secretion. dose reduction is not required in patients with mild to moderate renal impairment. for patients with severe renal impairment (estimated creatinine clearance < 30 ml/min) and for patients with end-stage renal disease undergoing hemodialysis, dosage adjustment is needed [see dosage and administration (2.2), clinical pharmacology (12.3)]. varenicline is not a controlled substance. humans fewer than 1 out of 1,000 patients reported euphoria in clinical trials with varenicline. at higher doses (greater than 2 mg), varenicline produced more frequent reports of gastrointestinal disturbances such as nausea and vomiting. there is no evidence of dose-escalation to maintain therapeutic effects in clinical studies, which suggests that tolerance does not develop. abrupt discontinuation of varenicline was associated with an increase in irritability and sleep disturbances in up to 3% of patients. this suggests that, in some patients, varenicline may produce mild physical dependence which is not associated with addiction. in a human laboratory abuse liability study, a single oral dose of 1 mg varenicline did not produce any significant positive or negative subjective responses in smokers. in non-smokers, 1 mg varenicline produced an increase in some positive subjective effects, but this was accompanied by an increase in negative adverse effects, especially nausea. a single oral dose of 3 mg varenicline uniformly produced unpleasant subjective responses in both smokers and non-smokers. animals studies in rodents have shown that varenicline produces behavioral responses similar to those produced by nicotine. in rats trained to discriminate nicotine from saline, varenicline produced full generalization to the nicotine cue. in self-administration studies, the degree to which varenicline substitutes for nicotine is dependent upon the requirement of the task. rats trained to self-administer nicotine under easy conditions continued to self-administer varenicline to a degree comparable to that of nicotine; however in a more demanding task, rats self-administered varenicline to a lesser extent than nicotine. varenicline pretreatment also reduced nicotine self- administration.

