Amerikas Savienotās Valstis - angļu - NLM (National Library of Medicine)

apotex corp. - butorphanol tartrate (unii: 2l7i72ruhn) (butorphanol - unii:qv897jc36d) - butorphanol tartrate 10 mg in 1 ml - butorphanol tartrate nasal spray is indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. limitations of use : because of the risks of addiction, abuse, and misuse, with opioids, which can occur at any dosage or duration [see warnings] reserve butorphanol tartrate nasal spray 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 butorphanol tartrate nasal spray 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. butorphanol tartrate nasal spray is contraindicated in: - patients with significant respiratory depression [see warnings] - patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see warnings] - patients with known or suspected gastrointestinal obstruction, including paralytic ileus [see warnings] - patients with hypersensitivity to butorphanol tartrate, the preservative benzethonium chloride, or any of the formulation excipients (e.g., anaphylaxis) [see warnings]) controlled substance butorphanol tartrate nasal spray contains butorphanol, a schedule iv controlled substance.   abuse butorphanol tartrate nasal spray contains butorphanol tartrate, a substance with a high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see warnings].   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 butorphanol tartrate nasal spray increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. the risk is increased with concurrent abuse of butorphanol tartrate nasal spray with alcohol and other cns depressants. abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. in addition, abuse of opioids can occur in the absence of addiction.   all patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. patients at high risk of butorphanol tartrate nasal spray abuse include those with a history of prolonged use of any opioid, including products containing butorphanol tartrate, those with a history of drug or alcohol abuse, or those who use butorphanol tartrate nasal spray 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.     butorphanol tartrate nasal spray, 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 butorphanol tartrate nasal spray abuse of butorphanol tartrate nasal spray poses a risk of overdose and death. the risk is increased with concurrent use of butorphanol tartrate nasal spray with alcohol and/or other cns depressants. parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and hiv.   dependence both tolerance and physical dependence can develop during use of opioid therapy.   tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).   physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.   withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use.   do not abruptly discontinue butorphanol tartrate nasal spray in a patient physically dependent on opioids. rapid tapering of butorphanol tartrate nasal spray 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 butorphanol tartrate nasal spray, gradually taper the dosage using a patient-specific plan that considers the following: the dose of butorphanol tartrate nasal spray 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, and warnings].   infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see  pregnancy].

Amerikas Savienotās Valstis - angļu - NLM (National Library of Medicine)

apotex corp - quinapril hydrochloride (unii: 33067b3n2m) (quinaprilat - unii:34ssx5lde5), hydrochlorothiazide (unii: 0j48lph2th) (hydrochlorothiazide - unii:0j48lph2th) - quinapril 10 mg - hypertension quinapril hydrochloride and hydrochlorothiazide tablets are indicated for the treatment of hypertension, to lower blood pressure. lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. these benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this drug principally belongs. there are no controlled trials demonstrating risk reduction with quinapril hydrochloride and hydrochlorothiazide. control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. many patients will require more than one drug to achieve blood pressure goals. for specific advice on goals and management, see published guidelines, such as those of the national high blood pressure education progr

Amerikas Savienotās Valstis - angļu - NLM (National Library of Medicine)

apotex corp. - cyclosporine (unii: 83hn0gtj6d) (cyclosporine - unii:83hn0gtj6d) - cyclosporine 25 mg - cyclosporine capsules, (non-modified) are indicated for the prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants. it is always to be used with adrenal corticosteroids. the drug may also be used in the treatment of chronic rejection in patients previously treated with other immunosuppressive agents.    cyclosporine capsules are contraindicated in patients with a hypersensitivity to cyclosporine or to any of the ingredients of the formulation.

