Clinical Studies Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The prescriber should be aware that the adverse reaction incidence figures in the following table, obtained when KEPPRA XR (levetiracetam extended-release tablets) 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 reaction incidences in the population studied.
KEPPRA XR (levetiracetam extended-release tablets) Tablets
In the well-controlled clinical study using KEPPRA XR (levetiracetam extended-release tablets) in patients with partial onset seizures, the most frequently reported adverse reactions in patients receiving KEPPRA XR (levetiracetam extended-release tablets) in combination with other AEDs, not seen at an equivalent frequency among placebo-treated patients, were irritability and somnolence.
Table 2 lists treatment-emergent adverse reactions that occurred in at least 5% of epilepsy patients treated with KEPPRA XR (levetiracetam extended-release tablets) participating in the placebo-controlled study and were numerically more common than in patients treated with placebo. In this study, either KEPPRA XR (levetiracetam extended-release tablets) or placebo was added to concurrent AED therapy. Adverse reactions were usually mild to moderate in intensity.
Table 2: Incidence (%) Of Treatment-Emergent Adverse Reactions
In The Placebo-Controlled, Add-On Study By Body System (Adverse Reactions Occurred
In At Least 5% Of KEPPRA XR (levetiracetam extended-release tablets) -Treated Patients And Occurred More Frequently Than
|Body System/Adverse Reaction||KEPPRA XR (levetiracetam extended-release tablets)
|Infections and Infestations|
|Nervous System Disorders|
Discontinuation Or Dose Reduction In The KEPPRA XR (levetiracetam extended-release tablets) Well-Controlled Clinical Study
In the well-controlled clinical study using KEPPRA XR (levetiracetam extended-release tablets) , 5.2% of patients receiving KEPPRA XR (levetiracetam extended-release tablets) and 2.5% receiving placebo discontinued as a result of an adverse event. The adverse reactions that resulted in discontinuation and that occurred more frequently in KEPPRA XR (levetiracetam extended-release tablets) -treated patients than in placebo-treated patients were asthenia, epilepsy, mouth ulceration, rash and respiratory failure. Each of these adverse reactions led to discontinuation in a KEPPRA XR (levetiracetam extended-release tablets) -treated patient and no placebo-treated patients.
Comparison Of Gender, Age And Race
There are insufficient data for KEPPRA XR (levetiracetam extended-release tablets) to support a statement regarding the distribution of adverse experience reports by gender, age and race.
Table 3 lists the adverse reactions seen in the well-controlled studies of immediate-release KEPPRA tablets in adult patients experiencing partial onset seizures. Although the pattern of adverse reactions in the KEPPRA XR (levetiracetam extended-release tablets) study seems somewhat different from that seen in partial onset seizure well-controlled studies for immediate-release KEPPRA tablets, this is possibly due to the much smaller number of patients in this study compared to the immediate-release tablet studies. The adverse reactions for KEPPRA XR (levetiracetam extended-release tablets) are expected to be similar to those seen with immediate-release KEPPRA tablets.
Immediate-Release KEPPRA Tablets
In well-controlled clinical studies of immediate-release KEPPRA tablets as adjunctive therapy to other AEDs in adults with partial onset seizures, the most frequently reported adverse reactions, not seen at an equivalent frequency among placebo-treated patients, were somnolence, asthenia, infection and dizziness.
Table 3 lists treatment-emergent adverse reactions that occurred in at least 1% of adult epilepsy patients treated with immediate-release KEPPRA tablets participating in placebo-controlled studies and were numerically more common than in patients treated with placebo. In these studies, either immediate-release KEPPRA tablets or placebo was added to concurrent AED therapy. Adverse reactions were usually mild to moderate in intensity.
