Australia - englanti - Department of Health (Therapeutic Goods Administration)

cardinal health australia 503 pty ltd - 47179 - hevea-latex surgical glove, powdered - a sterile device made of hevea natural rubber latex (nrl) intended as a protective barrier when worn on the hands of healthcare providers at the surgical site; its inner surface is covered with talcum powder primarily to facilitate donning and removal. the device is used mainly as a two-way barrier to protect both the patient and the staff against contamination from microorganisms. it will have appropriate characteristics regarding tactility and comfort of use, and should provide adequate conditions of sterility, appropriate physical properties (e.g., tensile strength, resistance to puncture, elasticity), and uniformity of dimensions (i.e., sizing consistency). this is a single-use device.

Australia - englanti - Department of Health (Therapeutic Goods Administration)

cardinal health australia 503 pty ltd - 47178 - hevea-latex surgical glove, non-powdered - a sterile device made of hevea natural rubber latex (nrl) intended as a protective barrier when worn on the hands of healthcare providers at the surgical site; its inner surface is not covered with talcum powder. the device is used mainly as a two-way barrier to protect both the patient and the staff against contamination from microorganisms. it will have appropriate characteristics regarding tactility and comfort of use, and should provide adequate conditions of sterility, appropriate physical properties (e.g., tensile strength, resistance to puncture, elasticity), and uniformity of dimensions (i.e., sizing consistency). this is a single-use device.

Yhdysvallat - englanti - NLM (National Library of Medicine)

cardinal health - trazodone hydrochloride (unii: 6e8zo8lrnm) (trazodone - unii:ybk48bxk30) - trazodone hydrochloride tablets are indicated for the treatment of major depressive disorder (mdd) in adults. trazodone hydrochloride tablets are contraindicated in: pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. healthcare providers are encouraged to register patients by calling the national pregnancy registry for antidepressants at 1-844-405- 6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/ risk summary published prospective cohort studies, case series, and case reports over several decades with trazodone use in pregnant women have not identified any drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see data). trazodone hydrochloride has been shown to cause increased fetal resorption and other adverse effects on the fetus in the rat when given at dose levels approximately 7.3 to 11

Yhdysvallat - englanti - NLM (National Library of Medicine)

