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sun pharmaceutical industries, inc. - ambrisentan (unii: hw6nv07qec) (ambrisentan - unii:hw6nv07qec) - ambrisentan is indicated for the treatment of pulmonary arterial hypertension (pah) (who group 1): • to improve exercise ability and delay clinical worsening. studies establishing effectiveness included predominantly patients with who functional class ii–iii symptoms and etiologies of idiopathic or heritable pah (60%) or pah associated with connective tissue diseases (34%). ambrisentan may cause fetal harm when administered to a pregnant female. ambrisentan is contraindicated in females who are pregnant. ambrisentan was consistently shown to have teratogenic effects when administered to animals. 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 a fetus [see warnings and precautions (5.1, 5.2) and use in specific populations (8.1)] . ambrisentan is contraindicated in patients with idiopathic pulmonary fibrosis (ipf), including ipf patients with pulmonary hypertension (who group 3) [see clinical studies (14.4)]. risk summary based on data from animal reproduction studies, ambrisentan may cause fetal harm when administered to a pregnant woman and is contraindicated during pregnancy. there are limited data on ambrisentan use in pregnant women. in animal reproduction studies, ambrisentan was teratogenic in rats and rabbits at doses which resulted in exposures of 3.5 and 1.7 times, respectively, the human dose of 10 mg per day [see animal data] . if this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential hazard to a fetus [see contraindications (4.1), warnings and precautions (5.1)] . 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 ambrisentan was teratogenic at oral dosages of ≥15 mg/kg/day (auc 51.7 h•mcg/ml) in rats and ≥7 mg/kg/day (24.7 h•mcg/ml) in rabbits; it was not studied at lower dosages. these dosages are of 3.5 and 1.7 times, respectively, the human dose of 10 mg per day (14.8 h•mcg/ml) based on auc. in both species, there were abnormalities of the lower jaw and hard and soft palate, malformation of the heart and great vessels, and failure of formation of the thymus and thyroid. a preclinical study in rats has shown decreased survival of newborn pups (mid and high dosages) and effects on testicle size and fertility of pups (high dosage) following maternal treatment with ambrisentan from late gestation through weaning. the mid and high dosages were 51 x, and 170 x (on a mg/m2 body surface area basis) the maximum oral human dose of 10 mg and an average adult body weight of 70 kg. these effects were absent at a maternal dosage 17 x the human dose based on mg/m2 . risk summary it is not known whether ambrisentan is present in human milk. because many drugs are present in human milk and because of the potential for serious adverse reactions in breastfed infants from ambrisentan, a decision should be made whether to discontinue breastfeeding or discontinue ambrisentan, taking into account the importance of the drug to the mother. pregnancy testing female patients of reproductive potential must have a negative pregnancy test prior to initiation of treatment, monthly pregnancy test during treatment, and pregnancy test 1 month after stopping treatment with ambrisentan. advise patients to contact their healthcare provider if they become pregnant or suspect they may be pregnant. perform a pregnancy test if pregnancy is suspected for any reason. for positive pregnancy tests, counsel patient on the potential risk to the fetus and patient options [see boxed warning and dosage and administration (2.2)].  contraception female patients of reproductive potential must use acceptable methods of contraception during treatment with ambrisentan and for 1 month after stopping treatment with ambrisentan. patients may choose one highly effective form of contraception (intrauterine device (iud), contraceptive implant, or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods). if a partner’s vasectomy is the chosen method of contraception, a hormone or barrier method must be used along with this method. counsel patients on pregnancy planning and prevention, including emergency contraception, or designate counseling by another healthcare provider trained in contraceptive counseling [see boxed warning]. infertility males in a 6-month study of another endothelin receptor antagonist, bosentan, 25 male patients with who functional