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

sun pharmaceutical industries, inc. - sumatriptan succinate (unii: j8bdz68989) (sumatriptan - unii:8r78f6l9vo) - sumatriptan 25 mg - sumatriptan succinate tablets are indicated for the acute treatment of migraine with or without aura in adults. limitations of use: - use only if a clear diagnosis of migraine headache has been established. if a patient has no response to the first migraine attack treated with sumatriptan succinate tablets, reconsider the diagnosis of migraine before sumatriptan succinate tablets are administered to treat any subsequent attacks. - sumatriptan succinate tablets are not indicated for the prevention of migraine attacks. - safety and effectiveness of sumatriptan succinate tablets have not been established for cluster headache. sumatriptan succinate tablets are contraindicated in patients with: - ischemic coronary artery disease (cad) (angina pectoris, history of myocardial infarction, or documented silent ischemia) or coronary artery vasospasm, including prinzmetal's angina [see warnings and precautions (5.1)] - wolff-parkinson-white syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders [see warnings and precautions (5.2)] - history of stroke or transient ischemic attack (tia) or history of hemiplegic or basilar migraine because these patients are at a higher risk of stroke [s ee warnings and precautions (5.4)] - peripheral vascular disease [see warnings and precautions (5.5)] - ischemic bowel disease [see warnings and precautions (5.5)] - uncontrolled hypertension [see warnings and precautions (5.8)] - recent use (i.e., within 24 hours) of ergotamine-containing medication, ergot-type medication (such as dihydroergotamine or methysergide), or another 5-hydroxytryptamine1 (5-ht1 ) agonist [see drug interactions (7.1, 7.3)] - concurrent administration of a monoamine oxidase (mao)-a inhibitor or recent (within 2 weeks) use of an mao-a inhibitor [see drug interactions (7.2), clinical pharmacology (12.3)] - hypersensitivity to sumatriptan succinate tablets (angioedema and anaphylaxis seen) [see warnings and precautions (5.9)] - severe hepatic impairment [see use in specific populations (8.6), clinical pharmacology (12.3)] risk summary data from a prospective pregnancy exposure registry and epidemiological studies of pregnant women have not detected an increased frequency of birth defects or a consistent pattern of birth defects among women exposed to sumatriptan compared with the general population (see data). in developmental toxicity studies in rats and rabbits, oral administration of sumatriptan to pregnant animals was associated with embryolethality, fetal abnormalities, and pup mortality. when administered by the intravenous route to pregnant rabbits, sumatriptan was embryolethal (see data) . in the u.s. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. the reported rate of major birth defects among deliveries to women with migraine ranged from 2.2% to 2.9% and the reported rate of miscarriage was 17%, which were similar to rates reported in women without migraine. clinical considerations disease-associated maternal and/or embryo/fetal risk: several studies have suggested that women with migraine may be at increased risk of preeclampsia during pregnancy. data human data: the sumatriptan/naratriptan/treximet* (sumatriptan and naproxen sodium) pregnancy registry, a population-based international prospective study, collected data for sumatriptan from january 1996 to september 2012. the registry documented outcomes of 626 infants and fetuses exposed to sumatriptan during pregnancy (528 with earliest exposure during the first trimester, 78 during the second trimester, 16 during the third trimester, and 4 unknown). the occurrence of major birth defects (excluding fetal deaths and induced abortions without reported defects and all spontaneous pregnancy losses) during first-trimester exposure to sumatriptan was 4.2% (20/478 [95% ci: 2.6% to 6.5%]) and during any trimester of exposure was 4.2% (24/576 [95% ci: 2.7% to 6.2%]). the sample size in this study had 80% power to detect at least a 1.73- to 1.91-fold increase in the rate of major malformations. the number of exposed pregnancy outcomes accumulated during the registry was insufficient to support definitive conclusions about overall malformation risk or for making comparisons of the frequencies of specific birth defects. of the 20 infants with reported birth defects after exposure to sumatriptan in the first trimester, 4 infants had ventricular septal defects, including one infant who was exposed to both sumatriptan and naratriptan, and 3 infants had pyloric stenosis. no other birth defect was reported for more than 2 infants in this group. in a study using data from the swedish medical birth register, live births to women who reported using triptans or ergots during pregnancy were compared with those of women who did not. of the 2,257 births with first-trimester exposure to sumatriptan, 107 infants were born with malformations (relative risk 0.99 [95% ci: 0.91 to 1.21]). a study using linked data from the medical birth registry of norway to the norwegian prescription database compared pregnancy outcomes in women who redeemed prescriptions for triptans during pregnancy, as well as a migraine disease comparison group who redeemed prescriptions for sumatriptan before pregnancy only, compared with a population control group. of the 415 women who redeemed prescriptions for sumatriptan during the first trimester, 15 had infants with major congenital malformations (or 1.16 [95% ci: 0.69 to 1.94]) while