cardinal health 107, llc - olanzapine (unii: n7u69t4szr) (olanzapine - unii:n7u69t4szr) - oral olanzapine is indicated for the treatment of schizophrenia. efficacy was established in three clinical trials in adult patients with schizophrenia: two 6-week trials and one maintenance trial. in adolescent patients with schizophrenia (ages 13 to 17), efficacy was established in one 6-week trial [ see clinical studies (14.1)].    when deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and dyslipidemia. clinicians should consider the potential long-term risks  when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents [see  warnings and precautions ( 5.5) ].  oral olanzapine is indicated for the acute treatment of manic or mixed episodes associated with bipolar i disorder and maintenance treatment of bipolar i disorder. efficacy was established in three clinical trials in adult patients with manic or mixed episodes of bipolar i disorder: two 3- to 4-week trials and one monotherapy maintenance trial. in adolescent patients with manic or mixed episodes associated with bipolar i disorder (ages 13 to 17), efficacy was established in one 3-week trial [see clinical studies (14.2) ].  when deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and dyslipidemia. clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them  to consider prescribing other drugs first in adolescents [see warnings and precautions (5.5) ]. oral olanzapine is indicated for the treatment of manic or mixed episodes associated with bipolar i disorder as an adjunct to lithium or valproate. efficacy was established in two 6-week clinical trials in adults. the effectiveness of adjunctive therapy for longer-term use has not been systematically evaluated in controlled trials [see clinical studies (14.2) ]. pediatric schizophrenia and bipolar i disorder are serious mental disorders; however, diagnosis can be challenging. for pediatric schizophrenia, symptom profiles can be variable, and for bipolar i disorder, pediatric patients may have variable patterns of periodicity of manic or mixed symptoms. it is recommended that medication therapy for pediatric schizophrenia and bipolar i disorder be initiated only after a thorough diagnostic evaluation has been performed and careful consideration given to the risks associated with medication treatment. medication treatment for both pediatric schizophrenia and bipolar i disorder should be part of a total treatment program that often includes psychological, educational and social interventions. oral olanzapine and fluoxetine in combination is indicated for the treatment of depressive episodes associated with bipolar i disorder, based on clinical studies. when using olanzapine and fluoxetine in combination, refer to the clinical studies section of the package insert for symbyax. olanzapine monotheraphy is not indicated for the treatment of depressive episodes associated with bipolar i disorder. oral olanzapine and fluoxetine in combination is indicated for the treatment of treatment resistant depression (major depressive disorder in patients who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode), based on clinical studies in adult patients. when using olanzapine and fluoxetine in combination, refer to the clinical studies section of the package insert for symbyax. olanzapine monotherapy is not indicated for the treatment of treatment resistant depression.  when using olanzapine and fluoxetine in combination, also refer to the use in specific populations section of the package insert for symbyax. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including olanzapine, during pregnancy. healthcare providers are encouraged to register patients by contacting the national pregnancy registry for atypical antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. risk summary neonates exposed to antipsychotic drugs, including olanzapine, 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 olanzapine 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 olanzapine, during pregnancy (see clinical considerations ). olanzapine was not teratogenic when administered orally to pregnant rats and rabbits at doses that are 9- and 30-times the daily oral maximum recommended human dose (mrhd), based on mg/m2 body surface area; some fetal toxicities were observed at these 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 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. clinical considerations disease-associated maternal and embryo/fetal risk there is a 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 olanzapine, 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 placental passage has been reported in published study reports; however, the placental passage ratio was highly variable ranging between 7% to 167% at birth following exposure during pregnancy. the clinical relevance of this finding is unknown. published data from observational studies, birth registries, and case reports that have evaluated the use of atypical antipsychotics during pregnancy do not establish an increased risk of 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 in oral reproduction studies in rats at doses up to 18 mg/kg/day and in rabbits at doses up to 30 mg/kg/day (9 and 30 times the daily oral mrhd based on mg/m2 body surface area, respectively), no evidence of teratogenicity was observed. in an oral rat teratology study, early resorptions and increased numbers of nonviable fetuses were observed at a dose of 18 mg/kg/day (9 times the daily oral mrhd based on mg/m2 body surface area), and gestation was prolonged at 10 mg/kg/day (5 times the daily oral mrhd based on mg/m2 body surface area). in an oral rabbit teratology study, fetal toxicity manifested as increased resorptions and decreased fetal weight, occurred at a maternally toxic dose of 30 mg/kg/day (30 times the daily oral mrhd based on mg/m2 body surface area). risk summary olanzapine is present in human milk. there are reports of excess sedation, irritability, poor feeding and extrapyramidal symptoms (tremors and abnormal muscle movements) in infants exposed to olanzapine through breast milk (see clinical considerations ). there is no information on the effects of olanzapine on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for olanzapine and any potential adverse effects on the breastfed child from olanzapine or from the mother’s underlying condition. clinical considerations infants exposed to olanzapine 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 olanzapine (d2 receptor antagonism), treatment with olanzapine 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 )]. the safety and effectiveness of oral olanzapine in the treatment of schizophrenia and manic or mixed episodes associated with bipolar i disorder were established in short-term studies in adolescents (ages 13 to 17 years). use of olanzapine in adolescents is supported by evidence from adequate and well-controlled studies of olanzapine in which 268 adolescents received olanzapine in a range of 2.5 to 20 mg/day [see clinical studies (14.1, 14.2) ]. recommended starting dose for adolescents is lower than that for adults [see dosage and administration (2.1, 2.2) ]. compared to patients from adult clinical trials, adolescents were likely to gain more weight, experience increased sedation, and have greater increases in total cholesterol, triglycerides, ldl cholesterol, prolactin and hepatic aminotransferase levels [see warnings and precautions (5.5, 5.15, 5.17) and adverse reactions (6.1 ]. when deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and dyslipidemia. clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents [see indications and usage (1.1, 1.2) ].  safety and effectiveness of olanzapine in children <13 years of age have not been established [see patient counseling information (17) ]. safety and efficacy of olanzapine and fluoxetine in combination in children and adolescents (10 to 17 years of age) have been established for the acute treatment of depressive episodes associated with bipolar i disorder. safety and effectiveness of olanzapine and fluoxetine in combination in children <10 years of age have not been established.   of the 2500 patients in premarketing clinical studies with oral olanzapine, 11% (263) were 65 years of age or over. in patients with schizophrenia, there was no indication of any different tolerability of olanzapine in the elderly compared to younger patients. studies in elderly patients with dementia-related psychosis have suggested that there may be a different tolerability profile in this population compared to younger patients with schizophrenia. elderly patients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo. in placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis, there was a higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) in patients treated with olanzapine compared to patients treated with placebo. in 5 placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis (n=1184), the following adverse reactions were reported in olanzapine-treated patients at an incidence of at least 2% and significantly greater than placebo-treated patients: falls, somnolence, peripheral edema, abnormal gait, urinary incontinence, lethargy, increased weight, asthenia, pyrexia, pneumonia, dry mouth and visual hallucinations. the rate of discontinuation due to adverse reactions was greater with olanzapine than placebo (13% vs 7%). elderly patients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo. olanzapine is not approved for the treatment of patients with dementia-related psychosis [ see boxed warning, warnings and precautions (5.1), and patient counseling information (17)] . olanzapine is not approved for the treatment of patients with dementia-related psychosis. also, the presence of factors that might decrease pharmacokinetic clearance or increase the pharmacodynamic response to olanzapine should lead to consideration of a lower starting dose for any geriatric patient [ see boxed warning, dosage and administration (2.1), and warnings and precautions (5.1)].   clinical studies of olanzapine and fluoxetine in combination did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently from younger patients. in studies prospectively designed to assess abuse and dependence potential, olanzapine was shown to have acute depressive cns effects but little or no potential of abuse or physical dependence in rats administered oral doses up to 15 times the daily oral mrhd (20 mg) and rhesus monkeys administered oral doses up to 8 times the daily oral mrhd based on mg/m2 body surface area.  olanzapine has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. while the clinical trials did not reveal any tendency for any 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 a cns-active drug 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 misuse or abuse of olanzapine (e.g., development of tolerance, increases in dose, drug-seeking behavior).

