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life molecular imaging, ltd - florbetaben f-18 (unii: tla7312toi) (florbetaben f-18 - unii:tla7312toi) - florbetaben f-18 135 mci in 1 ml - neuraceq is indicated for positron emission tomography (pet) imaging of the brain to estimate β-amyloid neuritic plaque density in adult patients with cognitive impairment who are being evaluated for alzheimer’s disease (ad) and other causes of cognitive decline. a negative neuraceq scan indicates sparse to no amyloid neuritic plaques and is inconsistent with a neuropathological diagnosis of ad at the time of image acquisition; a negative scan result reduces the likelihood that a patient’s cognitive impairment is due to ad. a positive neuraceq scan indicates moderate to frequent amyloid neuritic plaques; neuropathological examination has shown this amount of amyloid neuritic plaque is present in patients with ad, but may also be present in patients with other types of neurologic conditions as well as older people with normal cognition. neuraceq is an adjunct to other diagnostic evaluations. limitations of use • a positive neuraceq scan does not establish the diagnosis of ad or any other cognitive disorder. • safety and effectiveness of neuraceq have not been established for:    o predicting development of dementia or other neurologic conditions;    o monitoring responses to therapies. none risk summary there are no available data on neuraceq use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.  animal reproduction studies have not been conducted with neuraceq. all radiopharmaceuticals, including neuraceq, have a potential to cause fetal harm depending on the stage of fetal development and the magnitude of the radiopharmaceutical dose. if considering neuraceq administration to a pregnant woman, inform the patient about the potential for adverse pregnancy outcomes based on the radiation dose from the drug and the gestational timing of exposure. 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. risk summary there are no data on the presence of florbetaben f 18 injection in human milk, the effects on the breastfed infant, or the effects of florbetaben f 18 injection on milk production. exposure of neuraceq to a breastfed infant can be minimized by temporary discontinuation of breastfeeding [see clinical considerations ]. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for neuraceq and any potential adverse effects on the breastfed child from neuraceq or from the underlying maternal condition. clinical considerations to decrease radiation exposure to the breastfed infant, advise a lactating woman to pump and discard breast milk for 24 hours after administration of neuraceq. neuraceq is not indicated for use in pediatric patients. of the 872 subjects in clinical studies of neuraceq, 603 (69%) were 65 years or over, while 304 (35%) were 75 years or over. no overall differences in safety were observed between these subjects and younger subjects.

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glaxosmithkline llc - rosiglitazone maleate (unii: kx2339dp44) (rosiglitazone - unii:05v02f2kdg) - rosiglitazone 2 mg - avandia is a thiazolidinedione antidiabetic agent indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. important limitations of use: risk summary limited data with avandia in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. there are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see clinical considerations) . in animal reproduction studies, no adverse developmental effects were observed when rosiglitazone was administered to pregnant rats and rabbits during organogenesis at exposures up to 4 times the maximum recommended human dose (mrhd) of 8 mg daily (see data). the estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes with a hba1c >7 and has been reported to be as high as 20% to 25% in women with a hba1c >10. the estimated background risk of miscarriage for the indicated population is unknown. in the

