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vitruvias therapeutics, inc. - memantine hydrochloride (unii: jy0wd0ua60) (memantine - unii:w8o17sjf3t) - memantine hydrochloride extended-release capsules is indicated for the treatment of moderate to severe dementia of the alzheimer's type. memantine hydrochloride extended-release capsules is contraindicated in patients with known hypersensitivity to memantine hydrochloride or to any excipients used in the formulation. risk  summary there are no adequate data on the developmental risk associated with the use of memantine hydrochloride extended-release capsules in pregnant women.  adverse developmental effects (decreased body weight and skeletal ossification) were observed in the offspring of rats administered memantine during pregnancy at doses associated with minimal maternal toxicity. these doses are higher than those used in humans at the maximum recommended daily dose of memantine hydrochloride extended-release capsules [see  data]. 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. the background risk of major birth defects and miscarriage for the indicated population is unknown. data animal  data oral administration of memantine (0, 2, 6, or 18 mg/kg/day) to rats during the period of organogenesis resulted in decreased skeletal ossification in fetuses at the highest dose tested. the higher no-effect dose for adverse developmental effects (6 mg/kg) is 2 times the maximum recommended human daily dose (mrhd) of memantine hydrochloride extended-release capsules (28 mg) on a body surface area (mg/m2 ) basis. oral administration of memantine to rabbits (0, 3, 10, or 30 mg/kg/day) during the period of organogenesis resulted in no adverse developmental effects. the highest dose tested is approximately 20 times the mrhd of memantine hydrochloride extended-release capsules on a mg/m2  basis. in rats, memantine (0, 2, 6, or 18 mg/kg/day) was administered orally prior to and throughout mating and, in females, through the period of organogenesis or continuing throughout lactation to weaning. decreased skeletal ossification in fetuses and decreased body weight in pups were observed at the highest dose tested. the higher no-effect dose for adverse developmental effects (6 mg/kg/day) is 2 times the mrhd of memantine hydrochloride extended-release capsules on a mg/m2  basis. oral administration of memantine (0, 2, 6, or 18 mg/kg/day) to rats from late gestation throughout lactation to weaning, resulted in decreased pup weights at the highest dose tested. the higher no-effect dose (6 mg/kg/day) is approximately 2 times the mrhd of memantine hydrochloride extended-release capsules on a mg/m2  basis. risk  summary there are no data on the presence of memantine in human milk, the effects on the breastfed infant, or the effects of memantine hydrochloride extended-release capsules on milk production.   the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for memantine hydrochloride extended-release capsules and any potential adverse effects on the breastfed infant from memantine hydrochloride extended-release capsules or from the underlying maternal condition. safety and effectiveness in pediatric patients have not been established. memantine failed to demonstrate efficacy in two 12-week controlled clinical studies of 578 pediatric patients aged 6-12 years with autism spectrum disorders (asd), including autism, asperger's disorder and pervasive development disorder - not otherwise specified (pdd-nos).memantine has not been studied in pediatric patients under 6 years of age or over 12 years of age. memantine treatment was initiated at 3 mg/day and the dose was escalated to the target dose (weight-based) by week 6. oral doses of memantine 3, 6, 9, or 15 mg extended-release capsules were administered once daily to patients with weights < 20 kg, 20-39 kg, 40-59 kg and ≥ 60 kg, respectively. in a randomized, 12-week double-blind, placebo-controlled parallel study (study a) in patients with autism, there was no statistically significant difference in the social responsiveness scale (srs) total raw score between patients randomized to memantine (n=54) and those randomized to placebo (n=53). in a 12-week responder-enriched randomized withdrawal study (study b) in 471 patients with asd, there was no statistically significant difference in the loss of therapeutic response rates