Yhdysvallat - englanti - NLM (National Library of Medicine)

cardinal health 107, llc - fluoxetine hydrochloride (unii: i9w7n6b1kj) (fluoxetine - unii:01k63sup8d) - fluoxetine 10 mg - fluoxetine capsules are indicated for the treatment of: fluoxetine capsules and olanzapine in combination are indicated for the treatment of: fluoxetine capsules monotherapy is not indicated for the treatment of depressive episodes associated with bipolar i disorder or the treatment of treatment resistant depression. when using fluoxetine capsules and olanzapine in combination, also refer to the clinical studies section of the package insert for symbyax® . when using fluoxetine and olanzapine in combination, also refer to the contraindications section of the package insert for symbyax® . the use of maois intended to treat psychiatric disorders with fluoxetine or within 5 weeks of stopping treatment with fluoxetine is contraindicated because of an increased risk of serotonin syndrome. the use of fluoxetine within 14 days of stopping an maoi intended to treat psychiatric disorders is also contraindicated [see dosage and administration (2.9) and warnings and precautions (5.2)] . starting fluoxetine in a patient who is being treated with maois such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see dosage and administration (2.10) and warnings and precautions (5.2)] . the use of fluoxetine is contraindicated with the following: pimozide and thioridazine prolong the qt interval. fluoxetine can increase the levels of pimozide and thioridazine through inhibition of cyp2d6. fluoxetine can also prolong the qt interval. when using fluoxetine and olanzapine in combination, also refer to the use in specific populations section of the package insert for symbyax® . pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. healthcare providers are encouraged to register patients by calling the national pregnancy registry for antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/.   risk summary based on data from published observational studies, exposure to ssris, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see warnings and precautions (5.7) and clinical considerations] . available data from published epidemiologic studies and postmarketing reports over several decades have not established an increased risk of major birth defects or miscarriage. some studies have reported an increased incidence of cardiovascular malformations; however, these studies results do not establish a causal relationship (see data) . there are risks associated with untreated depression in pregnancy and risks of persistent pulmonary hypertension of the newborn (pphn) (see data) and poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (ssris), including fluoxetine, during pregnancy (see clinical considerations). in rats and rabbits treated with fluoxetine during the period of organogenesis, there was no evidence of developmental effects at doses up to 1.6 and 3.9 times, respectively, the maximum recommended human dose (mrhd) of 60 mg/day given to adolescents on a mg/m2 basis. however, in other reproductive studies in rats, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths early after birth occurred at doses that are 1.5 times (during gestation) and 0.97 time (during gestation and lactation) the mrhd given to adolescents on a mg/m2 basis. 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 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 women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. this finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. maternal adverse reactions use of fluoxetine in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see warnings and precautions (5.7)] . fetal/neonatal adverse reactions  neonates exposed to fluoxetine and other ssri or snris late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. such complications can arise immediately upon delivery. reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremors, jitteriness, irritability, and constant crying. these findings are consistent with either a direct toxic effect of ssris and snris or possibly a drug discontinuation syndrome. it should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see warnings and precautions (5.2)] . data human data — it has been shown that ssris (including fluoxetine) can cross the placenta. published epidemiological studies of pregnant women exposed to fluoxetine have not established an increased risk of major birth defects, miscarriage, and other adverse developmental outcomes. several publications reported an increased incidence of cardiovascular malformations in children with in utero exposure to fluoxetine. however, these studies results do not establish a causal relationship. methodologic limitations of these observational studies include possible exposure and outcome misclassification, lack of adequate controls, adjustment for confounders and confirmatory studies. however, these studies cannot definitely establish or exclude any drug-associated risk during pregnancy. exposure to ssris, particularly later in pregnancy, may have an increased risk for pphn. pphn occurs in 1 to 2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. animal data — in embryofetal development studies in rats and rabbits, there was no evidence of malformations or developmental variations following administration of fluoxetine at doses up to 12.5 and 15 mg/kg/day, respectively (1.6 and 3.9 times, respectively, the mrhd of 60 mg given to adolescents on a mg/m2 basis) throughout organogenesis. however, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the mrhd given to adolescents on a mg/m2 basis) during gestation or 7.5 mg/kg/day (0.97 time the mrhd given to adolescents on a mg/m2 basis) during gestation and lactation. there was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. the no-effect dose for rat pup mortality was 5 mg/kg/day (0.65 time the mrhd given to adolescents on a mg/m2 basis). risk summary data from published literature report the presence of fluoxetine and norfluoxetine in human milk (see data). there are reports of agitation, irritability, poor feeding, and poor weight gain in infants exposed to fluoxetine through breast milk (see clinical considerations). there are no data on the effect of fluoxetine or its metabolites on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for fluoxetine and any potential adverse effects on the breastfed child from fluoxetine or the underlying maternal condition. clinical considerations infants exposed to fluoxetine should be monitored for agitation, irritability, poor feeding, and poor weight gain. data a study of 19 nursing mothers on fluoxetine with daily doses of 10-60 mg showed that fluoxetine was detectable in 30% of nursing infant sera (range: 1 to 84 ng/ml) whereas norfluoxetine was found in 85% (range: <1 to 265 ng/ml). use of fluoxetine in children — the efficacy of fluoxetine for the treatment of major depressive disorder was