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takeda pharmaceuticals america, inc. - pioglitazone hydrochloride (unii: jqt35npk6c) (pioglitazone - unii:x4ov71u42s), metformin hydrochloride (unii: 786z46389e) (metformin - unii:9100l32l2n) - pioglitazone 15 mg - actoplus met is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both pioglitazone and metformin is appropriate [see clinical studies (14)] . important limitations of use pioglitazone exerts its antihyperglycemic effect only in the presence of endogenous insulin. actoplus met should not be used to treat type 1 diabetes or diabetic ketoacidosis, as it would not be effective in these settings. use caution in patients with liver disease [see warnings and precautions (5.5)] . risk summary limited data with actoplus met or pioglitazone in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk (see data). there are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see clinical considerations]. in animal reproduction studies, no adverse developmental effects were observed when pioglitazone was administered to pregnant rats and rabbits during organogenesis at exposures up to 5 and 35 times the 45 mg clinical dose, respectively, based on body surface area. no adverse developmental effects were observed when metformin was administered to pregnant sprague dawley rats and rabbits during the period of organogenesis at doses up to 2 to 6 times, respectively, a 2000 mg clinical dose, based on body surface area (see data). the estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a hba1c >7 and has been reported to be as high as 20 to 25% in women with a hba1c >10. the estimated background risk of miscarriage for the indicated population is unknown. in the us 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 poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, still birth and delivery complications. poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity. data human data published data from postmarketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. however, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups. animal data pioglitazone and metformin hydrochloride animal reproduction studies were not conducted with the combined products in actoplus met. the following data are based on studies conducted with the individual components of actoplus met. pioglitazone pioglitazone administered to pregnant rats during organogenesis did not cause adverse developmental effects at a dose of 20 mg/kg (~5 times the 45 mg clinical dose), but delayed parturition and reduced embryo-fetal viability at 40 and 80 mg/kg, or ≥9 times the 45 mg clinical dose, by body surface area. in pregnant rabbits administered pioglitazone during organogenesis, no adverse developmental effects were observed at 80 mg/kg (~35 times the 45 mg clinical dose), but reduced embryo-fetal viability at 160 mg/kg, or ~69 times the 45 mg clinical dose, by body surface area. when pregnant rats received pioglitazone during late gestation and lactation, delayed postnatal development, attributed to decreased body weight, occurred in offspring at maternal doses of 10 mg/kg and above or ≥2 times the 45 mg clinical dose, by body surface area. metformin hydrochloride metformin hydrochloride did not cause adverse developmental effects when administered to pregnant sprague dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis. this represents an exposure of about 2 to 6 times a 2000 mg clinical dose based on body surface area (mg/m2 ) for rats and rabbits, respectively. risk summary there is no information regarding the presence of actoplus met or pioglitazone in human milk, the effects on the breastfed infant, or the effects on milk production. pioglitazone is present in rat milk; however, due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk. limited published studies report that metformin is present in human milk (see data) . however, there is insufficient information on the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for actoplus met and any potential adverse effects on the breastfed infant from actoplus met or from the underlying maternal condition. data published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. however, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants. discuss the potential for unintended pregnancy with premenopausal women as therapy with actoplus met, may result in ovulation in some anovulatory women. safety and effectiveness of actoplus met in pediatric patients have not been established. actoplus met is not recommended for use in pediatric patients based on adverse effects observed in adults, including fluid retention and congestive heart failure, fractures, and urinary bladder tumors [see warnings and precautions (5.1, 5.3, 5.6, 5.7)]. pioglitazone a total of 92 patients (15.2%) treated with pioglitazone in the three pooled 16 to 26 week double-blind, placebo-controlled, monotherapy trials were ≥65 years old and two patients (0.3%) were ≥75 years old. in the two pooled 16 to 24 week add-on to sulfonylurea trials, 201 patients (18.7%) treated with pioglitazone were ≥65 years old and 19 (1.8%) were ≥75 years old. in the two pooled 16 to 24 week add-on to metformin trials, 155 patients (15.5%) treated with pioglitazone were ≥65 years old and 19 (1.9%) were ≥75 years old. in the two pooled 16 to 24 week add-on to insulin trials, 272 patients (25.4%) treated with pioglitazone were ≥65 years old and 22 (2.1%) were ≥75 years old. in proactive trial, 1068 patients (41.0%) treated with pioglitazone were ≥65 years old and 42 (1.6%) were ≥75 years old. in pharmacokinetic studies with pioglitazone, no significant differences were observed in pharmacokinetic parameters between elderly and younger patients [see clinical pharmacology (12.3)] . although clinical experiences have not identified differences in effectiveness and safety between the elderly (≥65 years) and younger patients, these conclusions are limited by small sample sizes for patients ≥75 years old. metformin hydrochloride controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young 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 and the higher risk of lactic acidosis. assess renal function more frequently in elderly patients [see warnings and precautions (5.2), dosage and administration (2.2)]. metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. actoplus met is contraindicated in severe renal impairment, patients with an egfr below 30 ml/min/1.73 m2 [see dosage and administration (2.2), contraindications (4), warnings and precautions (5.2), clinical pharmacology (12.3)]. use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. actoplus met is not recommended in patients with hepatic impairment [see warnings and precautions (5.2)] .

