Yhdysvallat - englanti - NLM (National Library of Medicine)

zydus pharmaceuticals usa inc. - omeprazole (unii: kg60484qx9) (omeprazole - unii:kg60484qx9), sodium bicarbonate (unii: 8mdf5v39qo) (bicarbonate ion - unii:hn1zra3q20) - omeprazole and sodium bicarbonate capsules are indicated in adults for the: - short-term treatment of active duodenal ulcer. most patients heal within four weeks. some patients may require an additional four weeks of therapy. - short-term treatment (4 to 8 weeks) of active benign gastric ulcer. - treatment of heartburn and other symptoms associated with gerd for up to 4 weeks. - short-term treatment (4 to 8 weeks) of ee due to acid-mediated gerd which has been diagnosed by endoscopy in adults. the efficacy of omeprazole and sodium bicarbonate capsules used for longer than 8 weeks in patients with ee has not been established. if a patient does not respond to 8 weeks of treatment, an additional 4 weeks of treatment may be given. if there is recurrence of ee or gerd symptoms (e.g., heartburn), additional 4 to 8 week courses of omeprazole and sodium bicarbonate capsules may be considered. - the efficacy of omeprazole and sodium bicarbonate capsules used for longer than 8 weeks in patients with ee has not been est

Yhdysvallat - englanti - NLM (National Library of Medicine)

zydus pharmaceuticals usa inc. - esomeprazole magnesium dihydrate (unii: 36h71644eq) (esomeprazole - unii:n3pa6559ft) - adults esomeprazole magnesium delayed-release capsules are indicated for the short-term treatment (4 weeks to 8 weeks) in the healing and symptomatic resolution of diagnostically confirmed ee in adults. for those patients who have not healed after 4 to 8 weeks of treatment, an additional 4 week to 8 week course of esomeprazole magnesium delayed-release capsules may be considered. pediatric patients 12 years to 17 years of age esomeprazole magnesium delayed-release capsules are indicated for the short-term treatment (4 weeks to 8 weeks) for the healing of ee in pediatric patients 12 years to 17 years of age. esomeprazole magnesium delayed-release capsules are indicated for the maintenance of healing of ee in adults. controlled studies do not extend beyond 6 months. adults esomeprazole magnesium delayed-release capsules are indicated for short-term treatment (4 weeks to 8 weeks) of heartburn and other symptoms associated with gerd in adults. pediatric patients 12 years to 17 years of age esomeprazole magnesium

Yhdysvallat - englanti - NLM (National Library of Medicine)

zydus pharmaceuticals usa inc. - deferasirox (unii: v8g4mof2v9) (deferasirox - unii:v8g4mof2v9) - deferasirox tablets are indicated for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age and older. deferasirox tablets are indicated for the treatment of chronic iron overload in patients 10 years of age and older with non-transfusion-dependent thalassemia (ntdt) syndromes and with a liver iron concentration (lic) of at least 5 milligrams of iron per gram of liver dry weight (mg fe/g dw) and a serum ferritin greater than 300 mcg/l. the safety and efficacy of deferasirox tablets when administered with other iron chelation therapy have not been established. deferasirox tablets are contraindicated in patients with: -   estimated gfr less than 40 ml/min/1.73 m2 [see dosage and administration (2.5), warnings and precautions (5.1)]; -   poor performance status [see warnings and precautions (5.1, 5.3)]; -   high-risk myelodysplastic syndromes (this patient population was not studied and is not expected to benefit from chelation therapy); -   adv

Yhdysvallat - englanti - NLM (National Library of Medicine)

zydus pharmaceuticals usa inc. - lamotrigine (unii: u3h27498ks) (lamotrigine - unii:u3h27498ks) - lamotrigine extended-release tablets are indicated as adjunctive therapy for primary generalized tonic-clonic (pgtc) seizures and partial-onset seizures with or without secondary generalization in patients aged 13 years and older. lamotrigine extended-release tablets are indicated for conversion to monotherapy in patients aged 13 years and older with partial-onset seizures who are receiving treatment with a single antiepileptic drug (aed). safety and effectiveness of lamotrigine extended-release have not been established (1) as initial monotherapy or (2) for simultaneous conversion to monotherapy from 2 or more concomitant aeds. safety and effectiveness of lamotrigine extended-release for use in patients younger than 13 years have not been established. lamotrigine extended-release is contraindicated in patients who have demonstrated hypersensitivity (e.g., rash, angioedema, acute urticaria, extensive pruritus, mucosal ulceration) to the drug or its ingredients [see boxed warning, warnings and precautions (5.1

Yhdysvallat - englanti - NLM (National Library of Medicine)