between patients randomized to remain on full-dose memantine (n=153) and those randomized to switch to placebo (n=158). the overall safety profile of memantine in pediatric patients was generally consistent with the known safety profile in adults [see adverse reactions ( 6.1 )] . in study a, the adverse reactions in the memantine group (n=56) that were reported in at least 5% of patients and at least twice the frequency of the placebo group (n=58) are listed in table 2. the adverse reactions that were reported in at least 5% of patients in the 12-48 week open-label study to identify responders to enroll in study b are listed in table 3. in the randomized withdrawal study (study b), the adverse reaction in patients randomized to placebo (n=160) and reported in at least 5% of patients and twice that of the full-dose memantine treatment group (n=157) was irritability (5.0% vs 2.5%). juvenile animal study in a juvenile animal study, male and female juvenile rats were administered memantine (15, 30, and 45 mg/kg/day) starting on postnatal day (pnd) 14 through pnd 70. body weights were reduced at 45 mg/kg/day. delays in sexual maturation were noted in male and female rats at doses ≥ 30 mg/kg/day. memantine induced neuronal lesions in several areas of the brain on pnd 15 and 17 at doses ≥ 30 mg/kg/day. behavioral toxicity (decrease percent of auditory startle habituation) was noted for animals in the 45 mg/kg/day dose group. the 15 mg/kg/day dose was considered the no-observed-adverse-effect-level (noael) for this study. in a second juvenile rat toxicity study, male and female juvenile rats were administered memantine (1, 3, 8, 15, 30, and 45 mg/kg/day) starting on postnatal day (pnd) 7 through pnd 70.  due to early memantine-related mortality, the 30 and 45 mg/kg/day dose groups were terminated without further evaluation. memantine induced apoptosis or neuronal degeneration in several areas of the brain on pnd 8, 10, and 17 at a dose of 15 mg/kg/day. the noael for apoptosis and neuronal degeneration was 8 mg/kg/day. behavioral toxicity (effects on motor activity, auditory startle habituation, and learning and memory) was noted at doses ≥ 3 mg/kg/day during treatment, but was not seen after drug discontinuation. therefore, the 1 mg/kg/day dose was considered the noael for the neurobehavioral effect in this study. the majority of people with alzheimer's disease are 65 years of age and older. in the clinical study of memantine hydrochloride extended-release, the mean age of patients was approximately 77 years; over 91% of patients were 65 years and older, 67% were 75 years and older, and 14% were at or above 85 years of age. the efficacy and safety data presented in the clinical trial sections were obtained from these patients. there were no clinically meaningful differences in most adverse reactions reported by patient groups ≥ 65 years old and < 65 years old. no dosage adjustment is needed in patients with mild or moderate renal impairment. a dosage reduction is recommended in patients with severe renal impairment [see dosage and administration ( 2.3 ) and clinical pharmacology ( 12.3 )] . no dosage adjustment is needed in patients with mild or moderate hepatic impairment. memantine hydrochloride extended-release capsules was not studied in patients with severe hepatic impairment [see clinical pharmacology ( 12.3 )] .

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pfizer laboratories div pfizer inc - abrocitinib (unii: 73sm5sf3or) (abrocitinib - unii:73sm5sf3or) - cibinqo is indicated for the treatment of adults and pediatric patients 12 years of age and older with refractory, moderate-to-severe atopic dermatitis whose disease is not adequately controlled with other systemic drug products, including biologics, or when use of those therapies is inadvisable. limitations of use cibinqo is not recommended for use in combination with other jak inhibitors, biologic immunomodulators, or other immunosuppressants. cibinqo is contraindicated in patients taking antiplatelet therapies, except for low-dose aspirin (≤81 mg daily), during the first 3 months of treatment [see warnings and precautions (5.6), drug interactions (7.2), and clinical pharmacology (12.2)].             pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to cibinqo during pregnancy. pregnant women exposed to cibinqo and health care providers are encouraged to call 1-877-311-3770. risk summary available data from pregnancies reported in clinical trials with cibinqo are not sufficient to establish a drug‑associated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes. in animal reproduction studies, oral administration of abrocitinib to pregnant rats and rabbits during organogenesis at exposure 11 or 4 times the maximum recommended human dose (mrhd) based on auc comparison, respectively, resulted in maternal dystocia and skeletal variations in rats and no adverse effects in rabbits (see data ). the background risks of major birth defects and miscarriage for the indicated population are unknown. all pregnancies carry some risk of birth defects, loss, or other adverse outcomes. the background risks in the u.s. general population of major birth defects and miscarriages are 2–4% and 15–20% of clinically recognized pregnancies, respectively. data animal data in an embryofetal development study, abrocitinib was administered orally to pregnant rats at doses of 10, 30, or 60 mg/kg/day during the period of organogenesis. no fetal malformations were observed. abrocitinib increased the incidence of skeletal variations of short 13th ribs at 30 mg/kg/day (11 times the mrhd based on auc comparison). increased embryofetal lethality and additional skeletal variations (cervical arches with reduced ventral processes, thickened ribs, and unossified metatarsals) were noted at 60 mg/kg/day (17 times the mrhd based on auc comparison). in an embryofetal development study, abrocitinib was administered orally to pregnant rabbits at doses of 10, 30, or 75 mg/kg/day during the period of organogenesis. no abrocitinib-related maternal or developmental toxicity was noted at doses up to 75 mg/kg/day (4 times the mrhd based on auc comparison). in a prenatal and postnatal development study, abrocitinib was administered orally to pregnant rats at doses of 10, 30, and 60 mg/kg/day beginning on gestation day 6 and continuing through lactation day 20. dystocia with prolonged parturition and reduced offspring body weights were noted at 30 mg/kg/day (11 times the mrhd based on auc comparison). postnatal survival was markedly decreased at 60 mg/kg/day (17 times the mrhd based on auc comparison). no maternal toxicity was observed at 10 mg/kg/day (2.4 times the mrhd based on auc comparison). no abrocitinib-related effects on postnatal developmental, neurobehavioral, or reproductive performance of offspring was noted at doses up to 30 mg/kg/day (11 times the mrhd based on auc comparison). risk summary there are no data on the presence of abrocitinib in human milk, the effects on the breast-fed infant, or the effects on milk production. abrocitinib was secreted in milk of lactating rats (see data ). when a drug is present in animal milk, it is likely that the drug will be present in human milk. because of the serious adverse findings in adults, including risks of serious infections, malignancy, and thrombosis, advise women not to breastfeed during treatment with cibinqo and for one day after the last dose (approximately 5–6 elimination half-lives). data animal data lactating female rats were orally administered a single dose of 10 mg/kg abrocitinib on lactation day 12. abrocitinib auc was approximately 5 times greater in milk than in plasma.       infertility females based on the findings in rats, oral administration of cibinqo may impair female fertility. impaired fertility in female rats was reversible 1 month after cessation of abrocitinib oral administration [see nonclinical toxicology (13.1)] . the safety and effectiveness of cibinqo in pediatric patients 12 years of age and older with atopic dermatitis have been established. in trials trial-ad-1 and trial-ad-2, 124 pediatric subjects 12 to less than 18 years old weighing 25 kg or more with moderate-to-severe atopic dermatitis were enrolled and randomized to receive either cibinqo 100 mg (n=51), 200 mg (n=48), or matching placebo (n=25) in monotherapy. additional 284 pediatric subjects 12 to less than 18 years of age weighing 25 kg or more with moderate-to-severe atopic dermatitis, were enrolled and randomized to receive either cibinqo 100 mg (n=95) or 200 mg (n=94) or matching placebo (n=95) in combination with topical corticosteroids in trial-ad-4. efficacy and adverse reaction profile were comparable between the pediatric patients and adults [see