Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/914
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Keppra (Tablet, Film Coated)
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KEPPRA is indicated as adjunctive treatment of partial onset seizures in adults and children 4 years of age and older with epilepsy. KEPPRA is indicated as adjunctive therapy in the treatment of myoclonic seizures in adults and adolescents 12 years of age and older with juvenile myoclonic epilepsy. KEPPRA is indicated as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults and children 6 years of age and older with idiopathic generalized epilepsy.<br/>Partial Onset Seizures:<br/>Adults 16 Years And Older: In clinical trials, daily doses of 1000 mg, 2000 mg, and 3000 mg, given as twice-daily dosing, were shown to be effective. Although in some studies there was a tendency toward greater response with higher dose , a consistent increase in response with increased dose has not been shown. Treatment should be initiated with a daily dose of 1000 mg/day, given as twice-daily dosing (500 mg BID). Additional dosing increments may be given (1000 mg/day additional every 2 weeks) to a maximum recommended daily dose of 3000 mg. Doses greater than 3000 mg/day have been used in open-label studies for periods of 6 months and longer. There is no evidence that doses greater than 3000 mg/day confer additional benefit.<br/>Pediatric Patients Ages 4 To<16 Years: Treatment should be initiated with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg BID). The daily dose should be increased every 2 weeks by increments of 20 mg/kg to the recommended daily dose of 60 mg/kg (30 mg/kg BID). If a patient cannot tolerate a daily dose of 60 mg/kg, the daily dose may be reduced. In the clinical trial, the mean daily dose was 52 mg/kg. Patients with body weight���20 kg should be dosed with oral solution. Patients with body weight above 20 kg can be dosed with either tablets or oral solution. Table 14 below provides a guideline for tablet dosing based on weight during titration to 60 mg/kg/day. Only whole tablets should be administered. KEPPRA is given orally with or without food. The following calculation should be used to determine the appropriate daily dose of oral solution for pediatric patients based on a daily dose of 20 mg/kg/day, 40 mg/kg/day or 60 mg/kg/day: A household teaspoon or tablespoon is not an adequate measuring device. It is recommended that a calibrated measuring device be obtained and used. Healthcare providers should recommend a device that can measure and deliver the prescribed dose accurately, and provide instructions for measuring the dosage.<br/>Myoclonic Seizures In Patients 12 Years Of Age And Older With Juvenile Myoclonic Epilepsy: Treatment should be initiated with a dose of 1000 mg/day, given as twice-daily dosing (500 mg BID). Dosage should be increased by 1000 mg/day every 2 weeks to the recommended daily dose of 3000 mg. The effectiveness of doses lower than 3000 mg/day has not been studied.<br/>Primary Generalized Tonic-Clonic Seizures:<br/>Adults 16 Years And Older: Treatment should be initiated with a dose of 1000 mg/day, given as twice-daily dosing (500 mg BID). Dosage should be increased by 1000 mg/day every 2 weeks to the recommended daily dose of 3000 mg. The effectiveness of doses lower than 3000 mg/day has not been adequately studied.<br/>Pediatric Patients Ages 6 To<16 Years: Treatment should be initiated with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg BID). The daily dose should be increased every 2 weeks by increments of 20 mg/kg to the recommended daily dose of 60 mg/kg (30 mg/kg BID). The effectiveness of doses lower than 60 mg/kg/day has not been adequately studied. Patients with body weight���20 kg should be dosed with oral solution. Patients with body weight above 20 kg can be dosed with either tablets or oral solution. See Table 14 for tablet dosing based on weight during titration to 60 mg/kg/day. Only whole tablets should be administered.<br/>Adult Patients With Impaired Renal Function: KEPPRA dosing must be individualized according to the patient's renal function status. Recommended doses and adjustment for dose for adults are shown in Table 15. To use this dosing table, an estimate of the patient's creatinine clearance (CLcr) in mL/min is needed. CLcr in mL/min may be estimated fromserum creatinine (mg/dL) determination using the following formula:
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KEPPRA is an antiepileptic drug available as 250 mg (blue), 500 mg (yellow), 750 mg (orange), and 1000 mg (white) tablets and as a clear, colorless, grape-flavored liquid (100 mg/mL) for oral administration. The chemical name of levetiracetam, a single enantiomer, is (-)-(S)-��-ethyl-2-oxo-1-pyrrolidine acetamide, its molecular formula is CHNOand its molecular weight is 170.21. Levetiracetam is chemically unrelated to existing antiepileptic drugs (AEDs). It has the following structural formula: Levetiracetam is a white to off-white crystalline powder with a faint odor and a bitter taste. It is very soluble in water (104.0 g/100 mL). It is freely soluble in chloroform (65.3 g/100 mL) and in methanol (53.6 g/100 mL), soluble in ethanol (16.5 g/100 mL), sparingly soluble in acetonitrile (5.7 g/100 mL) and practically insoluble in n-hexane. (Solubility limits are expressed as g/100 mL solvent.) KEPPRA tablets contain the labeled amount of levetiracetam. Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, polyethylene glycol 3350, polyethylene glycol 6000, polyvinyl alcohol, talc, titanium dioxide, and additional agents listed below: 250 mg tablets: FD&C Blue #2/indigo carmine aluminum lake500 mg tablets: iron oxide yellow750 mg tablets: FD&C yellow #6/sunset yellow FCF aluminum lake, iron oxide red KEPPRA oral solution contains 100 mg of levetiracetam per mL. Inactive ingredients: ammonium glycyrrhizinate, citric acid monohydrate, glycerin, maltitol solution, methylparaben, potassium acesulfame, propylparaben, purified water, sodium citrate dihydrate and natural and artificial flavor.
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Mechanism Of Action: The precise mechanism(s) by which levetiracetam exerts its antiepileptic effect is unknown. The antiepileptic activity of levetiracetam was assessed in a number of animal models of epileptic seizures. Levetiracetam did not inhibit single seizures induced by maximal stimulation with electrical current or different chemoconvulsants and showed only minimal activity in submaximal stimulation and in threshold tests. Protection was observed, however, against secondarily generalized activity from focal seizures induced by pilocarpine and kainic acid, two chemoconvulsants that induce seizures that mimic some features of human complex partial seizures with secondary generalization. Levetiracetam also displayed inhibitory properties in the kindling model inrats, another model of human complex partial seizures, both during kindling development and in the fully kindled state. The predictive value of these animal models for specific types of human epilepsy is uncertain. In vitro and in vivo recordings of epileptiform activity from the hippocampus have shown that levetiracetam inhibits burst firing without affecting normal neuronal excitability, suggesting that levetiracetam may selectively prevent hypersynchronization of epileptiform burst firing and propagation of seizure activity. Levetiracetam at concentrations of up to 10��M did not demonstrate binding affinity for a variety of known receptors, such as those associated with benzodiazepines, GABA (gamma-aminobutyric acid), glycine, NMDA (N-methyl-D-aspartate), re-uptake sites, and second messenger systems. Furthermore, in vitro studies have failed to find an effect of levetiracetam on neuronal voltage-gated sodium or T-type calcium currents and levetiracetam does not appear to directly facilitate GABAergic neurotransmission. However, in vitro studies have demonstrated that levetiracetam opposes the activity of negative modulators of GABA- and glycine-gated currents and partially inhibits N-type calcium currents in neuronal cells. A saturable and stereoselective neuronal binding site in rat brain tissue has been described for levetiracetam. Experimental data indicate that this binding site is the synaptic vesicle protein SV2A, thought to be involved in the regulation of vesicle exocytosis. Although the molecular significance of levetiracetam binding to synaptic vesicle protein SV2A is not understood, levetiracetam and related analogs showed a rank order of affinity for SV2A which correlated with the potency of their antiseizure activity in audiogenic seizure-prone mice. These findings suggest that the interaction of levetiracetam with the SV2A protein may contribute to the antiepileptic mechanism of action of the drug.