demonstrated in two 8- to 9-week placebo-controlled clinical trials with 315 pediatric outpatients ages 8 to ≤18 [see clinical studies (14.1)] . the efficacy of fluoxetine for the treatment of ocd was demonstrated in one 13-week placebo-controlled clinical trial with 103 pediatric outpatients ages 7 to <18 [see clinical studies (14.2)] . the safety and effectiveness in pediatric patients <8 years of age in major depressive disorder and <7 years of age in ocd have not been established. fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (ages 6 to ≤18) with major depressive disorder or ocd [see clinical pharmacology (12.3)] . the acute adverse reaction profiles observed in the 3 studies (n=418 randomized; 228 fluoxetine-treated, 190 placebo-treated) were generally similar to that observed in adult studies with fluoxetine. the longer-term adverse reaction profile observed in the 19-week major depressive disorder study (n=219 randomized; 109 fluoxetine-treated, 110 placebo-treated) was also similar to that observed in adult trials with fluoxetine [see adverse reactions (6.1)] . manic reaction, including mania and hypomania, was reported in 6 (1 mania, 5 hypomania) out of 228 (2.6%) fluoxetine-treated patients and in 0 out of 190 (0%) placebo-treated patients. mania/hypomania led to the discontinuation of 4 (1.8%) fluoxetine-treated patients from the acute phases of the 3 studies combined. consequently, regular monitoring for the occurrence of mania/hypomania is recommended. as with other ssris, decreased weight gain has been observed in association with the use of fluoxetine in children and adolescent patients. after 19 weeks of treatment in a clinical trial, pediatric subjects treated with fluoxetine gained an average of 1.1 cm less in height and 1.1 kg less in weight than subjects treated with placebo. in addition, fluoxetine treatment was associated with a decrease in alkaline phosphatase levels. the safety of fluoxetine treatment for pediatric patients has not been systematically assessed for chronic treatment longer than several months in duration. in particular, there are no studies that directly evaluate the longer-term effects of fluoxetine on the growth, development and maturation of children and adolescent patients. therefore, height and weight should be monitored periodically in pediatric patients receiving fluoxetine [see warnings and precautions (5.6)] . fluoxetine is approved for use in pediatric patients with mdd and ocd [see box warning and warnings and precautions (5.1)] . anyone considering the use of fluoxetine in a child or adolescent must balance the potential risks with the clinical need. animal data - significant toxicity on muscle tissue, neurobehavior, reproductive organs, and bone development has been observed following exposure of juvenile rats to fluoxetine from weaning through maturity. oral administration of fluoxetine to rats from weaning postnatal day 21 through adulthood day 90 at 3, 10, or 30 mg/kg/day was associated with testicular degeneration and necrosis, epididymal vacuolation and hypospermia (at 30 mg/kg/day corresponding to plasma exposures [auc] approximately 5 to 10 times the average auc in pediatric patients at the mrhd of 20 mg/day), increased serum levels of creatine kinase (at auc as low as 1 to 2 times the average auc in pediatric patients at the mrhd of 20 mg/day), skeletal muscle degeneration and necrosis, decreased femur length/growth and body weight gain (at auc 5 to 10 times the average auc in pediatric patients at the mrhd of 20 mg/day). the high dose of 30 mg/kg/day exceeded a maximum tolerated dose. when animals were evaluated after a drug-free period (up to 11 weeks after cessation of dosing), fluoxetine was associated with neurobehavioral abnormalities (decreased reactivity at auc as low as approximately 0.1 to 0.2 times the average auc in pediatric patients at the mrhd and learning deficit at the high dose), and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose). in addition, the testicular and epididymal microscopic lesions and decreased sperm concentrations found in high dose group were also observed, indicating that the drug effects on reproductive organs are irreversible. the reversibility of fluoxetine-induced muscle damage was not assessed. these fluoxetine toxicities in juvenile rats have not been observed in adult animals. plasma exposures (auc) to fluoxetine in juvenile rats receiving 3, 10, or 30 mg/kg/day doses in this study are approximately 0.1 to 0.2, 1 to 2, and 5 to 10 times, respectively, the average exposure in pediatric patients receiving the mrhd of 20 mg/day. rat exposures to the major metabolite, norfluoxetine, are approximately 0.3 to 0.8, 1 to 8, and 3 to 20 times, respectively, the pediatric exposure at the mrhd. a specific effect on bone development was reported in juvenile mice administered fluoxetine by the intraperitoneal route to 4 week old mice for 4 weeks at doses 0.5 and 2 times the oral mrhd of 20 mg/day on mg/m2 basis. there was a decrease in bone mineralization and density at both doses, but the overall growth (body weight gain or femur length) was not affected. use of fluoxetine in combination with olanzapine in children and adolescents: safety and efficacy of fluoxetine and olanzapine in combination in patients 10 to 17 years of age have been established for the acute treatment of depressive episodes associated with bipolar i disorder. safety and effectiveness of fluoxetine and olanzapine in combination in patients less than 10 years of age have not been established. us fluoxetine clinical trials included 687 patients ≥65 years of age and 93 patients ≥75 years of age. the efficacy in geriatric patients has been established [see clinical studies (14.1)] . for pharmacokinetic information in geriatric patients, [see clinical pharmacology (12.4)] . 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. snris and ssris, including fluoxetine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see warnings and precautions (5.9)] . clinical studies of olanzapine and fluoxetine in combination did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently from younger patients. in subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances. a lower or less frequent dose of fluoxetine should be used in patients with cirrhosis. caution is advised when using fluoxetine in patients with diseases or conditions that could affect its metabolism [see dosage and administration (2.7) and clinical pharmacology (12.4)] . fluoxetine has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. while the premarketing clinical experience with fluoxetine did not reveal any tendency for a withdrawal syndrome or any 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 a cns active drug will be misused, diverted, and/or abused once marketed. consequently, healthcare providers should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of fluoxetine (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).