for the 364 women who redeemed prescriptions for sumatriptan before, but not during, pregnancy, 20 had infants with major congenital malformations (or 1.83 [95% ci: 1.17 to 2.88]), each compared with the population comparison group. additional smaller observational studies evaluating use of sumatriptan during pregnancy have not suggested an increased risk of teratogenicity. animal data: oral administration of sumatriptan to pregnant rats during the period of organogenesis resulted in an increased incidence of fetal blood vessel (cervicothoracic and umbilical) abnormalities. the highest no-effect dose for embryofetal developmental toxicity in rats was 60 mg/kg/day, or approximately 3 times the maximum recommended human dose (mrhd) of 200 mg/day on a mg/m2 basis. oral administration of sumatriptan to pregnant rabbits during the period of organogenesis resulted in increased incidences of embryolethality and fetal cervicothoracic vascular and skeletal abnormalities. intravenous administration of sumatriptan to pregnant rabbits during the period of organogenesis resulted in an increased incidence of embryolethality. the highest oral and intravenous no-effect doses for developmental toxicity in rabbits were 15 (approximately 2 times the mrhd on a mg/m2 basis) and 0.75 mg/kg/day, respectively. oral administration of sumatriptan to rats prior to and throughout gestation resulted in embryofetal toxicity (decreased body weight, decreased ossification, increased incidence of skeletal abnormalities). the highest no-effect dose was 50 mg/kg/day, or approximately 2 times the mrhd on a mg/m2 basis. in offspring of pregnant rats treated orally with sumatriptan during organogenesis, there was a decrease in pup survival. the highest no-effect dose for this effect was 60 mg/kg/day, or approximately 3 times the mrhd on a mg/m2 basis. oral treatment of pregnant rats with sumatriptan during the latter part of gestation and throughout lactation resulted in a decrease in pup survival. the highest no-effect dose for this finding was 100 mg/kg/day, or approximately 5 times the mrhd on a mg/m2 basis. risk summary sumatriptan is excreted in human milk following subcutaneous administration (see data). there is no information regarding sumatriptan concentrations in milk from lactating women following administration of sumatriptan succinate tablets. there are no data on the effects of sumatriptan on the breastfed infant or the effects of sumatriptan on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for sumatriptan succinate tablets and any potential adverse effects on the breastfed infant from sumatriptan or from the underlying maternal condition. clinical considerations infant exposure to sumatriptan can be minimized by avoiding breastfeeding for 12 hours after treatment with sumatriptan succinate tablets. data following subcutaneous administration of a 6 mg dose of sumatriptan injection in 5 lactating volunteers, sumatriptan was present in milk. safety and effectiveness in pediatric patients have not been established. sumatriptan succinate tablets are not recommended for use in patients younger than 18 years of age. two controlled clinical trials evaluated sumatriptan nasal spray (5 mg to 20 mg) in 1,248 adolescent migraineurs aged 12 to 17 years who treated a single attack. the trials did not establish the efficacy of sumatriptan nasal spray compared with placebo in the treatment of migraine in adolescents. adverse reactions observed in these clinical trials were similar in nature to those reported in clinical trials in adults. five controlled clinical trials (2 single-attack trials, 3 multiple-attack trials) evaluating oral sumatriptan succinate tablets (25 mg to 100 mg) in pediatric patients aged 12 to 17 years enrolled a total of 701 adolescent migraineurs. these trials did not establish the efficacy of oral sumatriptan succinate tablets compared with placebo in the treatment of migraine in adolescents. adverse reactions observed in these clinical trials were similar in nature to those reported in clinical trials in adults. the frequency of all adverse reactions in these patients appeared to be both dose- and age-dependent, with younger patients reporting reactions more commonly than older adolescents. postmarketing experience documents that serious adverse reactions have occurred in the pediatric population after use of subcutaneous, oral, and/or intranasal sumatriptan succinate. these reports include reactions similar in nature to those reported rarely in adults, including stroke, visual loss, and death. a myocardial infarction has been reported in a 14-year-old male following the use of oral sumatriptan succinate tablets; clinical signs occurred within 1 day of drug administration. clinical data to determine the frequency of serious adverse reactions in pediatric patients who might receive subcutaneous, oral, or intranasal sumatriptan succinate are not presently available. clinical trials of sumatriptan succinate tablets did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients. other reported clinical experience has not identified differences in responses between the elderly and younger patients. in general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. a cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of cad) prior to receiving sumatriptan succinate tablets [see warnings and precautions (5.1)] . the maximum single dose in patients with mild to moderate hepatic impairment should not exceed 50 mg. sumatriptan succinate tablets are contraindicated in patients with severe hepatic impairment [see clinical pharmacology (12.3)] .

