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KEPPRA® (levetiracetam)
250 mg, 500 mg, 750 mg, and 1000 mg tablets
100 mg/mL oral solution
DESCRIPTION
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)-α-ethyl-2-oxo-1-pyrrolidine acetamide, its molecular formula is C8H14N2O2 and 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 uled below:
250 mg tablets: FD&C Blue #2/indigo carmine aluminum lake
500 mg tablets: iron oxide yellow
750 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.
CLINICAL PHARMACOLOGY
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 in rats, 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 µM 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.
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.
Special Populations
CLINICAL STUDIES
Effectiveness In Partial Onset Seizures in Adults With Epilepsy
The effectiveness of KEPPRA as adjunctive therapy (added to other antiepileptic drugs) in adults was established in three multicenter, randomized, double-blind, placebo-controlled clinical studies in patients who had refractory partial onset seizures with or without secondary generalization. The tablet formulation was used in all these studies. In these studies, 904 patients were randomized to placebo, 1000 mg, 2000 mg, or 3000 mg/day. Patients enrolled in Study 1 or Study 2 had refractory partial onset seizures for at least two years and had taken two or more classical AEDs. Patients enrolled in Study 3 had refractory partial onset seizures for at least 1 year and had taken one classical AED. At the time of the study, patients were taking a stable dose regimen of at least one and could take a maximum of two AEDs. During the baseline period, patients had to have experienced at least two partial onset seizures during each 4-week period.
Study 1
Study 1 was a double-blind, placebo-controlled, parallel-group study conducted at 41 sites in the United States comparing KEPPRA 1000 mg/day (N=97), KEPPRA 3000 mg/day (N=101), and placebo (N=95) given in equally divided doses twice daily. After a prospective baseline period of 12 weeks, patients were randomized to one of the three treatment groups described above. The 18-week treatment period consisted of a 6-week titration period, followed by a 12-week fixed dose evaluation period, during which concomitant AED regimens were held constant. The primary measure of effectiveness was a between group comparison of the percent reduction in weekly partial seizure frequency relative to placebo over the entire randomized treatment period (titration + evaluation period). Secondary outcome variables included the responder rate (incidence of patients with ≥50% reduction from baseline in partial onset seizure frequency). The results of the analysis of Study 1 are displayed in Table 1.
| Placebo (N=95) | KEPPRA 1000 mg/day (N=97) | KEPPRA 3000 mg/day (N=101) | |
| *P <0.001 | |||
| Percent reduction in partial seizure frequency over placebo | – | 26.1%* | 30.1%* |
The percentage of patients (y-axis) who achieved ≥50% reduction in weekly seizure rates from baseline in partial onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the three treatment groups (x-axis) is presented in Figure 1.
Figure 1: Responder Rate (≥50% Reduction From Baseline) In Study 1 
Study 2
Study 2 was a double-blind, placebo-controlled, crossover study conducted at 62 centers in Europe comparing KEPPRA 1000 mg/day (N=106), KEPPRA 2000 mg/day (N=105), and placebo (N=111) given in equally divided doses twice daily.
The first period of the study (Period A) was designed to be analyzed as a parallel-group study. After a prospective baseline period of up to 12 weeks, patients were randomized to one of the three treatment groups described above. The 16-week treatment period consisted of the 4-week titration period followed by a 12-week fixed dose evaluation period, during which concomitant AED regimens were held constant. The primary measure of effectiveness was a between group comparison of the percent reduction in weekly partial seizure frequency relative to placebo over the entire randomized treatment period (titration + evaluation period). Secondary outcome variables included the responder rate (incidence of patients with ≥50% reduction from baseline in partial onset seizure frequency). The results of the analysis of Period A are displayed in Table 2.
| Placebo (N=111) | KEPPRA 1000 mg/day (N=106) | KEPPRA 2000 mg/day (N=105) | |
| *P ≤0.001 | |||
| Percent reduction in partial seizure frequency over placebo | – | 17.1%* | 21.4%* |
The percentage of patients (y-axis) who achieved ≥50% reduction in weekly seizure rates from baseline in partial onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the three treatment groups (x-axis) is presented in Figure 2.
Figure 2: Responder Rate (≥50% Reduction From Baseline) In Study 2: Period A
The comparison of KEPPRA 2000 mg/day to KEPPRA 1000 mg/day for responder rate was statistically significant (P=0.02). Analysis of the trial as a cross-over yielded similar results.
