Evrópusambandið - enska - EMA (European Medicines Agency)

sanofi winthrop industrie - insulin aspart - diabetes mellitus - drugs used in diabetes - insulin aspart sanofi is indicated for the treatment of diabetes mellitus in adults, adolescents and children aged 1 year and above.

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cardinal health 107, llc - dronedarone (unii: jqz1l091y2) (dronedarone - unii:jqz1l091y2) - dronedarone 400 mg - multaq® is indicated to reduce the risk of hospitalization for atrial fibrillation in patients in sinus rhythm with a history of paroxysmal or persistent atrial fibrillation (af) [see clinical studies (14)]. multaq is contraindicated in patients with: pregnancy category x [see contraindications (4)] multaq may cause fetal harm when administered to a pregnant woman. in animal studies, dronedarone was teratogenic in rats at the maximum recommended human dose (mrhd), and in rabbits at half the mrhd. if this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. when pregnant rats received dronedarone at oral doses greater than or equal to the mrhd (on a mg/m2 basis), fetuses had increased rates of external, visceral and skeletal malformations (cranioschisis, cleft palate, incomplete evagination of pineal body, brachygnathia, partially fused carotid arteries, truncus arteriosus, abnormal lobation of the liver,

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winthrop u.s, a business of sanofi-aventis u.s. llc - oxaliplatin (unii: 04zr38536j) (oxaliplatin - unii:04zr38536j) - oxaliplatin 5 mg in 1 ml - oxaliplatin, in combination with infusional fluorouracil and leucovorin, is indicated for: - adjuvant treatment of stage iii colon cancer in patients who have undergone complete resection of the primary tumor. - treatment of advanced colorectal cancer. oxaliplatin is contraindicated in patients with a history of a hypersensitivity reaction to oxaliplatin or other platinum-based drugs. reactions have included anaphylaxis [see warnings and precautions (5.1)] . risk summary based on its direct interaction with dna, oxaliplatin can cause fetal harm when administered to a pregnant woman. the available human data do not establish the presence or absence of major birth defects or miscarriage related to the use of oxaliplatin. reproductive toxicity studies demonstrated adverse effects on embryo-fetal development in rats at maternal doses that were below the recommended human dose based on body surface area (see data) . advise a pregnant woman of the potential risk to a fetus. 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 pregnant rats were administered oxaliplatin at less than one-tenth the recommended human dose based on body surface area during gestation days (gd)1–5 (preimplantation), gd 6–10, or gd 11–16 (during organogenesis). oxaliplatin caused developmental mortality (increased early resorptions) when administered on days gd 6–10 and gd 11–16 and adversely affected fetal growth (decreased fetal weight, delayed ossification) when administered on days gd 6–10. risk summary there are no data on the presence of oxaliplatin or its metabolites in human or animal milk or its effects on the breastfed infant or on milk production. because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with oxaliplatin and for 3 months after the final dose. pregnancy testing verify pregnancy status in females of reproductive potential prior to initiating oxaliplatin [see use in specific populations (8.1)] . contraception oxaliplatin can cause embryo-fetal harm when administered to a pregnant woman [see use in specific populations (8.1)] . females advise female patients of reproductive potential to use effective contraception while receiving oxaliplatin and for 9 months after the final dose. males based on its mechanism action as a genotoxic drug, advise males with female partners of reproductive potential to use effective contraception while receiving oxaliplatin and for 6 months after the final dose [see nonclinical toxicology (13.1)] . infertility based on animal studies, oxaliplatin may impair fertility in males and females [see nonclinical toxicology (13.1)] . the safety and effectiveness of oxaliplatin in pediatrics have not been established. safety and effectiveness were assessed across 4 open-label studies in 235 patients aged 7 months to 22 years with solid tumors. in a multicenter, open-label, non-comparative, non-randomized study (ard5531), oxaliplatin was administered to 43 patients with refractory or relapsed malignant solid tumors, mainly neuroblastoma and osteosarcoma. the dose limiting toxicity (dlt) was sensory neuropathy at a dose of 110 mg/m 2 . the main adverse reactions were: paresthesia (60%, grade 3–4: 7%), fever (40%, grade 3–4: 7%), and thrombocytopenia (40%, grade 3–4: 27%). no responses were observed. in an open-label non-randomized study (dfi7434), oxaliplatin was administered to 26 pediatric patients with metastatic or unresectable solid tumors, mainly neuroblastoma and ganglioneuroblastoma. the dlt was sensory neuropathy at a dose of 160 mg/m 2 . no responses were observed. in an open-label, single-agent study (ard5021), oxaliplatin was administered to 43 pediatric patients with recurrent or refractory embryonal cns tumors. the most common adverse reactions reported were: leukopenia (67%, grade 3–4: 12%), anemia (65%, grade 3–4: 5%), thrombocytopenia (65%, grade 3–4: 26%), vomiting (65%, grade 3–4: 7%), neutropenia (58%, grade 3–4: 16%), and sensory neuropathy (40%, grade 3–4: 5%). in an open-label single-agent study (ard5530), oxaliplatin was administered to 123 pediatric patients with recurrent solid tumors, including neuroblastoma, osteosarcoma, ewing sarcoma or peripheral pnet, ependymoma, rhabdomyosarcoma, hepatoblastoma, high grade astrocytoma, brain stem glioma, low grade astrocytoma, malignant germ cell tumor and other tumors. the most common adverse reactions reported were: sensory neuropathy (52%, grade 3–4: 12%), thrombocytopenia (37%, grade 3–4: 17%), anemia (37%, grade 3–4: 9%), vomiting (26%, grade 3–4: 4%), increased alt (24%, grade 3–4: 6%), increased ast (24%, grade 3–4: 2%), and nausea (23%, grade 3–4: 3%). the pharmacokinetic parameters of ultrafiltrable platinum were evaluated in 105 pediatric patients during the first cycle. the mean clearance in pediatric patients estimated by the population pharmacokinetic analysis was 4.7 l/h (%cv, 41%). mean platinum pharmacokinetic parameters in ultrafiltrate were c max of 0.75 ± 0.24 mcg/ml, auc 0–48h of 7.52 ± 5.07 mcg∙h/ml and auc inf of 8.83 ± 1.57 mcg∙h/ml at 85 mg/m 2 of oxaliplatin and c max of 1.10 ± 0.43 mcg/ml, auc 0–48h of 9.74 ± 2.52 mcg∙h/ml and auc inf of 17.3 ± 5.34 mcg∙h/ml at 130 mg/m 2 of oxaliplatin. in the adjuvant treatment trial [see clinical studies (14.1)] , 400 patients who received oxaliplatin with fluorouracil/leucovorin were greater than or equal to 65 years. the effect of oxaliplatin in patients greater than or equal to 65 years was not conclusive. patients greater than or equal to 65 years receiving oxaliplatin experienced more diarrhea and grade 3–4 neutropenia (45% vs 39%) compared to patients less than 65 years. in the previously untreated advanced colorectal cancer trial [see clinical studies (14.2)] , 99 patients who received oxaliplatin with fluorouracil and leucovorin were greater than or equal to 65 years. the same efficacy improvements in response rate, time to tumor progression, and overall survival were observed in the greater than or equal to 65 years patients as in the overall study population. adverse reactions were similar in patients less than 65 and greater than or equal to 65 years, but older patients may have been more susceptible to diarrhea, dehydration, hypokalemia, leukopenia, fatigue, and syncope. in the previously treated advanced colorectal cancer trial [see clinical studies (14.3)] , 55 patients who received oxaliplatin with fluorouracil and leucovorin were greater than or equal to 65 years. no overall differences in effectiveness were observed between these patients and younger adults. adverse reactions were similar in patients less than 65 and greater than or equal to 65 years, but older patients may have been more susceptible to diarrhea, dehydration, hypokalemia, and fatigue. no significant effect of age on the clearance of ultrafiltrable platinum has been observed [see clinical pharmacology (12.3)] . the auc of unbound platinum in plasma ultrafiltrate was increased in patients with renal impairment [see clinical pharmacology (12.3)] . no dose reduction is recommended for patients with mild (creatinine clearance 50 to 79 ml/min) or moderate (creatinine clearance 30 to 49 ml/min) renal impairment, calculated by cockcroft-gault equation. reduce the dose of oxaliplatin in patients with severe renal impairment (creatinine clearance less than 30 ml/min) [see dosage and administration (2.3)].