class iii and iv pah and normal baseline sperm count were evaluated for effects on testicular function. there was a decline in sperm count of at least 50% in 25% of the patients after 3 or 6 months of treatment with bosentan. one patient developed marked oligospermia at 3 months, and the sperm count remained low with 2 follow-up measurements over the subsequent 6 weeks. bosentan was discontinued and after 2 months the sperm count had returned to baseline levels. in 22 patients who completed 6 months of treatment, sperm count remained within the normal range and no changes in sperm morphology, sperm motility, or hormone levels were observed. based on these findings and preclinical data [see nonclinical toxicology (13.1)] from endothelin receptor antagonists, it cannot be excluded that endothelin receptor antagonists such as ambrisentan have an adverse effect on spermatogenesis. counsel patients about the potential effects on fertility [see warnings and precautions (5.5)] . safety and effectiveness of ambrisentan in pediatric patients have not been established. juvenile animal data in juvenile rats administered ambrisentan orally once daily during postnatal day 7 to 26, 36, or 62, a decrease in brain weight (−3% to −8%) with no morphologic or neurobehavioral changes occurred after breathing sounds, apnea, and hypoxia were observed, at exposures approximately 1.8 to 7.0 times human pediatric exposures at 10 mg, based on auc. in the two placebo-controlled clinical studies of ambrisentan, 21% of patients were ≥65 years old and 5% were ≥75 years old. the elderly (age ≥65 years) showed less improvement in walk distances with ambrisentan than younger patients did, but the results of such subgroup analyses must be interpreted cautiously. peripheral edema was more common in the elderly than in younger patients. the impact of renal impairment on the pharmacokinetics of ambrisentan has been examined using a population pharmacokinetic approach in pah patients with creatinine clearances ranging between 20 and 150 ml/min. there was no significant impact of mild or moderate renal impairment on exposure to ambrisentan [see clinical pharmacology (12.3)] . dose adjustment of ambrisentan in patients with mild or moderate renal impairment is therefore not required. there is no information on the exposure to ambrisentan in patients with severe renal impairment. the impact of hemodialysis on the disposition of ambrisentan has not been investigated. preexisting hepatic impairment the influence of preexisting hepatic impairment on the pharmacokinetics of ambrisentan has not been evaluated. because there is in vitro and in vivo evidence of significant metabolic and biliary contribution to the elimination of ambrisentan, hepatic impairment might be expected to have significant effects on the pharmacokinetics of ambrisentan [see clinical pharmacology (12.3)] . ambrisentan is not recommended in patients with moderate or severe hepatic impairment. there is no information on the use of ambrisentan in patients with mild preexisting impaired liver function; however, exposure to ambrisentan may be increased in these patients. elevation of liver transaminases other endothelin receptor antagonists (eras) have been associated with aminotransferase (ast, alt) elevations, hepatotoxicity, and cases of liver failure [see adverse reactions (6.1, 6.2)]. in patients who develop hepatic impairment after ambrisentan initiation, the cause of liver injury should be fully investigated. discontinue ambrisentan if elevations of liver aminotransferases are >5 x uln or if elevations are accompanied by bilirubin >2 x uln, or by signs or symptoms of liver dysfunction and other causes are excluded.

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sun pharmaceutical industries, 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 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, 30, and 90 mg/kg/day (0.1, 0.3, and 1.0 times the mrhd on an mg/m2 basis). maternal toxicity, loss of litters, and decreased offspring viability occurred at 90 mg/kg/day (1.0 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 to < 12 years) and 119 adolescents (ages 12 to < 17 years) were exposed to deferasirox. a trial conducted in treatment-naïve pediatric patients, 2 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 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 and 60 ml/minute/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)].

