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

accord healthcare, inc. - letrozole (unii: 7lkk855w8i) (letrozole - unii:7lkk855w8i) - letrozole 2.5 mg - letrozole tablets are indicated for the adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer.  letrozole tablets are indicated for the extended adjuvant treatment of early breast cancer in postmenopausal women, who have received 5 years of adjuvant tamoxifen therapy. the effectiveness of letrozole tablets in extended adjuvant treatment of early breast cancer is based on an analysis of disease-free survival in patients treated with letrozole tablets for a median of 60 months [see clinical studies ( 14.2, 14.3)] . letrozole tablets are indicated for first-line treatment of postmenopausal women with hormone receptor positive or unknown, locally advanced or metastatic breast cancer. letrozole tablets are also indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy  [see clinical studies ( 14.4, 14.5)]. - pregnancy: letrozole can cause fetal harm [see use in specific populations ( 8.1)] . pregnancy: letrozole can cause fetal harm [see use in specific populations ( 8.1)] . - known hypersensitivity to the active substance, or to any of the excipients [see adverse reactions ( 6)] . known hypersensitivity to the active substance, or to any of the excipients [see adverse reactions ( 6)] . risk summary  based on postmarketing reports, findings from animal studies and the mechanism of action, letrozole can cause fetal harm and is contraindicated for use in pregnant women. in post-marketing reports, use of letrozole during pregnancy resulted in cases of spontaneous abortions and congenital birth defects; however, the data are insufficient to inform a drug-associated risk [see contraindications ( 4), warnings and precautions ( 5.6), adverse reactions ( 6.2) and clinical pharmacology ( 12.1)]. in animal reproduction studies, administration of letrozole to pregnant animals during organogenesis resulted in increased post-implantation pregnancy loss and resorption, fewer live fetuses, and fetal malformation affecting the renal and skeletal systems in rats and rabbits at doses approximately 0.1 times the daily maximum recommended human dose (mrhd) on a mg/m 2 basis (see data). the background risk of major birth defects and miscarriage for the indicated population is unknown. however, the background risk in the u.s. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. data animal data in a fertility and early embryonic development toxicity study in female rats, oral administration of letrozole starting 2 weeks before mating until pregnancy day 6 resulted in an increase in pre-implantation loss at doses ≥ 0.003 mg/kg/day (approximately 0.01 times the maximum recommended human dose on a mg/m 2 basis). in an embryo-fetal developmental toxicity study in rats, daily administration of oral letrozole during the period of organogenesis at doses ≥ 0.003 mg/kg (approximately 0.01 time the maximum recommended human dose on a mg/m 2 basis) resulted in embryo-fetal toxicity including intrauterine mortality, increased resorptions and postimplantation loss, decreased numbers of live fetuses and fetal anomalies including absence and shortening of renal papilla, dilation of ureter, edema and incomplete ossification of frontal skull and metatarsals. letrozole was teratogenic to rats at a dose of 0.03 mg/kg (approximately 0.01 times the maximum recommended human dose on a mg/m 2 basis) and caused fetal domed head and cervical/centrum vertebral fusion. in the embryo-fetal development toxicity study in rabbits, daily administration of oral letrozole during the period of organogenesis at doses ≥ 0.002 mg/kg (approximately 0.01 times the maximum recommended human dose on a mg/m 2 basis) resulted in embryo-fetal toxicity including intrauterine mortality, increased resorption, increased postimplantation loss and decreased numbers of live fetuses. fetal anomalies included incomplete ossification of the skull, sternebrae, and fore- and hind legs. risk summary it is not known if letrozole is present in human milk. there are no data on the effects of letrozole on the breastfed infant or milk production. exposure of lactating rats to letrozole was associated with impaired reproductive performance of the male offspring (see data). because of the potential for serious adverse reactions in breastfed infants from letrozole tablets, advise lactating women not to breastfeed while taking letrozole tablets and for at least 3 weeks after the last dose. data animal data in a postnatal developmental toxicity study in lactating rats, letrozole was administered orally at doses of 1, 0.003, 0.03 or 0.3 mg/kg/day on day 0 through day 20 of lactation. the reproductive performance of the male offspring was impaired at letrozole dose as low as 0.003 mg/kg/day (approximately 0.01 times the maximum recommended human dose on a mg/m 2 basis), as reflected by decreased mating and pregnancy ratios. there were no effects on the reproductive performance of female offspring. pregnancy testing based on animal studies, letrozole can cause fetal harm when administered to a pregnant woman [see use in specific populations ( 8.1)]. females of reproductive potential should have a pregnancy test prior to starting treatment with letrozole. contraception females based on animal studies, letrozole tablets can cause fetal harm when administered to a pregnant woman [see use in specific populations ( 8.1)]. . advise females of reproductive potential to use effective contraception during treatment with letrozole tablets and for at least 3 weeks after the last dose. infertility females based on studies in female animals, letrozole tablets may impair fertility in females of reproductive potential [see nonclinical toxicology ( 13.1)]. males based on studies in male animals, letrozole tablets may impair fertility in males of reproductive potential [see nonclinical toxicology ( 13.1)]. the safety and effectiveness in pediatric patients have not been established. letrozole administration to young (postnatal day 7) rats for 12 weeks duration at 0.003, 0.03, 0.3 mg/kg/day by oral gavage resulted in adverse skeletal/growth effects (bone maturation, bone mineral density) and neuroendocrine and reproductive developmental perturbations of the hypothalamic-pituitary axis. administration of 0.3 mg/kg/day resulted in auc values that were similar to the auc in adult patients receiving the recommended dose of 2.5 mg/day. decreased fertility was accompanied by hypertrophy of the hypophysis and testicular changes that included degeneration of the seminiferous tubular epithelium and atrophy of the female reproductive tract. young rats in this study were allowed to recover following discontinuation of letrozole treatment for 42 days. histopathological changes were not reversible at clinically relevant exposures. the median age of patients in all studies of first-line and second-line treatment of metastatic breast cancer was 64 to 65 years. about 1/3 of the patients were greater than or equal to 70 years old. in the first-line study, patients greater than or equal to 70 years of age experienced longer time to tumor progression and higher response rates than patients less than 70. for the extended adjuvant setting (ma-17), more than 5,100 postmenopausal women were enrolled in the clinical study. in total, 41% of patients were aged 65 years or older at enrollment, while 12% were 75 or older. in the extended adjuvant setting, no overall differences in safety or efficacy were observed between these older 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. in the adjuvant setting (big 1-98), more than 8,000 postmenopausal women were enrolled in the clinical study. in total, 36 % of patients were aged 65 years or older at enrollment, while 12% were 75 or older. more adverse reactions were generally reported in elderly patients irrespective of study treatment allocation. however, in comparison to tamoxifen, no overall differences with regards to the safety and efficacy profiles were observed between elderly patients and younger patients.