Yhdysvallat - englanti - NLM (National Library of Medicine)

cardinal health 107, llc - mirtazapine (unii: a051q2099q) (mirtazapine - unii:a051q2099q) - mirtazapine tablets are indicated for the treatment of major depressive disorder (mdd) in adults [see clinical studies (14)]. mirtazapine tablets are contraindicated in patients: • taking, or within 14 days of stopping, maois (including the maois linezolid and intravenous methylene blue) because of an increased risk of serotonin syndrome [see warnings and precautions (5.3), drug interactions (7)], drug interactions ( 7)]. • with a known hypersensitivity to mirtazapine or to any of the excipients in mirtazapine tablets. severe skin reactions, including stevens-johnson syndrome, bullous dermatitis, erythema multiforme and toxic epidermal necrolysis have been reported following the use of mirtazapine tablets [see adverse reactions (6.2)]. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. healthcare providers are encouraged to register patients by calling thenational pregnancy registry for antidepressants a

Yhdysvallat - englanti - NLM (National Library of Medicine)

cardinal health 107, llc - bupropion hydrochloride (unii: zg7e5poy8o) (bupropion - unii:01zg3tpx31) - bupropion hydrochloride extended-release tablets (sr) are indicated for the treatment of major depressive disorder (mdd), as defined by the diagnostic and statistical manual (dsm) . the efficacy of bupropion in the treatment of a major depressive episode was established in two 4-week controlled inpatient trials and one 6-week controlled outpatient trial of adult subjects with mdd [see clinical studies (14)]. the efficacy of bupropion hydrochloride extended-release tablets (sr) in maintaining an antidepressant response for up to 44 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial [see clinical studies (14)] . pregnancy exposure registry there is an independent pregnancy exposure registry that monitors pregnancy outcomes in women exposed to any antidepressants during pregnancy. healthcare providers are encouraged to register patients by calling the national pregnancy registry for antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clini

Yhdysvallat - englanti - NLM (National Library of Medicine)

