Estados Unidos - inglés - NLM (National Library of Medicine)

avkare - ramelteon (unii: 901as54i69) (ramelteon - unii:901as54i69) - ramelteon tablets are indicated for the treatment of insomnia characterized by difficulty with sleep onset. the clinical trials performed in support of efficacy were up to six months in duration. the final formal assessments of sleep latency were performed after two days of treatment during the crossover study (elderly only), at five weeks in the six week studies (adults and elderly), and at the end of the six month study (adults and elderly) [ see clinical studies (14) ]. patients who develop angioedema after treatment with ramelteon tablets should not be rechallenged with the drug. patients should not take ramelteon tablets in conjunction with fluvoxamine [see drug interactions (7) ]. risk summary available data from post marketing reported with ramelteon use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. in animal studies, ramelteon produced evidence of developmental toxicity, including teratogenic effects, in rats at doses greater than 36 times the recommended human dose (rhd) of 8 mg/day based on body surface area (mg/m) (see data). the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. data animal data oral administration of ramelteon (10, 40, 150 or 600 mg/kg/day) to pregnant rats during the period of organogenesis was associated with increased incidences of fetal structural abnormalities (malformations and variations) at doses greater than 40 mg/kg/day. the no-effect dose is approximately 50 times the rhd based on mg/m 2 . treatment of pregnant rabbits during the period of organogenesis produced no evidence of embryo-fetal toxicity at oral doses of up to 300 mg/kg/day (or up to 720 times the rhd based on mg/m 2 ). when rats were orally administered ramelteon (30, 100, or 300 mg/kg/day) throughout gestation and lactation, growth retardation, developmental delay, and behavioral changes were observed in the offspring at doses greater than 30 mg/kg/day. the no-effect dose is 36 times the rhd on a based on mg/m 2 . increased incidences of malformation and death among offspring were seen at the highest dose. risk summary there are no data regarding the presence of ramelteon or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. ramelteon and/or its metabolites are present in rat milk. when a drug is present in animal milk, it is likely that the drug will be present in human milk. because of the mechanism of action of ramelteon, there is a potential risk for somnolence in a breastfed infant ( see clinical considerations) . the developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for ramelteon tablets and any potential adverse effects on the breastfed infant from ramelteon tablets or from the underlying maternal condition. clinical considerations infants exposed to ramelteon tablets through breastmilk should be monitored for somnolence and feeding problems. a lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment and for 25 hours (approximately 5 elimination half-lives) after ramelteon tablets administration in order to minimize drug exposure to a breastfed infant. safety and effectiveness of ramelteon tablets in pediatric patients have not been established. further study is needed prior to determining that this product may be used safely in prepubescent and pubescent patients. a total of 654 subjects in double-blind, placebo-controlled, efficacy trials who received ramelteon tablets were at least 65 years of age; of these, 199 were 75 years of age or older. no overall differences in safety or efficacy were observed between elderly and younger adult subjects. a double-blind, randomized, placebo-controlled study in elderly subjects with insomnia (n=33) evaluated the effect of a single dose of ramelteon tablets on balance, mobility, and memory functions after middle of the night awakening. there is no information on the effect of multiple dosing. night time dosing of ramelteon tablets, 8 mg did not impair middle of the night balance, mobility, or memory functions relative to placebo. the effects on night balance in the elderly cannot be definitively known from this study. the respiratory depressant effect of ramelteon was evaluated in a crossover design study of subjects (n=26) with mild to moderate copd after administering a single 16 mg dose or placebo, and in a separate study (n=25), the effects of ramelteon on respiratory parameters were evaluated after administering an 8 mg dose or placebo in a crossover design to patients with moderate to severe copd, defined as patients who had forced expiratory volume at one second (fev 1 )/forced vital capacity ratio of <70%, and a fev 1 <80% of predicted with <12% reversibility to albuterol. treatment with a single dose of ramelteon tablets has no demonstrable respiratory depressant effects in subjects with mild to severe copd, as measured by arterial o 2 saturation (sao 2 ). there is no available information on the respiratory effects of multiple doses of ramelteon tablets in patients with copd. the respiratory depressant effects in patients with copd cannot be definitively known from this study. the effects of ramelteon tablets were evaluated after administering a 16 mg dose or placebo in a crossover design to subjects (n=26) with mild to moderate obstructive sleep apnea. treatment with ramelteon tablets 16 mg for one night showed no difference compared with placebo on the apnea/hypopnea index (the primary outcome variable), apnea index, hypopnea index, central apnea index, mixed apnea index, and obstructive apnea index. treatment with a single dose of ramelteon tablets does not exacerbate mild to moderate obstructive sleep apnea. there is no available information on the respiratory effects of multiple doses of ramelteon tablets in patients with sleep apnea. the effects on exacerbation in patients with mild to moderate sleep apnea cannot be definitively known from this study. ramelteon tablets have not been studied in subjects with severe obstructive sleep apnea; use of ramelteon tablets are not recommended in such patients. exposure to ramelteon tablets were increased by four-fold in subjects with mild hepatic impairment and by more than ten-fold in subjects with moderate hepatic impairment. ramelteon tablets should be used with caution in patients with moderate hepatic impairment [see clinical pharmacology (12.4) ]. ramelteon tablets are not recommended in patients with severe hepatic impairment. no effects on c max and auc 0-t of parent drug or m-ii were seen. no adjustment of ramelteon dosage is required in patients with renal impairment [see clinical pharmacology (12.4) ]. ramelteon tablet is not a controlled substance. discontinuation of ramelteon in animals or in humans after chronic administration did not produce withdrawal signs. ramelteon does not appear to produce physical dependence. human data a laboratory abuse potential study was performed with ramelteon tablets [see clinical studies (14.2) ] . animal data ramelteon did not produce any signals from animal behavioral studies indicating that the drug produces rewarding effects. monkeys did not self-administer ramelteon and the drug did not induce a conditioned place preference in rats. there was no generalization between ramelteon and midazolam. ramelteon did not affect rotorod performance, an indicator of disruption of motor function, and it did not potentiate the ability of diazepam to interfere with rotorod performance.

