Ameerika Ühendriigid - inglise - NLM (National Library of Medicine)

solco healthcare u.s., llc - metformin hydrochloride (unii: 786z46389e) (metformin - unii:9100l32l2n) - metformin hydrochloride tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults and children with type 2 diabetes mellitus. metformin hydrochloride tablets are contraindicated in patients with: metformin hydrochloride tablets should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function. (see also precautions .)

Austraalia - inglise - Department of Health (Therapeutic Goods Administration)

viatris pty ltd - latanoprost, quantity: 50 microgram/ml - eye drops, solution - excipient ingredients: dibasic sodium phosphate; sodium chloride; benzalkonium chloride; monobasic sodium phosphate monohydrate; water for injections; hydrochloric acid; sodium hydroxide - reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension.

Ameerika Ühendriigid - inglise - NLM (National Library of Medicine)

novartis pharmaceuticals corporation - sacubitril (unii: 17erj0mkgi) (sacubitrilat - unii:spi5pbf81s), valsartan (unii: 80m03yxj7i) (valsartan - unii:80m03yxj7i) - sacubitril 24 mg - entresto is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. benefits are most clearly evident in patients with left ventricular ejection fraction (lvef) below normal. lvef is a variable measure, so use clinical judgment in deciding whom to treat [see clinical studies (14.1)] . entresto is indicated for the treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged one year and older. entresto reduces nt-probnp and is expected to improve cardiovascular outcomes. entresto is contraindicated: - in patients with hypersensitivity to any component - in patients with a history of angioedema related to previous ace inhibitor or arb therapy [see warnings and precautions (5.2)] - with concomitant use of ace inhibitors. do not administer within 36 hours of switching from or to an ace inhibitor [see drug interactions (7.1)] - with concomitant use of aliskiren in patients with diabetes [see drug interactions (7.1)] risk summary entresto can cause fetal harm when administered to a pregnant woman. use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death (see clinical considerations ). most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. in animal reproduction studies, entresto treatment during organogenesis resulted in increased embryo-fetal lethality in rats and rabbits and teratogenicity in rabbits (see data ). when pregnancy is detected, consider alternative drug treatment and discontinue entresto. however, if there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system, and if the drug is considered lifesaving for the mother, advise a pregnant woman of 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. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations fetal/neonatal adverse reactions oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension, and death. perform serial ultrasound examinations to assess the intra-amniotic environment. fetal testing may be appropriate, based on the week of gestation. patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. if oligohydramnios is observed, consider alternative drug treatment. closely observe neonates with histories of in utero exposure to entresto for hypotension, oliguria, and hyperkalemia. in neonates with a history of in utero exposure to entresto, if oliguria or hypotension occurs, support blood pressure and renal perfusion. exchange transfusions or dialysis may be required as a means of reversing hypotension and replacing renal function. data animal data entresto treatment during organogenesis resulted in increased embryo-fetal lethality in rats at doses greater than or equal to 49 mg sacubitril/51 mg valsartan/kg/day (less than or equal to 0.06 [lbq657, the active metabolite] and 0.72 [valsartan]-fold the maximum recommended human dose [mrhd] of 97/103 mg twice-daily on the basis of the area under the plasma drug concentration-time curve [auc]) and rabbits at doses greater than or equal to 5 mg sacubitril/5 mg valsartan/kg/day (2-fold and 0.03-fold the mrhd on the basis of valsartan and lbq657 auc, respectively). entresto is teratogenic based on a low incidence of fetal hydrocephaly, associated with maternally toxic doses, which was observed in rabbits at an entresto dose of greater than or equal to 5 mg sacubitril/5 mg valsartan/kg/day. the adverse embryo-fetal effects of entresto are attributed to the angiotensin receptor antagonist activity. pre- and postnatal development studies in rats at sacubitril doses up to 750 mg/kg/day (2.2-fold the mrhd on the basis of lbq657 auc) and valsartan at doses up to 600 mg/kg/day (0.86-fold the mrhd on the basis of auc) indicate that treatment with entresto during organogenesis, gestation and lactation may affect pup development and survival. risk summary there is no information regarding the presence of sacubitril/valsartan in human milk, the effects on the breastfed infant, or the effects on milk production. sacubitril/valsartan is present in rat milk (see data ). because of the potential for serious adverse reactions in breastfed infants from exposure to sacubitril/valsartan, advise a nursing woman that breastfeeding is not recommended during treatment with entresto. data following an oral dose (15 mg sacubitril/15 mg valsartan/kg) of [14 c] entresto to lactating rats, transfer of lbq657 into milk was observed. after a single oral administration of 3 mg/kg [14 c] valsartan to lactating rats, transfer of valsartan into milk was observed. the safety and effectiveness of entresto have been established for the treatment of heart failure in pediatric patients 1 year to less than 18 years. use of entresto was evaluated in a multinational, randomized, double-blind trial comparing entresto and enalapril in 375 patients aged 1 month to less than 18 years (entresto n = 187; enalapril n = 188) (panorama-hf) [see clinical studies (14.2)] . the safety profile in pediatric patients (1 year to less than 18 years) receiving entresto was similar to that seen in adult patients. limited safety and efficacy data in patients aged 1 month to less than 1 year were inadequate to support conclusions on safety and efficacy in this age group. juvenile animal toxicity data sacubitril given orally to juvenile rats from postnatal day (pnd) 7 to pnd 35 or pnd 70 (an age approximately equivalent to neonatal through pre-pubertal development or adulthood in humans) at doses greater than or equal to 400 mg/kg/day (approximately 2-fold the auc exposure to the active metabolite of sacubitril, lbq657, at