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takeda pharmaceuticals america, inc. - pioglitazone hydrochloride (unii: jqt35npk6c) (pioglitazone - unii:x4ov71u42s), metformin hydrochloride (unii: 786z46389e) (metformin - unii:9100l32l2n) - pioglitazone 15 mg - actoplus met is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both pioglitazone and metformin is appropriate [see clinical studies (14)] . important limitations of use pioglitazone exerts its antihyperglycemic effect only in the presence of endogenous insulin. actoplus met should not be used to treat type 1 diabetes or diabetic ketoacidosis, as it would not be effective in these settings. use caution in patients with liver disease [see warnings and precautions (5.5)] . risk summary limited data with actoplus met or pioglitazone in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk (see data). there are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see clinical considerations]. in animal reproduction studies, no adverse developmental effects were observed when pioglitazone was administered to pregnant rats and rabbits during organogenesis at exposures up to 5 and 35 times the 45 mg clinical dose, respectively, based on body surface area. no adverse developmental effects were observed when metformin was administered to pregnant sprague dawley rats and rabbits during the period of organogenesis at doses up to 2 to 6 times, respectively, a 2000 mg clinical dose, based on body surface area (see data). the estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a hba1c >7 and has been reported to be as high as 20 to 25% in women with a hba1c >10. the estimated background risk of miscarriage for the indicated population is unknown. in the us general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, still birth and delivery complications. poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity. data human data published data from postmarketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. however, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups. animal data pioglitazone and metformin hydrochloride animal reproduction studies were not conducted with the combined products in actoplus met. the following data are based on studies conducted with the individual components of actoplus met. pioglitazone pioglitazone administered to pregnant rats during organogenesis did not cause adverse developmental effects at a dose of 20 mg/kg (~5 times the 45 mg clinical dose), but delayed parturition and reduced embryo-fetal viability at 40 and 80 mg/kg, or ≥9 times the 45 mg clinical dose, by body surface area. in pregnant rabbits administered pioglitazone during organogenesis, no adverse developmental effects were observed at 80 mg/kg (~35 times the 45 mg clinical dose), but reduced embryo-fetal viability at 160 mg/kg, or ~69 times the 45 mg clinical dose, by body surface area. when pregnant rats received pioglitazone during late gestation and lactation, delayed postnatal development, attributed to decreased body weight, occurred in offspring at maternal doses of 10 mg/kg and above or ≥2 times the 45 mg clinical dose, by body surface area. metformin hydrochloride metformin hydrochloride did not cause adverse developmental effects when administered to pregnant sprague dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis. this