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winthrop u.s, a business of sanofi-aventis u.s. llc - docetaxel (unii: 15h5577cqd) (docetaxel anhydrous - unii:699121phca) - docetaxel anhydrous 80 mg in 4 ml - docetaxel is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy. docetaxel in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with operable node-positive breast cancer. docetaxel as a single agent is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior platinum-based chemotherapy. docetaxel in combination with cisplatin is indicated for the treatment of patients with unresectable, locally advanced or metastatic non-small cell lung cancer who have not previously received chemotherapy for this condition. docetaxel in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer. docetaxel in combination with cisplatin and fluorouracil is indicated for the treatment of patients with advanced gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who have not received prior chemotherapy for advanced disease. docetaxel in combination with cisplatin and fluorouracil is indicated for the induction treatment of patients with locally advanced squamous cell carcinoma of the head and neck (scchn). docetaxel is contraindicated in patients with: - neutrophil counts of <1500 cells/mm 3 [see warnings and precautions (5.3)] . - a history of severe hypersensitivity reactions to docetaxel or to other drugs formulated with polysorbate 80. severe reactions, including anaphylaxis, have occurred [see warnings and precautions (5.5)] . risk summary based on findings in animal reproduction studies and its mechanism of action, docetaxel can cause fetal harm when administered to a pregnant woman [see clinical pharmacology (12.1)] . available data from case reports in the literature and pharmacovigilance with docetaxel use in pregnant women are not sufficient to inform the drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. docetaxel contains alcohol which can interfere with neurobehavioral development [see clinical considerations] . in animal reproductive studies, administration of docetaxel to pregnant rats and rabbits during the period of organogenesis caused an increased incidence of embryo-fetal toxicities, including intrauterine mortality, at doses as low as 0.02 and 0.003 times the recommended human dose based on body surface area, respectively [see data] . advise pregnant women and females of reproductive potential of the potential risk to a fetus. 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, miscarriage, 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 docetaxel contains alcohol [see warnings and precautions (5.13)] . published studies have demonstrated that alcohol is associated with fetal harm including central nervous system abnormalities, behavioral disorders, and impaired intellectual development. data animal data intravenous administration of ≥0.3 and 0.03 mg/kg/day docetaxel to pregnant rats and rabbits, respectively, during the period of organogenesis caused an increased incidence of intrauterine mortality, resorptions, reduced fetal weights, and fetal ossification delays. maternal toxicity was also observed at these doses, which were approximately 0.02 and 0.003 times the daily maximum recommended human dose based on body surface area, respectively. risk summary there is no information regarding the presence of docetaxel in human milk, or on its effects on milk production or the breastfed child. no lactation studies in animals have been conducted. because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with docetaxel and for 1 week after the last dose. based on findings in animals, docetaxel can cause fetal harm when administered to a pregnant woman [see use in specific populations (8.1)] . pregnancy testing verify pregnancy status in females of reproductive potential prior to initiating docetaxel. contraception females based on genetic toxicity findings, advise females of reproductive potential to use effective contraception during treatment and for 2 months after the last dose of docetaxel. males based on genetic toxicity findings, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of docetaxel. infertility based on findings in animal studies, docetaxel may impair fertility in males of reproductive potential [see nonclinical toxicology (13.1)] . the alcohol content of docetaxel injection should be taken into account when given to pediatric patients [see warnings and precautions (5.13)] . the efficacy of docetaxel in pediatric patients as monotherapy or in combination has not been established. the overall safety profile of docetaxel in pediatric patients receiving monotherapy or tcf was consistent with the known safety profile in adults. docetaxel has been studied in a total of 289 pediatric patients: 239 in 2 trials with monotherapy and 50 in combination treatment with cisplatin and 5-fluorouracil (tcf). docetaxel monotherapy docetaxel monotherapy was evaluated in a dose-finding phase 1 trial in 61 pediatric patients (median age 12.5 years, range 1–22 years) with a variety of refractory solid tumors. the recommended dose was 125 mg/m 2 as a 1-hour intravenous infusion every 21 days. the primary dose limiting toxicity was neutropenia. the recommended dose for docetaxel monotherapy was evaluated in a phase 2 single-arm trial in 178 pediatric patients (median age 12 years, range 1–26 years) with a variety of recurrent/refractory solid tumors. efficacy was not established with tumor response rates ranging from one complete response (cr) (0.6%) in a patient with undifferentiated sarcoma to four partial responses (2.2%) seen in one patient each with ewing sarcoma, neuroblastoma, osteosarcoma, and squamous cell carcinoma. docetaxel in combination docetaxel was studied in combination with