Israel - English - Ministry of Health

teva pharmaceutical industries ltd, israel - valproic acid - capsules - valproic acid 200 mg - valproic acid - valproic acid - sole or adjunctive therapy in the treatment of simple (petit mal) and complex absence seizures. may also be used adjunctively in patients with multiple seizure types which include absence seizures.

Israel - English - Ministry of Health

teva pharmaceutical industries ltd, israel - valproic acid as sodium - syrup - valproic acid as sodium 200 mg / 5 ml - valproic acid - valproic acid - sole or adjunctive therapy in the treatment of simple (petit mal) and complex absence seizures. valporal may also be used adjunctively in patients with multiple seizure types which include absence seizures.

Israel - English - Ministry of Health

glaxo smith kline (israel) ltd - atovaquone; proguanil hydrochloride - film coated tablets - atovaquone 62.5 mg; proguanil hydrochloride 25 mg - proguanil, combinations - proguanil, combinations - "- prevention of malaria:for the prophylaxis of p.falciparum malaria, including in areas where chloroquine resistance has been reported.- treatment of malaria: for the treatment of acute, uncomplicated p.flaciparum malaria.malarone has been shown to be effective in regions where the drugs chloroquine, halofantrine, mefloquine, and amodiaquine may have unacceptable failure rates, presumably due to drug resistance.

Israel - English - Ministry of Health

glaxo smith kline (israel) ltd - atovaquone; proguanil hydrochloride - film coated tablets - atovaquone 250 mg; proguanil hydrochloride 100 mg - proguanil, combinations - proguanil, combinations - prevention of malaria: for the prophylaxis of p.falciparum malaria, including in areas where chloroquine resistance has been reported. treatment of malaria: for the treatment of acute, uncomplicated p.flaciparum malaria. malarone has been shown to be effective in regions where the drugs chloroquine, halofantrine, mefloquine, and amodiaquine may have unacceptable failure rates, presumably due to drug resistance.

European Union - English - EMA (European Medicines Agency)

alfasigma s.p.a. - piperaquine tetraphosphate, artenimol - malaria - antiprotozoals - eurartesim is indicated for the treatment of uncomplicated plasmodium falciparum malaria in adults, children and infants 6 months and over and weighing 5 kg or more.consideration should be given to official guidance on the appropriate use of antimalarial agents.