represents an exposure of about 2 to 6 times a 2000 mg clinical dose based on body surface area (mg/m2 ) for rats and rabbits, respectively. risk summary there is no information regarding the presence of actoplus met or pioglitazone in human milk, the effects on the breastfed infant, or the effects on milk production. pioglitazone is present in rat milk; however, due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk. limited published studies report that metformin is present in human milk (see data) . however, there is insufficient information on the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for actoplus met and any potential adverse effects on the breastfed infant from actoplus met or from the underlying maternal condition. data published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. however, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants. discuss the potential for unintended pregnancy with premenopausal women as therapy with actoplus met, may result in ovulation in some anovulatory women. safety and effectiveness of actoplus met in pediatric patients have not been established. actoplus met is not recommended for use in pediatric patients based on adverse effects observed in adults, including fluid retention and congestive heart failure, fractures, and urinary bladder tumors [see warnings and precautions (5.1, 5.3, 5.6, 5.7)]. pioglitazone a total of 92 patients (15.2%) treated with pioglitazone in the three pooled 16 to 26 week double-blind, placebo-controlled, monotherapy trials were ≥65 years old and two patients (0.3%) were ≥75 years old. in the two pooled 16 to 24 week add-on to sulfonylurea trials, 201 patients (18.7%) treated with pioglitazone were ≥65 years old and 19 (1.8%) were ≥75 years old. in the two pooled 16 to 24 week add-on to metformin trials, 155 patients (15.5%) treated with pioglitazone were ≥65 years old and 19 (1.9%) were ≥75 years old. in the two pooled 16 to 24 week add-on to insulin trials, 272 patients (25.4%) treated with pioglitazone were ≥65 years old and 22 (2.1%) were ≥75 years old. in proactive trial, 1068 patients (41.0%) treated with pioglitazone were ≥65 years old and 42 (1.6%) were ≥75 years old. in pharmacokinetic studies with pioglitazone, no significant differences were observed in pharmacokinetic parameters between elderly and younger patients [see clinical pharmacology (12.3)] . although clinical experiences have not identified differences in effectiveness and safety between the elderly (≥65 years) and younger patients, these conclusions are limited by small sample sizes for patients ≥75 years old. metformin hydrochloride controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients. in general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. assess renal function more frequently in elderly patients [see warnings and precautions (5.2), dosage and administration (2.2)]. metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. actoplus met is contraindicated in severe renal impairment, patients with an egfr below 30 ml/min/1.73 m2 [see dosage and administration (2.2), contraindications (4), warnings and precautions (5.2), clinical pharmacology (12.3)]. use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. actoplus met is not recommended in patients with hepatic impairment [see warnings and precautions (5.2)] .