<br/>Pharmacokinetics: The pharmacokinetics of levetiracetam have been studied in healthy adult subjects, adults and pediatric patients with epilepsy, elderly subjects and subjects with renal and hepatic impairment.<br/>Overview: Levetiracetam is rapidly and almost completely absorbed after oral administration. Levetiracetam tablets and oral solution are bioequivalent. The pharmacokinetics are linear and time-invariant, with low intra- and inter-subject variability. The extent of bioavailability of levetiracetam is not affected by food. Levetiracetam is not significantly protein-bound (<10% bound) and its volume of distribution is close to the volume of intracellular and extracellular water. Sixty-six percent (66%) of the dose is renally excreted unchanged. The major metabolic pathway of levetiracetam (24% of dose) is an enzymatic hydrolysis of the acetamide group. It is not liver cytochrome P450 dependent. The metabolites have no known pharmacological activity and are renally excreted. Plasma half-life of levetiracetam across studies is approximately 6-8 hours. It is increased in the elderly (primarily due to impaired renal clearance) and in subjects with renal impairment.<br/>Absorption And Distribution: Absorption of levetiracetam is rapid, with peak plasma concentrations occurring in about an hour following oral administration in fasted subjects. The oral bioavailability of levetiracetam tablets is 100% and the tablets and oral solution are bioequivalent in rate and extent of absorption. Food does not affect the extent of absorption of levetiracetam but it decreases Cby 20% and delays Tby 1.5 hours. The pharmacokinetics of levetiracetam are linear over the dose range of 500-5000 mg. Steady state is achieved after 2 days of multiple twice-daily dosing. Levetiracetam and its major metabolite are less than 10% bound to plasma proteins; clinically significant interactions with other drugs through competition for protein binding sites are therefore unlikely.<br/>Metabolism: Levetiracetam is not extensively metabolized in humans. The major metabolic pathway is the enzymatic hydrolysis of the acetamide group, which produces the carboxylic acid metabolite, ucb L057 (24% of dose) and is not dependent on any liver cytochrome P450 isoenzymes. The major metabolite is inactive in animal seizure models. Two minor metabolites were identified as the product of hydroxylation of the 2-oxo-pyrrolidine ring (2% of dose) and opening of the 2-oxo-pyrrolidine ring in position 5 (1% of dose). There is no enantiomeric interconversion of levetiracetam or its major metabolite.<br/>Elimination: Levetiracetam plasma half-life in adults is 7��1 hour and is unaffected by either dose or repeated administration. Levetiracetam is eliminated from the systemic circulation by renal excretion as unchanged drug which represents 66% of administered dose. The total body clearance is 0.96 mL/min/kg and the renal clearance is 0.6 mL/min/kg. The mechanism of excretion is glomerular filtration with subsequent partial tubular reabsorption. The metabolite ucb L057 is excreted by glomerular filtration and active tubular secretion with a renal clearance of 4 mL/min/kg. Levetiracetam elimination is correlated to creatinine clearance. Levetiracetam clearance is reduced in patients with impaired renal function .<br/>Pharmacokinetic Interactions: In vitro data on metabolic interactions indicate that levetiracetam is unlikely to produce, or be subject to, pharmacokinetic interactions. Levetiracetam and its major metabolite, at concentrations well above Clevels achieved within the therapeutic dose range, are neither inhibitors of, nor high affinity substrates for, human liver cytochrome P450 isoforms, epoxide hydrolase or UDP-glucuronidation enzymes. In addition, levetiracetam does not affect the in vitro glucuronidation of valproic acid. Potential pharmacokinetic interactions of or with levetiracetam were assessed in clinical pharmacokinetic studies (phenytoin, valproate, warfarin, digoxin, oral contraceptive, probenecid) and through pharmacokinetic screening in the placebo-controlled clinical studies in epilepsy patients .<br/>Special Populations:
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This product should not be administered to patients who have previously exhibited hypersensitivity to levetiracetam or any of the inactive ingredients in KEPPRA tablets or oral solution.