zydus pharmaceuticals usa inc. - deferasirox (unii: v8g4mof2v9) (deferasirox - unii:v8g4mof2v9) - deferasirox tablets for oral suspension are indicated for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age and older. deferasirox tablets for oral suspension are indicated for the treatment of chronic iron overload in patients 10 years of age and older with non-transfusion-dependent thalassemia (ntdt) syndromes and with a liver iron concentration (lic) of at least 5 milligrams of iron per gram of liver dry weight (mg fe/g dw) and a serum ferritin greater than 300 mcg/l. the safety and efficacy of deferasirox when administered with other iron chelation therapy have not been established. deferasirox is contraindicated in patients with: - estimated gfr less than 40 ml/min/1.73 m2 [see dosage and administration (2.5), warnings and precautions (5.1)] ; - poor performance status; [see warnings and precautions (5.1, 5.3)] - high-risk myelodysplastic syndromes; (this patient population was not studied and is not expected to benefit from chelation therapy) - advanced malignancies. [see warnings and precautions (5.1, 5.3)] - platelet counts less than 50 x 109 /l [see warnings and precautions (5.3, 5.4)] - known hypersensitivity to deferasirox or any component of deferasirox [see warnings and precautions (5.7), adverse reactions (6.2)] . risk summary there are no studies with the use of deferasirox in pregnant women to inform drug-associated risks. administration of deferasirox to rats during pregnancy resulted in decreased offspring viability and an increase in renal anomalies in male offspring at doses that were about or less than the recommended human dose on an mg/m2 basis. no fetal effects were noted in pregnant rabbits at doses equivalent to the human recommended dose on an mg/m2 basis. deferasirox should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. the 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. 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 embryo-fetal developmental studies, pregnant rats and rabbits received oral deferasirox during the period of organogenesis at doses up to 100 mg/kg/day in rats and 50 mg/kg/day in rabbits (1.2 times the maximum recommended human dose (mrhd) on an mg/m2 basis). these doses resulted in maternal toxicity but no fetal harm was observed. in a prenatal and postnatal developmental study, pregnant rats received oral deferasirox daily from organogenesis through lactation day 20 at doses of 10 mg/kg/day, 30 mg/kg/day and 90 mg/kg/day (0.1 times, 0.3 times and 1 times the mrhd on an mg/m2 basis). maternal toxicity, loss of litters, and decreased offspring viability occurred at 90 mg/kg/day (1 times the mrhd on a mg/m2 basis) and increases in renal anomalies in male offspring occurred at 30 mg/kg/day (0.3 times the mrhd on a mg/m2 basis). risk summary no data are available regarding the presence of deferasirox or its metabolites in human milk, the effects of the drug on the breastfed child, or the effects of the drug on milk production. deferasirox and its metabolites were excreted in rat milk. because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in a breastfeeding child from deferasirox and its metabolites, a decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of the drug to the mother. contraception counsel patients to use non-hormonal method(s) of contraception since deferasirox can render hormonal contraceptives ineffective [see drug interactions (7.2)] . transfusional iron overload the safety and effectiveness of deferasirox have been established in pediatric patients 2 years of age and older for the treatment of transfusional iron overload [see dosage and administration (2.1)] . safety and effectiveness have not been established in pediatric patients less than 2 years of age for the treatment of transfusional iron overload. pediatric approval for treatment of transfusional iron overload was based on clinical studies of 292 pediatric patients 2 years to less than 16 years of age with various congenital and acquired anemias. seventy percent of these patients had beta-thalassemia [see indications and usage (1), dosage and administration (2.1), clinical studies (14)] . in those clinical studies, 173 children (ages 2 years to < 12 years) and 119 adolescents (ages 12 years to < 17 years) were exposed to deferasirox. a trial conducted in treatment-naïve pediatric patients, 2 years to < 18 years of age with transfusional iron overload (nct02435212) did not provide additional relevant information about the safety or effectiveness of the deferasirox granules dosage form (jadenu sprinkle) compared to the deferasirox oral tablets for suspension dosage form. iron overload in non-transfusion-dependent thalassemia syndromes the safety and effectiveness of deferasirox have been established in patients 10 years of age and older for the treatment of chronic iron overload with non-transfusion-dependent thalassemia (ntdt) syndromes [see dosage and administration (2.2)] . safety and effectiveness have not been established in patients less than 10 years of age with chronic iron overload in ntdt syndromes. pediatric approval for treatment of ntdt syndromes with liver iron (fe) concentration (lic) of at least 5 mg fe per gram of dry weight and a serum ferritin greater than 300 mcg/l was based on 16 pediatric patients treated with deferasirox therapy (10 years to less than 16 years of age) with chronic iron overload and ntdt. use of deferasirox in these age groups