Europäische Union - Englisch - EMA (European Medicines Agency)

glenmark arzneimittel gmbh - olanzapine - schizophrenia; bipolar disorder - psycholeptics - adultsolanzapine is indicated for the treatment of schizophrenia.olanzapine is effective in maintaining the clinical improvement during continuation therapy in patients who have shown an initial treatment response.olanzapine is indicated for the treatment of moderate to severe manic episode. in patients whose manic episode has responded to olanzapine treatment, olanzapine is indicated for the prevention of recurrence in patients with bipolar disorder.

Europäische Union - Englisch - EMA (European Medicines Agency)

glenmark arzneimittel gmbh - olanzapine - schizophrenia; bipolar disorder - psycholeptics - adultsolanzapine is indicated for the treatment of schizophrenia.olanzapine is effective in maintaining the clinical improvement during continuation therapy in patients who have shown an initial treatment response.olanzapine is indicated for the treatment of moderate to severe manic episode. in patients whose manic episode has responded to olanzapine treatment, olanzapine is indicated for the prevention of recurrence in patients with bipolar disorder.

Vereinigte Staaten - Englisch - NLM (National Library of Medicine)

glenmark pharmaceuticals inc., usa - alclometasone dipropionate (unii: s56pql4n1v) (alclometasone - unii:136h45tb7b) - alclometasone dipropionate 0.5 mg in 1 g - alclometasone dipropionate cream and ointment are low to medium potency corticosteroids indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. alclometasone dipropionate cream and ointment may be used in pediatric patients 1 year of age or older, although the safety and efficacy of drug use for longer than 3 weeks have not been established (see precautions: pediatric use ). since the safety and efficacy of alclometasone dipropionate cream and ointment have not been established in pediatric patients below 1 year of age, their use in this age-group is not recommended. alclometasone dipropionate cream and ointment are contraindicated in those patients with a history of hypersensitivity to any of the components in these preparations.

Vereinigte Staaten - Englisch - NLM (National Library of Medicine)

glenmark pharmaceuticals inc., usa - norethindrone acetate (unii: 9s44lic7oj) (norethindrone - unii:t18f433x4s), ethinyl estradiol (unii: 423d2t571u) (ethinyl estradiol - unii:423d2t571u) - norethindrone acetate 0.5 mg - limitation of use when prescribing solely for the prevention of postmenopausal osteoporosis, first consider the use of non-estrogen medications. consider estrogen therapy only for women at significant risk of osteoporosis. norethindrone acetate and ethinyl estradiol tablets are contraindicated in women with any of the following conditions: risk summary norethindrone acetate and ethinyl estradiol tablets are not indicated for use in pregnancy. there are no data with the use of norethindrone acetate and ethinyl estradiol tablets in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined (estrogens and progestins) product before conception or during early pregnancy. 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. risk summary estrogens plus progestogens are present in human milk and can reduce milk production in breast-feeding women. this reduction can occur at any time but is less likely to occur once breast-feeding is well-established. the development and health benefits of breastfeeding should be considered along with the mother’s clinical need for norethindrone acetate and ethinyl estradiol tablets and any potential adverse effects on the breastfed child from norethindrone acetate and ethinyl estradiol tablets or from the underlying maternal condition. norethindrone acetate and ethinyl estradiol tablets are not indicated for use in pediatric patients. clinical studies have not been conducted in the pediatric population. there have not been sufficient numbers of geriatric women involved in clinical studies utilizing norethindrone acetate and ethinyl estradiol tablets to determine whether those over 65 years of age differ from younger subjects in their response to norethindrone acetate and ethinyl estradiol tablets. the women’s health initiative studies in the whi estrogen plus progestin substudy (daily ce [0.625 mg] plus mpa [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see clinical studies (14.5)] . in the whi estrogen-alone substudy (daily ce [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see clinical studies (14.5)] . the women’s health initiative memory study in the whims ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen plus progestin or estrogen-alone when compared to placebo [see warnings and precautions (5.3), and clinical studies (14.6)] . since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8 [see warnings and precautions (5.3), and clinical studies (14.6)] .