cisplatin and 5-fluorouracil (tcf) versus cisplatin and 5-fluorouracil (cf) for the induction treatment of nasopharyngeal carcinoma (npc) in pediatric patients prior to chemoradiation consolidation. seventy-five patients (median age 16 years, range 9 to 21 years) were randomized (2:1) to docetaxel (75 mg/m 2 ) in combination with cisplatin (75 mg/m 2 ) and 5-fluorouracil (750 mg/m 2 ) (tcf) or to cisplatin (80 mg/m 2 ) and 5-fluorouracil (1000 mg/m 2 /day) (cf). the primary endpoint was the cr rate following induction treatment of npc. one patient out of 50 in the tcf group (2%) had a complete response while none of the 25 patients in the cf group had a complete response. pharmacokinetics pharmacokinetic parameters for docetaxel were determined in 2 pediatric solid tumor trials. following docetaxel administration at 55 mg/m 2 to 235 mg/m 2 in a 1-hour intravenous infusion every 3 weeks in 25 patients aged 1 to 20 years (median 11 years), docetaxel clearance was 17.3±10.9 l/h/m 2 . docetaxel was administered in combination with cisplatin and 5-fluorouracil (tcf), at dose levels of 75 mg/m 2 in a 1-hour intravenous infusion day 1 in 28 patients aged 10 to 21 years (median 16 years, 17 patients were older than 16). docetaxel clearance was 17.9±8.75 l/h/m 2 , corresponding to an auc of 4.20±2.57 μg∙h/ml. in summary, the body surface area adjusted clearance of docetaxel monotherapy and tcf combination in children were comparable to those in adults [see clinical pharmacology (12.3)] . 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 in elderly patients. non-small cell lung cancer in a study conducted in chemotherapy-naive patients with nsclc (tax326), 148 patients (36%) in the docetaxel+cisplatin group were 65 years of age or greater. there were 128 patients (32%) in the vinorelbine+cisplatin group 65 years of age or greater. in the docetaxel+cisplatin group, patients less than 65 years of age had a median survival of 10.3 months (95% ci: 9.1 months, 11.8 months) and patients 65 years or older had a median survival of 12.1 months (95% ci: 9.3 months, 14 months). in patients 65 years of age or greater treated with docetaxel+cisplatin, diarrhea (55%), peripheral edema (39%) and stomatitis (28%) were observed more frequently than in the vinorelbine+cisplatin group (diarrhea 24%, peripheral edema 20%, stomatitis 20%). patients treated with docetaxel+cisplatin who were 65 years of age or greater were more likely to experience diarrhea (55%), infections (42%), peripheral edema (39%) and stomatitis (28%) compared to patients less than the age of 65 administered the same treatment (43%, 31%, 31% and 21%, respectively). when docetaxel was combined with carboplatin for the treatment of chemotherapy-naive, advanced non-small cell lung carcinoma, patients 65 years of age or greater (28%) experienced higher frequency of infection compared to similar patients treated with docetaxel+cisplatin, and a higher frequency of diarrhea, infection and peripheral edema than elderly patients treated with vinorelbine+cisplatin. prostate cancer of the 333 patients treated with docetaxel every three weeks plus prednisone in the prostate cancer study (tax327), 209 patients were 65 years of age or greater and 68 patients were older than 75 years. in patients treated with docetaxel every three weeks, the following treatment-emergent adverse reactions occurred at rates ≥10% higher in patients 65 years of age or greater compared to younger patients: anemia (71% vs 59%), infection (37% vs 24%), nail changes (34% vs 23%), anorexia (21% vs 10%), weight loss (15% vs 5%), respectively. breast cancer in the adjuvant breast cancer trial (tax316), docetaxel in combination with doxorubicin and cyclophosphamide was administered to 744 patients of whom 48 (6%) were 65 years of age or greater. the number of elderly patients who received this regimen was not sufficient to determine whether there were differences in safety and efficacy between elderly and younger patients. gastric cancer among the 221 patients treated with docetaxel in combination with cisplatin and fluorouracil in the gastric cancer study, 54 were 65 years of age or older and 2 patients were older than 75 years. in this study, the number of patients who were 65 years of age or older was insufficient to determine whether they respond differently from younger patients. however, the incidence of serious adverse reactions was higher in the elderly patients compared to younger patients. the incidence of the following adverse reactions (all grades, regardless of relationship): lethargy, stomatitis, diarrhea, dizziness, edema, febrile neutropenia/neutropenic infection occurred at rates ≥10% higher in patients who were 65 years of age or older compared to younger patients. elderly patients treated with tcf should be closely monitored. head and neck cancer among the 174 and 251 patients who received the induction treatment with docetaxel in combination with cisplatin and fluorouracil (tpf) for scchn in the tax323 and tax324 studies, 18 (10%) and 32 (13%) of the patients were 65 years of age or older, respectively. these clinical studies of docetaxel in combination with cisplatin and fluorouracil in patients with scchn did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. other reported clinical experience with this treatment regimen has not identified differences in responses between elderly and younger patients. avoid docetaxel in patients with bilirubin >uln and patients with ast and/or alt >1.5 × uln concomitant with alkaline phosphatase >2.5 × uln [see boxed warning, warnings and precautions (5.2), clinical pharmacology (12.3)] . the alcohol content of docetaxel injection should be taken into account when given to patients with hepatic impairment [see warnings and precautions (5.13)] .