an entresto pediatric clinical dose of 3.1 mg/kg twice daily) resulted in decreases in body weight, bone length, and bone mass. the decrease in body weight was transient from pnd 10 to pnd 20 and the effects for most bone parameters were reversible after treatment stopped. exposure at the no-observed-adverse-effect-level (noael) of 100 mg/kg/day was approximately 0.5-fold the auc exposure to lbq657 at the 3.1 mg/kg twice daily dose of entresto. the mechanism underlying bone effects in rats and the translatability to pediatric patients are unknown. valsartan given orally to juvenile rats from pnd 7 to pnd 70 (an age approximately equivalent to neonatal through adulthood in humans) produced persistent, irreversible kidney damage at all dose levels. exposure at the lowest tested dose of 1 mg/kg/day was approximately 0.2-fold the exposure at 3.1 mg/kg twice daily dose of entresto based on auc. these kidney effects in neonatal rats represent expected exaggerated pharmacological effects that are observed if rats are treated during the first 13 days of life. this period coincides with 36 weeks of gestation in humans, which could occasionally extend up to 44 weeks after conception in humans. in humans, nephrogenesis is thought to be complete around birth; however, maturation of other aspects of kidney function (such as glomerular filtration and tubular function) may continue until approximately 2 years of age. it is unknown whether post-natal use of valsartan before maturation of renal function is complete has long-term deleterious effects on the kidney. there were 4,143 and 3,971 heart failure patients 65 years of age and older in paradigm-hf and paragon-hf, respectively [see clinical studies (14)] . of the total number of entresto-treated patients, 2,087 (49.6%) and 1,995 (82.9%) were 65 years of age and older, while 786 (18.7%) and 1,100 (45.7%) were 75 years of age and older in paradigm-hf and paragon-hf, respectively. no overall differences in safety or effectiveness of entresto have been observed between patients 65 years of age and older and younger adult patients in either study. no relevant pharmacokinetic differences have been observed in elderly (≥ 65 years) or very elderly (≥ 75 years) patients compared to the overall population [see clinical pharmacology (12.3)] . no dose adjustment is required when administering entresto to patients with mild hepatic impairment (child-pugh a classification). half of the starting dose is recommended in adult and pediatric patients with heart failure and with moderate hepatic impairment (child-pugh b classification). the use of entresto in patients with severe hepatic impairment (child-pugh c classification) is not recommended, as no studies have been conducted in these patients [see dosage and administration (2.8) and clinical pharmacology (12.3)] . no dose adjustment is required in patients with mild (egfr 60 to 90 ml/min/1.73 m2 ) to moderate (egfr 30 to 60 ml/min/1.73 m2 ) renal impairment. half of the starting dose is recommended in adult and pediatric patients with heart failure and with severe renal impairment (egfr less than 30 ml/min/1.73 m2 ). [see dosage and administration (2.7), warnings and precautions (5.4) and clinical pharmacology (12.3)] . - entresto sprinkle contains oral pellets inside of a capsule. the capsule must be opened and the oral pellets inside must be sprinkled on soft food before you take or give entresto sprinkle. do not swallow the capsule or the empty capsule shells. - the capsule must be opened and the oral pellets inside must be sprinkled on soft food before you take or give entresto sprinkle. - do not swallow the capsule or the empty capsule shells. - do not chew or crush the oral pellets. - use all of the oral pellets in the capsule. do not use part of a capsule to try to prepare a dose. - do not take or give entresto sprinkle through a nasogastric tube (ng tube), gastrostomy tube (g tube), or other feeding tubes because it may clog the tube. - entresto sprinkle is available in 2 strengths: 6 mg/6 mg (sacubitril 6 mg and valsartan 6 mg) and 15 mg/16 mg (sacubitril 15 mg and valsartan 16 mg). - you can see the difference between the 2 strengths by the color of the capsule cap and the imprint on it. the capsule containing the 6 mg/6 mg strength has a white cap with the number “04” printed on it. the capsule containing the 15 mg/16 mg strength has a yellow cap with the number “10” printed on it. - the capsule containing the 6 mg/6 mg strength has a white cap with the number “04” printed on it. - the capsule containing the 15 mg/16 mg strength has a yellow cap with the number “10” printed on it. - check to make sure you have received the prescribed strength of entresto sprinkle before taking or giving the dose. - a clean small bowl, cup, or spoon to measure and hold the soft food that you or your child likes, such as applesauce, yogurt, or pudding. - bottle with capsules containing entresto sprinkle. - place the following items on a clean flat surface: a small bowl, cup or spoon with about 1 to 2 teaspoonfuls of soft food that you or your child likes for each capsule of entresto sprinkle prescribed (see figure b ). bottle with capsules containing entresto sprinkle. - a small bowl, cup or spoon with about 1 to 2 teaspoonfuls of soft food that you or your child likes for each capsule of entresto sprinkle prescribed (see figure b ). - bottle with capsules containing entresto sprinkle. - check that you have the right strength of entresto sprinkle. - hold the capsule upright (with the colored cap on top) so that the oral pellets are in the bottom of the capsule (figure c ). - hold the capsule over the soft food. - gently pinch the middle of the capsule and pull slightly to separate the 2 ends of the capsule (figure d ). take care not to spill the contents while opening the capsule. - check the capsule to make sure that you did not miss any oral pellets. tap the capsule to remove any remaining oral pellets. - repeat steps 4 and 5 if you need more than 1 capsule for the prescribed dose. - take or give the food with the oral pellets right away after adding the oral pellets (figure f ). - make sure that you or your child eat all of the food containing the oral pellets. - make sure that you or your child do not chew the oral pellets to avoid a change of taste. - throw away the empty shells of the capsule in the household trash (figure g ). - wash your hands and all the items used to take or give entresto sprinkle. - store entresto sprinkle at room temperature between 68°f to 77°f (20°c to 25°c). - protect entresto sprinkle from moisture. t2024-30