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

novartis pharmaceuticals corporation - letrozole (unii: 7lkk855w8i) (letrozole - unii:7lkk855w8i) - letrozole 2.5 mg - femara (letrozole) is indicated for the adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer.  femara is indicated for the extended adjuvant treatment of early breast cancer in postmenopausal women, who have received 5 years of adjuvant tamoxifen therapy. the effectiveness of femara in extended adjuvant treatment of early breast cancer is based on an analysis of disease-free survival (dfs) in patients treated with femara for a median of 60 months [see clinical studies (14.2, 14.3)] .  femara is indicated for first-line treatment of postmenopausal women with hormone receptor positive or unknown, locally advanced or metastatic breast cancer. femara is also indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy [see clinical studies (14.4, 14.5)].   - pregnancy: letrozole can cause fetal harm [see use in specific populations (8.1)] . - known hypersensitivity to the active substance, or to any of the excipients [see adverse reactions (6)] . risk summary based on postmarketing reports, findings from animal studies and the mechanism of action, femara can cause fetal harm and is contraindicated for use in pregnant women. in post-marketing reports, use of letrozole during pregnancy resulted in cases of spontaneous abortions and congenital birth defects; however, the data are insufficient to inform a drug-associated risk [see contraindications (4), warnings and precautions (5.6), adverse reactions (6.2), and clinical pharmacology (12.1)] . in animal reproduction studies, administration of letrozole to pregnant animals during organogenesis resulted in increased post-implantation pregnancy loss and resorption, fewer live fetuses, and fetal malformation affecting the renal and skeletal systems in rats and rabbits at doses approximately 0.1 times the daily maximum recommended human dose (mrhd) on a mg/m2 basis (see data) . the background risk of major birth defects and miscarriage for the indicated population is unknown. however, the background risk in the u.s. general population of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies. data animal data in a fertility and early embryonic development toxicity study in female rats, oral administration of letrozole starting 2 weeks before mating until pregnancy day 6 resulted in an increase in pre-implantation loss at doses ≥ 0.003 mg/kg/day (approximately 0.01 times the maximum recommended human dose on a mg/m2 basis). in an embryo-fetal developmental toxicity study in rats, daily administration of oral letrozole during the period of organogenesis at doses ≥ 0.003 mg/kg (approximately 0.01 time the maximum recommended human dose on a mg/m2 basis) resulted in embryo-fetal toxicity including intrauterine mortality, increased resorptions and postimplantation loss, decreased numbers of live fetuses and fetal anomalies, including absence and shortening of renal papilla, dilation of ureter, edema, and incomplete ossification of frontal skull and metatarsals. letrozole was teratogenic to rats at a dose of 0.03 mg/kg (approximately 0.01 times the maximum recommended human dose on a mg/m2 basis) and caused fetal domed head and cervical/centrum vertebral fusion. in the embryo-fetal development toxicity study in rabbits, daily administration of oral letrozole during the period of organogenesis at doses ≥ 0.002 mg/kg (approximately 0.01 times the maximum recommended human dose on a mg/m2 basis) resulted in embryo-fetal toxicity, including intrauterine mortality, increased resorption, increased postimplantation loss and decreased numbers of live fetuses. fetal anomalies included incomplete ossification of the skull, sternebrae, and fore- and hind legs. risk summary it is not known if letrozole is present in human milk. there are no data on the effects of letrozole on the breastfed infant or milk production. exposure of lactating rats to letrozole was associated with impaired reproductive performance of the male offspring (see data) . because of the potential for serious adverse reactions in breastfed infants from femara, advise lactating women not to breastfeed while taking femara and for at least 3 weeks after the last dose. data animal data in a postnatal developmental toxicity study in lactating rats, letrozole was administered orally at doses of 1, 0.003, 0.03, or 0.3 mg/kg/day on day 0 through day 20 of lactation. the reproductive performance of the male offspring was impaired at letrozole dose as low as 0.003 mg/kg/day (approximately 0.01 times the maximum recommended human dose on a mg/m2 basis), as reflected by decreased mating and pregnancy ratios. there were no effects on the reproductive performance of female offspring. pregnancy testing based on animal studies, femara can cause fetal harm when administered to a pregnant woman [see use in specific populations (8.1)] . females of reproductive potential should have a pregnancy test prior to starting treatment with femara. contraception females based on animal studies, femara can cause fetal harm when administered to a pregnant woman [see use in specific populations (8.1)] . advise females of reproductive potential to use effective contraception during treatment with femara and for at least 3 weeks after the last dose. infertility females based on studies in female animals, femara may impair fertility in females of reproductive potential [see nonclinical toxicology (13.1)] . males based on studies in male animals, femara may impair fertility in males of reproductive potential [see nonclinical toxicology (13.1)] . the safety and effectiveness in pediatric patients have not been established. letrozole administration to young (postnatal day 7) rats for 12 weeks duration at 0.003, 0.03, 0.3 mg/kg/day by oral gavage resulted in adverse skeletal/growth effects (bone maturation, bone mineral density) and neuroendocrine and reproductive developmental perturbations of the hypothalamic-pituitary axis. administration of 0.3 mg/kg/day resulted in auc values that were similar to the auc in adult patients receiving the recommended dose of 2.5 mg/day. decreased fertility was accompanied by hypertrophy of the hypophysis and testicular changes that included degeneration of the seminiferous tubular epithelium and atrophy of the female reproductive tract. young rats in this study were allowed to recover following discontinuation of letrozole treatment for 42 days. histopathological changes were not reversible at clinically relevant exposures. the median age of patients in all studies of first-line and second-line treatment of metastatic breast cancer was 64-65 years. about 1/3 of the patients were greater than or equal to 70 years old. in the first-line study, patients greater than or equal to 70 years of age experienced longer time to tumor progression and higher response rates than patients less than 70. for the extended adjuvant setting (ma-17), more than 5,100 postmenopausal women were enrolled in the clinical study. in total, 41% of patients were aged 65 years or older at enrollment, while 12% were 75 or older. in the extended adjuvant setting, no overall differences in safety or efficacy were observed between these older 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. in the adjuvant setting (big 1-98), more than 8,000 postmenopausal women were enrolled in the clinical study. in total, 36% of patients were aged 65 years or older at enrollment, while 12% were 75 or older. more adverse reactions were generally reported in elderly patients irrespective of study treatment allocation. however, in comparison to tamoxifen, no overall differences with regards to the safety and efficacy profiles were observed between elderly patients and younger patients.