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

sun pharmaceutical industries, inc. - pregabalin (unii: 55jg375s6m) (pregabalin - unii:55jg375s6m) - pregabalin capsules are indicated for: - management of neuropathic pain associated with diabetic peripheral neuropathy - management of postherpetic neuralgia - adjunctive therapy for the treatment of partial-onset seizures in patients 1 month of age and older - management of fibromyalgia - management of neuropathic pain associated with spinal cord injury  pregabalin capsules are contraindicated in patients with known hypersensitivity to pregabalin or any of its components. angioedema and hypersensitivity reactions have occurred in patients receiving pregabalin therapy [see warnings and precautions (5.2)]. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to pregabalin during pregnancy. to provide information regarding the effects of in utero exposure to pregabalin, physicians are advised to recommend that pregnant patients taking pregabalin enroll in the north american antiepileptic drug (naaed) pregnancy registry. this can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. risk summary observational studies on the use of pregabalin during pregnancy suggest a possible small increase in the rate of overall major birth defects, but there was no consistent or specific pattern of major birth defects identified (see data) . available postmarketing data on miscarriage and other maternal, fetal, and long term developmental adverse effects were insufficient to identify risk associated with pregabalin. in animal reproduction studies, increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity, including skeletal malformations, retarded ossification, and decreased fetal body weight were observed in the offspring of rats and rabbits given pregabalin orally during organogenesis, at doses that produced plasma pregabalin exposures (auc) greater than or equal to 16 times human exposure at the maximum recommended dose (mrd) of 600 mg/day (see data) . in an animal development study, lethality, growth retardation, and nervous and reproductive system functional impairment were observed in the offspring of rats given pregabalin during gestation and lactation. the no-effect dose for developmental toxicity was approximately twice the human exposure at mrd. the background risk of major birth defects and miscarriage for the indicated populations are unknown. however, the background risk in the u.s. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.   data human data one database study, which included over 2,700 pregnancies exposed to pregabalin (monotherapy) during the first trimester compared to 3,063,251 pregnancies unexposed to antiepileptics demonstrated prevalence ratios for major malformations overall of 1.14 (ci 95% 0.96 to 1.35) for pregabalin, 1.29 (ci 95% 1.01 to 1.65) for lamotrigine, 1.39 (ci 95% 1.07 to 1.82) for duloxetine, and 1.24 (ci 95% 1.00 to 1.54) for exposure to either lamotrigine or duloxetine. important study limitations include uncertainty of whether women who filled a prescription took the medication and inability to adequately control for the underlying disease and other potential confounders. a published study included results from two separate databases. one database, which included 353 pregnancies exposed to pregabalin (monotherapy) during the first trimester compared to 368,489 pregnancies unexposed to antiepileptics, showed no increase in risk of major birth defects; adjusted relative risk 0.87 (ci 95% 0.53 to 1.42). the second database, which included 118 pregnancies exposed to pregabalin (monotherapy) during the first trimester compared to 380,347 pregnancies unexposed to antiepileptics, suggested a small increase in risk of major birth defects; adjusted relative risk 1.26 (ci 95% 0.64 to 2.49). the risk estimates crossed the null, and the study had limitations similar to the prior study. other published epidemiologic studies reported inconsistent findings. no specific pattern of birth defects was identified across studies. all of the studies had limitations due to their retrospective design.  animal data when pregnant rats were given pregabalin (500, 1,250, or 2,500 mg/kg) orally throughout the period of organogenesis, incidences of specific skull alterations attributed to abnormally advanced ossification (premature fusion of the jugal and nasal sutures) were increased at greater than or equal to 1,250 mg/kg, and incidences of skeletal variations and retarded ossification were increased at all doses. fetal body weights were decreased at the highest dose. the low dose in this study was associated with a plasma exposure (auc) approximately 17 times human exposure at the mrd of 600 mg/day. a no-effect dose for rat embryo-fetal developmental toxicity was not established. when pregnant rabbits were given pregabalin (250, 500, or 1,250 mg/kg) orally throughout the period of organogenesis, decreased fetal body weight and increased incidences of skeletal malformations, visceral variations, and retarded ossification were observed at the highest dose. the no-effect dose for developmental toxicity in rabbits (500 mg/kg) was associated with a