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

winthrop u.s, a business of sanofi-aventis u.s. llc - zolpidem tartrate (unii: wy6w63843k) (zolpidem - unii:7k383oqi23) - zolpidem tartrate 6.25 mg - zolpidem tartrate extended-release tablets are indicated for the short-term treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance (as measured by wake time after sleep onset). the clinical trials performed in support of efficacy were up to 3 weeks (using polysomnography measurement up to 2 weeks in both adult and elderly patients) and 24 weeks (using patient-reported assessment in adult patients only) in duration [see clinical studies (14)] . zolpidem tartrate extended-release tablets are contraindicated in patients - who have experienced complex sleep behaviors after taking zolpidem tartrate extended-release tablets [see warnings and precautions (5.1)]. - with known hypersensitivity to zolpidem. observed reactions include anaphylaxis and angioedema [see warnings and precautions (5.4)]. risk summary neonates born to mothers using zolpidem late in the third trimester of pregnancy have been reported to experience symptoms of respiratory depression and sedation [see clinical considerationsand data] . published data on the use of zolpidem during pregnancy have not reported a clear association with zolpidem and major birth defects [see data] . oral administration of zolpidem to pregnant rats and rabbits did not indicate a risk for adverse effects on fetal development at clinically relevant doses [see data] . the estimated background risk of major birth defects and miscarriage for the indicated populations are 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 fetal/neonatal adverse reactions zolpidem crosses the placenta and may produce respiratory depression and sedation in neonates. monitor neonates exposed to zolpidem tartrate extended-release tablets during pregnancy and labor for signs of excess sedation, hypotonia, and respiratory depression and manage accordingly. data human data published data from observational studies, birth registries, and case reports on the use of zolpidem during pregnancy do not report a clear association with zolpidem and major birth defects. there are limited postmarketing reports of severe to moderate cases of respiratory depression that occurred after birth in neonates whose mothers had taken zolpidem during pregnancy. these cases required artificial ventilation or intratracheal intubation. the majority of neonates recovered within hours to a few weeks after birth once treated. zolpidem has been shown to cross the placenta. animal data oral administration of zolpidem to pregnant rats during the period of organogenesis at 4, 20, and 100 mg base/kg/day, which are approximately 4, 20, and 100 times the maximum recommended human dose (mrhd) of 12.5 mg/day (10 mg zolpidem base) based on mg/m 2 body surface area, caused delayed fetal development (incomplete fetal skeletal ossification) at maternally toxic (ataxia) doses 20 and 100 times the mrhd based on mg/m 2 body surface area. oral administration of zolpidem to pregnant rabbits during the period of organogenesis at 1, 4, and 16 mg base/kg/day, which are approximately 2, 8, and 30 times the mrhd of 12.5 mg/day (10 mg zolpidem base) based on mg/m 2 body surface area, caused embryo-fetal death and delayed fetal development (incomplete fetal skeletal ossification) at a maternally toxic (decreased body weight gain) dose 30 times the mrhd based on mg/m 2 body surface area. oral administration of zolpidem to pregnant rats from day 15 of gestation through lactation at 4, 20, and 100 mg base/kg/day, which are approximately 4, 20, and 100 times the mrhd of 12.5 mg/day (10 mg zolpidem base) based on a mg/m 2 body surface area, delayed offspring growth and decreased survival at doses 20 and 100 times, respectively, the mrhd based on mg/m 2 body surface area. risk summary limited data from published literature report the presence of zolpidem in human milk. there are reports of excess sedation in infants exposed to zolpidem through breastmilk [see clinical considerations]. there is no information on the effects of zolpidem on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for zolpidem tartrate extended-release tablets and any potential adverse effects on the breastfed infant from zolpidem tartrate extended-release tablets or from the underlying maternal condition. clinical considerations infants exposed to zolpidem tartrate extended-release tablets through breastmilk should be monitored for excess sedation, hypotonia, and respiratory depression. a lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment and for 23 hours (approximately 5 elimination half-lives) after zolpidem tartrate extended-release tablets administration in order to minimize drug exposure to a breastfed infant. zolpidem tartrate extended-release tablets are not recommended for use in children. safety and effectiveness of zolpidem in pediatric patients below the age of 18 years have not been established. in an 8-week study in pediatric patients (aged 6–17 years) with insomnia associated with attention-deficit/hyperactivity disorder (adhd), an oral solution of zolpidem tartrate dosed at 0.25 mg/kg at bedtime did not decrease sleep latency compared to placebo. psychiatric and nervous system disorders comprised the most frequent (>5%) treatment-emergent adverse reactions observed with zolpidem versus placebo and included dizziness (23.5% vs 1.5%), headache (12.5% vs 9.2%), and hallucinations were reported in 7% of the pediatric patients who received zolpidem; none of the pediatric patients who received placebo reported hallucinations [see warnings and precautions (5.5)] . ten patients on zolpidem (7.4%) discontinued treatment due to an adverse reaction. fda has not required pediatric studies of zolpidem tartrate extended-release tablets in the pediatric population based on these efficacy and safety findings. a total of 99 elderly (≥65 years of age) received daily doses of 6.25 mg zolpidem tartrate extended-release tablets in a 3-week placebo-controlled study. the adverse reaction profile of zolpidem tartrate extended-release tablets 6.25 mg in this population was similar to that of zolpidem tartrate extended-release tablets 12.5 mg in younger adults (≤64 years of age). dizziness was reported in 8% of zolpidem tartrate extended-release tablets–treated patients compared with 3% of those treated with placebo. the dose of zolpidem tartrate extended-release tablets in elderly patients is 6.25 mg to minimize adverse effects related to impaired motor and/or cognitive performance and unusual sensitivity to sedative/hypnotic drugs [see warnings and precautions (5.2)] . women clear zolpidem tartrate from the body at a lower rate than men. c max and auc parameters of zolpidem from zolpidem tartrate extended-release tablets were, respectively, approximately 50% and 75% higher at the same dose in adult female subjects compared to adult male subjects. between 6 and 12 hours after dosing, zolpidem concentrations were 2 to 3 fold higher in adult female compared to adult male subjects. given the higher blood levels of zolpidem tartrate in women compared to men at a given dose, the recommended initial dose of zolpidem tartrate extended-release tablets for adult women is 6.25 mg, and the recommended dose for adult men is 6.25 or 12.5 mg. in geriatric patients, clearance of zolpidem is similar in men and women. the recommended dose of zolpidem tartrate extended-release tablets in geriatric patients is 6.25 mg regardless of gender. the recommended dose of zolpidem tartrate extended-release tablets in patients with mild to moderate hepatic impairment is 6.25 mg once daily immediately before bedtime. avoid zolpidem tartrate extended-release tablets use in patients with severe hepatic impairment as it may contribute to encephalopathy [see dosage and administration (2.2), warnings and precautions (5.8), clinical pharmacology (12.3)] . zolpidem tartrate is classified as a schedule iv controlled substance by federal regulation. abuse and addiction are separate and distinct from physical dependence and tolerance. abuse is characterized by misuse of the drug for non-medical purposes, often in combination with other psychoactive substances. tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug effects over time. tolerance may occur to both desired and undesired effects of drugs and may develop at different rates for different effects. addiction is a primary, chronic, neurobiological disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. it is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. drug addiction is a treatable disease, using a multidisciplinary approach, but relapse is common. studies of abuse potential in former drug abusers found that the effects of single doses of zolpidem tartrate 40 mg were similar, but not identical, to diazepam 20 mg, while zolpidem tartrate 10 mg effects were difficult to distinguish from placebo. because persons with a history of addiction to, or abuse of, drugs or alcohol are at increased risk for misuse, abuse and addiction of zolpidem, they should be monitored carefully when receiving zolpidem or any other hypnotic. use of zolpidem tartrate extended-release tablets may lead to development of physical and/or psychological dependence. this risk of dependence increases with dose and duration of treatment. the risk of abuse and dependence is also greater in patients with history of alcohol or drug abuse. zolpidem tartrate extended-release tablets should be used with extreme caution in patients with current or past alcohol or drug abuse. physical dependence is a state of adaptation that is manifested by a specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist. sedative/hypnotics have produced withdrawal signs and symptoms following abrupt discontinuation. these reported symptoms range from mild dysphoria and insomnia to a withdrawal syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors, convulsions, and delirium. the following adverse events, which are considered to meet the dsm-iii-r criteria for uncomplicated sedative/hypnotic withdrawal, were reported during zolpidem tartrate extended-release tablets clinical trials following placebo substitution occurring within 48 hours following last zolpidem treatment: fatigue, nausea, flushing, lightheadedness, uncontrolled crying, emesis, stomach cramps, panic attack, nervousness, and abdominal discomfort. these reported adverse events occurred at an incidence of 1% or less. however, available data cannot provide a reliable estimate of the incidence, if any, of dependence during treatment at recommended doses. there have been postmarketing reports of abuse, dependence and withdrawal with zolpidem.