Table 3: Incidence (%) Of Treatment-Emergent Adverse Reactions
In Placebo-Controlled, Add-On Studies In Adults Experiencing Partial Onset Seizures
By Body System (Adverse Reactions Occurred In At Least 1% Of Immediate-Release
KEPPRA-Treated Patients And Occurred More Frequently Than Placebo-Treated Patients)
|Body System/Adverse Reaction||Immediate-release
|Body as a Whole|
In addition, the following adverse reactions were seen in other well-controlled studies of immediate-release KEPPRA tablets: balance disorder, disturbance in attention, eczema, hyperkinesia, memory impairment, myalgia, personality disorders, pruritus, and vision blurred.
In addition to the adverse reactions listed above for immediate-release KEPPRA tablets [see ADVERSE REACTIONS], the following adverse events have been identified during postapproval use of immediate-release KEPPRA tablets. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 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), suicidal behavior (including completed suicide), thrombocytopenia and weight loss. Alopecia has been reported with immediate-release KEPPRA use; recovery was observed in majority of cases where immediate-release KEPPRA was discontinued.
Read the Keppra XR (levetiracetam extended-release tablets) Side Effects Center for a complete guide to possible side effects »
In vitro data on metabolic interactions indicate that KEPPRA XR (levetiracetam extended-release tablets) 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 with immediate-release KEPPRA tablets in the placebo-controlled clinical studies in epilepsy patients. The following are the results of these studies. The potential for drug interactions for KEPPRA XR is expected to be essentially the same as that with immediate-release KEPPRA tablets.
Immediate-release KEPPRA tablets (3000 mg daily) had no effect on the pharmacokinetic disposition of phenytoin in patients with refractory epilepsy. Pharmacokinetics of levetiracetam were also not affected by phenytoin.
Immediate-release KEPPRA tablets (1500 mg twice daily) did not alter the pharmacokinetics of valproate in healthy volunteers. Valproate 500 mg twice daily did not modify the rate or extent of levetiracetam absorption or its plasma clearance or urinary excretion. There also was no effect on exposure to and the excretion of the primary metabolite, ucb L057.
Other Antiepileptic Drugs
Potential drug interactions between immediate-release KEPPRA tablets and other AEDs (carbamazepine, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone and valproate) were also assessed by evaluating the serum concentrations of levetiracetam and these AEDs during placebo-controlled clinical studies. These data indicate that levetiracetam does not influence the plasma concentration of other AEDs and that these AEDs do not influence the pharmacokinetics of levetiracetam.
Immediate-release KEPPRA tablets (500 mg twice daily) did not influence the pharmacokinetics of an oral contraceptive containing 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel, or of the luteinizing hormone and progesterone levels, indicating that impairment of contraceptive efficacy is unlikely. Coadministration of this oral contraceptive did not influence the pharmacokinetics of levetiracetam.
Immediate-release KEPPRA tablets (1000 mg twice daily) did not influence the pharmacokinetics and pharmacodynamics (ECG) of digoxin given as a 0.25 mg dose every day. Coadministration of digoxin did not influence the pharmacokinetics of levetiracetam.
Immediate-release KEPPRA tablets (1000 mg twice daily) did not influence the pharmacokinetics of R and S warfarin. Prothrombin time was not affected by levetiracetam. Coadministration of warfarin did not affect the pharmacokinetics of levetiracetam.
Probenecid, a renal tubular secretion blocking agent, administered at a dose of 500 mg four times a day, did not change the pharmacokinetics of levetiracetam 1000 mg twice daily. Cssmax of the metabolite, ucb L057, was approximately doubled in the presence of probenecid while the fraction of drug excreted unchanged in the urine remained the same. Renal clearance of ucb L057 in the presence of probenecid decreased 60%, probably related to competitive inhibition of tubular secretion of ucb L057. The effect of immediate-release KEPPRA tablets on probenecid was not studied.
Drug Abuse And Dependence
The abuse and dependence potential of KEPPRA XR (levetiracetam extended-release tablets) has not been evaluated in human studies.
Last reviewed on RxList: 3/13/2009
This monograph has been modified to include the generic and brand name in many instances.
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