plasma exposure approximately 16 times human exposure at the mrd. in a study in which female rats were dosed with pregabalin (50, 100, 250, 1,250, or 2,500 mg/kg) throughout gestation and lactation, offspring growth was reduced at greater than or equal to 100 mg/kg and offspring survival was decreased at greater than or equal to 250 mg/kg. the effect on offspring survival was pronounced at doses greater than or equal to 1,250 mg/kg, with 100% mortality in high-dose litters. when offspring were tested as adults, neurobehavioral abnormalities (decreased auditory startle responding) were observed at greater than or equal to 250 mg/kg and reproductive impairment (decreased fertility and litter size) was seen at 1,250 mg/kg. the no-effect dose for pre- and postnatal developmental toxicity in rats (50 mg/kg) produced a plasma exposure approximately 2 times human exposure at the mrd.  in the prenatal-postnatal study in rats, pregabalin prolonged gestation and induced dystocia at exposures greater than or equal to 50 times the mean human exposure (auc (0 to 24) of 123 mcg∙hr/ml) at the mrd. risk summary small amounts of pregabalin have been detected in the milk of lactating women. a pharmacokinetic study in lactating women detected pregabalin in breast milk at average steady state concentrations approximately 76% of those in maternal plasma. the estimated average daily infant dose of pregabalin from breast milk (assuming mean milk consumption of 150 ml/kg/day) was 0.31 mg/kg/day, which on a mg/kg basis would be approximately 7% of the maternal dose (see data) . the study did not evaluate the effects of pregabalin on milk production or the effects of pregabalin on the breastfed infant. based on animal studies, there is a potential risk of tumorigenicity with pregabalin exposure via breast milk to the breastfed infant [see nonclinical toxicology (13.1)] . available clinical study data in patients greater than 12 years of age do not provide a clear conclusion about the potential risk of tumorigenicity with pregabalin [see warnings and precautions (5.9)] . because of the potential risk of tumorigenicity, breastfeeding is not recommended during treatment with pregabalin. data a pharmacokinetic study in ten lactating women, who were at least 12 weeks postpartum, evaluated the concentrations of pregabalin in plasma and breast milk. pregabalin 150 mg oral capsule was given every 12 hours (300 mg daily dose) for a total of four doses. pregabalin was detected in breast milk at average steady-state concentrations approximately 76% of those in maternal plasma. the estimated average daily infant dose of pregabalin from breast milk (assuming mean milk consumption of 150 ml/kg/day) was 0.31 mg/kg/day, which on a mg/kg basis would be approximately 7% of the maternal dose. the study did not evaluate the effects of pregabalin on milk production. infants did not receive breast milk obtained during the dosing period, therefore, the effects of pregabalin on the breast fed infant were not evaluated. infertility males effects on spermatogenesis in a randomized, double-blind, placebo-controlled non-inferiority study to assess the effect of pregabalin on sperm characteristics, healthy male subjects received pregabalin at a daily dose up to 600 mg (n=111) or placebo (n=109) for 13 weeks (one complete sperm cycle) followed by a 13-week washout period (off-drug). a total of 65 subjects in the pregabalin group (59%) and 62 subjects in the placebo group (57%) were included in the per protocol (pp) population. these subjects took study drug for at least 8 weeks, had appropriate timing of semen collections and did not have any significant protocol violations. among these subjects, approximately 9% of the pregabalin group (6/65) vs. 3% in the placebo group (2/62) had greater than or equal to 50% reduction in mean sperm concentrations from baseline at week 26 (the primary endpoint). the difference between pregabalin and placebo was within the pre-specified non-inferiority margin of 20%. there were no adverse effects of pregabalin on sperm morphology, sperm motility, serum fsh or serum testosterone levels as compared to placebo. in subjects in the pp population with greater than or equal to 50% reduction in sperm concentration from baseline, sperm concentrations were no longer reduced by greater than or equal to 50% in any affected subject after an additional 3 months off-drug. in one subject, however, subsequent semen analyses demonstrated reductions from baseline of greater than or equal to 50% at 9 and 12 months off-drug. the clinical relevance of these data is unknown. in the animal fertility study with pregabalin in male rats, adverse reproductive and developmental effects were observed [see nonclinical toxicology (13.1)] . neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, and neuropathic pain associated with spinal cord injury safety and effectiveness in pediatric patients have not been established. fibromyalgia safety and effectiveness in pediatric patients have not been established. a 15-week, placebo-controlled trial was conducted with 107 pediatric patients with fibromyalgia, ages 12 through 17 years, at pregabalin total daily doses of 75 to 450 mg per day. the primary efficacy endpoint of change from baseline to week 15 in mean pain intensity (derived from an 11-point numeric rating scale) showed numerically greater improvement for the pregabalin-treated patients compared to placebo-treated patients, but did not reach statistical significance. the most frequently observed adverse reactions in the clinical trial included dizziness, nausea, headache, weight increased, and fatigue. the overall safety profile in adolescents was similar to that observed in adults with fibromyalgia. adjunctive therapy for partial-onset seizures safety and effectiveness in pediatric patients below the age of 1 month have not been established. 