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

apotex corp. - ziprasidone hydrochloride (unii: 216x081oru) (ziprasidone - unii:6uka5vej6x) - ziprasidone 20 mg - ziprasidone capsules are indicated for the treatment of schizophrenia, as monotherapy for the acute treatment of bipolar manic or mixed episodes, and as an adjunct to lithium or valproate for the maintenance treatment of bipolar disorder. when deciding among the alternative treatments available for the condition needing treatment, the prescriber should consider the finding of ziprasidone’s greater capacity to prolong the qt/qtc interval compared to several other antipsychotic drugs [see warnings and precautions (5.3) ].  prolongation of the qtc interval is associated in some other drugs with the ability to cause torsade de pointes-type arrhythmia, a potentially fatal polymorphic ventricular tachycardia, and sudden death. in many cases this would lead to the conclusion that other drugs should be tried first. whether ziprasidone will cause torsade de pointes or increase the rate of sudden death is not yet known [see warnings and precautions ( 5.3 ) ] schizophrenia ziprasidone capsules are indicated for the treatment of schizophrenia in adults [see clinical studies (14.1)] . bipolar i disorder (acute mixed or manic episodes and maintenance treatment as an adjunct to lithium or valproate) - ziprasidone capsules are indicated as monotherapy for the acute treatment of adults with manic or mixed episodes associated with bipolar i disorder [see clinical studies (14.2)]. - ziprasidone capsules are indicated as an adjunct to lithium or valproate for the maintenance treatment of bipolar i disorder in adults [see clinical studies (14.2)]. because of ziprasidone’s dose-related prolongation of the qt interval and the known association of fatal arrhythmias with qt prolongation by some other drugs, ziprasidone is contraindicated: - in patients with a known history of qt prolongation (including congenital long qt syndrome) - in patients with recent acute myocardial infarction - in patients with uncompensated heart failure pharmacokinetic/pharmacodynamic studies between ziprasidone and other drugs that prolong the qt interval have not been performed. an additive effect of ziprasidone and other drugs that prolong the qt interval cannot be excluded. therefore, ziprasidone should not be given with: - dofetilide, sotalol, quinidine, other class ia and iii anti-arrhythmics, mesoridazine, thioridazine, chlorpromazine, droperidol, pimozide, sparfloxacin, gatifloxacin, moxifloxacin, halofantrine, mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol or tacrolimus. - other drugs that have demonstrated qt prolongation as one of their pharmacodynamic effects and have this effect described in the full prescribing information as a contraindication or a boxed or bolded warning [see warnings and precautions (5.3)] .   ziprasidone is contraindicated in individuals with a known hypersensitivity to the product. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including ziprasidone, during pregnancy. healthcare providers are encouraged to register patients by contacting the national pregnancy registry for atypical antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. risk summary neonates exposed to antipsychotic drugs, including ziprasidone, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see clinical considerations) . overall available data from published epidemiologic studies of pregnant women exposed to ziprasidone have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see data) . there are risks to the mother associated with untreated schizophrenia or bipolar i disorder and with exposure to antipsychotics, including ziprasidone, during pregnancy (see clinical considerations). in animal studies, ziprasidone administration to pregnant rats and rabbits during organogenesis caused developmental toxicity at doses similar to recommended human doses, and was teratogenic in rabbits at 3 times the maximum recommended human dose (mrhd). rats exposed to ziprasidone during gestation and lactation exhibited increased perinatal pup mortality and delayed neurobehavioral and functional development of offspring at doses less than or similar to human therapeutic doses.(see data) . the estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk there is risk to the mother from untreated schizophrenia or bipolar i disorder, including increased risk of relapse, hospitalization, and suicide. schizophrenia and bipolar i disorder are associated with increased adverse perinatal outcomes, including preterm birth. it is not known if this is a direct result of the illness or other comorbid factors. fetal/neonatal adverse reactions extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including ziprasidone, during the third trimester of pregnancy. these symptoms have varied in severity. monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. data human data published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. a retrospective cohort study from a medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. animal data when ziprasidone was administered to pregnant rabbits during the period of organogenesis, an increased incidence of fetal structural abnormalities (ventricular septal defects and other cardiovascular malformations, and kidney alterations) was observed at a dose of 30 mg/kg/day (3 times the mrhd of 200 mg/day based on mg/m2 body surface area). there was no