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golden state medical supply inc - alprazolam (unii: yu55mq3izy) (alprazolam - unii:yu55mq3izy) - alprazolam 0.25 mg - alprazolam tablets, usp (alprazolam) are indicated for the management of anxiety disorder (a condition corresponding most closely to the apa diagnostic and statistical manual [dsm-iii-r] diagnosis of generalized anxiety disorder) or the short-term relief of symptoms of anxiety. anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. generalized anxiety disorder is characterized by unrealistic or excessive anxiety and worry (apprehensive expectation) about two or more life circumstances, for a period of six months or longer, during which the person has been bothered more days than not by these concerns. at least 6 of the following 18 symptoms are often present in these patients: motor tension (trembling, twitching, or feeling shaky; muscle tension, aches, or soreness; restlessness; easy fatigability); autonomic hyperactivity (shortness of breath or smothering sensations; palpitations or accelerated heart rate; sweatin

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sun pharmaceutical industries, inc. - tamsulosin hydrochloride (unii: 11sv1951mr) (tamsulosin - unii:g3p28oml5i) - tamsulosin hydrochloride 0.4 mg - tamsulosin hydrochloride  capsules, usp are indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (bph) [see clinical studies (14) ]. tamsulosin hydrochloride capsules are not indicated for the treatment of hypertension. tamsulosin hydrochloride capsules are contraindicated in patients known to be hypersensitive to tamsulosin hydrochloride or any component of tamsulosin hydrochloride capsules. reactions have included skin rash, urticaria, pruritus, angioedema, and respiratory symptoms [see adverse reactions (6.2) ]. risk summary tamsulosin hydrochloride capsule is not indicated for use in women. there are no adequate data on the developmental risk associated with the use of tamsulosin hydrochloride capsules in pregnant women. no adverse developmental effects were observed in animal studies in which tamsulosin hydrochloride was administered to rats or rabbits during the period of organogenesis (gd 7 to 17 in the rat and gd 6 to 18 in the rabbit) [see data ]. in the u.s. general

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sun pharmaceutical industries, inc. - citalopram hydrobromide (unii: i1e9d14f36) (citalopram - unii:0dhu5b8d6v) - citalopram 10 mg - citalopram tablets, usp (citalopram hbr) is indicated for the treatment of depression. the efficacy of citalopram tablets, usp in the treatment of depression was established in 4-6 week, controlled trials of outpatients whose diagnosis corresponded most closely to the dsm-iii and dsm-iii-r category of major depressive disorder (see clinical pharmacology ). a major depressive episode (dsm-iv) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least five of the following nine symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation. the antidepressant action of citalopram tablets, usp in hospitalized depressed patients has no

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caraco pharmaceutical laboratories, ltd. - clonazepam (unii: 5pe9fde8gb) (clonazepam - unii:5pe9fde8gb) - clonazepam 0.5 mg - seizure disorders: clonazepam tablets usp are useful alone or as an adjunct in the treatment of the lennox-gastaut syndrome (petit mal variant), akinetic and myoclonic seizures. in patients with absence seizures (petit mal) who have failed to respond to succinimides, clonazepam tablets may be useful. in some studies, up to 30% of patients have shown a loss of anticonvulsant activity, often within 3 months of administration. in some cases, dosage adjustment may reestablish efficacy. panic disorder: clonazepam tablets usp are indicated for the treatment of panic disorder, with or without agoraphobia, as defined in dsm-iv. panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks. the efficacy of clonazepam tablets usp were established in two 6- to 9-week trials in panic disorder patients whose diagnoses correspon

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shertech laboratories, llc - sodium fluoride f-18 (unii: 9l75099x6r) (fluoride ion f-18 - unii:4m4we5n2ge) - fluoride ion f-18 200 mci in 1 ml - sodium fluoride f18 injection, usp is a radioactive diagnostic agent for positron emission tomography (pet) indicated for imaging of bone to define areas of altered osteogenic activity. none. pregnancy category c any radiopharmaceutical including sodium fluoride f18 injection has a potential to cause fetal harm. the likelihood of fetal harm depends on the stage of fetal development, and the radionuclide dose. animal reproduction and developmental toxicity studies have not been conducted with sodium fluoride f18 injection. prior to the administration of sodium fluoride f18 injection to women of childbearing potential, assess for presence of pregnancy. sodium fluoride f18 injection should be given to a pregnant woman only if clearly needed. it is not known whether sodium fluoride f18 injection is excreted into human milk. because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to interrupt nursing after admini