cardinal health 107, llc - bupropion hydrochloride (unii: zg7e5poy8o) (bupropion - unii:01zg3tpx31) - bupropion hydrochloride tablets are indicated for the treatment of major depressive disorder (mdd), as defined by the diagnostic and statistical manual (dsm). the efficacy of bupropion hydrochloride tablets in the treatment of a major depressive episode was established in two 4-week controlled inpatient trials and one 6-week controlled outpatient trial of adult subjects with mdd [see clinical studies (14)]. pregnancy exposure registry   there is an independent pregnancy exposure registry that monitors pregnancy outcomes in women exposed to any antidepressants during pregnancy. healthcare providers are encouraged to register patients by calling the national pregnancy registry for antidepressants at 1-844-4056185 or visiting online at https://womensmentalhealth.org/clinical-and-researchprograms/pregnancyregistry/antidepressants.   risk summary data from epidemiological studies of pregnant women exposed to bupropion in the first trimester have not identified an increased risk of congenital malformations overall (see data). there are risks to the mother associated with untreated depression in pregnancy (see clinical considerations). when bupropion was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 10 times the maximum recommended human dose (mrhd) of 450 mg/day. when given to pregnant rabbits during organogenesis, non-dose–related increases in incidence of fetal malformations and skeletal variations were observed at doses approximately equal to the mrhd and greater. decreased fetal weights were seen at doses twice the mrhd and greater (see animal data).   the estimated background risk for major birth defects and miscarriage is unknown for the indicated population. 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 of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.   clinical considerations   disease-associated maternal and/or embryo/fetal risk: a prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants during pregnancy at the beginning of pregnancy. the women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. consider the risks to the mother of untreated depression and potential effects on the fetus when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum.   data   human data data from the international bupropion pregnancy registry (675 first-trimester exposures) and a retrospective cohort study using the united healthcare database (1,213 first trimester exposures) did not show an increased risk for malformations overall. the registry was not designed or powered to evaluate specific defects but suggested a possible increase in cardiac malformations.   no increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester. the prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester from the international pregnancy registry was 1.3% (9 cardiovascular malformations/675 first-trimester maternal bupropion exposures), which is similar to the background rate of cardiovascular malformations (approximately 1%). data from the united healthcare database, which had a limited number of exposed cases with cardiovascular malformations, and a case-control study (6,853 infants with cardiovascular malformations and 5,763 with non-cardiovascular malformations) of self-reported bupropion use from the national birth defects prevention study (nbdps) did not show an increased risk for cardiovascular malformations overall after bupropion exposure during the first trimester.   study findings on bupropion exposure during the first trimester and risk for left ventricular outflow tract obstruction (lvoto) are inconsistent and do not allow conclusions regarding a possible association. the united healthcare database lacked sufficient power to evaluate this association; the nbdps found increased risk for lvoto (n = 10; adjusted or = 2.6; 95% ci: 1.2, 5.7), and the slone epidemiology case control study did not find increased risk for lvoto.   study findings on bupropion exposure during the first trimester and risk for ventricular septal defect (vsd) are inconsistent and do not allow conclusions regarding a possible association. the slone epidemiology study found an increased risk for vsd following first trimester maternal bupropion exposure (n = 17; adjusted or = 2.5; 95% ci: 1.3, 5.0) but did not find increased risk for any other cardiovascular malformations studied (including lvoto as above). the nbdps and united healthcare database study did not find an association between first trimester maternal bupropion exposure and vsd.   for the findings of lvoto and vsd, the studies were limited by the small number of exposed cases, inconsistent findings among studies, and the potential for chance findings from multiple comparisons in case control studies.   animal data: in studies conducted in pregnant rats and rabbits, bupropion was administered orally during the period of organogenesis at doses of up to 450 and 150 mg/kg/day, respectively (approximately 10 and 6 times the mrhd, respectively, on a mg/m2 basis). there was no evidence of fetal malformations in rats. when given to pregnant rabbits during organogenesis, non-dose–related increases in incidence of fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg/kg/day, approximately equal to the mrhd on a mg/m2 basis) and greater. decreased fetal weights were observed at doses of 50 mg/kg/day (approximately 2 times the mrhd on a mg/m2 basis) and greater. no maternal toxicity was evident at doses of 50 mg/kg/day or less. in a pre-and postnatal development study, bupropion administered orally to pregnant rats at doses of up to 150 mg/kg/day (approximately 3 times the mrhd on a mg/m2 basis) from embryonic implantation through lactation had no effect on pup growth or development. risk summary   data from published literature report the presence of bupropion and its metabolites in human milk (see data). there are no data on the effects of bupropion or its metabolites on milk production. limited data from postmarketing reports have not identified a clear association of adverse reactions in the breastfed infant. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for bupropion hydrochloride tablets and any potential adverse effects on the breastfed child from bupropion hydrochloride tablets or from the underlying maternal condition.   data in a lactation study of 10 women, levels of orally dosed bupropion and its active metabolites were measured in expressed milk. the average daily infant exposure (assuming 150 ml/kg daily consumption) to bupropion and its active metabolites was 2% of the maternal weight-adjusted dose. postmarketing reports have described seizures in breastfed infants. the relationship of bupropion exposure and these seizures is unclear. safety and effectiveness in the pediatric population have not been established [see boxed warning, warnings and precautions (5.1)] . of the approximately 6,000 subjects who participated in clinical trials with bupropion sustained-release tablets (depression and smoking cessation trials), 275 were aged ≥65 years and 47 were aged ≥75 years. in addition, several hundred subjects aged ≥65 years participated in clinical trials using the immediate-release formulation of bupropion (depression trials). no overall differences in safety or effectiveness were observed between these subjects and younger subjects. 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. bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and excreted by the kidneys. the risk of adverse reactions may be greater in patients with impaired renal function. because elderly patients are more likely to have decreased renal function, it may be necessary to consider this factor in dose selection; it may be useful to monitor renal function [see dosage and administration (2.3), use in specific populations (8.6),  clinical pharmacology (12.3)] . consider a reduced dose and/or dosing frequency of bupropion hydrochloride tablets in patients with renal impairment (glomerular filtration rate: less than 90 ml/min). bupropion and its metabolites are cleared renally and may accumulate in such patients to a greater extent than usual. monitor closely for adverse reactions that could indicate high bupropion or metabolite exposures [see dosage and administration (2.3), clinical pharmacology (12.3)] . in patients with moderate to severe hepatic impairment (child-pugh score: 7 to 15), the maximum dose of bupropion hydrochloride tablets is 75 mg daily. in patients with mild hepatic impairment (child-pugh score: 5 to 6), consider reducing the dose and/or frequency of dosing [see dosage and administration (2.2), clinical pharmacology (12.3)] . bupropion is not a controlled substance. humans controlled clinical trials conducted in normal volunteers, in subjects with a history of multiple drug abuse, and in depressed subjects showed some increase in motor activity and agitation/excitement, often typical of central stimulant activity. in a population of individuals experienced with drugs of abuse, a single oral dose of 400 mg of bupropion produced mild amphetamine-like activity as compared with placebo on the morphine-benzedrine subscale of the addiction research center inventories (arci) and a score greater than placebo but less than 15 mg of the schedule ii stimulant dextroamphetamine on the liking scale of the arci. these scales measure general feelings of euphoria and drug liking which are often associated with abuse potential. findings in clinical trials, however, are not known to reliably predict the abuse potential of drugs. nonetheless, evidence from single-dose trials does suggest that the recommended daily dosage of bupropion when administered orally in divided doses is not likely to be significantly reinforcing to amphetamine or cns stimulant abusers. however, higher doses (which could not be tested because of the risk of seizure) might be modestly attractive to those who abuse cns stimulant drugs. bupropion hydrochloride tablets are intended for oral use only. the inhalation of crushed tablets or injection of dissolved bupropion has been reported. seizures and/or cases of death have been reported when bupropion has been administered intranasally or by parenteral injection. animals studies in rodents and primates demonstrated that bupropion exhibits some pharmacologic actions common to psychostimulants. in rodents, it has been shown to increase locomotor activity, elicit a mild stereotyped behavior response, and increase rates of responding in several schedule-controlled behavior paradigms. in primate models assessing the positive-reinforcing effects of psychoactive drugs, bupropion was self-administered intravenously. in rats, bupropion produced amphetamine-like and cocaine-like discriminative stimulus effects in drug discrimination paradigms used to characterize the subjective effects of psychoactive drugs.