evidence to suggest that these developmental effects were secondary to maternal toxicity. the developmental no effect dose was 10 mg/kg/day (equivalent to the mrhd based on a mg/m2  body surface area). in rats, embryofetal toxicity (decreased fetal weights, delayed skeletal ossification) was observed following administration of 10 to 160 mg/kg/day (0.5 to 8 times the mrhd based on mg/m2 body surface area) during organogenesis or throughout gestation, but there was no evidence of teratogenicity. doses of 40 and 160 mg/kg/day (2 and 8 times the mrhd based on mg/m2 body surface area) were associated with maternal toxicity. the developmental no-effect dose is 5 mg/kg/day (0.2 times the mrhd based on mg/m2 body surface area). there was an increase in the number of pups born dead and a decrease in postnatal survival through the first 4 days of lactation among the offspring of female rats treated during gestation and lactation with doses of 10 mg/kg/day (0.5 times the mrhd based on mg/m2  body surface area) or greater. offspring developmental delays (decreased pup weights) and neurobehavioral functional impairment (eye opening air righting) were observed at doses of 5 mg/kg/day (0.2 times the mrhd based on mg/m2 body surface area) or greater. a no-effect level was not established for these effects. risk summary limited data from a published case report indicate the presence of ziprasidone in human milk. although there are no reports of adverse effects on a breastfed infant exposed to ziprasidone via breast milk, there are reports of excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements) in infants exposed to other atypical antipsychotics through breast milk (see clinical considerations) . there is no information on the effects of ziprasidone on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ziprasidone and any potential adverse effects on the breastfed child from ziprasidone or from the mother’s underlying condition. clinical considerations infants exposed to ziprasidone should be monitored for excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements).  infertility females based on the pharmacologic action of ziprasidone (d2 antagonism), treatment with ziprasidone may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see warnings and precautions (5.15) and nonclinical toxicology (13.1)]. the safety and effectiveness of ziprasidone have not been established in pediatric patients. ziprasidone was studied in one 4-week, placebo-controlled trial in patients 10 to 17 years of age with bipolar i disorder. however, the data were insufficient to fully assess the safety of ziprasidone in pediatric patients. therefore, a safe and effective dose for use could not be established.  of the total number of subjects in clinical studies of ziprasidone, 2.4 percent were 65 and over. 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. nevertheless, the presence of multiple factors that might increase the pharmacodynamic response to ziprasidone, or cause poorer tolerance or orthostasis, should lead to consideration of a lower starting dose, slower titration, and careful monitoring during the initial dosing period for some elderly patients.  because ziprasidone is highly metabolized, with less than 1% of the drug excreted unchanged, renal impairment alone is unlikely to have a major impact on the pharmacokinetics of ziprasidone. the pharmacokinetics of ziprasidone following 8 days of 20 mg twice daily dosing were similar among subjects with varying degrees of renal impairment (n=27), and subjects with normal renal function, indicating that dosage adjustment based upon the degree of renal impairment is not required. ziprasidone is not removed by hemodialysis. as ziprasidone is cleared substantially by the liver, the presence of hepatic impairment would be expected to increase the auc of ziprasidone; a multiple-dose study at 20 mg twice daily for 5 days in subjects (n=13) with clinically significant (childs-pugh class a and b) cirrhosis revealed an increase in auc 0 to 12 of 13% and 34% in childs-pugh class a and b, respectively, compared to a matched control group (n=14).  a half-life of 7.1 hours was observed in subjects with cirrhosis compared to 4.8 hours in the control group. in a multiple-dose (8 days of treatment) study involving 32 subjects, there was no difference in the pharmacokinetics of ziprasidone between men and women or between elderly (>65 years) and young (18 to 45 years) subjects. additionally, population pharmacokinetic evaluation of patients in controlled trials has revealed no evidence of clinically significant age or gender-related differences in the pharmacokinetics of ziprasidone. dosage modifications for age or gender are, therefore, not recommended. based on in vitro studies utilizing human liver enzymes, ziprasidone is not a substrate for cyp1a2; smoking should therefore not have an effect on the pharmacokinetics of ziprasidone. consistent with these in vitro results, population pharmacokinetic evaluation has not revealed any significant pharmacokinetic differences between smokers and nonsmokers. ziprasidone has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. while the clinical trials did not reveal any tendency for drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which ziprasidone will be misused, diverted, and/or abused once marketed. consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of ziprasidone misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).