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

alcon laboratories, inc. - loteprednol etabonate (unii: yeh1ez96k6) (loteprednol - unii:z8cbu6kr16) - eysuvis is a corticosteroid indicated for the short-term (up to two weeks) treatment of the signs and symptoms of dry eye disease. eysuvis, as with other ophthalmic corticosteroids, is contraindicated in most viral diseases of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also in mycobacterial infection of the eye and fungal diseases of ocular structures. risk summary there are no adequate and well controlled studies with loteprednol etabonate in pregnant women. loteprednol etabonate produced teratogenicity at clinically relevant doses in the rabbit and rat when administered orally during pregnancy. loteprednol etabonate produced malformations when administered orally to pregnant rabbits at doses 1.4 times the recommended human ophthalmic dose (rhod) and to pregnant rats at doses 34 times the rhod. in pregnant rats receiving oral doses of loteprednol etabonate during the period equivalent to the last trimester of pregnancy through lactation in humans, survival of offspring was reduced at doses 3.4 times the rhod. maternal toxicity was observed in rats at doses 347 times the rhod, and a maternal no observed adverse effect level (noael) was established at 34 times the rhod. the background risk in the u.s. general population of major birth defects is 2 to 4%, and of miscarriage is 15 to 20%, of clinically recognized pregnancies. data animal data embryofetal studies were conducted in pregnant rabbits administered loteprednol etabonate by oral gavage on gestation days 6 to 18, to target the period of organogenesis. loteprednol etabonate produced fetal malformations at 0.1 mg/kg (1.4 times the recommended human ophthalmic dose (rhod) based on body surface area, assuming 100% absorption). spina bifida (including meningocele) was observed at 0.1 mg/kg, and exencephaly and craniofacial malformations were observed at 0.4 mg/kg (5.6 times the rhod). at 3 mg/kg (41 times the rhod), loteprednol etabonate was associated with increased incidences of abnormal left common carotid artery, limb flexures, umbilical hernia, scoliosis, and delayed ossification. abortion and embryofetal lethality (resorption) occurred at 6 mg/kg (83 times the rhod). a noael for developmental toxicity was not established in this study. the noael for maternal toxicity in rabbits was 3 mg/kg/day. embryofetal studies were conducted in pregnant rats administered loteprednol etabonate by oral gavage on gestation days 6 to 15, to target the period of organogenesis. loteprednol etabonate produced fetal malformations, including absent innominate artery at 5 mg/kg (34 times the rhod); and cleft palate, agnathia, cardiovascular defects, umbilical hernia, decreased fetal body weight and decreased skeletal ossification at 50 mg/kg (347 times the rhod). embryofetal lethality (resorption) was observed at 100 mg/kg (695 times the rhod). the noael for developmental toxicity in rats was 0.5 mg/kg (3.4 times the rhod). loteprednol etabonate was maternally toxic (reduced body weight gain) at 50 mg/kg/day. the noael for maternal toxicity was 5 mg/kg. a peri-/postnatal study was conducted in rats administered loteprednol etabonate by oral gavage from gestation day 15 (start of fetal period) to postnatal day 21 (the end of lactation period). at 0.5 mg/kg (3.4 times the clinical dose), reduced survival