clinical studies (14) and adverse reactions (6.1)] . the safety and effectiveness of cibinqo have not been established in pediatric patients below 12 years of age. juvenile animal toxicity data in a juvenile animal toxicity study, abrocitinib was administered orally to juvenile rats at doses of 5, 25, and 75 mg/kg/day from postnatal day 10 (approximately equivalent to a human infant) through postnatal day 63 (approximately equivalent to an adolescent). abrocitinib caused a reversible, dose‑related decrease in the primary spongiosa in the metaphysis of the proximal tibia and distal femur and adverse effects on bone development at all dose levels. abrocitinib caused irreversible dose-related small or misshapen femoral heads at doses ≥5 mg/kg/day (0.8 times the mrhd based on auc comparison); irreversibly decreased femur size and caused paw malrotation and limb impairment at doses ≥25 mg/kg/day (7.2 times the mrhd based on auc comparison); and fractures at 75 mg/kg/day (27 times the mrhd based on auc comparison). in a follow-up study, abrocitinib (25 mg/kg/day, at least 4.5 times the mrhd based on auc comparison) was orally administered to juvenile rats from postnatal day (pnd) 10, 15, 21, or 30 through pnd day 63. administration beginning pnd 10 caused adverse macroscopic and microscopic bone findings consistent with the previous juvenile animal study. however, administration beginning pnd 15 (approximately equivalent to a 6- to 12-month old infant) caused non-adverse reversible microscopic bone findings. no bone findings were noted when administration began on pnd 21 or 30 (approximately equivalent to 2- and 6-year old children, respectively). a total of 145 (4.6%) subjects 65 years of age and older, while 25 (0.8%) were 75 years of age and older, were enrolled in cibinqo clinical trials. clinical trials of cibinqo did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger adult subjects. a higher proportion of subjects 65 years of age and older discontinued from clinical trials compared to younger subjects. among all subjects exposed to cibinqo, including the long-term extension trial, confirmed alc <500/mm3 occurred only in subjects 65 years of age and older. a higher proportion of subjects 65 years of age and older had platelet counts <75,000/mm3 . the incidence rate of herpes zoster in subjects 65 years of age and older treated with cibinqo (7.40 per 100 patient-years) was higher than that of subjects 18 to less than 65 years of age (3.44 per 100 patient-years). in patients with severe (egfr <30 ml/min) and moderate (egfr 30–59 ml/min) renal impairment, the combined exposure (aucinf,u ) of abrocitinib and its two active metabolites, m1 and m2, is increased compared to patients with normal renal function (egfr ≥90 ml/min) [see clinical pharmacology (12.3)]. this may increase the risk of adverse reactions such as infections. cibinqo is not recommended for use in patients with severe renal impairment and esrd including those on renal replacement therapy [see dosage and administration (2.3)]. a dosage reduction in patients with moderate renal impairment is recommended. no dosage adjustment is required in patients with mild renal impairment (egfr 60–89 ml/min) [see dosage and administration (2.3)] . cibinqo has not been studied in subjects on renal replacement therapy. in phase 3 clinical trials, cibinqo was not evaluated in subjects with atopic dermatitis with baseline creatinine clearance values less than 40 ml/min. avoid use of cibinqo in patients with severe (child pugh c) hepatic impairment. in clinical trials, cibinqo was not evaluated in subjects with severe (child pugh c) hepatic impairment. dosage adjustment is not required in patients with mild (child pugh a) or moderate (child pugh b) hepatic impairment based on similar combined exposure (aucinf,u ) of abrocitinib and its two active metabolites, m1 and m2 compared to patients with normal hepatic function [see clinical pharmacology (12.3)] . in patients who are cyp2c19 poor metabolizers, the auc of abrocitinib is increased compared to cyp2c19 normal metabolizers due to reduced metabolic clearance. dosage reduction of cibinqo is recommended in patients who are known or suspected to be cyp2c19 poor metabolizers based on genotype or previous history/experience with other cyp2c19 substrates [see dosage and administration (2.4) and clinical pharmacology (12.5)] .