Vereinigte Staaten - Englisch - NLM (National Library of Medicine)

glenmark pharmaceuticals inc., usa - acamprosate calcium (unii: 59375n1d0u) (acamprosate - unii:n4k14ygm3j) - acamprosate calcium 333 mg - acamprosate calcium delayed-release tablets are indicated for the maintenance of abstinence from alcohol in patients with alcohol dependence who are abstinent at treatment initiation. treatment with acamprosate calcium delayed-release tablets should be part of a comprehensive management program that includes psychosocial support. the efficacy of acamprosate calcium delayed-release tablets in promoting abstinence has not been demonstrated in subjects who have not undergone detoxification and not achieved alcohol abstinence prior to beginning acamprosate calcium delayed-release tablets treatment. the efficacy of acamprosate calcium delayed-release tablets in promoting abstinence from alcohol in polysubstance abusers has not been adequately assessed. acamprosate calcium is contraindicated in patients who previously have exhibited hypersensitivity to acamprosate calcium or any of its components. acamprosate calcium is contraindicated in patients with severe renal impairment (creatinine clearance of ≤30 ml/min) [s

Vereinigte Staaten - Englisch - NLM (National Library of Medicine)

glenmark pharmaceuticals inc., usa - voriconazole (unii: jfu09i87tr) (voriconazole - unii:jfu09i87tr) - voriconazole 50 mg - voriconazole tablets are indicated in adults and pediatric patients (2 years of age and older) for the treatment of invasive aspergillosis (ia). in clinical trials, the majority of isolates recovered were aspergillus fumigatus . there was a small number of cases of culture-proven disease due to species of aspergillus other than a. fumigatus [see clinical studies (14.1, 14.5) and microbiology (12.4)]. voriconazole tablets are indicated in adults and pediatric patients (2 years of age and older) for the treatment of candidemia in non-neutropenic patients and the following candida infections: disseminated infections in skin and infections in abdomen, kidney, bladder wall, and wounds [see clinical studies (14.2, 14.5) and microbiology (12.4)] . voriconazole tablets are indicated in adults and pediatric patients (2 years of age and older) for the treatment of esophageal candidiasis (ec) in adults and pediatric patients 2 years of age and older [see clinical studies (14.3, 14.5) and microbiology (12.4)] . voriconazole tablets are indicated for the treatment of serious fungal infections caused by scedosporium apiospermum (asexual form of pseudallescheria boydii ) and fusarium spp. including fusarium solani , in adults and pediatric patients (2 years of age and older) intolerant of, or refractory to, other therapy [see clinical studies (14.4) and microbiology (12.4)]. specimens for fungal culture and other relevant laboratory studies (including histopathology) should be obtained prior to therapy to isolate and identify causative organism(s). therapy may be instituted before the results of the cultures and other laboratory studies are known. however, once these results become available, antifungal therapy should be adjusted accordingly. risk summary voriconazole can cause fetal harm when administered to a pregnant woman. there are no available data on the use of voriconazole in pregnant women. in animal reproduction studies, oral voriconazole was associated with fetal malformations in rats and fetal toxicity in rabbits. cleft palates and hydronephrosis/hydroureter were observed in rat pups exposed to voriconazole during organogenesis at and above 10 mg/kg (0.3 times the rmd of 200 mg every 12 hours based on body surface area comparisons). in rabbits, embryomortality, reduced fetal weight and increased incidence of skeletal variations, cervical ribs and extrasternal ossification sites were observed in pups when pregnant rabbits were orally dosed at 100 mg/kg (6 times the rmd based on body surface area comparisons) during organogenesis. rats exposed to voriconazole from implantation to weaning experienced increased gestational length and dystocia, which were associated with increased perinatal pup mortality at the 10 mg/kg dose [see data] . if this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, inform the patient of the potential hazard to the fetus [see warnings and precautions (5.9)] . the background risk of major birth defects and miscarriage for the indicated populations is unknown. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20% respectively. data animal data voriconazole was administered orally to pregnant rats during organogenesis (gestation days 6 to 17) at 10, 30, and 60 mg/kg/day. voriconazole was associated with increased incidences of the malformations hydroureter and hydronephrosis at 10 mg/kg/day or greater, approximately 0.3 times the recommended human dose (rmd) based on body surface area comparisons, and cleft palate at 60 mg/kg, approximately 2 times the rmd based on body surface area comparisons. reduced ossification of sacral and caudal vertebrae, skull, pubic, and hyoid bone, supernumerary ribs, anomalies of the sternebrae, and dilatation of the ureter/renal pelvis were also observed at doses of 10 mg/kg or greater. there was no evidence of maternal toxicity at any dose. voriconazole was administered orally to pregnant rabbits during the period of organogenesis (gestation days 7 to 19) at 10, 40, and 100 mg/kg/day. voriconazole was associated with increased post-implantation loss and decreased fetal body weight, in association with maternal toxicity (decreased body weight gain and food consumption) at 100 mg/kg/day (6 times the rmd based on body surface area comparisons). fetal skeletal variations (increases in the incidence of cervical rib and extra sternebral ossification sites) were observed at 100 mg/kg/day. in a peri- and postnatal toxicity study in rats, voriconazole was administered orally to female rats from implantation through the end of lactation at 1, 3, and 10 mg/kg/day. voriconazole prolonged the duration of gestation and labor and produced dystocia with related increases in maternal mortality and decreases in perinatal survival of f1 pups at 10 mg/kg/day, approximately 0.3 times the rmd. risk summary no data are available regarding the presence of voriconazole in human milk, the effects of voriconazole on the breastfed infant, or the effects on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for voriconazole and any potential adverse effects on the breastfed child from voriconazole or from the underlying maternal condition. contraception advise females of reproductive potential to use effective contraception during treatment with voriconazole. the coadministration of voriconazole with the oral contraceptive, ortho-novum® (35 mcg ethinyl estradiol and 1 mg norethindrone), results in an interaction between these two drugs, but is unlikely to reduce the contraceptive effect. monitoring for adverse reactions associated with oral contraceptives and voriconazole is recommended [see drug interactions (7) and clinical pharmacology (12.3)] . the safety and effectiveness of voriconazole have been established in pediatric patients 2 years of age and older based on evidence from adequate and well-controlled studies in adult and pediatric patients and additional pediatric pharmacokinetic and safety data. a total of 105 pediatric patients aged 2 to less than 12 [n=26] and aged 12 to less than 18 [n=79] from two, non-comparative phase 3 pediatric studies and eight adult therapeutic trials provided safety information for voriconazole use in the pediatric population [see adverse reactions (6.1), clinical pharmacology (12.3), and clinical studies (14)] . safety and effectiveness in pediatric patients below the age of 2 years has not been established. therefore, voriconazole is not recommended for pediatric patients less than 2 years of age. a higher frequency of liver enzyme elevations was observed in the pediatric patients [see dosage and administration (2.5), warnings and precautions (5.1), and adverse reactions (6.1)] . the frequency of phototoxicity reactions is higher in the pediatric population. squamous cell carcinoma has been reported in patients who experience photosensitivity reactions. stringent measures for photoprotection are warranted. sun avoidance and dermatologic follow-up are recommended in pediatric patients experiencing photoaging injuries, such as lentigines or ephelides, even after treatment discontinuation [see warnings and precautions (5.6)]. voriconazole has not been studied in pediatric patients with hepatic or renal impairment [see dosage and administration (2.5, 2.6)]. hepatic function and serum creatinine levels should be closely monitored in pediatric patients [see dosage and administration (2.6) and warnings and precautions (5.1, 5.10)] . in multiple dose therapeutic trials of voriconazole, 9.2% of patients were ≥65 years of age and 1.8% of patients were ≥ 75 years of age. in a study in healthy subjects, the systemic exposure (auc) and peak plasma concentrations (cmax ) were increased in elderly males compared to young males. pharmacokinetic data obtained from 552 patients from 10 voriconazole therapeutic trials showed that voriconazole plasma concentrations in the elderly patients were approximately 80% to 90% higher than those in younger patients after either iv or oral administration. however, the overall safety profile of the elderly patients was similar to that of the young so no dosage adjustment is recommended [see clinical pharmacology (12.3)] .