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

golden state medical supply, inc. - ziprasidone hydrochloride (unii: 216x081oru) (ziprasidone - unii:6uka5vej6x) - ziprasidone 20 mg - ziprasidone capsules are indicated for the treatment of schizophrenia, as monotherapy for the acute treatment of bipolar manic or mixed episodes, and as an adjunct to lithium or valproate for the maintenance treatment of bipolar disorder. when deciding among the alternative treatments available for the condition needing treatment, the prescriber should consider the finding of ziprasidone’s greater capacity to prolong the qt/qtc interval compared to several other antipsychotic drugs [see warnings and precautions ( 5.3) ].  prolongation of the qtc interval is associated in some other drugs with the ability to cause torsade de pointes-type arrhythmia, a potentially fatal polymorphic ventricular tachycardia, and sudden death. in many cases this would lead to the conclusion that other drugs should be tried first. whether ziprasidone will cause torsade de pointes or increase the rate of sudden death is not yet known [see warnings and precautions ( 5.3 ) ] schizophrenia ziprasidone capsules are indicated for the treatment of schizophrenia in adults [see clinical studies ( 14.1)] . bipolar i disorder (acute mixed or manic episodes and maintenance treatment as an adjunct to lithium or valproate) - ziprasidone capsules are indicated as monotherapy for the acute treatment of adults with manic or mixed episodes associated with bipolar i disorder [see clinical studies ( 14.2)]. - ziprasidone capsules are indicated as an adjunct to lithium or valproate for the maintenance treatment of bipolar i disorder in adults [see clinical studies ( 14.2)]. because of ziprasidone’s dose-related prolongation of the qt interval and the known association of fatal arrhythmias with qt prolongation by some other drugs, ziprasidone is contraindicated: - in patients with a known history of qt prolongation (including congenital long qt syndrome) - in patients with recent acute myocardial infarction - in patients with uncompensated heart failure pharmacokinetic/pharmacodynamic studies between ziprasidone and other drugs that prolong the qt interval have not been performed. an additive effect of ziprasidone and other drugs that prolong the qt interval cannot be excluded. therefore, ziprasidone should not be given with: - dofetilide, sotalol, quinidine, other class ia and iii anti-arrhythmics, mesoridazine, thioridazine, chlorpromazine, droperidol, pimozide, sparfloxacin, gatifloxacin, moxifloxacin, halofantrine, mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol or tacrolimus. - other drugs that have demonstrated qt prolongation as one of their pharmacodynamic effects and have this effect described in the full prescribing information as a contraindication or a boxed or bolded warning [see warnings and precautions (5.3)] .   ziprasidone is contraindicated in individuals with a known hypersensitivity to the product. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including ziprasidone, during pregnancy. healthcare providers are encouraged to register patients by contacting the national pregnancy registry for atypical antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. risk summary neonates exposed to antipsychotic drugs, including ziprasidone, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see clinical considerations) . overall available data from published epidemiologic studies of pregnant women exposed to ziprasidone have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see data) . there are risks to the mother associated with untreated schizophrenia or bipolar i disorder and with exposure to antipsychotics, including ziprasidone, during pregnancy (see clinical considerations). in animal studies, ziprasidone administration to pregnant rats and rabbits during organogenesis caused developmental toxicity at doses similar to recommended human doses, and was teratogenic in rabbits at 3 times the maximum recommended human dose (mrhd). rats exposed to ziprasidone during gestation and lactation exhibited increased perinatal pup mortality and delayed neurobehavioral and functional development of offspring at doses less than or similar to human therapeutic doses. (see data) . the estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk there is risk to the mother from untreated schizophrenia or bipolar i disorder, including increased risk of relapse, hospitalization, and suicide. schizophrenia and bipolar i disorder are associated with increased adverse perinatal outcomes, including preterm birth. it is not known if this is a direct result of the illness or other comorbid factors. fetal/neonatal adverse reactions extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including ziprasidone, during the third trimester of pregnancy. these symptoms have varied in severity. monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. data human data published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. a retrospective cohort study from a medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. animal data when ziprasidone was administered to pregnant rabbits during the period of organogenesis, an increased incidence of fetal structural abnormalities (ventricular septal defects and other cardiovascular malformations, and kidney alterations) was observed at a dose of 30 mg/kg/day (3 times the mrhd of 200 mg/day based on mg/m 2 body surface area). there was no evidence to suggest that these developmental effects were secondary to maternal toxicity. the developmental no effect dose was 10 mg/kg/day (equivalent to the mrhd based on a