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

winthrop u.s, a business of sanofi-aventis u.s. llc - insulin glargine (unii: 2zm8cx04rz) (insulin glargine - unii:2zm8cx04rz) - insulin glargine u-300 is indicated to improve glycemic control in adults and pediatric patients 6 years of age and older with diabetes mellitus. limitations of use: insulin glargine u-300 is not recommended for the treatment of diabetic ketoacidosis. insulin glargine u-300 is contraindicated: - during episodes of hypoglycemia [see warnings and precautions (5.3)] . - in patients with hypersensitivity to insulin glargine or any excipients in insulin glargine u-300 [see warnings and precautions (5.5)] . risk summary published studies with use of insulin glargine during pregnancy have not reported a clear association with insulin glargine and adverse developmental outcomes (see data) . there are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see clinical considerations) . rats and rabbits were exposed to insulin glargine in animal reproduction studies during organogenesis, respectively 50 times and 10 times the human subcutaneous dose of 0.2 unit/kg/day. overall, the effects of insulin glargine did not generally differ from those observed with regular human insulin (see data) . in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. the estimated background risk of major birth defects is 6% to 10% in women with pregestational diabetes with a peri-conceptional hba1c >7 and has been reported to be as high as 20% to 25% in women with a peri-conceptional hba1c >10. the estimated background risk of miscarriage for the indicated population is unknown. clinical considerations disease-associated maternal and/or embryo/fetal risk hypoglycemia and hyperglycemia occur more frequently during pregnancy in patients with pre-gestational diabetes. poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, 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 do not report a clear association with insulin glargine and major birth defects, miscarriage, or adverse maternal or fetal outcomes when insulin glargine is used during pregnancy. however, these studies cannot definitely establish the absence of any risk because of methodological limitations including small sample size and some lacking comparator groups. animal data subcutaneous reproduction and teratology studies have been performed with insulin glargine and regular human insulin in rats and himalayan rabbits. insulin glargine was given to female rats before mating, during mating, and throughout pregnancy at doses up to 0.36 mg/kg/day, which is approximately 50 times the recommended human subcutaneous starting dosage of 0.2 units/kg/day (0.007 mg/kg/day). in rabbits, doses of 0.072 mg/kg/day, which is approximately 10 times the recommended human subcutaneous starting dosage of 0.2 units/kg/day (0.007 mg/kg/day), were administered during organogenesis. the effects of insulin glargine did not generally differ from those observed with regular human insulin in rats or rabbits. however, in rabbits, five fetuses from two litters of the high-dose group exhibited dilation of the cerebral ventricles. fertility and early embryonic development appeared normal. risk summary there are either no or only limited data on the presence of insulin glargine in human milk, the effects on breastfed infant, or the effects on milk production. endogenous insulin is present in human milk. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for insulin glargine u-300, and any potential adverse effects on the breastfed child from insulin glargine u-300 or from the underlying maternal condition. the safety and effectiveness of insulin glargine u-300 to improve glycemic control in pediatric patients 6 years of age and older with diabetes mellitus have been established. the use of insulin glargine u-300 for this indication is supported by evidence from an adequate and well-controlled study in 463 pediatric patients 6 to 17 years of age with type 1 diabetes mellitus [see clinical studies (14.2)] and from studies in adults with diabetes mellitus [see clinical pharmacology (12.3), clinical studies (14.3)] . the safety and effectiveness of insulin glargine u-300 have not been established in pediatric patients less than 6 years of age. in controlled clinical studies, 30 of 304 (9.8%) insulin glargine-treated patients with type 1 diabetes and 327 of 1242 (26.3%) insulin glargine-treated patients with type 2 diabetes were ≥65 years of age, among them 2.0% of the patients with type 1 and 3.0% of the patients with type 2 diabetes were ≥75 years of age. no overall differences in safety or effectiveness of insulin glargine have been observed between patients 65 years of age and older and younger adult patients. nevertheless, caution should be exercised when insulin glargine u-300 is administered to geriatric patients. in geriatric patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia [see warnings and precautions (5.3), adverse reactions (6), and clinical studies (14)] . the effect of kidney impairment on the pharmacokinetics of insulin glargine has not been studied. some studies with human insulin have shown increased circulating levels of insulin in patients with kidney failure. frequent glucose monitoring and dose adjustment may be necessary for insulin glargine in patients with kidney impairment [see warnings and precautions (5.3)] . the effect of hepatic impairment on the pharmacokinetics of insulin glargine has not been studied. frequent glucose monitoring and dose adjustment may be necessary for insulin glargine u-300 in patients with hepatic impairment [see warnings and precautions (5.3)] . instructions for use insulin glargine u-300 solostar ® (in-su-lin-glar-gine) (insulin glargine) injection, for subcutaneous use 1.5 ml single-patient-use prefilled pen read this first do not share your insulin glargine u-300 solostar pen with other people, even if the needle has been changed. you may give other people a serious infection, or get a serious infection from them. insulin glargine u-300 contains 300 units/ml of insulin glargine - do not re-use needles. if you do, you might not get your dose (underdosing) or get too much (overdosing) as the needle could block. - do not use a syringe to remove insulin from your pen. if you do, you will get too much insulin. the scale on most syringes is made for u-100 (non-concentrated) insulin only. - the dose selector of your insulin glargine u-300 solostar pen dials by 1 unit. people who are blind or have vision problems should not use the insulin glargine u-300 solostar pen without help from a person trained to use the insulin glargine u-300 solostar pen. important information - do not use your pen if it is damaged or if you are not sure that it is working properly. - always perform a safety test (see step 3 ). - always carry a spare pen and spare needles in case they are lost or stop working. - change (rotate) your injection sites within the area you choose for each dose (see " places to inject" ). learn to inject - talk with your healthcare provider about how to inject, before using your pen. - read all of these instructions before using your pen. if you do not follow all of these instructions, you may get too much or too little insulin. need help? if you have any questions about your pen or about diabetes, ask your healthcare provider, go to www.winthropus.com or call sanofi-aventis at 1-800-633-1610 . extra items you will need: - a new sterile needle (not included with the pen) (see step 2 ). - an alcohol swab. - a puncture-resistant container for used needles and pens (see " throwing your pen away" ). places to inject - inject your insulin exactly as your healthcare provider has shown you. - inject your insulin under the skin (subcutaneously) of your upper legs (thighs), upper arms, or stomach area (abdomen). - change (rotate) your injection sites within the area you choose for each dose to reduce your risk of getting pits or thickening of the skin (lipodystrophy) and lumps in the skin (localized cutaneous amyloidosis) at the injection sites. - do not inject where the skin has pits, is thickened, or has lumps. do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin. - do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin. get to know your pen step 1: check your pen take a new pen out of the refrigerator at least 1 hour before you inject. cold insulin is more painful to inject. - check the name and expiration date on the label of your pen. make sure you have the correct insulin. do not use your pen after the expiration date printed on the label. - make sure you have the correct insulin. - do not use your pen after the expiration date printed on the label. - pull off the pen cap. - check that the insulin is clear. do not use the pen if the insulin looks cloudy, colored or contains particles. - do not use the pen if the insulin looks cloudy, colored or contains particles. - wipe the rubber seal with an alcohol swab. if you have other injector pens - making sure you have the correct medicine is especially important if you have other injector pens. step 2: attach a new needle - do not re-use needles. always use a new sterile needle for each injection. this helps stop blocked needles, contamination and infection. - always use needles 2from bd (such as bd ultra-fine ® ), ypsomed (such as clickfine ® ), or owen mumford (such as unifine ® pentips ® ). - take a new needle and peel off the protective seal. - keep the needle straight and screw it onto the pen until fixed. do not over-tighten. - pull off the outer needle cap. keep this for later. - pull off the inner needle cap and throw away. handling needles - be careful when you are handling needles to help prevent accidental needle-stick injury. you may give other people a serious infection, or get a serious infection from them. step 3: do a safety test always do a safety test before each injection to: - check your pen and the needle to make sure they are working properly. - make sure that you get the correct insulin dose. if the pen is new, you must perform safety tests before you use the pen for the first time until you see insulin coming out of the needle tip. if you see insulin coming out of the needle tip, the pen is ready to use. if you do not see insulin coming out before taking your dose, you could get an underdose or no insulin at all. this could cause high blood sugar. - select 3 units by turning the dose selector until the dose pointer is at the mark between 2 and 4. - press the injection button all the way in. when insulin comes out of the needle tip, your pen is working correctly. - when insulin comes out of the needle tip, your pen is working correctly. if no insulin appears: - you may need to repeat this step up to 3 times before seeing insulin. - if no insulin comes out after the third time, the needle may be blocked. if this happens: change the needle (see step 6 and step 2 ), then repeat the safety test (see step 3 ). - change the needle (see step 6 and step 2 ), - then repeat the safety test (see step 3 ). - do not use your pen if there is still no insulin coming out of the needle tip. use a new pen. - do not use a syringe to remove insulin from your pen. if you see air bubbles - you may see air bubbles in the insulin. this is normal, they will not harm you. step 4: select the dose - do not select a dose or press the injection button without a needle attached. this may damage your pen. - insulin glargine u-300 solostar is made to deliver the number of insulin units that your healthcare provider prescribed. you do not need to do any dose calculations . - the dose selector of your insulin glargine u-300 solostar pen dials by 1 unit. - make sure a needle is attached and the dose is set to "0." - turn the dose selector until the dose pointer lines up with your dose. set the dose by turning the dose selector to a line in the dose window. each line equals 1 unit. the dose selector clicks as you turn it. always check the number in the dose window to make sure you dialed the correct dose. do not dial your dose by counting the clicks. you may dial the wrong dose. this may lead to you getting too much insulin or not enough insulin. if you turn past your dose, you can turn back down. if there are not enough units left in your pen for your dose, the dose selector will stop at the number of units left. if you cannot select your full prescribed dose, split the dose into 2 injections or use a new pen. if you use a new pen, perform a safety test (see step 3 ). - set the dose by turning the dose selector to a line in the dose window. each line equals 1 unit. - the dose selector clicks as you turn it. - always check the number in the dose window to make sure you dialed the correct dose. - do not dial your dose by counting the clicks. you may dial the wrong dose. this may lead to you getting too much insulin or not enough insulin. - if you turn past your dose, you can turn back down. - if there are not enough units left in your pen for your dose, the dose selector will stop at the number of units left. - if you cannot select your full prescribed dose, split the dose into 2 injections or use a new pen. if you use a new pen, perform a safety test (see step 3 ). how to read the dose window the dose selector dials by 1 unit. even numbers are shown in line with the dose pointer: odd numbers are shown as a line between even numbers: units of insulin in your pen - your pen contains a total of 450 units of insulin. you can select doses from 1 to 80 units. each pen contains more than 1 dose. - you can see roughly how many units of insulin are left by looking at where the plunger is on the insulin scale. step 5: inject your dose if you find it hard to press the injection button in, do not force it as this may break your pen. see the section below for help. - choose a place to inject as shown in the picture labeled "places to inject." the site you choose for the injection should be clean and dry. if your skin is dirty, clean it as instructed by your healthcare provider. - the site you choose for the injection should be clean and dry. - if your skin is dirty, clean it as instructed by your healthcare provider. - push the needle into your skin as shown by your healthcare provider. do not touch the injection button yet. - do not touch the injection button yet. - place your thumb on the injection button. then press all the way in and hold. do not press at an angle. your thumb could block the dose selector from turning. - do not press at an angle. your thumb could block the dose selector from turning. - keep the injection button held in and when you see "0" in the dose window, slowly count to 5. this will make sure you get your full dose. - this will make sure you get your full dose. - after holding and slowly counting to 5, release the injection button. then remove the needle from your skin. if you find it hard to press the injection button in: - change the needle (see step 6and step 2) then do a safety test (see step 3). - if you still find it hard to press in, get a new pen. - do not use a syringe to remove insulin from your pen. step 6: remove the needle - take care when handling needles to prevent needle injury and cross-infection. - do not put the inner needle cap back on. - grip the widest part of the outer needle cap. keep the needle straight and guide it into the outer needle cap. then push firmly on. the needle can puncture the cap if it is recapped at an angle. - the needle can puncture the cap if it is recapped at an angle. - grip and squeeze the widest part of the outer needle cap. turn your pen several times with your other hand to remove the needle. try again if the needle does not come off the first time. - try again if the needle does not come off