Vereinigte Staaten - Englisch - NLM (National Library of Medicine)

glenmark pharmaceuticals inc., usa - imiquimod (unii: p1qw714r7m) (imiquimod - unii:p1qw714r7m) - imiquimod 50 mg in 1 g - imiquimod cream is indicated for the topical treatment of clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratoses on the face or scalp in immunocompetent adults. imiquimod cream is indicated for the treatment of external genital and perianal warts/condyloma acuminata in patients 12 years old or older. imiquimod cream has been evaluated in children ages 2 to 12 years with molluscum contagiosum and these studies failed to demonstrate efficacy [see use in specific populations (8.4)] . the safety and efficacy of imiquimod cream in immunosuppressed patients have not been established. imiquimod cream should be used with caution in patients with pre-existing autoimmune conditions. the efficacy and safety of imiquimod cream have not been established for patients with basal cell nevus syndrome or xeroderma pigmentosum. none. pregnancy category c: note: the maximum recommended human dose (mrhd) was set at 2 packets per treatment of imiquimod cream (25 mg imiquimod) for the animal multiple of human exposure ratios presented in this label. if higher doses than 2 packets of imiquimod cream are used clinically, then the animal multiple of human exposure would be reduced for that dose. a non-proportional increase in systemic exposure with increased dose of imiquimod cream was noted in the clinical pharmacokinetic study conducted in actinic keratosis subjects [see clinical pharmacology (12.3)] . the auc after topical application of 6 packets of imiquimod cream was 8 fold greater than the auc after topical application of 2 packets of imiquimod cream in actinic keratosis subjects. therefore, if a dose of 6 packets per treatment of imiquimod cream was topically administered to an individual, then the animal multiple of human exposure would be either 1/3 of the value provided in the label (based on body surface area comparisons) or 1/8 of the value provided in the label (based on auc comparisons). the animal multiples of human exposure calculations were based on weekly dose comparisons for the carcinogenicity studies described in this label. the animal multiples of human exposure calculations were based on daily dose comparisons for the reproductive toxicology studies described in this label. systemic embryofetal development studies were conducted in rats and rabbits. oral doses of 1, 5 and 20 mg/kg/day imiquimod were administered during the period of organogenesis (gestational days 6 to 15) to pregnant female rats. in the presence of maternal toxicity, fetal effects noted at 20 mg/kg/day (577x mrhd based on auc comparisons) included increased resorptions, decreased fetal body weights, delays in skeletal ossification, bent limb bones, and two fetuses in one litter (2 of 1567 fetuses) demonstrated exencephaly, protruding tongues and low-set ears. no treatment related effects on embryofetal toxicity or teratogenicity were noted at 5 mg/kg/day (98x mrhd based on auc comparisons). intravenous doses of 0.5, 1 and 2 mg/kg/day imiquimod were administered during the period of organogenesis (gestational days 6 to 18) to pregnant female rabbits. no treatment related effects on embryofetal toxicity or teratogenicity were noted at 2 mg/kg/day (1.5x mrhd based on bsa comparisons), the highest dose evaluated in this study, or 1 mg/kg/day (407x mrhd based on auc comparisons). a combined fertility and peri- and post-natal development study was conducted in rats. oral doses of 1, 1.5, 3 and 6 mg/kg/day imiquimod were administered to male rats from 70 days prior to mating through the mating period and to female rats from 14 days prior to mating through parturition and lactation. no effects on growth, fertility, reproduction or post-natal development were noted at doses up to 6 mg/kg/day (87x mrhd based on auc comparisons), the highest dose evaluated in this study. in the absence of maternal toxicity, bent limb bones were noted in the f1 fetuses at a dose of 6 mg/kg/day (87x mrhd based on auc comparisons). this fetal effect was also noted in the oral rat embryofetal development study conducted with imiquimod. no treatment related effects on teratogenicity were noted at 3 mg/kg/day (41x mrhd based on auc comparisons). there are no adequate and well-controlled studies in pregnant women. imiquimod cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. it is not known whether imiquimod is excreted in human milk following use of imiquimod cream. because many drugs are excreted in human milk, caution should be exercised when imiquimod cream is administered to nursing women. ak is not a condition generally seen within the pediatric population. the safety and efficacy of imiquimod cream for ak in patients less than 18 years of age have not been established. safety and efficacy in patients with external genital/perianal warts below the age of 12 years have not been established. imiquimod cream was evaluated in two randomized, vehicle-controlled, double-blind trials involving 702 pediatric subjects with molluscum contagiosum (mc) (470 exposed to imiquimod; median age 5 years, range 2 to 12 years). subjects applied imiquimod cream or vehicle 3 times weekly for up to 16 weeks. complete clearance (no mc lesions) was assessed at week 18. in study 1, the complete clearance rate was 24% (52/217) in the imiquimod cream group compared with 26% (28/106) in the vehicle group. in study 2, the clearance rates were 24% (60/253) in the imiquimod cream group compared with 28% (35/126) in the vehicle group. these studies failed to demonstrate efficacy. similar to the studies conducted in adults, the most frequently reported adverse reaction from 2 studies in children with molluscum contagiosum was application site reaction. adverse events which occurred more frequently in imiquimod -treated subjects compared with vehicle-treated subjects generally resembled those seen in studies in indications approved for adults and also included otitis media (5% imiquimod vs. 3% vehicle) and conjunctivitis (3% imiquimod vs. 2% vehicle). erythema was the most frequently reported local skin reaction. severe local skin reactions reported by imiquimod -treated subjects in the pediatric studies included erythema (28%), edema (8%), scabbing/crusting (5%), flaking/scaling (5%), erosion (2%) and weeping/exudate (2%). systemic absorption of imiquimod across the affected skin of 22 subjects aged 2 to 12 years with extensive mc involving at least 10% of the total body surface area was observed after single and multiple doses at a dosing frequency of 3 applications per week for 4 weeks. the investigator determined the dose applied, either 1, 2 or 3 packets per dose, based on the size of the treatment area and the subject’s weight. the overall median peak serum drug concentrations at the end of week 4 was between 0.26 and 1.06 ng/ml except in a 2-year old female who was administered 2 packets of study drug per dose, had a cmax of 9.66 ng/ml after multiple dosing. children aged 2 to 5 years received doses of 12.5 mg (one packet) or 25 mg (two packets) of imiquimod and had median multiple-dose peak serum drug levels of approximately 0.2 or 0.5 ng/ml, respectively. children aged 6 to 12 years received doses of 12.5 mg, 25 mg, or 37.5 mg (three packets) and had median multiple dose serum drug levels of approximately 0.1, 0.15, or 0.3 ng/ml, respectively. among the 20 subjects with evaluable laboratory assessments, the median wbc count decreased by 1.4*109 /l and the median absolute neutrophil count decreased by 1.42*109 /l. of the 215 subjects treated with imiquimod cream in the ak clinical studies, 127 subjects (59%) were 65 years and older, while 60 subjects (28%) were 75 years and older. no overall differences in safety or effectiveness were observed between these subjects and younger subjects. no other clinical experience has identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