Study 3
Study 3 was a double-blind, placebo-controlled, parallel-group study conducted at 47 centers in Europe comparing KEPPRA 3000 mg/day (N=180) and placebo (N=104) in patients with refractory partial onset seizures, with or without secondary generalization, receiving only one concomitant AED. Study drug was given in two divided doses. After a prospective baseline period of 12 weeks, patients were randomized to one of two treatment groups described above. The 16-week treatment period consisted of a 4-week titration period, followed by a 12-week fixed dose evaluation period, during which concomitant AED doses were held constant. The primary measure of effectiveness was a between group comparison of the percent reduction in weekly seizure frequency relative to placebo over the entire randomized treatment period (titration + evaluation period). Secondary outcome variables included the responder rate (incidence of patients with ≥50% reduction from baseline in partial onset seizure frequency). Table 3 displays the results of the analysis of Study 3.
| Placebo (N=104) | KEPPRA 3000 mg/day (N=180) | |
| *P <0.001 | ||
| Percent reduction in partial seizure frequency over placebo | – | 23.0%* |
The percentage of patients (y-axis) who achieved ≥50% reduction in weekly seizure rates from baseline in partial onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the two treatment groups (x-axis) is presented in Figure 3.
Figure 3: Responder Rate (≥50% Reduction From Baseline) In Study 3
Effectiveness In Partial Onset Seizures In Pediatric Patients With Epilepsy
The effectiveness of KEPPRA as adjunctive therapy (added to other antiepileptic drugs) in pediatric patients was established in one multicenter, randomized double-blind, placebo-controlled study, conducted at 60 sites in North America, in children 4 to 16 years of age with partial seizures uncontrolled by standard antiepileptic drugs (AEDs). Eligible patients on a stable dose of 1-2 AEDs, who still experienced at least 4 partial onset seizures during the 4 weeks prior to screening, as well as at least 4 partial onset seizures in each of the two 4-week baseline periods, were randomized to receive either KEPPRA or placebo. The enrolled population included 198 patients (KEPPRA N=101, placebo N=97) with refractory partial onset seizures, whether or not secondarily generalized. The study consisted of an 8-week baseline period and 4-week titration period followed by a 10-week evaluation period. Dosing was initiated at a dose of 20 mg/kg/day in two divided doses. During the treatment period, KEPPRA doses were adjusted in 20 mg/kg/day increments, at 2-week intervals to the target dose of 60 mg/kg/day. The primary measure of effectiveness was a between group comparison of the percent reduction in weekly partial seizure frequency relative to placebo over the entire 14-week randomized treatment period (titration + evaluation period). Secondary outcome variables included the responder rate (incidence of patients with ≥ 50% reduction from baseline in partial onset seizure frequency per week). Table 4 displays the results of this study.
| Placebo (N=97) |
KEPPRA (N=101) | |
| *P =0.0002 | ||
| Percent reduction in partial seizure frequency over placebo | – | 26.8%* |
The percentage of patients (y-axis) who achieved ≥50% reduction in weekly seizure rates from baseline in partial onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the two treatment groups (x-axis) is presented in Figure 4.
Figure 4: Responder Rate (≥50% Reduction From Baseline)
Effectiveness In Myoclonic Seizures In Patients ≥12 Years Of Age With Juvenile Myoclonic Epilepsy (JME)
The effectiveness of KEPPRA as adjunctive therapy (added to other antiepileptic drugs) in patients 12 years of age and older with juvenile myoclonic epilepsy (JME) experiencing myoclonic seizures was established in one multicenter, randomized, double-blind, placebo-controlled study, conducted at 37 sites in 14 countries. Of the 120 patients enrolled, 113 had a diagnosis of confirmed or suspected JME. Eligible patients on a stable dose of 1 antiepileptic drug (AED) experiencing one or more myoclonic seizures per day for at least 8 days during the prospective 8-week baseline period were randomized to either KEPPRA or placebo (KEPPRA N=60, placebo N=60). Patients were titrated over 4 weeks to a target dose of 3000 mg/day and treated at a stable dose of 3000 mg/day over 12 weeks (evaluation period). Study drug was given in 2 divided doses.
The primary measure of effectiveness was the proportion of patients with at least 50% reduction in the number of days per week with one or more myoclonic seizures during the treatment period (titration + evaluation periods) as compared to baseline. Table 5 displays the results for the 113 patients with JME in this study.
| *P =0.0001 | ||
| Placebo (N=59) | KEPPRA (N=54) | |
| Percentage of responders | 23.7% | 60.4%* |
INDICATIONS AND USAGE
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.
CONTRAINDICATIONS
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.
WARNINGS
Neuropsychiatric Adverse Events
Partial Onset Seizures
Withdrawal Seizures
Antiepileptic drugs, including KEPPRA, should be withdrawn gradually to minimize the potential of increased seizure frequency.