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zydus pharmaceuticals usa inc. - indomethacin (unii: xxe1cet956) (indomethacin - unii:xxe1cet956) - indomethacin suppository is indicated for: - moderate to severe rheumatoid arthritis including acute flares of chronic disease - moderate to severe ankylosing spondylitis - moderate to severe osteoarthritis - acute painful shoulder (bursitis and/or tendinitis) - acute gouty arthritis indomethacin suppositories are contraindicated in the following patients: - known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to indomethacin or any components of the drug product [see warnings and precautions (5.7, 5.9)] - history of asthma, urticaria or other 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 (5.7, 5.8)] - in the setting of coronary artery bypass graft (cabg) surgery [see warnings and precautions (5.1)] - in patients with a history of proctitis or recent rectal bleeding risk  summary use of nsaids, including indomethacin, 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 indomethacin use between about 20 weeks and 30 weeks of gestation and avoid indomethacin 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 indomethacin, 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. in animal reproduction studies retarded fetal ossification was observed with administration of indomethacin to mice and rats during organogenesis at doses 0.1 times and 0.2 times, respectively, the maximum recommended human dose (mrhd, 200 mg). in published studies in pregnant mice, indomethacin produced maternal toxicity and death, increased fetal resorptions and fetal malformations at 0.1 times the mrhd. when rat and mice dams were dosed during the last three days of gestation, indomethacin produced neuronal necrosis in the offspring at 0.1 times and 0.05 times the mrhd, respectively [see 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 indomethacin, 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. the estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. all pregnancies have a background risk of birth defect, loss or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. clinical  considerations fetal/neonatal  adverse  reactions premature closure of fetal ductus arteriosus avoid use of nsaids in women at about 30 weeks gestation and later in pregnancy, because nsaids, including indomethacin, 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 indomethacin treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. if oligohydramnios occurs, discontinue indomethacin and follow up according to clinical practice (see  data ). data human  data 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 reproductive studies were conducted in mice and rats at dosages of 0.5 mg/kg/day, 1 mg/kg/day, 2 mg/kg/day and 4 mg/kg/day. except for retarded fetal ossification at 4 mg/kg/day (0.1 times [mice] and 0.2 times [rats] the mrhd on a mg/m2 basis, respectively) considered secondary to the decreased average fetal weights, no increase in fetal malformations was observed as compared with control groups. other studies in mice reported in the literature using higher doses (5 mg/kg/day to 15 mg/kg/day, 0.1 times to 0.4 times mrhd on a mg/m2 basis) have described maternal toxicity and death, increased fetal resorptions and fetal malformations. comparable studies in rodents using high doses of aspirin have shown similar maternal and fetal effects. in rats and mice, maternal indomethacin administration of 4 mg/kg/day (0.2 times and 0.1 times the mrhd on a mg/m2 basis) during the last 3 days of gestation was associated with an increased incidence of neuronal necrosis in the diencephalon in the live-born fetuses however no increase in neuronal necrosis was observed at 2 mg/kg/day as compared to the control groups (0.1 times and 0.05 times the mrhd on a mg/m2 basis). administration of 0.5 mg/kg/day or 4 mg/kg/day to offspring during the first 3 days of life did not cause an increase in neuronal necrosis at either dose level. risk  summary based on available published clinical data, indomethacin may be present in human milk. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for indomethacin and any potential adverse effects on the breastfed infant from the indomethacin or from the underlying maternal condition. data in one study, levels of indomethacin in breast milk were below the sensitivity of the assay (< 20 mcg/l) in 11 of 15 women using doses ranging from 75 mg orally to 300 mg rectally daily (0.94 mg/kg to 4.29 mg/kg daily) in the postpartum period. based on these levels, the average concentration present in breast milk was estimated to be 0.27% of the maternal weight-adjusted dose. in another study indomethacin levels were measured in breast milk of eight postpartum women using doses of 75 mg daily and the results were used to calculate an estimated infant daily dose. the estimated infant dose of indomethacin from breast milk was less than 30 mcg/day or 4.5 mcg/kg/day assuming breast milk intake of 150 ml/kg/day. this is 0.5% of the maternal weight-adjusted dosage or about 3% of the neonatal dose for treatment of patent ductus arteriosus. infertility females based on the mechanism of action, the use of prostaglandin-mediated nsaids, including indomethacin, 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 indomethacin, in women who have difficulties conceiving or who are undergoing investigation of infertility. safety and effectiveness in pediatric patients 14 years of age and younger has not been established. indomethacin should not be prescribed for pediatric patients 14 years of age and younger unless toxicity or lack of efficacy associated with other drugs warrants the risk. in experience with more than 900 pediatric patients reported in the literature or to the manufacturer who were treated with indomethacin capsules, side effects in pediatric patients were comparable to those reported in adults. experience in pediatric patients has been confined to the use of indomethacin capsules. if a decision is made to use indomethacin for pediatric patients two years of age or older, such patients should be monitored closely and periodic assessment of liver function is recommended. there have been cases of hepatotoxicity reported in pediatric patients with juvenile rheumatoid arthritis, including fatalities. if indomethacin treatment is instituted, a suggested starting dose is 1 mg/kg/day to 2 mg/kg/day given in divided doses. maximum daily dosage should not exceed 3 mg/kg/day or 150 mg/day to 200 mg/day, whichever is less. limited data are available to support the use of a maximum daily dosage of 4 mg/kg/day or 150 mg/day to 200 mg/day, whichever is less. as symptoms subside, the total daily dosage should be reduced to the lowest level required to control symptoms or the drug should be discontinued. elderly patients, compared to younger patients, are at greater risk for nsaid-associated serious cardiovascular, gastrointestinal and/or renal adverse reactions. if the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range and monitor patients for adverse effects [see warnings and precautions (5.1, 5.2, 5.3, 5.6, 5.13)]. indomethacin may cause confusion or rarely, psychosis [see adverse reactions (6.1)]; physicians should remain alert to the possibility of such adverse effects in the elderly. indomethacin and its metabolites are known to be substantially excreted by the kidneys 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, use caution in this patient population and it may be useful to monitor renal function [see clinical pharmacology (12.3)].

