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

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

a-s medication solutions - diazepam (unii: q3jtx2q7tu) (diazepam - unii:q3jtx2q7tu) - diazepam tablets usp are indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety. anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. in acute alcohol withdrawal, diazepam may be useful in the symptomatic relief of acute agitation, tremor, impending or acute delirium tremens and hallucinosis. diazepam is a useful adjunct for the relief of skeletal muscle spasm due to reflex spasm to local pathology (such as inflammation of the muscles or joints, or secondary to trauma); spasticity caused by upper motor neuron disorders (such as cerebral palsy and paraplegia); athetosis; and stiff-man syndrome. oral diazepam may be used adjunctively in convulsive disorders, although it has not proved useful as the sole therapy. the effectiveness of diazepam in long-term use, that is, more than 4 months, has not been assessed by systematic clinical studies. the physician should periodically reassess the usefulness

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

a-s medication solutions - diazepam (unii: q3jtx2q7tu) (diazepam - unii:q3jtx2q7tu) - diazepam tablets are indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety. anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. in acute alcohol withdrawal, diazepam tablets may be useful in the symptomatic relief of acute agitation, tremor, impending or acute delirium tremens and hallucinosis. diazepam is a useful adjunct for the relief of skeletal muscle spasm due to reflex spasm to local pathology (such as inflammation of the muscles or joints, or secondary to trauma), spasticity caused by upper motor neuron disorders (such as cerebral palsy and paraplegia), athetosis, and stiff-man syndrome. oral diazepam may be used adjunctively in convulsive disorders, although it has not proved useful as the sole therapy. the effectiveness of diazepam in long-term use, that is, more than 4 months, has not been assessed by systematic clinical studies. the physician should periodically reassess the usefulness of the drug for the individual patient. diazepam tablets are contraindicated in patients with a known hypersensitivity to diazepam and, because of lack of sufficient clinical experience, in pediatric patients under 6 months of age. diazepam tablets are also contraindicated in patients with myasthenia gravis, severe respiratory insufficiency, severe hepatic insufficiency, and sleep apnea syndrome. they may be used in patients with open-angle glaucoma who are receiving appropriate therapy, but are contraindicated in acute narrow-angle glaucoma. diazepam tablets contain diazepam, a schedule iv controlled substance. diazepam is a benzodiazepine and a cns depressant with a potential for abuse and addiction. 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. drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. abuse and misuse of benzodiazepines may lead to addiction. abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death. benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders (see warnings: abuse, misuse, and addiction ). the following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo. the following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. death is more often associated with polysubstance use (especially benzodiazepines with other cns depressants such as opioids and alcohol). diazepam may produce physical dependence from continued therapy. 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. abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses), those who have had longer durations of use (see warnings: dependence and withdrawal reactions ). to reduce the risk of withdrawal reactions, use a gradual taper to discontinue diazepam tablets or reduce the dosage (see dosage and administration: discontinuation or dosage reduction of diazepam tablets  and warnings: dependence and withdrawal reactions ). acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. more severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality. protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. protracted withdrawal symptoms may last weeks to more than 12 months. as a result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used. tolerance to diazepam may develop from continued therapy. tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). tolerance to the therapeutic effect of diazepam may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

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a-s medication solutions - citalopram hydrobromide (unii: i1e9d14f36) (citalopram - unii:0dhu5b8d6v) - citalopram tablets are indicated for the treatment of major depressive disorder (mdd) in adults [see clinical studies (14)] . citalopram tablets are contraindicated in patients: - taking, or within 14 days of stopping, maois (including maois such as linezolid or intravenous methylene blue) because of an increased risk of serotonin syndrome [see warnings and precautions (5.3), drug interactions (7)] . - taking pimozide because of risk of qt prolongation [see drug interactions (7)] . - with known hypersensitivity to citalopram or any of the inactive ingredients in citalopram tablets. reactions have included angioedema and anaphylaxis [see adverse reactions (6.2)]. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. healthcare providers are encouraged to register patients by calling the national pregnancy registry for antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/antidepressants . risk summary based on data from published observational studies, exposure to ssris, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see warnings and precautions (5.4) and clinical considerations]. available data from published epidemiologic studies and postmarketing reports with citalopram use in pregnancy have not established an increased risk of major birth defects or miscarriage. published studies demonstrated that citalopram levels in both cord blood and amniotic fluid are similar to those observed in maternal serum. there are risks of persistent pulmonary hypertension of the newborn (pphn) (see data) and/or poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (ssris), including citalopram, during pregnancy. there also are risks associated with untreated depression in pregnancy (see clinical considerations) .   