Amerikas Savienotās Valstis - angļu - NLM (National Library of Medicine)

apotex corp. - selegiline hydrochloride (unii: 6w731x367q) (selegiline - unii:2k1v7gp655) - selegiline hydrochloride tablets usp are indicated as an adjunct in the management of parkinsonian patients being treated with levodopa/carbidopa who exhibit deterioration in the quality of their response to this therapy. there is no evidence from controlled studies that selegiline has any beneficial effect in the absence of concurrent levodopa therapy. evidence supporting this claim was obtained in randomized controlled clinical investigations that compared the effects of added selegiline or placebo in patients receiving levodopa/carbidopa. selegiline was significantly superior to placebo on all three principal outcome measures employed: change from baseline in daily levodopa/carbidopa dose, the amount of 'off' time, and patient self-rating of treatment success. beneficial effects were also observed on other measures of treatment success (e.g., measures of reduced end of dose akinesia, decreased tremor and sialorrhea, improved speech and dressing ability and improved overall disability as assessed by walking and comparison to previous state). selegiline hydrochloride is contraindicated in patients with a known hypersensitivity to this drug. selegiline is contraindicated for use with meperidine. this contraindication is often extended to other opioids. (see drug interactions .)

Amerikas Savienotās Valstis - angļu - NLM (National Library of Medicine)

apotex corp - abacavir sulfate (unii: j220t4j9q2) (abacavir - unii:wr2tip26vs) - abacavir 300 mg - abacavir tablets, in combination with other antiretroviral agents, are indicated for the treatment of human immunodeficiency virus (hiv-1) infection. abacavir tablets are contraindicated in patients: - who have the hla-b*5701 allele [see warnings and precautions (5.1)]. - with prior hypersensitivity reaction to abacavir [see warnings and precautions (5.1)].  - with moderate or severe hepatic impairment [see use in specific populations (8.6)]. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to abacavir during pregnancy. healthcare providers are encouraged to register patients by calling the antiretroviral pregnancy registry (apr) at 1-800-258-4263. risk summary available data from the apr show no difference in the overall risk of birth defects for abacavir compared with the background rate for birth defects of 2.7% in the metropolitan atlanta congenital defects program (macdp) reference population (see data). the apr uses the macdp a

Amerikas Savienotās Valstis - angļu - NLM (National Library of Medicine)

apotex corp - teriflunomide (unii: 1c058ikg3b) (teriflunomide - unii:1c058ikg3b) - teriflunomide tablets are indicated for the treatment of relapsing forms of multiple sclerosis (ms), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. teriflunomide tablets are contraindicated in/with: - patients with severe hepatic impairment [see warnings and precautions (5.1)] . - pregnant women and females of reproductive potential not using effective contraception. teriflunomide tablets may cause fetal harm [see warnings and precautions (5.2, 5.3) and use in specific populations (8.1)] . - patients with a history of a hypersensitivity reaction to teriflunomide, leflunomide, or to any of the inactive ingredients in teriflunomide tablets. reactions have included anaphylaxis, angioedema, and serious skin reactions [see warnings and precautions (5.5)]. - coadministration with leflunomide [see clinical pharmacology (12.3)]. risk summary teriflunomide tablets are contraindicated for use in pregnant women and females of reproduct

Amerikas Savienotās Valstis - angļu - NLM (National Library of Medicine)