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

avpak - fluoxetine hydrochloride (unii: i9w7n6b1kj) (fluoxetine - unii:01k63sup8d) - fluoxetine 10 mg - fluoxetine capsules are indicated for the treatment of: - acute and maintenance treatment of major depressive disorder [see clinical studies (14.1)] . -  acute and maintenance treatment of obsessions and compulsions in patients with obsessive compulsive disorder (ocd) [see clinical studies (14.2)] . -  acute and maintenance treatment of binge-eating and vomiting behaviors in patients with moderate to severe bulimia nervosa [see clinical studies (14.3)] . - acute treatment of panic disorder, with or without agoraphobia [see clinical studies (14.4)] . fluoxetine capsules and olanzapine in combination are indicated for the treatment of: - acute treatment of depressive episodes associated with bipolar i disorder. - treatment resistant depression (major depressive disorder in patients, who do not respond to 2 sep

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contract pharmacy services-pa - fluoxetine hydrochloride (unii: i9w7n6b1kj) (fluoxetine - unii:01k63sup8d) - fluoxetine 20 mg - fluoxetine capsules are indicated for the treatment of: - acute and maintenance treatment of major depressive disorder [see clinical studies (14.1)] . -  acute and maintenance treatment of obsessions and compulsions in patients with obsessive compulsive disorder (ocd) [see clinical studies (14.2)] . -  acute and maintenance treatment of binge-eating and vomiting behaviors in patients with moderate to severe bulimia nervosa [see clinical studies (14.3)] . - acute treatment of panic disorder, with or without agoraphobia [see clinical studies (14.4)] . fluoxetine capsules and olanzapine in combination are indicated for the treatment of: - acute treatment of depressive episodes associated with bipolar i disorder. fluoxetine capsules monotherapy is not indicated for the treatment of depressive episodes associate

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bayer healthcare pharmaceuticals inc. - gadoxetate disodium (unii: hoy74vze0m) (gadolinium cation (3+) - unii:azv954tz9n) - gadoxetate disodium 181.43 mg in 1 ml - eovist is indicated for intravenous use in magnetic resonance imaging (mri) of the liver to detect and characterize lesions in patients with known or suspected focal liver disease. eovist is contraindicated in patients with history of severe hypersensitivity reactions to eovist [see warnings and precautions ( 5.3 )] . gbcas have been shown to cross the human placenta and result in fetal exposure and gadolinium retention. the human data on the association between gbcas and adverse fetal outcomes are limited and inconclusive (see data). in animal reproduction studies, no teratogenicity was observed with repeated daily intravenous administration of gadoxetate disodium to rats during organogenesis at doses up to 32 times the recommended single human dose; however, an increase in preimplantation loss was noted at doses 3.2 times the single human dose. post implantation loss was observed with repeated daily intravenous administration of gadoxetate disodium to rabbits on gestation days 6 through 18 at doses 26 times the recommended single human dose (see data) . because of the potential risks of gadolinium to the fetus, use eovist only if imaging is essential during pregnancy and cannot be delayed. the background risk in the u.s. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. contrast enhancement is visualized in the placenta and fetal tissues after maternal gbca administration. cohort studies and case reports on exposure to gbcas during pregnancy have not reported a clear association between gbcas and adverse effects in the exposed neonates. however, a retrospective cohort study, comparing pregnant women who had a gbca mri to pregnant women who did not have an mri, reported a higher occurrence of stillbirths and neonatal deaths in the group receiving gbca mri. limitations of this study include a lack of comparison with non-contrast mri and lack of information about the maternal indication for mri. overall, these data preclude a reliable evaluation of the potential risk of adverse fetal outcomes with the use of gbcas in pregnancy. animal data gbcas administered to pregnant non-human primates (0.1 mmol/kg on gestational days 85 and 135) result in measurable gadolinium concentration in the offspring in bone, brain, skin, kidney, and spleen for at least 7 months. gbcas administered to pregnant mice (2 mmol/kg daily on gestational days 16 through 19) result in measurable gadolinium concentrations in the pups in bone, brain, kidney, liver, blood, muscle, and spleen at one month postnatal age. animal reproductive and developmental toxicity studies were done in rats and rabbits. gadoxetate disodium was not teratogenic when given intravenously during organogenesis to pregnant rats at doses up to 32 times the recommended single human dose (mmol/m2 basis). however, an increase in preimplantation loss was noted at 3.2 times the human dose (mmol/m2 basis). compared to untreated controls, rates of postimplantation loss and absorption increased and litter size decreased when pregnant rabbits received gadoxetate disodium at doses 26 times the recommended human single dose (mmol/m2 basis). this occurred without evidence of maternal toxicity. because pregnant animals received repeated daily doses of gadoxetate disodium, their overall exposure was significantly higher than that achieved with the standard single dose administered to humans. risk summary there is no information regarding the presence of gadoxetate disodium in human milk, the effects of the drug in a breastfed infant, or the effects of the drug on milk production. however, published lactation data on other gbcas report that 0.01 to 0.04% of the maternal gadolinium dose is present in breast milk and there is limited gbca gastrointestinal absorption in the breastfed infant. in rat lactation studies with [153 gd] gadoxetate disodium, less than 0.5% of the total administered radioactivity was transferred to the nursing pup. clinical considerations a lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk for up to 10 hours after eovist administration in order to minimize exposure to a breastfed infant. data animal data in lactating rats given 0.1 mmol/kg [153 gd] gadoxetate disodium, less than 0.5% of the total administered radioactivity