in animal reproduction studies, citalopram caused adverse embryo/fetal effects at doses that caused maternal toxicity (see data) .   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 the clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.   clinical considerations disease-associated maternal and/or embryo/fetal risk women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. this finding is from a prospective longitudinal study of 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. maternal adverse reactions use of citalopram in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see warnings and precautions (5.4)].   fetal/neonatal adverse reactions neonates exposed to citalopram and other ssris late in third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. such complications can arise immediately upon delivery. reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. these findings are consistent with either a direct toxic effect of ssris or possibly, a drug discontinuation syndrome. it should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see warnings and precautions (5.3)] . data human data exposure during late pregnancy to ssris may have an increased risk for persistent pulmonary hypertension of the newborn (pphn). pphn occurs in 1 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. animal data citalopram was administered orally to pregnant rats during the period of organogenesis at doses of 32, 56, and 112 mg/kg/day, which are approximately 8, 14, and 27 times the maximum recommended human dose (mrhd) of 40 mg, based on mg/m2   body surface area. citalopram caused maternal toxicity of cns clinical signs and decreased weight gain at 112 mg/kg/day, which is 27 times the mrhd. at this maternally toxic dose, citalopram decreased embryo/fetal growth and survival and increased fetal abnormalities (including cardiovascular and skeletal defects). the no observed adverse effect level (noael) for maternal and embryofetal toxicity is 56 mg/kg/day, which is approximately 14 times the mrhd. citalopram was administered orally to pregnant rabbits during the period of organogenesis at doses up to 16 mg/kg/day, which is approximately 8 times the mrhd of 40 mg, based on mg/m2 body surface area. no maternal or embryofetal toxicity was observed. the noael for maternal and embryofetal toxicity is 16 mg/kg/day, which is approximately 8 times the mrhd. citalopram was administered orally to pregnant rats during late gestation and lactation periods at doses of 4.8, 12.8, and 32 mg/kg/day, which are approximately 1, 3, and 8 times the mrhd of 40 mg, based on mg/m2 body surface area. citalopram increased offspring mortality during the first 4 days of birth and decreased offspring growth at 32 mg/kg/day, which is approximately 8 times the mrhd. the noael for developmental toxicity is 12.8 mg/kg/day, which is approximately 3 times the mrhd. in a separate study, similar effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses ≥ 24 mg/kg/day, which is approximately 6 times the mrhd. a noael was not determined in that study. risk summary data from the published literature report the presence of citalopram in human milk at relative infant doses ranging between 0.7 to 9.4% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.78 to 4.3. there are reports of breastfed infants exposed to citalopram experiencing irritability, restlessness, excessive somnolence, decreased feeding, and weight loss (see clinical considerations). there is no information about effects of citalopram on milk production.   the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for citalopram and any potential adverse effects on the breastfed child from citalopram or from the underlying maternal condition.   clinical considerations monitor breastfeeding infants for adverse reactions, such as irritability, restlessness, excessive somnolence, decreased feeding, and weight loss. the safety and effectiveness of citalopram have not been established in pediatric patients. two placebo-controlled trials in 407 pediatric patients with mdd have been conducted with citalopram, and the data were not sufficient to support use in pediatric patients.   antidepressants increase the risk of suicidal thoughts and behaviors in pediatric patients [see boxed warning, warnings and precautions (5.1)] . decreased appetite and weight loss have been observed in association with the use of ssris in pediatric patients. of 4422 patients in clinical studies of citalopram, 1357 were 60 and over, 1034 were 65 and over, and 457 were 75 and over. in two pharmacokinetic studies, citalopram auc was increased by 23% and 30%, respectively, in subjects ≥ 60 years of age as compared to younger subjects, and its half-life was increased by 30% and 50%, respectively [see clinical pharmacology (12.3)] . therefore, the maximum recommended dosage in patients 60 years of age and older is lower than younger patients [see dosage and administration (2.3), warnings and precautions (5.2)] .   ssris, including citalopram, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see warnings and precautions (5.9)] . increased citalopram exposure occurs in patients with hepatic impairment. the maximum recommended dosage of citalopram is lower in patients with hepatic impairment [see dosage and administration (2.3), clinical pharmacology (12.3)]. citalopram hydrobromide is not a controlled substance. animal studies suggest that the abuse liability of citalopram is low. citalopram has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. the premarketing clinical experience with citalopram did not reveal any drug-seeking behavior. however, 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, health care providers should carefully evaluate citalopram patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse (e.g., development of tolerance, incrementations of dose, drug-seeking behavior).