4 to less than 17 years of age with partial-onset seizures the safety and effectiveness of pregabalin as adjunctive treatment for partial-onset seizures in pediatric patients 4 to less than 17 years of age have been established in a 12-week, double-blind, placebo-controlled study (n=295) [see clinical studies (14.3)] . patients treated with pregabalin 10 mg/kg/day had, on average, a 21.0% greater reduction in partial-onset seizures than patients treated with placebo (p=0.0185). patients treated with pregabalin 2.5 mg/kg/day had, on average, a 10.5% greater reduction in partial-onset seizures than patients treated with placebo, but the difference was not statistically significant (p=0.2577). responder rates (50% or greater reduction in partial-onset seizure frequency) were a key secondary efficacy parameter and showed numerical improvement with pregabalin compared with placebo: the responder rates were 40.6%, 29.1%, and 22.6%, for pregabalin 10 mg/kg/day, pregabalin 2.5 mg/kg/day, and placebo, respectively. the most common adverse reactions (≥5%) with pregabalin in this study were somnolence, weight increased, and increased appetite [see adverse reactions (6.1)] . the use of pregabalin 2.5 mg/kg/day in pediatric patients is further supported by evidence from adequate and well-controlled studies in adults with partial-onset seizures and pharmacokinetic data from adult and pediatric patients [see clinical pharmacology (12.3)] . 1 month to less than 4 years of age with partial-onset seizures the safety and effectiveness of pregabalin as adjunctive treatment for partial-onset seizures in pediatric patients 1 month to less than 4 years of age have been established in a 14-day double-blind, placebo-controlled study (n=175) [see clinical studies (14.3)]. the youngest subject evaluated was 3 months of age; use in patients 1 month to less than 3 months of age is supported by additional pharmacokinetic analyses. patients treated with pregabalin 14 mg/kg/day had, on average, 43.9% greater reduction in partial-onset seizures than patients treated with placebo (p=0.0223). in addition, pediatric patients treated with pregabalin 14 mg/kg/day showed numerical improvement in responder rates (≥50% reduction in partial-onset seizure frequency) compared with placebo (53.6% versus 41.5%). patients treated with pregabalin 7 mg/kg/day did not show improvement relative to placebo for either endpoint. the most common dose-related adverse reactions (>5%) with pregabalin in this study were somnolence, pneumonia, and viral infection [see adverse reactions (6.1)]. juvenile animal data in studies in which pregabalin (50 mg/kg to 500 mg/kg) was orally administered to young rats from early in the postnatal period (postnatal day 7) through sexual maturity, neurobehavioral abnormalities (deficits in learning and memory, altered locomotor activity, decreased auditory startle responding and habituation) and reproductive impairment (delayed sexual maturation and decreased fertility in males and females) were observed at doses greater than or equal to 50 mg/kg. the neurobehavioral changes of acoustic startle persisted at greater than or equal to 250 mg/kg and locomotor activity and water maze performance at greater than or equal to 500 mg/kg in animals tested after cessation of dosing and, thus, were considered to represent long-term effects. the low effect dose for developmental neurotoxicity and reproductive impairment in juvenile rats (50 mg/kg) was associated with a plasma pregabalin exposure (auc) approximately equal to human exposure at the maximum recommended dose of 600 mg/day. a no-effect dose was not established. in controlled clinical studies of pregabalin in neuropathic pain associated with diabetic peripheral neuropathy, 246 patients were 65 to 74 years of age, and 73 patients were 75 years of age or older. in controlled clinical studies of pregabalin in neuropathic pain associated with postherpetic neuralgia, 282 patients were 65 to 74 years of age, and 379 patients were 75 years of age or older. in controlled clinical studies of pregabalin in epilepsy, there were only 10 patients 65 to 74 years of age, and 2 patients who were 75 years of age or older. no overall differences in safety and efficacy were observed between these patients and younger patients. in controlled clinical studies of pregabalin in fibromyalgia, 106 patients were 65 years of age or older. although the adverse reaction profile was similar between the two age groups, the