Estados Unidos - inglés - NLM (National Library of Medicine)

regi u.s. inc - octocrylene (unii: 5a68wgf6wm) (octocrylene - unii:5a68wgf6wm), avobenzone (unii: g63qqf2nox) (avobenzone - unii:g63qqf2nox), octisalate (unii: 4x49y0596w) (octisalate - unii:4x49y0596w), homosalate (unii: v06sv4m95s) (homosalate - unii:v06sv4m95s) - sunscreen ■ helps prevent sunburn. ■ if used as directed with other sun protection measures (see directions), decreases the risk of skin cancer and early skin aging caused by the sun on damaged or broken skin rash occurs

Estados Unidos - inglés - NLM (National Library of Medicine)

forreal pharmaceuticals - lidocaine (unii: 98pi200987) (lidocaine - unii:98pi200987) - topical anesthetic for the temporary relief of pain do not use: - more than 1 patch at a time - on wounds or damaged skin - with a heating pad - if you are allergic to any ingredients of this product stop use and ask a doctor if: - localized skin reactions occur, such as rash, itching, redness, irritation, pain, swelling and blistering - conditions worsen - symptoms persist for more than 7 days - symptoms clear up and occur again within a few days

Estados Unidos - inglés - NLM (National Library of Medicine)

proficient rx lp - naproxen (unii: 57y76r9atq) (naproxen - unii:57y76r9atq) - naproxen tablets are indicated for: the relief of the signs and symptoms of: the management of: naproxen tablets are contraindicated in the following patients: risk summary use of nsaids, including naproxen can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. because of these risks, limit dose and duration of naproxen use between about 20 and 30 weeks of gestation, and avoid naproxen use at about 30 weeks of gestation and later in pregnancy (see error! hyperlink reference not valid. , error! hyperlink reference not valid. ). premature closure of fetal ductus arteriosus use of nsaids, including naproxen at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. oligohydramnios/neonatal renal impairment use of nsaids at about 20 weeks gestation or later in pregnancy has been associated with cases

Estados Unidos - inglés - NLM (National Library of Medicine)

kari gran - zinc oxide (unii: soi2loh54z) (zinc cation - unii:13s1s8sf37) - sunscreen - helps prevent sunburn - if used as directed with other sun protection measures (see directions), decreases the risk of skin cancer and early skin aging caused by the sun.