was transferred to the neonates via maternal milk, mostly within 2 hours. adequate and well-controlled studies of eovist in pediatric patients have not been conducted. an observational study with eovist was performed in 52 patients (aged > 2 months and < 18 years) referred for evaluation of suspected or known focal liver lesions. eovist improved border delineation and increased contrast of the primary lesion in the majority of patients when compared to non-contrast images. no safety issues were identified. no dose adjustment according to age is necessary in pediatric patients. the safety and effectiveness of eovist have not been established in premature infants. nsf risk no case of nsf associated with eovist or any other gbca has been identified in pediatric patients ages 6 years and younger. juvenile animal data single and repeat-dose toxicity studies in neonatal and juvenile rats did not reveal findings suggestive of a specific risk for use in pediatric patients including term neonates and infants. in clinical studies of eovist, 674 (34%) patients were 65 years of age and over, while 20 (1%) were 80 years of age 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. in general, use of eovist in an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy. in a clinical pharmacology study, slight to moderate differences in pharmacokinetic parameters of gadoxetate disodium (increased auc and terminal half-life, decreased total clearance) were found in a group of geriatric volunteers in comparison to non-geriatric volunteers. no clinically relevant differences in liver contrast enhancement were found. in a clinical pharmacology study in a group of patients with moderate renal impairment, a moderate increase in auc and terminal half-life was observed in comparison to healthy volunteers with normal renal function. hepatic contrast did not differ among the groups. end-stage renal failure may impair eovist imaging performance [see warnings and precautions (5.6)]. in a study of patients with end-stage renal failure, the terminal half-life was prolonged about 12-fold and the auc was increased about 6-fold. hepatic contrast was markedly reduced in these patients, which was attributed to significantly elevated serum ferritin levels [see warnings and precautions ( 5.2 )] . approximately 30% of the injected dose was removed by dialysis in a single 3-hour dialysis session, which started one hour after an eovist dose. eovist was almost completely eliminated via dialysis and biliary excretion within the observation period of 6 days, predominantly within the first 3 days. in a clinical pharmacology study in groups of patients with mild or moderate hepatic impairment, a slight to moderate increase in plasma auc, half-life and urinary excretion, as well as decrease in hepatobiliary excretion was observed in comparison to healthy subjects with normal liver function. hepatic contrast signal did not differ among the groups. severe hepatic impairment may impair eovist imaging performance [see warnings and precautions (5.6)] . in patients with severe hepatic impairment, especially in patients with abnormally high (> 3 mg/dl) serum bilirubin levels, the auc was increased up to 60% and the elimination half-life was increased up to 49%. the hepatobiliary excretion substantially decreased to about 5% of the administered dose and reduced hepatic contrast signal was observed. a dose adjustment is not necessary for patients with hepatic impairment. in clinical studies, 489 patients had a diagnosis of liver cirrhosis (child-pugh category a, n = 270; category b, n = 98; category c, n = 24; unknown category, n = 97). no difference in diagnostic performance and safety was observed among these patients.

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

allergan, inc. - risedronate sodium hemi-pentahydrate (unii: hu2yaq274o) (risedronic acid - unii:km2z91756z), risedronate sodium monohydrate (unii: f67l43ut5c) (risedronic acid - unii:km2z91756z) - risedronate sodium 4.3 mg - actonel is indicated for the treatment and prevention of osteoporosis in postmenopausal women. in postmenopausal women with osteoporosis, actonel reduces the incidence of vertebral fractures and a composite endpoint of nonvertebral osteoporosis-related fractures [see clinical studies ( 14.1 , 14.2 ) ]. actonel is indicated for treatment to increase bone mass in men with osteoporosis. actonel is indicated for the treatment and prevention of glucocorticoid-induced osteoporosis in men and women who are either initiating or continuing systemic glucocorticoid treatment (daily dosage of greater than or equal to 7.5 mg of prednisone or equivalent) for chronic diseases. patients treated with glucocorticoids should receive adequate amounts of calcium and vitamin d.   actonel is indicated for treatment of paget’s disease of bone in men and women. the optimal duration of use has not been determined. the safety and effectiveness of actonel for the treatment of osteoporosis are based on clinical data of three years duration. all patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis. patients at low-risk for fracture should be considered for drug discontinuation after 3 to 5 years of use. patients who discontinue therapy should have their risk for fracture re-evaluated periodically. actonel is contraindicated in patients with the following conditions: - abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia [see warnings and precautions ( 5.1 ) ] - inability to stand or sit upright for at least 30 minutes [see   dosage and administration ( 2 ), warnings and precautions ( 5.1 ) ] - hypocalcemia [see  warnings and precautions ( 5.2 ) ] - known hypersensitivity to actonel or any of its excipients. angioedema, generalized rash, bullous skin reactions, stevens-johnson syndrome and toxic epidermal necrolysis have been reported [see  adverse reactions ( 6.2 ) ] risk summary available data on the use of actonel in pregnant women are insufficient to inform a drug-associated risk of adverse maternal or fetal outcomes. discontinue actonel when pregnancy is recognized. in animal reproduction studies, daily oral administration of risedronate to pregnant rats during organogenesis decreased neonatal survival and body weight at doses approximately 5 and 26 times, respectively, the highest recommended human daily dose of 30 mg (based on body surface area, mg/m2 ). a low incidence of cleft palate was observed in