Spojené státy - angličtina - NLM (National Library of Medicine)

avkare - telmisartan (unii: u5syw473rq) (telmisartan - unii:u5syw473rq) - telmisartan 20 mg - telmisartan 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 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 variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. the largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmhg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). these considerations may guide selection of therapy. telmisartan tablets may be used alone or in combination with other antihypertensive agents [see clinical studies (14.1)]. use of telmisartan and ace inhibitor is not recommended see warnings and precautions (5.6). telmisartan tablets are contraindicated in patients with known hypersensitivity (e.g., anaphylaxis or angioedema) to telmisartan or any other component of this product [see adverse reactions (6.2)]. do not co-administer aliskiren with telmisartan in patients with diabetes [see drug interactions (7)]. risk summary telmisartan can cause fetal harm when administered to a pregnant woman. use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death (see clinical considerations) . most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. studies in rats and rabbits with telmisartan showed fetotoxicity only at maternally toxic doses (see data) . when pregnancy is detected, discontinue telmisartan as soon as possible. the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. pregnant women with hypertension should be carefully monitored and managed accordingly. fetal/neonatal adverse reactions use of drugs that act on the ras in the second and third trimesters of pregnancy can result in the following: oligohydramnios, reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension, and death. in the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. in patients taking telmisartan during pregnancy, perform serial ultrasound examinations to assess the intra-amniotic environment. fetal testing may be appropriate, based on the week of gestation. if oligohydramnios is observed, discontinue telmisartan, unless it is considered lifesaving for the mother. patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. closely observe infants with histories of in utero exposure to telmisartan for hypotension, oliguria, and hyperkalemia. if oliguria or hypotension occurs, support blood pressure and renal perfusion. exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function [see use in specific populations (8.4)]. data animal data no teratogenic effects were observed when telmisartan was administered to pregnant rats at oral doses of up to 50 mg/kg/day and to pregnant rabbits at oral doses up to 45 mg/kg/day. in rabbits, embryolethality associated with maternal toxicity (reduced body weight gain and food consumption) was observed at 45 mg/kg/day [about 12 times the maximum recommended human dose (mrhd) of 80 mg on a mg/m 2 basis]. in rats, maternally toxic (reduction in body weight gain and food consumption) telmisartan doses of 15 mg/kg/day (about 1.9 times the mrhd on a mg/m 2 basis), administered during late gestation and lactation, were observed to produce adverse effects in neonates, including reduced viability, low birth weight, delayed maturation, and decreased weight gain. the no observed effect doses for developmental toxicity in rats and rabbits, 5 and 15 mg/kg/day, respectively, are about 0.64 and 3.7 times, on a mg/m 2 basis, the maximum recommended human dose of telmisartan (80 mg/day). risk summary there is no information regarding the presence of telmisartan in human milk, the effects on the breastfed infant, or the effects on milk production. telmisartan is present in the milk of lactating rats (see data). because of the potential for serious adverse reactions in the breastfed infant including hypotension, hyperkalemia and renal impairment, advise a nursing woman not to breastfeed during treatment with telmisartan. data telmisartan was present in the milk of lactating rats at concentrations 1.5 to 2 times those found in plasma from 4 to 8 hours after administration. safety and effectiveness in pediatric patients have not been established [see clinical pharmacology ( 12.3)]. neonates with a history of in utero exposure to telmisartan: if oliguria or hypotension occurs, support blood pressure and renal perfusion. exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. of the total number of patients receiving telmisartan in hypertension clinical studies, 551 (19%) were 65 to 74 years of age and 130 (4%) were 75 years or older. no overall differences in effectiveness and safety were observed in these patients compared to younger patients 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. monitor carefully and uptitrate slowly in patients with biliary obstructive disorders or hepatic insufficiency [see warnings and precautions (5.4)].

Spojené státy - angličtina - NLM (National Library of Medicine)