Yhdysvallat - englanti - NLM (National Library of Medicine)

cardinal health - gabapentin (unii: 6cw7f3g59x) (gabapentin - unii:6cw7f3g59x) - gabapentin 300 mg - gabapentin is indicated for: gabapentin is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients. pregnancy category c there are no adequate and well-controlled studies in pregnant women. in nonclinical studies in mice, rats, and rabbits, gabapentin was developmentally toxic when administered to pregnant animals at doses similar to or lower than those used clinically. gabapentin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. when pregnant mice received oral doses of gabapentin (500, 1000, or 3000 mg/kg/day) during the period of organogenesis, embryo-fetal toxicity (increased incidences of skeletal variations) was observed at the two highest doses. the no-effect dose for embryo-fetal developmental toxicity in mice was 500 mg/kg/day or approximately ½ of the maximum recommended human dose (mrhd) of 3600 mg/kg on a body surface area (mg/m2 ) basis. in studies in which rats received oral doses of gabapentin (500

Yhdysvallat - englanti - NLM (National Library of Medicine)

cardinal health 107, llc - sertraline hydrochloride (unii: uti8907y6x) (sertraline - unii:quc7nx6wmb) - sertraline tablets are indicated for the treatment of the following [see clinical studies (14)]: sertraline is contraindicated in patients: risk summary overall, available published epidemiologic studies of pregnant women exposed to sertraline in the first trimester suggest no difference in major birth defect risk compared to the background rate for major birth defects in comparator populations. some studies have reported increases for specific major birth defects; however, these study results are inconclusive [see data] . there are clinical considerations regarding neonates exposed to ssris and snris, including sertraline, during the third trimester of pregnancy [see clinical considerations]. although no teratogenicity was observed in animal reproduction studies, delayed fetal ossification was observed when sertraline was administered during the period of organogenesis at doses less than the maximum recommended human dose (mrhd) in rats and doses 3.1 times the mrhd in rabbits on a mg/m 2 basis in adolescents. when sertraline was administered to female rats during the last third of gestation, there was an increase in the number of stillborn pups and pup deaths during the first four days after birth at the mrhd [see data] . the background risk of major birth defects and miscarriage for the indicated population are unknown. 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. advise a pregnant woman of possible risks to the fetus when prescribing sertraline. clinical considerations disease-associated maternal and/or embryo/fetal risk a prospective longitudinal study followed 201 pregnant women with a history of major depression who were euthymic taking antidepressants at the beginning of pregnancy. the women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. consider the risks of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. fetal/neonatal adverse reactions exposure to ssris and snris, including sertraline in late pregnancy may lead to an increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding, and/or persistent pulmonary hypertension of the newborn (pphn). when treating a pregnant woman with sertraline during the third trimester, carefully consider both the potential risks and benefits of treatment. monitor neonates who were exposed to sertraline in the third trimester of pregnancy for pphn and drug discontinuation syndrome [see data]. data human data third trimester exposure neonates exposed to sertraline and other ssris or snris late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. these findings are based on post-marketing reports. such complications can arise immediately upon delivery. reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. these features are consistent with either a direct toxic effect of ssris and snris or, possibly, a drug discontinuation syndrome. in some cases, the clinical picture was consistent with serotonin syndrome [see warnings and precautions (5.2)]. exposure during late pregnancy to ssris may have an increased risk for persistent pulmonary hypertension of the newborn (pphn). pphn occurs in 1-2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. in a retrospective case-control study of 377 women whose infants were born with pphn and 836 women whose infants were born healthy, the risk for developing pphn was approximately six-fold higher for infants exposed to ssris after the 20 th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. a study of 831,324 infants born in sweden in 1997-2005 found a pphn risk ratio of 2.4 (95% ci 1.2-4.3) associated with patient-reported maternal use of ssris “in early pregnancy” and a pphn risk ratio of 3.6 (95% ci 1.2-8.3) associated with a combination of patient-reported maternal use of ssris “in early pregnancy” and an antenatal ssri prescription “in later pregnancy”. first trimester exposure the weight of evidence from epidemiologic studies of pregnant women exposed to sertraline in the first trimester suggest no difference in major birth defect risk compared to the background rate for major birth defects in pregnant women who were not exposed to sertraline. a meta-analysis of studies suggest no increase in the risk of total malformations (summary odds ratio=1.01, 95% ci=0.88-1.17) or cardiac malformations (summary odds ratio=0.93, 95% ci=0.70-1.23) among offspring of women with first trimester exposure to sertraline. an increased risk of congenital cardiac defects, specifically septal defects, the most common type of congenital heart defect, was observed in some published epidemiologic studies with first trimester sertraline exposure; however, most of these studies were limited by the use of comparison populations that did not allow for the control of confounders such as the underlying depression and associated conditions and behaviors, which may be factors associated with increased risk of these malformations. animal data reproduction studies have been performed in rats and rabbits at doses up to 80 mg/kg/day and 40 mg/kg/day, respectively. these doses correspond to approximately 3.1 times the maximum recommended human dose (mrhd) of 200 mg/day on a mg/m 2 basis in adolescents. there was no evidence of teratogenicity at any dose level. when pregnant rats and rabbits were given sertraline during the period of organogenesis, delayed