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winthrop u.s, a business of sanofi-aventis u.s. llc - leflunomide (unii: g162gk9u4w) (leflunomide - unii:g162gk9u4w) - leflunomide 10 mg - leflunomide is indicated for the treatment of adults with active rheumatoid arthritis (ra). leflunomide is contraindicated in: - pregnant women. leflunomide may cause fetal harm. if a woman becomes pregnant while taking this drug, stop leflunomide, apprise the patient of the potential hazard to the fetus, and begin a drug elimination procedure [see warnings and precautions (5.1,5.3)and use in specific populations (8.1)]. - patients with severe hepatic impairment [see warnings and precautions (5.2)]. - patients with known hypersensitivity to leflunomide or any of the other components of leflunomide. known reactions include anaphylaxis [see adverse reactions (6.1)]. - patients being treated with teriflunomide [see drug interactions (7)]. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to leflunomide during pregnancy. health care providers and patients are encouraged to report pregnancies by calling 1-877-311-8972 or visit http://www.pregnancystudies.org/participate-in-a-study/. risk summary leflunomide is contraindicated for use in pregnant women because of the potential for fetal harm. in animal reproduction studies, oral administration of leflunomide during organogenesis at a dose of 1/10 of, and equivalent to, the maximum recommended human dose (mrhd) based on auc, respectively, in rats and rabbits, caused teratogenicity (rats and rabbits), and embryo-lethality (rats) [see data] . pregnancy exposure registry data are not available at this time to inform the presence or absence of drug-associated risk with the use of leflunomide during pregnancy. the background risk of major birth defects and miscarriage for the indicated populations is unknown. 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. if this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, stop treatment with leflunomide, apprise the patient of the potential hazard to a fetus, and perform the accelerated drug elimination procedure to achieve teriflunomide concentrations of less than 0.02 mg/l (0.02 mcg/ml) [see warnings and precautions (5.3)] . clinical considerations fetal/neonatal adverse reactions lowering the plasma concentration of the active metabolite, teriflunomide, by instituting an accelerated drug elimination procedure as soon as pregnancy is detected may decrease the risk to the fetus from leflunomide. the accelerated drug elimination procedure includes verification that the plasma teriflunomide concentration is less than 0.02 mg/l [see warnings and precautions (5.3)and clinical pharmacology (12.3)] . data animal data in an embryo-fetal development study, pregnant rats administered leflunomide during organogenesis from gestation days 7 to 19 at a dose approximately 1/10 of the mrhd (on an auc basis at a maternal oral dose of 15 mg/kg), teratogenic effects, most notably anophthalmia or microphthalmia and internal hydrocephalus, were observed. under these exposure conditions, leflunomide also caused a decrease in the maternal body weight and an increase in embryolethality with a decrease in fetal body weight for surviving fetuses. in an embryo-fetal development study, pregnant rabbits administered leflunomide during organogenesis from gestation days 6 to 18 at a dose approximately equivalent to the mrhd (on an auc basis at a maternal oral dose of 10 mg/kg), a teratogenic finding of fused, dysplastic sternebrae was observed. leflunomide was not teratogenic in rats and rabbits at doses approximately 1/150 and 1/10 of the mrhd, respectively (on an auc basis at maternal oral dose of 1 mg/kg in both rats and rabbits). in a pre and postnatal development study, when female rats were treated with leflunomide at a dose that was approximately 1/100 of the mrhd (on an auc basis at a maternal dose of 1.25 mg/kg) beginning 14 days before mating and continuing until the end of lactation, the offspring exhibited marked (greater than 90%) decreases in postnatal survival. risk summary clinical lactation studies have not been conducted to assess the presence of leflunomide in human milk, the effects of leflunomide on the breastfed child, or the effects of leflunomide on milk production. because of the potential for serious adverse reactions in a breastfed infant from leflunomide, advise a nursing woman to discontinue breastfeeding during treatment with leflunomide. leflunomide may cause fetal harm when administered during pregnancy. advise females of the potential risk to the fetus. advise females to notify their healthcare provider immediately if pregnancy occurs or is suspected during treatment [see use in specific populations (8.1)] . women receiving leflunomide treatment who wish to become pregnant should discontinue leflunomide and undergo an accelerated drug elimination procedure to achieve plasma teriflunomide concentrations of less than 0.02 mg/l (0.02 mcg/ml) [see warnings and precautions (5.3)] . pregnancy testing exclude pregnancy in females of reproductive potential before starting treatment with leflunomide. contraception females advise females of reproductive potential to use effective contraception during treatment with leflunomide and while undergoing a drug elimination procedure until verification that the plasma teriflunomide concentration is less than 0.02 mg/l [see warnings and precautions (5.3)] . the safety and effectiveness of leflunomide in pediatric patients have not been established. the safety and effectiveness of leflunomide in the treatment of polyarticular course juvenile idiopathic arthritis (jia) was evaluated in a single multicenter, double-blind, active-controlled trial in 94 pediatric patients (1:1 randomization) with polyarticular course juvenile idiopathic arthritis (jia) as defined by the american college of rheumatology (acr). in this population, leflunomide treatment was found not to be effective. the safety of leflunomide was studied in 74 patients with polyarticular course jia ranging in age from 3–17 years (47 patients from the active-controlled study and 27 from an open-label safety and pharmacokinetic study). the most common adverse events included abdominal pain, diarrhea, nausea, vomiting, oral ulcers, upper respiratory tract infections, alopecia, rash, headache, and dizziness. less common adverse events included anemia, hypertension, and weight loss. fourteen pediatric patients experienced alt and/or ast elevations, nine between 1.2 and 3-fold the upper limit of normal, and five between 3 and 8-fold the upper limit of normal. of the total number of subjects in controlled clinical trials (trials 1, 2, and 3) of leflunomide, 234 subjects were 65 years and over [see clinical studies (14)] . 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. no dosage adjustment is needed in patients over 65. dedicated studies of the effect of hepatic impairment on leflunomide pharmacokinetics have not been conducted. given the need to metabolize leflunomide into the active species, the role of the liver in drug elimination/recycling, and the possible risk of increased hepatic toxicity, the use of leflunomide in patients with hepatic impairment is not recommended. dedicated studies of the effect of renal impairment on leflunomide pharmacokinetics have not been conducted. given that the kidney plays an important role in drug elimination, caution should be used when leflunomide is administered to these patients.