is supported by evidence from adequate and well-controlled studies of deferasirox in adult and pediatric patients [see indications and usage (1.2), dosage and administration (2.2), clinical studies (14)] . in general, risk factors for deferasirox-associated kidney injury include preexisting renal disease, volume depletion, overchelation, and concomitant use of other nephrotoxic drugs. acute kidney injury, and acute liver injury and failure has occurred in pediatric patients. in a pooled safety analysis, pediatric patients with higher deferasirox exposures had a greater probability of renal toxicity and decreased renal function, resulting in increased deferasirox exposure and progressive renal toxicity/kidney injury. higher rates of renal adverse reactions have been identified among pediatric patients receiving deferasirox doses greater than 25 mg/kg/day when their serum ferritin values were less than 1,000 mcg/l [see dosage and administration (2.5), warnings and precautions (5.1, 5.6), adverse reactions (6.1, 6.2)] . monitoring recommendations for pediatric patients with transfusional iron overload and ntdt it is recommended that serum ferritin be monitored every month to assess the patient's response to therapy and to minimize the risk of overchelation [see  warnings and precautions (5.6)] . monitor renal function by estimating gfr using an egfr prediction equation appropriate for pediatric patients and evaluate renal tubular function. monitor renal function more frequently in pediatric patients in the presence of renal toxicity risk factors, including episodes of dehydration, fever and acute illness that may result in volume depletion or decreased renal perfusion. use the minimum effective dose [see  warnings and precautions (5.1)] . interrupt deferasirox in pediatric patients with transfusional iron overload and consider dose interruption in pediatric patients with non-transfusion-dependent iron overload, for acute illnesses, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake, and monitor more frequently. resume therapy as appropriate, based on assessments of renal function, when oral intake and volume status are normal. evaluate the risk benefit profile of continued deferasirox use in the setting of decreased renal function. avoid use of other nephrotoxic drugs [see  dosage and administration (2.5), warnings and precautions (5.1)] . juvenile animal toxicity data renal toxicity was observed in adult mice, rats, and marmoset monkeys administered deferasirox at therapeutic doses. in a neonatal and juvenile toxicity study in rats, deferasirox was administered orally from postpartum day 7 through 70, which equates to a human age range of term neonate through adolescence. increased renal toxicity was identified in juvenile rats compared to adult rats at a dose based on mg/m2 approximately 0.4 times the recommended dose of 20 mg/kg/day. a higher frequency of renal abnormalities was noted when deferasirox was administered to non-iron overloaded animals compared to iron overloaded animals. four hundred thirty-one (431) patients greater than or equal to 65 years of age were studied in clinical trials of deferasirox in the transfusional iron overload setting. two hundred twenty-five (225) of these patients were between 65 and 75 years of age while 206 were greater than or equal to 75 years of age. the majority of these patients had myelodysplastic syndrome (mds) (n=393). in these trials, elderly patients experienced a higher frequency of adverse reactions than younger patients. monitor elderly patients for early signs or symptoms of adverse reactions that may require a dose adjustment. elderly patients are at increased risk for toxicity due to the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range. in elderly patients, including those with mds, individualize the decision to remove accumulated iron based on clinical circumstances and the anticipated clinical benefit and risks of deferasirox therapy. deferasirox is contraindicated in patients with egfr less than 40 ml/min/1.73 m2  [see  contraindications (4)] . for patients with renal impairment (egfr 40 ml/min/1.73 m2 to 60 ml/min/1.73 m2 ), reduce the starting dose by 50% [see  dosage and administration (2.4)] . exercise caution in pediatric patients with egfr between 40 ml/min/1.73 m2 and 60 ml/min/1.73 m2  [see  dosage and administration (2.4)] . if treatment is needed, use the minimum effective dose with enhanced monitoring of glomerular and renal tubular function. individualize dose titration based on improvement in renal injury [see  dosage and administration (2.4, 2.5)] . deferasirox can cause glomerular dysfunction, renal tubular toxicity, or both, and can result in acute renal failure. monitor all patients closely for changes in egfr and renal tubular dysfunction during deferasirox treatment. if either develops, consider dose reduction, interruption or discontinuation of deferasirox until glomerular or renal tubular function returns to baseline [see  dosage and administration (2.4, 2.5), warnings and precautions (5.1)] . avoid the use of deferasirox in patients with severe (child-pugh c) hepatic impairment. for patients with moderate (child-pugh b) hepatic impairment, the starting dose should be reduced by 50%. closely monitor patients with mild (child-pugh a) or moderate (child-pugh b) hepatic impairment for efficacy and adverse reactions that may require dose titration [see  dosage and administration (2.4), warnings and precautions (5.2) ].