fetuses of dams treated at doses approximately equal to the 30 mg human daily dose. delayed skeletal ossification was observed in fetuses of dams treated at approximately 2.5 to 5 times the 30 mg human daily dose. periparturient mortality due to maternal hypocalcemia occurred in dams and neonates upon daily oral administration of risedronate to pregnant rats during mating and/or gestation starting at doses equivalent to the 30 mg daily human dose. bisphosphonates are incorporated into the bone matrix, from which they are gradually released over a period of years. the amount of bisphosphonate incorporated into adult bone and available for release into the systemic circulation is directly related to the dose and duration of bisphosphonate use. consequently, based on the mechanism of action of bisphosphonates, there is a potential risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. the impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been studied. the estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. all pregnancies have a background risk of birth defects, loss, or other adverse outcomes. in the u.s. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. data animal data in animal studies, pregnant rats received risedronate sodium during organogenesis at doses equivalent to 1 to 26 times the 30 mg human daily dose (based on body surface area, mg/m2 ). survival of neonates was decreased in dams treated during gestation with oral doses approximately 5 times the human dose, and body weight was decreased in neonates of dams treated with approximately 26 times the human dose. a low incidence of cleft palate was observed in fetuses of dams treated with oral doses approximately equal to the human dose. the number of fetuses exhibiting incomplete ossification of sternebrae or skull of dams treated with approximately 2.5 times the human dose was significantly increased compared to controls. both incomplete ossification and unossified sternebrae were increased in fetuses of dams treated with oral doses approximately 5 times the human dose. no significant ossification effects were seen in fetuses of rabbits treated with oral doses approximately 7 times the human dose (the highest dose tested). however, 1 of 14 litters were aborted and 1 of 14 litters were delivered prematurely. periparturient mortality due to maternal hypocalcemia occurred in dams and neonates when pregnant rats were treated daily during mating and/or gestation with oral doses equivalent to the human dose or higher. risk summary there are no data on the presence of risedronate in human milk, the effects on the breastfed infant, or the effects on milk production. a small degree of lacteal transfer occurred in nursing rats. the concentration of the drug in animal milk does not necessarily predict the concentration of drug in human milk. however, when a drug is present in animal milk, it is likely that the drug will be present in human milk. the developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for actonel and any potential adverse effects on the breast-fed child from actonel or from the underlying maternal condition. data animal data risedronate was detected in neonates of lactating rats given a single oral dose of risedronate at 24-hours post-dosing, indicating a small degree of lacteal transfer. actonel is not indicated for use in pediatric patients. the safety and effectiveness of risedronate was assessed in a one-year, randomized, double-blind, placebo-controlled study of 143 pediatric patients (94 received risedronate) with osteogenesis imperfecta (oi). the enrolled population was predominantly patients with mild osteogenesis imperfecta (85% type-i), aged 4 to less than 16 years, 50% male and 82% caucasian, with a mean lumbar spine bmd z-score of -2.08 (2.08 standard deviations below the mean for age-matched controls). patients received either a 2.5 mg (less than or equal to 30 kg body weight) or 5 mg (greater than 30 kg body weight) daily oral dose. after one year, an increase in lumbar spine bmd in the risedronate group compared to the placebo group was observed. however, treatment with risedronate did not result in a reduction in the risk of fracture in pediatric patients with osteogenesis imperfecta. in actonel-treated subjects, no mineralization defects were noted in paired bone biopsy specimens obtained at baseline and month 12. the overall safety profile of risedronate in oi patients treated for up to 12 months was generally similar to that of adults with osteoporosis. however, there was an increased incidence of vomiting compared to placebo. in this study, vomiting was observed in 15% of children treated with risedronate and 6% of patients treated with placebo. other adverse events reported in greater than or equal to 10% of patients treated with risedronate and with a higher frequency than placebo were: pain in the extremity (21% with risedronate versus 16% with placebo), headache (20% versus 8%), back pain (17% versus 10%), pain (15% versus 10%), upper abdominal pain (11% versus 8%), and bone pain (10% versus 4%). of the patients receiving actonel in postmenopausal osteoporosis studies [see  c linical s tudies ( 14 ) ], 47% were between 65 and 75 years of age, and 17% were over 75. the corresponding proportions were 26% and 11% in glucocorticoid-induced osteoporosis trials, and 40% and 26% in paget’s disease trials. no overall differences in efficacy between geriatric and younger patients were observed in these studies. in the male osteoporosis trial, 28% of patients receiving actonel were between 65 and 75 years of age and 9% were over 75. the lumbar spine bmd response for actonel compared to placebo was 5.6% for subjects less than 65 years and 2.9% for subjects greater than or equal to 65 years. no overall differences in safety between geriatric and younger patients were observed in the actonel trials, but greater sensitivity of some older individuals cannot be ruled out. actonel is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 ml/min) because of lack of clinical experience. no dosage adjustment is necessary in patients with a creatinine clearance greater than or equal to 30 ml/min. no studies have been performed to assess risedronate’s safety or efficacy in patients with hepatic impairment. risedronate is not metabolized in human liver preparations. dosage adjustment is unlikely to be needed in patients with hepatic impairment.