the first time. - throw away the used needle in a puncture-resistant container (see " throwing your pen away" at the end of this instructions for use). - put the pen cap back on. do not put the pen back in the refrigerator. - do not put the pen back in the refrigerator. use by - only use your pen for up to 56 days after its first use. how to store your pen before first use - keep new pens in the refrigerator between 36°f and 46°f (2°c and 8°c). - do not freeze. throw away your pen if it has been frozen (see " throwing your pen away "). after first use - keep your pen at room temperature up to 86°f (30°c) . - protect your pen from direct heat and light. - do not put your pen back in the refrigerator. - do not store your pen with the needle attached. - store your pen with the pen cap on. - keep insulin glargine u-300 solostar pens and needles out of the reach of children. how to care for your pen handle your pen with care - do not drop your pen or knock it against hard surfaces. - if you think that your pen may be damaged, do not try to fix it. use a new one. protect your pen from dust and dirt - you can clean the outside of your pen by wiping it with a damp cloth (water only). do not soak, wash or lubricate your pen. this may damage it. throwing your pen away - the used insulin glargine u-300 solostar pen may be thrown away in your household trash after you have removed the needle. - put the used needle in a fda-cleared sharps disposal container right away after use. do not throw away (dispose of) needles in your household trash. - if you do not have a fda-cleared sharps disposal container, you may use a household container that is: made of a heavy-duty plastic, can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, upright and stable during use, leak-resistant, and properly labeled to warn of hazardous waste inside the container. - made of a heavy-duty plastic, - can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, - upright and stable during use, - leak-resistant, and - properly labeled to warn of hazardous waste inside the container. - when your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. there may be state or local laws about how you should throw away used needles and syringes. for more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the fda's website at: http://www.fda.gov/safesharpsdisposal. - do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. do not recycle your used sharps disposal container. manufactured by: sanofi-aventis u.s. llc bridgewater, nj 08807 u.s. license no. 1752 manufactured for: winthrop u.s., a business of sanofi-aventis u.s. llc bridgewater, nj 08807 a sanofi company ©2022 sanofi-aventis u.s. llc this instructions for use has been approved by the u.s. food and drug administration. revised: august 2022 instructions for use insulin glargine u-300 max solostar ® (in-su-lin-glar-gine) (insulin glargine) injection, for subcutaneous use 3 ml single-patient-use prefilled pen read this first do not share your insulin glargine u-300 max solostar pen with other people, even if the needle has been changed. you may give other people a serious infection, or get a serious infection from them. insulin glargine u-300 contains 300 units/ml of insulin glargine - do not re-use needles. if you do, you might not get your dose (underdosing) or get too much (overdosing) as the needle could block. - do not use a syringe to remove insulin from your pen. if you do, you will get too much insulin. the scale on most syringes is made for u-100 (non-concentrated) insulin only. - the dose selector of your insulin glargine u-300 max solostar pen dials by 2 units . people who are blind or have vision problems should not use the insulin glargine u-300 max solostar pen without help from a person trained to use the insulin glargine u-300 max solostar pen. important information - do not use your pen if it is damaged or if you are not sure that it is working properly. - always perform a safety test (see step 3 ). - always carry a spare pen and spare needles in case they are lost or stop working. - change (rotate) your injection sites within the area you choose for each dose (see " places to inject" ). learn to inject - talk with your healthcare provider about how to inject, before using your pen. - read all of these instructions before using your pen. if you do not follow all of these instructions, you may get too much or too little insulin. need help? if you have any questions about your pen or about diabetes, ask your healthcare provider, go to www.winthropus.com or call sanofi-aventis at 1-800-633-1610 . extra items you will need: - a new sterile needle (not included with the pen) (see step 2 ). - an alcohol swab. - a puncture-resistant container for used needles and pens (see " throwing your pen away" ). places to inject - inject your insulin exactly as your healthcare provider has shown you. - inject your insulin under the skin (subcutaneously) of your upper legs (thighs), upper arms, or stomach area (abdomen). - change (rotate) your injection sites within the area you choose for each dose to reduce your risk of getting pits or thickening of the skin (lipodystrophy) and lumps in the skin (localized cutaneous amyloidosis) at the injection sites. - do not inject where the skin has pits, is thickened, or has lumps. do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin. - do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin. get to know your pen step 1: check your pen take a new pen out of the refrigerator at least 1 hour before you inject. cold insulin is more painful to inject. - check the name and expiration date on the label of your pen. make sure you have the correct insulin. do not use your pen after the expiration date printed on the label. - make sure you have the correct insulin. - do not use your pen after the expiration date printed on the label. - pull off the pen cap. - check that the insulin is clear. do not use the pen if the insulin looks cloudy, colored or contains particles. - do not use the pen if the insulin looks cloudy, colored or contains particles. - wipe the rubber seal with an alcohol swab. if you have other injector pens - making sure you have the correct medicine is especially important if you have other injector pens. step 2: attach a new needle - do not re-use needles. always use a new sterile needle for each injection. this helps stop blocked needles, contamination and infection. - always use needles 3from bd (such as bd ultra-fine ® ), ypsomed (such as clickfine ® ), or owen mumford (such as unifine ® pentips ® ) that are 8 mm long or shorter. - take a new needle and peel off the protective seal. - keep the needle straight and screw it onto the pen until fixed. do not over-tighten. - pull off the outer needle cap. keep this for later. - pull off the inner needle cap and throw away. handling needles - be careful when you are handling needles to help prevent accidental needle-stick injury. you may give other people a serious infection, or get a serious infection from them. step 3: do a safety test always do a safety test before each injection to: - check your pen and the needle to make sure they are working properly. - make sure that you get the correct insulin dose. if the pen is new, you must perform safety tests before you use the pen for the first time until you see insulin coming out of the needle tip. if you see insulin coming out of the needle tip, the pen is ready to use. if you do not see insulin coming out before taking your dose, you could get an underdose or no insulin at all. this could cause high blood sugar. - select 4 units by turning the dose selector until the dose pointer is at the 4 mark. - press the injection button all the way in. when insulin comes out of the needle tip, your pen is working correctly. - when insulin comes out of the needle tip, your pen is working correctly. if no insulin appears: - you may need to repeat this step up to 6 times before seeing insulin. - if no insulin comes out after the sixth time, the needle may be blocked. if this happens: change the needle (see step 6 and step 2 ), then repeat the safety test (see step 3 ). - change the needle (see step 6 and step 2 ), - then repeat the safety test (see step 3 ). - do not use your pen if there is still no insulin coming out of the needle tip. use a new pen. - do not use a syringe to remove insulin from your pen. if you see air bubbles - you may see air bubbles in the insulin. this is normal, they will not harm you. step 4: select the dose - do not select a dose or press the injection button without a needle attached. this may damage your pen. - insulin glargine u-300 max solostar is made to deliver the number of insulin units that your healthcare provider prescribed. you do not need to do any dose calculations . - the dose selector of your insulin glargine u-300 max solostar pen dials by 2 units and can only dial even doses of insulin. - make sure a needle is attached and the dose is set to "0." - turn the dose selector until the dose pointer lines up with your dose. set the dose by turning the dose selector to a line in the dose window. each line equals 2 units. the dose selector clicks as you turn it. always check the number in the dose window to make sure you dialed the correct dose. do not dial your dose by counting the clicks. you may dial the wrong dose. this may lead to you getting too much insulin or not enough insulin. if you turn past your dose, you can turn back down. if there are not enough units left in your pen for your dose, the dose selector will stop at the number of units left. if you cannot select your full prescribed dose, split the dose into 2 injections or use a new pen. if you use a new pen, perform a safety test (see step 3 ). - set the dose by turning the dose selector to a line in the dose window. each line equals 2 units. - the dose selector clicks as you turn it. - always check the number in the dose window to make sure you dialed the correct dose. - do not dial your dose by counting the clicks. you may dial the wrong dose. this may lead to you getting too much insulin or not enough insulin. - if you turn past your dose, you can turn back down. - if there are not enough units left in your pen for your dose, the dose selector will stop at the number of units left. - if you cannot select your full prescribed dose, split the dose into 2 injections or use a new pen. if you use a new pen, perform a safety test (see step 3 ). how to read the dose window the dose selector dials by 2 units. each line in the dose window is an even number. units of insulin in your pen - your pen contains a total of 900 units of insulin. you can select doses from 2 to 160 units. the dose is adjusted by 2 units at a time. each pen contains more than 1 dose. - you can see roughly how many units of insulin are left by looking at where the plunger is on the insulin scale. step 5: inject your dose if you find it hard to press the injection button in, do not force it as this may break your pen. see the section below for help. - choose a place to inject as shown in the picture labeled "places to inject." the site you choose for the injection should be clean and dry. if your skin is dirty, clean it as instructed by your healthcare provider. - the site you choose for the injection should be clean and dry. - if your skin is dirty, clean it as instructed by your healthcare provider. - push the needle into your skin as shown by your healthcare provider. do not touch the injection button yet. - do not touch the injection button yet. - place your thumb on the injection button. then press all the way in and hold. do not press at an angle. your thumb could block the dose selector from turning. - do not press at an angle. your thumb could block the dose selector from turning. - keep the injection button held in and when you see "0" in the dose window, slowly count to 5. this will make sure you get your full dose. - this will make sure you get your full dose. - after holding and slowly counting to 5, release the injection button. then remove the needle from your skin. if you find it hard to press the injection button in: - change the needle (see step 6 and step 2 ) then do a safety test (see step 3 ). - if you still find it hard to press in, get a new pen. - do not use a syringe to remove insulin from your pen. step 6: remove the needle - take care when handling needles to prevent needle injury and cross-infection. - do not put the inner needle cap back on. - grip the widest part of the outer needle cap. keep the needle straight and guide it into the outer needle cap. then push firmly on. the needle can puncture the cap if it is recapped at an angle. - the needle can puncture the cap if it is recapped at an angle. - grip and squeeze the widest part of the outer needle cap. turn your pen several times with your other hand to remove the needle. try again if the needle does not come off the first time. - try again if the needle does not come off the first time. - throw away the used needle in a puncture-resistant container (see " throwing your pen away" at the end of this instructions for use). - put the pen cap back on. do not put the pen back in the refrigerator. - do not put the pen back in the refrigerator. use by - only use your pen for up to 56 days after its first use. how to store your pen before first use - keep new pens in the refrigerator between 36°f and 46°f (2°c and 8°c) . - do not freeze. throw away your pen if it has been frozen (see " throwing your pen away" ). after first use - keep your pen at room temperature up to 86°f (30°c) . - protect your pen from direct heat and light. - do not put your pen back in the refrigerator. - do not store your pen with the needle attached. - store your pen with the pen cap on. - keep insulin glargine u-300 max solostar pens and needles out of the reach of children. how to care for your pen handle your pen with care - do not drop your pen or knock it against hard surfaces. - if you think that your pen may be damaged, do not try to fix it. use a new one. protect your pen from dust and dirt - you can clean the outside of your pen by wiping it with a damp cloth (water only). do not soak, wash or lubricate your pen. this may damage it. throwing your pen away - the used insulin glargine u-300 max solostar pen may be thrown away in your household trash after you have removed the needle. - put the used needle in a fda-cleared sharps disposal container right away after use. do not throw away (dispose of) needles in your household trash. - if you do not have a fda-cleared sharps disposal container, you may use a household container that is: made of a heavy-duty plastic, can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, upright and stable during use, leak-resistant, and properly labeled to warn of hazardous waste inside the container. - made of a heavy-duty plastic, - can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, - upright and stable during use, - leak-resistant, and - properly labeled to warn of hazardous waste inside the container. - when your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. there may be state or local laws about how you should throw away used needles and syringes. for more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the fda's website at: http://www.fda.gov/safesharpsdisposal. - do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. do not recycle your used sharps disposal container. manufactured by: sanofi-aventis u.s. llc bridgewater, nj 08807 u.s. license no. 1752 manufactured for: winthrop u.s., a business of sanofi-aventis u.s. llc bridgewater, nj 08807 a sanofi company ©2022 sanofi-aventis u.s. llc this instructions for use has been approved by the u.s. food and drug administration. revised: august 2022