a-s medication solutions - darunavir ethanolate (unii: 33o78xf0bw) (darunavir - unii:yo603y8113), cobicistat (unii: lw2e03m5pg) (cobicistat - unii:lw2e03m5pg) - darunavir 800 mg - prezcobix is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (hiv-1) infection in treatment-naïve and treatment-experienced adults and pediatric patients weighing at least 40 kg with no darunavir resistance-associated substitutions (v11i, v32i, l33f, i47v, i50v, i54l, i54m, t74p, l76v, i84v, l89v). darunavir and cobicistat are both inhibitors of the cytochrome p450 3a (cyp3a) isoform. prezcobix should not be co-administered with medicinal products that are highly dependent on cyp3a for clearance and for which increased plasma concentrations are associated with serious and/or life threatening events (narrow therapeutic index). darunavir and cobicistat are both substrates of the cytochrome p450 3a (cyp3a) isoform. co-administration of prezcobix with cyp3a inducers may lead to lower exposures of darunavir and cobicistat and potential loss of efficacy of darunavir and possible resistance. examples of drugs that are contraindicated for co-administration with prezcobix [see drug interactions (7.3)and clinical pharmacology (12.3)] are listed below. - alpha 1-adrenoreceptor antagonist: alfuzosin - anticonvulsants: carbamazepine, phenobarbital, phenytoin - anti-gout: colchicine, in patients with renal and/or hepatic impairment - antimycobacterial: rifampin - antipsychotics: lurasidone, pimozide - cardiac disorders: dronedarone, ivabradine, ranolazine - ergot derivatives, e.g. dihydroergotamine, ergotamine, methylergonovine - herbal product: st. john's wort ( hypericum perforatum ) - hepatitis c direct acting antiviral: elbasvir/grazoprevir - lipid modifying agents: lomitapide, lovastatin, simvastatin - opioid antagonist: naloxegol - pde-5 inhibitor: sildenafil when used for treatment of pulmonary arterial hypertension - sedatives/hypnotics: orally administered midazolam, triazolam pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to prezcobix during pregnancy. healthcare providers are encouraged to register patients by calling the antiretroviral pregnancy registry (apr) 1-800-258-4263. risk summary prezcobix is not recommended during pregnancy because of substantially lower exposures of darunavir and cobicistat during the second and third trimesters [see dosage and administration (2.5)] . a study evaluating the pharmacokinetics of antiretrovirals during pregnancy demonstrated substantially lower exposures of darunavir and cobicistat in the second and third trimesters compared to the post-partum period (see data) and [see clinical pharmacology (12.3)]. prospective pregnancy data from the apr are not sufficient to adequately assess the risk of birth defects or miscarriage. however, available data from the apr show no statistically significant difference in the overall risk of major birth defects for darunavir and cobicistat compared with the background rate for major birth defects of 2.7% in a u.s. reference population of the metropolitan atlanta congenital defects program (macdp) (see data) . the rate of miscarriage is not reported in the apr. the estimated background rate of miscarriage in clinically recognized pregnancies in the u.s. general population is 15–20%. the background risk of major birth defects and miscarriage for the indicated population is unknown. in animal reproduction studies, no adverse developmental effects were observed when the components of prezcobix were administered separately at darunavir exposures less than 1 (mice and rabbits) and 3-times (rats), and at cobicistat exposures 1.6 (rats) and 3.8 (rabbits) times human exposures at the recommended daily dose of these components in prezcobix (see data) . no adverse developmental effects were seen when cobicistat was administered to rats through lactation at cobicistat exposures up to 1.2 times the human exposure at the recommended therapeutic dose. clinical considerations not recommended during pregnancy prezcobix is not recommended for use during pregnancy because of substantially lower exposures of darunavir and cobicistat during pregnancy (see data) and [see clinical pharmacology (12.3)] . prezcobix should not be initiated in pregnant individuals. an alternative regimen is recommended for individuals who become pregnant during therapy with prezcobix. data human data prezcobix in combination with a background regimen was evaluated in a clinical trial of 7 pregnant individuals taking prezcobix prior to enrollment and who were willing to remain on prezcobix throughout the study. the study period included the second and third trimesters, and through 12 weeks postpartum. six pregnant individuals completed the trial. exposure to darunavir and cobicistat as part of an antiretroviral regimen was substantially lower during the second and third trimesters of pregnancy compared with postpartum [see clinical pharmacology (12.3)] . one out of 6 pregnant individuals who completed the study experienced virologic failure with hiv-1 rna >1,000 copies/ml from the third trimester visit through the postpartum period. five pregnant individuals had sustained virologic response (hiv rna <50 copies/ml) throughout the study period. there are no clinical data on the virologic response when prezcobix is initiated during pregnancy. prospective reports from the apr of overall major birth defects in pregnancies exposed to the components of prezcobix are compared with a u.s. background major birth defect rate. methodological limitations of the apr include the use of macdp as the external comparator group. limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease. there were no new clinically relevant safety findings compared with the known safety profile of prezcobix in adults with hiv-1 infection. darunavir : based on prospective reports to the apr of over 980 exposures to darunavir-containing regimens during pregnancy resulting in live births (including over 660 exposed in the first trimester and over 320 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.6% (95% ci: 2.3% to 5.3%) with first trimester exposure to darunavir-containing regimens and 2.5% (95% ci: 1.1% to 4.8%) with second/third trimester exposure to darunavir-containing regimens. cobicistat : based on prospective reports to the apr of over 570 exposures to cobicistat-containing regimens during pregnancy resulting in live births (including over 480 exposed in the first trimester and over 80 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.7% (95% ci: 2.2% to 5.7%) and 1.1% (95% ci: 0.0% to 6.2%) with first and second/third trimester, respectively, to cobicistat-containing regimens. animal data darunavir : reproduction studies conducted with darunavir showed no embryotoxicity or teratogenicity in mice (doses up to 1000 mg/kg from gestation day (gd) 6–15 with darunavir alone) and rats (doses up to 1000 mg/kg from gd 7–19 in the presence or absence of ritonavir) as well as in rabbits (doses up to 1000 mg/kg/day from gd 8–20 with darunavir alone). in these studies, darunavir exposures (based on auc) were higher in rats (3-fold), whereas in mice and rabbits, exposures were lower (less than 1-fold) compared to those obtained in humans at the recommended clinical dose of darunavir co-administered with ritonavir. cobicistat : cobicistat was administered orally to pregnant rats at doses up to 125 mg/kg/day on gd 6–17. increases in post-implantation loss and decreased fetal weights were observed at a maternal toxic dose of 125 mg/kg/day. no malformations were noted at doses up to 125 mg/kg/day. systemic exposures (auc) at 50 mg/kg/day in pregnant females were 1.6 times higher than human exposures at the recommended daily dose of cobicistat. in pregnant rabbits, cobicistat was administered orally at doses up to 100 mg/kg/day during gd 7–20. no maternal or embryo/fetal effects were noted at the highest dose of 100 mg/kg/day. systemic exposures (auc) at 100 mg/kg/day were 3.8 times higher than human exposures at the recommended daily dose of cobicistat. in a pre/postnatal developmental study in rats, cobicistat was administered orally at doses up to 75 mg/kg from gd 6 to postnatal day 20, 21, or 22. at doses of 75 mg/kg/day, neither maternal nor developmental toxicity was noted. systemic exposures (auc) at this dose were 1.2 times the human exposures at the recommended daily dose of cobicistat. risk summary the centers for disease control and prevention recommend that hiv infected mothers in the united states not breastfeed their infants to avoid risking postnatal transmission of hiv. there are no data on the presence of darunavir or cobicistat in human milk, the effects on the breastfed infant, or the effects on milk production. darunavir and cobicistat are present in the milk of lactating rats (see data) . because of the potential for (1) hiv transmission (in hiv-negative infants), (2) developing viral resistance (in hiv-positive infants), and (3) serious adverse reactions in breastfed infants, instruct mothers not to breastfeed if they are receiving prezcobix. data animal data darunavir : studies in rats (with darunavir alone or with ritonavir) have demonstrated that darunavir is excreted in milk. in the rat pre- and postnatal development study, a reduction in pup body weight gain was observed due to exposure of pups to drug substances via milk. the maximal maternal plasma exposures achieved with darunavir (up to 1000 mg/kg with ritonavir) were approximately 50% of those obtained in humans at the recommended clinical dose of darunavir with ritonavir. cobicistat : during the pre/postnatal developmental toxicology study at doses up to 75 mg/kg/day, mean cobicistat milk to plasma ratio of up to 1.9 was measured 2 hours after administration to rats on lactation day 10. contraception additional or alternative (non-hormonal) forms of contraception should be considered when estrogen-containing contraceptives are co-administered with prezcobix. for co-administration with drospirenone, clinical monitoring is recommended due to the potential for hyperkalemia. no data are available to make recommendations on co-administration with other hormonal contraceptives [see drug interactions (7.3)]. the safety and effectiveness of prezcobix for the treatment of hiv-1 infection in pediatric patients weighing at least 40 kg was established through a trial with components of prezcobix. use of prezcobix in this group is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic, safety, and virologic data from a study of components of prezcobix (trial gs-us-216-0128) in pediatric subjects with hiv-1 infection aged 12 to less than 18 years [see adverse reactions (6.1), clinical pharmacology (12.3), and clinical studies (14.2)] . the safety and effectiveness of prezcobix have not been established in pediatric patients weighing less than 40 kg. darunavir, a component of prezcobix is not recommended in pediatric patients below 3 years of age because of toxicity and mortality observed in juvenile rats dosed with darunavir. juvenile animal toxicity data darunavir: in a juvenile toxicity study where rats were directly dosed with darunavir (up to 1000 mg/kg), deaths occurred from post-natal day 5 at plasma exposure levels ranging from 0.1 to 1.0 of the human exposure levels. in a 4-week rat toxicology study, when dosing was initiated on post-natal day 23 (the human equivalent of 2 to 3 years of age), no deaths were observed with a plasma exposure (in combination with ritonavir) 2 times the human plasma exposure levels. clinical trials of prezcobix did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. in general, caution should be exercised in the administration and monitoring of prezcobix in elderly patients, reflecting the greater frequency of decreased hepatic function, and of concomitant disease or other drug therapy [see clinical pharmacology (12.3)] . no clinical trials were conducted with darunavir co-administered with cobicistat in hepatically impaired subjects and the effect of hepatic impairment on darunavir exposure when co-administered with cobicistat has not been evaluated. based on the recommendations for darunavir co-administered with ritonavir, a dose adjustment for patients with mild or moderate hepatic impairment is not necessary. no pharmacokinetic or safety data are available regarding the use of darunavir in subjects with severe hepatic impairment. therefore, prezcobix is not recommended for use in patients with severe hepatic impairment [see clinical pharmacology (12.3)] . a renal impairment trial was not conducted for darunavir co-administered with cobicistat [see clinical pharmacology (12.3)] . cobicistat has been shown to decrease estimated creatinine clearance without affecting actual renal glomerular function. dosing recommendations are not available for drugs that require dosage adjustment for renal impairment when used in combination with prezcobix [see warnings and precautions (5.3)and clinical pharmacology (12.2)] .