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KEPPRA 250 mg tablets are blue, oblong-shaped, scored, film-coated tablets debossed with "ucb 250" on one side. They are supplied in white HDPE bottles containing 120 tablets (NDC 50474-594-40). KEPPRA 500 mg tablets are yellow, oblong-shaped, scored, film-coated tablets debossed with "ucb 500" on one side. They are supplied in white HDPE bottles containing 120 tablets (NDC 50474-595-40). KEPPRA 750 mg tablets are orange, oblong-shaped, scored, film-coated tablets debossed with "ucb 750" on one side. They are supplied in white HDPE bottles containing 120 tablets (NDC 50474-596-40). KEPPRA 1000 mg tablets are white, oblong-shaped, scored, film-coated tablets debossed with���ucb 1000���on one side. They are supplied in white HDPE bottles containing 60 tablets (NDC 50474-597-66). KEPPRA 100 mg/mL oral solution is a clear, colorless, grape-flavored liquid. It is supplied in 16 fl. oz. white HDPE bottles (NDC 50474-001-48).<br/>Storage: Store at 25��C (77��F); excursions permitted to 15-30��C (59-86��F)
[see USP Controlled Room Temperature].<br/>For Medical Information: Contact: Medical Affairs DepartmentPhone: (866) 822-0068Fax: (770) 970-8859
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dailymed-ingredient:FD&C_Blue_#2/indigo_carmine_aluminum_lake,
dailymed-ingredient:colloidal_silicon_dioxide,
dailymed-ingredient:croscarmellose_sodium,
dailymed-ingredient:magnesium_stearate,
dailymed-ingredient:polyethylene_glycol_3350,
dailymed-ingredient:polyethylene_glycol_6000,
dailymed-ingredient:polyvinyl_alcohol,
dailymed-ingredient:talc,
dailymed-ingredient:titanium_dioxide
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Hematologic Abnormalities:<br/>Partial Onset Seizures:<br/>Juvenile Myoclonic Epilepsy: Although there were no obvious hematologic abnormalities observed in patients with JME, the limited number of patients makes any conclusion tentative. The data from the partial seizure patients should be considered to be relevant for JME patients.<br/>Hepatic Abnormalities: There were no meaningful changes in mean liver function tests (LFT) in controlled trials in adult or pediatric patients; lesser LFT abnormalities were similar in drug and placebo treated patients in controlled trials (1.4%). No adult or pediatric patients were discontinued from controlled trials for LFT abnormalities except for 1 (0.07%) adult epilepsy patient receiving open treatment.<br/>Information For Patients: Patients should be instructed to take KEPPRA only as prescribed. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Patients should be advised that KEPPRA may cause dizziness and somnolence. Accordingly, patients should be advised not to drive or operate machinery or engage in other hazardous activities until they have gained sufficient experience on KEPPRA to gauge whether it adversely affects their performance of these activities. Patients should be advised that KEPPRA may cause changes in behavior (e.g. aggression, agitation, anger, anxiety, apathy, depression, hostility, and irritability) and in rare cases patients may experience psychotic symptoms. Patients should be advised to immediately report any symptoms of depression and/or suicidal ideation to their prescribing physician as suicide, suicide attempt and suicidal ideation have been reported in patients treated with levetiracetam. Physicians should advise patients and caregivers to read the patient information leaflet which appears as the last section of the labeling.<br/>Laboratory Tests: Although most laboratory tests are not systematically altered with KEPPRA treatment, there have been relatively infrequent abnormalities seen in hematologic parameters and liver function tests.<br/>Drug Interactions: In vitro data on metabolic interactions indicate that KEPPRA is unlikely to produce, or be subject to, pharmacokinetic interactions. Levetiracetam and its major metabolite, at concentrations well above Clevels achieved within the therapeutic dose range, are neither inhibitors of nor high affinity substrates for human liver cytochrome P450 isoforms, epoxide hydrolase or UDP-glucuronidation enzymes. In addition, levetiracetam does not affect the in vitro glucuronidation of valproic acid. Levetiracetam circulates largely unbound (<10% bound) to plasma proteins; clinically significant interactions with other drugs through competition for protein binding sites are therefore unlikely. Potential pharmacokinetic interactions were assessed in clinical pharmacokinetic studies (phenytoin, valproate, oral contraceptive, digoxin, warfarin, probenecid) and through pharmacokinetic screening in the placebo-controlled clinical studies in epilepsy patients.