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

winthrop u.s, a business of sanofi-aventis u.s. llc - enoxaparin sodium (unii: 8nz41mik1o) (enoxaparin - unii:e47c0nf7lv) - enoxaparin sodium 30 mg in 0.3 ml - enoxaparin sodium is indicated for the prophylaxis of deep vein thrombosis (dvt), which may lead to pulmonary embolism (pe): - in patients undergoing abdominal surgery who are at risk for thromboembolic complications [see clinical studies (14.1)] - in patients undergoing hip replacement surgery, during and following hospitalization - in patients undergoing knee replacement surgery - in medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness enoxaparin sodium is indicated for: - the inpatient treatment of acute deep vein thrombosis with or without pulmonary embolism , when administered in conjunction with warfarin sodium - the outpatient treatment of acute deep vein thrombosis without pulmonary embolism, when administered in conjunction with warfarin sodium enoxaparin sodium is indicated for the prophylaxis of ischemic complications of unstable angina and non–q-wave myocardial infarction, when concurrently administered with aspirin. enoxaparin sodium, when administered concurrently with aspirin, has been shown to reduce the rate of the combined endpoint of recurrent myocardial infarction or death in patients with acute st-segment elevation myocardial infarction (stemi) receiving thrombolysis and being managed medically or with percutaneous coronary intervention (pci). enoxaparin sodium is contraindicated in patients with: - active major bleeding - history of immune-mediated heparin-induced thrombocytopenia (hit) within the past 100 days or in the presence of circulating antibodies [see warnings and precautions (5.4)] - known hypersensitivity to enoxaparin sodium (e.g., pruritus, urticaria, anaphylactic/anaphylactoid reactions) [see adverse reactions (6.2)] - known hypersensitivity to heparin or pork products - known hypersensitivity to benzyl alcohol (which is in only the multiple-dose formulation of enoxaparin sodium) [see warnings and precautions (5.8)] risk summary placental transfer of enoxaparin was observed in the animal studies. human data from a retrospective cohort study, which included 693 live births, suggest that enoxaparin does not increase the risk of major developmental abnormalities (see data) . based on animal data, enoxaparin is not predicted to increase the risk of major developmental abnormalities (see data) . 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% to 4% and 15% to 20%, respectively. clinical considerations pregnancy alone confers an increased risk for thromboembolism that is even higher for women with thromboembolic disease and certain high risk pregnancy conditions. while not adequately studied, pregnant women with mechanical prosthetic heart valves may be at even higher risk for thrombosis [see warnings and precautions (5.7)and use in specific populations (8.6)] . pregnant women with thromboembolic disease, including those with mechanical prosthetic heart valves and those with inherited or acquired thrombophilias, have an increased risk of other maternal complications and fetal loss regardless of the type of anticoagulant used. all patients receiving anticoagulants, including pregnant women, are at risk for bleeding. pregnant women receiving enoxaparin should be carefully monitored for evidence of bleeding or excessive anticoagulation. consideration for use of a shorter acting anticoagulant should be specifically addressed as delivery approaches [see boxed warning] . hemorrhage can occur at any site and may lead to death of mother and/or fetus. pregnant women should be apprised of the potential hazard to the fetus and the mother if enoxaparin is administered during pregnancy. it is not known if monitoring of anti-factor xa activity and dose adjustment (by weight or anti-factor xa activity) of enoxaparin sodium affect the safety and the efficacy of the drug during pregnancy. cases of "gasping syndrome" have occurred in premature infants when large amounts of benzyl alcohol have been administered (99–405 mg/kg/day). the multiple-dose vial of enoxaparin sodium contains 15 mg benzyl alcohol per 1 ml as a preservative [see warnings and precautions (5.8)] . data human data there are no adequate and well-controlled studies in pregnant women. a retrospective study reviewed the records of 604 women who used enoxaparin during pregnancy. a total of 624 pregnancies resulted in 693 live births. there were 72 hemorrhagic events (11 serious) in 63 women. there were 14 cases of neonatal hemorrhage. major congenital anomalies in live births occurred at rates (2.5%) similar to background rates. there have been postmarketing reports of fetal death when pregnant women received enoxaparin sodium. causality for these cases has not been determined. insufficient data, the underlying disease, and the possibility of inadequate anticoagulation complicate the evaluation of these cases. a clinical study using enoxaparin in pregnant women with mechanical prosthetic heart valves has been conducted [see warnings and precautions (5.7)] . animal data teratology studies have been conducted in pregnant rats and rabbits at subcutaneous doses of enoxaparin up to 15 times the recommended human dose (by comparison with 2 mg/kg as the maximum recommended daily dose). there was no evidence of teratogenic effects or fetotoxicity due to enoxaparin. because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. risk summary it is unknown whether enoxaparin sodium is excreted in human milk. in lactating rats, the passage of enoxaparin or its metabolites in the milk is very limited. there is no information available on the effect of enoxaparin or its metabolites on the breastfed child, or on the milk production. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for enoxaparin sodium and any potential adverse effects on the breastfed child from enoxaparin sodium or from the underlying maternal condition. safety and effectiveness of enoxaparin sodium in pediatric patients have not been established. enoxaparin sodium is not approved for use in neonates or infants. serious adverse reactions including fatal reactions and the "gasping syndrome" occurred in premature neonates and low-birth-weight infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. in these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/l). additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. preterm, low-birth-weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. the minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known. enoxaparin sodium multiple-dose vials contain 15 mg/ml of benzyl alcohol (at the dose of 1.5 mg/kg twice a day, benzyl alcohol exposure in patients is 0.45 mg/kg daily) [see warnings and precautions (5.8)] . prevention of deep vein thrombosis in hip, knee and abdominal surgery; treatment of deep vein thrombosis, prevention of ischemic complications of unstable angina and non–q-wave myocardial infarction over 2800 patients, 65 years and older, have received enoxaparin sodium in clinical trials. the efficacy of enoxaparin sodium in the geriatric (≥65 years) was similar to that seen in younger patients (<65 years). the incidence of bleeding complications was similar between geriatric and younger patients when 30 mg every 12 hours or 40 mg once a day doses of enoxaparin sodium were employed. the incidence of bleeding complications was higher in geriatric patients as compared to younger patients when enoxaparin sodium was administered at doses of 1.5 mg/kg once a day or 1 mg/kg every 12 hours. the risk of enoxaparin sodium–associated bleeding increased with age. serious adverse events increased with age for patients receiving enoxaparin sodium. other clinical experience (including postmarketing surveillance and literature reports) has not revealed additional differences in the safety of enoxaparin sodium between geriatric and younger patients. careful attention to dosing intervals and concomitant medications (especially antiplatelet medications) is advised. enoxaparin sodium should be used with care in geriatric patients who may show delayed elimination of enoxaparin. monitoring of geriatric patients with low body weight (<45 kg) and those predisposed to decreased renal function should be considered [see warnings and precautions (2.6)and clinical pharmacology (12.3)] . treatment of acute st-segment elevation myocardial infarction in the clinical study for treatment of acute st-segment elevation myocardial infarction, there was no evidence of difference in efficacy between patients ≥75 years of age (n=1241) and patients less than 75 years of age (n=9015). patients ≥75 years of age did not receive a 30 mg intravenous bolus prior to the normal dosage regimen and had their subcutaneous dose adjusted to 0.75 mg/kg every 12 hours [see dosage and administration (2.4)] . the incidence of bleeding complications was higher in patients ≥65 years of age as compared to younger patients (<65 years). the use of enoxaparin sodium has not been adequately studied for thromboprophylaxis in patients with mechanical prosthetic heart valves and has not been adequately studied for long-term use in this patient population. isolated cases of prosthetic heart valve thrombosis have been reported in patients with mechanical prosthetic heart valves who have received enoxaparin for thromboprophylaxis. some of these cases were pregnant women in whom thrombosis led to maternal and fetal deaths. insufficient data, the underlying disease and the possibility of inadequate anticoagulation complicate the evaluation of these cases. pregnant women with mechanical prosthetic heart valves may be at higher risk for thromboembolism [see warnings and precautions (5.7)] . in patients with renal impairment, there is an increase in exposure of enoxaparin sodium. all such patients should be observed carefully for signs and symptoms of bleeding. because exposure of enoxaparin sodium is significantly increased in patients with severe renal impairment (creatinine clearance <30 ml/min), a dosage adjustment is recommended for therapeutic and prophylactic dosage ranges. no dosage adjustment is recommended in patients with creatinine clearance 30 to <50 ml/min and creatinine clearance 50 to 80 ml/min [see dosage and administration (2.3)and clinical pharmacology (12.3)] . in patients with renal failure, treatment with enoxaparin has been associated with the development of hyperkalemia [see adverse reactions (6.2)]. an increase in exposure of enoxaparin sodium with prophylactic dosages (non-weight adjusted) has been observed in low-weight women (<45 kg) and low-weight men (<57 kg). observe low-weight patients frequently for signs and symptoms of bleeding [see clinical pharmacology (12.3)] . obese patients are at higher risk for thromboembolism. the safety and efficacy of prophylactic doses of enoxaparin sodium in obese patients (bmi >30 kg/m 2 ) has not been fully determined and there is no consensus for dose adjustment. observe these patients carefully for signs and symptoms of thromboembolism. enoxaparin sodium injection for subcutaneous use single-dose prefilled syringe this instructions for use contains information on how to prepare and inject enoxaparin sodium prefilled syringe. read this instructions for use before using the enoxaparin sodium prefilled syringe and each time you get a new prescription. there may be new information. do not inject yourself or someone else until you have been shown how to inject enoxaparin sodium. your healthcare provider can show you or your caregiver how to prepare and inject a dose of enoxaparin sodium. call your healthcare provider if you have any questions. important information: - your healthcare provider will tell you the prescribed dose that you should take and how often you will need to inject enoxaparin sodium. if your dose is based on your body weight, your dose of enoxaparin sodium might be less than what is in the prefilled syringe. - enoxaparin sodium is injected as a subcutaneous (under the skin) injection only. do not inject enoxaparin sodium into muscle. - do not use the enoxaparin sodium prefilled syringe if the needle cap is missing or not securely attached. - do not remove the needle cap until just before you give the injection. - do not touch the syringe plunger rod until you are ready to inject. do not pull back on the plunger rod at any time. - do not get rid of any air bubble(s) in the enoxaparin sodium prefilled syringe. this can lead to a loss of the medicine. - to avoid bruising, do not rub the injection site after you have injected yourself. - to protect from needle-stick injuries, each prefilled syringe has a safety system that covers the needle after injection. - throw away (dispose of) the used enoxaparin sodium prefilled syringe and needle cap right away after use, even if there is medicine left in the prefilled syringe. see " step 13: dispose of used enoxaparin sodium prefilled syringes and needle caps " below. - enoxaparin sodium injection is for one time use only. do not reuse an enoxaparin sodium prefilled syringe. storing enoxaparin sodium prefilled syringes: - store enoxaparin sodium prefilled syringes at 77°f (25°c). - store enoxaparin sodium prefilled syringes in the original carton or packaging until ready to use. - keep enoxaparin sodium injection and all medicines out of the reach of children. parts of enoxaparin sodium prefilled syringe: preparing to inject enoxaparin sodium: step 1: gather the following supplies for your injection (see figure a) : - 1 enoxaparin sodium prefilled syringe - 1 alcohol wipe 1 - 1 cotton ball or gauze 1 - a small adhesive bandage, if needed 1 - a sharps disposal container 1(see step 13) figure a step 2: wash your hands well with soap and water. step 3: preparing a dose of enoxaparin sodium injection take the prefilled syringe out of the package. open the packaging by peeling the lid at the arrow as directed. take the prefilled syringe out of the plastic container by holding the middle of the syringe body (see figure b). - do not remove the prefilled syringe by pulling on the plunger rod or the needle cap as this may damage the syringe. - do not pull off the needle cap until you are ready to inject. - do not use the enoxaparin sodium prefilled syringe if it has been dropped on a hard surface or damaged. figure b step 4: check the enoxaparin sodium prefilled syringe - when you receive your enoxaparin sodium syringes, always check to see that: you have the correct medicine and dose. the expiration date on the prefilled syringe has not passed (see figure c). - you have the correct medicine and dose. - the expiration date on the prefilled syringe has not passed (see figure c). - do not use the enoxaparin sodium prefilled syringe if the expiration date has passed. figure c step 5: check the medicine - look at the medicine inside the enoxaparin sodium prefilled syringe: the liquid should be clear and colorless to pale yellow (see figure d). note: you may see air bubble(s), this is normal. do not try to remove any air bubbles. - the liquid should be clear and colorless to pale yellow (see figure d). - note: you may see air bubble(s), this is normal. do not try to remove any air bubbles. - do not use the enoxaparin sodium prefilled syringe if the liquid is discolored or cloudy, or if it contains visible flakes or particles. figure d step 6: choose your injection site - you can inject into either the right or left side of your stomach area (abdomen), at least 2 inches away from your belly button and out towards your side (see figure e). - you should alternate between the left or right side of your stomach each time you give yourself an injection. - do not inject into skin that has bruises or scars. - do not inject through clothes. figure e step 7: clean the injection site clean the injection site with an alcohol wipe (see figure f). let your skin dry before injecting. figure f step 8: remove the needle cap hold the prefilled syringe in the middle of the body with the needle pointing away from you. remove the needle cap by pulling it straight off the syringe (see figure g). - do not twist the needle cap to avoid bending the needle. - do not put the needle cap back on. - do not touch the needle. figure g step 9: injecting a dose that is less than the full amount in the prefilled syringe. if your prescribed dose is the same as the amount in the prefilled syringe, go to step 10. if your dose is based on your bodyweight, your healthcare provider may prescribe less than the full amount in the syringe. you will have to get rid of (discard) some of the medicine from the prefilled syringe before you inject enoxaparin sodium. to measure your prescribed dose, hold the prefilled syringe with the needle pointing down. carefully watch the numbers on the syringe as you push the plunger down until the amount left in the syringe is the same as your prescribed dose. the tip of the plunger should line up with the number for your prescribed dose (see figure h). figure h step 10: injecting enoxaparin sodium hold the prefilled syringe like a pencil in your hand with the needle pointing down. with your other hand, pinch the cleaned stomach (abdomen) area between your forefinger and thumb to make a fold in the skin (see figure i). make sure you hold the skin fold during the entire injection. figure i insert the full length of the needle straight into the skin fold at about a 90° angle (see figure j). figure j push the plunger rod down slowly and steadily with your thumb until the enoxaparin sodium prefilled syringe is empty (see figure k). figure k step 11: remove the needle remove the needle from the injection site by pulling it straight out while keeping your fingers on the plunger rod (see figure l). - do not put the needle cap back on. - do not rub your skin after the injection. figure l step 12: activate the safety system point the needle away from yourself and other people, and firmly push the plunger rod again to activate the safety system. the protective sleeve will automatically come down and cover the needle. you will hear a "click" when the protective sleeve is released (see figure m). - you will feel some resistance. this is normal. keep pushing until you hear the "click." - the safety system can only be activated after the syringe has been emptied. - only activate the safety system after you have removed the needle from your skin. - activation of the safety system may cause a small amount of liquid to leak out of the syringe. activate the system while facing the syringe away from yourself and other people. figure m step 13: dispose of used enoxaparin sodium prefilled syringes and needle caps put the used enoxaparin sodium prefilled syringe and needle cap in an fda-cleared sharps disposal container right away after use (see figure n). do not dispose of enoxaparin sodium prefilled syringes or needle caps in your household trash. if you do not have an fda-cleared sharps disposal container, you may use a household container that is: - made of a heavy-duty plastic, - can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, - upright and stable during use, - leak-resistant, and - properly labeled to warn of hazardous waste inside the container. when your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. there may be state or local laws about how you should throw away used needles, syringes, and prefilled syringes. for more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the fda's website at http://www.fda.gov/safesharpsdisposal. figure n winthrop u.s. a business of sanofi-aventis u.s. llc bridgewater, nj 08807 a sanofi company ©2021 sanofi-aventis u.s. llc this instructions for use has been approved by the u.s. food and drug administration. issued: december 2021