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

proficient rx lp - zolpidem tartrate (unii: wy6w63843k) (zolpidem - unii:7k383oqi23) - zolpidem tartrate 12.5 mg - zolpidem tartrate extended-release tablets are indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance (as measured by wake time after sleep onset). the clinical trials performed in support of efficacy were up to 3 weeks (using polysomnography measurement up to 2 weeks in both adult and elderly patients) and 24 weeks (using patient-reported assessment in adult patients only) in duration [see clinical studies (14)] . zolpidem tartrate extended-release tablets are contraindicated in patients with known hypersensitivity to zolpidem. observed reactions include anaphylaxis and angioedema [see warnings and precautions (5.3)]. pregnancy category c there are no adequate and well-controlled studies of zolpidem tartrate extended-release tablets in pregnant women. studies in children to assess the effects of prenatal exposure to zolpidem have not been conducted; however, cases of severe neonatal respiratory depression have been reported when zolpidem was used at th

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contract pharmacy services-pa - divalproex sodium (unii: 644vl95ao6) (valproic acid - unii:614oi1z5wi) - valproic acid 500 mg - divalproex sodium extended-release tablets, usp are a valproate and are indicated for the treatment of acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features. a manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgment, aggressiveness and possible hostility. a mixed episode is characterized by the criteria for a manic episode in conjunction with those for a major depressive episode (depressed mood, loss of interest or pleasure in nearly all activities). the efficacy of divalproex sodium extended-release tablets, usp is based in part on studies of divalproex sodium delayed-release tablets, usp in this indication, and was confirmed in a 3-week trial with patients meeting dsm-iv tr criteria for bipolar i disorder, manic or mixed type, who were hospitalized for acute mania

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avpak - sildenafil citrate (unii: bw9b0ze037) (sildenafil - unii:3m7ob98y7h) - sildenafil 20 mg - sildenafil tablets are indicated for the treatment of pulmonary arterial hypertension (who group i) in adults to improve exercise ability and delay clinical worsening. the delay in clinical worsening was demonstrated when sildenafil tablets were added to background epoprostenol therapy [see clinical studies (14) ]. studies establishing effectiveness were short-term (12 to 16 weeks), and included predominately patients with new york heart association (nyha) functional class ii-iii symptoms and idiopathic etiology (71%) or associated with connective tissue disease (ctd) (25%). sildenafil tablets are contraindicated in patients with: - concomitant use of organic nitrates in any form, either regularly or intermittently, because of the greater risk of hypotension [see warnings and precautions (5.2)] . - concomitant use of riociguat, a guanylate cyclase stimulator. pde-5 inhibitors, including sildenafil, may potentiate the hypotensive effects of riociguat. - known hypersensitivity to sildenafil or any component of the tablet. hypersensitivity, including anaphylactic reaction, anaphylactic shock and anaphylactoid reaction, has been reported in association with the use of sildenafil. pregnancy category b there are no adequate and well-controlled studies of sildenafil in pregnant women. no evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m 2 basis, 32- and 68-times, respectively, the recommended human dose (rhd) of 20 mg three times a day. in a rat pre- and postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the rhd on a mg/m 2 basis). the safety and efficacy of sildenafil citrate during labor and delivery have not been studied. it is not known if sildenafil or its metabolites are excreted in human breast milk. because many drugs are excreted in human milk, caution should be exercised when sildenafil citrate is administered to a nursing woman. in a randomized, double-blind, multi-center, placebo-controlled, parallel-group, dose-ranging study, 234 patients with pah, aged 1 to 17 years, body weight greater than or equal to 8 kg, were randomized, on the basis of body weight, to three dose levels of sildenafil citrate, or placebo, for 16 weeks of treatment. most patients had mild to moderate symptoms at baseline: who functional class i (32%), ii (51%), iii (15%), or iv (0.4%). one-third of patients had primary pah; two-thirds had secondary pah (systemic-to-pulmonary shunt in 37%; surgical repair in 30%). sixty-two percent of patients were female. drug or placebo was administered three times a day. the primary objective of the study was to assess the effect of sildenafil citrate on exercise capacity as measured by cardiopulmonary exercise testing in pediatric patients developmentally able to perform the test (n = 115). administration of sildenafil citrate did not result in a statistically significant improvement in exercise capacity in those patients. no patients died during the 16-week controlled study. after completing the 16-week controlled study, a patient originally randomized to sildenafil citrate remained on his/her dose of sildenafil citrate or, if originally randomized to placebo, was randomized to low-, medium-, or high-dose sildenafil citrate. after all patients completed 16 weeks of follow-up in the controlled study, the blind was broken and doses were adjusted as clinically indicated. patients treated with sildenafil were followed for a median of 4.6 years (range 2 days to 8.6 years). mortality during the long-term study, by originally assigned dose, is shown in figure 6: figure 6: kaplan-meier plot of mortality by sildenafil citrate dose during the study, there were 42 reported deaths, with 37 of these deaths reported prior to a decision to titrate subjects to a lower dosage because of a finding of increased mortality with increasing sildenafil citrate doses. for the survival analysis which included 37 deaths, the hazard ratio for high dose compared to low dose was 3.9, p=0.007. causes of death were typical of patients with pah. use of sildenafil citrate, particularly chronic use, is not recommended in children. clinical studies of sildenafil citrate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. other reported clinical experience has not identified differences in responses between the elderly and younger patients. in general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see clinical pharmacology (12.3) ] . no dose adjustment for mild to moderate impairment is required. severe impairment has not been studied [see clinical pharmacology (12.3) ] . no dose adjustment is required (including severe impairment clcr < 30 ml/min) [see clinical pharmacology (12.3) ] .