apotex corp. - levetiracetam (unii: 44yrr34555) (levetiracetam - unii:44yrr34555) - levetiracetam 500 mg - levetiracetam extended-release tablets are indicated for the treatment of partial-onset seizures in patients 12 years of age and older. levetiracetam extended-release tablets are contraindicated in patients with a hypersensitivity to levetiracetam. reactions have included anaphylaxis and angioedema [see warnings and precautions (5.4)]. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (aeds), including levetiracetam extended-release tablets, during pregnancy. encourage women who are taking levetiracetam extended-release tablets during pregnancy to enroll in the north american antiepileptic drug (naaed) pregnancy registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/. risk summary prolonged experience with levetiracetam tablets in pregnant women has not identified a drug-associated risk of major birth defects or miscarriage, based on published literature, which includes data from pregnancy registries and reflects experience over two decades [see human data] . in animal studies, levetiracetam produced developmental toxicity (increased embryofetal and offspring mortality, increased incidences of fetal structural abnormalities, decreased embryofetal and offspring growth, neurobehavioral alterations in offspring) at doses similar to human therapeutic doses [see animal data] . in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. the background risk of major birth defects and miscarriage for the indicated population is unknown. clinical considerations levetiracetam extended-release tablets levels may decrease during pregnancy [see warnings and precautions (5.10)]. physiological changes during pregnancy may affect levetiracetam concentration. decrease in levetiracetam plasma concentrations has been observed during pregnancy. this decrease is more pronounced during the third trimester. dose adjustments may be necessary to maintain clinical response. data human data while available studies cannot definitively establish the absence of risk, data from the published literature and pregnancy registries have not established an association with levetiracetam use during pregnancy and major birth defects or miscarriage. animal data when levetiracetam (0, 400, 1,200, or 3,600 mg/kg/day) was administered orally to pregnant rats during the period of organogenesis, reduced fetal weights and increased incidence of fetal skeletal variations were observed at the highest dose tested. there was no evidence of maternal toxicity. the no-effect dose for adverse effects on embryofetal developmental in rats (1,200 mg/kg/day) is approximately 4 times the maximum recommended human dose (mrhd) of 3,000 mg on a body surface area (mg/m2 ) basis. oral administration of levetiracetam (0, 200, 600, or 1,800 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in increased embryofetal mortality and incidence of fetal skeletal variations at the mid and high dose and decreased fetal weights and increased incidence of fetal malformations at the high dose, which was associated with maternal toxicity. the no-effect dose for adverse effects on embryofetal development in rabbits (200 mg/kg/day) is approximately equivalent to the mrhd on a mg/m2  basis. oral administration of levetiracetam (0, 70, 350, or 1,800 mg/kg/day) to female rats throughout pregnancy and lactation led to an increased incidence of fetal skeletal variations, reduced fetal body weight, and decreased growth in offspring at the mid and high doses and increased pup mortality and neurobehavioral alterations in offspring at the highest dose tested. there was no evidence of maternal toxicity. the no-effect dose for adverse effects on pre-and postnatal development in rats (70 mg/kg/day) is less than the mrhd on a mg/m2  basis. oral administration of levetiracetam to rats during the latter part of gestation and throughout lactation produced no adverse developmental or maternal effects at doses of up to 1,800 mg/kg/day (6 times the mrhd on a mg/m2  basis). risk summary levetiracetam is excreted in human milk. there are no data on the effects of levetiracetam extended-release tablets on the breastfed infant, or the effects on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for levetiracetam extended-release tablets and any potential adverse effects on the breastfed infant from levetiracetam extended-release tablets or from the underlying maternal condition.  safety and effectiveness in patients 12 years of age and older have been established based on pharmacokinetic data in adults and adolescents using levetiracetam extended-release tablets and efficacy and safety data in controlled pediatric studies using immediate-release levetiracetam tablets [see adverse reactions (6.1), clinical pharmacology (12.3), and clinical studies (14.1)]. safety and effectiveness in pediatric patients below the age of 12 have not been established. a 3-month, randomized, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of immediate-release levetiracetam tablets as adjunctive therapy in 98 pediatric patients with inadequately controlled partial seizures, ages 4 to 16 years (levetiracetam tablets n=64; placebo n=34). the target dose of immediate-release levetiracetam tablets was 60 mg/kg/day. neurocognitive effects were measured by the leiter-r attention and memory (am) battery, which assesses various aspects of a child's memory and attention. although no substantive differences were observed between the placebo- and levetiracetam-treated groups in the median change from baseline in this battery, the study was not adequate to assess formal statistical non-inferiority between the drug and placebo. the achenbach child behavior checklist (cbcl/6-18), a standardized validated tool used to assess a child’s competencies and behavioral/emotional problems, was also assessed in this study. an analysis of the cbcl/6-18 indicated a worsening in aggressive behavior, one of the eight syndrome scores, in patients treated with levetiracetam tablets [see warnings and precautions (5.1)] . juvenile animal toxicity data studies of levetiracetam in juvenile rats (dosed on postnatal days 4 through 52) and dogs (dosed from postnatal weeks 3 through 7) at doses of up to 1,800 mg/kg/day (approximately 7 and 24 times, respectively, the maximum recommended pediatric dose of 60 mg/kg/day on a mg/m2 basis) did not demonstrate adverse effects on postnatal development. there were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the effectiveness of levetiracetam extended-release in these patients. it is expected that the safety of levetiracetam extended-release in elderly patients 65 and over would be comparable to the safety observed in clinical studies of immediate-release levetiracetam tablets. there were 347 subjects in clinical studies of immediate-release levetiracetam that were 65 and over. no overall differences in safety were observed between these subjects and younger subjects. there were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the effectiveness of immediate-release levetiracetam in these patients. levetiracetam 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 [see clinical pharmacology (12.3)]. the effect of levetiracetam extended-release on renally impaired patients was not assessed in the controlled study. however, it is expected that the effect on levetiracetam extended-release-treated patients would be similar to the effect seen in controlled studies of immediate-release levetiracetam tablets. clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance [see clinical pharmacology (12.3)] . dose adjustment is recommended for patients with impaired renal function [see dosage and administration (2.2)].

