Julitam/Julitam I.V.

Levetiracetam.

Julitam: Tablet: Each film-coated tablet contains: Levetiracetam USP 500 mg or 1 g.
Oral solution: Each mL contains: Levetiracetam 100 mg.
Levetiracetam is an antiepileptic drug available as 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).
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.) Levetiracetam Oral Solution contains the labeled amount of levetiracetam.
Julitam I.V.: Each mL contains: Levetiracetam 100 mg (500 mg/5 mL).
Levetiracetam is an anti-convulsant agent. Levetiracetam is chemically described as (αS)-α-Ethyl-2-oxo-1-pyrrolidine acetamide. Its empirical formula is C₈H₁₄N₂O₂. It is white to off white crystalline powder with a molecular weight of 170.21.
Excipients/Inactive Ingredients: Julitam: Oral solution: Sodium citrate, citric acid monohydrate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, ammonium glycyrrhizate, glycerol, maltitol liquid, acesulfame potassium, ART grape flavour, purified water.

Pharmacotherapeutic Group: Antiepileptics, other antiepileptics. ATC Code: N03AX14.
The active substance, levetiracetam, is a pyrrolidone derivative (S-enantiomer of α-ethyl-2-oxo-1-pyrrolidine acetamide), chemically unrelated to existing antiepileptic active substances.
Pharmacology: Julitam: Mechanism of Action: Tablet: The mechanism of action of levetiracetam still remains to be fully elucidated but appears to be different from the mechanisms of current antiepileptic medicinal products. In vitro and in vivo experiments suggest that levetiracetam does not alter basic cell characteristics and normal neurotransmission.
In vitro studies show that levetiracetam affects intraneuronal Ca²⁺ levels by partial inhibition of N-type Ca²⁺ currents and by reducing the release of Ca²⁺ from intraneuronal stores. In addition, it partially reverses the reductions in GABA- and glycine-gated currents induced by zinc and β-carbolines. Furthermore, levetiracetam has been shown in in vitro studies to bind to a specific site in rodent brain tissue. This binding site is the synaptic vesicle protein 2A, believed to be involved in vesicle fusion and neurotransmitter exocytosis. Levetiracetam and related analogs show a rank order of affinity for binding to the synaptic vesicle protein 2A which correlates with the potency of their anti-seizure protection in the mouse audiogenic model of epilepsy. This finding suggests that the interaction between levetiracetam and the synaptic vesicle protein 2A seems to contribute to the antiepileptic mechanism of action of the medicinal product.
Oral solution: 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 hyper synchronization 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.
Pharmacodynamics: Tablet: Levetiracetam induces seizure protection in a broad range of animal models of partial and primary generalised seizures without having a pro-convulsant effect. The primary metabolite is inactive.
In man, an activity in both partial and generalised epilepsy conditions has confirmed the broad spectrum pharmacological profile of levetiracetam.
Clinical efficacy and safety: Adjunctive therapy in the treatment of partial onset seizures with or without secondary generalisation in adults, adolescents, children and infants from 1 month of age with epilepsy.
In adults, levetiracetam efficacy has been demonstrated in 3 double-blind, placebo-controlled studies at 1000 mg, 2000 mg, or 3000 mg/day, given in 2 divided doses, with a treatment duration of up to 18 weeks. In a pooled analysis, the percentage of patients who achieved 50% or greater reduction from baseline in the partial onset seizure frequency per week at stable dose (12/14 weeks) was of 27.7%, 31.6% and 41.3% for patients on 1000, 2000 or 3000 mg levetiracetam respectively and of 12.6% for patients on placebo.
Julitam I.V.: Mechanism of Action: The exact mechanism through which levetiracetam exerts its anti-epileptic effects is unclear, but is thought to be unique amongst other anti-epileptic medications. Current knowledge suggests that levetiracetam's binding to synaptic vesicle protein 2A (SV2A) is a key driver of its action.
SV2A is a membrane-bound protein that is found on synaptic vesicles and is ubiquitous throughout the CNS4 - it appears to play a role in vesicle exocytosis, and in the modulation of synaptic transmission by increasing the available amount of secretory vesicles available for neurotransmission. Stimulation of pre-synaptic SV2A by levetiracetam may inhibit neurotransmitter release, but this action does not appear to affect normal neurotransmission. This has led to the suggestion that levetiracetam exclusively modulates the function of SV2A only under pathophysiological conditions. Levetiracetam and related analogues showed a correlation between affinity for SV2A and anti-epileptic potency, further suggesting that action at this site contributes to the anti-epileptic activity of the drug.