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a-s medication solutions - dabigatran etexilate mesylate (unii: sc7nuw5iit) (dabigatran - unii:i0vm4m70gc) - pradaxa is indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. pradaxa is indicated for the treatment of deep venous thrombosis and pulmonary embolism in patients who have been treated with a parenteral anticoagulant for 5-10 days. pradaxa is indicated to reduce the risk of recurrence of deep venous thrombosis and pulmonary embolism in patients who have been previously treated. pradaxa is indicated for the prophylaxis of deep vein thrombosis and pulmonary embolism, in patients who have undergone hip replacement surgery. pradaxa is contraindicated in patients with: - active pathological bleeding [see warnings and precautions (5.2) and adverse reactions (6.1)] . - history of a serious hypersensitivity reaction to pradaxa (e.g., anaphylactic reaction or anaphylactic shock) [see adverse reactions (6.1)] . - mechanical prosthetic heart valve [see warnings and precautions (5.4)]. risk summary the limited available data on pradaxa use in pregnant wo

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a-s medication solutions - diclofenac sodium (unii: qtg126297q) (diclofenac - unii:144o8ql0l1) - diclofenac sodium topical solution is indicated for the treatment of signs and symptoms of osteoarthritis of the knee(s) (1). diclofenac sodium topical solution is contraindicated in the following patients: - known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac or any components of the drug product. [see warnings and precautions (5.7, 5.9)] - history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other nsaids. severe, sometimes fatal, anaphylactic reactions to nsaids have been reported in such patients [see warnings and precautions (5.7, 5.8)] - in the setting of coronary artery bypass graft (cabg) surgery [see warnings and precautions (5.1)] . pregnancy category c prior to 30 weeks gestation; category d starting 30 weeks gestation risk summary use of nsaids, including diclofenac sodium topical solution , during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. avoid use of nsai

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a-s medication solutions - diazepam (unii: q3jtx2q7tu) (diazepam - unii:q3jtx2q7tu) - diazepam tablets are indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety. anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. in acute alcohol withdrawal, diazepam tablets may be useful in the symptomatic relief of acute agitation, tremor, impending or acute delirium tremens and hallucinosis. diazepam tablets are a useful adjunct for the relief of skeletal muscle spasm due to reflex spasm to local pathology (such as inflammation of the muscles or joints, or secondary to trauma), spasticity caused by upper motor neuron disorders (such as cerebral palsy and paraplegia), athetosis, and stiff-man syndrome. oral diazepam tablets may be used adjunctively in convulsive disorders, although it has not proved useful as the sole therapy. the effectiveness of diazepam tablets in long-term use, that is, more than 4 months, has not been assessed by systematic clinical studies. the physician should periodically reassess the usefulness of the drug for the individual patient. diazepam tablets are contraindicated in patients with a known hypersensitivity to diazepam and, because of lack of sufficient clinical experience, in pediatric patients under 6 months of age. diazepam tablets are also contraindicated in patients with myasthenia gravis, severe respiratory insufficiency, severe hepatic insufficiency, and sleep apnea syndrome. they may be used in patients with open-angle glaucoma who are receiving appropriate therapy, but is contraindicated in acute narrow-angle glaucoma. diazepam tablets contain diazepam, a schedule iv controlled substance. diazepam tablets are a benzodiazepine and a cns depressant with a potential for abuse and addiction. 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. drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. abuse and misuse of benzodiazepines may lead to addiction. abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death. benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders (see warnings: abuse, misuse, and addiction). the following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo. the following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. death is more often associated with polysubstance use (especially benzodiazepines with other cns depressants such as opioids and alcohol). diazepam tablets may produce physical dependence from continued therapy. 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. abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses), those who have had longer durations of use (see warnings: dependence and withdrawal reactions). to reduce the risk of withdrawal reactions, use a gradual taper to discontinue diazepam tablets or reduce the dosage (see dosage and administration: discontinuation or dosage reduction of diazepam tablets and warnings: dependence and withdrawal reactions). acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. more severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality. protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. protracted withdrawal symptoms may last weeks to more than 12 months. as a result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines. tolerance to diazepam tablets may develop from continued therapy. tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). tolerance to the therapeutic effect of diazepam tablets may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

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a-s medication solutions - naproxen (unii: 57y76r9atq) (naproxen - unii:57y76r9atq) - naproxen tablets are indicated for: the relief of the signs and symptoms of: - rheumatoid arthritis - osteoarthritis - ankylosing spondylitis - polyarticular juvenile idiopathic arthritis - tendonitis - bursitis - acute gout the management of: - pain - primary dysmenorrhea naproxen tablets are contraindicated in the following patients: - known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to naproxen or any components of the drug product [see warnings and precautions (5.7, 5.9)] - history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other nsaids. severe, sometimes fatal, anaphylactic reactions to nsaids have been reported in such patients [see warnings and precautions (5.7, 5.8)] - in the setting of coronary artery bypass graft (cabg) surgery [see warnings and precautions (5.1)] r isk summary use of nsaids, including naproxen, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. because of these risks, limit dose and duration of naproxen use between about 20 and 30 weeks of gestation, and avoid naproxen use at about 30 weeks of gestation  and later in pregnancy (see clinical considerations, data). premature closure of fetal ductus arteriosus use of nsaids, including naproxen, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. oligohydramnios/neonatal renal impairment use of