was observed in live-born offspring. doses ≥ 5 mg/kg (34 times the rhod) caused umbilical hernia/incomplete gastrointestinal tract. doses ≥ 50 mg/kg (347 times the rhod) produced maternal toxicity (reduced body weight gain, death), decreased number of live-born offspring, decreased birth weight, and delays in postnatal development. a developmental noael was not established in this study. the noael for maternal toxicity was 5 mg/kg. there are no data on the presence of loteprednol etabonate in human milk, the effects on the breastfed infant, or the effects on milk production. the developmental and health benefits of breastfeeding should be considered, along with the mother's clinical need for eysuvis and any potential adverse effects on the breastfed infant from eysuvis. safety and effectiveness in pediatric patients have not been established. no overall differences in safety and effectiveness have been observed between elderly and younger adult patients. instructions for use eysuvis [eye-su-vis] (loteprednol etabonate ophthalmic suspension) 0.25% for topical ophthalmic use this instructions for use contains information on how to properly administer eysuvis. important information you need to know before using eysuvis - eysuvis is for use in the eye. - wash your hands before using eysuvis. - do not use if the tamper-evident seal is not intact. - do not let the eysuvis dropper tip touch your eye, fingers, or any other surfaces to avoid contamination or injury to your eye. - use eysuvis exactly as your doctor tells you to. - if you are using eysuvis with other eye (ophthalmic) medicines, you should wait at least 5 minutes between using eysuvis and the other medicine. - if you wear contact lenses, remove them before using eysuvis. - put the pink cap back on eysuvis after each use. before you use eysuvis for the first time: there are two caps on your bottle of eysuvis. hold the bottle firmly by its neck. remove the white cap by twisting it clockwise (see figure a) . throw away the white cap. eysuvis is now ready to use. figure a follow steps 1 to 6 each time you use eysuvis. - wash your hands well. - shake the eysuvis bottle for 2 to 3 seconds before using (see figure b) . figure b figure b - remove the pink cap from the top of the eysuvis dropper by turning it counterclockwise (see figure c) . keep the pink cap. do not let the eysuvis dropper tip touch your eye, fingers, or any other surface. figure c figure c - turn the eysuvis bottle upside down (see figure d) . figure d figure d - tilt your head back. hold the bottle directly above your affected eye. squeeze the middle of the eysuvis bottle gently to put 1 to 2 drops (follow your doctor's instruction) into the affected eye (see figure e) . figure e figure e - place the pink cap back onto the eysuvis bottle and tighten by turning clockwise (see figure f) . figure f figure f if you use contact lenses, wait for 15 minutes before placing them back in. how should i store eysuvis? - store eysuvis upright between 59ºf to 77ºf (15ºc to 25ºc). - do not freeze. - after opening, eysuvis can be used until the expiration date (exp) on the bottle. the expiration date can be found on the lower right side of the label on the bottle. keep eysuvis and all medicines out of the reach of children. this instructions for use has been approved by the u.s. food and drug administration. manufactured for: alcon laboratories, inc. fort worth, texas 76134 usa approved 11/2023