<br/>Drug-Drug Interactions Between KEPPRA And Other Antiepileptic Drugs (AEDs):<br/>Other Drug Interactions:<br/>Carcinogenesis, Mutagenesis, Impairment Of Fertility:<br/>Carcinogenesis: Rats were dosed with levetiracetam in the diet for 104 weeks at doses of 50, 300 and 1800 mg/kg/day. The highest dose corresponds to 6 times the maximum recommended daily human dose (MRHD) of 3000 mg on a mg/mbasis and it also provided systemic exposure (AUC) approximately 6 times that achieved in humans receiving the MRHD. There was no evidence of carcinogenicity. A study was conducted in which mice received levetiracetam in the diet for 80 weeks at doses of 60, 240 and 960 mg/kg/day (high dose is equivalent to 2 times the MRHD on a mg/mor exposure basis). Although no evidence for carcinogenicity was seen, the potential for a carcinogenic response has not been fully evaluated in that species because adequate doses have not been studied.<br/>Mutagenesis: Levetiracetam was not mutagenic in the Ames test or in mammalian cells in vitro in the Chinese hamster ovary/HGPRT locus assay. It was not clastogenic in an in vitro analysis of metaphase chromosomes obtained from Chinese hamster ovary cells or in an in vivo mouse micronucleus assay. The hydrolysis product and major human metabolite of levetiracetam (ucb L057) was not mutagenic in the Ames test or the in vitro mouse lymphoma assay.<br/>Impairment Of Fertility: No adverse effects on male or female fertility or reproductive performance were observed in rats at doses up to 1800 mg/kg/day (approximately 6 times the maximum recommended human dose on a mg/mor exposure basis).<br/>Pregnancy:<br/>Pregnancy Category C: In animal studies, levetiracetam produced evidence of developmental toxicity at doses similar to or greater than human therapeutic doses. Administration to female rats throughout pregnancy and lactation was associated with increased incidences of minor fetal skeletal abnormalities and retarded offspring growth pre- and/or postnatally at doses���350 mg/kg/day (approximately equivalent to the maximum recommended human dose of 3000 mg [MRHD] on a mg/mbasis) and with increased pup mortality and offspring behavioral alterations at a dose of 1800 mg/kg/day (6 times the MRHD on a mg/mbasis). The developmental no effect dose was 70 mg/kg/day (0.2 times the MRHD on a mg/mbasis). There was no overt maternal toxicity at the doses used in this study. Treatment of pregnant rabbits during the period of organogenesis resulted in increased embryofetal mortality and increased incidences of minor fetal skeletal abnormalities at doses���600 mg/kg/day (approximately 4 times MRHD on a mg/mbasis) and in decreased fetal weights and increased incidences of fetal malformations at a dose of 1800 mg/kg/day (12 times the MRHD on a mg/mbasis). The developmental no effect dose was 200 mg/kg/day (1.3 times the MRHD on a mg/mbasis). Maternal toxicity was also observed at 1800 mg/kg/day. When pregnant rats were treated during the period of organogenesis, fetal weights were decreased and the incidence of fetal skeletal variations was increased at a dose of 3600 mg/kg/day (12 times the MRHD). 1200 mg/kg/day (4 times the MRHD) was a developmental no effect dose. There was no evidence of maternal toxicity in this study. Treatment of rats during the last third of gestation and throughout lactation produced no adverse developmental or maternal effects at doses of up to 1800 mg/kg/day (6 times the MRHD on a mg/mbasis). There are no adequate and well-controlled studies in pregnant women. KEPPRA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. As with other antiepileptic drugs, physiological changes during pregnancy may affect levetiracetam concentration. There have been reports of decreased levetiracetam concentration during pregnancy. Discontinuation of antiepileptic treatments may result in disease worsening, which can be harmful to the mother and the fetus.<br/>UCB AED Pregnancy Registry: UCB, Inc. has established the UCB AED Pregnancy Registry to advance scientific knowledge about safety and outcomes associated with pregnant women being treated with all UCB antiepileptic drugs including KEPPRA. To ensure broad program access and reach, either a healthcare provider or the patient can initiate enrollment in the UCB AED Pregnancy Registry by calling (888) 537-7734 (toll free). Patients may also enroll in the North American Antiepileptic Drug Pregnancy Registry by calling (888) 233-2334 (toll free).