Spojené státy - angličtina - NLM (National Library of Medicine)

amneal pharmaceuticals llc - irbesartan (unii: j0e2756z7n) (irbesartan - unii:j0e2756z7n) - irbesartan 75 mg - irbesartan tablets are indicated for the treatment of hypertension, to lower blood pressure. lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular (cv) events, primarily strokes and myocardial infarction. these benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including this drug. 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 1 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 variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. the largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmhg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). these considerations may guide selection of therapy. irbesartan tablets may be used alone or in combination with other antihypertensive agents. irbesartan tablets are indicated for the treatment of diabetic nephropathy in patients with type 2 diabetes and hypertension, an elevated serum creatinine, and proteinuria (> 300 mg/day). in this population, irbesartan tablets reduces the rate of progression of nephropathy as measured by the occurrence of doubling of serum creatinine or end-stage renal disease (need for dialysis or renal transplantation) [see clinical studies (14.2)] . irbesartan tablets are contraindicated in patients who are hypersensitive to any component of this product. do not co-administer aliskiren with irbesartan in patients with diabetes. risk summary irbesartan can cause fetal harm when administered to a pregnant woman. use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death [see clinical considerations] . most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. when pregnancy is detected, discontinue irbesartan as soon as possible. all pregnancies have a background risk of birth defect, loss or other adverse outcomes regardless of drug exposure. 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 hypertension in pregnancy increases the maternal risk for preeclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and postpartum hemorrhage). hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. pregnant women with hypertension should be carefully monitored and managed accordingly. fetal/neonatal adverse reactions oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension, and death. in the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. perform serial ultrasound examinations to assess the intra-amniotic environment. fetal testing may be appropriate, based on the week of pregnancy. patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. if oligohydramnios is observed, consider alternative treatment. closely observe infants with histories of in utero exposure to irbesartan for hypotension, oliguria, and hyperkalemia and other symptoms of renal impairment. in neonates with a history of in utero exposure to irbesartan, if oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function. data animal data irbesartan crosses the placenta in rats and rabbits. in female rats given irbesartan prior to mating though gestation and lactation at oral doses of 50 mg/kg/day, 180 mg/kg/day, or 650 mg/kg/day (1.6 to 21.1 times the maximum recommended human dose (mrhd) based on body surface area), fetuses examined on gestation day 20 showed increased incidences of hydroureter and renal pelvic cavitation and/or absence of renal papilla in all irbesartan-treated groups. subcutaneous edema also occurred in fetuses at maternal doses ≥ 180 mg/kg/day (5.8   times the mrhd). these anomalies occurred when female rats received irbesartan from prior to mating through day 20 of gestation but were not observed in pups postnatally in the same study, or when irbesartan was given to pregnant rats only during organogenesis (gestation day 6 through gestation day 15) at oral doses from 50 mg/kg/day to 450 mg/kg/day (up to 14.6 times the mrhd). in addition, no adverse effects on kidney development were observed in pups from dams given irbesartan from gestation day 15 through lactation day 24 at doses of 50 mg/kg/day, 180 mg/kg/day, or 650 mg/kg/day (up to 21.1 times the mrhd). the observed effects are believed to be late gestational effects of the drug. pregnant rabbits given oral doses of irbesartan of 30 mg/kg/day (1.9 times the mrhd based on body surface area) experienced a high rate of maternal mortality and abortion. surviving females had a slight increase in early resorptions and a corresponding decrease in live fetuses. radioactivity was present in the rat and rabbit fetuses during late gestation following oral doses of radiolabeled irbesartan. there are no available data on the presence of irbesartan in human milk, effects on milk production, or the breastfed infant. irbesartan or some metabolite of irbesartan is secreted in the milk of lactating rats [see clinical pharmacology (12.3)]. because of the potential for adverse effects on the nursing infant, the use of irbesartan in breastfeeding women is not recommended. irbesartan, in a study at a dose of up to 4.5 mg/kg/day, once daily, did not appear to lower blood pressure effectively in pediatric patients ages 6 to 16 years. irbesartan has not been studied in pediatric patients less than 6 years old. of 4,925 subjects receiving irbesartan in controlled clinical studies of hypertension, 911 (18.5%) were 65 years and over, while 150 (3.0%) were 75 years and over. no overall differences in effectiveness or safety were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out [see clinical pharmacology (12.3) and clinical studies (14.1) ] .