Amerikas Savienotās Valstis - angļu - NLM (National Library of Medicine)

apotex corp. - tetrabenazine (unii: z9o08yrn8o) (tetrabenazine - unii:z9o08yrn8o) - tetrabenazine tablets are indicated for the treatment of chorea associated with huntington's disease. tetrabenazine tablets are contraindicated in patients: - who are actively suicidal, or in patients with untreated or inadequately treated depression [see warnings and precautions (5.1)] . who are actively suicidal, or in patients with untreated or inadequately treated depression [see warnings and precautions (5.1)] . - with hepatic impairment [see use in specific populations (8.6), clinical pharmacology (12.3)] . with hepatic impairment [see use in specific populations (8.6), clinical pharmacology (12.3)] . - taking monoamine oxidase inhibitors (maois). tetrabenazine tablets should not be used in combination with an maoi, or within a minimum of 14 days of discontinuing therapy with an maoi [see drug interactions (7.3)] . taking monoamine oxidase inhibitors (maois). tetrabenazine tablets should not be used in combination with an maoi, or within a minimum of 14 days of discontinuing therapy with an maoi [see drug interactions (7.3)] . - taking reserpine. at least 20 days should elapse after stopping reserpine before starting tetrabenazine tablets [see drug interactions (7.2)] . taking reserpine. at least 20 days should elapse after stopping reserpine before starting tetrabenazine tablets [see drug interactions (7.2)] . - taking deutetrabenazine or valbenazine [see drug interactions (7.7)] . taking deutetrabenazine or valbenazine [see drug interactions (7.7)] . risk summary there are no adequate data on the developmental risk associated with the use of tetrabenazine in pregnant women. administration of tetrabenazine to rats throughout pregnancy and lactation resulted in an increase in stillbirths and postnatal offspring mortality. administration of a major human metabolite of tetrabenazine to rats during pregnancy or during pregnancy and lactation produced adverse effects on the developing fetus and offspring (increased mortality, decreased growth, and neurobehavioral and reproductive impairment). the adverse developmental effects of tetrabenazine and a major human metabolite of tetrabenazine in rats occurred at clinically relevant doses [see data] .   in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. the background risk of major birth defects and miscarriage for the indicated population is unknown.   data   animal data tetrabenazine had no clear effects on embryofetal development when administered to pregnant rats throughout the period of organogenesis at oral doses up to 30 mg/kg/day (or 3 times the maximum recommended human dose [mrhd] of 100 mg/day on a mg/m2 basis). tetrabenazine had no effects on embryofetal development when administered to pregnant rabbits during the period of organogenesis at oral doses up to 60 mg/kg/day (or 12 times the mrhd on a mg/m2 basis).   when tetrabenazine (5, 15, and 30 mg/kg/day) was orally administered to pregnant rats from the beginning of organogenesis through the lactation period, an increase in stillbirths and offspring postnatal mortality was observed at 15 and 30 mg/kg/day and delayed pup maturation was observed at all doses. a no-effect dose for pre- and postnatal developmental toxicity in rats was not identified. the lowest dose tested (5 mg/kg/day) was less than the mrhd on a mg/m2 basis.   