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Signs, Symptoms And Laboratory Findings Of Acute Overdosage In Humans: The highest known dose of KEPPRA received in the clinical development program was 6000 mg/day. Other than drowsiness, there were no adverse events in the few known cases of overdose in clinical trials. Cases of somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with KEPPRA overdoses in postmarketing use.<br/>Treatment Or Management Of Overdose: There is no specific antidote for overdose with KEPPRA. If indicated, elimination of unabsorbed drug should be attempted by emesis or gastric lavage; usual precautions should be observed to maintain airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the patient's clinical status. A Certified Poison Control Center should be contacted for up to date information on the managementof overdose with KEPPRA.<br/>Hemodialysis: Standard hemodialysis procedures result in significant clearance of levetiracetam (approximately 50% in 4 hours) and should be considered in cases of overdose. Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient's clinical state or in patients with significant renal impairment.
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levetiracetam
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Keppra (Tablet, Film Coated)
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The prescriber should be aware that the adverse event incidence figures in the following tables, obtained when KEPPRA was added to concurrent AED therapy, cannot be used to predict the frequency of adverse experiences in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis to estimate the relative contribution of drug and non-drug factors to the adverse event incidences in the population studied.<br/>Partial Onset Seizures: In well-controlled clinical studies in adults with partial onset seizures, the most frequently reported adverse events associated with the use of KEPPRA in combination with other AEDs, not seen at an equivalent frequency among placebo-treated patients, were somnolence, asthenia, infection and dizziness. In the well-controlled pediatric clinical study in children 4 to 16 years of age with partial onset seizures, the adverse events most frequently reported with the use of KEPPRA in combination withother AEDs, not seen at an equivalent frequency among placebo-treated patients, were somnolence, accidental injury, hostility, nervousness, and asthenia. Table 7 lists treatment-emergent adverse events that occurred in at least 1% of adult epilepsy patients treated with KEPPRA participating in placebo-controlled studies and were numerically more common than in patients treated with placebo. Table 8 lists treatment-emergent adverse events that occurred in at least 2% of pediatric epilepsy patients (ages 4-16 years) treated with KEPPRA participating in the placebo-controlled study and were numerically more common than in pediatric patients treated with placebo. In these studies, either KEPPRA or placebo was added to concurrent AED therapy. Adverse events were usually mild to moderate in intensity. Other events reported by at least 1% of adult KEPPRA-treated patients but as or more frequent in the placebo group were the following: abdominal pain, accidental injury, amblyopia, arthralgia, back pain, bronchitis, chest pain, confusion, constipation, convulsion, diarrhea, drug level increased, dyspepsia, ecchymosis, fever, flu syndrome, fungal infection, gastroenteritis, gingivitis, grand mal convulsion, insomnia, nausea, otitis media, rash, thinking abnormal, tremor, urinarytract infection, vomiting and weight gain. Other events occurring in at least 2% of pediatric KEPPRA-treated patients but as or more
frequent in the placebo group were the following: abdominal pain, allergic reaction, ataxia,
convulsion, epistaxis, fever, headache, hyperkinesia, infection, insomnia, nausea, otitis media,
rash, sinusitis, status epilepticus (not otherwise specified), thinking abnormal, tremor, and
urinary incontinence.<br/>Myoclonic Seizures: Although the pattern of adverse events in this study seems somewhat different from that seen in patients with partial seizures, this is likely due to the much smaller number of patients in this study compared to partial seizure studies. The adverse event pattern for patients with JME is expected to be essentially the same as for patients with partial seizures. In the well-controlled clinical study that included both adolescent (12 to 16 years of age) and adult patients with myoclonic seizures, the most frequently reported adverse events associated with the use of KEPPRA in combination with other AEDs, not seen at an equivalent frequency among placebo-treated patients, were somnolence, neck pain, and pharyngitis. Table 9 lists treatment-emergent adverse events that occurred in at least 5% of juvenile myoclonic epilepsy patients experiencing myoclonic seizures treated with KEPPRA and were numerically more common than in patients treated with placebo. In this study, either KEPPRA or placebo was added to concurrent AED therapy. Adverse events were usually mild to moderate in intensity. Other events occurring in at least 5% of KEPPRA-treated patients with myoclonic seizures but as or more frequent in the placebo group were the following: fatigue and headache.