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

northwind pharmaceuticals, llc - naproxen (unii: 57y76r9atq) (naproxen - unii:57y76r9atq) - carefully consider the potential benefits and risks of naproxen and other treatment options before deciding to use naproxen tablets. use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see warnings: gastrointestinal bleeding, ulceration, and perforation). naproxen tablets are indicated:    for the relief of the signs and symptoms of rheumatoid arthritis.    for the relief of the signs and symptoms of osteoarthritis    for the relief of the signs and symptoms of ankylosing spondylitis    for the relief of the signs and symptoms of juvenile arthritis    naproxen tablets are also indicated:    for relief of the signs and symptoms of tendonitis    for relief of the signs and symptoms of bursitis    for relief of the signs and symptoms of acute gout    for the management of pain    for the management of primary dysmenorrhea

New Zealand - English - Medsafe (Medicines Safety Authority)

regional health ltd - barium sulfate 83.5%{relative} - enema - 83.5% w/w - active: barium sulfate 83.5%{relative}

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

sun pharmaceutical industries, inc. - riluzole (unii: 7lj087rs6f) (riluzole - unii:7lj087rs6f) - riluzole 50 mg - riluzole tablets, usp are indicated for the treatment of amyotrophic lateral sclerosis (als). riluzole tablets are contraindicated in patients with a history of severe hypersensitivity reactions to riluzole or to any of its components (anaphylaxis has occurred) [see adverse reactions (6.1)] . risk summary there are no studies of riluzole in pregnant women, and case reports have been inadequate to inform the drug-associated risk. the background risk for major birth defects and miscarriage in patients with amyotrophic lateral sclerosis is unknown. in the u.s. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. in studies in which riluzole was administered orally to pregnant animals, developmental toxicity (decreased embryofetal/offspring viability, growth, and functional development) was observed at clinically relevant doses [see data] . based on these results, women should be advised of a possible risk to th

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

genentech, inc. - ibandronate sodium (unii: j12u072ql0) (ibandronic acid - unii:umd7g2653w) - ibandronic acid 150 mg - boniva is indicated for the treatment and prevention of osteoporosis in postmenopausal women. boniva increases bone mineral density (bmd) and reduces the incidence of vertebral fractures. the optimal duration of use has not been determined. the safety and effectiveness of boniva for the treatment of osteoporosis are based on clinical data of three years duration. all patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis. patients at low-risk for fracture should be considered for drug discontinuation after 3 to 5 years of use. patients who discontinue therapy should have their risk for fracture re-evaluated periodically. boniva is contraindicated in patients with the following conditions: - abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia (see warnings and precautions [5.1]) - inability to stand or sit upright for at least 60 minutes (see dosage and administration [2.2], and warnings and precautions [5.1]) - h

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

sun pharmaceutical industries, inc. - hydrocodone bitartrate (unii: no70w886kk) (hydrocodone - unii:6yks4y3wq7), ibuprofen (unii: wk2xyi10qm) (ibuprofen - unii:wk2xyi10qm) - hydrocodone bitartrate 2.5 mg - carefully consider the potential benefits and risks of hydrocodone bitartrate and ibuprofen tablets and other treatment options before deciding to use hydrocodone bitartrate and ibuprofen tablets. use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see warnings ). hydrocodone bitartrate and ibuprofen tablets are indicated for the short-term (generally less than 10 days) management of acute pain. hydrocodone bitartrate and ibuprofen tablets are not indicated for the treatment of such conditions as osteoarthritis or rheumatoid arthritis. hydrocodone bitartrate and ibuprofen tablets are contraindicated in patients with known hypersensitivity to hydrocodone or ibuprofen. patients known to be hypersensitive to other opioids may exhibit cross-sensitivity to hydrocodone. hydrocodone bitartrate and ibuprofen tablets should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other nsaids. severe, rar