nsaids at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. data from observational studies regarding other potential embryofetal risks of nsaid use in women in the first or second trimesters of pregnancy are inconclusive. in animal reproduction studies in rats, rabbits, and mice no evidence of teratogenicity or fetal harm when naproxen was administered during the period of organogenesis at doses 0.13, 0.26, and 0.6 times the maximum recommended human daily dose of 1,500 mg/day, respectively [see data] . based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. in animal studies, administration of prostaglandin synthesis inhibitors such as naproxen, resulted in increased pre- and post-implantation loss. prostaglandins also have been shown to have an important role in fetal kidney development. in published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. the estimated background risk of major birth defects and miscarriage for the indicated population(s) 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. c linical considerations fetal/neonatal adverse reactions premature closure of fetal ductus arteriosus: avoid use of nsaids in women at about 30 weeks gestation and later in pregnancy, because nsaids, including naproxen, can cause premature closure of the fetal ductus arteriosus (see data ). oligohydramnios/neonatal renal impairment: if an nsaid is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. if naproxen treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. if oligohydramnios occurs, discontinue naproxen, and follow up according to clinical practice (see data ). labor or delivery there are no studies on the effects of naproxen during labor or delivery. in animal studies, nsaids, including naproxen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. data human data there is some evidence to suggest that when inhibitors of prostaglandin synthesis are used to delay preterm labor, there is an increased risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus, and intracranial hemorrhage. naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction, and abnormal prostaglandin e levels in preterm infants. because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly starting at 30-weeks of gestation, or third trimester) should be avoided. premature closure of fetal ductus arteriosus: published literature reports that the use of nsaids at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. oligohydramnios/neonatal renal impairment: published studies and postmarketing reports describe maternal nsaid use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. these adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after nsaid initiation. in many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. there have been a limited number of case reports of maternal nsaid use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. these limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal nsaid use. because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to nsaids through maternal use is uncertain. an imal data reproduction studies have been performed in rats at 20 mg/kg/day (0.13 times the maximum recommended human daily dose of 1,500 mg/day based on body surface area comparison), rabbits at 20 mg/kg/day (0.26 times the maximum recommended human daily dose, based on body surface area comparison), and mice at 170 mg/kg/day (0.6 times the maximum recommended human daily dose based on body surface area comparison) with no evidence of impaired fertility or harm to the fetus due to the drug. r isk summary the naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for naproxen and any potential adverse effects on the breastfed infant from the naproxen or from the underlying maternal condition. i n f ertility f emales based on the mechanism of action, the use of prostaglandin-mediated nsaids, including naproxen, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. small studies in women treated with nsaids have also shown a reversible delay in ovulation. consider withdrawal of nsaids, including naproxen, in women who have difficulties conceiving or who are undergoing investigation of infertility. safety and effectiveness in pediatric patients below the age of 2 years have not been established. pediatric dosing recommendations for polyarticular juvenile idiopathic arthritis are based on well-controlled studies [see dosage and administration (2)] . there are no adequate effectiveness or dose-response data for other pediatric conditions, but the experience in polyarticular juvenile idiopathic arthritis and other use experience have established that single doses of 2.5 to 5 mg/kg as naproxen suspension, with total daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric patients over 2 years of age. the hepatic and renal tolerability of long-term naproxen administration was studied in two double-blind clinical trials involving 586 patients. of the patients studied, 98 patients were age 65 and older and 10 of the 98 patients were age 75 and older. naproxen was administered at doses of 375 mg twice daily or 750 mg twice daily for up to 6 months. transient abnormalities of laboratory tests assessing hepatic and renal function were noted in some patients, although there were no differences noted in the occurrence of abnormal values among different age groups. elderly patients, compared to younger patients, are at greater risk for nsaid-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. if the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see warnings and precautions (5.1, 5.2, 5.3, 5.6, 5.14)]. studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. the clinical significance of this finding is unclear, although it is possible that the increase in free naproxen concentration could be associated with an increase in the rate of adverse events per a given dosage in some elderly patients. caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. as with other drugs used in the elderly, it is prudent to use the lowest effective dose. experience indicates that geriatric patients may be particularly sensitive to certain adverse effects of nonsteroidal anti-inflammatory drugs. elderly or debilitated patients seem to tolerate peptic ulceration or bleeding less well when these events do occur. most spontaneous reports of fatal gi events are in the geriatric population [see warnings and precautions (5.2)] . naproxen 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 it may be useful to monitor renal function [see clinical pharmacology (12.3)] . geriatric patients may be at a greater risk for the development of a form of renal toxicity precipitated by reduced prostaglandin formation during administration of nonsteroidal anti-inflammatory drugs [see warnings and precautions (5.6)] . caution is advised when high doses are required and some adjustment of dosage may be required in these patients. it is prudent to use the lowest effective dose [see clinical pharmacology (12.3)] . naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance < 30 ml/min) [see warnings and precautions (5.6), clinical pharmacology (12.3)] .