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zydus pharmaceuticals usa inc. - venlafaxine hydrochloride (unii: 7d7rx5a8mo) (venlafaxine - unii:grz5rcb1qg) - venlafaxine 25 mg - venlafaxine tablets, usp are indicated for the treatment of major depressive disorder. the efficacy of venlafaxine tablets, usp in the treatment of major depressive disorder was established in 6 week controlled trials of adult outpatients whose diagnoses corresponded most closely to the dsm-iii or dsm-iii-r category of major depression and in a 4 week controlled trial of inpatients meeting diagnostic criteria for major depression with melancholia (see clinical trials ). a major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation. the efficacy of ven

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zydus pharmaceuticals usa inc. - telmisartan (unii: u5syw473rq) (telmisartan - unii:u5syw473rq) - telmisartan 20 mg - telmisartan tablets, usp are indicated for the treatment of hypertension, to lower blood pressure. lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. these benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this drug principally belongs.   control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. many patients will require more than one drug to achieve blood pressure goals. for specific advice on goals and management, see published guidelines, such as those of the national high blood pressure education program's joint national committee on prevention, detection, evaluation, and treatment of high blood pressure (jnc). numerous antihypertensive drugs, from a vari

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zydus lifesciences limited - telmisartan (unii: u5syw473rq) (telmisartan - unii:u5syw473rq), hydrochlorothiazide (unii: 0j48lph2th) (hydrochlorothiazide - unii:0j48lph2th) - telmisartan 40 mg - telmisartan and hydrochlorothiazide tablets are indicated for the treatment of hypertension, to lower blood pressure. lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. these benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the classes to which this drug principally belongs. there are no controlled trials demonstrating risk reduction with telmisartan and hydrochlorothiazide tablets. control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. many patients will require more than one drug to achieve blood pressure goals. for specific advice on goals and management, see published guidelines, such as those of the national high blood pressure education program's joint national committ

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zydus pharmaceuticals usa inc. - nitroglycerin (unii: g59m7s0ws3) (nitroglycerin - unii:g59m7s0ws3) - nitroglycerin 0.2 mg in 1 h - transdermal nitroglycerin is indicated for the prevention of angina pectoris due to coronary artery disease. the onset of action of transdermal nitroglycerin is not sufficiently rapid for this product to be useful in aborting an acute attack. allergic reactions to organic nitrates are extremely rare, but they do occur. nitroglycerin is contraindicated in patients who are allergic to it. allergy to the adhesives used in nitroglycerin patches has also been reported, and it similarly constitutes a contraindication to the use of this product. do not use nitroglycerin transdermal systems in patients who are taking phosphodiesterase inhibitors (such as sildenafil, tadalafil, or vardenafil) for erectile dysfunction or pulmonary arterial hypertension. concomitant use can cause severe drops in blood pressure. do not use nitroglycerin transdermal systems in patients who are taking the soluble guanylate cyclase stimulator riociguat. concomitant use can cause hypotension.

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zydus pharmaceuticals (usa) inc. - dextroamphetamine sulfate (unii: jj768o327n) (dextroamphetamine - unii:tz47u051fi) - dextroamphetamine sulfate 5 mg - dextroamphetamine sulfate tablets usp are indicated for: - narcolepsy . - attention deficit disorder with hyperactivity , as an integral part of a total treatment program which typically includes other remedial measures (psychological, educational, social) for a stabilizing effect in pediatric patients (ages 3 to 16 years) with a behavioral syndrome characterized by the following group of developmentally inappropriate symptoms: moderate to severe distractibility, short attention span, hyperactivity, emotional lability, and impulsivity. the diagnosis of this syndrome should not be made with finality when these symptoms are only of comparatively recent origin. nonlocalizing (soft) neurological signs, learning disability, and abnormal eeg may or may not be present, and a diagnosis of central nervous system dysfunction may or may not be warranted. advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, hyperthyroidism, known hypersensitivity or idiosyncrasy to the sympath

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zydus lifesciences limited - acyclovir (unii: x4hes1o11f) (acyclovir - unii:x4hes1o11f) - acyclovir 200 mg - herpes zoster infections: acyclovir capsules are indicated for the acute treatment of herpes zoster (shingles). genital herpes: acyclovir capsules are indicated for the treatment of initial episodes and the management of recurrent episodes of genital herpes. chickenpox: acyclovir capsules are indicated for the treatment of chickenpox (varicella). acyclovir capsules are contraindicated for patients who develop hypersensitivity to acyclovir or valacyclovir.