Estados Unidos - inglés - NLM (National Library of Medicine)

torrent pharmaceuticals limited - lurasidone hydrochloride (unii: o0p4i5851i) (lurasidone - unii:22ic88528t) - lurasidone hydrochloride tablets are indicated for: • treatment of adult and adolescent patients (13 to 17 years) patients with schizophrenia [see clinical studies ( 14.1)] . • monotherapy treatment of adult and pediatric patients (10 to 17 years) with major depressive episode associated with bipolar i disorder (bipolar depression) [see clinical studies ( 14.2)]. • adjunctive treatment with lithium or valproate in adult patients with major depressive episode associated with bipolar i disorder (bipolar depression) [see clinical studies ( 14.2)]. • known hypersensitivity to lurasidone hcl or any components in the formulation.  angioedema has been observed with lurasidone [see adverse reactions ( 6.1)] . • strong cyp3a4 inhibitors (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc.) [see drug interactions ( 7.1)]. • strong cyp3a4 inducers (e.g., rifampin, avasimibe, st. john's wort, phenytoin, carbamazepine, etc.) [see drug interactions ( 7.1)]. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to lurasidone hydrochloride tablets during pregnancy. for more information, contact the national pregnancy registry for atypical antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. risk summary neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery  [see clinical considerations] . there are no studies of lurasidone hydrochloride tablets use in pregnant women. the limited available data are not sufficient to inform a drug-associated risk of birth defects or miscarriage. in animal reproduction studies, no teratogenic effects were seen in pregnant rats and rabbits given lurasidone during the period of organogenesis at doses approximately 1.5- and 6-times, the maximum recommended human dose (mrhd) of 160 mg/day, respectively based on mg/m 2 body surface area  [see data] . the estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. all pregnancies have a background risk of birth defect, loss or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations fetal/neonatal adverse reactions extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs during the third trimester of pregnancy. these symptoms have varied in severity. some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. data animal data pregnant rats were treated with oral lurasidone at doses of 3, 10, and 25 mg/kg/day during the period of organogenesis. these doses are 0.2, 0.6, and 1.5 times the mrhd of 160 mg/day based on mg/m2 body surface area. no teratogenic or embryo-fetal effects were observed up to 1.5 times the mhrd of 160 mg/day, based on mg/m 2 . pregnant rabbits were treated with oral lurasidone at doses of 2, 10, and 50 mg/kg/day during the period of organogenesis. these doses are 0.2, 1.2 and 6 times the mrhd of 160 mg/day based on mg/m2. no teratogenic or embryo-fetal effects were observed up to 6 times the mhrd of 160 mg/day based on mg/m 2 . pregnant rats were treated with oral lurasidone at doses of 0.4, 2, and 10 mg/kg/day during the periods of organogenesis and lactation. these doses are 0.02, 0.1 and 0.6 times the mrhd of 160 mg/day based on mg/m2. no pre- and postnatal developmental effects were observed up to 0.6 times the mrhd of 160 mg/day, based on mg/m 2 . risk summary lactation studies have not been conducted to assess the presence of lurasidone in human milk, the effects on the breastfed infant, or the effects on milk production. lurasidone is present in rat milk. the development and health benefits of breastfeeding should be considered along with the mother's clinical need for lurasidone hydrochloride and any potential adverse effects on the breastfed infant from lurasidone hydrochloride or from the underlying maternal condition. schizophrenia the safety and effectiveness of lurasidone hydrochloride tablets 40-mg/day and 80-mg/day for the treatment of schizophrenia in adolescents (13 to 17 years) was established in a 6-week, placebo-controlled clinical study in 326 adolescent patients [see dosage and administration (2.1), adverse reactions (6.1), and clinical studies (14.1)]. the safety and effectiveness of lurasidone hydrochloride have not been established in pediatric patients less than 13 years of age with schizophrenia.  bipolar depression the safety and effectiveness of lurasidone hydrochloride tablets 20 to 80 mg/day for the treatment of bipolar depression in pediatric patients (10 to 17 years) was established in a 6-week, placebo-controlled clinical study in 347 pediatric patients [see dosage and administration (2.2), adverse reactions (6.1), and clinical studies (14.2)]. the safety and effectiveness of lurasidone hydrochloride have not been established in pediatric patients less than 10 years of age with bipolar depression.   