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

a-s medication solutions - rivaroxaban (unii: 9ndf7jz4m3) (rivaroxaban - unii:9ndf7jz4m3) - xarelto is indicated to reduce the risk of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation. there are limited data on the relative effectiveness of xarelto and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well-controlled [see clinical studies (14.1)]. xarelto is indicated for the treatment of deep vein thrombosis (dvt). xarelto is indicated for the treatment of pulmonary embolism (pe). xarelto is indicated for the reduction in the risk of recurrence of dvt and/or pe in adult patients at continued risk for recurrent dvt and/or pe after completion of initial treatment lasting at least 6 months. xarelto is indicated for the prophylaxis of dvt, which may lead to pe in adult patients undergoing knee or hip replacement surgery. xarelto is indicated for the prophylaxis of venous thromboembolism (vte) and vte related death during hospitalization and post hospital discharge in adult patients admitted for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for vte and not at high risk of bleeding [see warnings and precautions (5.2) and clinical studies (14.5)] . xarelto, in combination with aspirin, is indicated to reduce the risk of major cardiovascular events (cardiovascular death, myocardial infarction, and stroke) in adult patients with coronary artery disease. xarelto, in combination with aspirin, is indicated to reduce the risk of major thrombotic vascular events (myocardial infarction, ischemic stroke, acute limb ischemia, and major amputation of a vascular etiology) in adult patients with pad, including patients who have recently undergone a lower extremity revascularization procedure due to symptomatic pad. xarelto is indicated for the treatment of venous thromboembolism (vte) and the reduction in the risk of recurrent vte in pediatric patients from birth to less than 18 years after at least 5 days of initial parenteral anticoagulant treatment. xarelto is indicated for thromboprophylaxis in pediatric patients aged 2 years and older with congenital heart disease who have undergone the fontan procedure. xarelto is contraindicated in patients with: - active pathological bleeding [see warnings and precautions (5.2)] - severe hypersensitivity reaction to xarelto (e.g., anaphylactic reactions) [see adverse reactions (6.2)] risk summary the limited available data on xarelto in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. use xarelto with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery. the anticoagulant effect of xarelto cannot be reliably monitored with standard laboratory testing. consider the benefits and risks of xarelto for the mother and possible risks to the fetus when prescribing xarelto to a pregnant woman [see warnings and precautions (5.2, 5.7)] . adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. the estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. 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 pregnancy is a risk factor for venous thromboembolism and that risk is increased in women with inherited or acquired thrombophilias. pregnant women with thromboembolic disease have an increased risk of maternal complications including pre-eclampsia. maternal thromboembolic disease increases the risk for intrauterine growth restriction, placental abruption and early and late pregnancy loss. fetal/neonatal adverse reactions based on the pharmacologic activity of factor xa inhibitors and the potential to cross the placenta, bleeding may occur at any site in the fetus and/or neonate. labor or delivery all patients receiving anticoagulants, including pregnant women, are at risk for bleeding and this risk may be increased during labor or delivery [see warnings and precautions (5.7)]. the risk of bleeding should be balanced with the risk of thrombotic events when considering the use of xarelto in this setting. data human data there are no adequate or well-controlled studies of xarelto in pregnant women, and dosing for pregnant women has not been established. post-marketing experience is currently insufficient to determine a rivaroxaban-associated risk for major birth defects or miscarriage. in an in vitro placenta perfusion model, unbound rivaroxaban was rapidly transferred across the human placenta. animal data rivaroxaban crosses the placenta in animals. rivaroxaban increased fetal toxicity (increased resorptions, decreased number of live fetuses, and decreased fetal body weight) when pregnant rabbits were given oral doses of ≥10 mg/kg rivaroxaban during the period of organogenesis. this dose corresponds to about 4 times the human exposure of unbound drug, based on auc comparisons at the highest recommended human dose of 20 mg/day. fetal body weights decreased when pregnant rats were given oral doses of 120 mg/kg during the period of organogenesis. this dose corresponds to about 14 times the human exposure of unbound drug. in rats, peripartal maternal bleeding and maternal and fetal death occurred at the rivaroxaban dose of 40 mg/kg (about 6 times maximum human exposure of the unbound drug at the human dose of 20 mg/day). risk summary rivaroxaban has been detected in human milk. there are insufficient data to determine the effects of rivaroxaban on the breastfed child or on milk production. rivaroxaban and/or its metabolites were present in the milk of rats. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for xarelto and any potential adverse effects on the breastfed infant from xarelto or from the underlying maternal condition (see data) . data animal data following a single oral administration of 3 mg/kg of radioactive [ 14 c]-rivaroxaban to lactating rats between day 8 to 10 postpartum, the concentration of total radioactivity was determined in milk samples collected up to 32 hours post-dose. the estimated amount of radioactivity excreted with milk within 32 hours after administration was 2.1% of the maternal dose. females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician. the risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions, identified with oral anticoagulants including xarelto should be assessed in females of reproductive potential and those with abnormal uterine bleeding. the safety and effectiveness of xarelto have been established in pediatric patients from birth to less than 18 years for the treatment of vte and the reduction in risk of recurrent vte. use of xarelto is supported in these age groups by evidence from adequate and well-controlled studies of xarelto in adults with additional pharmacokinetic, safety and efficacy data from a multicenter, prospective, open-label, active-controlled randomized study in 500 pediatric patients from birth to less than 18 years of age. xarelto was not studied and therefore dosing cannot be reliably determined or recommended in children less than 6 months who were less than 37 weeks of gestation at birth; had less than 10 days of oral feeding, or had a body weight of less than 2.6 kg [see dosage and administration (2.2), adverse reactions (6.1), clinical pharmacology (12.3) and clinical studies (14.8)] . the safety and effectiveness of xarelto have been established for use in pediatric patients aged 2 years and older with congenital heart disease who have undergone the fontan procedure. use of xarelto is supported in these age groups by evidence from adequate and well-controlled studies of xarelto in adults with additional data from a multicenter, prospective, open-label, active controlled study in 112 pediatric patients to evaluate the single- and multiple-dose pharmacokinetic properties of xarelto and the safety and efficacy of xarelto when used for thromboprophylaxis for 12 months in children with single ventricle physiology who had the fontan procedure [see dosage and administration (2.2), adverse reactions (6.1), clinical pharmacology (12.3) and clinical studies (14.9)] . clinical studies that evaluated safety, efficacy, pharmacokinetic and pharmacodynamic data support the use of xarelto 10 mg, 15 mg, and 20 mg tablets in pediatric patients. for the xarelto 2.5 mg tablets, there are no safety, efficacy, pharmacokinetic and pharmacodynamic data to support the use in pediatric patients. therefore, xarelto 2.5 mg tablets are not recommended for use in pediatric patients. although not all adverse reactions identified in the adult population have been observed in clinical trials of children and adolescent patients, the same warnings and precautions for adults should be considered for children and adolescents. of the total number of adult patients in clinical trials for the approved indications of xarelto (n=64,943 patients), 64 percent were 65 years and over, with 27 percent 75 years and over. in clinical trials the efficacy of xarelto in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. both thrombotic and bleeding event rates were higher in these older patients [see clinical pharmacology (12.3) and clinical studies (14)] . in pharmacokinetic studies, compared to healthy adult subjects with normal creatinine clearance, rivaroxaban exposure increased by approximately 44 to 64% in adult subjects with renal impairment. increases in pharmacodynamic effects were also observed [see clinical pharmacology (12.3)] . nonvalvular atrial fibrillation patients with chronic kidney disease not on dialysis in the rocket af trial, patients with crcl 30 to 50 ml/min were administered xarelto 15 mg once daily resulting in serum concentrations of rivaroxaban and clinical outcomes similar to those in patients with better renal function administered xarelto 20 mg once daily. patients with crcl <30 ml/min were not studied, but administration of xarelto 15 mg once daily is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment [see clinical pharmacology (12.3)] . patients with end-stage renal disease on dialysis clinical efficacy and safety studies with xarelto did not enroll patients with end-stage renal disease (esrd) on dialysis. in patients with esrd maintained on intermittent hemodialysis, administration of xarelto 15 mg once daily will result in concentrations of rivaroxaban and pharmacodynamic activity similar to those observed in the rocket af study [see clinical pharmacology (12.2, 12.3)] . it is not known whether these concentrations will lead to similar stroke reduction and bleeding risk in patients with esrd on dialysis as was seen in rocket af. treatment of dvt and/or pe and reduction in the risk of recurrence of dvt and/or pe in the einstein trials, patients with crcl values <30 ml/min at screening were excluded from the studies, but administration of xarelto is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment (crcl 30 to <50 ml/min) [see clinical pharmacology (12.3)]. observe closely and promptly evaluate any signs or symptoms of blood loss in patients with crcl 15 to <30 ml/min. avoid the use of xarelto in patients with crcl <15 ml/min. prophylaxis of dvt following hip or knee replacement surgery the combined analysis of the record 1–3 clinical efficacy studies did not show an increase in bleeding risk for patients with crcl 30 to 50 ml/min and reported a possible increase in total venous thromboemboli in this population. in the record 1–3 trials, patients with crcl values <30 ml/min at screening were excluded from the studies, but administration of xarelto 10 mg once daily is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment (crcl 30 to <50 ml/min) [see clinical pharmacology (12.3)]. observe closely and promptly evaluate any signs or symptoms of blood loss in patients with crcl 15 to <30 ml/min. avoid the use of xarelto in patients with crcl <15 ml/min. prophylaxis of venous thromboembolism in acutely ill medical patients at risk for thromboembolic complications not at high risk of bleeding patients with crcl values <30 ml/min at screening were excluded from the magellan study. in patients with crcl <30 ml/min a dose of xarelto 10 mg once daily is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment (crcl 30 to <50 ml/min) [see clinical pharmacology (12.3)] . observe closely and promptly evaluate any signs or symptoms of blood loss in patients with crcl 15 to <30 ml/min. avoid use of xarelto in patients with crcl <15 ml/min. reduction of risk of major cardiovascular events in patients with cad and reduction of risk of major thrombotic vascular events in patients with