Ameerika Ühendriigid - inglise - NLM (National Library of Medicine)

solco healthcare u.s., llc - voriconazole (unii: jfu09i87tr) (voriconazole - unii:jfu09i87tr) - voriconazole 50 mg - voriconazole tablets are indicated in adults and pediatric patients (aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight) for the treatment of invasive apergillosis (ia). in clinical trials, the majority of isolates recovered were aspergillus fumigatus . there was a small number of cases of culture-proven disease due to species of aspergillus other than a. fumigatus[see clinical studies (14.1, 14.5) and microbiology (12.4)]. voriconazole tablets are indicated in adults and pediatric patients (aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight) for the treatment of candidemia in non-neutropenic patients and the following candida infections: disseminated infections in skin and infections in abdomen, kidney, bladder wall, and wounds [see clinical studies (14.2, 14.5) and microbiology (12.4)]. voriconazole tablets are indicated in adults and pediatric patients (aged 12 to 14

Ameerika Ühendriigid - inglise - NLM (National Library of Medicine)

amneal pharmaceuticals llc - divalproex sodium (unii: 644vl95ao6) (valproic acid - unii:614oi1z5wi) - valproic acid 250 mg - divalproex sodium extended-release tablets are a valproate and are indicated for the treatment of acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features. a manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgment, aggressiveness, and possible hostility. a mixed episode is characterized by the criteria for a manic episode in conjunction with those for a major depressive episode (depressed mood, loss of interest or pleasure in nearly all activities). the efficacy of divalproex sodium extended-release tablets is based in part on studies of divalproex sodium delayed-release tablets in this indication, and was confirmed in a 3-week trial with patients meeting dsm-iv tr criteria for bipolar i disorder, manic or mixed type, who were hospitalized for acute mania [see clinical studies (14.1)] . the effectiveness of valproate for long-term use in mania, i.e. more than 3 weeks, has not been demonstrated in controlled clinical trials. therefore, healthcare providers who elect to use divalproex sodium extended-release tablets for extended periods should continually reevaluate the long-term risk-benefits of the drug for the individual patient. divalproex sodium extended-release tablets are indicated as monotherapy and adjunctive therapy in the treatment of adult patients and pediatric patients down to the age of 10 years with complex partial seizures that occur either in isolation or in association with other types of seizures. divalproex sodium extended-release tablets are also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures in adults and children 10 years of age or older, and adjunctively in adults and children 10 years of age or older with multiple seizure types that include absence seizures. simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. complex absence is the term used when other signs are also present. divalproex sodium extended-release tablets are indicated for prophylaxis of migraine headaches. there is no evidence that divalproex sodium extended-release tablets are useful in the acute treatment of migraine headaches. because of the risk to the fetus of decreased iq, neurodevelopmental disorders, neural tube defects, and other major congenital malformations, which may occur very early in pregnancy, valproate should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable. valproate should not be administered to a woman of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable [see warnings and precautions (5.2, 5.3, 5.4), use in specific populations (8.1)  and patient counseling information (17)] . for prophylaxis of migraine headaches, divalproex sodium extended-release tablets are contraindicated  in women who are pregnant and in women of childbearing potential who are not using effective contraception [see contraindications (4)] . - divalproex sodium extended-release tablets should not be administered to patients with hepatic disease or significant hepatic dysfunction [see warnings and precautions (5.1)] . - divalproex sodium extended-release tablets are contraindicated in patients known to have mitochondrial disorders caused by mutations in mitochondrial dna polymerase γ (polg; e.g., alpers-huttenlocher syndrome) and children under two years of age who are suspected of having a polg-related disorder [see warnings and precautions (5.1)] . - divalproex sodium extended-release tablets are contraindicated in patients with known hypersensitivity to the drug [see warnings and precautions (5.12)] . - divalproex sodium extended-release tablets are contraindicated in patients with known urea cycle disorders [see warnings and precautions (5.6)] . - for use in prophylaxis of migraine headaches: divalproex sodium extended-release tablets are contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception [see warnings and precautions (5.2, 5.3, 5.4) and use in specific populations (8.1)] . pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (aeds), including divalproex sodium extended-release, during pregnancy. encourage women who are taking divalproex sodium extended-release during pregnancy to enroll in the north american antiepileptic drug (naaed) pregnancy registry by calling toll-free 1-888-233-2334 or visiting the website, http://www.aedpregnancyregistry.org/. this must be done by the patient herself. risk summary for use in prophylaxis of migraine headaches, valproate is contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception [see contraindications (4)] . for use in epilepsy or bipolar disorder, valproate should not be used to treat women who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable [see boxed warning and warnings and precautions (5.2, 5.3)] . women with epilepsy who become pregnant while taking valproate should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects including spina bifida, but also malformations involving other body systems (e.g., craniofacial defects including oral clefts, cardiovascular malformations, hypospadias, limb malformations). this risk is dose-dependent; however, a threshold dose below which no risk exists cannot be established. in utero exposure to valproate may also result in hearing impairment or hearing loss. valproate polytherapy with other aeds has been associated with an increased frequency of congenital malformations compared with aed monotherapy. the risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy. the rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who used other anti-seizure monotherapies [see warnings and precautions (5.2) and data (human)] . epidemiological studies have indicated that children exposed to valproate in utero have lower iq scores and a higher risk of neurodevelopmental disorders compared to children exposed to either another aed in utero or to no aeds in utero [see warnings and precautions (5.3) and data (human)] . an observational study has suggested that exposure to valproate products during pregnancy increases the risk of autism spectrum disorders [see data (human)] . in animal studies, valproate administration during pregnancy resulted in fetal structural malformations similar to those seen in humans and neurobehavioral deficits in the offspring at clinically relevant doses [see data (animal)] . there have been reports of hypoglycemia in neonates and fatal cases of hepatic failure in infants following maternal use of valproate during pregnancy. pregnant women taking valproate may develop hepatic failure or clotting abnormalities including thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which may result in hemorrhagic complications in the neonate including death [see warnings and precautions (5.1, 5.8)] . available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate. evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. it is not known whether the risk of neural tube defects or decreased iq in the offspring of women receiving valproate is reduced by folic acid supplementation. dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate [see warnings and precautions (5.2, 5.4)]. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk to prevent major seizures, women with epilepsy should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. even minor seizures may pose some hazard to the developing embryo or fetus [see warnings and precautions (5.4)] . however, discontinuation of the drug may be considered prior to and during pregnancy in individual cases if the seizure disorder severity and frequency do not pose a serious threat to the patient. maternal adverse reactions pregnant women taking valproate may develop clotting abnormalities including thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which may result in hemorrhagic complications in the neonate including death [see warnings and precautions (5.8)] . if valproate is used in pregnancy, the clotting parameters should be monitored carefully in the mother. if abnormal in the mother, then these parameters should also be monitored in the neonate. patients taking valproate may develop hepatic failure [see boxed warning and warnings and precautions (5.1)] . fatal cases of hepatic failure in infants exposed to valproate in utero have also been reported following maternal use of valproate during pregnancy. hypoglycemia has been reported in neonates whose mothers have taken valproate during pregnancy. data human neural tube defects and other structural abnormalities there is an extensive body of evidence demonstrating that exposure to valproate in utero increases the risk of neural tube defects and other structural abnormalities. based on published data from the cdc’s national birth defects prevention network, the risk of spina bifida in the general population is about 0.06% to 0.07% (6 to 7 in 10,000 births) compared to the risk following in utero valproate exposure estimated to be approximately 1% to 2% (100 to 200 in 10,000 births). the naaed pregnancy registry has reported a major malformation rate of 9% to 11% in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during pregnancy. these data show an up to a five-fold increased risk for any major malformation following valproate exposure in utero compared to the risk following exposure in utero to other aeds taken as monotherapy. the major congenital malformations included cases of neural tube defects, cardiovascular malformations, craniofacial defects (e.g., oral clefts, craniosynostosis), hypospadias, limb malformations (e.g., clubfoot, polydactyly), and other malformations of varying severity involving other body systems [see warnings and precautions (5.2)] . effect on iq and neurodevelopmental effects published epidemiological