Yhdysvallat - englanti - NLM (National Library of Medicine)

zydus pharmaceuticals usa inc. - lacosamide (unii: 563ks2pqy5) (lacosamide - unii:563ks2pqy5) - lacosamide is indicated for the treatment of partial-onset seizures in patients 4 years of age and older. pediatric use information is approved for ucb, inc.'s vimpat® (lacosamide) injection. however, due to ucb, inc.'s marketing exclusivity rights, this drug product is not labeled with that information. lacosamide is indicated as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in patients 4 years of age and older. none. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (aeds), such as lacosamide, during pregnancy. encourage women who are taking lacosamide during pregnancy to enroll in the north american antiepileptic drug (naaed) pregnancy registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/. risk summary available data from the north american antiepileptic drug (naaed) pregnancy registry, a prospective cohort study, case reports, and a case series with la

Yhdysvallat - englanti - NLM (National Library of Medicine)

zydus pharmaceuticals usa inc. - lenalidomide (unii: f0p408n6v4) (lenalidomide - unii:f0p408n6v4) - lenalidomide in combination with dexamethasone is indicated for the treatment of adult patients with multiple myeloma (mm). lenalidomide is indicated for the treatment of adult patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (mds) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. lenalidomide is not indicated and is not recommended for the treatment of patients with cll outside of controlled clinical trials [see warnings and precautions (5.5)] . lenalidomide can cause fetal harm when administered to a pregnant female. limb abnormalities were seen in the offspring of monkeys that were dosed with lenalidomide during organogenesis. this effect was seen at all doses tested. due to the results of this developmental monkey study, and lenalidomide's structural similarities to thalidomide, a known human teratogen, lenalidomide is contraindicated in females who are pregnant [see boxed warning ]. 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 risk to a fetus [see warnings and precautions (5.1, 5.2), use in special populations (8.1, 8.3)] . lenalidomide is contraindicated in patients who have demonstrated severe hypersensitivity (e.g., angioedema, stevens-johnson syndrome, toxic epidermal necrolysis) to lenalidomide [see warnings and precautions (5.9, 5.15)]. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in females exposed to lenalidomide during pregnancy as well as female partners of male patients who are exposed to lenalidomide. this registry is also used to understand the root cause for the pregnancy. report any suspected fetal exposure to lenalidomide to the fda via the medwatch program at 1-800-fda-1088 and also to the rems call center at 1‐888‐423‐5436. risk summary based on the mechanism of action [see clinical pharmacology (12.1)] and findings from animal studies [see data ], lenalidomide can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy [see boxed warning, contraindications (4.1), and use in specific populations (5.1)] . lenalidomide is a thalidomide analogue. thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants. lenalidomide caused thalidomide-type limb defects in monkey offspring. lenalidomide crossed the placenta after administration to pregnant rabbits and pregnant rats [see data ]. 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 risk to a fetus. if pregnancy does occur during treatment, immediately discontinue the drug. under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. report any suspected fetal exposure to lenalidomide to the fda via the medwatch program at 1-800-fda-1088 and also to rems call center at 1‐888‐423‐5436. 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. the estimated 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 an embryo-fetal developmental toxicity study in monkeys, teratogenicity, including thalidomide-like limb defects, occurred in offspring when pregnant monkeys received oral lenalidomide during organogenesis. exposure (auc) in monkeys at the lowest dose was 0.17 times the human exposure at the maximum recommended human dose (mrhd) of 25 mg. similar studies in pregnant rabbits and rats at 20 times and 200 times the mrhd respectively, produced embryo lethality in rabbits and no adverse reproductive effects in rats. in a pre- and post-natal development study in rats, animals received lenalidomide from organogenesis through lactation. the study revealed a few adverse effects on the offspring of female rats treated with lenalidomide at doses up to 500 mg/kg (approximately 200 times the human dose of 25 mg based on body surface area). the male offspring exhibited slightly delayed sexual maturation and the female offspring had slightly lower body weight gains during gestation when bred to male offspring. as with thalidomide, the rat model may not adequately address the full spectrum of potential human embryo-fetal developmental effects for lenalidomide. following daily oral administration of lenalidomide from gestation day 7 through gestation day 20 in pregnant rabbits, fetal plasma lenalidomide concentrations were approximately 20-40% of the maternal cmax . following a single oral dose to pregnant rats, lenalidomide was detected in fetal plasma and tissues; concentrations of radioactivity in fetal tissues were generally lower than those in maternal tissues. these data indicated that lenalidomide crossed the placenta. risk summary there is no information regarding the presence of lenalidomide in human milk, the effects of lenalidomide on the breastfed child, or the effects of lenalidomide on milk production. because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed children from lenalidomide, advise women not to breastfeed during treatment with lenalidomide. pregnancy testing lenalidomide can cause fetal harm when administered during pregnancy [see use in specific populations (8.1)] . verify the pregnancy status of females of reproductive potential prior to initiating lenalidomide therapy and during therapy. advise females of reproductive potential that they must avoid pregnancy 4 weeks before therapy, while taking lenalidomide, during dose interruptions and for at least 4 weeks after completing therapy. females of reproductive potential must have 2 negative pregnancy tests before initiating lenalidomide. the first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing lenalidomide. once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. if menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. lenalidomide treatment must be discontinued during this evaluation. contraception females females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously: one highly effective form of contraception – tubal ligation, iud, hormonal (birth control pills, injections, hormonal patches, vaginal rings, or implants), or partner's vasectomy, and 1 additional effective contraceptive method – male latex or synthetic condom, diaphragm, or cervical cap. contraception must begin 4 weeks prior to initiating treatment with lenalidomide, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of lenalidomide therapy. reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed. males lenalidomide is present in the semen of males who take lenalidomide. therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking lenalidomide and for up to 4 weeks after discontinuing lenalidomide, even if they have undergone a successful vasectomy. male patients taking lenalidomide must not donate sperm and for up to 4 weeks after discontinuing lenalidomide. safety and effectiveness have not been established in pediatric patients. mm in combination : overall, of the 1613 patients in the ndmm study who received study treatment, 94% (1521 /1613) were 65 years of age or older, while 35% (561/1613) were over 75 years of age. the percentage of patients over age 75 was similar between study arms (rd continuous: 33%; rd18: 34%; mpt: 33%). overall, across all treatment arms, the frequency in most of the adverse reaction categories (e.g., all adverse reactions, grade 3/4 adverse reactions, serious adverse reactions) was higher in older (> 75 years of age) than in younger (≤ 75 years of age) subjects. grade 3 or 4 adverse reactions in the general disorders and administration site conditions body system were consistently reported at a higher frequency (with a difference of at least 5%) in older subjects than in younger subjects across all treatment arms. grade 3 or 4 adverse reactions in the infections and infestations, cardiac disorders (including cardiac failure and congestive cardiac failure), skin and subcutaneous tissue disorders, and renal and urinary disorders (including renal failure) body systems were also reported slightly, but consistently, more frequently (<5% difference), in older subjects than in younger subjects across all treatment arms. for other body systems (e.g., blood and lymphatic system disorders, infections and infestations, cardiac disorders, vascular disorders), there was a less consistent trend for increased frequency of grade 3/4 adverse reactions in older vs younger subjects across all treatment arms serious adverse reactions were generally reported at a higher frequency in the older subjects than in the younger subjects across all treatment arms. of the 703 mm patients who received study treatment in studies 1 and 2, 45% were age 65 or over while 12% of patients were age 75 and over. the percentage of patients age 65 or over was not significantly different between the lenalidomide/dexamethasone and placebo/dexamethasone groups. of the 353 patients who received lenalidomide/dexamethasone, 46% were age 65 and over. in both studies, patients > 65 years of age were more likely than patients ≤ 65 years of age to experience dvt, pulmonary embolism, atrial fibrillation, and renal failure following use of lenalidomide. no differences in efficacy were observed between patients over 65 years of age and younger patients. of the 148 patients with del 5q mds enrolled in the major study, 38% were age 65 and over, while 33% were age 75 and over. although the overall frequency of adverse reactions (100%) was the same in patients over 65 years of age as in younger patients, the frequency of serious adverse reactions was higher in patients over 65 years of age than in younger patients (54% vs. 33%). a greater proportion of patients over 65 years of age discontinued from the clinical studies because of adverse reactions than the proportion of younger patients (27% vs.16%). no differences in efficacy were observed between patients over 65 years of age and younger patients. since elderly patients are more likely to have decreased renal function, care should be taken in dose selection. monitor renal function. adjust the starting dose of lenalidomide based on the creatinine clearance value and for patients on dialysis [see dosage and administration (2.6)] .