<br/>Primary Generalized Tonic-Clonic Seizures: Although the pattern of adverse events in this study seems somewhat different from that seen in patients with partial seizures, this is likely due to the much smaller number of patients in this study compared to partial seizure studies. The adverse event pattern for patients with PGTC seizures is expected to be essentially the same as for patients with partial seizures. In the well-controlled clinical study that included patients 4 years of age and older with primary generalized tonic-clonic (PGTC) seizures, the most frequently reported adverse event associated with the use of KEPPRA in combination with other AEDs, not seen at an equivalent frequency among placebo-treated patients, was nasopharyngitis. Table 10 lists treatment-emergent adverse events that occurred in at least 5% of idiopathic generalized epilepsy patients experiencing PGTC seizures treated with KEPPRA and were numerically more common than in patients treated with placebo. In this study, either KEPPRA or placebo was added to concurrent AED therapy. Adverse events were usually mild to moderate in intensity. Other events occurring in at least 5% of KEPPRA-treated patients with PGTC seizures but as or more frequent in the placebo group were the following: dizziness, headache, influenza, and somnolence.<br/>Time Course Of Onset Of Adverse Events For Partial Onset Seizures: Of the most frequently reported adverse events in adults experiencing partial onset seizures, asthenia, somnolence and dizziness appeared to occur predominantly during the first 4 weeks of treatment with KEPPRA.<br/>Discontinuation Or Dose Reduction In Well-Controlled Clinical Studies:<br/>Partial Onset Seizures: In well-controlled adult clinical studies, 15.0% of patients receiving KEPPRA and 11.6% receiving placebo either discontinued or had a dose reduction as a result of an adverse event. Table 11 lists the most common (>1%) adverse events that resulted in discontinuation or dose reduction. In the well-controlled pediatric clinical study, 16.8% of patients receiving KEPPRA and 20.6% receiving placebo either discontinued or had a dose reduction as a result of an adverse event. The adverse events most commonly associated (���3% in patients receiving KEPPRA) with discontinuation or dose reduction in the well-controlled study are presented in Table 12.<br/>Myoclonic Seizures: In the placebo-controlled study, 8.3% of patients receiving KEPPRA and 1.7% receiving placebo either discontinued or had a dose reduction as a result of an adverse event. The adverse events that led to discontinuation or dose reduction in the well-controlled study are presented in Table 13.<br/>Primary Generalized Tonic-Clonic Seizures: In the placebo-controlled study, 5.1% of patients receiving KEPPRA and 8.3% receiving placebo either discontinued or had a dose reduction during the treatment period as a result of a treatment-emergent adverse event. This study was too small to adequately characterize the adverse events leading to discontinuation. It is expected that the adverse events that would lead to discontinuation in this population would be similar to those resulting in discontinuation in other epilepsy trials (see tables 11 - 13).<br/>Comparison Of Gender, Age And Race: The overall adverse experience profile of KEPPRA was similar between females and males. There are insufficient data to support a statement regarding the distribution of adverse experience reports by age and race.<br/>Postmarketing Experience: In addition to the adverse experiences listed above, the following have been reported in patients receiving marketed KEPPRA worldwide. The listing is alphabetized: abnormal liver function test, hepatic failure, hepatitis, leukopenia, neutropenia, pancreatitis, pancytopenia (with bone marrow suppression identified in some of these cases), thrombocytopenia, and weight loss. Alopecia has been reported with KEPPRA use; recovery was observed in majority of cases where KEPPRA was discontinued. There have been reportsof suicidal behavior (including completed suicide, suicide attempt and suicidal ideation) with marketed KEPPRA . These adverse experiences have not been listed above, and data are insufficient to support an estimate of their incidence or to establish causation.