mg/m 2  body surface area). in rats, embryofetal toxicity (decreased fetal weights, delayed skeletal ossification) was observed following administration of 10 to 160 mg/kg/day (0.5 to 8 times the mrhd based on mg/m 2 body surface area) during organogenesis or throughout gestation, but there was no evidence of teratogenicity. doses of 40 and 160 mg/kg/day (2 and 8 times the mrhd based on mg/m 2 body surface area) were associated with maternal toxicity. the developmental no-effect dose is 5 mg/kg/day (0.2 times the mrhd based on mg/m 2 body surface area). there was an increase in the number of pups born dead and a decrease in postnatal survival through the first 4 days of lactation among the offspring of female rats treated during gestation and lactation with doses of 10 mg/kg/day (0.5 times the mrhd based on mg/m 2  body surface area) or greater. offspring developmental delays (decreased pup weights) and neurobehavioral functional impairment (eye opening air righting) were observed at doses of 5 mg/kg/day (0.2 times the mrhd based on mg/m 2 body surface area) or greater. a no-effect level was not established for these effects. risk summary limited data from a published case report indicate the presence of ziprasidone in human milk. although there are no reports of adverse effects on a breastfed infant exposed to ziprasidone via breast milk, there are reports of excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements) in infants exposed to other atypical antipsychotics through breast milk (see clinical considerations) . there is no information on the effects of ziprasidone on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ziprasidone and any potential adverse effects on the breastfed child from ziprasidone or from the mother’s underlying condition. clinical considerations infants exposed to ziprasidone should be monitored for excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements).  infertility females based on the pharmacologic action of ziprasidone (d 2 antagonism), treatment with ziprasidone may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see warnings and precautions ( 5.15) and nonclinical toxicology ( 13.1)]. the safety and effectiveness of ziprasidone have not been established in pediatric patients. ziprasidone was studied in one 4-week, placebo-controlled trial in patients 10 to 17 years of age with bipolar i disorder. however, the data were insufficient to fully assess the safety of ziprasidone in pediatric patients. therefore, a safe and effective dose for use could not be established.  of the total number of subjects in clinical studies of ziprasidone, 2.4 percent were 65 and over. 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. nevertheless, the presence of multiple factors that might increase the pharmacodynamic response to ziprasidone, or cause poorer tolerance or orthostasis, should lead to consideration of a lower starting dose, slower titration, and careful monitoring during the initial dosing period for some elderly patients.  because ziprasidone is highly metabolized, with less than 1% of the drug excreted unchanged, renal impairment alone is unlikely to have a major impact on the pharmacokinetics of ziprasidone. the pharmacokinetics of ziprasidone following 8 days of 20 mg twice daily dosing were similar among subjects with varying degrees of renal impairment (n=27), and subjects with normal renal function, indicating that dosage adjustment based upon the degree of renal impairment is not required. ziprasidone is not removed by hemodialysis. as ziprasidone is cleared substantially by the liver, the presence of hepatic impairment would be expected to increase the auc of ziprasidone; a multiple-dose study at 20 mg twice daily for 5 days in subjects (n=13) with clinically significant (childs-pugh class a and b) cirrhosis revealed an increase in auc 0 to 12 of 13% and 34% in childs-pugh class a and b, respectively, compared to a matched control group (n=14).  a half-life of 7.1 hours was observed in subjects with cirrhosis compared to 4.8 hours in the control group. in a multiple-dose (8 days of treatment) study involving 32 subjects, there was no difference in the pharmacokinetics of ziprasidone between men and women or between elderly (>65 years) and young (18 to 45 years) subjects. additionally, population pharmacokinetic evaluation of patients in controlled trials has revealed no evidence of clinically significant age or gender-related differences in the pharmacokinetics of ziprasidone. dosage modifications for age or gender are, therefore, not recommended. based on in vitro studies utilizing human liver enzymes, ziprasidone is not a substrate for cyp1a2; smoking should therefore not have an effect on the pharmacokinetics of ziprasidone. consistent with these in vitro results, population pharmacokinetic evaluation has not revealed any significant pharmacokinetic differences between smokers and nonsmokers. ziprasidone has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. while the clinical trials did not reveal any tendency for drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which ziprasidone will be misused, diverted, and/or abused once marketed. consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of ziprasidone misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).

United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)

a a h pharmaceuticals ltd - bisoprolol fumarate - oral tablet - 5mg

United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)

actavis uk ltd - bisoprolol fumarate - oral tablet - 5mg

United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)

teva uk ltd - bisoprolol fumarate - oral tablet - 5mg