following neurological adverse reactions were more frequent in patients 65 years of age or older: dizziness, vision blurred, balance disorder, tremor, confusional state, coordination abnormal, and lethargy. pregabalin is known to be substantially excreted by the kidney, and the risk of toxic reactions to pregabalin may be greater in patients with impaired renal function. because pregabalin is eliminated primarily by renal excretion, adjust the dose for elderly patients with renal impairment [see dosage and administration (2.7)] . pregabalin is eliminated primarily by renal excretion and dose adjustment is recommended for adult patients with renal impairment [see dosage and administration (2.7) and clinical pharmacology (12.3)] . the use of pregabalin in pediatric patients with compromised renal function has not been studied. pregabalin is a schedule v controlled substance. pregabalin is not known to be active at receptor sites associated with drugs of abuse. as with any cns active drug, carefully evaluate patients for history of drug abuse and observe them for signs of pregabalin misuse or abuse (e.g., development of tolerance, dose escalation, drug-seeking behavior). in a study of recreational users (n=15) of sedative/hypnotic drugs, including alcohol, pregabalin (450 mg, single dose) received subjective ratings of "good drug effect," "high" and "liking" to a degree that was similar to diazepam (30 mg, single dose). in controlled clinical studies in over 5500 patients, 4% of pregabalin-treated patients and 1% of placebo-treated patients overall reported euphoria as an adverse reaction, though in some patient populations studied, this reporting rate was higher and ranged from 1 to 12%. in clinical studies, following abrupt or rapid discontinuation of pregabalin, some patients reported symptoms including insomnia, nausea, headache or diarrhea [see warnings and precautions (5.6)] , consistent with physical dependence. in the postmarketing experience, in addition to these reported symptoms there have also been reported cases of anxiety and hyperhidrosis.

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sun pharmaceutical industries, inc. - methylphenidate hydrochloride (unii: 4b3sc438hi) (methylphenidate - unii:207zz9qz49) - methylphenidate hydrochloride extended-release tablets are indicated for the treatment of attention deficit hyperactivity disorder (adhd) in children 6 years of age and older, adolescents, and adults up to the age of 65 [see clinical studies (14)]. hypersensitivity reactions, such as angioedema and anaphylactic reactions, have been observed in patients treated with methylphenidate hydrochloride extended-release tablets. therefore, methylphenidate hydrochloride extended-release tablets are contraindicated in patients known to be hypersensitive to methylphenidate or other components of the product [see adverse reactions (6.5)]. methylphenidate hydrochloride extended-release tablets are contraindicated during treatment with monoamine oxidase (mao) inhibitors, and also within a minimum of 14 days following discontinuation of a mao inhibitor (hypertensive crises may result) [see drug interactions (7.1)]. pregnancy category c methylphenidate has been shown to have teratogenic effects in rabbits when given in doses of 200 mg/kg/day, which is approximately 100 times and 40 times the maximum recommended human dose on a mg/kg and mg/m 2 basis, respectively. a reproduction study in rats revealed no evidence of harm to the fetus at oral doses up to 30 mg/kg/day, approximately 15-fold and 3-fold the maximum recommended human dose of methylphenidate hydrochloride extended-release tablets on a mg/kg and mg/m 2 basis, respectively. the approximate plasma exposure to methylphenidate plus its main metabolite ppaa in pregnant rats was 1-2 times that seen in trials in volunteers and patients with the maximum recommended dose of methylphenidate hydrochloride extended-release tablets based on the auc. the safety of methylphenidate for use during human pregnancy has not been established. there are no adequate and well-controlled studies in pregnant women. methylphenidate hydrochloride extended-release tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. the effect of methylphenidate hydrochloride extended-release tablets on labor and delivery in humans is unknown. it is not known whether methylphenidate is excreted in human milk. because many drugs are excreted in human milk, caution should be exercised if methylphenidate hydrochloride extended-release tablets are administered to a nursing woman. in lactating female rats treated with a single oral dose of 5 mg/kg radiolabeled methylphenidate, radioactivity (representing methylphenidate and/or its metabolites) was observed in milk and levels were generally similar to those in plasma. methylphenidate hydrochloride extended-release tablets should not be used in children under six years, since safety and efficacy in this age group have not been established. long-term effects of methylphenidate in children have not been well established. methylphenidate hydrochloride extended-release tablets have not been studied in patients greater than 65 years of age. methylphenidate