Yhdysvallat - englanti - NLM (National Library of Medicine)

zydus pharmaceuticals usa inc. - fingolimod hydrochloride (unii: g926ec510t) (fingolimod - unii:3qn8byn5qf) - fingolimod is indicated for the treatment of relapsing forms of multiple sclerosis (ms), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in patients 10 years of age and older. fingolimod is contraindicated in patients who have: - in the last 6 months experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (tia), decompensated heart failure requiring hospitalization or class iii/iv heart failure - a history or presence of mobitz type ii second-degree or third-degree av block or sick sinus syndrome, unless patient has a functioning pacemaker [see warnings and precautions (5.1)] - a baseline qtc interval ≥ 500 msec - cardiac arrhythmias requiring anti-arrhythmic treatment with class ia or class iii anti-arrhythmic drugs - had a hypersensitivity reaction to fingolimod or any of the excipients in fingolimod capsules. observed reactions include rash, urticaria and angioedema upon treatment initiation [see warnings and prec

Yhdysvallat - englanti - NLM (National Library of Medicine)

zydus pharmaceuticals usa inc. - topiramate (unii: 0h73wjj391) (topiramate - unii:0h73wjj391) - topiramate extended-release capsules are indicated as initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients 2 years of age and older. topiramate extended-release capsules are indicated as adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-clonic seizures, and seizures associated with lennox-gastaut syndrome in patients 2 years of age and older. topiramate extended-release capsules are indicated for the preventive treatment of migraine in patients 12 years of age and older. none. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (aeds), such as topiramate extended-release capsules, during pregnancy. patients should be encouraged to enroll in the north american antiepileptic drug (naaed) pregnancy registry if they become pregnant. this registry is collecting information about the safety of antiepileptic drugs during pregnancy. to enroll, patients can call the toll-free number 1-888-233-2334. information about the north american drug pregnancy registry can be found at http://www.aedpregnancyregistry.org/. risk summary topiramate extended-release capsules can cause fetal harm when administered to a pregnant woman. data from pregnancy registries indicate that infants exposed to topiramate in utero have increased risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts) and of being small for gestational age (sga) [see human data] . sga has been observed at all doses and appears to be dose-dependent. the prevalence of sga is greater in infants of women who received higher doses of topiramate during pregnancy. in addition, the prevalence of sga in infants of women who continued topiramate use until later in pregnancy is higher compared to the prevalence in infants of women who stopped topiramate use before the third trimester. in multiple animal species, topiramate demonstrated developmental toxicity, including increased incidences of fetal malformations, in the absence of maternal toxicity at clinically relevant doses [see animal data] . all pregnancies have a background risk of birth defects, loss, or other adverse outcomes. the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. in the u.s. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively. clinical considerations fetal/neonatal adverse reactions consider the benefits and risks of topiramate when prescribing this drug to women of childbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death. because of the risk of oral clefts to the fetus, which occur in the first trimester of pregnancy before many women know they are pregnant, all women of childbearing potential should be informed of the potential risk to the fetus from exposure to topiramate. women who are planning a pregnancy should be counseled regarding the relative risks and benefits of topiramate use during pregnancy, and alternative therapeutic options should be considered for these patients. labor or delivery although the effect of topiramate on labor and delivery in humans has not been established, the development of topiramate-induced metabolic acidosis in the mother and/or in the fetus might affect the fetus' ability to tolerate labor. topiramate extended-release capsules treatment can cause metabolic acidosis [see warnings and precautions (5.4)] . the effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus' ability to tolerate labor. pregnant patients should be monitored for metabolic acidosis and treated as in the nonpregnant state [see warnings and precautions (5.4)] . newborns of mothers treated with topiramate extended-release capsules should be monitored for metabolic acidosis because of transfer of topiramate to the fetus and possible occurrence of transient metabolic acidosis following birth. based on limited information, topiramate has also been associated with pre-term labor and premature delivery. data human data data from pregnancy registries indicate an increased risk of major congenital malformations, including but not limited to oral clefts in infants exposed to topiramate during the first trimester of pregnancy. other than oral clefts, no specific pattern of major congenital malformations or grouping of major congenital malformation types were observed. in the naaed pregnancy registry, when topiramate-exposed infants with only oral clefts were excluded, the prevalence of major congenital malformations (4.1%) was higher than that in infants exposed to a reference aed (1.8%) or in infants with mothers without epilepsy and without exposure to aeds (1.1%). the prevalence of oral clefts among topiramate-exposed infants (1.4%) was higher than the prevalence in infants exposed to a reference aed (0.3%) or the prevalence in infants with mothers without epilepsy and without exposure to aeds (0.11%). it was also higher than the background prevalence in the united states (0.17%) as estimated by the centers for disease control and prevention (cdc). the relative risk of oral clefts in topiramate-exposed pregnancies in the naaed pregnancy registry was 12.5 (95% confidence interval=[ci] 5.9 to 26.37) as compared to the risk in a background population of untreated women. the uk epilepsy and pregnancy register reported a prevalence of oral clefts among infants exposed to topiramate monotherapy (3.2%) that was 16 times higher than the background rate in the uk (0.2%). data from the naaed pregnancy registry and a population-based