pad, including patients after recent lower extremity revascularization due to symptomatic pad patients with chronic kidney disease not on dialysis patients with a crcl <15 ml/min at screening were excluded from compass and voyager, and limited data are available for patients with a crcl of 15 to 30 ml/min. in patients with crcl <30 ml/min, a dose of 2.5 mg xarelto twice daily is expected to give an exposure similar to that in patients with moderate renal impairment (crcl 30 to <50 ml/min) [see clinical pharmacology (12.3)] , whose efficacy and safety outcomes were similar to those with preserved renal function. patients with end-stage renal disease on dialysis no clinical outcome data is available for the use of xarelto with aspirin in patients with esrd on dialysis since these patients were not enrolled in compass or voyager. in patients with esrd maintained on intermittent hemodialysis, administration of xarelto 2.5 mg twice daily will result in concentrations of rivaroxaban and pharmacodynamic activity similar to those observed in moderate renal impaired patients in the compass study [see clinical pharmacology (12.2, 12.3)] . it is not known whether these concentrations will lead to similar cv risk reduction and bleeding risk in patients with esrd on dialysis as was seen in compass. pediatric use no dosage adjustment is required in patients 1 year of age or older with mild renal impairment (egfr 50 to ≤ 80 ml/min/1.73 m 2 ). there are limited clinical data in pediatric patients 1 year or older with moderate or severe renal impairment (egfr <50 ml/min/1.73 m 2 ); therefore, avoid the use of xarelto in these patients. there are no clinical data in pediatric patients younger than 1 year with serum creatinine results above 97.5 th percentile; therefore, avoid the use of xarelto in these patients [see dosage and administration (2.2)] . in a pharmacokinetic study, compared to healthy adult subjects with normal liver function, auc increases of 127% were observed in adult subjects with moderate hepatic impairment (child-pugh b). the safety or pk of xarelto in patients with severe hepatic impairment (child-pugh c) has not been evaluated [see clinical pharmacology (12.3)] . avoid the use of xarelto in patients with moderate (child-pugh b) and severe (child-pugh c) hepatic impairment or with any hepatic disease associated with coagulopathy. no clinical data are available in pediatric patients with hepatic impairment. this instructions for use contains information on how to give a dose of xarelto oral suspension. read this instructions for use before giving xarelto and each time you get a refill. there may be new information. this leaflet does not take the place of talking with your doctor about your child's medical condition or treatment. important information: - xarelto suspension is for oral use only. - give xarelto to your child exactly as prescribed by your doctor. the adult caregiver should give the dose. if you have questions, contact your doctor or pharmacist for more information on giving a dose. - only use the oral dosing syringe provided with xarelto oral suspension. contact your doctor or pharmacist if the oral dosing syringe is missing, lost or damaged. storage information store xarelto oral suspension at room temperature between 68°f to 77°f (20°c to 25°c). do not freeze. store the bottle upright with the oral dosing syringes in the original carton. keep xarelto and all medicines out of reach of children. xarelto oral dosing syringe: xarelto bottle check "discard after" date on the xarelto bottle. if "discard after" date has passed, do not use and call your doctor or pharmacist. wash hands. wash your hands well with soap and warm water. shake bottle slowly for 10 seconds before each use. check xarelto oral suspension. if there are lumps or granules at the bottom of the bottle, shake the bottle slowly again for 10 seconds . find your dose line. you can use either side of the syringe to set your dose. if using ml side of syringe: top of the plunger should line up with the prescribed ml. if using color side of syringe: top of the plunger should line up with the prescribed ml dose line at the bottom of the color band. if your dose is more than 5 ml. you will need to use the same syringe more than one time. repeat steps 4 and 5 to complete your dose. ask your pharmacist if you are not sure. push plunger all the way in to remove air. insert oral dosing syringe into bottle adaptor. twist off the cap from the bottle. do not remove the bottle adaptor from the bottle. insert the syringe tip into the bottle adaptor. fill oral dosing syringe. turn the bottle upside down, as shown. pull the plunger to fill the oral dosing syringe slightly past your prescribed dose line to help remove any air bubbles. caution: make sure you have enough medicine for a full dose. do not take a partial dose. tap syringe to move air bubbles to the top. doing this helps set the correct dose. adjust to your prescribed dose. if using ml side of syringe: push plunger to align with the prescribed dose line. if using color side of syringe: push plunger to align with the prescribed ml dose line at the bottom of the color band. remove oral dosing syringe. place the bottle on a flat surface. remove the oral dosing syringe from the bottle. give the dose. place the oral dosing syringe gently into the child's mouth with the tip of the syringe pointing toward the cheek and slowly press the plunger. this allows the child to swallow naturally. make sure the child swallows the full dose. if your child vomits or spits out the medicine repeatedly, contact your child's doctor right away. close xarelto bottle and rinse oral dosing syringe. rinse the oral dosing syringe with tap water and let it air dry. disposing xarelto bottle and syringe - throw the xarelto bottle away in your household trash. - throw away any used oral dosing syringe with the opening of a new xarelto bottle. - do not pour xarelto suspension down the drain (for example: sink, toilet, shower or tub). - do not recycle the bottle. manufactured for: janssen pharmaceuticals, inc. titusville, nj 08560 licensed from: bayer healthcare ag 51368 leverkusen, germany for patent information: www.janssenpatents.com © 2021 janssen pharmaceutical companies this instructions for use has been approved by the u.s. food and drug administration. issued: 02/2023