hydrochloride extended-release tablets contain methylphenidate, a schedule ii controlled substance. methylphenidate hydrochloride extended-release tablets have a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction [see warnings and precautions (5.1)]. methylphenidate hydrochloride extended-release tablets can be diverted for non-medical use into illicit channels or distribution. abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. misuse and abuse of methylphenidate may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with cns stimulants abuse and/or misuse. misuse and abuse of cns stimulants, including methylphenidate hydrochloride extended-release tablets, can result in overdose and death [see overdosage (10)] , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. in two placebo-controlled human abuse potential studies, single oral doses of methylphenidate hydrochloride extended-release tablets were compared to single oral doses of immediate-release methylphenidate (ir mph) and placebo in subjects with a history of recreational stimulant use to assess relative abuse potential. for the purpose of this assessment, the response for each of the subjective measures was defined as the maximum effect within the first 8 hours after dose administration. in one study (n=40), both methylphenidate hydrochloride extended-release tablets (108 mg) and 60 mg ir mph compared to placebo produced statistically significantly greater responses on the five subjective measures suggestive of abuse potential. in comparisons between the two active treatments, however, methylphenidate hydrochloride extended-release tablets (108 mg) produced variable responses on positive subjective measures that were either statistically indistinguishable from (abuse potential, drug liking, amphetamine, and morphine benzedrine group [euphoria]) or statistically less than (stimulation – euphoria) responses produced by 60 mg ir mph. in another study (n=49), both doses of methylphenidate hydrochloride extended-release tablets (54 mg and 108 mg) and both doses of ir mph (50 mg and 90 mg) produced statistically significantly greater responses compared to placebo on the two primary scales used in the study (drug liking, euphoria). when doses of methylphenidate hydrochloride extended-release tablets (54 mg and 108 mg) were compared to ir mph (50 mg and 90 mg), respectively, methylphenidate hydrochloride extended-release tablets produced statistically significantly lower subjective responses on these two scales than ir mph. methylphenidate hydrochloride extended-release tablets (108 mg) produced responses that were statistically indistinguishable from the responses on these two scales produced by ir mph (50 mg). differences in subjective responses to the respective doses should be considered in the context that only 22% of the total amount of methylphenidate in methylphenidate hydrochloride extended-release tablets is available for immediate release from the drug overcoat [see system components and performance (11.1)]. although these findings reveal a relatively lower response to methylphenidate hydrochloride extended-release tablets on subjective measures suggestive of abuse potential compared to ir mph at roughly equivalent total mph doses, the relevance of these findings to the abuse potential of methylphenidate hydrochloride extended-release tablets in the community is unknown. physical dependence methylphenidate hydrochloride extended-release tablets may produce physical dependence. physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. withdrawal signs and symptoms after abrupt discontinuation or dose reduction following prolonged use of cns stimulants including methylphenidate hydrochloride extended-release tablets include dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation. tolerance methylphenidate hydrochloride extended-release tablets may produce tolerance. tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

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sun pharmaceutical industries, inc. - lacosamide (unii: 563ks2pqy5) (lacosamide - unii:563ks2pqy5) - lacosamide tablets are indicated for the treatment of partial-onset seizures in patients 4 years of age and older. lacosamide tablets are indicated as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in patients 4 years of age and older. additional pediatric use information is approved for ucb, inc.’s vimpat® (lacosamide) tablets. however, due to ucb, inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 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,

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sun pharmaceutical industries, inc. - ketorolac tromethamine (unii: 4eve5946bq) (ketorolac - unii:yzi5105v0l) - carefully consider the potential benefits and risks of ketorolac tromethamine and other treatment options before deciding to use ketorolac. use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see warnings ).  acute pain in adult patients ketorolac tromethamine is indicated for the short-term (≤5 days) management of moderately severe acute pain that requires analgesia at the opioid level, usually in a postoperative setting. therapy should always be initiated with intravenous or intramuscular dosing of ketorolac tromethamine, and oral ketorolac tromethamine is to be used only as continuation treatment, if necessary. the total combined duration of use of ketorolac tromethamine injection and oral ketorolac tromethamine is not to exceed 5 days of use because of the potential of increasing the frequency and severity of adverse reactions associated with the recommended doses (see warnings , precautions , dosage and administration , and adverse reactio