Bandaríkin - enska - NLM (National Library of Medicine)

winthrop u.s, a business of sanofi-aventis u.s. llc - clofarabine (unii: 762rdy0y2h) (clofarabine - unii:762rdy0y2h) - clofarabine 1 mg in 1 ml - clofarabine is indicated for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. this indication is based upon response rate. there are no trials verifying an improvement in disease-related symptoms or increased survival with clofarabine. none. risk summary in animal reproduction studies, intravenous administration of clofarabine to pregnant rats and rabbits during organogenesis at doses approximately 0.2 to 1-times the maximum recommended human dose of 52 mg/m 2 based on body surface area (bsa) resulted in embryo-fetal mortality, alterations to growth, and structural abnormalities (see data) . advise pregnant women of the potential risk to a fetus. there are no available data on clofarabine use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. clofarabine should be used during pregnancy only if the potential benefits to the mother outweigh the potential risks, including those to the fetus. 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. data animal data intravenous administration of clofarabine to pregnant rats during organogenesis (gestation days [gd] 7–17) at doses of 1, 3 or 9 mg/kg/day (equivalent to 6, 18, 54 mg/m 2 /day) resulted in maternal toxicities at the 9 mg/kg dose, as indicated by reduced body weights and food consumption. developmental toxicity (i.e., reduced fetal body weights and increased postimplantation loss) and increased incidences of external, soft tissue, and skeletal malformations and variations (including retarded ossification) were observed at 9 mg/kg/day (54 mg/m 2 ; approximately equivalent to the recommended human dose based on bsa). altered ossification patterns (extra metacarpal or metatarsal ossification) were observed in single fetuses at lower doses of clofarabine (1 and 3 mg/kg/day; 0.1- and 0.3-times the recommended human dose based on bsa). when clofarabine was administered intravenously to pregnant rabbits during organogenesis (gd 6–18) at doses of 0.1, 0.3, or 1 mg/kg/day (equivalent to 1.2, 3.6, 12 mg/m 2 /day), developmental toxicity (i.e., reduced fetal body weights and increased postimplantation loss) and increased incidences of external, soft tissue, and skeletal malformations and variations (including retarded ossification) were observed at the 1 mg/kg/day dose (12 mg/m 2 ; 0.2-times the recommended human dose based on bsa). alterations in ossification patterns (increase in the average numbers of ossified thoracic vertebrae and rib pairs, and reduction in the average number of forepaw metacarpals) and abdominal wall defect were observed at 0.3 mg/kg/day (3.6 mg/m 2 ; 0.1-times the recommended human dose based on bsa). risk summary there are no data on the presence of clofarabine in human milk, the effects on the breastfed child, or the effects on milk production. because of the potential for serious adverse reactions in the breastfed child including genotoxicity, advise patients not to breastfeed during treatment with clofarabine, and for at least 2 weeks after the last dose. pregnancy testing pregnancy testing is recommended for females of reproductive potential prior to initiating clofarabine. contraception females clofarabine can cause embryo-fetal harm when administered to pregnant women [see use in specific populations (8.1)] . advise female patients to use effective contraception during treatment with clofarabine and for 6 months after the last dose. males based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with clofarabine and for at least 3 months after the last dose [see nonclinical toxicology (13.1)] . infertility females based on findings from animal studies, clofarabine may impair female fertility [see nonclinical toxicology (13.1)]. the reversibility of the effect on fertility is unknown. males based on findings from animal studies, clofarabine may impair male fertility [see nonclinical toxicology (13.1)]. the reversibility of the effect on fertility is unknown. safety and effectiveness have been established in pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia. safety and effectiveness of clofarabine has not been established in geriatric patients aged 65 and older. safety and effectiveness have not been established in adults. reduce the clofarabine starting dose by 50% in patients with crcl of 30 to 60 ml/min. there is insufficient information to make a dosage recommendation in patients with crcl less than 30 ml/min or in patients on dialysis. the pharmacokinetics of clofarabine in patients with renal impairment and normal renal function were obtained from a population pharmacokinetic analysis of three pediatric and two adult studies. in patients with crcl 60 to less than 90 ml/min (n=47) and crcl 30 to less than 60 ml/min (n=30), the average auc of clofarabine increased by 60% and 140%, respectively, compared to patients with normal (n=66) renal function (crcl greater than 90 ml/min).

Bandaríkin - enska - NLM (National Library of Medicine)