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aurobindo pharma limited - ribavirin (unii: 49717awg6k) (ribavirin - unii:49717awg6k) - ribavirin 200 mg - ribavirin capsules in combination with interferon alfa-2b (pegylated and nonpegylated) are indicated for the treatment of chronic hepatitis c (chc) in patients 3 years of age and older with compensated liver disease [see warnings and precautions (5.9, 5.10), and use in specific populations (8.4)]. the following points should be considered when initiating ribavirin capsules combination therapy with pegintron® or intron a® : - combination therapy with ribavirin capsules/pegintron is preferred over ribavirin capsules/intron a as this combination provides substantially better response rates [see clinical studies (14)]. - patients with the following characteristics are less likely to benefit from re-treatment after failing a course of therapy: previous nonresponse, previous pegylated interferon treatment, significant bridging fibrosis or cirrhosis, and genotype 1 infection [see clinical studies (14)]. - no safety and efficacy data are available for treatment duration lasting longer than one year.     ribavirin capsules combination therapy is contraindicated in: - pregnancy. ribavirin capsules may cause fetal harm when administered to a pregnant woman. ribavirin capsules are contraindicated in women who are pregnant or planning to become pregnant. if a patient becomes pregnant while taking ribavirin capsules, the patient should be apprised of the potential hazard to the fetus [see warnings and precautions (5.1) , and use in specific populations (8.1, 8.3)]. - men whose female partners are pregnant [see use in specific populations (8.3)] - patients with known hypersensitivity reactions such as stevens-johnson syndrome, toxic, epidermal necrolysis, and erythema multiforme to ribavirin or any component of the product - patients with autoimmune hepatitis - patients with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia) - patients with creatinine clearance less than 50 ml/min [see clinical pharmacology (12.3)] - when coadministered with didanosine because exposure to the active metabolite of didanosine (dideoxyadenosine 5’-triphosphate) is increased. fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis, has been reported in patients receiving didanosine in combination with ribavirin [see drug interactions (7.1)].    risk summary ribavirin is contraindicated for use in pregnant women and in men whose female partners are pregnant [see contraindications (4)] . based on animal data, ribavirin use in pregnancy may be associated with birth defects. data from the ribavirin pregnancy registry are insufficient to identify a drug-associated risk of birth defects, miscarriage, or adverse maternal or fetal outcomes (see data) . ribavirin is known to accumulate in intracellular components from where it is cleared very slowly. in animal studies, ribavirin exposure was shown to have teratogenic and/or embryocidal effects (see data) . all pregnancies have a background risk of birth defect, 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 risk of major birth defects and miscarriage is 2 to 4% and 15 to 20%, respectively. data human data available data from the ribavirin pregnancy registry on 88 live births from pregnancies in women directly exposed and 98 live births from pregnancies in women indirectly exposed (by a male partner) to ribavirin during pregnancy or during the 6 months prior to pregnancy show a higher rate of birth defects (9.09% and 6.12%, respectively) compared to a background birth defect rate of 2.72% in the metropolitan atlanta congenital defects program (macdp) birth defects surveillance system. no pattern of birth defects can be identified from these reports. the miscarriage rate was approximately 21%. the current sample size is insufficient for reaching definitive conclusions based on statistical analysis. trends suggesting a common etiology or relationship with ribavirin exposure were not observed. methodologic limitations of the ribavirin pregnancy registry include the use of macdp as the external comparator group. limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease and comorbidities. animal data embryotoxicity/teratogenicity studies with ribavirin were conducted in rats (oral doses of 0.3, 1 and 10 mg/kg on gestation days 6 to 15) and rabbits (oral dose of 0.1, 0.3 and 1 mg/kg on gestation days 6 to 18). ribavirin demonstrated significant embryocidal and teratogenic effects at doses well below the recommended human dose in all animal species in which adequate studies have been conducted. malformations of the skull, palate, eye, jaw, limbs, skeleton, and gastrointestinal tract were noted. the incidence and severity of teratogenic effects increased with escalation of the drug dose. survival of fetuses and offspring was reduced [see contraindications (4) and warnings and precautions (5.1)]. risk summary there are no data on the presence of ribavirin in human milk or the effects on the breastfed infant or milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ribavirin and any potential adverse effects on the breastfed infant from ribavirin or from the underlying maternal condition. ribavirin may cause fetal harm when administered to a pregnant woman [see use in specific populations (8.1)]. pregnancy testing ribavirin therapy should not be started until a report of a negative pregnancy test has been obtained immediately prior to planned initiation of treatment. patients should have periodic pregnancy tests during treatment and during the 9-month period after treatment has been stopped [see warnings and precautions (5.1)]. contraception female patients of reproductive potential should use effective contraception during treatment and for 9 months post-therapy. male patients and their female partners should use effective contraception during treatment with ribavirin and for the 6-month post-therapy period [see warnings and precautions (5.1)] . infertility based on animal data, ribavirin may impair male fertility. in animal studies, these effects were mostly reversible within a few months after drug cessation [see nonclinical toxicology (13.1)] .     safety and effectiveness of ribavirin in combination with pegintron has not been established in pediatric patients below the age of 3 years. for treatment with ribavirin/intron a, evidence of disease progression, such as hepatic inflammation and fibrosis, as well as prognostic factors for response, hcv genotype and viral load should be considered when deciding to treat a pediatric patient. the benefits of treatment should be weighed against the observed safety findings. long-term follow-up data in pediatric subjects indicates that ribavirin in combination with pegintron or with intron a may induce a growth inhibition that results in reduced height in some patients [see warnings and precautions (5.9) and adverse reactions (6.1)] . suicidal ideation or attempts occurred more frequently among pediatric patients, primarily adolescents, compared to adult patients (2.4% vs. 1%) during treatment and off-therapy follow-up [see warnings and precautions (5.10)]. as in adult patients, pediatric patients experienced other psychiatric adverse reactions (e.g., depression, emotional lability, somnolence), anemia, and neutropenia [see warnings and precautions (5.2) ]. juvenile animal toxicity data in a study in which rat pups were dosed postnatally with ribavirin at doses of 10, 25, and 50 mg/kg/day, drug-related deaths occurred at 50 mg/kg (at rat pup plasma concentrations below human plasma concentrations at the human therapeutic dose) between study days 13 and 48. rat pups dosed from postnatal days 7 through 63 demonstrated a minor, dose-related decrease in overall growth at all doses, which was subsequently manifested as slight decreases in body weight, crown-rump length, and bone length. these effects showed evidence of reversibility, and no histopathological effects on bone were observed. no ribavirin effects were observed regarding neurobehavioral or reproductive development. clinical trials of ribavirin combination therapy did not include sufficient numbers of subjects aged 65 and over to determine if they respond differently from younger subjects. ribavirin is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. because elderly patients often have decreased renal function, care should be taken in dose selection. renal function should be monitored and dosage adjustments made accordingly. ribavirin should not be used in patients with creatinine clearance less than 50 ml/min [see contraindications (4)] . in general, ribavirin capsules should be administered to elderly patients cautiously, starting at the lower end of the dosing range, reflecting the greater frequency of decreased hepatic and cardiac function, and of concomitant disease or other drug therapy. in clinical trials, elderly subjects had a higher frequency of anemia (67%) than younger patients (28%) [see warnings and precautions (5.2)].   the safety and efficacy of intron a and pegintron alone or in combination with ribavirin for the treatment of hepatitis c in liver or other organ transplant recipients have not been established. in a small (n=16) single-center, uncontrolled case experience, renal failure in renal allograft recipients receiving interferon alpha and ribavirin combination therapy was more frequent than expected from the center’s previous experience with renal allograft recipients not receiving combination therapy. the relationship of the renal failure to renal allograft rejection is not clear. the safety and efficacy of pegintron/ribavirin and intron a/ribavirin for the treatment of patients with hcv co-infected with hiv or hbv have not been established.