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Neuropsychiatric Adverse Events:<br/>Partial Onset Seizures:<br/>Myoclonic Seizures: During clinical development, the number of patients with myoclonic seizures exposed to KEPPRA was considerably smaller than the number with partial seizures. Therefore, under-reporting of certain adverse events was more likely to occur in the myoclonic seizure population. In adult and adolescent patients experiencing myoclonic seizures, KEPPRA is associated with somnolence and behavioral abnormalities. It is expected that the events seen in partial seizure patients would occur in patients with JME. In the double-blind, controlled trial in adults and adolescents with juvenile myoclonic epilepsy experiencing myoclonic seizures, 11.7% of KEPPRA-treated patients experienced somnolence compared to 1.7% of placebo patients. No patient discontinued treatment as a result of somnolence. In 1.7% of KEPPRA-treated patients and in 0% of placebo patients the dose was reduced as a result of somnolence. Non-psychotic behavioral disorders (reported as aggression and irritability) occurred in 5% of the KEPPRA-treated patients compared to 0% of placebo patients. Non-psychotic mood disorders (reported as depressed mood, depression, and mood swings) occurred in 6.7% of KEPPRA-treated patients compared to 3.3% of placebo patients. A total of 5.0% of KEPPRA-treated patients had a reduction in dose or discontinued treatment due to behavioral or psychiatric events (reported as anxiety, depressed mood, depression, irritability, and nervousness), compared to 1.7% of placebo patients.<br/>Primary Generalized Tonic-Clonic Seizures: During clinical development, the number of patients with primary generalized tonic-clonic epilepsy exposed to KEPPRA was considerably smaller than the number with partial epilepsy, described above. As in the partial seizure patients, behavioral symptoms appeared to be associated with KEPPRA treatment. Gait disorders and somnolence were also described in the study in primary generalized seizures, but with no difference between placebo and KEPPRA treatment groups and no appreciable discontinuations. Although it may be expected that drug related events seen in partial seizure patients would be seen in primary generalized epilepsy patients (e.g. somnolence and gait disturbance), these events may not have been observed because of the smaller sample size. In patients 6 years of age and older experiencing primary generalized tonic-clonic seizures, KEPPRA is associated with behavioral abnormalities. In the double-blind, controlled trial in patients with idiopathic generalized epilepsy experiencing primary generalized tonic-clonic seizures, irritability was the most frequently reported psychiatric adverse event occurring in 6.3% of KEPPRA-treated patients compared to 2.4% of placebo patients. Additionally, non-psychotic behavioral disorders (reported as abnormal behavior, aggression, conduct disorder, and irritability) occurred in 11.4% of the KEPPRA-treated patients compared to 3.6% of placebo patients. Of the KEPPRA-treated patients experiencing non-psychotic behavioral disorders, one patient discontinued treatment due to aggression. Non-psychotic mood disorders (reported as anger, apathy, depression, mood altered, mood swings, negativism, suicidal ideation , and tearfulness) occurred in 12.7% of KEPPRA-treated patients compared to 8.3% of placebo patients. No KEPPRA-treated patients discontinued or had a dose reduction as a result of these events. One KEPPRA-treated patient experienced suicidal ideation . One patient experienced delusional behavior that required the lowering of the dose of KEPPRA. In a long-term open label study that examined patients with various forms of primary generalized epilepsy, along with the non-psychotic behavioral disorders, 2 of 192 patients studied exhibited psychotic-like behavior. Behavior in one case was characterized by auditory hallucinations and suicidal thoughts and led to KEPPRA discontinuation. The other case was described as worsening of pre-existent schizophrenia and did not lead to drug discontinuation.<br/>Withdrawal Seizures: Antiepileptic drugs, including KEPPRA, should be withdrawn gradually to minimize the potential of increased seizure frequency.
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KEPPRA is indicated as adjunctive therapy in the treatment of partial onset seizures in adults and children 4 years of age and older with epilepsy. KEPPRA is indicated as adjunctive therapy in the treatment of myoclonic seizures in adults and adolescents 12 years of age and older with juvenile myoclonic epilepsy. KEPPRA is indicated as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults and children 6 years of age and older with idiopathic generalized epilepsy.
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Keppra
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