Levetiracetam ER

The adverse reactions for levetiracetam extended-release tablets are expected to be similar to those seen with immediate-release levetiracetam tablets. Adults In controlled clinical studies of immediate-release levetiracetam tablets as adjunctive therapy to other AEDs in adults with partial-onset seizures, the most common adverse reactions, for events with rates greater than placebo, were somnolence, asthenia, infection, and dizziness.

Table 4 lists adverse reactions that occurred in at least 1% of adult epilepsy patients receiving immediate-release levetiracetam tablets in placebo-controlled studies and were numerically more common than in patients treated with placebo.

In these studies, either immediate-release levetiracetam tablets or placebo was added to concurrent AED therapy. 3)], the adverse reactions most frequently reported with the use of immediate-release levetiracetam tablets in combination with other AEDs, and with greater frequency than in patients on placebo, were fatigue, aggression, nasal congestion, decreased appetite, and irritability.

Table 5 lists adverse reactions that occurred in at least 2% of pediatric patients treated with immediate-release levetiracetam tablets and were more common than in pediatric patients on placebo. In these studies, either immediate-release levetiracetam tablets or placebo was added to concurrent AED therapy.

Adverse reactions were usually mild to moderate in intensity.

Table 5:

Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Studies in Pediatric Patients Ages 4 to 16 Years Experiencing Partial-onset Seizures Levetiracetam Tablets (N=165) % Placebo (N=131) % Headache 19 15 Nasopharyngitis 15 12 Vomiting 15 12 Somnolence 13 9 Fatigue 11 5 Aggression 10 5 Upper Abdominal Pain 9 8 Cough 9 5 Nasal Congestion 9 2 Decreased Appetite 8 2 Abnormal Behavior 7 4 Dizziness 7 5 Irritability 7 1 Pharyngolaryngeal Pain 7 4 Diarrhea 6 2 Lethargy 6 5 Insomnia 5 3 Agitation 4 1 Anorexia 4 3 Head Injury 4 0 Constipation 3 1 Contusion 3 1 Depression 3 1 Fall 3 2 Influenza 3 1 Mood Altered 3 1 Affect Lability 2 1 Anxiety 2 1 Arthralgia 2 0 Confusional State 2 0 Conjunctivitis 2 0 Ear Pain 2 1 Gastroenteritis 2 0 Joint Sprain 2 1 Mood Swings 2 1 Neck Pain 2 1 Rhinitis 2 0 Sedation 2 1 In controlled pediatric clinical studies in patients 4-16 years of age, 7% of patients treated with immediate-release levetiracetam tablets and 9% of patients on placebo discontinued as a result of an adverse event.

In addition, the following adverse reactions were seen in other controlled studies of immediate-release levetiracetam tablets: balance disorder, disturbance in attention, eczema, hyperkinesia, memory impairment, myalgia, personality disorders, pruritus, and blurred vision.

Comparison of Gender, Age and Race There are insufficient data for levetiracetam extended-release tablets to support a statement regarding the distribution of adverse reactions by gender, age, and race. 2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of immediate-release levetiracetam tablets.

Because these reactions 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, acute kidney injury, anaphylaxis, angioedema, agranulocytosis, choreoathetosis, drug reaction with eosinophilia and systemic symptoms (DRESS), dyskinesia, erythema multiforme, hepatic failure, hepatitis, hyponatremia, muscular weakness, pancreatitis, pancytopenia (with bone marrow suppression identified in some of these cases), panic attack, thrombocytopenia, weight loss, and worsening of seizures..

Alopecia has been reported with immediate-release levetiracetam tablets use; recovery was observed in majority of cases where immediate-release levetiracetam tablets was discontinued.

2% of placebo-treated patients. 5% of placebo-treated patients. 2% of placebo-treated pediatric patients. 2% and 2%, respectively, in adult and placebo-treated pediatric patients. 6% levetiracetam tablets-treated patients experienced paranoia, compared to no placebo-treated patients.

4)]. 2% of placebo-treated patients. 3%) levetiracetam tablets-treated adult patients were hospitalized and their treatment was discontinued due to psychosis. Both events, reported as psychosis, developed within the first week of treatment and resolved within 1 to 2 weeks following treatment discontinuation.

There was no difference between drug and placebo-treated patients in the incidence of pediatric patients who discontinued treatment due to psychotic and non-psychotic adverse reactions. 2 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including levetiracetam extended-release tablets, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication.

Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. 7) of suicidal thinking or behavior compared to patients randomized to placebo.

24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication.

The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs. 9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing levetiracetam extended-release tablets or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.

Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. 3 Somnolence and Fatigue Levetiracetam extended-release tablets may cause somnolence and fatigue.

Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on levetiracetam extended-release tablets to gauge whether it adversely affects their ability to drive or operate machinery.

Somnolence Levetiracetam Extended-Release Tablets In the levetiracetam extended-release tablets double-blind, controlled trial in patients experiencing partial-onset seizures, 8% of levetiracetam extended-release tablets-treated patients experienced somnolence compared to 3% of placebo-treated patients.

