Levetiracetam (Page 5 of 10)

Primary Generalized Tonic-Clonic Seizures

During clinical development, the number of patients with primary generalized tonic-clonic epilepsy exposed to levetiracetam was considerably smaller than the number with partial epilepsy, described above. As in the partial seizure patients, behavioral symptoms appeared to be associated with levetiracetam treatment. Gait disorders and somnolence were also described in the study in primary generalized seizures, but with no difference between placebo and levetiracetam 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, levetiracetam 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 levetiracetam-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 levetiracetam-treated patients compared to 3.6% of placebo patients. Of the levetiracetam-treated patients experiencing non-psychotic behavioral disorders, one patient discontinued treatment due to aggression. Non-psychotic mood disorders (including anger, apathy, depression, mood altered, mood swings, negativism, and tearfulness) occurred in 12.7% of levetiracetam-treated patients compared to 8.3% of placebo patients. No levetiracetam-treated patients discontinued or had a dose reduction as a result of these events. One patient experienced delusional behavior that required the lowering of the dose of levetiracetam.

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 levetiracetam discontinuation. The other case was described as worsening of pre-existent schizophrenia and did not lead to drug discontinuation.

Withdrawal Seizures

Antiepileptic drugs, including levetiracetam, should be withdrawn gradually to minimize the potential of increased seizure frequency.

PRECAUTIONS

Hematologic Abnormalities

Partial Onset Seizures

Adults

Minor, but statistically significant, decreases compared to placebo in total mean RBC count (0.03 x 106 /mm3), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in levetiracetam-treated patients in controlled trials.

A total of 3.2% of treated and 1.8% of placebo patients had at least one possibly significant (≤2.8 x 109 /L) decreased WBC, and 2.4% of treated and 1.4% of placebo patients had at least one possibly significant (≤1 x 109 /L) decreased neutrophil count. Of the treated patients with a low neutrophil count, all but one rose towards or to baseline with continued treatment. No patient was discontinued secondary to low neutrophil counts.

Pediatric Patients

Minor, but statistically significant, decreases in WBC and neutrophil counts were seen in levetiracetam-treated patients as compared to placebo. The mean decreases from baseline in the levetiracetam-treated group were -0.4 × 109 /L and -0.3 × 109 /L, respectively, whereas there were small increases in the placebo group. Mean relative lymphocyte counts increased by 1.7% in levetiracetam-treated patients, compared to a decrease of 4% in placebo patients (statistically significant).

In the well-controlled trial, more levetiracetam-treated patients had a possibly clinically significant abnormally low WBC value (3% levetiracetam-treated versus 0% placebo), however, there was no apparent difference between treatment groups with respect to neutrophil count (5% levetiracetam-treated versus 4.2% placebo). No patient was discontinued secondary to low WBC or neutrophil counts.

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.

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 and caregivers should be informed of the availability of a Medication Guide, and they should be instructed to read the Medication Guide prior to taking levetiracetam. The Medication Guide may also be found in the full prescribing information for levetiracetam. Patients should be instructed to take levetiracetam only as prescribed.

Patients, their caregivers, and families should be counseled that AEDs, including levetiracetam, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Patients should be advised that levetiracetam 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 notify their physician if they become pregnant or intend to become pregnant during therapy. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334. (See Pregnancy Section).

Patients should be advised that levetiracetam 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 levetiracetam to gauge whether it adversely affects their performance of these activities.

Laboratory Tests

Although most laboratory tests are not systematically altered with levetiracetam 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 levetiracetam 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 Levetiracetam And Other Antiepileptic Drugs (AEDs)

Phenytoin

Levetiracetam (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.

Valproate

Levetiracetam (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.

Potential drug interactions between levetiracetam 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.

Effect of AEDs in Pediatric Patients

There was about a 22% increase of apparent total body clearance of levetiracetam when it was co-administered with enzyme-inducing AEDs. Dose adjustment is not recommended. Levetiracetam had no effect on plasma concentrations of carbamazepine, valproate, topiramate, or lamotrigine.

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