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liberty pharmaceuticals, inc. - temazepam (unii: chb1qd2qss) (temazepam - unii:chb1qd2qss) - temazepam 7.5 mg - temazepam capsules, usp are indicated for the short-term treatment of insomnia (generally 7 to 10 days). for patients with short-term insomnia, instructions in the prescription should indicate that temazepam capsules should be used for short periods of time (7 to 10 days). the clinical trials performed in support of efficacy were 2 weeks in duration with the final formal assessment of sleep latency performed at the end of treatment. benzodiazepines may cause fetal harm when administered to a pregnant woman. an increased risk of congenital malformations associated with the use of diazepam and chlordiazepoxide during the first trimester of pregnancy has been suggested in several studies. transplacental distribution has resulted in neonatal cns depression following the ingestion of therapeutic doses of a benzodiazepine hypnotic during the last weeks of pregnancy. reproduction studies in animals with temazepam were performed in rats and rabbits. in a perinatal-postnatal study in rats, oral doses of 60 mg/kg/day r

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golden state medical supply, inc. - paricalcitol (unii: 6702d36og5) (paricalcitol - unii:6702d36og5) - paricalcitol 1 ug - paricalcitol capsules are indicated for the prevention and treatment of secondary hyperparathyroidism associated with chronic kidney disease (ckd) stages 3 and 4. paricalcitol capsules are indicated for the prevention and treatment of secondary hyperparathyroidism associated with ckd stage 5 in patients on hemodialysis (hd) or peritoneal dialysis (pd). paricalcitol capsules should not be given to patients with evidence of - hypercalcemia or - vitamin d toxicity [see warnings and precautions (5.1) ]. pregnancy category c. paricalcitol has been shown to cause minimal decreases in fetal viability (5%) when administered daily to rabbits at a dose 0.5 times a human dose of 14 mcg or 0.24 mcg/kg (based on body surface area, mcg/m 2 ), and when administered to rats at a dose two times the 0.24 mcg/kg human dose (based on body surface area, mcg/m 2 ). at the highest dose tested, 20 mcg/kg administered three times per week in rats (13 times the 14 mcg human dose based on

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lake erie medical dba quality care products llc - levothyroxine sodium (unii: 9j765s329g) (levothyroxine - unii:q51bo43mg4) - levothyroxine sodium anhydrous 25 ug - levothyroxine sodium is used for the following indications: hypothyroidism – as replacement or supplemental therapy in congenital or acquired hypothyroidism of any etiology, except transient hypothyroidism during the recovery phase of subacute thyroiditis.  specific indications include: primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) hypothyroidism and subclinical hypothyroidism. primary hypothyroidism may result from functional deficiency, primary atrophy, partial or total congenital absence of the thyroid gland, or from the effects of surgery, radiation, or drugs, with or without the presence of goiter. pituitary tsh suppression – in the treatment or prevention of various types of euthyroid goiters (see warnings and precautions ), including thyroid nodules (see warnings and precautions ), subacute or chronic lymphocytic thyroiditis (hashimoto’s thyroiditis), multinodular goiter (see warnings  and precautions ) and, as an adjunct to surgery and radioiodine therapy in the managem

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citron pharma llc - famciclovir (unii: qic03ani02) (penciclovir - unii:359hue8fjc) - herpes labialis (cold sores): famciclovir tablets are indicated for the treatment of recurrent herpes labialis. genital herpes: recurrent episodes: famciclovir tablets are indicated for the treatment of recurrent episodes of genital herpes. the efficacy of famciclovir tablets when initiated more than 6 hours after onset of symptoms or lesions has not been established. suppressive therapy: famciclovir tablets are indicated for chronic suppressive therapy of recurrent episodes of genital herpes. the efficacy and safety of famciclovir tablets for the suppression of recurrent genital herpes beyond 1 year have not been established. herpes zoster (shingles): famciclovir tablets are indicated for the treatment of herpes zoster. the efficacy of famciclovir tablets when initiated more than 72 hours after onset of rash has not been established. recurrent orolabial or genital herpes: famciclovir tablets are indicated for the treatment of recurrent episodes of orolabial or genital herpes in hiv-

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dr. reddy's laboratories, inc. - nitroglycerin (unii: g59m7s0ws3) (nitroglycerin - unii:g59m7s0ws3) - transdermal nitroglycerin is indicated for the prevention of angina pectoris due to coronary artery disease. the onset of action of transdermal nitroglycerin is not sufficiently rapid for this product to be useful in aborting an acute attack. nitroglycerin is contraindicated in patients who are allergic to it. allergy to the adhesives used in nitroglycerin patches has also been reported, and it similarly constitutes a contraindication to the use of this product. do not use nitroglycerin transdermal infusion system in patients who are taking phosphodiesterase inhibitors (such as sildenafil, tadalafil, or vardenafil) for erectile dysfunction or pulmonary arterial hypertension. concomitant use can cause severe drops in blood pressure. do not use nitroglycerin transdermal infusion system in patients who are taking the soluble guanylate cyclase stimulator riociguat. concomitant use can cause hypotension.

