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janssen pharmaceuticals, inc. - canagliflozin (unii: 0sac974z85) (canagliflozin anhydrous - unii:6s49dgr869), metformin hydrochloride (unii: 786z46389e) (metformin - unii:9100l32l2n) - canagliflozin anhydrous 50 mg - invokamet and invokamet xr are a combination of canagliflozin and metformin hcl indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. canagliflozin is indicated 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). canagliflozin is indicated 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 invokamet or invokamet xr is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus [see warnings and precautions (5.2)] . invokamet or invokamet xr is contraindicated in patients: - with severe renal impairment (egfr less than 30 ml/min/1.73 m 2 ) [see warnings and precautions (5.1)and use in specific populations (8.6)] . - with acute or chronic metabolic acidosis, including diabetic ketoacidosis [see warnings and precautions (5.2)] . - with serious hypersensitivity reaction to canagliflozin or metformin hcl, such as anaphylaxis or angioedema [see warnings and precautions (5.9)and adverse reactions (6)] . risk summary based on animal data showing adverse renal effects from canagliflozin, invokamet or invokamet xr is not recommended during the second and third trimesters of pregnancy. limited data with invokamet, invokamet xr or canagliflozin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. published studies with metformin hcl use during pregnancy have not reported a clear association with metformin hcl and major birth defect or miscarriage risk [see data]. there are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see clinical considerations]. in animal studies, adverse renal pelvic and tubule dilatations that were not reversible were observed in rats when canagliflozin was administered at an exposure 0.5-times the 300 mg clinical dose, based on auc during a period of renal development corresponding to the late second and third trimesters of human pregnancy. no adverse developmental effects were observed when metformin hcl was administered to pregnant sprague dawley rats and rabbits during the period of organogenesis at doses up to 2- and 6-times, respectively, a 2000 mg clinical dose, based on body surface area [see data] . the estimated background risk of major birth defects is 6–10% in women with pre-gestational diabetes with an 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. data human data published data from post-marketing studies have not reported a clear association with metformin hcl and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin hcl was used during pregnancy. however, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups. animal data canagliflozin 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. metformin hcl metformin hcl did not cause adverse developmental effects when administered to pregnant sprague dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis. this represents an exposure of about 2- and 6-times a 2000 mg clinical dose based on body surface area (mg/m 2 ) for rats and rabbits, respectively. canagliflozin and metformin hcl no adverse developmental effects were observed when canagliflozin and metformin hcl were co-administered to pregnant rats during the period of organogenesis at exposures up to 11 and 13 times, respectively, the 300 mg and 2000 mg clinical doses of canagliflozin and metformin hcl based on auc. risk summary there is no information regarding the presence of invokamet, invokamet xr or canagliflozin in human milk, the effects on the breastfed infant, or the effects on milk production. limited published studies report that metformin is present in human milk [see data] . however, there is insufficient information on the effects of metformin hcl on the breastfed infant and no available information on the effects of metformin hcl 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 invokamet or invokamet xr is not recommended while breastfeeding. data published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. however, the studies were not designed to definitely establish the risk of use of metformin hcl during lactation because of small sample size and limited adverse event data collected in infants. 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. discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin hcl may result in ovulation in some anovulatory women. safety and effectiveness of invokamet or invokamet xr in pediatric patients under 18 years of age have not been established. invokamet and invokamet xr because renal function abnormalities can occur after initiating canagliflozin, metformin is substantially excreted by the kidney, and aging can be associated with reduced renal function, monitor renal function more frequently after initiating invokamet or invokamet xr in the elderly and then adjust dose based on renal function [see dosage and administration (2.4)and warnings and precautions (5.1, 5.4)] . canagliflozin in 13 clinical trials of canagliflozin, 2,294 patients 65 years and older, and 351 patients 75 years and older were exposed to canagliflozin. of these patients, 1,534 patients 65 years and older and 196 patients 75 years and older were exposed to the combination of canagliflozin and metformin hcl [see clinical studies (14)] . patients 65 years and older had a higher incidence of adverse reactions related to reduced intravascular volume with canagliflozin (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 canagliflozin relative to placebo were seen in older (65 years and older; -0.61% with canagliflozin 100 mg and -0.74% with canagliflozin 300 mg relative to placebo) compared to younger patients (-0.72% with canagliflozin 100 mg and -0.87% with canagliflozin 300 mg relative to placebo). metformin hcl controlled clinical trials of metformin hcl did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and younger patients. the initial and maintenance dosing of metformin hcl should be conservative in patients with advanced age due to the potential for decreased renal function in this population. any dose adjustment should be based on a careful assessment of renal function [see contraindications (4), warnings and precautions (5.4), and clinical pharmacology (12.3)] . canagliflozin the efficacy and safety of canagliflozin 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 ). these patients had less overall glycemic efficacy, and patients treated with canagliflozin 300 mg per day had increases in serum potassium, which were transient and similar by the end of study. patients with renal impairment using canagliflozin 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 (5.4)] . efficacy and safety studies with canagliflozin 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)] . metformin hcl metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. invokamet or invokamet xr is contraindicated in severe renal impairment (egfr less than 30 ml/min/1.73 m 2 ) or in patients on dialysis [see dosage and administration (2.4), contraindications (4), warnings and precautions (5.1), and clinical pharmacology (12.3)]. use of metformin hcl in patients with hepatic impairment has been associated with some cases of lactic acidosis. invokamet or invokamet xr is not recommended in patients with hepatic impairment [see warnings and precautions (5.1)].