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sun pharmaceutical industries, inc. - citalopram hydrobromide (unii: i1e9d14f36) (citalopram - unii:0dhu5b8d6v) - citalopram 10 mg - citalopram tablets, usp (citalopram hbr) is indicated for the treatment of depression. the efficacy of citalopram tablets, usp in the treatment of depression was established in 4-6 week, controlled trials of outpatients whose diagnosis corresponded most closely to the dsm-iii and dsm-iii-r category of major depressive disorder (see clinical pharmacology ). a major depressive episode (dsm-iv) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least five of the following nine symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation. the antidepressant action of citalopram tablets, usp in hospitalized depressed patients has no

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sun pharmaceutical industries, inc. - topiramate (unii: 0h73wjj391) (topiramate - unii:0h73wjj391) - topiramate 25 mg - topiramate tablets 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 tablets 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 tablets 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 topiramate 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 can cause fetal harm when administered to a pregnant woman. data from pregnancy registries indicate that infants exposed to topiramate in utero have an 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 produced 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, 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 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 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 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 unexposed to aeds. the long-term consequences of the sga findings are not known. animal data when topiramate (0, 20, 100, or 500 mg/kg/day) was administered to pregnant mice during the period of organogenesis, incidences 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 increased 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, 20, 100, and 500 mg/kg/day or 0, 0.2, 2.5, 30, 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 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, 20, 60, and 180 mg/kg/day or 0, 10, 35, and 120 mg/kg/day) orally during organogenesis, embryofetal mortality was increased at 35 mg/kg/day, and increased incidences of fetal malformations (primarily rib and vertebral malformations) were 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, 0.2, 4, 20, and 100 mg/kg/day or 0, 2, 20, 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, 0.2, 2.5, 30, and 400 mg/kg) 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 and any potential adverse effects on the breastfed infant from topiramate 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 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 [see adverse reactions (6.1) and clinical studies (14.2)] . 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 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 topiramate oral liquid and sprinkle formulations as an adjunct to concurrent antiepileptic drug therapy in pediatric patients 1 to 24 months of age with refractory partial-onset seizures were assessed. after 20 days of double-blind treatment, topiramate (at fixed doses of 5, 15, and 25 mg/kg/day) did not demonstrate efficacy compared with placebo in controlling seizures. in general, the adverse reaction profile for 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 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 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)]. 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. the significance of these findings is uncertain. 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. 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 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)]. 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/1000 patient years. it is not possible to know whether this mortality rate is related to topiramate treatment, because the background mortality rate for a similar, significantly refractory, young pediatric population (1 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 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 [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 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 10 summarizes effects of topiramate at 12 months for key safety outcomes including bmd, height, height velocity, and weight. all least square mean values for 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).   table 10 summary of topiramate treatment difference results at 12 months for key safety outcomes metabolic acidosis (serum bicarbonate < 20 meq/l) was observed in all topiramate-treated patients at some time in the study [see warnings and precautions (5.4)] . over the whole study, 76% more 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 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. 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 to 200 mg/day, or 2 to 3 mg/kg/day. these comprised a fixed dose study in 103 pediatric patients 12 to 17 years of age [see clinical studies (14.3) ], a flexible dose (2 to 3 mg/kg/day), placebo-controlled study in 157 pediatric patients 6 to 16 years of age (including 67 pediatric patients 12 to 16 years of age), and a total of 49 pediatric patients 12 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 to 17 years of age is demonstrated for a 100 mg daily dose in study 13 [see clinical studies (14.3)] . efficacy of topiramate (2 to 3 mg/kg/day) for the preventive treatment of migraine was not demonstrated in a placebo- controlled trial of 157 pediatric  patients  (6  to  16 years  of  age)  that  included  treatment  of 67 pediatric patients (12 to 16 years of age) for 20 weeks. in the pediatric trials (12 to 17 years of age) in which patients were randomized to placebo or a fixed daily dose of topiramate, the most common adverse reactions with 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) ]. the most common cognitive adverse reaction in pooled double-blind studies in pediatric patients 12 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 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 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   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 to 17 years of age. the most common adverse reactions that occurred in topiramate-treated pediatric patients 6 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 to 11 years of age) than in older patients (12 to 17 years of age) [see warnings and precautions (5.6)]. juvenile animal studies when topiramate (0, 30, 90, and 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. the no-effect dose (90 mg/kg/day) for adverse developmental effects is approximately 2 times the maximum recommended pediatric dose (9 mg/kg/day) on a body surface area (mg/m2 ) basis. in clinical trials, 3% of patients were over age 60. no age-related differences in effectiveness or adverse effects were evident. however, clinical studies of 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 age-related renal impairment (creatinine clearance rate <70 ml/min/1.73 m2 ) resulting in reduced clearance [see dosage and administration (2.5), clinical pharmacology (12.3)]. the clearance of topiramate is reduced in patients with moderate (creatinine clearance 30 to 69 ml/min/1.73 m2 ) and severe (creatinine clearance <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 (2.5), clinical pharmacology (12.3)]. topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than in a normal individual. a dosage adjustment may be required [see dosage and administration (2.6), clinical pharmacology (12.3)].