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xiamen lp pharmaceutical co., ltd. - memantine hydrochloride (unii: jy0wd0ua60) (memantine - unii:w8o17sjf3t) - memantine hydrochloride extended-release capsules is indicated for the treatment of moderate to severe dementia of the alzheimer’s type. memantine hydrochloride extended-release capsules is contraindicated in patients with known hypersensitivity to memantine hydrochloride or to any excipients used in the formulation . risk  summary there are no adequate data on the developmental risk associated with the use of memantine hydrochloride extended-release capsules in pregnant women.  adverse developmental effects (decreased body weight and skeletal ossification) were observed in the offspring of rats administered memantine during pregnancy at doses associated with minimal maternal toxicity. these doses are higher than those used in humans at the maximum recommended daily dose of memantine hydrochloride extended-release capsules  [see  data]. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and

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specgx llc - fentanyl citrate (unii: mun5lyg46h) (fentanyl - unii:uf599785jz) - fentanyl 200 ug - oral transmucosal fentanyl citrate is indicated for the management of breakthrough pain in cancer patients 16 years of age and older who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. patients considered opioid tolerant are those who are taking, for one week or longer, around-the-clock medicine consisting of at least 60 mg of oral morphine per day, at least 25 mcg of transdermal fentanyl per hour, at least 30 mg of oral oxycodone per day, at least 8 mg of oral hydromorphone per day, at least 25 mg oral oxymorphone per day, at least 60 mg of oral hydrocodone per day, or an equianalgesic dose of another opioid. patients must remain on around-the-clock opioids when taking oral transmucosal fentanyl citrate. limitations of use : - not for use in opioid non-tolerant patients. not for use in opioid non-tolerant patients. - not for use in the management of acute or postoperative pain, including headache/migraine and dental pain [see contraindications (4)] . not for use in the management of acute or postoperative pain, including headache/migraine and dental pain [see contraindications (4)] . - as a part of the tirf rems, oral transmucosal fentanyl citrate may be dispensed by outpatient pharmacies only to outpatients enrolled in the program [see warnings and precautions (5.7)] . for inpatient administration of oral transmucosal fentanyl citrate, patient and prescriber enrollment are not required. as a part of the tirf rems, oral transmucosal fentanyl citrate may be dispensed by outpatient pharmacies only to outpatients enrolled in the program [see warnings and precautions (5.7)] . for inpatient administration of oral transmucosal fentanyl citrate, patient and prescriber enrollment are not required. oral transmucosal fentanyl citrate is contraindicated in: - opioid non-tolerant patients: life-threatening respiratory depression and death could occur at any dose in opioid non-tolerant patients [see indications and usage (1)]; warnings and precautions (5.1) [see indications and usage (1)] . - significant respiratory depression [see warnings and precautions (5.1)] . significant respiratory depression [see warnings and precautions (5.1)] . - acute or postoperative pain including headache/migraine and dental pain, or acute pain in the emergency department. acute or postoperative pain including headache/migraine and dental pain, or acute pain in the emergency department. - acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see warnings and precautions (5.9)] . acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see warnings and precautions (5.9)] . - known or suspected gastrointestinal obstruction, including paralytic ileus [see warnings and precautions (5.14)] . known or suspected gastrointestinal obstruction, including paralytic ileus [see warnings and precautions (5.14)] . - known hypersensitivity to fentanyl or components of oral transmucosal fentanyl citrate (e.g., anaphylaxis, hypersensitivity) [see adverse reactions (6.2)] . known hypersensitivity to fentanyl or components of oral transmucosal fentanyl citrate (e.g., anaphylaxis, hypersensitivity) [see adverse reactions (6.2)] . risk summary prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see warnings and precautions (5.8)] . available data with oral transmucosal fentanyl citrate in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. in animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing. when administered during gestation through lactation fentanyl administration to pregnant rats resulted in reduced pup survival at doses within the range of the human recommended dosing. no evidence of malformations were noted in animal studies completed to date [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. clinical considerations fetal/neonatal adverse reactions prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. the onset of neonatal withdrawal symptoms usually occurs in the first days after birth. the duration and severity of neonatal opioid withdrawal syndrome may vary. observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see warnings and precautions (5.8)] . 