because  rats dosed orally with tetrabenazine do not produce 9-desmethyl-β-dhtbz, a major human metabolite of tetrabenazine, the metabolite was directly administered to pregnant and lactating rats. oral administration of 9-desmethyl-β-dhtbz (8, 15, and 40 mg/kg/day) throughout the period of organogenesis produced increases in embryofetal mortality at 15 and 40 mg/kg/day and reductions in fetal body weights at 40 mg/kg/day, which was also maternally toxic. when 9-desmethyl-β-dhtbz (8, 15, and 40 mg/kg/day) was orally administered to pregnant rats from the beginning of organogenesis through the lactation period, increases in gestation duration, stillbirths, and offspring postnatal mortality (40 mg/kg/day); decreases in pup weights (40 mg/kg/day); and neurobehavioral (increased activity, learning and memory deficits) and reproductive (decreased litter size) impairment (15 and 40 mg/kg/day) were observed. maternal toxicity was seen at the highest dose. the no-effect dose for developmental toxicity in rats (8 mg/kg/day) was associated with plasma exposures (auc) of 9-desmethyl-β-dhtbz in pregnant rats lower than that in humans at the mrhd. risk summary there are no data on the presence of tetrabenazine or its metabolites in human milk, the effects on the breastfed infant, or the effects of the drug on milk production.   the  developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for tetrabenazine and any potential adverse effects on the breastfed infant from tetrabenazine or from the underlying maternal condition.   safety and effectiveness in pediatric patients have not been established. the pharmacokinetics of tetrabenazine and its primary metabolites have not been formally studied in geriatric subjects. because the safety and efficacy of the increased exposure to tetrabenazine and other circulating metabolites are unknown, it is not possible to adjust the dosage of tetrabenazine in hepatic impairment to ensure safe use. the use of tetrabenazine in patients with hepatic impairment is contraindicated [see contraindications (4), clinical pharmacology (12.3)] . patients who require doses of tetrabenazine tablets greater than 50 mg per day, should be first tested and genotyped to determine if they are poor (pms) or extensive metabolizers (ems) by their ability to express the drug metabolizing enzyme, cyp2d6. the dose of tetrabenazine should then be individualized accordingly to their status as either poor (pms) or extensive metabolizers (ems) [see dosage and administration (2.2), warnings and precautions (5.3), clinical pharmacology (12.3)] .   poor metabolizers   poor cyp2d6 metabolizers (pms) will have substantially higher levels of exposure to the primary metabolites (about 3-fold for α-htbz and 9-fold for β-htbz) compared to ems. the dosage should, therefore, be adjusted according to a patient’s cyp2d6 metabolizer status by limiting a single dose to a maximum of 25 mg and the recommended daily dose to not exceed a maximum of 50 mg/day in patients who are cyp2d6 pms [see dosage and administration (2.2), warnings and precautions (5.3), clinical pharmacology (12.3)] .   extensive/intermediate metabolizers   in extensive (ems) or intermediate metabolizers (ims), the dosage of tetrabenazine can be titrated to a maximum single dose of 37.5 mg and a recommended maximum daily dose of 100 mg [see dosage and administration (2.2), drug interactions (7.1), clinical pharmacology (12.3)]. tetrabenazine is not a controlled substance. clinical trials did not reveal patients developed drug seeking behaviors, though these observations were not systematic. abuse has not been reported from the postmarketing experience in countries where tetrabenazine has been marketed. as with any cns-active drug, prescribers should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of tetrabenazine misuse or abuse (such as development of tolerance, increasing dose requirements, drug-seeking behavior). abrupt discontinuation of tetrabenazine from patients did not produce symptoms of withdrawal or a discontinuation syndrome; only symptoms of the original disease were observed to re-emerge [see dosage and administration (2.4)].

Amerikas Savienotās Valstis - angļu - NLM (National Library of Medicine)