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

a-s medication solutions - canagliflozin (unii: 0sac974z85) (canagliflozin anhydrous - unii:6s49dgr869) - invokana (canagliflozin) is indicated: - as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. - to reduce the risk of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction and nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease (cvd). - to reduce the risk of end-stage kidney disease (eskd), doubling of serum creatinine, cardiovascular (cv) death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria greater than 300 mg/day. limitations of use invokana is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus [see warnings and precautions (5.1)] . invokana is not recommended for use to improve glycemic control in adults with type 2 diabetes mellitus with an egfr less than 30 ml/min/1.73 m 2 . invokana is likely to be ineffective in this setting based upon its mechanism of action. invokana is contraindicated in patients with a serious hypersensitivity reaction to invokana, such as anaphylaxis or angioedema [see warnings and precautions (5.8)and adverse reactions (6.1, 6.2)] . risk summary based on animal data showing adverse renal effects, invokana is not recommended during the second and third trimesters of pregnancy. limited data with invokana in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. there are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see clinical considerations]. in animal studies, adverse renal pelvic and tubule dilatations that were not reversible were observed in rats when canagliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy, at an exposure 0.5-times the 300 mg clinical dose, based on auc. the estimated background risk of major birth defects is 6–10% in women with pre-gestational diabetes with a hba 1c >7 and has been reported to be as high as 20–25% in women with a hba 1c >10. the estimated background risk of miscarriage for the indicated population is unknown. 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 poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. animal data canagliflozin dosed directly to juvenile rats from postnatal day (pnd) 21 until pnd 90 at doses of 4, 20, 65, or 100 mg/kg increased kidney weights and dose dependently increased the incidence and severity of renal pelvic and tubular dilatation at all doses tested. exposure at the lowest dose was greater than or equal to 0.5-times the 300 mg clinical dose, based on auc. these outcomes occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimester of human renal development. the renal pelvic dilatations observed in juvenile animals did not fully reverse within a 1-month recovery period. in embryo-fetal development studies in rats and rabbits, canagliflozin was administered for intervals coinciding with the first trimester period of organogenesis in humans. no developmental toxicities independent of maternal toxicity were observed when canagliflozin was administered at doses up to 100 mg/kg in pregnant rats and 160 mg/kg in pregnant rabbits during embryonic organogenesis or during a study in which maternal rats were dosed from gestation day (gd) 6 through pnd 21, yielding exposures up to approximately 19-times the 300 mg clinical dose, based on auc. risk summary there is no information regarding the presence of invokana in human milk, the effects on the breastfed infant, or the effects on milk production. canagliflozin is present in the milk of lactating rats [see data] . since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney. because of the potential for serious adverse reactions in a breastfed infant, advise women that use of invokana is not recommended while breastfeeding. data animal data radiolabeled canagliflozin administered to lactating rats on day 13 post-partum was present at a milk/plasma ratio of 1.40, indicating that canagliflozin and its metabolites are transferred into milk at a concentration comparable to that in plasma. juvenile rats directly exposed to canagliflozin showed a risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. safety and effectiveness of invokana in pediatric patients under 18 years of age have not been established. in 13 clinical trials of invokana, 2,294 patients 65 years and older, and 351 patients 75 years and older were exposed to invokana [see clinical studies (14.1)] . patients 65 years and older had a higher incidence of adverse reactions related to reduced intravascular volume with invokana (such as hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300 mg daily dose, compared to younger patients; a more prominent increase in the incidence was seen in patients who were 75 years and older [see dosage and administration (2.1)and adverse reactions (6.1)]. smaller reductions in hba 1c with invokana relative to placebo were seen in older (65 years and older; -0.61% with invokana 100 mg and -0.74% with invokana 300 mg relative to placebo) compared to younger patients (-0.72% with invokana 100 mg and -0.87% with invokana 300 mg relative to placebo). the efficacy and safety of invokana for glycemic control were evaluated in a trial that included patients with moderate renal impairment (egfr 30 to less than 50 ml/min/1.73 m 2 ) [see clinical studies (14.1)] . these patients had less overall glycemic efficacy, and patients treated with 300 mg per day had increases in serum potassium, which were transient and similar by the end of study. patients with renal impairment using invokana for glycemic control may also be more likely to experience hypotension and may be at higher risk for acute kidney injury [see warnings and precautions (5.3)] . efficacy and safety studies with invokana did not enroll patients with eskd on dialysis or patients with an egfr less than 30 ml/min/1.73 m 2 [see clinical pharmacology (12.3)] . no dosage adjustment is necessary in patients with mild or moderate hepatic impairment. the use of invokana has not been studied in patients with severe hepatic impairment and is therefore not recommended [see clinical pharmacology (12.3)] .