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aurobindo pharma limited - valacyclovir hydrochloride (unii: g447s0t1vc) (acyclovir - unii:x4hes1o11f) - valacyclovir 500 mg - cold sores (herpes labialis) valacyclovir tablets are indicated for treatment of cold sores (herpes labialis). the efficacy of valacyclovir tablets initiated after the development of clinical signs of a cold sore (e.g., papule, vesicle, or ulcer) has not been established. genital herpes initial episode: valacyclovir tablets are indicated for treatment of the initial episode of genital herpes in immunocompetent adults. the efficacy of treatment with valacyclovir tablets when initiated more than 72 hours after the onset of signs and symptoms has not been established. recurrent episodes:  valacyclovir tablets are indicated for treatment of recurrent episodes of genital herpes in immunocompetent adults. the efficacy of treatment with valacyclovir tablets when initiated more than 24 hours after the onset of signs and symptoms has not been established. suppressive therapy:  valacyclovir tablets are indicated for chronic suppressive therapy of recurrent episodes of genital herpes in immunocompetent and in hiv-1-infected adults. the efficacy and safety of valacyclovir tablets for the suppression of genital herpes beyond 1 year in immunocompetent patients and beyond 6 months in hiv-1-infected patients have not been established. reduction of transmission:  valacyclovir tablets are indicated for the reduction of transmission of genital herpes in immunocompetent adults. the efficacy of valacyclovir tablets for the reduction of transmission of genital herpes beyond 8 months in discordant couples has not been established. the efficacy of valacyclovir tablets for the reduction of transmission of genital herpes in individuals with multiple partners and non-heterosexual couples has not been established. safer sex practices should be used with suppressive therapy (see current centers for disease control and prevention [cdc] sexually transmitted diseases treatment guidelines ). herpes zoster valacyclovir tablets are indicated for the treatment of herpes zoster (shingles) in immunocompetent adults. the efficacy of valacyclovir tablets when initiated more than 72 hours after the onset of rash and the efficacy and safety of valacyclovir tablets for treatment of disseminated herpes zoster have not been established. cold sores (herpes labialis) valacyclovir tablets are indicated for the treatment of cold sores (herpes labialis) in pediatric patients aged greater than or equal to 12 years. the efficacy of valacyclovir tablets initiated after the development of clinical signs of a cold sore (e.g., papule, vesicle, or ulcer) has not been established. chickenpox valacyclovir tablets are indicated for the treatment of chickenpox in immunocompetent pediatric patients aged 2 to less than 18 years. based on efficacy data from clinical trials with oral acyclovir, treatment with valacyclovir tablets should be initiated within 24 hours after the onset of rash [see clinical studies (14.4) ] . the efficacy and safety of valacyclovir tablets have not been established in: - immunocompromised patients other than for the suppression of genital herpes in hiv-1-infected patients with a cd4+ cell count greater than or equal to 100 cells/mm3 . - patients aged less than 12 years with cold sores (herpes labialis). - patients aged less than 2 years or greater than or equal to 18 years with chickenpox. - patients aged less than 18 years with genital herpes. - patients aged less than 18 years with herpes zoster. - neonates and infants as suppressive therapy following neonatal herpes simplex virus (hsv) infection. valacyclovir tablets are contraindicated in patients who have had a demonstrated clinically significant hypersensitivity reaction (e.g., anaphylaxis) to valacyclovir, acyclovir, or any component of the formulation [see adverse reactions (6.3)] . risk summary clinical data over several decades with valacyclovir and its metabolite, acyclovir, in pregnant women, have not identified a drug associated risk of major birth defects. there are  insufficient data on the use of valacyclovir regarding miscarriage or adverse maternal or fetal outcomes (see data). there are risks to the fetus associated with untreated herpes simplex during pregnancy (see clinical considerations). in animal reproduction studies, no evidence of adverse developmental outcomes was observed with valacyclovir when administered to pregnant rats and rabbits at system exposures (auc) 4 (rats) and 7 (rabbits) times the human exposure at the maximum recommended human dose (mrhd) (see data). the estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk: the risk of neonatal hsv infection varies from 30% to 50% for genital hsv acquired in late pregnancy (third trimester), whereas with hsv acquisition in early pregnancy, the risk of neonatal infection is about 1%. a primary herpes occurrence during the first trimester of pregnancy has been associated with neonatal chorioretinitis, microcephaly, and, in rare cases, skin lesions. in very rare cases, transplacental transmission can occur resulting in congenital infection, including microcephaly, hepatosplenomegaly, intrauterine growth restriction, and stillbirth. co-infection with hsv increases the risk of perinatal hiv transmission in women who had a clinical diagnosis of genital herpes during pregnancy. data human data: clinical data over several decades with valacyclovir and its metabolite, acyclovir, in pregnant women, based on published literature, have not identified a drug-associated risk of major birth defects. there are insufficient data on the use of valacyclovir regarding miscarriage or adverse maternal or fetal outcomes. the acyclovir and the valacyclovir pregnancy registries, both population-based international prospective studies, collected pregnancy data through april 1999. the acyclovir registry documented outcomes of 1,246 infants and fetuses exposed to acyclovir during pregnancy (756 with earliest exposure during the first trimester, 197 during the second trimester, 291 during the third trimester, and 2 unknown). the occurrence of major birth defects during first-trimester exposure to acyclovir was 3.2% (95% ci: 2.0% to 5.0%) and during any trimester of exposure was 2.6% (95% ci: 1.8% to 3.8%). the valacyclovir pregnancy registry documented outcomes of 111 infants and fetuses exposed to valacyclovir during pregnancy (28 with earliest exposure in the first trimester, 31 during the second trimester, and 52 during the third trimester).the occurrence of major birth defects during first-trimester exposure to valacyclovir was 4.5% (95% ci: 0.24% to 24.9%) and during any trimester of exposure was 3.9% (95% ci: 1.3% to 10.7%). available studies have methodological limitations including insufficient sample size to support conclusions about overall malformation risk or for making comparisons of the frequencies of specific birth defects. animal data: valacyclovir was administered orally to pregnant rats and rabbits (up to  400 mg/kg/day) during organogenesis (gestation days 6 through 15, and 6 through 