studies have indicated that children exposed to valproate in utero have lower iq scores than children exposed to either another aed in utero or to no aeds in utero . the largest of these studies1 is a prospective cohort study conducted in the united states and united kingdom that found that children with prenatal exposure to valproate (n=62) had lower iq scores at age 6 (97 [95% c.i. 94 to 101]) than children with prenatal exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% c.i. 105 to 110]), carbamazepine (105 [95% c.i. 102 to 108]) and phenytoin (108 [95% c.i. 104 to 112]). it is not known when during pregnancy cognitive effects in valproate-exposed children occur. because the women in this study were exposed to aeds throughout pregnancy, whether the risk for decreased iq was related to a particular time period during pregnancy could not be assessed [see warnings and precautions (5.3)] . although the available studies have methodological limitations, the weight of the evidence supports a causal association between valproate exposure in utero and subsequent adverse effects on neurodevelopment, including increases in autism spectrum disorders and attention deficit/hyperactivity disorder (adhd). an observational study has suggested that exposure to valproate products during pregnancy increases the risk of autism spectrum disorders. in this study, children born to mothers who had used valproate products during pregnancy had 2.9 times the risk (95% confidence interval [ci]: 1.7 to 4.9) of developing autism spectrum disorders compared to children born to mothers not exposed to valproate products during pregnancy. the absolute risks for autism spectrum disorders were 4.4% (95% ci: 2.6% to 7.5%) in valproate-exposed children and 1.5% (95% ci: 1.5% to 1.6%) in children not exposed to valproate products. another observational study found that children who were exposed to valproate in utero had an increased risk of adhd (adjusted hr 1.48; 95% ci, 1.09 to 2.00) compared with the unexposed children. because these studies were observational in nature, conclusions regarding a causal association between in utero valproate exposure and an increased risk of autism spectrum disorder and adhd cannot be considered definitive. other there are published case reports of fatal hepatic failure in offspring of women who used valproate during pregnancy. animal in developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred following administration of valproate to pregnant animals during organogenesis at clinically relevant doses (calculated on a body surface area [mg/m2 ] basis). valproate induced malformations of multiple organ systems, including skeletal, cardiac, and urogenital defects. in mice, in addition to other malformations, fetal neural tube defects have been reported following valproate administration during critical periods of organogenesis, and the teratogenic response correlated with peak maternal drug levels. behavioral abnormalities (including cognitive, locomotor, and social interaction deficits) and brain histopathological changes have also been reported in mice and rat offspring exposed prenatally to clinically relevant doses of valproate. risk summary   valproate is excreted in human milk. data in the published literature describe the presence of valproate in human milk (range: 0.4 mcg/ml to 3.9 mcg/ml), corresponding to 1% to 10% of maternal serum levels. valproate serum concentrations collected from breastfed infants aged 3 days postnatal to 12 weeks following delivery ranged from 0.7 mcg/ml to 4 mcg/ml, which were 1% to 6% of maternal serum valproate levels. a published study in children up to six years of age did not report adverse developmental or cognitive effects following exposure to valproate via breast milk [see data (human)] . there are no data to assess the effects of divalproex sodium delayed-release on milk production or excretion. clinical considerations the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for divalproex sodium delayed-release and any potential adverse effects on the breastfed infant from divalproex sodium delayed-release or from the underlying maternal condition. monitor the breastfed infant for signs of liver damage including jaundice and unusual bruising or bleeding. there have been reports of hepatic failure and clotting abnormalities in offspring of women who used valproate during pregnancy [see use in specific populations (8.1)] . data human in a published study, breast milk and maternal blood samples were obtained from 11 epilepsy patients taking valproate at doses ranging from 300 mg/day to 2,400 mg/day on postnatal days 3 to 6. in 4 patients who were taking valproate only, breast milk contained an average valproate concentration of 1.8 mcg/ml (range: 1.1 mcg/ml to 2.2 mcg/ml), which corresponded to 4.8% of the maternal plasma concentration (range: 2.7% to 7.4%). across all patients (7 of whom were taking other aeds concomitantly), similar results were obtained for breast milk concentration  (1.8 mcg/ml, range: 0.4 mcg/ml to 3.9 mcg/ml) and maternal plasma ratio (5.1%, range: 1.3% to 9.6%). a published study of 6 breastfeeding mother-infant pairs measured serum valproate levels during maternal treatment for bipolar disorder (750 mg/day or 1,000 mg/day). none of the mothers received valproate during pregnancy, and infants were aged from 4 weeks to 19 weeks at the time of evaluation. infant serum levels ranged from 0.7 mcg/ml to 1.5 mcg/ml. with maternal serum valproate levels near or within the therapeutic range, infant exposure was 0.9% to 2.3% of maternal levels. similarly, in 2 published case reports with maternal doses of 500 mg/day or 750 mg/day during breastfeeding of infants aged 3 months and 1 month, infant exposure was 1.5% and 6% that of the mother, respectively. a prospective observational multicenter study evaluated the long-term neurodevelopmental effects of aed use on children. pregnant women receiving monotherapy for epilepsy were enrolled with assessments of their children at ages 3 years and 6 years. mothers continued aed therapy during the breastfeeding period. adjusted iqs measured at 3 years for breastfed and non-breastfed children were 93 (n=11) and 90 (n=24), respectively. at 6 years, the scores for breastfed and non-breastfed children were 106 (n=11) and 94 (n=25), respectively (p=0.04). for other cognitive domains evaluated at 6 years, no adverse cognitive effects of continued exposure to an aed (including valproate) via breast milk were observed. contraception women of childbearing potential should use effective contraception while taking valproate [see boxed warning, warnings and precautions (5.4), drug interactions (7)  and use in specific populations (8.1)] . this is especially important when valproate use is considered for a condition not usually associated with permanent injury or death such as prophylaxis of migraine headaches [see contraindications (4)] . infertility there have been reports of male infertility coincident with valproate therapy [see adverse reactions (6.4)] . in animal studies, oral administration of valproate at clinically relevant doses resulted in adverse reproductive effects in males [see nonclinical toxicology (13.1)] . experience has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions [see boxed warning  and warnings and precautions (5.1)] . when divalproex sodium extended-release is used in this patient group, it should be used with extreme caution and as a sole agent. the benefits of therapy should be weighed against the risks. above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. younger children, especially those receiving enzyme inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproate concentrations. pediatric patients (i.e. between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e. ml/min/kg) than do adults. over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. the variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations. interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding. pediatric clinical trials divalproex sodium delayed-release was studied in seven pediatric clinical trials. two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the efficacy of divalproex sodium extended-release for the indications of mania (150 patients aged 10 to 17 years, 76 of whom were on divalproex sodium extended-release) and migraine (304 patients aged 12 to 17 years, 231 of whom were on divalproex sodium extended-release). efficacy was not established for either the treatment of migraine or the treatment of mania. the most common drug-related adverse reactions (reported >5% and twice the rate of placebo) reported in the controlled pediatric mania study were nausea, upper abdominal pain, somnolence, increased ammonia, gastritis and rash. the remaining five trials were long term safety studies. two six-month pediatric studies were conducted to evaluate the long-term safety of divalproex sodium extended-release for the indication of mania (292 patients aged 10 to 17 years). two twelve-month pediatric studies were conducted to evaluate the long-term safety of divalproex sodium extended-release for the indication of migraine (353 patients aged 12 to 17 years). one twelve-month study was conducted to evaluate the safety of divalproex sodium sprinkle capsules in the indication of partial seizures (169 patients aged 3 to 10 years). in these seven clinical trials, the safety and tolerability of divalproex sodium delayed-release in pediatric patients were shown to be comparable to those in adults [see adverse reactions (6)] . juvenile animal toxicology in studies of valproate in immature animals, toxic effects not observed in adult animals included retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods. the no-effect dose for these findings was less than the maximum recommended human dose on a mg/m2 basis. no patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. in a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. a higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. discontinuation of valproate was occasionally associated with the latter two events. it is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients. a study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence [see warnings and precautions (5.14)] . the starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence [see dosage and administration (2.5)] . there is insufficient information available to discern the safety and effectiveness of valproate for the prophylaxis of migraines in patients over 65. the capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced compared to younger adults (age range: 22 to 26 years) [see clinical pharmacology (12.3)] . liver disease liver disease impairs the capacity to eliminate valproate [see boxed warning, contraindications (4), warnings and precautions (5.1), and clinical pharmacology (12.3)] .