irritability associated with autistic disorder the effectiveness of lurasidone hydrochloride in pediatric patients for the treatment of irritability associated with autistic disorder has not been established. efficacy was not demonstrated in a 6-week study evaluating lurasidone hydrochloride 20 mg/day and 60 mg/day for the treatment of pediatric patients 6 to 17 years of age with irritability associated with autistic disorder diagnosed by diagnostic and statistical manual of mental disorders, 4th ed., text revision [dsm-iv-tr] criteria. the primary objective of the study as measured by improvement from baseline in the irritability subscale of the aberrant behavior checklist (abc) at endpoint (week 6) was not met. a total of 149 patients were randomized to lurasidone hydrochloride or placebo. vomiting occurred at a higher rate than reported in other lurasidone hydrochloride studies (4/49 or 8% for 20mg, 14/51 or 27% for 60mg, and 2/49 or 4% for placebo), particularly in children ages 6 to 12 (13 out of 18 patients on lurasidone hydrochloride with vomiting). in a long-term, open-label study that enrolled pediatric patients (age 6 to 17 years) with schizophrenia, bipolar depression, or autistic disorder from three short-term, placebo-controlled trials, 54% (378/701) received lurasidone for 104 weeks. there was one adverse event in this trial that was considered possibly drug-related and has not been reported in adults receiving lurasidone: a 10 year old male experienced a prolonged, painful erection, consistent with priapism, that led to treatment discontinuation. in this trial, the mean increase in height from open-label baseline to week 104 was 4.94 cm. to adjust for normal growth, z-scores were derived (measured in standard deviations [sd]), which normalize for the natural growth of children and adolescents by comparisons to age- and sex-matched population standards. a z-score change <0.5 sd is considered not clinically significant. in this trial, the mean change in height z-score from open-label baseline to week 104 was +0.05 sd, indicating minimal deviation from the normal growth curve. juvenile animal studies adverse effects were seen on growth, physical and neurobehavioral development at doses as low as 0.2 times the mrhd based on mg/m 2 . lurasidone was orally administered to rats from postnatal days 21 through 91 (this period corresponds to childhood, adolescence, and young adulthood in humans) at doses of 3, 30, and 150 (males) or 300 (females) mg/kg/day which are 0.2 to 10 times (males) and 20 times (females) the maximum recommended adult human dose (mrhd) of 160 mg/day based on mg/m 2 . the adverse effects included dose-dependent decreases in femoral length, bone mineral content, body and brain weights at 2 times the mrhd in both sexes, and motor hyperactivity at 0.2 and 2 times the mrhd in both sexes based on mg/m 2 . in females, there was a delay in attainment of sexual maturity at 2 times the mrhd, associated with decreased serum estradiol. mortality occurred in both sexes during early post- weaning period and some of the male weanlings died after only 4 treatments at doses as low as 2 times the mrhd based on mg/m 2 . histopathological findings included increased colloid in the thyroids and inflammation of the prostate in males at 10 times mrhd based on mg/m 2  and mammary gland hyperplasia, increased vaginal mucification, and increased ovarian atretic follicles at doses as low as 0.2 times the mrhd based on mg/m 2 . some of these findings were attributed to transiently elevated serum prolactin which was seen in both sexes at all doses. however, there were no changes at any dose level in reproductive parameters (fertility, conception indices, spermatogenesis, estrous cycle, gestation length, parturition, number of pups born). the no effect dose for neurobehavioral changes in males is 0.2 times the mhrd based on mg/m 2  and could not be determined in females. the no effect dose for growth and physical development in both sexes is 0.2 times the mrhd based on mg/m 2 . clinical studies with lurasidone hydrochloride did not include sufficient numbers of patients aged 65 and older to determine whether or not they respond differently from younger patients. in elderly patients with psychosis (65 to 85), lurasidone hydrochloride concentrations (20 mg/day) were similar to those in young subjects. it is unknown whether dose adjustment is necessary on the basis of age alone. elderly patients with dementia-related psychosis treated with lurasidone hydrochloride are at an increased risk of death compared to placebo. lurasidone hydrochloride is not approved for the treatment of patients with dementia-related psychosis  [see boxed warning, warnings and precautions ( 5.1,  5.3)]. reduce the maximum recommended dosage in patients with moderate or severe renal impairment (clcr<50 ml/minute). patients with impaired renal function (clcr<50 ml/minute) had higher exposure to lurasidone than patients with normal renal function [ see clinical pharmacology ( 12.3) ]. greater exposure may increase the risk of lurasidone hydrochloride-associated adverse reactions [ see dosage and administration ( 2.4) ] reduce the maximum recommended dosage in patients with moderate to severe hepatic impairment (child-pugh score ≥7). patients with moderate to severe hepatic impairment (child-pugh score ≥7) generally had higher exposure to lurasidone than patients with normal hepatic function [ see clinical pharmacology ( 12.3) ]. greater exposure may increase the risk of lurasidone hydrochloride-associated adverse reactions [ see dosage and administration ( 2.5) ]. no dosage adjustment for lurasidone hydrochloride is required on the basis of a patient's sex, race, or smoking status [ see clinical pharmacology ( 12.3) ]. lurasidone hydrochloride is not a controlled substance. lurasidone hydrochloride has not been systematically studied in humans for its potential for abuse or physical dependence or its ability to induce tolerance. while clinical studies with lurasidone hydrochloride did not reveal any tendency for drug-seeking behavior, these observations were not systematic and it is not possible to predict the extent to which a cns-active drug will be misused, diverted and/or abused once it is marketed. patients should be evaluated carefully for a history of drug abuse, and such patients should be observed carefully for signs of lurasidone hydrochloride misuse or abuse (e.g., development of tolerance, drug-seeking behavior, increases in dose).