PRECAUTIONS
Hematologic Abnormalities
Partial Onset Seizures
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.
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.
Physicians should advise patients and caregivers to read the patient information leaflet which appears as the last section of the labeling.
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.
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 Cmax levels 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.
Drug-Drug Interactions Between KEPPRA And Other Antiepileptic Drugs (AEDs)
Other Drug Interactions
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Pregnancy
Labor And Delivery
The effect of KEPPRA on labor and delivery in humans is unknown.
Nursing Mothers
Levetiracetam is excreted in breast milk. Because of the potential for serious adverse reactions in nursing infants from KEPPRA, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in patients below 4 years of age have not been established.
Studies of levetiracetam in juvenile rats (dosing from day 4 through day 52 of age) and dogs (dosing from week 3 through week 7 of age) at doses of up to 1800 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 indicate a potential for age-specific toxicity.
Geriatric Use
Of the total number of subjects in clinical studies of levetiracetam, 347 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 KEPPRA in these patients.
A study in 16 elderly subjects (age 61-88 years) with oral administration of single dose and multiple twice-daily doses for 10 days showed no pharmacokinetic differences related to age alone.
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.
Use In Patients With Impaired Renal Function
Clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance. Caution should be taken in dosing patients with moderate and severe renal impairment and in patients undergoing hemodialysis. The dosage should be reduced in patients with impaired renal function receiving KEPPRA and supplemental doses should be given to patients after dialysis (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION, Adult Patients with Impaired Renal Function).
ADVERSE REACTIONS
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.
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 with other AEDs, not seen at an equivalent frequency among placebo-treated patients, were somnolence, accidental injury, hostility, nervousness, and asthenia.
Table 6 uls 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 7 uls 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.
| Body System/ Adverse Event | KEPPRA (N=769) % | Placebo (N=439) % |
|---|---|---|
| Body as a Whole | ||
| Asthenia | 15 | 9 |
| Headache | 14 | 13 |
| Infection | 13 | 8 |
| Pain | 7 | 6 |
| Digestive System | ||
| Anorexia | 3 | 2 |
| Nervous System | ||
| Somnolence | 15 | 8 |
| Dizziness | 9 | 4 |
| Depression | 4 | 2 |
| Nervousness | 4 | 2 |
| Ataxia | 3 | 1 |
| Vertigo | 3 | 1 |
| Amnesia | 2 | 1 |
| Anxiety | 2 | 1 |
| Hostility | 2 | 1 |
| Paresthesia | 2 | 1 |
| Emotional Lability | 2 | 0 |
| Respiratory System | ||
| Pharyngitis | 6 | 4 |
| Rhinitis | 4 | 3 |
| Cough Increased | 2 | 1 |
| Sinusitis | 2 | 1 |
| Special Senses | ||
| Diplopia | 2 | 1 |
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, urinary tract infection, vomiting and weight gain.
| Body System/ Adverse Event | KEPPRA (N=101) % | Placebo (N=97) % |
|---|---|---|
| Body as a Whole | ||
| Accidental Injury | 17 | 10 |
| Asthenia | 9 | 3 |
| Pain | 6 | 3 |
| Flu Syndrome | 3 | 2 |
| Face Edema | 2 | 1 |
| Neck Pain | 2 | 1 |
| Viral Infection | 2 | 1 |
| Digestive System | ||
| Vomiting | 15 | 13 |
| Anorexia | 13 | 8 |
| Diarrhea | 8 | 7 |
| Gastroenteritis | 4 | 2 |
| Constipation | 3 | 1 |
| Hemic and Lymphatic System | ||
| Ecchymosis | 4 | 1 |
| Metabolic and Nutritional | ||
| Dehydration | 2 | 1 |
| Nervous System | ||
| Somnolence | 23 | 11 |
| Hostility | 12 | 6 |
| Nervousness | 10 | 2 |
| Personality Disorder | 8 | 7 |
| Dizziness | 7 | 2 |
| Emotional Lability | 6 | 4 |
| Agitation | 6 | 1 |
| Depression | 3 | 1 |
| Vertigo | 3 | 1 |
| Reflexes Increased | 2 | 1 |
| Confusion | 2 | 0 |
| Respiratory System | ||
| Rhinitis | 13 | 8 |
| Cough Increased | 11 | 7 |
| Pharyngitis | 10 | 8 |
| Asthma | 2 | 1 |
| Skin and Appendages | ||
| Pruritus | 2 | 0 |
| Skin Discoloration | 2 | 0 |
| Vesiculobullous Rash | 2 | 0 |
| Special Senses | ||
| Conjunctivitis | 3 | 2 |
| Amblyopia | 2 | 0 |
| Ear Pain | 2 | 0 |
| Urogenital System | ||
| Albuminuria | 4 | 0 |
| Urine Abnormality | 2 | 1 |
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.