Ameerika Ühendriigid - inglise - NLM (National Library of Medicine)

avkare - lamotrigine (unii: u3h27498ks) (lamotrigine - unii:u3h27498ks) - lamotrigine 25 mg - adjunctive therapy lamotrigine tablets are indicated as adjunctive therapy for the following seizure types in patients aged 2 years and older: - partial-onset seizures. - primary generalized tonic-clonic (pgtc) seizures. - generalized seizures of lennox-gastaut syndrome. monotherapy lamotrigine tablets are indicated for conversion to monotherapy in adults (aged 16 years and older) with partial-onset seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug (aed). safety and effectiveness of lamotrigine have not been established (1) as initial monotherapy; (2) for conversion to monotherapy from aeds other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate; or (3) for simultaneous conversion to monotherapy from 2 or more concomitant aeds. lamotrigine tablets are indicated for the maintenance treatment of bipolar i disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixe

Ameerika Ühendriigid - inglise - NLM (National Library of Medicine)

vistapharm, inc. - hydrocodone bitartrate (unii: no70w886kk) (hydrocodone - unii:6yks4y3wq7), acetaminophen (unii: 362o9itl9d) (acetaminophen - unii:362o9itl9d) - hydrocodone bitartrate 7.5 mg in 15 ml - hydrocodone bitartrate and acetaminophen oral solution is indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. limitations of use because of the risks of addiction, abuse, and misuse, with opioids, even at recommended doses [see warnings ], reserve hydrocodone bitartrate and acetaminophen oral solution for use in patients for whom alternative treatment options (e.g., non-opioid analgesics): - have not been tolerated, or are not expected to be tolerated - have not provided adequate analgesia, or are not expected to provide adequate analgesia hydrocodone bitartrate and acetaminophen oral solution is contraindicated in patients with: - significant respiratory depression [see warnings ] - acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see warnings ] - known or suspected gastrointestinal obstruction, including paralytic ileus [see warnings ] - hypersensitivity to hydrocodone o

Ameerika Ühendriigid - inglise - NLM (National Library of Medicine)