Estados Unidos - inglés - NLM (National Library of Medicine)

proven skincare - homosalate (unii: v06sv4m95s) (homosalate - unii:v06sv4m95s), octisalate (unii: 4x49y0596w) (octisalate - unii:4x49y0596w), zinc oxide (unii: soi2loh54z) (zinc cation - unii:13s1s8sf37) - - helps prevent sunburn. - if used as directed with other sun protection measures (see directions ), decreases the risk of skin caner and early skin aging caused by sun. 

Estados Unidos - inglés - NLM (National Library of Medicine)

kowa pharmaceuticals america, inc. - celecoxib (unii: jcx84q7j1l) (celecoxib - unii:jcx84q7j1l), tramadol hydrochloride (unii: 9n7r477wck) (tramadol - unii:39j1lgj30j) - seglentis is indicated for the management of acute pain in adults that is 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 seglentis for use in patients for whom alternative treatment options [e.g., non-opioid analgesics]: - have not been tolerated or are not expected to be tolerated, - have not provided adequate analgesia or are not expected to provide adequate analgesia. seglentis 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. seglentis is contraindicated in: - all patients younger than 12 years of age [see warnings and precautions (5.8)] . - post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see warnings and precautions (5.8)] . seglentis is also contraindicated in patients with: - significant respiratory depression [see warnings and precautions (5.2)]. - in the setting of coronary artery bypass graft (cabg) surgery [see warnings and precautions (5.6)]. - acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see warnings and precautions (5.14)]. - known or suspected gastrointestinal obstruction, including paralytic ileus [see warnings and precautions (5.18)]. - previous hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to tramadol, opioids, celecoxib, sulfonamides, or any other component of the drug product [see warnings and precautions (5.19)]. - concurrent use of monoamine oxidase inhibitors (maois) or use of maois within the last 14 days [see drug interactions (7)] . - history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other nsaids. severe, sometimes fatal, anaphylactic reactions to nsaids, have been reported in such patients [see warnings and precautions (5.19, 5.24)] . risk summary based on animal data, advise pregnant women of the potential risk to fetus. use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome (see warnings and precautions (5.4)). use of nsaids, including seglentis, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. because of these risks, limit dose and duration of seglentis use between about 20 and 30 weeks of gestation and avoid seglentis use at about 30 weeks of gestation and later in pregnancy (see clinical considerations, data) . there are no available data on use of seglentis in pregnant women. in an animal reproduction study, oral administration of celecoxib and tramadol co-crystal to pregnant rabbits during the period of organogenesis, resulted in embryo-fetal deaths and an increase of incidence of vertebral defects at approximately 4.7 and 0.11 times the dose of celecoxib and tramadol, respectively, at the maximum recommended human dose (mrhd) of seglentis at 400 mg/day (224 mg celecoxib/176 mg tramadol) (see data) . tramadol available data with tramadol use in pregnant women are insufficient to inform a drug-associated risk for major birth defects, miscarriage, or adverse maternal outcomes. there are adverse outcomes reported with fetal exposure to opioid analgesics (see clinical considerations) . in animal reproduction studies, tramadol administration during organogenesis decreased fetal weights and reduced ossification in mice, rats, and rabbits at 3.2, 1.4, and 8.2 times the tramadol dose of 176 mg at the mrhd of seglentis. in a pre- and post-natal development study, tramadol decreased pup body weight and increased pup mortality at 2.7 and 4.3 times the mrhd, respectively. in a published study, tramadol caused structural abnormalities in the brains of fetuses when administered to female sprague dawley rats from gestation days 10 to 21 at 2.7 times the mrhd (see data). celecoxib premature closure of fetal ductus arteriosus: use of nsaids, including seglentis, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. oligohydramnios/neonatal renal impairment: use of nsaids at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. data from observational studies regarding other potential embryofetal risks of nsaid use in women in the first or second trimesters of pregnancy are inconclusive. in animal reproduction studies, embryo-fetal deaths and an increase in diaphragmatic hernias were observed in rats administered celecoxib daily during the period of organogenesis at oral doses approximately 13 times the celecoxib dose of 224 mg at the mrhd of seglentis. in addition, structural abnormalities (e.g., septal defects, ribs fused, sternebrae fused and sternebrae misshapen) were observed in rabbits given daily oral doses of celecoxib during the period of organogenesis at approximately 4 times the mrhd (see data) . based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. in animal studies, administration of prostaglandin synthesis inhibitors such as celecoxib, resulted in increased pre- and post-implantation loss. prostaglandins also have been shown to have an important role in fetal kidney development. in published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. the 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 tramadol: 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 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 hydrochloride during postmarketing. celecoxib: premature closure of fetal ductus arteriosus: avoid use of nsaids in women at about 30 weeks gestation and later in pregnancy, because nsaids, including seglentis, can cause premature closure of the fetal ductus arteriosus (see data ). oligohydramnios/neonatal renal impairment: if an nsaid is necessary, including seglentis, at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. if seglentis treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. if