Spojené státy - angličtina - NLM (National Library of Medicine)

a-s medication solutions - irbesartan (unii: j0e2756z7n) (irbesartan - unii:j0e2756z7n) - irbesartan 150 mg - irbesartan tablets are indicated for the treatment of hypertension, to lower blood pressure. lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular (cv) events, primarily strokes and myocardial infarction. these benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including this drug. 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 1 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 variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. the largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmhg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). these considerations may guide selection of therapy. irbesartan tablets may be used alone or in combination with other antihypertensive agents. irbesartan tablets are indicated for the treatment of diabetic nephropathy in patients with type 2 diabetes and hypertension, an elevated serum creatinine, and proteinuria (>300 mg/day). in this population, irbesartan reduces the rate of progression of nephropathy as measured by the occurrence of doubling of serum creatinine or end-stage renal disease (need for dialysis or renal transplantation) [see clinical studies ( 14.2)]. irbesartan tablets are contraindicated in patients who are hypersensitive to any component of this product. do not co-administrate aliskiren with irbesartan tablets in patients with diabetes. risk summary   irbesartan can cause fetal harm when administered to a pregnant woman. use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death [see clinical considerations]. most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. when pregnancy is detected, discontinue irbesartan as soon as possible.  all pregnancies have a background risk of birth defect, loss or other adverse outcomes regardless of drug exposure. 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  hypertension in pregnancy increases the maternal risk for preeclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and postpartum hemorrhage). hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. pregnant women with hypertension should be carefully monitored and managed accordingly.  fetal/neonatal adverse reactions  oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension, and death. in the unusual case that there is no appropriate alternative to therapy with drugs affecting the reninangiotensin system for a particular patient, apprise the mother of the potential risk to the fetus.  perform serial ultrasound examinations to assess the intra-amniotic environment. fetal testing may be appropriate, based on the week of pregnancy. patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. if oligohydramnios is observed, consider alternative treatment. closely observe infants with histories of in utero exposure to irbesartan for hypotension, oliguria, and hyperkalemia and other symptoms of renal impairment. in neonates with a history of in utero exposure to irbesartan, if oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.  data  animal data  irbesartan crosses the placenta in rats and rabbits. in female rats given irbesartan prior to mating though gestation and lactation at oral doses of 50, 180, or 650 mg/kg/day (1.6 to 21.1 times the maximum recommended human dose (mrhd) based on body surface area), fetuses examined on gestation day 20 showed increased incidences of hydroureter and renal pelvic cavitation and/or absence of renal papilla in all irbesartan-treated groups. subcutaneous edema also occurred in fetuses at maternal doses ≥180 mg/kg/day (5.8 times the mrhd). these anomalies occurred when female rats received irbesartan from prior to mating through day 20 of gestation but were not observed in pups postnatally in the same study, or when irbesartan was given to pregnant rats only during organogenesis (gestation day 6 through gestation day 15) at oral doses from 50 to 450 mg/kg/day (up to 14.6 times the mrhd). in addition, no adverse effects on kidney development were observed in pups from dams given irbesartan from gestation day 15 through lactation day 24 at doses of 50, 180, or 650 mg/kg/day (up to 21.1 times the mrhd). the observed effects are believed to be late gestational effects of the drug. pregnant rabbits given oral doses of irbesartan of 30 mg/kg/day (1.9 times the mrhd based on body surface area) experienced a high rate of maternal mortality and abortion. surviving females had a slight increase in early resorptions and a corresponding decrease in live fetuses.  radioactivity was present in the rat and rabbit fetuses during late gestation following oral doses of radiolabeled irbesartan. there are no available data on the presence of irbesartan in human milk, effects on milk production, or the breastfed infant. irbesartan or some metabolite of irbesartan is secreted in the milk of lactating rats [see clinical pharmacology (12.3)] . because of the potential for adverse effects on the nursing infant, the use of irbesartan in breastfeeding women is not recommended.  irbesartan, in a study at a dose of up to 4.5 mg/kg/day, once daily, did not appear to lower blood pressure effectively in pediatric patients ages 6 to 16 years. irbesartan has not been studied in pediatric patients less than 6 years old. of 4925 subjects receiving irbesartan in controlled clinical studies of hypertension, 911 (18.5%) were 65 years and over, while 150 (3.0%) were 75 years and over. no overall differences in effectiveness or safety were observed between these subjects and younger  subjects, but greater sensitivity of some older individuals cannot be ruled out. [see clinical pharmacology ( 12.3) and clinical studies ( 14.1).]

Spojené státy - angličtina - NLM (National Library of Medicine)

preferred pharmaceuticals inc. - benazepril hydrochloride (unii: n1sn99t69t) (benazeprilat - unii:jrm708l703) - benazepril hydrochloride 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 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 variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. the largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mm hg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). these considerations may guide selection of therapy. it may be used alone or in combination with thiazide diuretics. benazepril hydrochloride tablets are contraindicated in patients: benazepril hydrochloride tablets are contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). do not administer benazepril hydrochloride tablets within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor [see warnings and precautions (5.2)]. do not coadminister aliskiren with angiotensin receptor blockers, ace inhibitors; including benazepril hydrochloride tablets in patients with diabetes [see drug interactions (7.4)] . risk summary benazepril hydrochloride can cause fetal harm when administered to a pregnant woman. use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. when pregnancy is detected, discontinue benazepril hydrochloride as soon as possible. the estimated background risk of major birth defects and miscarriage for the indicated population are unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the general u.s. population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. pregnant women with hypertension should be carefully monitored and managed accordingly. fetal/neonatal adverse reactions oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia and skeletal deformations, including skull hypoplasia, hypotension, and death. in the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. perform serial ultrasound examinations to assess the intra-amniotic environment. fetal testing may be appropriate, based on the week of pregnancy. patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. closely observe infants with histories of in utero exposure to benazepril hydrochloride for hypotension, oliguria, and hyperkalemia. if oliguria or hypotension occur in neonates with a history of in utero exposure to benazepril hydrochloride, support blood pressure and renal perfusion. exchange transfusions or dialysis may be required as a means of reversing hypotension and substituting for disordered renal function. minimal amounts of unchanged benazepril and of benazeprilat are excreted into the breast milk of lactating women treated with benazepril. a newborn child ingesting entirely breast milk would receive less than 0.1% of the mg/kg maternal dose of benazepril and benazeprilat. the antihypertensive effects of benazepril hydrochloride have been evaluated in a double-blind study in pediatric patients 7 to 16 years of age [see clinical pharmacology (12.3)]. the pharmacokinetics of benazepril hydrochloride have been evaluated in pediatric patients 6 to 16 years of age [see clinical pharmacology (12.3)]. infants below the age of 1 year should not be given benazepril hydrochloride because of the risk of effects on kidney development. safety and effectiveness of benazepril hydrochloride have not been established in pediatric patients less than 6 years of age or in children with glomerular filtration rate < 30 ml/min/1.73m² [see dosage and administration (2.1) and clinical pharmacology 12.3)]. of the total number of patients who received benazepril in u.s. clinical studies of benazepril hydrochloride, 18% were 65 or older while 2% were 75 or older. no overall differences in effectiveness or safety were observed between these patients and younger patients, 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. benazepril and benazeprilat are substantially excreted by the kidney. 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)] . ace inhibitors, including benazepril hydrochloride, as monotherapy, have an effect on blood pressure that is less in black patients than in non-blacks. dose adjustment of benazepril hydrochloride is required in patients undergoing hemodialysis or whose creatinine clearance is ≤ 30 ml/min. no dose adjustment of benazepril hydrochloride is required in patients with creatinine clearance > 30 ml/min [see dosage and administration (2.2) and clinical pharmacology (12.3)] .