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

caraco pharmaceutical laboratories, ltd. - indomethacin (unii: xxe1cet956) (indomethacin - unii:xxe1cet956) - indomethacin 25 mg - carefully consider the potential benefits and risks of indomethacin capsules and other treatment options before deciding to use indomethacin. use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see warnings ). indomethacin has been found effective in active stages of the following: - moderate to severe rheumatoid arthritis including acute flares of chronic disease. - moderate to severe ankylosing spondylitis. - moderate to severe osteoarthritis. - acute painful shoulder (bursitis and/or tendinitis). - acute gouty arthritis. indomethacin is contraindicated in patients with known hypersensitivity to indomethacin or the excipients (see description ). indomethacin should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other nsaids. severe, rarely fatal, anaphylactic/anaphylactoid reactions to nsaids have been reported in such patients (see warnings: anaphylactic/anaphylactoid reactions , and

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

cipla usa inc., - calcium acetate (unii: y882yxf34x) (calcium cation - unii:2m83c4r6zb) - calcium acetate 667 mg - calcium acetate is a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (esrd). patients with hypercalcemia. pregnancy category c calcium acetate capsules contain calcium acetate. animal reproduction studies have not been conducted with calcium acetate, and there are no adequate and well controlled studies of calcium acetate use in pregnant women. patients with end stage renal disease may develop hypercalcemia with calcium acetate treatment [see warnings and precautions (5.1)] . maintenance of normal serum calcium levels is important for maternal and fetal well being. hypercalcemia during pregnancy may increase the risk for maternal and neonatal complications such as stillbirth, preterm delivery, and neonatal hypocalcemia and hypoparathyroidism. calcium acetate treatment, as recommended, is not expected to harm a fetus if maternal calcium levels are properly monitored during and following treatment. the effects of calcium acetate on labor and delivery are unknown. a