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

aurobindo pharma limited - gabapentin (unii: 6cw7f3g59x) (gabapentin - unii:6cw7f3g59x) - gabapentin 100 mg - gabapentin capsules are indicated for: - management of postherpetic neuralgia in adults - adjunctive therapy in the treatment of partial onset seizures, with and without secondary generalization, in adults and pediatric patients 3 years and older with epilepsy gabapentin capsules are contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (aeds), such as gabapentin, during pregnancy. encourage women who are taking gabapentin during pregnancy to enroll in the north american antiepileptic drug (naaed) pregnancy registry by calling the toll free number 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/ . risk summary there are no adequate data on the developmental risks associated with the use of gabapentin in pregnant women. in nonclinical studies in mice, rats, and rabbits, gabapentin was developmentally toxic (increased fetal skeletal and visceral abnormalities, and increased embryofetal mortality) when administered to pregnant animals at doses similar to or lower than those used clinically [see data]. 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. the background risk of major birth defects and miscarriage for the indicated population is unknown. data animal data when pregnant mice received oral doses of gabapentin (500, 1000, or 3000 mg/kg/day) during the period of organogenesis, embryofetal toxicity (increased incidences of skeletal variations) was observed at the two highest doses. the no-effect dose for embryofetal developmental toxicity in mice (500 mg/kg/day) is less than the maximum recommended human dose (mrhd) of 3600 mg on a body surface area (mg/m2 ) basis. in studies in which rats received oral doses of gabapentin (500 to 2000 mg/kg/day) during pregnancy, adverse effect on offspring development (increased incidences of hydroureter and/or hydronephrosis) were observed at all doses. the lowest dose tested is similar to the mrhd on a mg/m2 basis. when pregnant rabbits were treated with gabapentin during the period of organogenesis, an increase in embryofetal mortality was observed at all doses tested (60, 300, or 1500 mg/kg). the lowest dose tested is less than the mrhd on a mg/m2 basis. in a published study, gabapentin (400 mg/kg/day) was administered by intraperitoneal injection to neonatal mice during the first postnatal week, a period of synaptogenesis in rodents (corresponding to the last trimester of pregnancy in humans). gabapentin caused a marked decrease in neuronal synapse formation in brains of intact mice and abnormal neuronal synapse formation in a mouse model of synaptic repair. gabapentin has been shown in vitro to interfere with activity of the α2δ subunit of voltage-activated calcium channels, a receptor involved in neuronal synaptogenesis. the clinical significance of these findings is unknown. risk summary gabapentin is secreted in human milk following oral administration. the effects on the breastfed infant and on milk production are unknown. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for gabapentin and any potential adverse effects on the breastfed infant from gabapentin or from the underlying maternal condition. safety and effectiveness of gabapentin in the management of postherpetic neuralgia in pediatric patients have not been established. safety and effectiveness as adjunctive therapy in the treatment of partial seizures in pediatric patients below the age of 3 years has not been established [see clinical studies (14.2)] . the total number of patients treated with gabapentin in controlled clinical trials in patients with postherpetic neuralgia was 336, of which 102 (30%) were 65 to 74 years of age, and 168 (50%) were 75 years of age and older. there was a larger treatment effect in patients 75 years of age and older compared to younger patients who received the same dosage. since gabapentin is almost exclusively eliminated by renal excretion, the larger treatment effect observed in patients ≥75 years may be a consequence of increased gabapentin exposure for a given dose that results from an age-related decrease in renal function. however, other factors cannot be excluded. the types and incidence of adverse reactions were similar across age groups except for peripheral edema and ataxia, which tended to increase in incidence with age. clinical studies of gabapentin in epilepsy did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. other reported clinical experience has not identified differences in responses between the elderly and younger patients. in general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. this drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and dose should be adjusted based on creatinine clearance values in these patients [see dosage and administration (2.4), adverse reactions (6), and clinical pharmacology (12.3)] . dosage adjustment in adult patients with compromised renal function is necessary [see dosage and administration (2.3) and clinical pharmacology (12.3)] . pediatric patients with renal insufficiency have not been studied. dosage adjustment in patients undergoing hemodialysis is necessary [see dosage and administration (2.3) and clinical pharmacology (12.3)] . gabapentin is not a scheduled drug. abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. 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. gabapentin does not exhibit affinity for benzodiazepine, opioid (mu, delta or kappa), or cannabinoid 1 receptor sites. gabapentin misuse and abuse have been reported in the postmarketing setting and published literature. most of the individuals described in these reports had a history of polysubstance abuse. some of these individuals were taking higher than recommended doses of gabapentin for unapproved uses. when prescribing gabapentin, carefully evaluate patients for a history of drug abuse and observe them for signs and symptoms of gabapentin misuse or abuse (e.g., self-dose escalation and drug-seeking behavior). the abuse potential of gabapentin has not been evaluated in human studies. 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. there are rare postmarketing reports of individuals experiencing withdrawal symptoms shortly after discontinuing higher than recommended doses of gabapentin used to treat illnesses for which the drug is not approved. such symptoms included agitation, disorientation and confusion after suddenly discontinuing gabapentin that resolved after restarting gabapentin. the dependence potential of gabapentin has not been evaluated in human studies.