Spojené státy - angličtina - NLM (National Library of Medicine)

a-s medication solutions - aliskiren hemifumarate (unii: c8a0p8g029) (aliskiren - unii:502fwn4q32) - tekturna is indicated for the treatment of hypertension in adults and in pediatric patients weighing 50 kg or greater who are at least 6 years of age and older 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. there are no controlled trials demonstrating risk reduction with tekturna. 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 1 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 variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. the largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality have also been seen regularly. elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmhg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (e.g., patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). these considerations may guide selection of therapy. do not use tekturna with arbs or aceis in patients with diabetes [see warnings and precautions ( 5.2) and clinical studies ( 14.3)]. tekturna is contraindicated in patients with known hypersensitivity to any of the components [see warnings and precautions ( 5.3)]. tekturna is contraindicated in pediatric patients less than 2 years of age because of the risk of high aliskiren exposures identified in juvenile animals due to immaturity of transporters and metabolic enzymes [see use in specific populations ( 8.4)]. risk summary tekturna can cause fetal harm when administered to a pregnant woman. use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death [see clinical considerations] . most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. when pregnancy is detected, discontinue tekturna as soon as possible. the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major malformations and miscarriage in clinically recognized pregnancies is 2-4%, and 15-20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. pregnant women with hypertension should be carefully monitored and managed accordingly. fetal/neonatal adverse reactions use of drugs that act on the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, oligohydramnios, fetal lung hypoplasia and skeletal deformations, including skull hypoplasia, hypotension, and death. in the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. in patients taking tekturna during pregnancy, perform serial ultrasound examinations to assess the intra- amniotic environment. fetal testing may be appropriate, based on the week of gestation. patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. closely observe infants with histories of in utero exposure to tekturna for hypotension, oliguria, and hyperkalemia. if oliguria or hypotension occur in neonates with a history of in utero exposure to aliskiren, support blood pressure and renal perfusion. exchange transfusions or dialysis may be required as a means of reversing hypotension and substituting for disordered renal function. data animal data in developmental toxicity studies, pregnant rats and rabbits received oral aliskiren hemifumarate during organogenesis at doses up to 20 and 7 times the maximum recommended human dose (mrhd) based on body surface area (mg/m 2 ), respectively, in rats and rabbits. (actual animal doses were up to 600 mg/kg/day in rats and up to 100 mg/kg/day in rabbits.) no teratogenicity was observed; however, fetal birth weight was decreased in rabbits at doses 3.2 times the mrhd based on body surface area (mg/m 2 ). aliskiren was present in placentas, amniotic fluid and fetuses of pregnant rabbits. risk summary there is no information regarding the presence of aliskiren in human milk, the effects on the breastfed infant, or the effects on milk production. because of the potential for serious adverse reactions, including hypotension, hyperkalemia and renal impairment in nursing infants, advise a nursing woman that breastfeeding is not recommended during treatment with tekturna. tekturna is contraindicated in patients less than 2 years of age [see contraindications ( 4)]. tekturna is indicated for treatment of hypertension in pediatric patients 6 years of age and older weighing 50 kg or more. the safety and effectiveness of aliskiren have been established in pediatric patients 6 years of age and older weighing 20 kg or more, but tekturna is not approved in patients 6 years of age and older weighing 20 kg to less than 50 kg because of the lack of an appropriate dosage form. use of tekturna in pediatric patients 6 years and older is supported by evidence from a pharmacokinetic trial and two randomized, double-blind clinical trials in pediatric patients with hypertension 6 years to 17 years of age weighing 20 kg or more [see clinical pharmacology ( 12.3), clinical studies ( 14.4 ) ] . the safety and effectiveness of tekturna have not been established in pediatric patients younger than 6 years of age and patients less than 20 kg. avoid use in patients 2 years to less than 6 years and patients weighing less than 20 kg due to the limited information about aliskiren metabolism and exposures in this age group. no data are available in pediatric patients weighing less than 20 kg or in pediatric patients with a glomerular filtration rate <30 ml/min/1.73 m 2 . juvenile animal toxicity data toxicology studies in juvenile animals the approximate human age equivalent of children less than 2 years of age identified 85- to 385-fold increased systemic exposure to aliskiren compared to adult rats. the increased aliskiren exposure in juvenile rats was attributed to immaturity in aliskiren drug transporters and metabolizing enzymes. increased aliskiren exposures were associated with premature deaths. although a definitive pathology-based cause of death could not be ascertained, the premature deaths were attributed to the immaturity in aliskiren metabolism. the nonclinical findings suggest a distinct age-dependent relationship between dose and exposure. neonates with a history of in utero exposure to tekturna if oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. of the total number of patients receiving aliskiren in clinical studies, 1,275 (19%) were 65 years or older and 231 (3.4%) were 75 years or older. no overall differences in safety or effectiveness were observed between these subjects and younger subjects. other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. safety and effectiveness of tekturna in patients with severe renal impairment [creatinine clearance (crcl) less than 30 ml/min] have not been established as these patients were excluded in efficacy trials [see clinical studies ( 14)].

Spojené státy - angličtina - NLM (National Library of Medicine)