winthrop u.s, a business of sanofi-aventis u.s. llc - oxaliplatin (unii: 04zr38536j) (oxaliplatin - unii:04zr38536j) - oxaliplatin 5 mg in 1 ml - oxaliplatin, in combination with infusional fluorouracil and leucovorin, is indicated for: - adjuvant treatment of stage iii colon cancer in patients who have undergone complete resection of the primary tumor. - treatment of advanced colorectal cancer. oxaliplatin is contraindicated in patients with a history of a hypersensitivity reaction to oxaliplatin or other platinum-based drugs. reactions have included anaphylaxis [see warnings and precautions (5.1)] . risk summary based on its direct interaction with dna, oxaliplatin can cause fetal harm when administered to a pregnant woman. the available human data do not establish the presence or absence of major birth defects or miscarriage related to the use of oxaliplatin. reproductive toxicity studies demonstrated adverse effects on embryo-fetal development in rats at maternal doses that were below the recommended human dose based on body surface area (see data) . advise a pregnant woman of the potential risk to a fetus. 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 pregnant rats were administered oxaliplatin at less than one-tenth the recommended human dose based on body surface area during gestation days (gd)1–5 (preimplantation), gd 6–10, or gd 11–16 (during organogenesis). oxaliplatin caused developmental mortality (increased early resorptions) when administered on days gd 6–10 and gd 11–16 and adversely affected fetal growth (decreased fetal weight, delayed ossification) when administered on days gd 6–10. risk summary there are no data on the presence of oxaliplatin or its metabolites in human or animal milk or its effects on the breastfed infant or on milk production. because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with oxaliplatin and for 3 months after the final dose. pregnancy testing verify pregnancy status in females of reproductive potential prior to initiating oxaliplatin [see use in specific populations (8.1)] . contraception oxaliplatin can cause embryo-fetal harm when administered to a pregnant woman [see use in specific populations (8.1)] . females advise female patients of reproductive potential to use effective contraception while receiving oxaliplatin and for 9 months after the final dose. males based on its mechanism action as a genotoxic drug, advise males with female partners of reproductive potential to use effective contraception while receiving oxaliplatin and for 6 months after the final dose [see nonclinical toxicology (13.1)] . infertility based on animal studies, oxaliplatin may impair fertility in males and females [see nonclinical toxicology (13.1)] . the safety and effectiveness of oxaliplatin in pediatrics have not been established. safety and effectiveness were assessed across 4 open-label studies in 235 patients aged 7 months to 22 years with solid tumors. in a multicenter, open-label, non-comparative, non-randomized study (ard5531), oxaliplatin was administered to 43 patients with refractory or relapsed malignant solid tumors, mainly neuroblastoma and osteosarcoma. the dose limiting toxicity (dlt) was sensory neuropathy at a dose of 110 mg/m 2 . the main adverse reactions were: paresthesia (60%, grade 3–4: 7%), fever (40%, grade 3–4: 7%), and thrombocytopenia (40%, grade 3–4: 27%). no responses were observed. in an open-label non-randomized study (dfi7434), oxaliplatin was administered to 26 pediatric patients with metastatic or unresectable solid tumors, mainly neuroblastoma and ganglioneuroblastoma. the dlt was sensory neuropathy at a dose of 160 mg/m 2 . no responses were observed. in an open-label, single-agent study (ard5021), oxaliplatin was administered to 43 pediatric patients with recurrent or refractory embryonal cns tumors. the most common adverse reactions reported were: leukopenia (67%, grade 3–4: 12%), anemia (65%, grade 3–4: 5%), thrombocytopenia (65%, grade 3–4: 26%), vomiting (65%, grade 3–4: 7%), neutropenia (58%, grade 3–4: 16%), and sensory neuropathy (40%, grade 3–4: 5%). in an open-label single-agent study (ard5530), oxaliplatin was administered to 123 pediatric patients with recurrent solid tumors, including neuroblastoma, osteosarcoma, ewing sarcoma or peripheral pnet, ependymoma, rhabdomyosarcoma, hepatoblastoma, high grade astrocytoma, brain stem glioma, low grade astrocytoma, malignant germ cell tumor and other tumors. the most common adverse reactions reported were: sensory neuropathy (52%, grade 3–4: 12%), thrombocytopenia (37%, grade 3–4: 17%), anemia (37%, grade 3–4: 9%), vomiting (26%, grade 3–4: 4%), increased alt (24%, grade 3–4: 6%), increased ast (24%, grade 3–4: 2%), and nausea (23%, grade 3–4: 3%). the pharmacokinetic parameters of ultrafiltrable platinum were evaluated in 105 pediatric patients during the first cycle. the mean clearance in pediatric patients estimated by the population pharmacokinetic analysis was 4.7 l/h (%cv, 41%). mean platinum pharmacokinetic parameters in ultrafiltrate were c max of 0.75 ± 0.24 mcg/ml, auc 0–48h of 7.52 ± 5.07 mcg∙h/ml and auc inf of 8.83 ± 1.57 mcg∙h/ml at 85 mg/m 2 of oxaliplatin and c max of 1.10 ± 0.43 mcg/ml, auc 0–48h of 9.74 ± 2.52 mcg∙h/ml and auc inf of 17.3 ± 5.34 mcg∙h/ml at 130 mg/m 2 of oxaliplatin. in the adjuvant treatment trial [see clinical studies (14.1)] , 400 patients who received oxaliplatin with fluorouracil/leucovorin were greater than or equal to 65 years. the effect of oxaliplatin in patients greater than or equal to 65 years was not conclusive. patients greater than or equal to 65 years receiving oxaliplatin experienced more diarrhea and grade 3–4 neutropenia (45% vs 39%) compared to patients less than 65 years. in the previously untreated advanced colorectal cancer trial [see clinical studies (14.2)] , 99 patients who received oxaliplatin with fluorouracil and leucovorin were greater than or equal to 65 years. the same efficacy improvements in response rate, time to tumor progression, and overall survival were observed in the greater than or equal to 65 years patients as in the overall study population. adverse reactions were similar in patients less than 65 and greater than or equal to 65 years, but older patients may have been more susceptible to diarrhea, dehydration, hypokalemia, leukopenia, fatigue, and syncope. in the previously treated advanced colorectal cancer trial [see clinical studies (14.3)] , 55 patients who received oxaliplatin with fluorouracil and leucovorin were greater than or equal to 65 years. no overall differences in effectiveness were observed between these patients and younger adults. adverse reactions were similar in patients less than 65 and greater than or equal to 65 years, but older patients may have been more susceptible to diarrhea, dehydration, hypokalemia, and fatigue. no significant effect of age on the clearance of ultrafiltrable platinum has been observed [see clinical pharmacology (12.3)] . the auc of unbound platinum in plasma ultrafiltrate was increased in patients with renal impairment [see clinical pharmacology (12.3)] . no dose reduction is recommended for patients with mild (creatinine clearance 50 to 79 ml/min) or moderate (creatinine clearance 30 to 49 ml/min) renal impairment, calculated by cockcroft-gault equation. reduce the dose of oxaliplatin in patients with severe renal impairment (creatinine clearance less than 30 ml/min) [see dosage and administration (2.3)].

