Keppra Oral Solution

/ CTS

The oral solution may be diluted in a glass of water and may be taken with or without food. A graduated oral syringe, an adaptor for the syringe and instructions for use in the package leaflet are provided with Keppra. The daily dose is administered in two equally divided doses.
Monotherapy for Adults and adolescents from 16 years of age:  The recommended starting dose is 250 mg twice daily which should be increased to an initial therapeutic dose of 500 mg twice daily after two weeks. The dose can be further increased by 250 mg twice daily every two weeks depending upon the clinical response. The maximum dose is 1500 mg twice daily.
Add-on therapy for Adults (≥18 years) and adolescents (12 to 17 years) weighing 50 kg or more: The initial therapeutic dose is 500 mg twice daily. This dose can be started on the first day of treatment. Depending upon the clinical response and tolerability, the daily dose can be increased up to 1,500 mg twice daily. Dose changes can be made in 500 mg twice daily increases or decreases every two to four weeks.
Elderly (65 years and older): Adjustment of the dose is recommended in elderly patients with compromised renal function. Children aged 4 to 11 years and adolescents (12 to 17 years) weighing less than 50 kg The initial therapeutic dose is 10 mg/kg twice daily. Depending upon the clinical response and tolerability, the dose can be increased up to 30 mg/kg twice daily. Dose changes should not exceed increases or decreases of 10 mg/kg twice daily every two weeks. The lowest effective dose should be used. Dosage in children 50 kg or greater is the same as in adults. The physician should prescribe the most appropriate pharmaceutical form and strength according to weight and dose.

Levetiracetam is indicated as monotherapy in the treatment of partial onset seizures with or without secondary generalisation in patients from 16 years of age with newly diagnosed epilepsy.
Levetiracetam is indicated as adjunctive therapy:
• in the treatment of partial onset seizures with or without secondary generalisation in adults and children from 4 years of age with epilepsy.
• in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy.
• in the treatment of primary generalised tonic-clonic seizures in adults and adolescents from 12 years of age with Idiopathic Generalised Epilepsy.

Hypersensitivity to levetiracetam or other pyrrolidone derivatives or any of the excipients.

Renal impairment: The administration of levetiracetam to patients with renal impairment may require dose adjustment. In patients with severely impaired hepatic function, assessment of renal function is recommended before dose selection.
Acute Kidney injury: The use of levetiracetam has been very rarely associated with acute kidney injury, with a time to onset ranging from a few days to several months.
Blood cell counts: Rare cases of decreased blood cell counts (neutropenia, agranulocytosis, leucopenia, thrombocytopenia and pancytopenia) have been described in association with levetiracetam administration, generally at the beginning of the treatment. Complete blood cell counts are advised in patients experiencing important weakness, pyrexia, recurrent infections or coagulation disorders.
Suicide: Suicide, suicide attempt and suicidal ideation have been reported in patients treated with anti-epileptic medicinal products (including levetiracetam). A meta-analysis of randomized placebo-controlled trials of anti-epileptic drugs has shown a small increased risk of suicidal thoughts and behaviour. The mechanism of the risk is not known. Therefore patients should be monitored for signs of depression and /or suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of depression and/or suicidal ideation or behaviour emerge.
Abnormal and aggressive behaviours: Levetiracetam may cause psychotic symptoms and behavioural abnormalities including irritability and aggressiveness. Patients treated with levetiracetam should be monitored for developing psychiatric signs suggesting important mood and/or personality changes. If such behaviours are noticed, treatment adaptation or gradual discontinuation should be considered.
Worsening of seizures: As with other types of antiepileptic drugs, levetiracetam may rarely exacerbate seizure frequency or severity. This paradoxical effect was mostly reported within the first month after levetiracetam initiation or increase of the dose, and was reversible upon drug discontinuation or dose decrease. Patients should be advised to consult their physician immediately in case of aggravation of epilepsy. Lack of efficacy or seizure worsening has for example been reported in patients with epilepsy associated with sodium voltage-gated channel alpha subunit 8 (SCN8A) mutations.
Electrocardiogram QT interval prolongation: Rare cases of ECG QT interval prolongation have been observed during the post-marketing surveillance. Levetiracetam should be used with caution in patients with QTc-interval prolongation, in patients concomitantly treated with drugs affecting the QTc-interval, or in patients with relevant pre-existing cardiac disease or electrolyte disturbances.
Paediatric population: The tablet formulation is not adapted for use in children under the age of 6 years. Available data in children did not suggest impact on growth and puberty. However, long term effects on learning, intelligence, growth, endocrine function, puberty and childbearing potential in children remain unknown.
Excipients – oral solution: The 100 mg/ml oral solution contains methyl parahydroxybenzoate (E218) and propyl parahydroxybenzoate (E216) which may cause allergic reactions (possibly delayed).
It also s contains maltitol liquid; patients with rare hereditary problems of fructose intolerance should not take this medicinal product.
See prescribing information for full details.