kvk-tech,inc - oxycodone hydrochloride (unii: c1enj2te6c) (oxycodone - unii:cd35pmg570) - oxycodone hydrochloride 5 mg - oxycodone hydrochloride tablets are indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. limitations of use because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses [see  warnings and precautions ( 5.1)] , reserve oxycodone hydrochloride tablets for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or opioid combination products): - have not been tolerated or are not expected to be tolerated, - have not provided adequate analgesia or are not expected to provide adequate analgesia. oxycodone hydrochloride tablets are contraindicated in patients with: - significant respiratory depression [see warnings and precautions ( 5.2)] - acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment or hypercarbia [see warnings and precautions ( 5.6)] - known or suspected gastrointestinal obstruction, including paralytic ileus [see warnings and precautions ( 5.10)] - known hypersensitivity (e.g., anaphylaxis) to oxycodone [see adverse reactions ( 6.2)] risk summary prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see warnings and precautions ( 5.3)] . available data with oxycodone hydrochloride tablets in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. animal reproduction studies with oral administrations of oxycodone hcl in rats and rabbits during the period of organogenesis at doses 2.6 and 8.1 times, respectively, the human dose of 60 mg/day did not reveal evidence of teratogenicity or embryo-fetal toxicity. in several published studies, treatment of pregnant rats with oxycodone at clinically relevant doses and below, resulted in neurobehavioral effects in offspring [see data] . based on animal data, advise pregnant women of the potential risk to a fetus. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations fetal/neonatal adverse reactions prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. neonatal opioid withdrawal syndrome presents irritability, hyperactivity, and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. the onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid use, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see warnings and precautions ( 5.3)] . labor or delivery opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. an opioid antagonist such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. oxycodone hydrochloride tablets are not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. opioid analgesics, including oxycodone hydrochloride tablets, can prolong labor through actions which temporarily reduce the strength, duration and frequency of uterine contractions. however, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. data animal data in embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of oxycodone hcl administered during the period of organogenesis up to 16 mg/kg/day and up to 25 mg/kg/day, respectively. these studies revealed no evidence of teratogenicity or embryo-fetal toxicity due to oxycodone. the highest doses tested in rats and rabbits were equivalent to approximately 2.6 and 8.1 times an adult human dose of 60 mg/day, respectively, on a mg/m 2 basis. in published studies, offspring of pregnant rats administered oxycodone during gestation have been reported to exhibit neurobehavioral effects including altered stress responses, increased anxiety-like behavior (2 mg/kg/day iv from gestation day 8 to 21 and postnatal day 1, 3, and 5; 0.3-times an adult human dose of 60 mg/day, on a mg/m 2 basis) and altered learning and memory (15 mg/kg/day orally from breeding through parturition; 2.4 times an adult human dose of 60 mg/day, on a mg/m 2 basis). risk summary oxycodone is present in breast milk. published lactation studies report variable concentrations of oxycodone in breast milk with administration of immediate-release oxycodone to nursing mothers in the early postpartum period. the lactation studies did not assess breastfed infants for potential adverse reactions. lactation studies have not been conducted with oxycodone hydrochloride tablets, and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for oxycodone hydrochloride tablets and any potential adverse effects on the breastfed infant from oxycodone hydrochloride tablets or from the underlying maternal condition. clinical considerations infants exposed to oxycodone hydrochloride tablets through breast milk should be monitored for excess sedation and respiratory depression. withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped or when breast-feeding is stopped. infertility chronic use of opioids may cause reduced fertility in females and males of reproductive potential. it is not known whether these effects on fertility are reversible [see adverse reactions ( 6.2), clinical pharmacology ( 12.2)]. the safety and efficacy of oxycodone hydrochloride tablets in pediatric patients have not been evaluated. of the total number of subjects in clinical studies of oxycodone hydrochloride tablets, 20.8% (112/538) were 65 and over, while 7.2% (39/538) were 75 and over. no overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. elderly patients (aged 65 years or older) may have increased sensitivity to oxycodone. in general, use caution when selecting a dosage for an elderly patient, 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. respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. titrate the dosage of oxycodone hydrochloride tablets slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see warnings and precautions ( 5.6)] . oxycodone is known to be substantially excreted by the kidney, and the risk of adverse 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 it may be useful to monitor renal function. because oxycodone is extensively metabolized in the liver, its clearance may decrease in patients with hepatic impairment. initiate therapy in these patients with a lower than usual dosage of oxycodone hydrochloride tablets and titrate carefully. monitor closely for adverse events such as respiratory depression, sedation, and hypotension [see clinical pharmacology ( 12.3)] . because oxycodone is known to be substantially excreted by the kidney, its clearance may decrease in patients with renal impairment. initiate therapy with a lower than usual dosage of oxycodone hydrochloride tablets and titrate carefully. monitor closely for adverse events such as respiratory depression, sedation, and hypotension [see clinical pharmacology ( 12.3)] . oxycodone hydrochloride tablets contains oxycodone, a schedule ii controlled substance. oxycodone hydrochloride tablets contains oxycodone, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxymorphone, and tapentadol. oxycodone hydrochloride tablets can be abused and is subject to misuse, addiction, and criminal diversion [see warnings and precautions ( 5.1)]. all patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. “drug-seeking” behavior is very common in persons with substance use disorders. drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. abuse and addiction are separate and distinct from physical dependence and tolerance. healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. in addition, abuse of opioids can occur in the absence of true addiction. oxycodone hydrochloride tablets, like other opioids, can be diverted for non-medical use into illicit channels of distribution. careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. risks specific to abuse of oxycodone hydrochloride tablets oxycodone hydrochloride tablets is for oral use only. abuse of oxycodone hydrochloride tablets poses a risk of overdose and death. the risk is increased with concurrent abuse of oxycodone hydrochloride tablets with alcohol and other central nervous system depressants. parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and hiv. both tolerance and physical dependence can develop during chronic opioid therapy. tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. oxycodone hydrochloride tablets should not be abruptly discontinued in a physically-dependent patient [see dosage and administration ( 2.4)]. if oxycodone hydrochloride tablets are abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur. some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see use in specific populations ( 8.1)] .

Ameerika Ühendriigid - inglise - NLM (National Library of Medicine)

trupharma, llc - paroxetine hydrochloride anhydrous (unii: 3i3t11ud2s) (paroxetine - unii:41vrh5220h) - paroxetine 10 mg - major depressive disorder: paroxetine tablets are indicated for the treatment of major depressive disorder. the efficacy of paroxetine tablets 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 in hospitalized depressed patients have not been adequately studied.

Ameerika Ühendriigid - inglise - NLM (National Library of Medicine)