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 8 uls 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.
| Body System / MedDRA preferred term | KEPPRA (N=60) % | Placebo (N=60) % |
|---|---|---|
| Ear and labyrinth disorders | ||
| Vertigo | 5 | 3 |
| Infections and infestations | ||
| Pharyngitis | 7 | 0 |
| Influenza | 5 | 2 |
| Musculoskeletal and connective tissue disorders | ||
| Neck pain | 8 | 2 |
| Nervous system disorders | ||
| Somnolence | 12 | 2 |
| Psychiatric disorders | ||
| Depression | 5 | 2 |
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.
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.
Discontinuation Or Dose Reduction In Well-Controlled Clinical Studies
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.
Postmarketing Experience
In addition to the adverse experiences uled above, the following have been reported in patients receiving marketed KEPPRA worldwide. The uling 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 reports of suicidal behavior (including completed suicide) with marketed KEPPRA. These adverse experiences have not been uled above, and data are insufficient to support an estimate of their incidence or to establish causation.
DRUG ABUSE AND DEPENDENCE
The abuse and dependence potential of KEPPRA has not been evaluated in human studies.
OVERDOSAGE
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.
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 management of overdose with KEPPRA.
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.
DOSAGE AND ADMINISTRATION
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.
Partial Onset Seizures
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.
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 13. 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 from serum creatinine (mg/dL) determination using the following formula:
[140-age (years)] x weight (kg)
CLcr = ————————————————— (x 0.85 for female patients)
72 x serum creatinine (mg/dL)
| Group | Creatinine Clearance (mL/min) | Dosage (mg) | Frequency |
| 1 Following dialysis, a 250 to 500 mg supplemental dose is recommended. | |||
| Normal | > 80 | 500 to 1,500 | Every 12 h |
| Mild | 50 – 80 | 500 to 1,000 | Every 12 h |
| Moderate | 30 – 50 | 250 to 750 | Every 12 h |
| Severe | < 30 | 250 to 500 | Every 12 h |
| ESRD patients using dialysis | ---- | 500 to 1,000 | 1Every 24 h |
HOW SUPPLIED
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).
Storage
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
For Medical Information
Contact: Medical Affairs Department
Phone: (866) 822-0068
Fax: (770) 970-8859
KEPPRA Tablets and KEPPRA Oral Solution
Manufactured for
UCB, Inc.
Smyrna, GA 30080
Rev. 23E 10/2006
KEPPRA is a registered trademark of UCB S.A.
©2006, UCB, Inc., Smyrna, GA 30080. All rights reserved. Printed in the U.S.A.
PATIENT INFORMATION
KEPPRA®
(pronounced KEPP-ruh) (levetiracetam)
250 mg, 500 mg, 750 mg, and 1000 mg tablets and 100 mg/mL oral solution
Read the Patient Information that comes with KEPPRA before you start using it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your condition or your treatment.
Before taking your medicine, make sure you have received the correct medicine. Compare the name above with the name on your bottle and the appearance of your medicine with the description of KEPPRA provided below. Contact your pharmacist immediately if you believe a dispensing error may have occurred.
250 mg KEPPRA tablets are blue, oblong-shaped, scored, film-coated tablets marked with “ucb 250” on one side.
500 mg KEPPRA tablets are yellow, oblong-shaped, scored, film-coated tablets marked with “ucb 500” on one side.
750 mg KEPPRA tablets are orange, oblong-shaped, scored, film-coated tablets marked with “ucb 750” on one side.
1000 mg KEPPRA tablets are white, oblong-shaped, scored, film-coated tablets marked with “ucb 1000” on one side.
KEPPRA oral solution is a clear, colorless, grape-flavored liquid.
What is KEPPRA?
KEPPRA is a medicine taken by mouth that is used with other medicines to treat:
- partial onset seizures in patients 4 years of age and older with epilepsy
- myoclonic seizures in patients 12 years of age and older with juvenile myoclonic epilepsy
Who should not take KEPPRA?
Do not take KEPPRA if you are allergic to any of its ingredients. The active ingredient is levetiracetam. See the end of this leaflet for a ul of all the ingredients in KEPPRA.
What should I tell my healthcare provider before starting KEPPRA?