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sun pharmaceutical industries, inc. - tetrabenazine (unii: z9o08yrn8o) (tetrabenazine - unii:z9o08yrn8o) - tetrabenazine 12.5 mg - tetrabenazine tablets are indicated for the treatment of chorea associated with huntington's disease. tetrabenazine is contraindicated in patients: - who are actively suicidal, or in patients with untreated or inadequately treated depression [see warnings and precautions (5.1)]. - with hepatic impairment [see use in specific populations (8.6), clinical pharmacology (12.3)]. - taking monoamine oxidase inhibitors (maois). tetrabenazine should not be used in combination with an maoi, or within a minimum of 14 days of discontinuing therapy with an maoi [see drug interactions (7.3)]. - taking reserpine. at least 20 days should elapse after stopping reserpine before starting tetrabenazine [see drug interactions (7.2)]. - taking deutetrabenazine or valbenazine [see drug interactions (7.7)]. risk summary there are no adequate data on the developmental risk associated with the use of tetrabenazine in pregnant women. administration of tetrabenazine to rats throughout pregnancy and lactation resulted in an increase in s

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sun pharmaceutical industries, inc. - buprenorphine hydrochloride (unii: 56w8mw3en1) (buprenorphine - unii:40d3scr4gz), naloxone hydrochloride dihydrate (unii: 5q187997ee) (naloxone - unii:36b82amq7n) - buprenorphine 2 mg - buprenorphine and naloxone sublingual tablet is indicated for the maintenance treatment of opioid dependence. buprenorphine and naloxone sublingual tablet should be used as part of a complete treatment plan that includes counseling and psychosocial support. buprenorphine and naloxone sublingual tablet is contraindicated in patients with a history of hypersensitivity to buprenorphine or naloxone as serious adverse reactions, including anaphylactic shock, have been reported [see warnings and precautions (5.9)] . risk summary the data on use of buprenorphine, one of the active ingredients in buprenorphine and naloxone sublingual tablets, in pregnancy, are limited; however, these data do not indicate an increased risk of major malformations specifically due to buprenorphine exposure. there are limited data from randomized clinical trials in women maintained on buprenorphine that were not designed appropriately to assess the risk of major malformations [see data]. observational studies have reported on congenit

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

sun pharmaceutical industries, inc. - buprenorphine hydrochloride (unii: 56w8mw3en1) (buprenorphine - unii:40d3scr4gz) - buprenorphine 2 mg - buprenorphine sublingual tablet is indicated for the treatment of opioid dependence and is preferred for induction. buprenorphine sublingual tablet should be used as part of a complete treatment plan to include counseling and psychosocial support. buprenorphine sublingual tablet is contraindicated in patients with a history of hypersensitivity to buprenorphine, as serious adverse reactions, including anaphylactic shock, have been reported [see warnings and precautions (5.9)]. risk summary the data on use of buprenorphine, the active ingredient in buprenorphine sublingual tablets, in pregnancy, are limited; however, these data do not indicate an increased risk of major malformations specifically due to buprenorphine exposure. there are limited data from randomized clinical trials in women maintained on buprenorphine that were not designed appropriately to assess the risk of major malformations [see data]. observational studies have reported on congenital malformations among buprenorphine‐exposed pregnanci

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

sun pharmaceutical industries, inc. - phenytoin sodium (unii: 4182431bjh) (phenytoin - unii:6158tkw0c5) - phenytoin sodium 200 mg - extended phenytoin sodium capsules are indicated for the treatment of tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures and prevention and treatment of seizures occurring during or following neurosurgery. extended phenytoin sodium capsules are contraindicated in patients with: - a history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins [see warnings and precautions (5.5)] . reactions have included angioedema. -  a history of prior acute hepatotoxicity attributable to phenytoin [see warnings and precautions (5.8)] . - coadministration with delavirdine because of the potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (aeds), such as extended phenytoin sodium capsules, during pregnancy. physicians are advised to recommend that pregn