a-s medication solutions - benazepril hydrochloride (unii: n1sn99t69t) (benazeprilat - unii:jrm708l703) - benazepril hydrochloride 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 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 variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. the largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mm hg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). these considerations may guide selection of therapy. it may be used alone or in combination with thiazide diuretics. benazepril hydrochloride tablets are contraindicated in patients: benazepril hydrochloride tablets are contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). do not administer benazepril hydrochloride tablets within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor [see warnings and precautions (5.2)]. do not coadminister aliskiren with angiotensin receptor blockers, ace inhibitors; including benazepril hydrochloride tablets in patients with diabetes [see drug interactions (7.4)] . risk summary benazepril hydrochloride can cause fetal harm when administered to a pregnant woman. use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. when pregnancy is detected, discontinue benazepril hydrochloride as soon as possible. the estimated background risk of major birth defects and miscarriage for the indicated population are unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the general u.s. population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. pregnant women with hypertension should be carefully monitored and managed accordingly. fetal/neonatal adverse reactions oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia and skeletal deformations, including skull hypoplasia, hypotension, and death. in the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. perform serial ultrasound examinations to assess the intra-amniotic environment. fetal testing may be appropriate, based on the week of pregnancy. patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. closely observe infants with histories of in utero exposure to benazepril hydrochloride for hypotension, oliguria, and hyperkalemia. if oliguria or hypotension occur in neonates with a history of in utero exposure to benazepril hydrochloride, support blood pressure and renal perfusion. exchange transfusions or dialysis may be required as a means of reversing hypotension and substituting for disordered renal function. minimal amounts of unchanged benazepril and of benazeprilat are excreted into the breast milk of lactating women treated with benazepril. a newborn child ingesting entirely breast milk would receive less than 0.1% of the mg/kg maternal dose of benazepril and benazeprilat. the antihypertensive effects of benazepril hydrochloride have been evaluated in a double-blind study in pediatric patients 7 to 16 years of age [see clinical pharmacology (12.3)]. the pharmacokinetics of benazepril hydrochloride have been evaluated in pediatric patients 6 to 16 years of age [see clinical pharmacology (12.3)]. infants below the age of 1 year should not be given benazepril hydrochloride because of the risk of effects on kidney development. safety and effectiveness of benazepril hydrochloride have not been established in pediatric patients less than 6 years of age or in children with glomerular filtration rate < 30 ml/min/1.73m² [see dosage and administration (2.1) and clinical pharmacology 12.3)]. of the total number of patients who received benazepril in u.s. clinical studies of benazepril hydrochloride, 18% were 65 or older while 2% were 75 or older. no overall differences in effectiveness or safety were observed between these patients and younger patients, 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. benazepril and benazeprilat are substantially excreted by the kidney. 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)] . ace inhibitors, including benazepril hydrochloride, as monotherapy, have an effect on blood pressure that is less in black patients than in non-blacks. dose adjustment of benazepril hydrochloride is required in patients undergoing hemodialysis or whose creatinine clearance is ≤ 30 ml/min. no dose adjustment of benazepril hydrochloride is required in patients with creatinine clearance > 30 ml/min [see dosage and administration (2.2) and clinical pharmacology (12.3)] .

Spojené státy - angličtina - NLM (National Library of Medicine)

a-s medication solutions - olmesartan medoxomil (unii: 6m97xtv3hd) (olmesartan - unii:8w1iqp3u10) - olmesartan medoxomil tablets are indicated for the treatment of hypertension in adults and children six years of age and older, 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. there are no controlled trials demonstrating risk reduction with olmesartan medoxomil 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 committee on prevention, detection, evaluation, and treatment of high blood pressure (jnc). numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. the largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmhg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). these considerations may guide selection of therapy. it may be used alone or in combination with other antihypertensive agents. do not co-administer aliskiren with olmesartan medoxomil tablets  in patients with diabetes [see drug interactions (7.3 ) ]. risk summary olmesartan medoxomil tablets can cause fetal harm when administered to a pregnant woman. use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. in animal reproduction studies, olmesartan medoxomil tablets treatment during organogenesis resulted in increased embryofetal toxicity in rats at doses lower than maternally toxic doses. when pregnancy is detected, discontinue olmesartan medoxomil tablets  as soon as possible. consider alternative antihypertensive therapy during pregnancy. the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and post-partum hemorrhage). hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. pregnant women with hypertension should be carefully monitored and managed accordingly. fetal/neonatal adverse reactions oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension and death. in patients taking olmesartan medoxomil tablets during pregnancy, perform serial ultrasound examinations to assess the intra-amniotic environment. fetal testing may be appropriate, based on the week of gestation. patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. closely observe infants with histories of in utero exposure to olmesartan medoxomil tablets for hypotension, oliguria, and hyperkalemia. in neonates with a history of in utero exposure to olmesartan medoxomil tablets, if oliguria or hypotension occurs, utilize measures to maintain adequate blood pressure and renal perfusion. exchange transfusions or dialysis may be required as a means of reversing hypotension and supporting renal function. data animal data no teratogenic effects were observed when olmesartan medoxomil was administered to pregnant rats at oral doses up to 1000 mg/kg/day (240 times the maximum recommended human dose (mrhd) on a mg/m2 basis) or pregnant rabbits at oral doses up to 1 mg/kg/day (half the mrhd on a mg/m2 basis; higher doses could not be evaluated for effects on fetal development as they were lethal to the does). in rats, significant decreases in pup birth weight and weight gain were observed at doses ≥1.6 mg/kg/day, and delays in developmental milestones (delayed separation of ear auricula, eruption of lower incisors, appearance of abdominal hair, descent of testes, and separation of eyelids) and dose-dependent increases in the incidence of dilation of the renal pelvis were observed at doses ≥ 8 mg/kg/day. the no observed effect dose for developmental toxicity in rats is 0.3 mg/kg/day, about one-tenth the mrhd of 40 mg/day. risk summary there is no information regarding the presence of olmesartan in human milk, the effects on the breastfed infant, or the effects on milk production. olmesartan is secreted at low concentration in the milk of lactating rats (see data) . because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. data presence of olmesartan in milk was observed after a single oral administration of 5 mg/kg [14 c] olmesartan medoxomil to lactating rats. the antihypertensive effects of olmesartan medoxomil tablets were evaluated in one randomized, double-blind clinical study in pediatric patients 1 to 16 years of age [see clinical studies (14.2)] . the pharmacokinetics of olmesartan medoxomil tablets were evaluated in pediatric patients 1 to 16 years of age [see clinical pharmacology (12.3)] . olmesartan medoxomil tablets was generally well tolerated in pediatric patients, and the adverse experience profile was similar to that described for adults. olmesartan medoxomil tablets has not been shown to be effective for hypertension in children less than 6 years of age. use of olmesartan medoxomil tablets in children less than 1 year of age is not recommended [see warnings and precautions (5.2)] . the renin-angiotensin-aldosterone system (raas) plays a critical role in kidney development. raas blockade has been shown to lead to abnormal kidney development in very young mice. administering drugs that act directly on the renin-angiotensin-aldosterone system (raas) can alter normal renal development. of the total number of hypertensive patients receiving olmesartan medoxomil tablets  in clinical studies, more than 20% were 65 years of age and over, while more than 5% were 75 years of age and older. no overall differences in effectiveness or safety were observed between elderly patients and younger patients. 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 [see clinical pharmacology (12.3) ]. increases in auc0-∞ and cmax were observed in patients with moderate hepatic impairment compared to those in matched controls, with an increase in auc of about 60%. no initial dosage adjustment is recommended for patients with moderate to marked hepatic dysfunction [see clinical pharmacology (12.3) ]. patients with renal insufficiency have elevated serum concentrations of olmesartan compared to subjects with normal renal function. after repeated dosing, the auc was approximately tripled in patients with severe renal impairment (creatinine clearance < 20 ml/min). no initial dosage adjustment is recommended for patients with moderate to marked renal impairment (creatinine clearance < 40 ml/min) [see dosage and administration (2.1), warnings and precautions (5.4) and clinical pharmacology (12.3) ]. the antihypertensive effect of olmesartan medoxomil tablets  was smaller in black patients (usually a low-renin population), as has been seen with ace inhibitors, beta-blockers and other angiotensin receptor blockers.