birth registry cohort indicate that exposure to topiramate in utero is associated with an increased risk of sga newborns (birth weight < 10th percentile). in the naaed pregnancy registry, 19.7% of topiramate-exposed newborns were sga compared to 7.9% of newborns exposed to a reference aed, and 5.4% of newborns of mothers without epilepsy and without aed exposure. in the medical birth registry of norway (mbrn), a population-based pregnancy registry, 25% of newborns in the topiramate monotherapy exposure group were sga compared to 9% in the comparison group who were unexposed to aeds. the long-term consequences of the sga findings are not known. animal data when topiramate (0 mg/kg/day, 20 mg/kg/day, 100 mg/kg/day, or 500 mg/kg/day) was administered orally to pregnant mice during the period of organogenesis, the incidence of fetal malformations (primarily craniofacial defects) were increased at all doses. fetal body weights and skeletal ossification were reduced at the highest dose tested in conjunction with decreased maternal body weight gain. a no-effect dose for embryofetal developmental toxicity in mice was not identified. the lowest dose tested, which was associated with an increased incidence of malformations, is less than the maximum recommended human dose (mrhd) for epilepsy (400 mg/day) or migraine (100 mg/day) on a body surface area (mg/m2 ) basis. in pregnant rats administered topiramate (0 mg/kg/day, 20 mg/kg/day, 100 mg/kg/day, and 500 mg/kg/day or 0 mg/kg/day, 0.2 mg/kg/day, 2.5 mg/kg/day, 30 mg/kg/day, and 400 mg/kg/day) orally during the period of organogenesis, the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased in fetuses at 400 mg/kg/day and 500 mg/kg/day. embryotoxicity (reduced fetal body weights, increased incidences of structural variations) was observed at doses as low as 20 mg/kg/day. clinical signs of maternal toxicity were seen at 400 mg/kg/day and above, and maternal body weight gain was reduced at doses of 100 mg/kg/day or greater. the no-effect dose (2.5 mg/kg/day) for embryofetal developmental toxicity in rats is less than the mrhd for epilepsy or migraine on a mg/m2 basis. in pregnant rabbits administered topiramate (0 mg/kg/day, 20 mg/kg/day, 60 mg/kg/day, and 180 mg/kg/day or 0 mg/kg/day, 10 mg/kg/day, 35 mg/kg/day, and 120 mg/kg/day) orally during organogenesis, embryofetal mortality was increased at 35 mg/kg/day and an increased incidence of fetal malformations (primarily rib and vertebral malformations) was observed at 120 mg/kg/day. evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35 mg/kg/day and above. the no-effect dose (20 mg/kg/day) for embryofetal developmental toxicity in rabbits is equivalent to the mrhd for epilepsy and approximately 4 times the mrhd for migraine on a mg/m2 basis. when topiramate (0 mg/kg/day, 0.2 mg/kg/day, 4 mg/kg/day, 20 mg/kg/day, and 100 mg/kg/day or 0 mg/kg/day, 2 mg/kg/day, 20 mg/kg/day, and 200 mg/kg/day) was administered orally to female rats during the latter part of gestation and throughout lactation, offspring exhibited decreased viability and delayed physical development at 200 mg/kg/day and reductions in pre- and/or postweaning body weight gain at 2 mg/kg/day and above. maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/kg/day or greater. in a rat embryofetal development study which included postnatal assessment of offspring, oral administration of topiramate (0 mg/kg/day, 0.2 mg/kg/day, 2.5 mg/kg/day, 30 mg/kg/day, and 400 mg/kg/day) to pregnant animals during the period of organogenesis resulted in delayed physical development in offspring at 400 mg/kg/day and persistent reductions in body weight gain in offspring at 30 mg/kg/day and higher. the no-effect dose (0.2 mg/kg/day) for pre- and postnatal developmental toxicity in rats is less than the mrhd for epilepsy or migraine on a mg/m2 basis. risk summary topiramate is excreted in human milk [see data]. the effects of topiramate on milk production are unknown. diarrhea and somnolence have been reported in breastfed infants whose mothers receive topiramate treatment. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for topiramate extended-release capsules and any potential adverse effects on the breastfed infant from topiramate extended-release capsules or from the underlying maternal condition. data human data limited data from 5 women with epilepsy treated with topiramate during lactation showed drug levels in milk similar to those in maternal plasma. contraception women of childbearing potential who are not planning a pregnancy should use effective contraception because of the risk of major congenital malformations, including oral clefts, and the risk of infants being sga [see drug interactions (7.4) and use in specific populations (8.1)]. adjunctive treatment for epilepsy pediatric patients 2 years of age and older the safety and effectiveness of topiramate extended-release capsules as adjunctive therapy for the treatment of partial onset seizures, primary generalized tonic-clonic seizures, or seizures associated with lennox-gastaut syndrome have been established in pediatric patients 2 years of age and older and is based on controlled trials with immediate-release topiramate [see adverse reactions (6.1) and clinical studies (14.3, 14.4)] . the adverse reactions (both common and serious) in pediatric patients are similar to those seen in adults [see warnings and precautions (5) and adverse reactions (6)] . these include, but are not limited to: - oligohydrosis and hyperthermia [see warnings and precautions (5.3)] - dose-related increased incidence of metabolic acidosis [see warnings and precautions (5.4)] - dose-related increased incidence of hyperammonemia [see warnings and precautions (5.12)] pediatric patients below the age of 2 years   the following pediatric use information is based on studies conducted with immediate-release topiramate. safety and effectiveness in patients below the age of 2 years have not been established for the adjunctive therapy treatment of partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with lennox-gastaut syndrome. in a single randomized, double-blind, placebo-controlled investigational trial, the efficacy, safety, and tolerability of immediate-release topiramate oral liquid and sprinkle formulations as an adjunct to concurrent antiepileptic drug therapy in pediatric patients 1 month to 24 months of age with refractory partial-onset seizures were assessed. after 20 days of double-blind treatment, immediate-release topiramate (at fixed doses of 5 mg/kg/day, 15 mg/kg/day, and 25 mg/kg/day) did not demonstrate efficacy compared