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janssen pharmaceuticals inc. - esketamine hydrochloride (unii: l8p1h35p2z) (esketamine - unii:50lfg02txd) - spravato ® is indicated, in conjunction with an oral antidepressant, for the treatment of: - treatment-resistant depression (trd) in adults - depressive symptoms in adults with major depressive disorder (mdd) with acute suicidal ideation or behavior limitations of use: - the effectiveness of spravato in preventing suicide or in reducing suicidal ideation or behavior has not been demonstrated [see clinical studies (14.2)] . use of spravato does not preclude the need for hospitalization if clinically warranted, even if patients experience improvement after an initial dose of spravato. - spravato is not approved as an anesthetic agent. the safety and effectiveness of spravato as an anesthetic agent have not been established. spravato is contraindicated in patients with: - aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial, and peripheral arterial vessels) or arteriovenous malformation [see warnings and precautions (5.7)] - history of intracere

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janssen pharmaceuticals, inc. - tapentadol hydrochloride (unii: 71204kii53) (tapentadol - unii:h8a007m585) - tapentadol 50 mg - nucynta (tapentadol) tablets are indicated for the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate in adults. 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 nucynta 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 nucynta 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 [see warnings and precautions (5.5)] - known or suspected gastrointestinal obstruction, including suspected paralytic ileus [see warnings and precauti

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janssen pharmaceuticals, inc. - levofloxacin (unii: 6gnt3y5lmf) (levofloxacin anhydrous - unii:rix4e89y14) - levofloxacin anhydrous 250 mg - levaquin® is indicated in adult patients for the treatment of nosocomial pneumonia due to methicillin-susceptible staphylococcus aureus , pseudomonas aeruginosa , serratia marcescens , escherichia coli , klebsiella pneumoniae , haemophilus influenzae , or streptococcus pneumoniae . adjunctive therapy should be used as clinically indicated. where pseudomonas aeruginosa is a documented or presumptive pathogen, combination therapy with an anti-pseudomonal β-lactam is recommended [see clinical studies (14.1)] . levaquin® is indicated in adult patients for the treatment of community-acquired pneumonia due to methicillin-susceptible staphylococcus aureus , streptococcus pneumoniae (including multi-drug-resistant streptococcus pneumoniae [mdrsp]), haemophilus influenzae , haemophilus parainfluenzae , klebsiella pneumoniae , moraxella catarrhalis , chlamydophila pneumoniae , legionella pneumophila , or mycoplasma pneumoniae [see dosage and administration (2.1) and clinical studies (14.2)] . mdrsp isolates are is