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. oral transmucosal fentanyl citrate is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. opioid analgesics, including oral transmucosal fentanyl citrate, 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. data human data in women treated acutely with intravenous or epidural fentanyl during labor, symptoms of neonatal respiratory or neurological depression were no more frequent than would be expected in infants of untreated mothers. transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl. animal data fentanyl (25, 50, or 100 mcg/kg) citrate was administered subcutaneously to pregnant rats during the period of organogenesis (gestation day, gd 6 to 17). maternal toxicity and a decrease in fetal weights were observed at 100 mcg/kg but no teratogenicity was seen in the study (the no observed effect level of 50 mcg/kg is equivalent to 0.7 times the exposure of a single human dose of 1600 mcg per pain episode, based on an auc comparison). fentanyl (50, 100, or 250 mcg/kg) was also administered subcutaneously to pregnant rabbits during the period of organogenesis (gd 6 to 18). maternal toxicity was noted at doses >100 mcg/kg. no teratogenicity was seen in the study (250 mcg/kg dose is equivalent to 3.5 times the exposure of a single human dose of 1600 mcg per pain episode, based on an auc comparison). fentanyl has been shown to embryocidal in pregnant rats at doses of 30 mcg/kg intravenously (0.2 times the 1600 mcg dose of oral transmucosal fentanyl citrate on a mg/m2 basis) from gd 6 to 18 and 160 mcg/kg subcutaneously (1 times the 1600 mcg dose of oral transmucosal fentanyl citrate based on a mg/m2 basis). no evidence of teratogenicity was reported. no evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered fentanyl continuously via subcutaneously implanted osmotic minipumps at doses of 10, 100, or 500 mcg/kg/day starting 2-weeks prior to breeding and throughout pregnancy. the high dose was approximately 3 times the human dose of 1600 mcg oral transmucosal fentanyl citrate per pain episode on a mg/m2 basis and produced mean steady-state plasma levels that are 3.4 times higher than the mean cmax observed following administration of 1600 mcg dose of oral transmucosal fentanyl citrate in humans. in a postnatal development study, pregnant rats were treated from gd 6 through lactation day (ld) 20 with subcutaneous doses of fentanyl (25, 50, 100, and 400 mcg/kg). maternal toxicity was noted at doses >100 mcg/kg. a reduction in pup growth and delayed attainment of developmental indices were observed at >100 mcg/kg. no difference in the number of live pups/litter was seen at birth, however, pup survival at ld 4 was reduced to 48% at 400 mcg/kg and by ld 21 pup survival was reduced to 30% and 26% at 100 and 400 mcg/kg, respectively. during lactation, fentanyl-related clinical signs (decreased activity, skin cold to touch, and moribund appearance) were noted in the f1 pups, most prominently in the 400 mcg/kg group. pups from this group also had significantly reduced body weights throughout the lactation period. the dose of fentanyl administered to rats at which no developmental toxicity in the f1 generation was seen was 50 mcg/kg which is 0.6 times the exposure of a single human dose of 1600 mcg per pain episode, based on an auc comparison. risk summary fentanyl is present in breast milk. one published lactation study reports a relative infant dose of fentanyl of 0.024%. however, there is insufficient information to determine the effects of fentanyl on the breastfed infant and the effects of fentanyl on milk production. 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 oral transmucosal fentanyl citrate. clinical considerations monitor infants exposed to oral transmucosal fentanyl citrate through breast milk 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. infertility chronic use of opioids may cause reduced fertility in females and males of reproductive potential. it is not known whether these effects on fertility are reversible [see adverse reactions (6.2), clinical pharmacology (12.2), nonclinical toxicology (13.1)] . safety and effectiveness in pediatric patients below 16 years of age have not been established. in a clinical study, 15 opioid-tolerant pediatric patients with breakthrough pain, ranging in age from 5 to 15 years, were treated with oral transmucosal fentanyl citrate. the study was too small to allow conclusions on safety and efficacy in