with placebo in controlling seizures. in general, the adverse reaction profile for immediate-release topiramate in this population was similar to that of older pediatric patients, although results from the above controlled study, and an open-label, long-term extension study in these pediatric patients 1 month to 24 months old suggested some adverse reactions/toxicities not previously observed in older pediatric patients and adults; i.e., growth/length retardation, certain clinical laboratory abnormalities, and other adverse reactions/toxicities that occurred with a greater frequency and/or greater severity than had been recognized previously from studies in older pediatric patients or adults for various indications. these very young pediatric patients appeared to experience an increased risk for infections (any topiramate dose 12%, placebo 0%) and of respiratory disorders (any topiramate dose 40%, placebo 16%). the following adverse reactions were observed in at least 3% of patients on immediate-release topiramate and were 3% to 7% more frequent than in patients on placebo: viral infection, bronchitis, pharyngitis, rhinitis, otitis media, upper respiratory infection, cough, and bronchospasm. a generally similar profile was observed in older pediatric patients [see adverse reactions (6.1)] . immediate-release topiramate resulted in an increased incidence of patients with increased creatinine (any topiramate dose 5%, placebo 0%), bun (any topiramate dose 3%, placebo 0%), and protein (any topiramate dose 34%, placebo 6%), and an increased incidence of decreased potassium (any topiramate dose 7%, placebo 0%). this increased frequency of abnormal values was not dose related. creatinine was the only analyte showing a noteworthy increased incidence (topiramate 25 mg/kg/day 5%, placebo 0%) of a markedly abnormal increase [see adverse  reactions (6.1)] . the significance of these findings is uncertain. immediate-release topiramate treatment also produced a dose-related increase in the percentage of patients who had a shift from normal at baseline to high/increased (above the normal reference range) in total eosinophil count at the end of treatment. the incidence of these abnormal shifts was 6% for placebo, 10% for 5 mg/kg/day, 9% for 15 mg/kg/day, 14% for 25 mg/kg/day, and 11% for any topiramate dose [see adverse reactions (6.1)] . there was a mean dose-related increase in alkaline phosphatase. the significance of these findings is uncertain. topiramate produced a dose-related increased incidence of hyperammonemia [see warnings and precautions (5.12)] . treatment with immediate-release topiramate for up to 1 year was associated with reductions in z scores for length, weight, and head circumference [see warnings and precautions (5.4), adverse reactions (6.1)] . in open-label, uncontrolled experience, increasing impairment of adaptive behavior was documented in behavioral testing over time in this population. there was a suggestion that this effect was dose-related. however, because of the absence of an appropriate control group, it is not known if this decrement in function was treatment related or reflects the patient's underlying disease (e.g., patients who received higher doses may have more severe underlying disease) [see warnings and precautions (5.6)] . in this open-label, uncontrolled study, the mortality was 37 deaths/1,000 patient years. it is not possible to know whether this mortality rate is related to immediate-release topiramate treatment, because the background mortality rate for a similar, significantly refractory, young pediatric population (1 month to 24 months) with partial epilepsy is not known. monotherapy treatment for epilepsy pediatric patients 2 years of age and older the safety and effectiveness of topiramate extended-release capsules as monotherapy for the treatment of partial-onset seizures or primary generalized tonic-clonic seizures have been established in pediatric patients aged 2 years and older and is based on controlled trials with immediate-release topiramate [see adverse reactions (6.1), clinical studies (14.1)]. a one-year, active-controlled, open-label study with blinded assessments of bone mineral density (bmd) and growth in pediatric patients 4 to 15 years of age, including 63 patients with recent or new onset of epilepsy, was conducted to assess effects of immediate-release topiramate (n=28, 6 to 15 years of age) versus levetiracetam (n=35, 4 to 15 years of age) monotherapy on bone mineralization and on height and weight, which reflect growth. effects on bone mineralization were evaluated via dual-energy x-ray absorptiometry and blood markers. table 11 summarizes effects of immediate-release topiramate at 12 months for key safety outcomes including bmd, height, height velocity, and weight. all least square mean values for immediate-release topiramate and the comparator were positive. therefore, the least square mean treatment differences shown reflect a topiramate induced attenuation of the key safety outcomes. statistically significant effects were observed for decreases in bmd (and bone mineral content) in lumbar spine and total body less head and in weight. subgroup analyses according to age demonstrated similar negative effects for all key safety outcomes (i.e., bmd, height, weight). * tblh = total body less head ** whereas no patients were randomized to 2 to 5 year of age subgroup for immediate-release topiramate, 5 patients (4 to 5 years) were randomized to the active control group. metabolic acidosis (serum bicarbonate < 20 meq/l) was observed in all immediate-release topiramate-treated patients at some time in the study [see warnings and precautions (5.4)]. over the whole study, 76% more immediate-release topiramate-treated patients experienced persistent metabolic acidosis (i.e., 2 consecutive visits with or final serum bicarbonate < 20 meq/l) compared to levetiracetam-treated patients. over the whole study, 35% more immediate-release topiramate-treated patients experienced a markedly abnormally low serum bicarbonate (i.e., absolute value < 17 meq/l and ≥ 5 meq/l decrease from pre-treatment), indicating the frequency of more severe metabolic acidosis, compared to levetiracetam-treated patients. the decrease in bmd at 12 months was correlated with decreased serum bicarbonate, suggesting that metabolic acidosis was at least a partial factor contributing to this adverse effect on bmd. immediate-release topiramate-treated patients exhibited an increased risk for developing an increased serum creatinine and an increased serum glucose above the normal reference range compared