Bandaríkin - enska - NLM (National Library of Medicine)

winthrop u.s, a business of sanofi-aventis u.s. llc - irbesartan (unii: j0e2756z7n) (irbesartan - unii:j0e2756z7n), hydrochlorothiazide (unii: 0j48lph2th) (hydrochlorothiazide - unii:0j48lph2th) - irbesartan and hydrochlorothiazide tablets are indicated for the treatment of hypertension. irbesartan and hydrochlorothiazide may be used in patients whose blood pressure is not adequately controlled on monotherapy. irbesartan and hydrochlorothiazide may also be used as initial therapy in patients who are likely to need multiple drugs to achieve their blood pressure goals. the choice of irbesartan and hydrochlorothiazide as initial therapy for hypertension should be based on an assessment of potential benefits and risks. patients with stage 2 (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 may be shaped by considerations such as the baseline blood pressure, the target goal, and the incremental likelihood of achieving goal with a combination compared with monotherapy. data from studies v and vi [see clinical studies (14.2)] provide estimates of the probability of reaching a blood pressure goal with irbesartan and hydrochlorothiazide compared to irbesartan or hydrochlorothiazide (hctz) monotherapy. the relationship between baseline blood pressure and achievement of a sesbp <140 or <130 mmhg or sedbp <90 or <80 mmhg in patients treated with irbesartan and hydrochlorothiazide compared to patients treated with irbesartan or hctz monotherapy are shown in figures 1a through 2b. the above graphs provide a rough approximation of the likelihood of reaching a targeted blood pressure goal (e.g., week 8 sitting systolic blood pressure ≤140 mmhg) for the treatment groups. the curve of each treatment group in each study was estimated by logistic regression modeling from all available data of that treatment group. the estimated likelihood at the right tail of each curve is less reliable due to small numbers of subjects with high baseline blood pressures. for example, a patient with a blood pressure of 180/105 mmhg has about a 25% likelihood of achieving a goal of <140 mmhg (systolic) and 50% likelihood of achieving <90 mmhg (diastolic) on irbesartan alone (and lower still likelihoods on hctz alone). the likelihood of achieving these goals on irbesartan and hydrochlorothiazide rises to about 40% (systolic) or 70% (diastolic). - irbesartan and hydrochlorothiazide is contraindicated in patients who are hypersensitive to any component of this product. - because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs. - do not coadminister aliskiren with irbesartan and hydrochlorothiazide in patients with diabetes [see drug interactions (7)] . risk summary irbesartan and hydrochlorothiazide can cause fetal harm when administered to a pregnant woman. use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death [see clinical considerations] . most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. when pregnancy is detected, discontinue irbesartan and hydrochlorothiazide as soon as possible. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes regardless of drug exposure. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. clinical considerations disease-associated maternal and/or embryo-fetal risk hypertension in pregnancy increases the maternal risk for preeclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and postpartum hemorrhage). hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. pregnant women with hypertension should be carefully monitored and managed accordingly. fetal/neonatal adverse reactions oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension, and death. perform serial ultrasound examinations to assess the intra-amniotic environment. fetal testing may be appropriate, based on the week of pregnancy. patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. closely observe infants with histories of in utero exposure to irbesartan and hydrochlorothiazide for hypotension, oliguria, and hyperkalemia and other symptoms of renal impairment. in neonates with a history of in utero exposure to irbesartan and hydrochlorothiazide, if oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function. thiazides cross the placenta, and use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults [see warnings and precautions (5.1)] . data animal data irbesartan crosses the placenta in rats and rabbits. in female rats given irbesartan prior to mating through gestation and lactation at oral doses of 50, 180, or 650 mg/kg/day (1.6 to 21.1 times the maximum recommended human dose (mrhd) based on body surface area), fetuses examined on gestation day 20 showed increased incidences of hydroureter and renal pelvic cavitation and/or absence of renal papilla in all irbesartan-treated groups. subcutaneous edema also occurred in fetuses at maternal doses ≥180 mg/kg/day (5.8 times the mrhd). these anomalies occurred when female rats received irbesartan from prior to mating through day 20 of gestation but were not observed in pups postnatally in the same study, or when irbesartan was given to pregnant rats only during organogenesis (gestation day 6 through gestation day 15) at oral doses from 50 to 450 mg/kg/day (up to 14.6 times the mrhd). in addition, no adverse effects on kidney development were observed in pups from dams given irbesartan from gestation day 15 through lactation day 24 at doses of 50, 180, or 650 mg/kg/day (up to 21.1 times the mrhd). the observed effects are believed to be late gestational effects of the drug. pregnant rabbits given oral doses of irbesartan of 30 mg/kg/day (1.9 times the mrhd based on body surface area) experienced a high rate of maternal mortality and abortion. surviving females had a slight increase in early resorptions and a corresponding decrease in live fetuses. radioactivity was present in the rat and rabbit fetuses during late gestation following oral doses of radiolabeled irbesartan. when pregnant mice and rats were given hydrochlorothiazide at doses up to 3000 and 1000 mg/kg/day, respectively (about 600 and 400 times the mrhd) during their respective periods of major organogenesis, there was no evidence of fetal harm. a development toxicity study was performed in rats with doses of 50/50 mg/kg/day and 150/150 mg/kg/day irbesartan and hydrochlorothiazide. although the high dose combination appeared to be more toxic to the dams than either drug alone, there did not appear to be an increase in toxicity to the developing embryos. there are no available data on the presence of irbesartan in human milk, effects on milk production, or the breastfed infant. irbesartan or some metabolite of irbesartan is secreted in the milk of lactating rats. thiazides appear in human milk [see clinical pharmacology (12.3)] . because of the potential for adverse effects on the nursing infant, the use of irbesartan and hydrochlorothiazide in breastfeeding women is not recommended. safety and effectiveness in pediatric patients have not been established. of 1694 patients receiving irbesartan and hydrochlorothiazide in controlled clinical studies of hypertension, 264 (15.6%) were 65 years and over, while 45 (2.7%) were 75 years and over. no overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. [see clinical pharmacology (12.3)and clinical studies (14).]