Pharmacokinetics: Julitam: Tablet: Levetiracetam is readily absorbed from the gastrointestinal tract with a bioavailability of almost 100%; peak plasma concentration usually occur within 1.3 hours of oral doses and steady state after 2 days. Plasma protein binding is minimal at less than 10%. Levetiracetam is not extensively metabolized; about 25% of a dose is metabolized by hydroxylation to inactive metabolites. Around 95% of a dose is excreted as unchanged drug and metabolites in the urine. The plasma elimination half-life has been reported to be about 7 hours in adults and children aged 12 years and over; the half-life may be shorter in younger children. Levetiracetam is distributed into breast milk.
Oral solution: 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.
Absorption and Distribution: Absorption of levetiracetam is rapid, with peak plasma concentrations occurring in about an hour following oral administration in fasted subjects. The oral bioavailability of levetiracetam tablets is 100% and the tablets and oral solution are bioequivalent in rate and extent of absorption. Food does not affect the extent of absorption of levetiracetam but it decreases Cmax by 20% and delays Tmax by 1.5 hours. The pharmacokinetics of levetiracetam are linear over the dose range of 500-5000 mg. Steady state is achieved after 2 days of multiple twice-daily dosing. Levetiracetam and its major metabolite are less than 10% bound to plasma proteins; clinically significant interactions with other drugs through competition for protein binding sites are therefore unlikely.
Metabolism: Levetiracetam is not extensively metabolized in humans. The major metabolic pathway is the enzymatic hydrolysis of the acetamide group, which produces the carboxylic acid metabolite, ucb L057 (24% of dose) and is not dependent on any liver cytochrome P450 isoenzymes. The major metabolite is inactive in animal seizure models. Two minor metabolites were identified as the product of hydroxylation of the 2-oxo-pyrrolidine ring (2% of dose) and opening of the 2-oxopyrrolidine ring in position 5 (1% of dose). There is no enantiomeric inter conversion of levetiracetam or its major metabolite.
Elimination: Levetiracetam plasma half-life in adults is 7 ± 1 hour and is unaffected by either dose or repeated administration. Levetiracetam is eliminated from the systemic circulation by renal excretion as unchanged drug which represents 66% of administered dose. The total body clearance is 0.96 mL/min/kg and the renal clearance is 0.6 mL/min/kg. The mechanism of excretion is glomerular filtration with subsequent partial tubular reabsorption. The metabolite ucb L057 is excreted by glomerular filtration and active tubular secretion with a renal clearance of 4mL/min/kg. Levetiracetam elimination is correlated to creatinine clearance. Levetiracetam clearance is reduced in patients with impaired renal function.
Pharmacokinetic 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.
Potential pharmacokinetic interactions of or with levetiracetam were assessed in clinical pharmacokinetic studies (phenytoin, valproate, warfarin, digoxin, oral contraceptive, probenecid) and through pharmacokinetic screening in the placebo-controlled clinical studies in epilepsy patients.
Special Populations: Elderly: Pharmacokinetics of levetiracetam were evaluated in 16 elderly subjects (age 61-88 years) with creatinine clearance ranging from 30 to 74 mL/min. Following oral administration of twice-daily dosing for 10 days, total body clearance decreased by 38% and the half-life was 2.5 hours longer in the elderly compared to healthy adults. This is most likely due to the decrease in renal function in these subjects.
Pediatric Patients: Pharmacokinetics of levetiracetam were evaluated in 24 pediatric patients (age 6-12 years) after single dose (20 mg/kg). The body weight adjusted apparent clearance of levetiracetam was approximately 40% higher than in adults.
A repeat dose pharmacokinetic study was conducted in pediatric patients (age 4-12 years) at doses of 20 mg/kg/day, 40 mg/kg/day, and 60 mg/kg/day. The evaluation of the pharmacokinetic profile of levetiracetam and its metabolite (ucb L057) in 14 pediatric patients demonstrated rapid absorption of levetiracetam at all doses with a Tmax of about 1 hour and a t1/2 of 5 hours across the three dosing levels. The pharmacokinetics of levetiracetam in children was linear between 20 to 60 mg/kg/day. The potential interaction of levetiracetam with other AEDs was also evaluated in these patients. Levetiracetam had no significant effect on the plasma concentrations of carbamazepine, valproic acid, topiramate or lamotrigine. However, there was about a 22% increase of apparent clearance of levetiracetam when it was co-administered with an enzyme-inducing AED (e.g. carbamazepine). Population pharmacokinetic analysis showed that body weight was significantly correlated to clearance of levetiracetam in pediatric patients; clearance increased with an increase in body weight.