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

sun pharmaceutical industries, inc. - paroxetine hydrochloride hemihydrate (unii: x2els050d8) (paroxetine - unii:41vrh5220h) - paroxetine 10 mg - major depressive disorder paroxetine tablets, usp is indicated for the treatment of major depressive disorder. the efficacy of paroxetine tablets, usp in the treatment of a major depressive episode was established in 6-week controlled trials of outpatients whose diagnoses corresponded most closely to the dsm-iii category of major depressive disorder (see clinical pharmacology–clinical trials). a major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation. the effects of paroxetine tablets, usp in hospitalized depressed patients have not been adequ

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.

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

pharmaceutical associates, inc. - atovaquone (unii: y883p1z2lt) (atovaquone - unii:y883p1z2lt) - atovaquone oral suspension usp is indicated for the prevention of pneumocystis jirovecii pneumonia (pcp) in adults and adolescents (aged 13 years and older) who cannot tolerate trimethoprim-sulfamethoxazole (tmp-smx). atovaquone oral suspension usp is indicated for the acute oral treatment of mild-to-moderate pcp in adults and adolescents (aged 13 years and older) who cannot tolerate tmp-smx. clinical experience with atovaquone oral suspension usp for the treatment of pcp has been limited to subjects with mild-to-moderate pcp (alveolar-arterial oxygen diffusion gradient [(a-a)do 2 ] ≤45 mm hg). treatment of more severe episodes of pcp with atovaquone oral suspension usp has not been studied. the efficacy of atovaquone oral suspension usp in subjects who are failing therapy with tmp-smx has also not been studied. atovaquone oral suspension is contraindicated in patients who develop or have a history of hypersensitivity reactions (e.g., angioedema, bronchospasm, throat tightness, u

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

indoco remedies limited - apixaban (unii: 3z9y7uwc1j) (apixaban - unii:3z9y7uwc1j) - apixaban tablets are indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. apixaban tablets are indicated for the prophylaxis of deep vein thrombosis (dvt), which may lead to pulmonary embolism (pe), in patients who have undergone hip or knee replacement surgery. apixaban tablets are indicated for the treatment of dvt. apixaban tablets are indicated for the treatment of pe. apixaban tablets are indicated to reduce the risk of recurrent dvt and pe following initial therapy. apixaban tablets are contraindicated in patients with the following conditions: • active pathological bleeding [see warnings and precautions (5.2) and adverse  reactions(6.1)] • severe  hypersensitivity  reaction  to  apixaban (e.g.,  anaphylactic  reactions)  [see  adverse reactions (6.1)] risk summary the limited available data on apixaban tablets  use in pregnant women are insufficient to inform drug-associated risks of major birth defects, miscarriage, or adverse developmental

New Zealand - English - Medsafe (Medicines Safety Authority)

pharmacy retailing (nz) ltd t/a healthcare logistics - irinotecan hydrochloride trihydrate 20 mg/ml ((equivalent to 17.33 mg irinotecan));   - solution for infusion - 20 mg/ml - active: irinotecan hydrochloride trihydrate 20 mg/ml ((equivalent to 17.33 mg irinotecan))   excipient: hydrochloric acid lactic acid sodium hydroxide sorbitol water for injection - irinotecan hydrochloride trihydrate injection is indicated as a component of first-line therapy for patients with metastatic carcinoma of the colon or rectum, in combination with 5fu/leucovorin. irinotecan hydrochloride trihydrate injection is also indicated for patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial therapy.