Bandaríkin - enska - NLM (National Library of Medicine)

winthrop u.s, a business of sanofi-aventis u.s. llc - irbesartan (unii: j0e2756z7n) (irbesartan - unii:j0e2756z7n) - irbesartan is indicated for the treatment of hypertension, to lower blood pressure. lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular (cv) events, primarily strokes and myocardial infarction. these benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including this drug. control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. many patients will require more than 1 drug to achieve blood pressure goals. for specific advice on goals and management, see published guidelines, such as those of the national high blood pressure education program's joint national committee on prevention, detection, evaluation, and treatment of high blood pressure (jnc). numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. the largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmhg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). these considerations may guide selection of therapy. irbesartan may be used alone or in combination with other antihypertensive agents. irbesartan is indicated for the treatment of diabetic nephropathy in patients with type 2 diabetes and hypertension, an elevated serum creatinine, and proteinuria (>300 mg/day). in this population, irbesartan reduces the rate of progression of nephropathy as measured by the occurrence of doubling of serum creatinine or end-stage renal disease (need for dialysis or renal transplantation) [see clinical studies (14.2)] . irbesartan is contraindicated in patients who are hypersensitive to any component of this product. do not coadminister aliskiren with irbesartan in patients with diabetes. risk summary irbesartan can cause fetal harm when administered to a pregnant woman. use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death [see clinical considerations]. most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. when pregnancy is detected, discontinue irbesartan as soon as possible. all pregnancies have a background risk of birth defect, loss or other adverse outcomes regardless of drug exposure. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. clinical considerations disease-associated maternal and/or embryo-fetal risk hypertension in pregnancy increases the maternal risk for preeclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and postpartum hemorrhage). hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. pregnant women with hypertension should be carefully monitored and managed accordingly. fetal/neonatal adverse reactions oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension, and death. in the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. perform serial ultrasound examinations to assess the intra-amniotic environment. fetal testing may be appropriate, based on the week of pregnancy. patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. if oligohydramnios is observed, consider alternative treatment. closely observe infants with histories of in utero exposure to irbesartan for hypotension, oliguria, and hyperkalemia and other symptoms of renal impairment. in neonates with a history of in utero exposure to irbesartan, if oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function. data animal data irbesartan crosses the placenta in rats and rabbits. in female rats given irbesartan prior to mating through gestation and lactation at oral doses of 50, 180, or 650 mg/kg/day (1.6 to 21.1 times the maximum recommended human dose (mrhd) based on body surface area), fetuses examined on gestation day 20 showed increased incidences of hydroureter and renal pelvic cavitation and/or absence of renal papilla in all irbesartan-treated groups. subcutaneous edema also occurred in fetuses at maternal doses ≥180 mg/kg/day (5.8 times the mrhd). these anomalies occurred when female rats received irbesartan from prior to mating through day 20 of gestation but were not observed in pups postnatally in the same study, or when irbesartan was given to pregnant rats only during organogenesis (gestation day 6 through gestation day 15) at oral doses from 50 to 450 mg/kg/day (up to 14.6 times the mrhd). in addition, no adverse effects on kidney development were observed in pups from dams given irbesartan from gestation day 15 through lactation day 24 at doses of 50, 180, or 650 mg/kg/day (up to 21.1 times the mrhd). the observed effects are believed to be late gestational effects of the drug. pregnant rabbits given oral doses of irbesartan of 30 mg/kg/day (1.9 times the mrhd based on body surface area) experienced a high rate of maternal mortality and abortion. surviving females had a slight increase in early resorptions and a corresponding decrease in live fetuses. radioactivity was present in the rat and rabbit fetuses during late gestation following oral doses of radiolabeled irbesartan. there are no available data on the presence of irbesartan in human milk, effects on milk production, or the breastfed infant. irbesartan or some metabolite of irbesartan is secreted in the milk of lactating rats [see clinical pharmacology (12.3)] . because of the potential for adverse effects on the nursing infant, the use of irbesartan in breastfeeding women is not recommended. irbesartan, in a study at a dose of up to 4.5 mg/kg/day, once daily, did not appear to lower blood pressure effectively in pediatric patients ages 6 to 16 years. irbesartan has not been studied in pediatric patients less than 6 years old. of 4925 subjects receiving irbesartan in controlled clinical studies of hypertension, 911 (18.5%) were 65 years and over, while 150 (3.0%) were 75 years and over. no overall differences in effectiveness or safety were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out. [see clinical pharmacology (12.3)and clinical studies (14.1).]

Bandaríkin - enska - NLM (National Library of Medicine)

winthrop u.s, a business of sanofi-aventis u.s. llc - doxercalciferol (unii: 3diz9lf5y9) (doxercalciferol - unii:3diz9lf5y9) - doxercalciferol 0.5 ug - - doxercalciferol capsules are indicated for the treatment of secondary hyperparathyroidism in adult patients with stage 3 or stage 4 chronic kidney disease (ckd) and adult patients with ckd on dialysis. - hectorol injection is indicated for the treatment of secondary hyperparathyroidism in adult patients with ckd on dialysis. doxercalciferol is contraindicated in patients with: - hypercalcemia [see warnings and precautions (5.1)] - vitamin d toxicity [see warnings and precautions (5.1)] - known hypersensitivity to doxercalciferol or any of the inactive ingredients of doxercalciferol capsules or hectorol injection; serious hypersensitivity reactions including anaphylaxis and angioedema have been reported [see warnings and precautions (5.3), adverse reactions (6.2)]. risk summary the limited available data with doxercalciferol in pregnant women are insufficient to identify a drug-associated risk for major birth defects, miscarriage or adverse maternal or fetal outcomes. there are risks to the mother and fetus