Gender: Levetiracetam Cmax and AUC were 20% higher in women (N=11) compared to men (N=12). However, clearances adjusted for body weight were comparable.
Race: Formal pharmacokinetic studies of the effects of race have not been conducted. Cross study comparisons involving Caucasians (N=12) and Asians (N=12), however, show that pharmacokinetics of levetiracetam were comparable between the two races. Because levetiracetam is primarily renally excreted and there are no important racial differences in creatinine clearance, pharmacokinetic differences due to race are not expected.
Renal Impairment: The disposition of levetiracetam was studied in adult subjects with varying degrees of renal function. Total body clearance of levetiracetam is reduced in patients with impaired renal function by 40% in the mild group (CLcr=50-80 mL/min), 50% in the moderate group (CLcr=30-50 mL/min) and 60% in the severe renal impairment group (CLcr <30 mL/min). Clearance of levetiracetam is correlated with creatinine clearance.
In anuric (end stage renal disease) patients, the total body clearance decreased 70% compared to normal subjects (CLcr >80mL/min). Approximately 50% of the pool of levetiracetam in the body is removed during a standard 4-hour hemodialysis procedure.
Dosage should be reduced in patients with impaired renal function receiving levetiracetam, and supplemental doses should be given to patients after dialysis.
Hepatic Impairment: In subjects with mild (Child-Pugh A) to moderate (Child-Pugh B) hepatic impairment, the pharmacokinetics of levetiracetam were unchanged. In patients with severe hepatic impairment (Child-Pugh C), total body clearance was 50% that of normal subjects, but decreased renal clearance accounted for most of the decrease. No dose adjustment is needed for patients with hepatic impairment.
Julitam I.V.: Absorption: Not applicable as it is administered by intravenous infusion.
Distribution: Peak plasma concentration (Cmax) observed in 17 subjects following a single intravenous dose of 1500 mg infused over 15 minutes was 51 ± 19 μg/ml (arithmetic average ± standard deviation). No tissue distribution data are available in humans. Neither levetiracetam nor its primary metabolite are significantly bound to plasma proteins (<10%). The volume of distribution of levetiracetam is approximately 0.5 to 0.7 l/kg, a value close to the total body water volume.
Biotransformation: Levetiracetam is not extensively metabolised in humans. The major metabolic pathway (24% of the dose) is an enzymatic hydrolysis of the acetamide group. Production of the primary metabolite, ucb L057, is not supported by liver cytochrome P450 isoforms. Hydrolysis of the acetamide group was measurable in a large number of tissues including blood cells. The metabolite ucb L057 is pharmacologically inactive.
Two minor metabolites were also identified. One was obtained by hydroxylation of the pyrrolidone ring (1.6% of the dose) and the other one by opening of the pyrrolidone ring (0.9% of the dose). Other unidentified components accounted only for 0.6% of the dose.
No enantiomeric interconversion was evidenced in vivo for either levetiracetam or its primary metabolite.
In vitro, levetiracetam and its primary metabolite have been shown not to inhibit the major human liver cytochrome P450 isoforms (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), glucuronyl transferase (UGT1A1 AND UGT1A6) and epoxide hydroxylase activities. In addition, levetiracetam does not affect the in vitro glucuronidation of valproic acid.
In human hepatocytes in culture, levetiracetam had little or no effect on CYP1A2, SULT1E1 or UGT1A1. Levetiracetam caused mild induction of CYP2B6 and CYP3A4. The in vitro data and in vivo interaction data on oral contraceptives, digoxin and warfarin indicate that no significant enzyme induction is expected in vivo. Therefore, the interaction of JULITAM IV with other drugs, or of other drugs with JULITAM IV is unlikely.
Elimination: The plasma half-life in adults was 7±1 hours and did not vary either with dose, route of administration or repeated administration. The mean total body clearance was 0.96 ml/min/kg.
The major route of excretion was via urine, accounting for a mean 95% of the dose (approximately 93% of the dose was excreted within 48 hours). Excretion via faces accounted for only 0.3% of the dose.
The cumulative urinary excretion of levetiracetam and its primary metabolite accounted for 66% and 24% of the dose, respectively during the first 48 hours.
The renal clearance of levetiracetam and ucb L057 is 0.6 and 4.2 ml/min/kg respectively. This indicates that levetiracetam is excreted by glomerular filtration with subsequent tubular reabsorption and that the primary metabolite is also excreted by active tubular secretion in addition to glomerular filtration. Levetiracetam elimination is correlated to creatinine clearance.