this patient population. twelve of the fifteen opioid-tolerant children and adolescents aged 5 to 15 years in this study received oral transmucosal fentanyl citrate at doses ranging from 200 mcg to 600 mcg. the mean (cv%; range) dose-normalized (to 200 mcg) cmax and auc0-8 values were 0.87 ng/ml (51%; 0.42-1.30) and 4.54 ng•h/ml (42%; 2.37-6.0), respectively, for children ages 5 to <11 years old (n = 3) and 0.68 ng/ml (72%; 0.15-1.44) and 8.38 (192%; 0.84-50.78), respectively, for children ages ≥11 to <16 y (n = 9). of the 257 patients in clinical studies of oral transmucosal fentanyl citrate in breakthrough cancer pain, 61 (24%) were 65 years of age and older, while 15 (6%) were 75 years of age and older. those patients over the age of 65 years were titrated to a mean dose that was about 200 mcg less than the mean dose titrated to by younger patients. no difference was noted in the safety profile of the group over 65 years of age as compared to younger patients in oral transmucosal fentanyl citrate clinical trials. elderly patients have been shown to be more sensitive to the effects of fentanyl when administered intravenously, compared with the younger population. therefore, exercise caution when individually titrating oral transmucosal fentanyl citrate in elderly patients to provide adequate efficacy while minimizing risk. 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 oral transmucosal fentanyl citrate slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see warnings and precautions (5.9)] . fentanyl is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. insufficient information exists to make recommendations regarding the use of oral transmucosal fentanyl citrate in patients with impaired renal or hepatic function. fentanyl is metabolized primarily via human cytochrome p450 3a4 isoenzyme system and mostly eliminated in urine. if the drug is used in these patients, it should be used with caution because of the hepatic metabolism and renal excretion of fentanyl. both male and female opioid-tolerant cancer patients were studied for the treatment of breakthrough cancer pain. no clinically relevant sex differences were noted either in dosage requirement or in observed adverse reactions. oral transmucosal fentanyl citrate contains fentanyl, a schedule ii controlled substance. oral transmucosal fentanyl citrate contains fentanyl, a substance with a high potential for abuse similar to other opioids including hydrocodone, hydromorphone, methadone, morphine oxycodone, oxymorphone, and tapentadol. oral transmucosal fentanyl citrate can be abused and is subject to misuse, addiction, and criminal diversion [see warnings and precautions (5.6)] . all patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. “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 drug abusers and people suffering from untreated addiction. preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. abuse and addiction are separate and distinct from physical dependence and tolerance. healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. in addition, abuse of opioids can occur in the absence of true addiction. oral transmucosal fentanyl citrate, 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 re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. risks specific to the abuse of oral transmucosal fentanyl citrate oral transmucosal fentanyl citrate is for oral transmucosal use only. abuse of oral transmucosal fentanyl citrate poses a risk of overdose and death. the risk is increased with concurrent abuse of oral transmucosal fentanyl citrate with alcohol and other central nervous system depressants. both tolerance and physical dependence can develop during chronic opioid therapy. tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), 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 opioid usage. 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)] .

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

rebel distributors corp - diltiazem hydrochloride (unii: olh94387te) (diltiazem - unii:ee92bbp03h) - diltiazem hydrochloride 120 mg - diltiazem hydrochloride extended-release capsules are indicated for the treatment of hypertension. they may be used alone or in combination with other antihypertensive medications. diltiazem hydrochloride extended-release capsules are indicated for the management of chronic stable angina and angina due to coronary artery spasm. diltiazem is contraindicated in (1) patients with sick sinus syndrome except in the presence of a functioning ventricular pacemaker, (2) patients with second-or third-degree av block except in the presence of a functioning ventricular pacemaker, (3) patients with hypotension (less than 90 mm hg systolic), (4) patients who have demonstrated hypersensitivity to the drug, and (5) patients with acute myocardial infarction and pulmonary congestion documented by x-ray on admission.