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

winthrop u.s, a business of sanofi-aventis u.s. llc - oxaliplatin (unii: 04zr38536j) (oxaliplatin - unii:04zr38536j) - oxaliplatin 5 mg in 1 ml - oxaliplatin, in combination with infusional fluorouracil and leucovorin, is indicated for: - adjuvant treatment of stage iii colon cancer in patients who have undergone complete resection of the primary tumor. - treatment of advanced colorectal cancer. oxaliplatin is contraindicated in patients with a history of a hypersensitivity reaction to oxaliplatin or other platinum-based drugs. reactions have included anaphylaxis [see warnings and precautions (5.1)] . risk summary based on its direct interaction with dna, oxaliplatin can cause fetal harm when administered to a pregnant woman. the available human data do not establish the presence or absence of major birth defects or miscarriage related to the use of oxaliplatin. reproductive toxicity studies demonstrated adverse effects on embryo-fetal development in rats at maternal doses that were below the recommended human dose based on body surface area (see data) . advise a pregnant woman of the potential risk to a fetus. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. data animal data pregnant rats were administered oxaliplatin at less than one-tenth the recommended human dose based on body surface area during gestation days (gd)1–5 (preimplantation), gd 6–10, or gd 11–16 (during organogenesis). oxaliplatin caused developmental mortality (increased early resorptions) when administered on days gd 6–10 and gd 11–16 and adversely affected fetal growth (decreased fetal weight, delayed ossification) when administered on days gd 6–10. risk summary there are no data on the presence of oxaliplatin or its metabolites in human or animal milk or its effects on the breastfed infant or on milk production. because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with oxaliplatin and for 3 months after the final dose. pregnancy testing verify pregnancy status in females of reproductive potential prior to initiating oxaliplatin [see use in specific populations (8.1)] . contraception oxaliplatin can cause embryo-fetal harm when administered to a pregnant woman [see use in specific populations (8.1)] . females advise female patients of reproductive potential to use effective contraception while receiving oxaliplatin and for 9 months after the final dose. males based on its mechanism action as a genotoxic drug, advise males with female partners of reproductive potential to use effective contraception while receiving oxaliplatin and for 6 months after the final dose [see nonclinical toxicology (13.1)] . infertility based on animal studies, oxaliplatin may impair fertility in males and females [see nonclinical toxicology (13.1)] . the safety and effectiveness of oxaliplatin in pediatrics have not been established. safety and effectiveness were assessed across 4 open-label studies in 235 patients aged 7 months to 22 years with solid tumors. in a multicenter, open-label, non-comparative, non-randomized study (ard5531), oxaliplatin was administered to 43 patients with refractory or relapsed malignant solid tumors, mainly neuroblastoma and osteosarcoma. the dose limiting toxicity (dlt) was sensory neuropathy at a dose of 110 mg/m 2 . the main adverse reactions were: paresthesia (60%, grade 3–4: 7%), fever (40%, grade 3–4: 7%), and thrombocytopenia (40%, grade 3–4: 27%). no responses were observed. in an open-label non-randomized study (dfi7434), oxaliplatin was administered to 26 pediatric patients with metastatic or unresectable solid tumors, mainly neuroblastoma and ganglioneuroblastoma. the dlt was sensory neuropathy at a dose of 160 mg/m 2 . no responses were observed. in an open-label, single-agent study (ard5021), oxaliplatin was administered to 43 pediatric patients with recurrent or refractory embryonal cns tumors. the most common adverse reactions reported were: leukopenia (67%, grade 3–4: 12%), anemia (65%, grade 3–4: 5%), thrombocytopenia (65%, grade 3–4: 26%), vomiting (65%, grade 3–4: 7%), neutropenia (58%, grade 3–4: 16%), and sensory neuropathy (40%, grade 3–4: 5%). in an open-label single-agent study (ard5530), oxaliplatin was administered to 123 pediatric patients with recurrent solid tumors, including neuroblastoma, osteosarcoma, ewing sarcoma or peripheral pnet, ependymoma, rhabdomyosarcoma, hepatoblastoma, high grade astrocytoma, brain stem glioma, low grade astrocytoma, malignant germ cell tumor and other tumors. the most common adverse reactions reported were: sensory neuropathy (52%, grade 3–4: 12%), thrombocytopenia (37%, grade 3–4: 17%), anemia (37%, grade 3–4: 9%), vomiting (26%, grade 3–4: 4%), increased alt (24%, grade 3–4: 6%), increased ast (24%, grade 3–4: 2%), and nausea (23%, grade 3–4: 3%). the pharmacokinetic parameters of ultrafiltrable platinum were evaluated in 105 pediatric patients during the first cycle. the mean clearance in pediatric patients estimated by the population pharmacokinetic analysis was 4.7 l/h (%cv, 41%). mean platinum pharmacokinetic parameters in ultrafiltrate were c max of 0.75 ± 0.24 mcg/ml, auc 0–48h of 7.52 ± 5.07 mcg∙h/ml and auc inf of 8.83 ± 1.57 mcg∙h/ml at 85 mg/m 2 of oxaliplatin and c max of 1.10 ± 0.43 mcg/ml, auc 0–48h of 9.74 ± 2.52 mcg∙h/ml and auc inf of 17.3 ± 5.34 mcg∙h/ml at 130 mg/m 2 of oxaliplatin. in the adjuvant treatment trial [see clinical studies (14.1)] , 400 patients who received oxaliplatin with fluorouracil/leucovorin were greater than or equal to 65 years. the effect of oxaliplatin in patients greater than or equal to 65 years was not conclusive. patients greater than or equal to 65 years receiving oxaliplatin experienced more diarrhea and grade 3–4 neutropenia (45% vs 39%) compared to patients less than 65 years. in the previously untreated advanced colorectal cancer trial [see clinical studies (14.2)] , 99 patients who received oxaliplatin with fluorouracil and leucovorin were greater than or equal to 65 years. the same efficacy improvements in response rate, time to tumor progression, and overall survival were observed in the greater than or equal to 65 years patients as in the overall study population. adverse reactions were similar in patients less than 65 and greater than or equal to 65 years, but older patients may have been more susceptible to diarrhea, dehydration, hypokalemia, leukopenia, fatigue, and syncope. in the previously treated advanced colorectal cancer trial [see clinical studies (14.3)] , 55 patients who received oxaliplatin with fluorouracil and leucovorin were greater than or equal to 65 years. no overall differences in effectiveness were observed between these patients and younger adults. adverse reactions were similar in patients less than 65 and greater than or equal to 65 years, but older patients may have been more susceptible to diarrhea, dehydration, hypokalemia, and fatigue. no significant effect of age on the clearance of ultrafiltrable platinum has been observed [see clinical pharmacology (12.3)] . the auc of unbound platinum in plasma ultrafiltrate was increased in patients with renal impairment [see clinical pharmacology (12.3)] . no dose reduction is recommended for patients with mild (creatinine clearance 50 to 79 ml/min) or moderate (creatinine clearance 30 to 49 ml/min) renal impairment, calculated by cockcroft-gault equation. reduce the dose of oxaliplatin in patients with severe renal impairment (creatinine clearance less than 30 ml/min) [see dosage and administration (2.3)].