Julitam: Tablet: For monotherapy and adjunctive treatment of partial seizures with or without secondary generalization and for adjunctive therapy of myoclonic seizures and primarily generalized tonic clonic seizures.
Oral solution: 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 1 month 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.
Levetiracetam Oral Solution concentrate is an alternative for patients (adults and children from 4 years of age) when oral administration is temporarily not feasible.
Julitam I.V.: It is used as an alternative for patients when oral administration is temporarily not feasible: as adjunctive therapy in the treatment of partial onset seizures with or without secondary generalization in adults and children from 4 years of age; in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy; in the treatment of primary generalized tonic-clonic seizures in adults and adolescents from 12 years of age with Idiopathic Generalized Epilepsy; as monotherapy in the treatment of partial onset seizures with or without secondary generalization in patients from 16 years of age.

Julitam: Tablet: Adults 16 years and older: 1 g/day initial daily dose in two divided doses (500 mg twice daily) thereafter the daily dose may be increased in steps of 1 g every 2 to 4 weeks until effective antiepileptic control is achieved up to a maximum dose of 3 g daily.
Children: Less than 50 kg weight 20 mg/kg daily may be increased in steps of 20 mg/kg every weeks to a maximum of 60 mg/kg daily.
More than 50 kg weight may be given the adult dose (see previously).
As monotherapy: 500 mg daily increased after 2 weeks to 1 g daily. Further increases may be made in steps of 500 mg every 2 weeks up to maximum of 3 g daily.
Oral solution: 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.
Hepatic impairment: No dose adjustment is needed in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the creatinine clearance may underestimate the renal insufficiency. Therefore a 50% reduction of the daily maintenance dose is recommended when the creatinine clearance is <60 ml/min/1.73 m².
Paediatric population: The physician should prescribe the most appropriate pharmaceutical form, presentation and strength according to weight and dose.
The safety and efficacy of Levetiracetam Oral Solution concentrate for solution for infusion in infants and children less than 4 years have not been established.
Monotherapy: The safety and efficacy of Levetiracetam Oral Solution in children and adolescents below 16 years as monotherapy treatment have not been established.
There are no data available.
Add-on therapy for infants aged from 6 to 23 months, children (2 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.
Dose in children 50 kg or greater is the same as in adults.
Dose recommendations for infants from 6 months of age, children and adolescents: See Table 1.

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Add-on therapy for infants from 1 month to less than 6 months.
The tablet formulation is not adapted for use in infants under the age of 6 months. The oral solution is the formulation to use in infants.
The initial therapeutic dose is 7 mg/kg twice daily.
Depending upon the clinical response and tolerability, the dose can be increased up to 21 mg/kg twice daily. Dose changes should not exceed increases or decreases of 7 mg/kg twice daily every two weeks. The lowest effective dose should be used.
Infants should start the treatment with Levetiracetam Oral Solution 100 mg/mL oral solution.
Dose recommendations for infants less than 6 months: See Table 2.

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This presentation should be prescribed for children older than 4 years, adolescents and adults.
A 150 mL bottle with graduated oral syringe containing up to 300 mg levetiracetam (corresponding to 3 ml) with a graduation every 0.1 mL (corresponding to 10 mg).
In order to ensure the accuracy of the dosing, the smaller bottle (150 mL) and syringe graduated from 0.1 to 3 mL per graduation of 0.1 mL should be prescribed for infants older than 6 months and young children.
A 150 mL bottle with graduated oral syringe containing up to 100 mg levetiracetam (corresponding to 1 mL) with a graduation every 0.05 mL (corresponding to 5 mg).
In order to ensure the accuracy of the dosing, the smaller bottle (150 mL) and syringe graduated from 0.05 to 1 mL per graduation of 0.05 mL should be prescribed for infants less than 6 months.
Method of administration oral solution: 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 Levetiracetam Oral Solution 100 mg/mL.
The daily dose is administered in two equally divided doses.
Julitam I.V.: Posology/frequency and duration of administration: The total daily dose and frequency of administration should be maintained. JULITAM IV concentrate for solution for infusion is for intravenous administration only.
There is no experience with administration of intravenous levetiracetam for longer period than 4 days.
Monotherapy: Adults and adolescents from 16 years of age: The recommended starting dose is 250 mg twice daily. The dose 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: Adults (≥18 years) and adolescents weighing 50 kg or more (12 to 17 years): 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 1500 mg twice daily. Dose changes can be made in 500 mg twice daily increases or decreases every 2 to 4 weeks.
Children aged 4 to 11 years and adolescents weighing less than 50 kg (12 to 17 years): The initial therapeutic dose is 10 mg/kg twice daily.
Depending upon the clinical response and tolerability, the daily 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.
Dose in children 50 kg or greater is the same as in adults.
The physician should prescribe the most appropriate pharmaceutical form, presentation and strength according to weight and dose.
Dose recommendations for children and adolescents: See Table 3.