oligohydramnios occurs, discontinue seglentis and follow up according to clinical practice (see data ). labor or delivery tramadol: 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. seglentis is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. opioid analgesics, including seglentis, 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 seglentis, if any, on the later growth, development, and functional maturation of the child is unknown. celecoxib: there are no studies on the effects of seglentis during labor or delivery. in animal studies, nsaids, including celecoxib, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. data human data celecoxib: the available data do not establish the presence or absence of developmental toxicity related to the use of celecoxib. premature closure of fetal ductus arteriosus published literature reports that the use of nsaids at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. oligohydramnios/neonatal renal impairment published studies and postmarketing reports describe maternal nsaid use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. these adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after nsaid initiation. in many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. there have been a limited number of case reports of maternal nsaid use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. these limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal nsaid use. because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to nsaids through maternal use is uncertain. animal data treatment of pregnant rabbits during organogenesis with celecoxib and tramadol co-crystal resulted in an increase in the incidence of scoliosis and other vertebral defects (including absent thoracic hemicentrum/a and neural arch(es) and fused thoracic vertebral centra and/or neural arch(es)) at an oral dose of 100 mg/kg/day (56 mg celecoxib/44 mg tramadol/kg/day; approximately 4.7 and 0.11 times the mrhd on the basis of celecoxib and tramadol, respectively, on an auc basis), which is a dose that also caused maternal toxicity (decreased body weight gain). in addition, there was a slight increase of post-implantation loss in rabbits at 100 mg/kg/day. the no observed adverse effect level (noael) for embryofetal toxicity was 55 mg/kg/day (approximately 3.3 and 0.02 times the mrhd of celecoxib and tramadol, respectively, on an auc basis). tramadol: 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 3.2, 1.4, and 8.2 times the mrhd of tramadol (176 mg) 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 3.9, 4.3, and 33 times the mrhd of tramadol (176 mg), respectively, on a mg/m2 basis. tramadol was evaluated in pre-and post-natal studies in rats. progeny of dams receiving oral (gavage) dose levels of 50 mg/kg (2.7 times the mrhd of tramadol on a mg/m2 basis) or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (4.3 times the mrhd of tramadol on a mg/m2 basis). in a published study, oral administration of tramadol at 50 mg/kg (2.7 times the mrhd of tramadol on a mg/m2 basis) to pregnant female rats from gestation days 10 to 21 caused structural abnormalities in the brains of the offspring. celecoxib: celecoxib at oral doses ≥150 mg/kg/day (approximately 4 times the level of celecoxib of 224 mg at the mrhd of seglentis based on auc), caused an increased incidence of ventricular septal defects, a rare event, and fetal alterations, such as ribs fused, sternebrae fused and sternebrae misshapen when rabbits were treated throughout organogenesis. a dose-dependent increase in diaphragmatic hernias was observed when rats were given celecoxib at oral doses ≥30 mg/kg/day (approximately 13 times the mrhd based on auc) throughout organogenesis. in rats, exposure to celecoxib during early embryonic development resulted in pre-implantation and post-implantation losses at oral doses ≥50 mg/kg/day (approximately 13 times the mrhd based on auc). celecoxib produced no evidence of delayed labor or parturition at oral doses up to 100 mg/kg in rats (approximately 15 times the mrhd based on auc). the effects of seglentis on labor and delivery in pregnant women are unknown. risk summary seglentis is not recommended for obstetrical preoperative medication or for post-delivery analgesia in lactating women because the safety of tramadol in infants and newborns has not been studied. tramadol 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 (12.1)] . published studies have reported tramadol and m1 in colostrum with administration of tramadol to breastfeeding 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 seglentis (see data) [see warnings and precautions (5.8)] . celecoxib limited data from 3 published reports that included a total of 12 breastfeeding women showed low levels of celecoxib in breast milk. the calculated average daily infant dose was 10 to 40 mcg/kg/day, less than 1% of the weight-based therapeutic dose for a two-year old-child. a report of two breastfed infants 17 and 22 months of age did not show any adverse events. clinical considerations if infants are exposed to seglentis 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 breastfeeding is stopped. data tramadol 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 tramadol 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)]. published studies in adult male rodents report that tramadol, at clinically relevant doses, can produce adverse effects on male reproductive hormones and tissues [see nonclinical toxicology (13.1) ]. celecoxib females: based on the mechanism of action, the use of prostaglandin-mediated nsaids, including celecoxib, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin mediated follicular rupture required for ovulation. small studies in women treated with nsaids have also shown a reversible delay in ovulation. consider withdrawal of nsaids, including celecoxib, in women who have difficulties conceiving or who are undergoing investigation of infertility. the safety and effectiveness of seglentis in pediatric patients have not been established. tramadol life-threatening respiratory depression and death have occurred in children who received tramadol [see warnings and precautions (5.8)] . 