Vereinigte Staaten - Englisch - NLM (National Library of Medicine)

glenmark pharmaceuticals inc., usa - riluzole (unii: 7lj087rs6f) (riluzole - unii:7lj087rs6f) - riluzole 50 mg - riluzole tablets are indicated for the treatment of amyotrophic lateral sclerosis (als). riluzole tablets are contraindicated in patients with a history of severe hypersensitivity reactions to riluzole or to any of its components (anaphylaxis has occurred) [see adverse reactions (6.1)]. risk summary there are no studies of riluzole in pregnant women, and case reports have been inadequate to inform the drug-associated risk. the background risk for major birth defects and miscarriage in patients with amyotrophic lateral sclerosis is unknown. in the u.s. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. in studies in which riluzole was administered orally to pregnant animals, developmental toxicity (decreased embryofetal/offspring viability, growth, and functional development) was observed at clinically relevant doses [see data]. based on these results, women should be advised of a possible risk to the fetus associated with use of riluzole during pregnancy. data risk summary it is not known if riluzole is excreted in human milk. riluzole or its metabolites have been detected in milk of lactating rats. women should be advised that many drugs are excreted in human milk and that the potential for serious adverse reactions in nursing infants from riluzole is unknown. in rats, oral administration of riluzole resulted in decreased fertility indices and increases in embryolethality [see nonclinical toxicology (13.1)]. safety and effectiveness of riluzole in pediatric patients have not been established. in clinical studies of riluzole, 30% of patients were 65 years and over. no overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. patients with mild [child-pugh’s (cp) score a] or moderate (cp score b) hepatic impairment had increases in auc compared to patients with normal hepatic function. thus, patients with mild or moderate hepatic impairment may be at increased risk of adverse reactions. the impact of severe hepatic impairment on riluzole exposure is unknown. use of riluzole is not recommended in patients with baseline elevations of serum aminotransferases greater than 5 times upper limit of normal or evidence of liver dysfunction (e.g., elevated bilirubin) [clinical pharmacology (12.3)]. japanese patients are more likely to have higher riluzole concentrations. consequently, the risk of adverse reactions may be greater in japanese patients [see clinical pharmacology (12.3)].