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wisconsin medical cyclotron llc - fludeoxyglucose f-18 (unii: 0z5b2cjx4d) (fludeoxyglucose f-18 - unii:0z5b2cjx4d) - fludeoxyglucose f-18 500 mci in 1 ml - fludeoxyglucose f18 injection, usp is indicated for positron emission tomography (pet) imaging in the following settings: for assessment of abnormal glucose metabolism to assist in the evaluation of malignancy in patients with known or suspected abnormalities found by other testing modalities, or in patients with an existing diagnosis of cancer. for the identification of left ventricular myocardium with residual glucose metabolism and reversible loss of systolic function in patients with coronary artery disease and left ventricular dysfunction, when used together with myocardial perfusion imaging. for the identification of regions of abnormal glucose metabolism associated with foci of epileptic seizures. none. pregnancy category c animal reproduction studies have not been conducted with fludeoxyglucose f18 injection, usp. it is also not known whether fludeoxyglucose f18 injection, usp can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. consider alternative diagnost

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sun pharmaceutical industries, inc. - tramadol hydrochloride (unii: 9n7r477wck) (tramadol - unii:39j1lgj30j) - tramadol hydrochloride 50 mg - tramadol hydrochloride tablets are indicated in adults for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. limitations of use because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [see warnings and precautions (5.1)], reserve tramadol hydrochloride tablets for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]: - have not been tolerated or are not expected to be tolerated. - have not provided adequate analgesia or are not expected to provide adequate analgesia. tramadol hydrochloride tablets should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate. tramadol hydrochloride tablets are contraindicated for: - all children younger than 12 years of age [see warnings and precautions (5.6)]. - postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see warnings and precautions (5.6)] . tramadol hydrochloride 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, any other component of this product or opioids [see warnings and precautions (5.17)]. - 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 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 2-4% and 15-20%, 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 respiratory depression and physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. neonatal opioid withdrawal syndrome can present 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 still birth have been reported during postmarketing. 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 tablets are not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. opioid analgesics, including tramadol hydrochloride tablets, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. however, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. 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 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/m 2 basis are 1.4, 0.6, and 3.6 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 1.7, 1.9 and 14.6 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 1.2 times the mrhd) or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (1.9 times the mrhd). risk summary tramadol hydrochloride 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-desmethyltramadol (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)] . 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 tablets [ see warnings and precautions (5.6)] . clinical considerations if infants are exposed to tramadol hydrochloride 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)] . the safety and effectiveness of tramadol hydrochloride 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 tablets are contraindicated for all children younger than 12 years of age [see contraindications (4)] . - tramadol hydrochloride 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 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. a total of 455 elderly (65 years of age or older) subjects were exposed to tramadol hydrochloride tablets in controlled clinical trials. of those, 145 subjects were 75 years of age and older. in studies including geriatric patients, treatment-limiting adverse events were higher in subjects over 75 years of age compared to those under 65 years of age. specifically, 30% of those over 75 years of age had gastrointestinal treatment-limiting adverse events compared to 17% of those under 65 years of age. constipation resulted in discontinuation of treatment in 10% of those over 75. respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. titrate the dosage of tramadol hydrochloride tablets slowly in geriatric patients starting at the low end of the dosing range 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 regularly evaluate renal function. impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, m1. in patients with creatinine clearances of less than 30 ml/min, dosing reduction is recommended [see dosage and administration ( 2.3)] . metabolism of tramadol and m1 is reduced in patients with severe hepatic impairment based on a study in patients with advanced cirrhosis of the liver. in patients with severe hepatic impairment, dosing reduction is recommended [see dosage and administratio n (2.3)] . with the prolonged half-life in these conditions, achievement of steady-state is delayed, so that it may take several days for elevated plasma concentrations to develop. tramadol hydrochloride tablets contain tramadol, a schedule iv controlled substance. tramadol hydrochloride tablets contain tramadol, a substance with 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 health care 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 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 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 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 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 tablets, like other opioids, can be diverted for non-medical use into illicit channels of distribution. careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. proper assessment of the patient, proper prescribing practices, periodic 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 tablets abuse of tramadol hydrochloride tablets poses a risk of overdose and death. the risk is increased with concurrent use of tramadol hydrochloride tablets with alcohol and/or other cns depressants. tramadol hydrochloride tablets are approved for oral use only. parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and hiv. 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 tablets in a patient physically dependent on opioids. rapid tapering of tramadol hydrochloride 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 tablets, gradually taper the dosage using a patient-specific plan that considers the following: the dose of tramadol hydrochloride 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)].