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: - seglentis is contraindicated for all children younger than age 12 years of age [see contraindications (4)] . - seglentis is 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 seglentis 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. in the randomized, double-blind, active- and placebo-controlled, parallel group study comparing seglentis to tramadol, celecoxib, and placebo in patients with acute post-operative pain following unilateral first metatarsal osteotomy with internal fixation, 9.1% of patients were ≥65 years of age. age subgroup examination was planned by protocol and it revealed a similar trend in efficacy compared to younger patients and no untoward or unexpected adverse reactions were seen in the elderly patients who received seglentis. no dose adjustments are required for elderly patients. tramadol 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. frequently reevaluate the patient for signs of central nervous system and respiratory depression [see warnings and precautions (5.14)] . 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, it may be useful to regularly evaluate renal function. celecoxib elderly patients, compared to younger patients, are at greater risk for nsaid-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. if the anticipated benefit for the elderly patient outweighs these potential risks, monitor patients for adverse effects [see warnings and precautions (5.6, 5.7, 5.20, 5.23, 5.31)] . because seglentis is approved at a unique dosage of celecoxib, seglentis is not recommended in patients that require dosages other than 2 tablets every 12 hours, containing a total daily dose of celecoxib of 224 mg. of the total number of patients who received celecoxib in pre-approval clinical trials, more than 3,300 were 65-74 years of age, while approximately 1,300 additional patients were 75 years and over. no substantial differences in effectiveness were observed between these subjects and younger subjects. in clinical studies comparing renal function as measured by the gfr, bun and creatinine, and platelet function as measured by bleeding time and platelet aggregation, the results were not different between elderly and young volunteers. however, as with other nsaids, including those that selectively inhibit cox-2, there have been more spontaneous post-marketing reports of fatal gi events and acute renal failure in the elderly than in younger patients [see warnings and precautions (5.7, 5.23)] . because seglentis contains celecoxib, the use of seglentis in patients with severe renal impairment is not recommended [see warnings and precautions (5.23) and clinical pharmacology (12.3)] . the pharmacokinetics and tolerability of seglentis in patients with renal impairment has not been studied. tramadol impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, m1. 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. as tramadol and celecoxib are both extensively metabolized by the liver, the use of seglentis in patients with moderate and severe hepatic impairment is not recommended [see warnings and precautions (5.20), clinical pharmacology (12.3)] . the pharmacokinetics and tolerability of seglentis in patients with impaired hepatic function have not been studied. tramadol 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. celecoxib the daily recommended dose of celecoxib capsules in patients with moderate hepatic impairment (child-pugh class b) should be reduced by 50%. because the dose of celecoxib and tramadol cannot be adjusted individually for seglentis, the use in moderate hepatic impairment is not recommended. the use of celecoxib in patients with severe hepatic impairment is not recommended [see clinical pharmacology (12.3)]. celecoxib in patients who are known or suspected to be poor cyp2c9 metabolizers (i.e., cyp2c9*3/*3), based on genotype or previous history/experience with other cyp2c9 substrates (such as warfarin, phenytoin) celecoxib is administered starting with half the lowest recommended dose [see clinical pharmacology (12.5)] . because seglentis is not available in lower strengths of celecoxib, seglentis is not recommended in patients who are known or suspected to be poor cyp2c9 metabolizers [see clinical pharmacology (12.5)] . seglentis contains tramadol, a schedule iv controlled substance. seglentis contains 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 seglentis increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. the risk is increased with concurrent use of seglentis with alcohol and/or other cns depressants. abuse and addiction to opioids 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 seglentis 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 seglentis 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. seglentis, 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 seglentis abuse of seglentis poses a risk of overdose and death. the risk is increased with concurrent use of seglentis with alcohol and/or other cns depressants. seglentis is 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., 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 seglentis in a patient physically dependent on opioids. rapid tapering of seglentis 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 seglentis, gradually taper the dosage using a patient-specific plan that considers the following: the dose of seglentis 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 (2.4), warnings and precautions (5.29)] . if seglentis is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur. some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. 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)] .

Jordania - inglés - JFDA (Jordan Food & Drug Administration - المؤسسة العامة للغذاء والدواء)

مستودع أدوية ابن رشد - ibn rushd drug store - aripiprazole 30 milligram - 30 milligram

Jordania - inglés - JFDA (Jordan Food & Drug Administration - المؤسسة العامة للغذاء والدواء)

مستودع أدوية أداتكو - adatco drug store - filgrastim 30 miu/0.5ml - 30 miu/0.5ml