Vereinigte Staaten - Englisch - NLM (National Library of Medicine)

glenmark pharmaceuticals inc., usa - tretinoin (unii: 5688utc01r) (tretinoin - unii:5688utc01r) - tretinoin 10 mg - tretinoin capsules are indicated for the induction of remission in adults and pediatric patients 1 year of age and older with acute promyelocytic leukemia (apl) characterized by the presence of the t(15;17) translocation or pml/rarα gene expression, and who are refractory to or who have relapsed from anthracycline chemotherapy or for whom anthracycline-based chemotherapy is contraindicated. tretinoin is contraindicated in patients with a known hypersensitivity to tretinoin, any of its components, or other retinoids. reactions have included rash, pruritus, face edema, and dyspnea. [see adverse reactions (6.1)]. click here to enter use in specific populations risk summary based on findings in animals and its mechanism of action [see clinical pharmacology (12.1)], tretinoin can cause embryo-fetal loss and malformations when administered to a pregnant woman. tretinoin is a retinoid and there is an increased risk of major congenital malformations, spontaneous abortions and premature births following exposure to r

Vereinigte Staaten - Englisch - NLM (National Library of Medicine)

glenmark pharmaceuticals inc., usa - amlodipine besylate (unii: 864v2q084h) (amlodipine - unii:1j444qc288), olmesartan medoxomil (unii: 6m97xtv3hd) (olmesartan - unii:8w1iqp3u10) - amlodipine 5 mg - amlodipine and olmesartan medoxomil 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 amlodipine and 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. amlodipine and olmesartan medoxomil tablets may also be used as initial therapy in patients who are likely to need multiple antihypertensive agents to achieve their blood pressure goals. patients with moderate or severe hypertension are at relatively high risk for cardiovascular events (such as strokes, heart attacks, and heart failure), kidney failure, and vision problems, so prompt treatment is clinically relevant. the decision to use a combination as initial therapy should be individualized and should be shaped by considerations such as baseline blood pressure, the target goal, and the incremental likelihood of achieving goal with a combination compared to monotherapy. individual blood pressure goals may vary based upon the patient’s risk. data from an 8-week, placebo-controlled, parallel-group factorial study [see clinical studies (14.1) ] provide estimates of the probability of reaching a blood pressure goal with amlodipine and olmesartan medoxomil tablets compared to amlodipine or olmesartan medoxomil monotherapy. the figures below provide estimates of the likelihood of achieving the targeted systolic or diastolic blood pressure goals with amlodipine and olmesartan medoxomil tablets 10/40 mg compared with amlodipine or olmesartan medoxomil monotherapy, based upon baseline systolic or diastolic blood pressure. the curve of each treatment group was estimated by logistic regression modeling from all available data of that treatment group. the right tail of each curve is less reliable because of small numbers of subjects with high baseline blood pressures. figure 1: probability of achieving systolic blood pressure (sbp) < 140 mmhg at week 8 with locf figure 2: probability of achieving diastolic blood pressure (dbp) < 90 mmhg at week 8 with locf figure 3: probability of achieving systolic blood pressure (sbp) < 130 mmhg at week 8 with locf figure 4: probability of achieving diastolic blood pressure (dbp) < 80 mmhg at week 8 with locf the figures above provide an approximation of the likelihood of reaching a targeted blood pressure goal (e.g., week 8 sbp <140 mmhg or <130 mmhg or a dbp <90 mmhg or <80 mmhg) for the high-dose treatment groups evaluated in the study. amlodipine and olmesartan medoxomil tablets 5/20 mg, the lowest dose combination treatment group, increases the probability of reaching blood pressure goal compared with the highest dose monotherapies, amlodipine 10 mg and olmesartan medoxomil 40 mg. for example, a patient with a baseline blood pressure of 160/100 mmhg has about a 48% likelihood of achieving a goal of <140 mmhg (systolic) and a 51% likelihood of achieving a goal of <90 mmhg (diastolic) on monotherapy with olmesartan medoxomil 40 mg, and about a 46% likelihood of achieving a goal of <140 mmhg (systolic) and a 60% likelihood of achieving a goal of <90 