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winthrop u.s, a business of sanofi-aventis u.s. llc - docetaxel (unii: 15h5577cqd) (docetaxel anhydrous - unii:699121phca) - docetaxel anhydrous 80 mg in 4 ml - docetaxel is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy. docetaxel in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with operable node-positive breast cancer. docetaxel as a single agent is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior platinum-based chemotherapy. docetaxel in combination with cisplatin is indicated for the treatment of patients with unresectable, locally advanced or metastatic non-small cell lung cancer who have not previously received chemotherapy for this condition. docetaxel in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer. docetaxel in combination with cisplatin and fluorouracil is indicated for the treatment of patients with advanced gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who have not received prior chemotherapy for advanced disease. docetaxel in combination with cisplatin and fluorouracil is indicated for the induction treatment of patients with locally advanced squamous cell carcinoma of the head and neck (scchn). docetaxel is contraindicated in patients with: - neutrophil counts of <1500 cells/mm 3 [see warnings and precautions (5.3)] . - a history of severe hypersensitivity reactions to docetaxel or to other drugs formulated with polysorbate 80. severe reactions, including anaphylaxis, have occurred [see warnings and precautions (5.5)] . risk summary based on findings in animal reproduction studies and its mechanism of action, docetaxel can cause fetal harm when administered to a pregnant woman [see clinical pharmacology (12.1)] . available data from case reports in the literature and pharmacovigilance with docetaxel use in pregnant women are not sufficient to inform the drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. docetaxel contains alcohol which can interfere with neurobehavioral development [see clinical considerations] . in animal reproductive studies, administration of docetaxel to pregnant rats and rabbits during the period of organogenesis caused an increased incidence of embryo-fetal toxicities, including intrauterine mortality, at doses as low as 0.02 and 0.003 times the recommended human dose based on body surface area, respectively [see data] . advise pregnant women and females of reproductive potential of the potential risk to a fetus. the estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. all pregnancies have a background risk of birth defect, miscarriage, 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 docetaxel contains alcohol [see warnings and precautions (5.13)] . published studies have demonstrated that alcohol is associated with fetal harm including central nervous system abnormalities, behavioral disorders, and impaired intellectual development. data animal data intravenous administration of ≥0.3 and 0.03 mg/kg/day docetaxel to pregnant rats and rabbits, respectively, during the period of organogenesis caused an increased incidence of intrauterine mortality, resorptions, reduced fetal weights, and fetal ossification delays. maternal toxicity was also observed at these doses, which were approximately 0.02 and 0.003 times the daily maximum recommended human dose based on body surface area, respectively. risk summary there is no information regarding the presence of docetaxel in human milk, or on its effects on milk production or the breastfed child. no lactation studies in animals have been conducted. because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with docetaxel and for 1 week after the last dose. based on findings in animals, docetaxel can cause fetal harm when administered to a pregnant woman [see use in specific populations (8.1)] . pregnancy testing verify pregnancy status in females of reproductive potential prior to initiating docetaxel. contraception females based on genetic toxicity findings, advise females of reproductive potential to use effective contraception during treatment and for 2 months after the last dose of docetaxel. males based on genetic toxicity findings, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of docetaxel. infertility based on findings in animal studies, docetaxel may impair fertility in males of reproductive potential [see nonclinical toxicology (13.1)] . the alcohol content of docetaxel injection should be taken into account when given to pediatric patients [see warnings and precautions (5.13)] . the efficacy of docetaxel in pediatric patients as monotherapy or in combination has not been established. the overall safety profile of docetaxel in pediatric patients receiving monotherapy or tcf was consistent with the known safety profile in adults. docetaxel has been studied in a total of 289 pediatric patients: 239 in 2 trials with monotherapy and 50 in combination treatment with cisplatin and 5-fluorouracil (tcf). docetaxel monotherapy docetaxel monotherapy was evaluated in a dose-finding phase 1 trial in 61 pediatric patients (median age 12.5 years, range 1–22 years) with a variety of refractory solid tumors. the recommended dose was 125 mg/m 2 as a 1-hour intravenous infusion every 21 days. the primary dose limiting toxicity was neutropenia. the recommended dose for docetaxel monotherapy was evaluated in a phase 2 single-arm trial in 178 pediatric patients (median age 12 years, range 1–26 years) with a variety of recurrent/refractory solid tumors. efficacy was not established with tumor response rates ranging from one complete response (cr) (0.6%) in a patient with undifferentiated sarcoma to four partial responses (2.2%) seen in one patient each with ewing sarcoma, neuroblastoma, osteosarcoma, and squamous cell carcinoma. docetaxel in combination docetaxel was studied in combination with cisplatin and 5-fluorouracil (tcf) versus cisplatin and 5-fluorouracil (cf) for the induction treatment of nasopharyngeal carcinoma (npc) in pediatric patients prior to chemoradiation consolidation. seventy-five patients (median age 16 years, range 9 to 21 years) were randomized (2:1) to docetaxel (75 mg/m 2 ) in combination with cisplatin (75 mg/m 2 ) and 5-fluorouracil (750 mg/m 2 ) (tcf) or to cisplatin (80 mg/m 2 ) and 5-fluorouracil (1000 mg/m 2 /day) (cf). the primary endpoint was the cr rate following induction treatment of npc. one patient out of 50 in the tcf group (2%) had a complete response while none of the 25 patients in the cf group had a complete response. pharmacokinetics pharmacokinetic parameters for docetaxel were determined in 2 pediatric solid tumor trials. following docetaxel administration at 55 mg/m 2 to 235 mg/m 2 in a 1-hour intravenous infusion every 3 weeks in 25 patients aged 1 to 20 years (median 11 years), docetaxel clearance was 17.3±10.9 l/h/m 2 . docetaxel was administered in combination with cisplatin and 5-fluorouracil (tcf), at dose levels of 75 mg/m 2 in a 1-hour intravenous infusion day 1 in 28 patients aged 10 to 21 years (median 16 years, 17 patients were older than 16). docetaxel clearance was 17.9±8.75 l/h/m 2 , corresponding to an auc of 4.20±2.57 μg∙h/ml. in summary, the body surface area adjusted clearance of docetaxel monotherapy and tcf combination in children were comparable to those in adults [see clinical pharmacology (12.3)] . in general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in elderly patients. non-small cell lung cancer in a study conducted in chemotherapy-naive patients with nsclc (tax326), 148 patients (36%) in the docetaxel+cisplatin group were 65 years of age or greater. there were 128 patients (32%) in the vinorelbine+cisplatin group 65 years of age or greater. in the docetaxel+cisplatin group, patients less than 65 years of age had a median survival of 10.3 months (95% ci: 9.1 months, 11.8 months) and patients 65 years or older had a median survival of 12.1 months (95% ci: 9.3 months, 14 months). in patients 65 years of age or greater treated with docetaxel+cisplatin, diarrhea (55%), peripheral edema (39%) and stomatitis (28%) were observed more frequently than in the vinorelbine+cisplatin group (diarrhea 24%, peripheral edema 20%, stomatitis 20%). patients treated with docetaxel+cisplatin who were 65 years of age or greater were more likely to experience diarrhea (55%), infections (42%), peripheral edema (39%) and stomatitis (28%) compared to patients less than the age of 65 administered the same treatment (43%, 31%, 31% and 21%, respectively). when docetaxel was combined with carboplatin for the treatment of chemotherapy-naive, advanced non-small cell lung carcinoma, patients 65 years of age or greater (28%) experienced higher frequency of infection compared to similar patients treated with docetaxel+cisplatin, and a higher frequency of diarrhea, infection and peripheral edema than elderly patients treated with vinorelbine+cisplatin. prostate cancer of the 333 patients treated with docetaxel every three weeks plus prednisone in the prostate cancer study (tax327), 209 patients were 65 years of age or greater and 68 patients were older than 75 years. in patients treated with docetaxel every three weeks, the following treatment-emergent adverse reactions occurred at rates ≥10% higher in patients 65 years of age or greater compared to younger patients: anemia (71% vs 59%), infection (37% vs 24%), nail changes (34% vs 23%), anorexia (21% vs 10%), weight loss (15% vs 5%), respectively. breast cancer in the adjuvant breast cancer trial (tax316), docetaxel in combination with doxorubicin and cyclophosphamide was administered to 744 patients of whom 48 (6%) were 65 years of age or greater. the number of elderly patients who received this regimen was not sufficient to determine whether there were differences in safety and efficacy between elderly and younger patients. gastric cancer among the 221 patients treated with docetaxel in combination with cisplatin and fluorouracil in the gastric cancer study, 54 were 65 years of age or older and 2 patients were older than 75 years. in this study, the number of patients who were 65 years of age or older was insufficient to determine whether they respond differently from younger patients. however, the incidence of serious adverse reactions was higher in the elderly patients compared to younger patients. the incidence of the following adverse reactions (all grades, regardless of relationship): lethargy, stomatitis, diarrhea, dizziness, edema, febrile neutropenia/neutropenic infection occurred at rates ≥10% higher in patients who were 65 years of age or older compared to younger patients. elderly patients treated with tcf should be closely monitored. head and neck cancer among the 174 and 251 patients who received the induction treatment with docetaxel in combination with cisplatin and fluorouracil (tpf) for scchn in the tax323 and tax324 studies, 18 (10%) and 32 (13%) of the patients were 65 years of age or older, respectively. these clinical studies of docetaxel in combination with cisplatin and fluorouracil in patients with scchn did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. other reported clinical experience with this treatment regimen has not identified differences in responses between elderly and younger patients. avoid docetaxel in patients with bilirubin >uln and patients with ast and/or alt >1.5 × uln concomitant with alkaline phosphatase >2.5 × uln [see boxed warning, warnings and precautions (5.2), clinical pharmacology (12.3)] . the alcohol content of docetaxel injection should be taken into account when given to patients with hepatic impairment [see warnings and precautions (5.13)] .

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winthrop u.s, a business of sanofi-aventis u.s. llc - leflunomide (unii: g162gk9u4w) (leflunomide - unii:g162gk9u4w) - leflunomide 10 mg - leflunomide is indicated for the treatment of adults with active rheumatoid arthritis (ra). leflunomide is contraindicated in: - pregnant women. leflunomide may cause fetal harm. if a woman becomes pregnant while taking this drug, stop leflunomide, apprise the patient of the potential hazard to the fetus, and begin a drug elimination procedure [see warnings and precautions (5.1,5.3)and use in specific populations (8.1)]. - patients with severe hepatic impairment [see warnings and precautions (5.2)]. - patients with known hypersensitivity to leflunomide or any of the other components of leflunomide. known reactions include anaphylaxis [see adverse reactions (6.1)]. - patients being treated with teriflunomide [see drug interactions (7)]. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to leflunomide during pregnancy. health care providers and patients are encouraged to report pregnancies by calling 1-877-311-8972 or visit http://www.pregnancystudies.org/participate-in-a-study/. risk summary leflunomide is contraindicated for use in pregnant women because of the potential for fetal harm. in animal reproduction studies, oral administration of leflunomide during organogenesis at a dose of 1/10 of, and equivalent to, the maximum recommended human dose (mrhd) based on auc, respectively, in rats and rabbits, caused teratogenicity (rats and rabbits), and embryo-lethality (rats) [see data] . pregnancy exposure registry data are not available at this time to inform the presence or absence of drug-associated risk with the use of leflunomide during pregnancy. the background risk of major birth defects and miscarriage for the indicated populations is unknown. the background risk in the u.s. general population of major birth defects is 2%–4% and of miscarriage is 15%–20% of clinically recognized pregnancies. if this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, stop treatment with leflunomide, apprise the patient of the potential hazard to a fetus, and perform the accelerated drug elimination procedure to achieve teriflunomide concentrations of less than 0.02 mg/l (0.02 mcg/ml) [see warnings and precautions (5.3)] . clinical considerations fetal/neonatal adverse reactions lowering the plasma concentration of the active metabolite, teriflunomide, by instituting an accelerated drug elimination procedure as soon as pregnancy is detected may decrease the risk to the fetus from leflunomide. the accelerated drug elimination procedure includes verification that the plasma teriflunomide concentration is less than 0.02 mg/l [see warnings and precautions (5.3)and clinical pharmacology (12.3)] . data animal data in an embryo-fetal development study, pregnant rats administered leflunomide during organogenesis from gestation days 7 to 19 at a dose approximately 1/10 of the mrhd (on an auc basis at a maternal oral dose of 15 mg/kg), teratogenic effects, most notably anophthalmia or microphthalmia and internal hydrocephalus, were observed. under these exposure conditions, leflunomide also caused a decrease in the maternal body weight and an increase in embryolethality with a decrease in fetal body weight for surviving fetuses. in an embryo-fetal development study, pregnant rabbits administered leflunomide during organogenesis from gestation days 6 to 18 at a dose approximately equivalent to the mrhd (on an auc basis at a maternal oral dose of 10 mg/kg), a teratogenic finding of fused, dysplastic sternebrae was observed. leflunomide was not teratogenic in rats and rabbits at doses approximately 1/150 and 1/10 of the mrhd, respectively (on an auc basis at maternal oral dose of 1 mg/kg in both rats and rabbits). in a pre and postnatal development study, when female rats were treated with leflunomide at a dose that was approximately 1/100 of the mrhd (on an auc basis at a maternal dose of 1.25 mg/kg) beginning 14 days before mating and continuing until the end of lactation, the offspring exhibited marked (greater than 90%) decreases in postnatal survival. risk summary clinical lactation studies have not been conducted to assess the presence of leflunomide in human milk, the effects of leflunomide on the breastfed child, or the effects of leflunomide on milk production. because of the potential for serious adverse reactions in a breastfed infant from leflunomide, advise a nursing woman to discontinue breastfeeding during treatment with leflunomide. leflunomide may cause fetal harm when administered during pregnancy. advise females of the potential risk to the fetus. advise females to notify their healthcare provider immediately if pregnancy occurs or is suspected during treatment [see use in specific populations (8.1)] . women receiving leflunomide treatment who wish to become pregnant should discontinue leflunomide and undergo an accelerated drug elimination procedure to achieve plasma teriflunomide concentrations of less than 0.02 mg/l (0.02 mcg/ml) [see warnings and precautions (5.3)] . pregnancy testing exclude pregnancy in females of reproductive potential before starting treatment with leflunomide. contraception females advise females of reproductive potential to use effective contraception during treatment with leflunomide and while undergoing a drug elimination procedure until verification that the plasma teriflunomide concentration is less than 0.02 mg/l [see warnings and precautions (5.3)] . the safety and effectiveness of leflunomide in pediatric patients have not been established. the safety and effectiveness of leflunomide in the treatment of polyarticular course juvenile idiopathic arthritis (jia) was evaluated in a single multicenter, double-blind, active-controlled trial in 94 pediatric patients (1:1 randomization) with polyarticular course juvenile idiopathic arthritis (jia) as defined by the american college of rheumatology (acr). in this population, leflunomide treatment was found not to be effective. the safety of leflunomide was studied in 74 patients with polyarticular course jia ranging in age from 3–17 years (47 patients from the active-controlled study and 27 from an open-label safety and pharmacokinetic study). the most common adverse events included abdominal pain, diarrhea, nausea, vomiting, oral ulcers, upper respiratory tract infections, alopecia, rash, headache, and dizziness. less common adverse events included anemia, hypertension, and weight loss. fourteen pediatric patients experienced alt and/or ast elevations, nine between 1.2 and 3-fold the upper limit of normal, and five between 3 and 8-fold the upper limit of normal. of the total number of subjects in controlled clinical trials (trials 1, 2, and 3) of leflunomide, 234 subjects were 65 years and over [see clinical studies (14)] . 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. no dosage adjustment is needed in patients over 65. dedicated studies of the effect of hepatic impairment on leflunomide pharmacokinetics have not been conducted. given the need to metabolize leflunomide into the active species, the role of the liver in drug elimination/recycling, and the possible risk of increased hepatic toxicity, the use of leflunomide in patients with hepatic impairment is not recommended. dedicated studies of the effect of renal impairment on leflunomide pharmacokinetics have not been conducted. given that the kidney plays an important role in drug elimination, caution should be used when leflunomide is administered to these patients.