The most frequently reported adverse reactions were nasopharyngitis, somnolence, headache, fatigue and dizziness. The safety profile of levetiracetam is generally similar across age groups (adult and paediatric patients) and across the approved epilepsy indications.
Rare: Aggravation of the  seizures, QT prolongation.
For full details see prescribing information.

Combinations that require specific consideration
Hepatic injury, including a fatal case, have been reported in patients treated with temozolomide (TMZ) and levetiracetam (LEV) concomitantly.
Some of the reactions occurred in patients with underlying hepatic disease or taking concomitant medications known to have the potential for hepatic injury.
A suggested mechanism for the interaction is the inhibition of O-6-methylguanine-DNA methyltransferase (MGMT) by LEV causing accumulation of TMZ in the circulation resulting in potential increase in the risk of hepatic injury.
Before treatment initiation with LEV and TMZ combination:
Baseline liver function tests should be performed prior to treatment initiation. If abnormal, physicians should assess the benefit/risk prior to initiating the combination including the potential for fatal hepatic failure.
During Treatment with LEV and TMZ combination:
Liver function tests should be performed regularly during treatment.
For patients with liver function abnormalities, physicians should assess the benefit/risk of continuing treatment.
In case of development of signs and symptoms of liver dysfunction or active liver disease, treatment with this combination should be suspended pending the outcome of the benefit/risk evaluation.
Antiepileptic medicinal products
Pre-marketing data from clinical studies conducted in adults indicate that levetiracetam did not influence the serum concentrations of existing antiepileptic medicinal products (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone) and that these antiepileptic medicinal products did not influence the pharmacokinetics of levetiracetam.
As in adults, there is no evidence of clinically significant medicinal product interactions in paediatric patients receiving up to 60 mg/kg/day levetiracetam.
A retrospective assessment of pharmacokinetic interactions in children and adolescents with epilepsy (4 to 17 years) confirmed that adjunctive therapy with orally administered levetiracetam did not influence the steady-state serum concentrations of concomitantly administered carbamazepine and valproate. However, data suggested a 20% higher levetiracetam clearance in children taking enzyme-inducing antiepileptic medicinal products. Dosage adjustment is not required.
Probenecid
Probenecid (500 mg four times daily), a renal tubular secretion blocking agent, has been shown to inhibit the renal clearance of the primary metabolite but not of levetiracetam. Nevertheless, the concentration of this metabolite remains low. 6
Methotrexate
Concomitant administration of levetiracetam and methotrexate has been reported to decrease methotrexate clearance, resulting in increased/prolonged blood methotrexate concentration to potentially toxic levels. Blood methotrexate and levetiracetam levels should be carefully monitored in patients treated concomitantly with the two drugs.
Oral contraceptives and other pharmacokinetics interactions
Levetiracetam 1,000 mg daily did not influence the pharmacokinetics of oral contraceptives (ethinyl-estradiol and levonorgestrel); endocrine parameters (luteinizing hormone and progesterone) were not modified. Levetiracetam 2,000 mg daily did not influence the pharmacokinetics of digoxin and warfarin; prothrombin times were not modified. Co-administration with digoxin, oral contraceptives and warfarin did not influence the pharmacokinetics of levetiracetam.
Laxatives
There have been isolated reports of decreased levetiracetam efficacy when the osmotic laxative macrogol has been concomitantly administered with oral levetiracetam. Therefore, macrogol should not be taken orally for one hour before and for one hour after taking levetiracetam.
Food and alcohol
The extent of absorption of levetiracetam was not altered by food, but the rate of absorption was slightly reduced.
No data on the interaction of levetiracetam with alcohol are available.

Pregnancy:
A large amount of postmarketing data on pregnant women exposed to levetiracetam monotherapy (more than 1800, among which in more than 1500 exposure occurred during the 1st trimester) do not suggest an increase in the risk for major congenital malformations. Only limited evidence is available on the neurodevelopment of children exposed to levetiracetam monotherapy in utero. However, current epidemiological studies (on about 100 children) do not suggest an increased risk of neurodevelopmental disorders or delays.
Levetiracetam can be used during pregnancy, if after careful assessment it is considered clinically needed. In such case, the lowest effective dose is recommended. Physiological changes during pregnancy may affect levetiracetam concentration. Decrease in levetiracetam plasma concentrations has been observed during pregnancy. This decrease is more pronounced during the third trimester (up to 60% of baseline concentration before pregnancy). Appropriate clinical management of pregnant women treated with levetiracetam should be ensured.
Breastfeeding:
Levetiracetam is excreted in human breast milk. Therefore, breast-feeding is not recommended.
However, if levetiracetam treatment is needed during breastfeeding, the benefit/risk of the treatment should be weighed considering the importance of breastfeeding.

Symptoms: Somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with Keppra overdoses.
Management of overdose:  After an acute overdose, the stomach may be emptied by gastric lavage or by induction of emesis. There is no specific antidote for levetiracetam. Treatment of an overdose will be symptomatic and may include haemodialysis. The dialyser extraction efficiency is 60 % for levetiracetam and 74 % for the primary metabolite.