mmhg (diastolic) on monotherapy with amlodipine 10 mg. the likelihood of achieving these same goals increases to 63% (systolic) and 71% (diastolic) on amlodipine and olmesartan medoxomil tablets 5/20 mg, and to 68% (systolic) and 85% (diastolic) on amlodipine and olmesartan medoxomil tablets 10/40 mg. do not co-administer aliskiren with amlodipine and olmesartan medoxomil tablets in patients with diabetes [see drug interactions (7.2)] . risk summary amlodipine and 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 [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 amlodipine and 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 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)]. data animal data no reproductive studies have been conducted with the combination of olmesartan medoxomil, and amlodipine. however, these studies have been conducted for olmesartan medoxomil and amlodipine alone. 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/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 dose). 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. 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/m2 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. risk summary there is limited information regarding the presence of amlodipine and olmesartan medoxomil tablets in human milk, the effects on the breastfed infant, or the effects on milk production. amlodipine is 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 amlodipine and olmesartan medoxomil tablets. data presence of olmesartan in milk was observed after a single oral administration of 5 mg/kg [14c] olmesartan medoxomil to lactating rats. the safety and effectiveness of amlodipine and olmesartan medoxomil tablets in pediatric patients have not been established. of the total number of subjects in the double-blind clinical study of amlodipine and olmesartan medoxomil tablets, 20% (384/1940) were 65 years of age or older and 3% (62/1940) were 75 years or older. no overall differences in safety or effectiveness were observed between subjects 65 years of age or older and younger subjects. elderly patients have decreased clearance of amlodipine. starting amlodipine or adding amlodipine at 2.5 mg in patients ≥75 years old is recommended. the lowest dose of amlodipine and olmesartan medoxomil tablets is 5/20 mg; therefore, initial therapy with amlodipine and olmesartan medoxomil tablets is not recommended in patients ≥75 years old. amlodipine. reported clinical experience has not identified differences in responses between the elderly and younger patients. in general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. elderly patients have decreased clearance of amlodipine with a resulting increase of auc of approximately 40% to 60%, and a lower initial dose may be required. olmesartan medoxomil. of the total number of hypertensive patients receiving olmesartan medoxomil 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. there are no studies of amlodipine and olmesartan medoxomil tablets in patients with hepatic insufficiency, but both amlodipine and olmesartan medoxomil show moderate increases in exposure in patients with hepatic impairment. the recommended initial dose of amlodipine in patients with severe hepatic impairment is 2.5 mg, a dose not available with amlodipine and olmesartan medoxomil tablets. amlodipine. amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t½) is 56 hours in patients with severely impaired hepatic function [see warnings and precautions (5.5)] . olmesartan medoxomil . increases in auc0-∞ and peak plasma concentration (cmax ) for olmesartan were observed with moderate hepatic impairment compared to those in matched controls with an increase in auc of about 60%. there are no studies of amlodipine and olmesartan medoxomil tablets in patients with renal impairment. amlodipine. the pharmacokinetics of amlodipine are not significantly influenced by renal impairment. patients with renal failure may therefore receive the usual initial dose. 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). of the total number of subjects in the double-blind clinical study of amlodipine and olmesartan medoxomil tablets, 25% (481/1940) were black patients. amlodipine and olmesartan medoxomil tablets was effective in treating black patients (usually a low-renin population), and the magnitude of blood pressure reduction in black patients approached that observed for non-black patients.