No patient discontinued treatment or had a dose reduction as a result of these adverse reactions. The number of patients exposed to levetiracetam extended-release tablets was considerably smaller than the number of patients exposed to immediate-release levetiracetam tablets in controlled trials.

Therefore, certain adverse reactions observed in the immediate-release levetiracetam tablets controlled trials will likely occur in patients receiving levetiracetam extended-release tablets. Immediate-Release Levetiracetam Tablets In controlled trials of adult patients with epilepsy experiencing partial-onset seizures, 15% of levetiracetam tablets-treated patients reported somnolence, compared to 8% of placebo-treated patients.

There was no clear dose response up to 3,000 mg/day. In a study where there was no titration, about 45% of patients receiving 4,000 mg/day reported somnolence. 3% of the levetiracetam tablets-treated patients, compared to 0% in the placebo group.

7% of placebo-treated patients. 3% of the treated patients were hospitalized due to somnolence. Asthenia Immediate-Release Levetiracetam Tablets In controlled trials of adult patients with epilepsy experiencing partial-onset seizures, 15% of levetiracetam tablets-treated patients reported asthenia, compared to 9% of placebo-treated patients.

5% of placebo-treated patients. 2% of placebo-treated patients, the dose was reduced due to asthenia. Somnolence and asthenia occurred most frequently within the first 4 weeks of treatment. 4 Anaphylaxis and Angioedema Levetiracetam extended-release tablets can cause anaphylaxis or angioedema after the first dose or at any time during treatment.

Signs and symptoms in cases reported in the postmarketing setting in patients treated with levetiracetam have included hypotension, hives, rash, respiratory distress, and swelling of the face, lip, mouth, eye, tongue, throat, and feet.

In some reported cases, reactions were life-threatening and required emergency treatment. If a patient develops signs or symptoms of anaphylaxis or angioedema, levetiracetam extended-release tablets should be discontinued and the patient should seek immediate medical attention.

Levetiracetam extended-release tablets should be discontinued permanently if a clear alternative etiology for the reaction cannot be established [see Contraindications (4)]. 5 Serious Dermatological Reactions Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in patients treated with levetiracetam.

The median time of onset is reported to be 14 to 17 days, but cases have been reported at least four months after initiation of treatment. Recurrence of the serious skin reactions following rechallenge with levetiracetam has also been reported.

Levetiracetam extended-release tablets should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.

6 Coordination Difficulties Coordination difficulties were not observed in the levetiracetam extended-release tablets controlled trial, however, the number of patients exposed to levetiracetam extended-release tablets was considerably smaller than the number of patients exposed to immediate-release levetiracetam tablets in controlled trials.

However, adverse reactions observed in the immediate-release levetiracetam tablets controlled trials may also occur in patients receiving levetiracetam extended-release tablets. 6% of placebo-treated patients. 4% of patients in controlled trials discontinued levetiracetam tablets treatment due to ataxia, compared to 0% of placebo-treated patients.

2% of placebo-treated patients, the dose was reduced due to coordination difficulties, while one of the levetiracetam tablets-treated patients was hospitalized due to worsening of pre-existing ataxia. These events occurred most frequently within the first 4 weeks of treatment.

Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on levetiracetam tablets to gauge whether it could adversely affect their ability to drive or operate machinery.

7 Withdrawal Seizures As with most antiepileptic drugs, levetiracetam extended-release tablets should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus. If withdrawal is needed because of a serious adverse reaction, rapid discontinuation can be considered.

8 Hematologic Abnormalities Levetiracetam extended-release tablets can cause hematologic abnormalities. Hematologic abnormalities occurred in clinical trials and included decreases in white blood cell (WBC), neutrophil, and red blood cell (RBC) counts; decreases in hemoglobin and hematocrit; and increases in eosinophil counts.

Cases of agranulocytosis, pancytopenia, and thrombocytopenia have also been reported in the postmarketing setting. A complete blood count is recommended in patients experiencing significant weakness, pyrexia, recurrent infections, or coagulation disorders.

38%), were seen in immediate-release levetiracetam tablets-treated patients. 0 × 109/L) decreased neutrophil count. Of the levetiracetam tablets-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. In pediatric patients (4 to <16 years of age), statistically significant decreases in WBC and neutrophil counts were seen in patients treated with immediate-release levetiracetam tablets, as compared to placebo.

3 × 109/L, respectively, whereas there were small increases in the placebo group. 7% of patients treated with immediate-release levetiracetam tablets compared to a decrease of 4% in patients on placebo. In the controlled pediatric trial, a possibly clinically significant abnormal low WBC value was observed in 3% of patients treated with immediate-release levetiracetam tablets, compared to no patients on placebo.

However, there was no apparent difference between treatment groups with respect to neutrophil count. No patient was discontinued secondary to low WBC or neutrophil counts. 7 × 109/L). 9 Seizure Control During Pregnancy Physiological changes may gradually decrease plasma levels of levetiracetam throughout pregnancy.

This decrease is more pronounced during the third trimester. It is recommended that patients be monitored carefully during pregnancy. Close monitoring should continue through the postpartum period especially if the dose was changed during pregnancy.