Spojené státy - angličtina - NLM (National Library of Medicine)

a-s medication solutions - olmesartan medoxomil (unii: 6m97xtv3hd) (olmesartan - unii:8w1iqp3u10) - olmesartan medoxomil tablets are indicated for the treatment of hypertension in adults and children six years of age and older, 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. there are no controlled trials demonstrating risk reduction with olmesartan medoxomil 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 committee on prevention, detection, evaluation, and treatment of high blood pressure (jnc). numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. the largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmhg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). these considerations may guide selection of therapy. it may be used alone or in combination with other antihypertensive agents. do not co-administer aliskiren with olmesartan medoxomil tablets  in patients with diabetes [see drug interactions (7.3 ) ]. risk summary olmesartan medoxomil tablets can cause fetal harm when administered to a pregnant woman. use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. in animal reproduction studies, olmesartan medoxomil tablets treatment during organogenesis resulted in increased embryofetal toxicity in rats at doses lower than maternally toxic doses. when pregnancy is detected, discontinue olmesartan medoxomil tablets  as soon as possible. consider alternative antihypertensive therapy during pregnancy. the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and post-partum hemorrhage). hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. pregnant women with hypertension should be carefully monitored and managed accordingly. fetal/neonatal adverse reactions oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension and death. in patients taking olmesartan medoxomil tablets during pregnancy, perform serial ultrasound examinations to assess the intra-amniotic environment. fetal testing may be appropriate, based on the week of gestation. patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. closely observe infants with histories of in utero exposure to olmesartan medoxomil tablets for hypotension, oliguria, and hyperkalemia. in neonates with a history of in utero exposure to olmesartan medoxomil tablets, if oliguria or hypotension occurs, utilize measures to maintain adequate blood pressure and renal perfusion. exchange transfusions or dialysis may be required as a means of reversing hypotension and supporting renal function. data animal data no teratogenic effects were observed when olmesartan medoxomil was administered to pregnant rats at oral doses up to 1000 mg/kg/day (240 times the maximum recommended human dose (mrhd) on a mg/m2 basis) or pregnant rabbits at oral doses up to 1 mg/kg/day (half the mrhd on a mg/m2 basis; higher doses could not be evaluated for effects on fetal development as they were lethal to the does). in rats, significant decreases in pup birth weight and weight gain were observed at doses ≥1.6 mg/kg/day, and delays in developmental milestones (delayed separation of ear auricula, eruption of lower incisors, appearance of abdominal hair, descent of testes, and separation of eyelids) and dose-dependent increases in the incidence of dilation of the renal pelvis were observed at doses ≥ 8 mg/kg/day. the no observed effect dose for developmental toxicity in rats is 0.3 mg/kg/day, about one-tenth the mrhd of 40 mg/day. risk summary there is no information regarding the presence of olmesartan in human milk, the effects on the breastfed infant, or the effects on milk production. olmesartan is secreted at low concentration in the milk of lactating rats (see data) . because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. data presence of olmesartan in milk was observed after a single oral administration of 5 mg/kg [14 c] olmesartan medoxomil to lactating rats. the antihypertensive effects of olmesartan medoxomil tablets were evaluated in one randomized, double-blind clinical study in pediatric patients 1 to 16 years of age [see clinical studies (14.2)] . the pharmacokinetics of olmesartan medoxomil tablets were evaluated in pediatric patients 1 to 16 years of age [see clinical pharmacology (12.3)] . olmesartan medoxomil tablets was generally well tolerated in pediatric patients, and the adverse experience profile was similar to that described for adults. olmesartan medoxomil tablets has not been shown to be effective for hypertension in children less than 6 years of age. use of olmesartan medoxomil tablets in children less than 1 year of age is not recommended [see warnings and precautions (5.2)] . the renin-angiotensin-aldosterone system (raas) plays a critical role in kidney development. raas blockade has been shown to lead to abnormal kidney development in very young mice. administering drugs that act directly on the renin-angiotensin-aldosterone system (raas) can alter normal renal development. of the total number of hypertensive patients receiving olmesartan medoxomil tablets  in clinical studies, more than 20% were 65 years of age and over, while more than 5% were 75 years of age and older. no overall differences in effectiveness or safety were observed between elderly patients and younger patients. 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 [see clinical pharmacology (12.3) ]. increases in auc0-∞ and cmax were observed in patients with moderate hepatic impairment compared to those in matched controls, with an increase in auc of about 60%. no initial dosage adjustment is recommended for patients with moderate to marked hepatic dysfunction [see clinical pharmacology (12.3) ]. patients with renal insufficiency have elevated serum concentrations of olmesartan compared to subjects with normal renal function. after repeated dosing, the auc was approximately tripled in patients with severe renal impairment (creatinine clearance < 20 ml/min). no initial dosage adjustment is recommended for patients with moderate to marked renal impairment (creatinine clearance < 40 ml/min) [see dosage and administration (2.1), warnings and precautions (5.4) and clinical pharmacology (12.3) ]. the antihypertensive effect of olmesartan medoxomil tablets  was smaller in black patients (usually a low-renin population), as has been seen with ace inhibitors, beta-blockers and other angiotensin receptor blockers.

Spojené státy - angličtina - NLM (National Library of Medicine)