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

sun pharmaceutical industries, inc. - tramadol hydrochloride (unii: 9n7r477wck) (tramadol - unii:39j1lgj30j) - tramadol hydrochloride 100 mg - tramadol hydrochloride extended-release tablets are indicated for the management of severe and persistent pain that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options are inadequate. limitations of use - because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosages or duration, and because of the greater risks of overdose and death with extended-release/long-acting opioid formulations [see warnings and precautions (5.1)] , reserve tramadol hydrochloride extended-release tablets for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. - tramadol hydrochloride extended-release tablets are not indicated as an as-needed (prn) analgesic. tramadol hydrochloride extended-release tablets are contraindicated for: - all children younger than 12 years of age [see warnings and precautions (5.6)] - post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see warnings and precautions (5.6)] . tramadol hydrochloride extended-release tablets are also contraindicated in patients with: - significant respiratory depression [see warnings and precautions (5.2)] - acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see warnings and precautions (5.12)] - known or suspected gastrointestinal obstruction, including paralytic ileus [see warnings and precautions (5.16)] - hypersensitivity to tramadol (e.g., anaphylaxis) [see warnings and precautions (5.17), adverse reactions (6.2)] - concurrent use of monoamine oxidase inhibitors (maois) or use within the last 14 days [see drug interactions (7)] . risk summary use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see warnings and precautions (5.4)] . available data with tramadol hydrochloride extended-release tablets in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. in animal reproduction studies, tramadol administration during organogenesis decreased fetal weights and reduced ossification in mice, rats, and rabbits at 1.4, 0.6, and 3.6 times the maximum recommended human daily dosage (mrhd). tramadol decreased pup body weight and increased pup mortality at 1.2 and 1.9 times the mrhd [see data]. based on animal data, advise pregnant women of the potential risk to a 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. clinical considerations fetal/neonatal adverse reactions use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. the onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. observe newborns for symptoms and signs of neonatal opioid withdrawal syndrome and manage accordingly [see warnings and precautions (5.4)] . neonatal seizures, neonatal withdrawal syndrome, fetal death and stillbirth have been reported with tramadol during post-approval use of tramadol immediate-release products. labor or delivery opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. an opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. tramadol hydrochloride extended-release tablets are not recommended for use in pregnant women during or immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. opioid analgesics, including tramadol hydrochloride extended-release tablets, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. however, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. tramadol has been shown to cross the placenta. the mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labor. the effect of tramadol hydrochloride extended-release tablets, if any, on the later growth, development, and functional maturation of the child is unknown. data animal data tramadol has been shown to be embryotoxic and fetotoxic in mice, (120 mg/kg), rats (25 mg/kg) and rabbits (75 mg/kg) at maternally toxic dosages, but was not teratogenic at these dose levels. these doses on a mg/m2 basis are 1.9, 0.8, and 4.9 times the maximum recommended human daily dosage (mrhd) for mouse, rat and rabbit, respectively. no drug-related teratogenic effects were observed in progeny of mice (up to 140 mg/kg), rats (up to 80 mg/kg) or rabbits (up to 300 mg/kg) treated with tramadol by various routes. embryo and fetal toxicity consisted primarily of decreased fetal weights, decreased skeletal ossification, and increased supernumerary ribs at maternally toxic dose levels. transient delays in developmental or behavioral parameters were also seen in pups from rat dams allowed to deliver. embryo and fetal lethality were reported only in one rabbit study at 300 mg/kg, a dose that would cause extreme maternal toxicity in the rabbit. the dosages listed for mouse, rat, and rabbit are 2.3, 2.6, and 19 times the mrhd, respectively. tramadol was evaluated in pre- and post-natal studies in rats. progeny of dams receiving oral (gavage) dose levels of 50 mg/kg (1.6 times the mrhd) or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (2.6 times the mrhd). risk summary tramadol hydrochloride extended-release tablets are not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied. tramadol and its metabolite, o-desmethyl tramadol (m1), are present in human milk. there is no information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. the m1 metabolite is more potent than tramadol in mu opioid receptor binding [see clinical pharmacology (12.1) ]. published studies have reported tramadol and m1 in colostrum with administration of tramadol to nursing mothers in the early post-partum period. women who are ultra-rapid metabolizers of tramadol may have higher than expected serum levels of m1, potentially leading to higher levels of m1 in breast milk that can be dangerous in their breastfed infants. in women with normal tramadol metabolism, the amount of tramadol secreted into human milk is low and dose-dependent. because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with tramadol hydrochloride extended-release tablets. clinical considerations if infants are exposed to tramadol hydrochloride extended-release tablets through breast milk, they should be monitored for excess sedation and respiratory depression. withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. data  following a single iv 100 mg dose of tramadol, the cumulative excretion in breast milk within 16 hours post dose was 100 mcg of tramadol (0.1% of the maternal dose) and 27 mcg of m1. infertility use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. it is not known whether these effects on fertility are reversible [see adverse reactions (6.2), clinical pharmacology (12.2), nonclinical toxicology (13.1) ]. the safety and effectiveness of tramadol hydrochloride extended-release