to control patients. pediatric patients below the age of 2 years safety and effectiveness in patients below the age of 2 years have not been established for the monotherapy treatment of epilepsy. preventive treatment of migraine pediatric patients 12 to 17 years of age safety and effectiveness of topiramate for the preventive treatment of migraine was studied in 5 double-blind, randomized, placebo-controlled, parallel-group trials in a total of 219 pediatric patients, at doses of 50 mg/day to 200 mg/day, or 2 mg/kg/day to 3 mg/kg/day. these comprised a fixed dose study in 103 pediatric patients 12 years to 17 years of age [see clinical studies (14.5)] , a flexible dose (2 mg/kg/day to 3 mg/kg/day), placebo-controlled study in 157 pediatric patients 6 years to 16 years of age (including 67 pediatric patients 12 years to 16 years of age), and a total of 49 pediatric patients 12 years to 17 years of age in 3 studies for the preventive treatment of migraine primarily in adults. open-label extension phases of 3 studies enabled evaluation of long-term safety for up to 6 months after the end of the double-blind phase. efficacy of topiramate for the preventive treatment of migraine in pediatric patients 12 years to 17 years of age is demonstrated for a 100 mg daily dose in study 13 [see clinical studies (14.5)] . efficacy of topiramate (2 mg/kg/day to 3 mg/kg/day) for the preventive treatment of migraine was not demonstrated in a placebo-controlled trial of 157 pediatric patients (6 years to 16 years of age) that included treatment of 67 pediatric patients (12 years to 16 years of age) for 20 weeks. in the pediatric trials (12 years to 17 years of age) in which patients were randomized to placebo or a fixed daily dose of immediate-release topiramate, the most common adverse reactions with immediate-release topiramate that were seen at an incidence higher (≥ 5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain [see adverse reactions (6.1)] . the most common cognitive adverse reaction in pooled double-blind studies in pediatric patients 12 years to 17 years of age was difficulty with concentration/attention [see warnings and precautions (5.6)] . markedly abnormally low serum bicarbonate values indicative of metabolic acidosis were reported in topiramate-treated pediatric migraine patients [see warnings and precautions (5.4)] . in topiramate-treated pediatric patients (12 years to 17 years of age) compared to placebo-treated patients, abnormally increased results were more frequent for creatinine, bun, uric acid, chloride, ammonia, total protein, and platelets. abnormally decreased results were observed with topiramate vs placebo treatment for phosphorus and bicarbonate [see warnings and precautions (5.4) and adverse reactions (6.1)] . notable changes (increases and decreases) from baseline in systolic blood pressure, diastolic blood pressure, and pulse were observed occurred more commonly in pediatric patients treated with topiramate compared to pediatric patients treated with placebo [see clinical pharmacology (12.2)] . pediatric patients below the age of 12 years safety and effectiveness in pediatric patients below the age of 12 years have not been established for the preventive treatment of migraine. in a double-blind study in 90 pediatric patients 6 years to 11 years of age (including 59 topiramate-treated and 31 placebo patients), the adverse reaction profile was generally similar to that seen in pooled double-blind studies of pediatric patients 12 years to 17 years of age. the most common adverse reactions that occurred in immediate-release topiramate-treated pediatric patients 6 years to 11 years of age, and at least twice as frequently than placebo, were gastroenteritis (12% topiramate, 6% placebo), sinusitis (10% topiramate, 3% placebo), weight loss (8% topiramate, 3% placebo) and paresthesia (7% topiramate, 0% placebo). difficulty with concentration/attention occurred in 3 topiramate-treated patients (5%) and 0 placebo-treated patients. the risk for cognitive adverse reaction was greater in younger patients (6 years to 11 years of age) than in older patients (12 years to 17 years of age) [see warnings and precautions (5.6)] . juvenile animal studies when topiramate (0 mg/kg/day, 30 mg/kg/day, 90 mg/kg/day or 300 mg/kg/day) was administered orally to rats during the juvenile period of development (postnatal days 12 to 50), bone growth plate thickness was reduced in males at the highest dose, which is approximately 5 times to 8 times the maximum recommended pediatric dose (9 mg/kg/day) on a body surface area (mg/m2 ) basis. clinical studies of immediate-release topiramate did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently than younger subjects. dosage adjustment may be necessary for elderly with creatinine clearance less than 70 ml/min/1.73 m2 . estimate gfr should be measured prior to dosing [see dosage and administration (2.3) and clinical pharmacology (12.3)] . the clearance of topiramate is reduced in patients with moderate (creatinine clearance 30 ml/min/1.73 m2 to 69 ml/min/1.73 m2 ) and severe (creatinine clearance less than 30 ml/min/1.73 m2 ) renal impairment. a dosage adjustment is recommended in patients with moderate or severe renal impairment [see dosage and administration (2.4) and clinical pharmacology (12.3)] . topiramate is cleared by hemodialysis at a rate that is 4 times to 6 times greater than in a normal individual. a dosage adjustment may be required [see dosage and administration (2.5) and clinical pharmacology (12.3)] .

Yhdysvallat - englanti - NLM (National Library of Medicine)

zydus pharmaceuticals usa inc. - teriflunomide (unii: 1c058ikg3b) (teriflunomide - unii:1c058ikg3b) - teriflunomide is indicated for the treatment of relapsing forms of multiple sclerosis (ms), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. teriflunomide is contraindicated in/with: - patients with severe hepatic impairment [see warnings and precautions (5.1)] . - pregnant women and females of reproductive potential not using effective contraception. teriflunomide may cause fetal harm [see warnings and precautions (5.2 and 5.3) and use in specific populations (8.1)] . - patients with a history of a hypersensitivity reaction to teriflunomide, leflunomide, or to any of the inactive ingredients in teriflunomide. reactions have included anaphylaxis, angioedema, and serious skin reactions [see warnings and precautions (5.5)]. - coadministration with leflunomide [see clinical pharmacology (12.3)]. risk summary teriflunomide is contraindicated for use in pregnant women and females of reproductive po