18, respectively). no adverse embryo-fetal effects were observed in rats and rabbits at acyclovir exposures (auc) of up to approximately 4 (rats) and 7 (rabbits) times the exposure in humans at the mrhd. early embryo death, fetal growth retardation (weight and length), and variations in fetal skeletal development (primarily extra ribs and delayed ossification of sternebrae) were observed in rats and associated with maternal toxicity (200 mg/kg/day; approximately 6 times higher than human exposure at the mrhd). in a pre/postnatal development study, valacyclovir was administered orally to pregnant rats (up to 200 mg/kg/day from gestation day 15 to post-partum day 20) from late gestation through lactation. no significant adverse effects were observed in offspring exposed daily from before birth through lactation at maternal exposures (auc) of approximately 6 times higher than human exposures at the mrhd. risk summary although there is no information on the presence of valacyclovir in human milk, its metabolite, acyclovir, is present in human milk following oral administration of valacyclovir. based on published data, a 500 mg maternal dose of valacyclovir hydrochloride twice daily would provide a breastfed child with an oral acyclovir dosage of approximately 0.6 mg/kg/day (see data). there is no data on the effects of valacyclovir or acyclovir on the breastfed child or on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for valacyclovir hydrochloride and any potential adverse effects on the breastfed child from valacyclovir hydrochloride or from the underlying maternal condition. data following oral administration of a 500 mg dose of valacyclovir hydrochloride to 5 lactating women, peak acyclovir concentrations (cmax ) in breast milk ranged from 0.5 to 2.3 times (median 1.4) the corresponding maternal acyclovir serum concentrations. the acyclovir breast milk auc ranged from 1.4 to 2.6 times (median 2.2) maternal serum auc. a 500 mg maternal dose of valacyclovir hydrochloride twice daily would provide a breastfed child with an oral acyclovir dosage of approximately 0.6 mg/kg/day. unchanged valacyclovir was not detected in maternal serum, breast milk or infant urine. valacyclovir hydrochloride is indicated for treatment of cold sores in pediatric patients aged greater than or equal to 12 years and for treatment of chickenpox in pediatric patients aged 2 to less than 18 years [see indications and usage (1.2), dosage and administration (2.2)]. the use of valacyclovir hydrochloride for treatment of cold sores is based on 2 double‑blind, placebo‑controlled clinical trials in healthy adults and adolescents (aged greater than or equal to 12 years) with a history of recurrent cold sores [see clinical studies (14.1)] . the use of valacyclovir hydrochloride for treatment of chickenpox in pediatric patients aged 2 to less than 18 years is based on single-dose pharmacokinetic and multiple-dose safety data from an open-label trial with valacyclovir and supported by efficacy and safety data from 3 randomized, double-blind, placebo-controlled trials evaluating oral acyclovir in pediatric subjects with chickenpox [see dosage and administration (2.2), adverse reactions (6.2), clinical pharmacology (12.3), clinical studies (14.4)] . the efficacy and safety of valacyclovir have not been established in pediatric patients: - aged less than 12 years with cold sores - aged less than 18 years with genital herpes - aged less than 18 years with herpes zoster - aged less than 2 years with chickenpox - for suppressive therapy following neonatal hsv infection. the pharmacokinetic profile and safety of valacyclovir oral suspension in children aged less than 12 years were studied in 3 open-label trials. no efficacy evaluations were conducted in any of the 3 trials. trial 1 was a single-dose pharmacokinetic, multiple-dose safety trial in 27 pediatric subjects aged 1 to less than 12 years with clinically suspected varicella-zoster virus (vzv) infection [see dosage and administration (2.2), adverse reactions (6.2), clinical pharmacology (12.3), clinical studies (14.4)]. trial 2 was a single-dose pharmacokinetic and safety trial in pediatric subjects aged 1 month to less than 6 years who had an active herpes virus infection or who were at risk for herpes virus infection. fifty-seven subjects were enrolled and received a single dose of 25 mg/kg valacyclovir oral suspension. in infants and children aged 3 months to less than 6 years, this dose provided comparable systemic acyclovir exposures to that from a 1 gram dose of valacyclovir in adults (historical data). in infants aged 1 month to less than 3 months, mean acyclovir exposures resulting from a 25 mg/kg dose were higher (cmax : ↑30%, auc: ↑60%) than acyclovir exposures following a 1 gram dose of valacyclovir in adults. acyclovir is not approved for suppressive therapy in infants and children following neonatal hsv infections; therefore, valacyclovir is not recommended for this indication because efficacy cannot be extrapolated from acyclovir. trial 3 was a single-dose pharmacokinetic, multiple-dose safety trial in 28 pediatric subjects aged 1 to less than 12 years with clinically suspected hsv infection. none of the subjects enrolled in this trial had genital herpes. each subject was dosed with valacyclovir oral suspension 10 mg/kg twice daily for 3 to 5 days. acyclovir systemic exposures in pediatric subjects following valacyclovir oral suspension were compared with historical acyclovir systemic exposures in immunocompetent adults receiving the solid oral dosage form of valacyclovir or acyclovir for the treatment of recurrent genital herpes. the mean projected daily acyclovir systemic exposures in pediatric subjects across all age-groups (1 to less than 12 years) were lower (cmax : ↓20%, auc: ↓33%) compared with the acyclovir systemic exposures in adults receiving valacyclovir 500 mg twice daily but were higher (daily auc: ↑16%) than systemic exposures in adults receiving acyclovir 200 mg 5 times daily. insufficient data are available to support valacyclovir for the treatment of recurrent genital herpes in this age-group because clinical information on recurrent genital herpes in young children is limited; therefore, extrapolating efficacy data from adults to this population is not possible. moreover, valacyclovir has not been studied in children aged 1 to less than 12 years with recurrent genital herpes. of the total number of subjects in clinical trials of valacyclovir hydrochloride, 906 were 65 and over, and 352 were 75 and over. in a clinical trial of herpes zoster, the duration of pain after healing (post-herpetic neuralgia) was longer in subjects 65 and older compared with younger adults. elderly patients are more likely to have reduced renal function and require dose reduction. elderly patients are also more likely to have renal or cns adverse events [see dosage and administration (2.4), warnings and precautions (5.2, 5.3), clinical pharmacology (12.3)] . dosage reduction is recommended when administering valacyclovir hydrochloride to patients with renal impairment [see dosage and administration (2.4), warnings and precautions (5.2, 5.3)] .