apotex corp. - pazopanib (unii: 7rn5dr86ck) (pazopanib - unii:7rn5dr86ck) - pazopanib tablets are indicated for the treatment of adults with advanced renal cell carcinoma (rcc). pazopanib tablets are indicated for the treatment of adults with advanced soft tissue sarcoma (sts) who have received prior chemotherapy. limitations of use : the efficacy of pazopanib tablets for the treatment of patients with adipocytic sts or gastrointestinal stromal tumors has not been demonstrated. none. risk summary based on animal reproduction studies and its mechanism of action [see clinical pharmacology (12.1)], pazopanib tablets can cause fetal harm when administered to a pregnant woman. there are no available data on pazopanib tablets use in pregnant women to evaluate for a drug-associated risk. in animal developmental and reproductive toxicology studies, oral administration of pazopanib to pregnant rats and rabbits throughout organogenesis resulted in teratogenicity, and abortion at systemic exposures lower than that observed at the mrhd of 800 mg/day (based on auc) (see data). advise pregnant women of the potential risk to a fetus. the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects in clinically recognized pregnancies and miscarriage is 2% to 4% and 15% to 20%, respectively. data animal data in a female fertility and early embryonic development study, female rats were administered oral pazopanib at least 15 days prior to mating and for 6 days after mating, which resulted in increased pre-implantation loss and early resorptions at dosages greater than or equal to 30 mg/kg/day (approximately 0.4-fold the auc at the mrhd of 800 mg/day). total litter resorption was seen at 300 mg/kg/day (approximately 0.8-fold the auc at the mrhd of 800 mg/day). postimplantation loss, embryolethality, and decreased fetal body weights were noted in females administered doses greater than or equal to 10 mg/kg/day (approximately 0.3-fold the auc at the mrhd of 800 mg/day). in embryo-fetal developmental toxicity studies in rats and rabbits, oral pazopanib was administered to pregnant animals during organogenesis. in rats, dose levels of greater than or equal to 3 mg/kg/day (approximately 0.1-fold the auc at the mrhd of 800 mg/day) resulted in teratogenic effects, including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch), incomplete or absent ossification, increases in postimplantation loss, embryolethality and reduced fetal body weight. in rabbits, maternal toxicity, increased postimplantation loss and abortion were observed at doses greater than or equal to 30 mg/kg/day (approximately 0.007-fold the auc at the mrhd of 800 mg/day). in addition, severe maternal body weight loss and 100% litter loss were observed at doses greater than or equal to 100 mg/kg/day (0.02-fold the auc at the mrhd of 800 mg/day), while fetal weight was reduced at doses greater than or equal to 3 mg/kg/day (auc not calculated). risk summary there is no data on the presence of pazopanib or its metabolites in human milk or their effects on the breastfed infant or milk production. because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with pazopanib tablets and for 2 weeks after the final dose. pazopanib tablets can cause fetal harm when administered to a pregnant woman [see use in specific populations (8.1)). pregnancy testing verify pregnancy status of females of reproductive potential prior to starting treatment with pazopanib tablets. contraception females advise females of reproductive potential to use effective contraception during treatment with pazopanib tablets and for at least 2 weeks after the last dose. males advise males (including those who have had vasectomies) with female partners of reproductive potential to use condoms during treatment with pazopanib tablets and for at least 2 weeks after the last dose. infertility based on findings from animal studies, pazopanib tablets may impair fertility in females and males of reproductive potential while receiving treatment [see nonclinical toxicology (13.1) ]. the safety and effectiveness of pazopanib tablets in pediatric patients have not been established. pazopanib tablets are not indicated for use in pediatric patients [see warnings and precautions (5.18)] . based on its mechanism of action, pazopanib may have severe effects on organ growth and maturation during early postnatal development. administration of pazopanib to juvenile rats < 21 days old resulted in toxicity to the lungs, liver, heart, and kidney and in death at doses significantly lower than the clinically recommended dose or doses tolerated in older animals (see juvenile animal toxicity data). the safety and efficacy of pazopanib tablets or an unapproved pazopanib formulation were investigated but not established in two open-label studies: a study in 37 pediatric patients 2 to < 17 years with recurrent or refractory solid tumors [nct00929903] and a study in 46 pediatric patients 1 year to < 17 years with refractory solid tumors, including sarcoma [nct01956669]. meaningful anti-tumor activity was