ajanta pharma usa inc. - risperidone (unii: l6uh7zf8hc) (risperidone - unii:l6uh7zf8hc) - risperidone 0.25 mg - risperidone tablets are indicated for the treatment of schizophrenia. efficacy was established in 4 short-term trials in adults, 2 short-term trials in adolescents (ages 13 to 17 years), and one long-term maintenance trial in adults [see clinical studies (14.1)] . monotherapy risperidone tablets are indicated for the treatment of acute manic or mixed episodes associated with bipolar i disorder. efficacy was established in 2 short-term trials in adults and one short-term trial in children and adolescents (ages 10 to 17 years) [see clinical studies (14.2)] .  adjunctive therapy risperidone tablets adjunctive therapy with lithium or valproate is indicated for the treatment of acute manic or mixed episodes associated with bipolar i disorder. efficacy was established in one short-term trial in adults [see clinical studies (14.3)] . risperidone tablets are indicated for the treatment of irritability associated with autistic disorder, including symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods. efficacy was established in 3 short-term trials in children and adolescents (ages 5 to 17 years)  [see clinical studies (14.4)] . risperidone tablets are contraindicated in patients with a known hypersensitivity to either risperidone or paliperidone, or to any of the excipients in the risperidone tablets formulation. hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone. paliperidone is a metabolite of risperidone. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including risperidone, during pregnancy. healthcare providers are encouraged to register patients by contacting the national pregnancy registry for atypical antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/ . risk summary neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see clinical considerations) . overall, available data from published epidemiologic studies of pregnant women exposed to risperidone have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see data). there are risks to the mother associated with untreated schizophrenia or bipolar i disorder and with exposure to antipsychotics, including risperidone, during pregnancy (see clinical considerations) . oral administration of risperidone to pregnant mice caused cleft palate at doses 3 to 4 times the maximum recommended human dose (mrhd) with maternal toxicity observed at 4-times mrhd based on mg/m2 body surface area. risperidone was not teratogenic in rats or rabbits at doses up to 6-times the mrhd based on mg/m2 body surface area. increased stillbirths and decreased birth weight occurred after oral risperidone administration to pregnant rats at 1.5-times the mrhd based on mg/m2 body surface area. learning was impaired in offspring of rats when the dams were dosed at 0.6-times the mrhd and offspring mortality increased at doses 0.1 to 3 times the mrhd based on mg/m2 body surface area. 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 2-4% and 15-20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk there is a risk to the mother from untreated schizophrenia or bipolar i disorder, including increased risk of relapse, hospitalization, and suicide. schizophrenia and bipolar i disorder are associated with increased adverse perinatal outcomes, including preterm birth. it is not known if this is a direct result of the illness or other comorbid factors. fetal/neonatal adverse reactions extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including risperidone, during the third trimester of pregnancy. these symptoms have varied in severity. monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. data human data published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. a prospective observational study including 6 women treated with risperidone demonstrated placental passage of risperidone. a retrospective cohort study from a medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. there was a small increase in the risk of major birth defects (rr=1.26, 95% ci 1.02-1.56) and of cardiac malformations (rr=1.26, 95% ci 0.88-1.81) in a subgroup of 1566 women exposed to risperidone during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates. animal data oral administration of risperidone to pregnant mice during organogenesis caused cleft palate at 10 mg/kg/day which is 3 times the mrhd of 16 mg/day based on mg/m2 body surface area: maternal toxicity occurred at 4 times the mrhd. risperidone was not teratogenic when administered orally to rats at 0.6 to 10 mg/kg/day and rabbits at 0.3 to 5 mg/kg/day, which are up to 6 times the mrhd of 16 mg/day risperidone based on mg/m2 body surface area. learning was impaired in offspring of rats dosed orally throughout pregnancy at 1 mg/kg/day which is 0.6 times the mrhd and neuronal cell death increased in fetal brains of offspring of rats dosed during pregnancy at 1 and 2 mg/kg/day which are 0.6 and 1.2 times the mrhd based on mg/m2 body surface area; postnatal development and growth of the offspring were also delayed. rat offspring mortality increased during the first 4 days of lactation when pregnant rats were dosed throughout gestation at 0.16 to 5 mg/kg/day which are 0.1 to 3 times the mrhd of 16 mg/day based on mg/m2 body surface area. it is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams; a no-effect dose could not be determined. the rate of stillbirths was increased at 2.5 mg/kg or 1.5 times the mrhd based on mg/m2 body surface area. in a rat cross-fostering study the number of live offspring was decreased, the number of stillbirths increased, and the birth weight was decreased in offspring of drug-treated pregnant rats. in addition, the number of deaths increased by day 1 among offspring of drug-treated pregnant rats, regardless of whether or not the offspring were cross-fostered. risperidone also appeared to impair maternal behavior in that offspring body weight gain and survival (from day 1 to 4 of lactation) were reduced in offspring born to control but reared by drug-treated dams. all of these effects occurred at 5 mg/kg which is 3 times the mrhd based on mg/m2 and the only dose tested in the study. risk summary limited data from published literature reports the presence of risperidone and its metabolite, 9-hydroxyrisperidone, in human breast milk at relative infant dose ranging between 2.3% and 4.7% of the maternal weight-adjusted dosage. there are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to risperidone (see clinical considerations). there is no information on the effects of risperidone on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for risperidone  and any potential adverse effects on the breastfed child from risperidone or from the mother’s underlying condition. clinical considerations infants exposed to risperidone through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements). infertility females based on the pharmacologic action of risperidone (d2 receptor antagonism), treatment with risperidone may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see warnings and precautions (5.6)]. approved pediatric indications schizophrenia the efficacy and safety of risperidone tablets in the treatment of schizophrenia were demonstrated in 417 adolescents, aged 13 to 17 years, in two short-term (6 and 8 weeks, respectively) double-blind controlled trials [see indications and usage (1.1), adverse reactions (6.1), and clinical studies (14.1)] . additional safety and efficacy information was also assessed in one long-term (6-month) open-label extension study in 284 of these adolescent patients with schizophrenia. safety and effectiveness of risperidone tablets in children less than 13 years of age with schizophrenia have not been established. bipolar i disorder the efficacy and safety of risperidone tablets in the short-term treatment of acute manic or mixed episodes associated with bipolar i disorder in 169 children and adolescent patients, aged 10 to 17 years, were demonstrated in one double-blind, placebo-controlled, 3-week trial [see indications and usage (1.2), adverse reactions (6.2), and clinical studies (14.2)] . safety and effectiveness of risperidone tablets in children less than 10 years of age with bipolar disorder have not been established. autistic disorder the efficacy and safety of risperidone tablets in the treatment of irritability associated with autistic disorder were established in two 8-week, double-blind, placebo-controlled trials in 156 children and adolescent patients, aged 5 to 16 years [see indications and usage (1.3), adverse reactions (6.1) and clinical studies (14.4)] . additional safety information was also assessed in a long-term study in patients with autistic disorder, or in short- and long-term studies in more than 1200 pediatric patients with psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania who were of similar age and weight, and who received similar dosages of risperidone tablets as patients treated for irritability associated with autistic disorder. a third study was a 6-week, multicenter, randomized, double-blind, placebo-controlled, fixed-dose study to evaluate the efficacy and safety of a lower than recommended dose of risperidone in subjects 5 to 17 years of age with autistic disorder and associated irritability, and related behavioral symptoms. there were two weight-based, fixed doses of risperidone (high-dose and low-dose). the high dose was 1.25 mg per day for patients weighing 20 to < 45 kg, and it was 1.75 mg per day for patients weighing ≥ 45 kg.the low dose was 0.125 mg per day for patients weighing 20 to < 45 kg, and it was 0.175 mg per day for patients weighing ≥ 45 kg. the study demonstrated the efficacy of high-dose risperidone, but it did not demonstrate efficacy for low-dose risperidone. adverse reactions in pediatric patients tardive dyskinesia in clinical trials in 1885 children and adolescents treated with risperidone tablets, 2 (0.1%) patients were reported to have tardive dyskinesia, which resolved on discontinuation of risperidone tablets treatment [see also warnings and precautions (5.4)] . weight gain weight gain has been observed in children and adolescents during treatment with risperidone tablets. clinical monitoring of weight is recommended during treatment. data derive from short-term placebo-controlled trials and longer-term uncontrolled studies in pediatric patients (ages 5 to 17 years) with schizophrenia, bipolar disorder, autistic disorder, or other psychiatric disorders. in the short-term trials (3 to 8 weeks), the mean weight gain for risperidone tablets-treated patients was 2 kg, compared to 0.6 kg for placebo-treated patients. in these trials, approximately 33% of the risperidone tablets group had weight gain ≥7%, compared to 7% in the placebo group. in longer-term, uncontrolled, open-label pediatric studies, the mean weight gain was 5.5 kg at week 24 and 8 kg at week 48 [see warnings and precautions (5.5) and adverse reactions (6.1)]. somnolence somnolence was frequently observed in placebo-controlled clinical trials of pediatric patients with autistic disorder. most cases were mild or moderate in severity. these events were most often of early onset with peak incidence occurring during the first two weeks of treatment, and transient with a median duration of 16 days. somnolence was the most commonly observed adverse reaction in the clinical trial of bipolar disorder in children and adolescents, as well as in the schizophrenia trials in adolescents. as was seen in the autistic disorder trials, these adverse reactions were most often of early onset and transient in duration [see adverse reactions (6.1, 6.2)] . patients experiencing persistent somnolence may benefit from a change in dosing regimen [see dosage & administration (2.1, 2.2, and 2.3)] . hyperprolactinemia risperidone tablets have been shown to elevate prolactin levels in children and adolescents as well as in adults [see warnings and precautions (5.6)] . in double-blind, placebo-controlled studies of up to 8 weeks duration in children and adolescents (aged 5 to 17 years) with autistic disorder or psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania, 49% of patients who received risperidone tablets had elevated prolactin levels compared to 2% of patients who received placebo. similarly, in placebo-controlled trials in children and adolescents (aged 10 to 17 years) with bipolar disorder, or adolescents (aged 13 to 17 years) with schizophrenia, 82–87% of patients who received risperidone tablets had elevated levels of prolactin compared to 3–7% of patients on placebo. increases were dose-dependent and generally greater in females than in males across indications. in clinical trials in 1885 children and adolescents, galactorrhea was reported in 0.8% of risperidone tablets-treated patients and gynecomastia was reported in 2.3% of risperidone tablets-treated patients. growth and sexual maturation the long-term effects of risperidone tablets on growth and sexual maturation have not been fully evaluated in children and adolescents. juvenile animal studies juvenile dogs were treated with oral risperidone from weeks 10 to 50 of age (equivalent to the period of childhood through adolescence in humans), at doses of 0.31, 1.25, or 5 mg/kg/day, which are 1.2, 3.4, and 13.5 times the mrhd of  6 mg/day for children, based on mg/m2 body surface area. bone length and density were decreased with a no-effect dose of 0.31 mg/kg/day; this dose produced plasma auc of risperidone plus its active metabolite paliperidone (9-hydroxy-risperidone) that were similar to those in children and adolescents receiving the mrhd of 6 mg/day. in addition, sexual maturation was delayed at all doses in both males and females. the above effects showed little or no reversibility in females after a 12 week drug-free recovery period. juvenile rats, treated with oral risperidone from days 12 to 50 of age (equivalent to the period of infancy through adolescence in humans) showed impaired learning and memory performance (reversible only in females), with a no-effect dose of 0.63 mg/kg/day which is 0.5 times the mrhd of 6 mg/day for children, based on mg/m2 body surface area. this dose produced plasma auc of risperidone plus paliperidone about half the exposure observed in humans at the mrhd. no other consistent effects on neurobehavioral or reproductive development were seen up to the highest tested dose of 1.25 mg/kg/day which is 1 time the mrhd and produced plasma auc of risperidone plus paliperidone that were about two thirds of those observed in humans at the mrhd of 6 mg/day for children. clinical studies of risperidone tablets in the treatment of schizophrenia did not include sufficient numbers of patients aged 65 and over to determine whether or not they respond differently than younger patients. other reported clinical experience has not identified differences in responses between elderly and younger patients. in general, a lower starting dose is recommended for an elderly patient, reflecting a decreased pharmacokinetic clearance in the elderly, as well as a greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see clinical pharmacology (12.3) and dosage & administration (2.4, 2.5)] . while elderly patients exhibit a greater tendency to orthostatic hypotension, its risk in the elderly may be minimized by limiting the initial dose to 0.5 mg twice daily followed by careful titration [see warnings and precautions (5.7)] . monitoring of orthostatic vital signs should be considered in patients for whom this is of concern. this drug is substantially excreted by the kidneys, 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 it may be useful to monitor renal function [see dosage & administration (2.4)] . in patients with moderate to severe (clcr 59 to 15 ml/min) renal disease, clearance of the sum of risperidone and its active metabolite decreased by 60%, compared to young healthy subjects. risperidone tablets doses should be reduced in patients with renal disease [see dosage and administration (2.4)] . while the pharmacokinetics of risperidone in subjects with liver disease were comparable to those in young healthy subjects, the mean free fraction of risperidone in plasma was increased by about 35% because of the diminished concentration of both albumin and α1 -acid glycoprotein. risperidone tablets doses should be reduced in patients with liver disease [see dosage and administration (2.4)] . patients with parkinsons disease or dementia with lewy bodies can experience increased sensitivity to risperidone tablets. manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome. risperidone tablets are not a controlled substance. risperidone tablets have not been systematically studied in animals or humans for its potential for abuse. while the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a cns-active drug will be misused, diverted, and/or abused once marketed. consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of risperidone tablets misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior). risperidone tablets have not been systematically studied in animals or humans for its potential for tolerance or physical dependence.