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janssen pharmaceuticals, inc - ponesimod (unii: 5g7akv2mkp) (ponesimod - unii:5g7akv2mkp) - ponvory is indicated for the treatment of relapsing forms of multiple sclerosis (ms), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. ponvory is contraindicated in patients who: - in the last 6 months, have experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (tia), decompensated heart failure requiring hospitalization, or class iii or iv heart failure [see warnings and precautions (5.2)] - have presence of mobitz type ii second-degree, third-degree atrioventricular (av) block, sick sinus syndrome, or sino-atrial block, unless patient has a functioning pacemaker [see warnings and precautions (5.2)] risk summary there are no adequate and well-controlled studies of ponvory in pregnant women. in animal studies, administration of ponesimod during pregnancy produced adverse effects on development, including embryo lethality and fetal malformations, in the absence of maternal toxic

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janssen pharmaceuticals, inc. - canagliflozin (unii: 0sac974z85) (canagliflozin anhydrous - unii:6s49dgr869) - canagliflozin anhydrous 100 mg - 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 i

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janssen pharmaceuticals, inc. - methylphenidate hydrochloride (unii: 4b3sc438hi) (methylphenidate - unii:207zz9qz49) - methylphenidate hydrochloride 18 mg - concerta is indicated for the treatment of attention deficit hyperactivity disorder (adhd) in children 6 years of age and older, adolescents, and adults up to the age of 65 [see clinical studies (14)] . hypersensitivity reactions, such as angioedema and anaphylactic reactions, have been observed in patients treated with concerta. therefore, concerta is contraindicated in patients known to be hypersensitive to methylphenidate or other components of the product [see adverse reactions (6.5)] . concerta is contraindicated during treatment with monoamine oxidase (mao) inhibitors, and also within a minimum of 14 days following discontinuation of a mao inhibitor (hypertensive crises may result) [see drug interactions (7.1)] . pregnancy category c methylphenidate has been shown to have teratogenic effects in rabbits when given in doses of 200 mg/kg/day, which is approximately 100 times and 40 times the maximum recommended human dose on a mg/kg and mg/m 2 basis

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janssen pharmaceuticals, inc. - fentanyl (unii: uf599785jz) (fentanyl - unii:uf599785jz) - fentanyl 12.5 ug in 1 h - duragesic is indicated for the management of pain in opioid-tolerant patients, severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. patients considered opioid-tolerant are those who are taking, for one week or longer, at least 60 mg morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid. limitations of use - because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release/long-acting opioid formulations [see warnings and precautions (5.1)] , reserve duragesic for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide suffi

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janssen pharmaceuticals, inc. - tapentadol hydrochloride (unii: 71204kii53) (tapentadol - unii:h8a007m585) - tapentadol 50 mg - nucynta er (tapentadol) is indicated for the management of: - pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate - neuropathic pain associated with diabetic peripheral neuropathy (dpn) severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. limitations of use - because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations [see warnings and precautions (5.1)] , reserve nucynta er for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. nucynta er is not indicated as an as-needed (prn) analgesic. - nucynta er is not indicated as an as-neede

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janssen pharmaceuticals, inc. - tramadol hydrochloride (unii: 9n7r477wck) (tramadol - unii:39j1lgj30j) - tramadol hydrochloride 50 mg - ultram is indicated in adults 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 ultram 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. ultram is contraindicated for: - all children younger than 12 years of age [see warnings and precautions (5.4)] . - postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see warnings and precautions (5.4)] . ultram is also contraindicated in patients with: - significant respiratory depression [see warnings and precautions (5.3)] . - acute or severe bronchial asthma in an unmonitored setting or in th