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winthrop u.s, a business of sanofi-aventis u.s. llc - clofarabine (unii: 762rdy0y2h) (clofarabine - unii:762rdy0y2h) - clofarabine 1 mg in 1 ml - clofarabine is indicated for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. this indication is based upon response rate. there are no trials verifying an improvement in disease-related symptoms or increased survival with clofarabine. none. risk summary in animal reproduction studies, intravenous administration of clofarabine to pregnant rats and rabbits during organogenesis at doses approximately 0.2 to 1-times the maximum recommended human dose of 52 mg/m 2 based on body surface area (bsa) resulted in embryo-fetal mortality, alterations to growth, and structural abnormalities (see data) . advise pregnant women of the potential risk to a fetus. there are no available data on clofarabine use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. clofarabine should be used during pregnancy only if the potential benefits to the mother outweigh the potential risks, including those to the fetus. the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. data animal data intravenous administration of clofarabine to pregnant rats during organogenesis (gestation days [gd] 7–17) at doses of 1, 3 or 9 mg/kg/day (equivalent to 6, 18, 54 mg/m 2 /day) resulted in maternal toxicities at the 9 mg/kg dose, as indicated by reduced body weights and food consumption. developmental toxicity (i.e., reduced fetal body weights and increased postimplantation loss) and increased incidences of external, soft tissue, and skeletal malformations and variations (including retarded ossification) were observed at 9 mg/kg/day (54 mg/m 2 ; approximately equivalent to the recommended human dose based on bsa). altered ossification patterns (extra metacarpal or metatarsal ossification) were observed in single fetuses at lower doses of clofarabine (1 and 3 mg/kg/day; 0.1- and 0.3-times the recommended human dose based on bsa). when clofarabine was administered intravenously to pregnant rabbits during organogenesis (gd 6–18) at doses of 0.1, 0.3, or 1 mg/kg/day (equivalent to 1.2, 3.6, 12 mg/m 2 /day), developmental toxicity (i.e., reduced fetal body weights and increased postimplantation loss) and increased incidences of external, soft tissue, and skeletal malformations and variations (including retarded ossification) were observed at the 1 mg/kg/day dose (12 mg/m 2 ; 0.2-times the recommended human dose based on bsa). alterations in ossification patterns (increase in the average numbers of ossified thoracic vertebrae and rib pairs, and reduction in the average number of forepaw metacarpals) and abdominal wall defect were observed at 0.3 mg/kg/day (3.6 mg/m 2 ; 0.1-times the recommended human dose based on bsa). risk summary there are no data on the presence of clofarabine in human milk, the effects on the breastfed child, or the effects on milk production. because of the potential for serious adverse reactions in the breastfed child including genotoxicity, advise patients not to breastfeed during treatment with clofarabine, and for at least 2 weeks after the last dose. pregnancy testing pregnancy testing is recommended for females of reproductive potential prior to initiating clofarabine. contraception females clofarabine can cause embryo-fetal harm when administered to pregnant women [see use in specific populations (8.1)] . advise female patients to use effective contraception during treatment with clofarabine and for 6 months after the last dose. males based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with clofarabine and for at least 3 months after the last dose [see nonclinical toxicology (13.1)] . infertility females based on findings from animal studies, clofarabine may impair female fertility [see nonclinical toxicology (13.1)]. the reversibility of the effect on fertility is unknown. males based on findings from animal studies, clofarabine may impair male fertility [see nonclinical toxicology (13.1)]. the reversibility of the effect on fertility is unknown. safety and effectiveness have been established in pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia. safety and effectiveness of clofarabine has not been established in geriatric patients aged 65 and older. safety and effectiveness have not been established in adults. reduce the clofarabine starting dose by 50% in patients with crcl of 30 to 60 ml/min. there is insufficient information to make a dosage recommendation in patients with crcl less than 30 ml/min or in patients on dialysis. the pharmacokinetics of clofarabine in patients with renal impairment and normal renal function were obtained from a population pharmacokinetic analysis of three pediatric and two adult studies. in patients with crcl 60 to less than 90 ml/min (n=47) and crcl 30 to less than 60 ml/min (n=30), the average auc of clofarabine increased by 60% and 140%, respectively, compared to patients with normal (n=66) renal function (crcl greater than 90 ml/min).

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winthrop u.s, a business of sanofi-aventis u.s. llc - oxaliplatin (unii: 04zr38536j) (oxaliplatin - unii:04zr38536j) - oxaliplatin 5 mg in 1 ml - oxaliplatin, in combination with infusional fluorouracil and leucovorin, is indicated for: - adjuvant treatment of stage iii colon cancer in patients who have undergone complete resection of the primary tumor. - treatment of advanced colorectal cancer. oxaliplatin is contraindicated in patients with a history of a hypersensitivity reaction to oxaliplatin or other platinum-based drugs. reactions have included anaphylaxis [see warnings and precautions (5.1)] . risk summary based on its direct interaction with dna, oxaliplatin can cause fetal harm when administered to a pregnant woman. the available human data do not establish the presence or absence of major birth defects or miscarriage related to the use of oxaliplatin. reproductive toxicity studies demonstrated adverse effects on embryo-fetal development in rats at maternal doses that were below the recommended human dose based on body surface area (see data) . advise a pregnant woman of the potential risk to a fetus. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. data animal data pregnant rats were administered oxaliplatin at less than one-tenth the recommended human dose based on body surface area during gestation days (gd)1–5 (preimplantation), gd 6–10, or gd 11–16 (during organogenesis). oxaliplatin caused developmental mortality (increased early resorptions) when administered on days gd 6–10 and gd 11–16 and adversely affected fetal growth (decreased fetal weight, delayed ossification) when administered on days gd 6–10. risk summary there are no data on the presence of oxaliplatin or its metabolites in human or animal milk or its effects on the breastfed infant or on milk production. because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with oxaliplatin and for 3 months after the final dose. pregnancy testing verify pregnancy status in females of reproductive potential prior to initiating oxaliplatin [see use in specific populations (8.1)] . contraception oxaliplatin can cause embryo-fetal harm when administered to a pregnant woman [see use in specific populations (8.1)] . females advise female patients of reproductive potential to use effective contraception while receiving oxaliplatin and for 9 months after the final dose. males based on its mechanism action as a genotoxic drug, advise males with female partners of reproductive potential to use effective contraception while receiving oxaliplatin and for 6 months after the final dose [see nonclinical toxicology (13.1)] . infertility based on animal studies, oxaliplatin may impair fertility in males and females [see nonclinical toxicology (13.1)] . the safety and effectiveness of oxaliplatin in pediatrics have not been established. safety and effectiveness were assessed across 4 open-label studies in 235 patients aged 7 months to 22 years with solid tumors. in a multicenter, open-label, non-comparative, non-randomized study (ard5531), oxaliplatin was administered to 43 patients with refractory or relapsed malignant solid tumors, mainly neuroblastoma and osteosarcoma. the dose limiting toxicity (dlt) was sensory neuropathy at a dose of 110 mg/m 2 . the main adverse reactions were: paresthesia (60%, grade 3–4: 7%), fever (40%, grade 3–4: 7%), and thrombocytopenia (40%, grade 3–4: 27%). no responses were observed. in an open-label non-randomized study (dfi7434), oxaliplatin was administered to 26 pediatric patients with metastatic or unresectable solid tumors, mainly neuroblastoma and ganglioneuroblastoma. the dlt was sensory neuropathy at a dose of 160 mg/m 2 . no responses were observed. in an open-label, single-agent study (ard5021), oxaliplatin was administered to 43 pediatric patients with recurrent or refractory embryonal cns tumors. the most common adverse reactions reported were: leukopenia (67%, grade 3–4: 12%), anemia (65%, grade 3–4: 5%), thrombocytopenia (65%, grade 3–4: 26%), vomiting (65%, grade 3–4: 7%), neutropenia (58%, grade 3–4: 16%), and sensory neuropathy (40%, grade 3–4: 5%). in an open-label single-agent study (ard5530), oxaliplatin was administered to 123 pediatric patients with recurrent solid tumors, including neuroblastoma, osteosarcoma, ewing sarcoma or peripheral pnet, ependymoma, rhabdomyosarcoma, hepatoblastoma, high grade astrocytoma, brain stem glioma, low grade astrocytoma, malignant germ cell tumor and other tumors. the most common adverse reactions reported were: sensory neuropathy (52%, grade 3–4: 12%), thrombocytopenia (37%, grade 3–4: 17%), anemia (37%, grade 3–4: 9%), vomiting (26%, grade 3–4: 4%), increased alt (24%, grade 3–4: 6%), increased ast (24%, grade 3–4: 2%), and nausea (23%, grade 3–4: 3%). the pharmacokinetic parameters of ultrafiltrable platinum were evaluated in 105 pediatric patients during the first cycle. the mean clearance in pediatric patients estimated by the population pharmacokinetic analysis was 4.7 l/h (%cv, 41%). mean platinum pharmacokinetic parameters in ultrafiltrate were c max of 0.75 ± 0.24 mcg/ml, auc 0–48h of 7.52 ± 5.07 mcg∙h/ml and auc inf of 8.83 ± 1.57 mcg∙h/ml at 85 mg/m 2 of oxaliplatin and c max of 1.10 ± 0.43 mcg/ml, auc 0–48h of 9.74 ± 2.52 mcg∙h/ml and auc inf of 17.3 ± 5.34 mcg∙h/ml at 130 mg/m 2 of oxaliplatin. in the adjuvant treatment trial [see clinical studies (14.1)] , 400 patients who received oxaliplatin with fluorouracil/leucovorin were greater than or equal to 65 years. the effect of oxaliplatin in patients greater than or equal to 65 years was not conclusive. patients greater than or equal to 65 years receiving oxaliplatin experienced more diarrhea and grade 3–4 neutropenia (45% vs 39%) compared to patients less than 65 years. in the previously untreated advanced colorectal cancer trial [see clinical studies (14.2)] , 99 patients who received oxaliplatin with fluorouracil and leucovorin were greater than or equal to 65 years. the same efficacy improvements in response rate, time to tumor progression, and overall survival were observed in the greater than or equal to 65 years patients as in the overall study population. adverse reactions were similar in patients less than 65 and greater than or equal to 65 years, but older patients may have been more susceptible to diarrhea, dehydration, hypokalemia, leukopenia, fatigue, and syncope. in the previously treated advanced colorectal cancer trial [see clinical studies (14.3)] , 55 patients who received oxaliplatin with fluorouracil and leucovorin were greater than or equal to 65 years. no overall differences in effectiveness were observed between these patients and younger adults. adverse reactions were similar in patients less than 65 and greater than or equal to 65 years, but older patients may have been more susceptible to diarrhea, dehydration, hypokalemia, and fatigue. no significant effect of age on the clearance of ultrafiltrable platinum has been observed [see clinical pharmacology (12.3)] . the auc of unbound platinum in plasma ultrafiltrate was increased in patients with renal impairment [see clinical pharmacology (12.3)] . no dose reduction is recommended for patients with mild (creatinine clearance 50 to 79 ml/min) or moderate (creatinine clearance 30 to 49 ml/min) renal impairment, calculated by cockcroft-gault equation. reduce the dose of oxaliplatin in patients with severe renal impairment (creatinine clearance less than 30 ml/min) [see dosage and administration (2.3)].