- have kidney disease.You may need a lower dose of KEPPRA.
- are pregnant or planning to become pregnant. It is not known if KEPPRA can harm your unborn baby. If you use KEPPRA while you are pregnant, ask your healthcare provider about being in the KEPPRA Pregnancy Registry. You can join this registry by calling (888) 537-7734 (toll free). You may also join the North American Antiepileptic Drug Pregnancy Registry by calling (888) 233-2334 (toll free).
- are breast feeding. KEPPRA can pass into your milk and may harm your baby. You should choose to either take KEPPRA or breast feed, but not both.
Tell your healthcare provider about all the medicines you take, including prescription, nonprescription, vitamins, and herbal supplements.
Know the medicines you take. Keep a ul of them to show your healthcare provider and pharmacist each time you get a new medicine.
- Take KEPPRA exactly as prescribed. KEPPRA is usually taken twice a day. Once in the morning and once at night. Take KEPPRA at the same times each day.
- Your healthcare provider may start you on a lower dose of KEPPRA and increase it as your body gets used to the medicine.
- Take KEPPRA with or without food. Swallow the tablets whole. Do not chew or crush tablets. Use the KEPPRA oral solution if you cannot swallow tablets. Use a medicine dropper or medicine cup to measure KEPPRA oral solution. Do not use a teaspoon. Ask your pharmacist for a medicine dropper or medicine cup to help you measure KEPPRA. If your healthcare provider has given you KEPPRA oral solution for your child, be sure to ask your pharmacist for a medicine syringe to help you measure the correct amount of KEPPRA oral solution. Ask your pharmacist for instructions on how to properly use the medicine syringe or dosing device that has been provided to you.
- If you miss a dose of KEPPRA, do not double your next dose to make up for the missed dose. If it has only been a few hours since your missed dose, take KEPPRA as soon as you remember then return to your regular schedule. If it is almost time for the next dose, skip the missed dose and resume your regular schedule. Talk with your healthcare provider for more detailed instructions.
- If you take too much KEPPRA or overdose, call your local Poison Control Center or emergency room right away.
- Do not stop taking KEPPRA or any other seizure medicine unless your healthcare provider told you to. Stopping a seizure medicine all at once can cause seizures that will not stop (status epilepticus), a very serious problem.
- Tell your healthcare provider if your seizures get worse or if you have any new types of seizures.
What should I avoid while taking KEPPRA?
Do not drive, operate machinery or other dangerous activities until you know how KEPPRA affects you. KEPPRA may make you dizzy or sleepy.
What are the possible side effects of KEPPRA?
Adults
KEPPRA may cause the following serious problems in adults. Call your healthcare provider right away if you get any of the following symptoms:
- extreme sleepiness, tiredness, and weakness
- problems with muscle coordination (problems walking and moving)
- mood and behavior changes such as aggression, agitation, anger, anxiety, apathy, depression, hostility, and irritability. A few people may get psychotic symptoms such as hallucinations (seeing or hearing things that are really not there).
The most common side effects with KEPPRA in adults are:
- sleepiness
- weakness
- dizziness
- infection
These side effects could happen at any time but happen most often within the first four weeks of treatment except for infection.
Children
KEPPRA may cause the following serious problems in children. Call your child’s healthcare provider right away if they get any of the following symptoms:
- extreme sleepiness, tiredness, and weakness
- mood and behavior changes such as aggression, agitation, anger, anxiety, apathy, depression, hostility, and irritability
The most common side effects with KEPPRA in children are:
- sleepiness
- accidental injury
- hostility
- irritability
- weakness
These side effects could happen at any time.
These are not all the side effects of KEPPRA. For more information, ask your healthcare provider or pharmacist. If you get any side effects that concern you, call your healthcare provider.
How should I store KEPPRA?
- Store KEPPRA at room temperature away from heat and light.
- Keep KEPPRA and all medicines out of the reach of children.
General information about KEPPRA.
Medicines are sometimes prescribed for conditions other than those described in patient information leaflets. Do not use KEPPRA for a condition for which it was not prescribed. Do not give your KEPPRA to other people, even if they have the same symptoms that you have. It may harm them.
This leaflet summarizes the most important information about KEPPRA. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about KEPPRA that is written for healthcare professionals. You can also get information about KEPPRA at www.keppra.com.
What are the ingredients of KEPPRA?
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 uled below:
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.
KEPPRA does not contain lactose or gluten. KEPPRA oral solution does contain carbohydrates. The liquid is dye-free.
This patient leaflet has been approved by the US Food and Drug Administration.
Distributed by
UCB, Inc.
Smyrna, GA 30080