remedyrepack inc. - olmesartan medoxomil (unii: 6m97xtv3hd) (olmesartan - unii:8w1iqp3u10), amlodipine besylate (unii: 864v2q084h) (amlodipine - unii:1j444qc288), hydrochlorothiazide (unii: 0j48lph2th) (hydrochlorothiazide - unii:0j48lph2th) - olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets are indicated for the treatment of hypertension, alone or with other antihypertensive agents, to lower blood pressure. lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular (cv) 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. there are no controlled trials demonstrating risk reduction with olmesartan medoxomil, amlodipine 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 committee on prevention, detection, evaluation, and treatment of high blood pressure (jnc). numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. the largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmhg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). these considerations may guide selection of therapy. limitations of use this fixed combination drug is not indicated for the initial therapy of hypertension . because of the hydrochlorothiazide component, olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets are contraindicated in patients with anuria, hypersensitivity to any component, or hypersensitivity to other sulfonamide-derived drugs. do not co-administer aliskiren with olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets in patients with diabetes [see drug interactions (7.2)]. risk summary olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets can cause fetal harm when administered to a pregnant woman. use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death [see clinical considerations]. most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. when pregnancy is detected, discontinue olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets as soon as possible. consider alternative antihypertensive therapy during pregnancy. the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and post-partum hemorrhage). hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. pregnant women with hypertension should be carefully monitored and managed accordingly. fetal/neonatal adverse reactions olmesartan medoxomil oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension, and death. perform serial ultrasound examinations to assess the intra-amniotic environment. fetal testing may be appropriate, based on the week of gestation. patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. closely observe infants with histories of in utero exposure to olmesartan for hypotension, oliguria, and hyperkalemia. in neonates with a history of in utero exposure to olmesartan, if oliguria or hypotension occur, utilize measures to maintain adequate blood pressure and renal perfusion. exchange transfusions or dialysis may be required as a means of reversing hypotension and supporting renal function [see use in specific populations (8.4)]. hydrochlorothiazide thiazides can cross the placenta, and concentrations reached in the umbilical vein approach those in the maternal plasma. hydrochlorothiazide, like other diuretics, can cause placental hypoperfusion. it accumulates in the amniotic fluid, with reported concentrations up to 19 times that in umbilical vein plasma. use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice or thrombocytopenia. since they do not prevent or alter the course of preeclampsia, these drugs should not be used to treat hypertension in pregnant women. the use of hctz for other indications (e.g., heart disease) in pregnancy should be avoided. data animal data no reproductive studies have been conducted with the combination of olmesartan medoxomil, amlodipine and hydrochlorothiazide. however, these studies have been conducted for olmesartan medoxomil, amlodipine and hydrochlorothiazide alone, and olmesartan medoxomil and hydrochlorothiazide together. olmesartan medoxomil. no teratogenic effects were observed when olmesartan medoxomil was administered to pregnant rats at oral doses up to 1000 mg/kg/day (240 times the maximum recommended human dose [mrhd] on a mg/m 2 basis) or pregnant rabbits at oral doses up to 1 mg/kg/day (half the mrhd on a mg/m 2 basis; higher doses could not be evaluated for effects on fetal development as they were lethal to the does). in rats, significant decreases in pup birth weight and weight gain were observed at doses ≥1.6 mg/kg/day, and delays in developmental milestones (delayed separation of ear auricular, eruption of lower incisors, appearance of abdominal hair, descent of testes, and separation of eyelids) and dose-dependent increases in the incidence of dilation of the renal pelvis were observed at doses ≥8 mg/kg/day. the no observed effect dose for developmental toxicity in rats is 0.3 mg/kg/day, about one-tenth the mrhd of 40 mg/day. olmesartan medoxomil and hydrochlorothiazide. no teratogenic effects were observed when 1.6:1 combinations of olmesartan medoxomil and hydrochlorothiazide were administered to pregnant mice at oral doses up to 1625 mg/kg/day (122 times the mrhd on a mg/m 2 basis) or pregnant rats up to 1625 mg/kg/day (243 times the mrhd on a mg/m 2 basis) or pregnant rabbits at oral doses up to 1 mg/kg/day (0.3 times the mrhd on a mg/m 2 basis). in rats, however, fetal body weights at 1625 mg/kg/day (a toxic, sometimes lethal dose in the dams) were significantly lower than control. the no observed effect dose for developmental toxicity in rats is 162.5 mg/kg/day, about 24 times, on a mg/m 2 basis, the mrhd of 40 mg olmesartan medoxomil/25 mg hydrochlorothiazide/day. (calculations based on a 60 kg patient.) amlodipine. no evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses of up to 10 mg amlodipine/kg/day (respectively about 10 and 20 times the maximum recommended human dose of 10 mg amlodipine on a mg/m 2 basis) during their respective periods of major organogenesis (calculations based on a patient weight of 60 kg). however, litter size was significantly decreased (by about 50%), and the number of intrauterine deaths was significantly increased (about 5-fold) in rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. amlodipine maleate has been shown to prolong both the gestational period and the duration of labor in rats at this dose. hydrochlorothiazide. no teratogenic effects were observed when hydrochlorothiazide was administered to mice and rats via gavage at doses up to 3000 and 1000 mg/kg/day, respectively (about 600 and 400 times the mrhd), on gestation days 6 through 15. risk summary there is limited information regarding the presence olmesartan medoxomil, amlodipine and hydrochlorothiazide in human milk, the effects on the breastfed infant, or the effects on milk production. amlodipine and hydrochlorothiazide are present in human milk. olmesartan is present in rat milk [see data] . because of the potential for adverse effects on the nursing infant, advise a nursing woman that breastfeeding is not recommended during treatment with olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets. data presence of olmesartan in milk was observed after a single oral administration of 5 mg/kg [ 14 c] olmesartan medoxomil to lactating rats. the safety and effectiveness of olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets in pediatric patients have not been established. olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets. in a controlled clinical trial, 123 hypertensive patients treated with olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets were ≥65 years of age and 18 patients were ≥75 years of age. no overall differences in the efficacy or safety of olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets were observed in these patient populations; however, greater sensitivity of some older individuals cannot be ruled out. the recommended initial dose of amlodipine in patients ≥ 75 years of age is 2.5 mg, a dose not available with olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets. there are no studies of olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets in patients with hepatic insufficiency, but both amlodipine and olmesartan medoxomil show moderate increases in exposure in patients with severe hepatic impairment. the recommended initial dose of amlodipine in patients with severe hepatic impairment is 2.5 mg, a dose not available with olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets [see warnings and precautions (5.5)]. amlodipine. amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t ½ ) is 56 hours in patients with severely impaired hepatic function. olmesartan medoxomil. increases in auc 0-∞ and peak plasma concentration (c max ) for olmesartan were observed with moderate hepatic impairment compared to those in matched controls with an increase in auc of about 60%. hydrochlorothiazide. in patients with impaired hepatic function or progressive liver disease, minor alterations of fluid and electrolyte balance may precipitate hepatic coma. there are no studies of olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets in patients with renal impairment. avoid use in patients with severe renal impairment (creatinine clearance <30 ml/min). olmesartan medoxomil. patients with renal insufficiency have elevated serum concentrations of olmesartan compared with patients with normal renal function. after repeated dosing, auc was approximately tripled in patients with severe renal impairment (creatinine clearance <20 ml/min). no initial dosage adjustment is recommended for patients with moderate to marked renal impairment (creatinine clearance <40 ml/min). the pharmacokinetics of olmesartan in patients undergoing hemodialysis has not been studied. amlodipine. the pharmacokinetics of amlodipine are not significantly influenced by renal impairment. hydrochlorothiazide. thiazide should be used with caution in patients with severe renal disease. in patients with renal disease, thiazides may precipitate azotemia. cumulative effects of the drug may develop in patients with impaired renal function. of the total number of patients who received olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets in a randomized trial, 29% (184/627) were black. olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets were effective in lowering both systolic and diastolic blood pressure in black patients (usually a low-renin population) to the same extent as in non-black patients.