not observed in these studies. juvenile animal toxicity data in rats, weaning occurs at day 21 postpartum which approximately equates to a human pediatric age of 2 years. in a juvenile animal toxicology study performed in rats, when animals were dosed from day 9 through day 14 postpartum (pre-weaning), pazopanib caused abnormal organ growth/maturation in the kidney, lung, liver, and heart at approximately 0.1-fold the auc in adults at the mrhd of 800 mg/day of pazopanib. at approximately 0.4-fold the auc in adults at the mrhd of 800 mg/day, pazopanib administration resulted in mortality. in repeat-dose toxicology studies in rats, including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses greater than or equal to 3 mg/kg/day (approximately 0.07-fold the auc at the mrhd of 800 mg/day). doses of 300 mg/kg/day (approximately 0.8-fold the auc at the mrhd of 800 mg/day) were not tolerated in 13- and 26-week studies and animals required dose reductions due to body weight loss and morbidity. hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken, and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at doses greater than or equal to 30 mg/kg/day (approximately 0.35-fold the auc at the mrhd of 800 mg/day) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. similar findings were noted in repeat-dose studies in juvenile rats dosed with pazopanib beginning day 21 postpartum (post-weaning). in the post-weaning animals, the occurrence of changes in teeth and bones occurred earlier and with greater severity than in older animals. there was evidence of tooth degeneration and decreased bone growth at doses greater than or equal to 30 mg/kg (approximately 0.1- to 0.2-fold the auc at the mrhd of 800 mg/day). pazopanib exposure in juvenile rats was lower than that seen at the same dose levels in adult animals, based on comparative auc values. at pazopanib doses approximately 0.5- to 0.7-fold the auc at the mrhd of 800 mg/day, decreased bone growth in juvenile rats persisted even after the end of the dosing period. finally, despite lower pazopanib exposures than those reported in adult animals or adult humans, juvenile animals administered 300 mg/kg/dose pazopanib required dose reduction within 4 weeks of dosing initiation due to significant toxicity, although adult animals could tolerate this same dose for at least 3 times as long [see warnings and precautions (5.18)].  in pooled clinical trials with pazopanib tablets, 30% of 2,080 patients were aged ≥ 65 years. more patients ≥ 65 years had alt elevations > 3 x uln compared to patients < 65 years (23% versus 18%) [see warnings and precautions (5.1)]. in the rcc trials, 33% of 586 patients were aged ≥ 65 years. no overall differences in safety or effectiveness of pazopanib tablets were observed between these patients and younger patients. in the sts trials, 24% of 382 patients were aged ≥ 65 years. patients aged ≥ 65 years had a higher incidence of grade 3 or 4 fatigue (19% versus 12% for patients aged < 65 years), hypertension (10% versus 6%), decreased appetite (11% versus 2%), alt elevations (3% versus 2%) and ast elevations (4% versus 1%). in the randomized sts trial (veg110727), no overall differences in effectiveness of pazopanib tablets were observed between patients aged ≥ 65 years and younger patients. no dose adjustment is recommended for patients with renal impairment. pazopanib tablets have not been studied in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. no dose adjustment is required in patients with mild hepatic impairment (either total bilirubin ≤ uln and alt > uln or bilirubin > 1 to 1.5 x uln and any alt value). pazopanib tablets are not recommended in patients with moderate (total bilirubin > 1.5 to 3 x uln and any alt value) and severe (total bilirubin > 3 x uln and any alt value) hepatic impairment [see dosage and administration (2.3), clinical pharmacology (12.3) ].

Amerikas Savienotās Valstis - angļu - NLM (National Library of Medicine)

apotex corp. - clopidogrel bisulfate (unii: 08i79htp27) (clopidogrel - unii:a74586sno7) - clopidogrel 75 mg - - clopidogrel tablets are indicated to reduce the rate of myocardial infarction (mi) and stroke in patients with non-st-segment elevation acs (unstable angina [ua]/non-st-elevation myocardial infarction [nstemi]), including patients who are to be managed medically and those who are to be managed with coronary revascularization. clopidogrel should be administered in conjunction with aspirin. - clopidogrel tablets are indicated to reduce the rate of myocardial infarction and stroke in patients with acute st-elevation myocardial infarction (stemi) who are to be managed medically. clopidogrel tablets should be administered in conjunction with aspirin. in patients with established peripheral arterial disease or with a history of recent myocardial infarction (mi) or recent stroke clopidogrel tablets are indicated to reduce the rate of mi and stroke. clopidogrel tablets are contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage. clopidogrel tablets are contrai