tablets in pediatric patients have not been established. life-threatening respiratory depression and death have occurred in children who received tramadol [see warnings and precautions (5.6)] . in some of the reported cases, these events followed tonsillectomy and/or adenoidectomy, and one of the children had evidence of being an ultra-rapid metabolizer of tramadol (i.e., multiple copies of the gene for cytochrome p450 isoenzyme 2d6). children with sleep apnea may be particularly sensitive to the respiratory depressant effects of tramadol. because of the risk of life-threatening respiratory depression and death: - tramadol hydrochloride extended-release tablets are contraindicated for all children younger than age 12 years of age [see contraindications (4) ]. - tramadol hydrochloride extended-release tablets are contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see  contraindications (4) ]. - avoid the use of tramadol hydrochloride extended-release tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol unless the benefits outweigh the risks. risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression. [see warnings and precautions (5.6)] . nine-hundred-one elderly (65 years of age or older) subjects were exposed to tramadol hydrochloride extended-release tablets in clinical trials. of those subjects, 156 were 75 years of age and older. in general, higher incidence rates of adverse events were observed for patients older than 65 years of age compared with patients 65 years and younger, particularly for the following adverse events: constipation, fatigue, weakness, postural hypotension and dyspepsia. for this reason, tramadol hydrochloride extended-release tablets should be used with caution in patients over 65 years of age, and with even greater caution in patients older than 75 years of age [see dosage and administration (2.5), clinical pharmacology (12.3)]. respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioidtolerant or when opioids were co-administered with other agents that depress respiration. titrate the dosage of tramadol hydrochloride extended-release tablets slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see warnings and precautions (5.12)] . tramadol is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. metabolism of tramadol and m1 is reduced in patients with advanced cirrhosis of the liver. tramadol hydrochloride extended-release tablets have not been studied in patients with severe hepatic impairment. the limited availability of dose strengths and once daily dosing of tramadol hydrochloride extended-release tablets do not permit the dosing flexibility required for safe use in patients with severe hepatic impairment (child-pugh class c). therefore, tramadol hydrochloride extended-release tablets should not be used in patients with severe hepatic impairment [see clinical pharmacology (12.3) ]. impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, m1. tramadol hydrochloride extended-release tablets have not been studied in patients with severe renal impairment (clcr < 30 ml/min). the limited availability of dose strengths and once daily dosing of tramadol hydrochloride extended-release tablets do not permit the dosing flexibility required for safe use in patients with severe renal impairment (child-pugh class c). therefore, tramadol hydrochloride extended-release tablets should not be used in patients with severe renal impairment [see clinical pharmacology (12.3)] . tramadol hydrochloride extended-release tablet contains tramadol, a scheduled iv controlled substance. tramadol hydrochloride extended-release tablets contain tramadol, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see warnings and precautions (5.1)] . misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. misuse and abuse of tramadol hydrochloride extended-release tablets increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. the risk is increased with concurrent abuse of tramadol hydrochloride extended-release tablets with alcohol and other cns depressants. abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. in addition, abuse of opioids can occur in the absence of addiction. all patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. patients at high risk of tramadol hydrochloride extended-release tablets abuse include those with a history of prolonged use of any opioid, including products containing tramadol, those with a history of drug or alcohol abuse, or those who use tramadol hydrochloride extended-release tablets in combination with other abused drugs. “drug-seeking” behavior is very common in persons with substance use disorders. drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. tramadol hydrochloride extended-release tablets, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. risks specific to abuse of tramadol hydrochloride extended-release tablets abuse of tramadol hydrochloride extended-release tablets poses a risk of overdose and death. this is increased with concurrent use of tramadol hydrochloride extended-release tablets with alcohol and/or other cns depressants. tramadol hydrochloride extended-release tablets is approved for oral use only. inappropriate intravenous, intramuscular, or subcutaneous use of tramadol hydrochloride extended-release tablets can result in death, local tissue necrosis, infection, pulmonary granulomas, increased risk of endocarditis, and valvular heart injury, and embolism. parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and hiv. with parenteral abuse the inactive ingredients can result in local tissue necrosis, infection, pulmonary granulomas, increased risk of endocarditis and valvular heart injury, embolism, and death. both tolerance and physical dependence can develop during use of opioid therapy. tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. do not abruptly discontinue tramadol hydrochloride extended-release tablets in a patient physically dependent on opioids. rapid tapering of tramadol hydrochloride extended-release tablets in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. when discontinuing tramadol hydrochloride extended-release tablets, gradually taper the dosage using a patient-specific plan that considers the following: the dose of tramadol hydrochloride extended-release tablets the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. to improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. in patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see dosage and administration (2.5), and warnings and precautions (5.18)] . infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see use in specific populations (8.1 )].