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

winthrop u.s, a business of sanofi-aventis u.s. llc - irbesartan (unii: j0e2756z7n) (irbesartan - unii:j0e2756z7n), hydrochlorothiazide (unii: 0j48lph2th) (hydrochlorothiazide - unii:0j48lph2th) - irbesartan and hydrochlorothiazide tablets are indicated for the treatment of hypertension. irbesartan and hydrochlorothiazide may be used in patients whose blood pressure is not adequately controlled on monotherapy. irbesartan and hydrochlorothiazide may also be used as initial therapy in patients who are likely to need multiple drugs to achieve their blood pressure goals. the choice of irbesartan and hydrochlorothiazide as initial therapy for hypertension should be based on an assessment of potential benefits and risks. patients with stage 2 (moderate or severe) hypertension are at relatively high risk for cardiovascular events (such as strokes, heart attacks, and heart failure), kidney failure, and vision problems, so prompt treatment is clinically relevant. the decision to use a combination as initial therapy should be individualized and may be shaped by considerations such as the baseline blood pressure, the target goal, and the incremental likelihood of achieving goal with a combination compared with monotherapy. data from studies v and vi [see clinical studies (14.2)] provide estimates of the probability of reaching a blood pressure goal with irbesartan and hydrochlorothiazide compared to irbesartan or hydrochlorothiazide (hctz) monotherapy. the relationship between baseline blood pressure and achievement of a sesbp <140 or <130 mmhg or sedbp <90 or <80 mmhg in patients treated with irbesartan and hydrochlorothiazide compared to patients treated with irbesartan or hctz monotherapy are shown in figures 1a through 2b. the above graphs provide a rough approximation of the likelihood of reaching a targeted blood pressure goal (e.g., week 8 sitting systolic blood pressure ≤140 mmhg) for the treatment groups. the curve of each treatment group in each study was estimated by logistic regression modeling from all available data of that treatment group. the estimated likelihood at the right tail of each curve is less reliable due to small numbers of subjects with high baseline blood pressures. for example, a patient with a blood pressure of 180/105 mmhg has about a 25% likelihood of achieving a goal of <140 mmhg (systolic) and 50% likelihood of achieving <90 mmhg (diastolic) on irbesartan alone (and lower still likelihoods on hctz alone). the likelihood of achieving these goals on irbesartan and hydrochlorothiazide rises to about 40% (systolic) or 70% (diastolic). - irbesartan and hydrochlorothiazide is contraindicated in patients who are hypersensitive to any component of this product. - because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs. - do not coadminister aliskiren with irbesartan and hydrochlorothiazide in patients with diabetes [see drug interactions (7)] . risk summary irbesartan and hydrochlorothiazide 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. when pregnancy is detected, discontinue irbesartan and hydrochlorothiazide as soon as possible. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes regardless of drug exposure. 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 hypertension in pregnancy increases the maternal risk for preeclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and postpartum hemorrhage). hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. pregnant women with hypertension should be carefully monitored and managed accordingly. 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 pregnancy. patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. closely observe infants with histories of in utero exposure to irbesartan and hydrochlorothiazide for hypotension, oliguria, and hyperkalemia and other symptoms of renal impairment. in neonates with a history of in utero exposure to irbesartan and hydrochlorothiazide, if oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function. thiazides cross the placenta, and use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults [see warnings and precautions (5.1)] . data animal data irbesartan crosses the placenta in rats and rabbits. in female rats given irbesartan prior to mating through gestation and lactation at oral doses of 50, 180, or 650 mg/kg/day (1.6 to 21.1 times the maximum recommended human dose (mrhd) based on body surface area), fetuses examined on gestation day 20 showed increased incidences of hydroureter and renal pelvic cavitation and/or absence of renal papilla in all irbesartan-treated groups. subcutaneous edema also occurred in fetuses at maternal doses ≥180 mg/kg/day (5.8 times the mrhd). these anomalies occurred when female rats received irbesartan from prior to mating through day 20 of gestation but were not observed in pups postnatally in the same study, or when irbesartan was given to pregnant rats only during organogenesis (gestation day 6 through gestation day 15) at oral doses from 50 to 450 mg/kg/day (up to 14.6 times the mrhd). in addition, no adverse effects on kidney development were observed in pups from dams given irbesartan from gestation day 15 through lactation day 24 at doses of 50, 180, or 650 mg/kg/day (up to 21.1 times the mrhd). the observed effects are believed to be late gestational effects of the drug. pregnant rabbits given oral doses of irbesartan of 30 mg/kg/day (1.9 times the mrhd based on body surface area) experienced a high rate of maternal mortality and abortion. surviving females had a slight increase in early resorptions and a corresponding decrease in live fetuses. radioactivity was present in the rat and rabbit fetuses during late gestation following oral doses of radiolabeled irbesartan. when pregnant mice and rats were given hydrochlorothiazide at doses up to 3000 and 1000 mg/kg/day, respectively (about 600 and 400 times the mrhd) during their respective periods of major organogenesis, there was no evidence of fetal harm. a development toxicity study was performed in rats with doses of 50/50 mg/kg/day and 150/150 mg/kg/day irbesartan and hydrochlorothiazide. although the high dose combination appeared to be more toxic to the dams than either drug alone, there did not appear to be an increase in toxicity to the developing embryos. there are no available data on the presence of irbesartan in human milk, effects on milk production, or the breastfed infant. irbesartan or some metabolite of irbesartan is secreted in the milk of lactating rats. thiazides appear in human milk [see clinical pharmacology (12.3)] . because of the potential for adverse effects on the nursing infant, the use of irbesartan and hydrochlorothiazide in breastfeeding women is not recommended. safety and effectiveness in pediatric patients have not been established. of 1694 patients receiving irbesartan and hydrochlorothiazide in controlled clinical studies of hypertension, 264 (15.6%) were 65 years and over, while 45 (2.7%) were 75 years and over. no overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. [see clinical pharmacology (12.3)and clinical studies (14).]

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

winthrop u.s, a business of sanofi-aventis u.s. llc - irbesartan (unii: j0e2756z7n) (irbesartan - unii:j0e2756z7n) - irbesartan is indicated for the treatment of hypertension, to lower blood pressure. lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular (cv) events, primarily strokes and myocardial infarction. these benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including this drug. control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. many patients will require more than 1 drug to achieve blood pressure goals. for specific advice on goals and management, see published guidelines, such as those of the national high blood pressure education program's joint national committee on prevention, detection, evaluation, and treatment of high blood pressure (jnc). numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. the largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmhg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). these considerations may guide selection of therapy. irbesartan may be used alone or in combination with other antihypertensive agents. irbesartan is indicated for the treatment of diabetic nephropathy in patients with type 2 diabetes and hypertension, an elevated serum creatinine, and proteinuria (>300 mg/day). in this population, irbesartan reduces the rate of progression of nephropathy as measured by the occurrence of doubling of serum creatinine or end-stage renal disease (need for dialysis or renal transplantation) [see clinical studies (14.2)] . irbesartan is contraindicated in patients who are hypersensitive to any component of this product. do not coadminister aliskiren with irbesartan in patients with diabetes. risk summary irbesartan 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. when pregnancy is detected, discontinue irbesartan as soon as possible. all pregnancies have a background risk of birth defect, loss or other adverse outcomes regardless of drug exposure. 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 hypertension in pregnancy increases the maternal risk for preeclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and postpartum hemorrhage). hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. pregnant women with hypertension should be carefully monitored and managed accordingly. 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. in the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. perform serial ultrasound examinations to assess the intra-amniotic environment. fetal testing may be appropriate, based on the week of pregnancy. 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 treatment. closely observe infants with histories of in utero exposure to irbesartan for hypotension, oliguria, and hyperkalemia and other symptoms of renal impairment. in neonates with a history of in utero exposure to irbesartan, if oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function. data animal data irbesartan crosses the placenta in rats and rabbits. in female rats given irbesartan prior to mating through gestation and lactation at oral doses of 50, 180, or 650 mg/kg/day (1.6 to 21.1 times the maximum recommended human dose (mrhd) based on body surface area), fetuses examined on gestation day 20 showed increased incidences of hydroureter and renal pelvic cavitation and/or absence of renal papilla in all irbesartan-treated groups. subcutaneous edema also occurred in fetuses at maternal doses ≥180 mg/kg/day (5.8 times the mrhd). these anomalies occurred when female rats received irbesartan from prior to mating through day 20 of gestation but were not observed in pups postnatally in the same study, or when irbesartan was given to pregnant rats only during organogenesis (gestation day 6 through gestation day 15) at oral doses from 50 to 450 mg/kg/day (up to 14.6 times the mrhd). in addition, no adverse effects on kidney development were observed in pups from dams given irbesartan from gestation day 15 through lactation day 24 at doses of 50, 180, or 650 mg/kg/day (up to 21.1 times the mrhd). the observed effects are believed to be late gestational effects of the drug. pregnant rabbits given oral doses of irbesartan of 30 mg/kg/day (1.9 times the mrhd based on body surface area) experienced a high rate of maternal mortality and abortion. surviving females had a slight increase in early resorptions and a corresponding decrease in live fetuses. radioactivity was present in the rat and rabbit fetuses during late gestation following oral doses of radiolabeled irbesartan. there are no available data on the presence of irbesartan in human milk, effects on milk production, or the breastfed infant. irbesartan or some metabolite of irbesartan is secreted in the milk of lactating rats [see clinical pharmacology (12.3)] . because of the potential for adverse effects on the nursing infant, the use of irbesartan in breastfeeding women is not recommended. irbesartan, in a study at a dose of up to 4.5 mg/kg/day, once daily, did not appear to lower blood pressure effectively in pediatric patients ages 6 to 16 years. irbesartan has not been studied in pediatric patients less than 6 years old. of 4925 subjects receiving irbesartan in controlled clinical studies of hypertension, 911 (18.5%) were 65 years and over, while 150 (3.0%) were 75 years and over. no overall differences in effectiveness or safety were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out. [see clinical pharmacology (12.3)and clinical studies (14.1).]