ossification was observed in fetuses at doses of 10 mg/kg (0.4 times the mrhd on a mg/m 2 basis) in rats and 40 mg/kg (3.1 times the mrhd on a mg/m 2 basis) in rabbits. when female rats received sertraline during the last third of gestation and throughout lactation, there was an increase in stillborn pups and pup deaths during the first 4 days after birth. pup body weights were also decreased during the first four days after birth. these effects occurred at a dose of 20 mg/kg (0.8 times the mrhd on a mg/m 2 basis). the no effect dose for rat pup mortality was 10 mg/kg (0.4 times the mrhd on a mg/m 2 basis). the decrease in pup survival was shown to be due to in utero exposure to sertraline. the clinical significance of these effects is unknown. risk summary available data from published literature demonstrate low levels of sertraline and its metabolites in human milk [see data] . there are no data on the effects of sertraline on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for sertraline and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition. data in a published pooled analysis of 53 mother-infant pairs, exclusively human milk-fed infants had an average of 2% (range 0% to 15%) of the sertraline serum levels measured in their mothers. no adverse reactions were observed in these infants. the safety and efficacy of sertraline have been established in the treatment of ocd in pediatric patients aged 6 to 17 [see adverse reactions (6.1), clinical pharmacology (12.3), clinical studies (14.2)]. safety and effectiveness in pediatric patients in patients with ocd below the age of 6 have not been established. safety and effectiveness have not been established in pediatric patients for indications other than ocd. two placebo-controlled trials were conducted in pediatric patients with mdd, but the data were not sufficient to support an indication for use in pediatric patients. monitoring pediatric patients treated with sertraline monitor all patients being treated with antidepressants for clinical worsening, suicidal thoughts, and unusual changes in behavior, especially during the initial few months of treatment, or at times of dose increases or decreases [see boxed warning, warnings and precautions (5.1)]. decreased appetite and weight loss have been observed with the use of ssris. monitor weight and growth in pediatric patients treated with an ssri such as sertraline. weight loss in studies in pediatric patients with mdd in a pooled analysis of two 10-week, double-blind, placebo-controlled, flexible dose (50-200 mg) outpatient trials for mdd (n=373), there was a difference in weight change between sertraline and placebo of roughly 1 kg, for both children (ages 6-11) and adolescents (ages 12-17), in both age groups representing a slight weight loss for the sertraline group compared to a slight gain for the placebo group. for children, about 7% of the sertraline-treated patients had a weight loss greater than 7% of body weight compared to 0% of the placebo-treated patients; for adolescents, about 2% of sertraline-treated patients had a weight loss > 7% of body weight compared to about 1% of placebo-treated patients. a subset of patients who completed the randomized controlled trials in patients with mdd (sertraline n=99, placebo n=122) were continued into a 24-week, flexible-dose, open-label, extension study. those subjects who completed 34 weeks of sertraline treatment (10 weeks in a placebo-controlled trial + 24 weeks open-label, n=68) had weight gain that was similar to that expected using data from age-adjusted peers. however, there are no studies that directly evaluate the long-term effects of sertraline on the growth, development, and maturation in pediatric patients. juvenile animal data a study conducted in juvenile rats at clinically relevant doses showed delay in sexual maturation, but there was no effect on fertility in either males or females. in this study in which juvenile rats were treated with oral doses of sertraline at 0, 10, 40 or 80 mg/kg/day from postnatal day 21 to 56, a delay in sexual maturation was observed in males treated with 80 mg/kg/day and females treated with doses ≥10 mg/kg/day. there was no effect on male and female reproductive endpoints or neurobehavioral development up to the highest dose tested (80 mg/kg/day), except a decrease in auditory startle response in females at 40 and 80 mg/kg/day at the end of treatment but not at the end of the drug –free period. the highest dose of 80 mg/kg/day produced plasma levels (auc) of sertraline 5 times those seen in pediatric patients (6 – 17 years of age) receiving the maximum recommended dose of sertraline (200 mg/day). of the total number of patients in clinical studies of sertraline in patients with mdd, ocd, pd, ptsd, sad and pmdd, 797 (17%) were ≥ 65 years old, while 197 (4%) were ≥ 75 years old. 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. in general, dose selection for an elderly patient should be conservative, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. in 354 geriatric subjects treated with sertraline in mdd placebo-controlled trials, the overall profile of adverse reactions was generally similar to that shown in table 3 [see adverse reactions (6.1)], except for tinnitus, arthralgia with an incidence of at least 2% and at a rate greater than placebo in geriatric patients. snris and ssris, including sertraline, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see warnings and precautions (5.8)]. the recommended dosage in patients with mild hepatic impairment (child-pugh score 5 or 6) is half the recommended dosage due to increased exposure in this patient population. the use of sertraline in patients with moderate (child-pugh score 7 to 10) or severe hepatic impairment (child-pugh score 10-15) is not recommended, because sertraline is extensively metabolized, and the effects of sertraline in patients with moderate and severe hepatic impairment have not been studied [see dosage and administration (2.4), clinical pharmacology (12.3)]. no dose adjustment is needed in patients with mild to severe renal impairment. sertraline exposure does not appear to be affected by renal impairment [see clinical pharmacology (12.3)]. sertraline is not a controlled substance. in a placebo-controlled, double-blind, randomized study of the comparative abuse liability of sertraline, alprazolam, and d-amphetamine in humans, sertraline did not produce the positive subjective effects indicative of abuse potential, such as euphoria or drug liking, that were observed with the other two drugs.