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Additional information on special populations: Renal/Hepatic failure: The daily dose must be individualized according to renal function.
For adult patients, refer to the following table and adjust the dose as indicated. To use this dosing table, an estimate of the patient's creatinine clearance (CLcr) in ml/min is needed. The CLcr in ml/min may be estimated from serum creatinine (mg/dl) determination, for adults and adolescents weighting 50 kg or more, the following formula: See Equation 1.

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Then CLcr is adjusted for body surface area (BSA) as follows: See Equation 2.

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Dosing adjustment for adult and adolescent patients weighing more than 50 kg with impaired renal function: See Table 4.

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For children with renal impairment, levetiracetam dose needs to be adjusted based on the renal function as levetiracetam clearance is related to renal function. This recommendation is based on a study in adult renally impaired patients.
The CLcr in ml/min/1.73 m² may be estimated from serum creatinine (mg/dl) determination, for young adolescents and children, using the following formula (Schwartz formula): See Equation 3.

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Dosing adjustment for children and adolescents patients weighing less than 50 kg with impaired renal function: See Table 5.

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No dose adjustment is needed in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the creatinine clearance may underestimate the renal insufficiency. Therefore a 50% reduction of the daily maintenance dose is recommended when the creatinine clearance is <60 ml/min/1.73 m².
Pediatric population: JULITAM I.V. concentrated solution for infusion is not recommended in children less than 4 years because of lack of sufficient data on safety and efficacy.
The efficacy and safety as a monotherapy treatment in children and adolescents under 16 years of age have not been established. Therefore, it is not used as monotherapy in children and adolescents under 16 years of age.
Geriatric population: Adjustment of the dose is recommended in elderly (65 years and older) patients with compromised renal function (see Renal/Hepatic failure as previously mentioned).
Method of Administration: Treatment can be initiated with either intravenous or oral administration. Conversion to or from oral to intravenous administration can be done directly without titration. JULITAM IV concentrate for solution for infusion is for intravenous administration only.
The recommended dose must be diluted in at least 100 ml of a compatible diluent an administered intravenously as a 15-minute intravenous infusion (for the preparation and information of compatibility, see Special precautions for disposal and other handling under Cautions for Usage).

Symptoms: Somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with Levetiracetam 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.

Hypersensitivity to the active substance or other pyrrolidone derivatives or to any of the excipients.

Julitam: Oral solution: Discontinuation: In accordance with current clinical practice, if Levetiracetam Oral Solution has to be discontinued it is recommended to withdraw it gradually (e.g. in adults and adolescents weighing more than 50 kg: 500 mg decreases twice daily every two to four weeks; in children and adolescents weighting less than 50 kg: dose decrease should not exceed 10 mg/kg twice daily every two weeks).
Renal insufficiency: The administration of Levetiracetam Oral Solution 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.
Suicide: Suicide, suicide attempt, suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents (including levetiracetam). A meta analysis of randomized placebo-controlled trials of anti-epileptic medicinal products has shown a small increased risk of suicidal thoughts and behaviour.
The mechanism of this 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.
Paediatric population: 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: Levetiracetam 100 mg/ml oral solution includes methyl parahydroxybenzoate and propyl parahydroxybenzoate which may cause allergic reactions (possibly delayed).
It also includes maltitol liquid; patients with rare hereditary problems of fructose intolerance should not take this medicinal product.

Julitam: Tablet: Discontinuation: In accordance with current clinical practice, if Levetiracetam has to be discontinued, it is recommended to withdraw it gradually.
Renal insufficiency: 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.
Suicide: Suicide, suicide attempt, suicidal ideation and behaviour have been reported in patients treated with levetiracetam. A meta-analysis of randomized placebo-controlled trials of anti-epileptic medicinal products has shown a small increased risk of suicidal thoughts and behaviour. The mechanism of this 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 should be advised to seek medical advice should signs of depression and/or suicidal ideation or behaviour emerge.
Effects on Ability to Drive and Use Machines: No studies on the effects on the ability to drive and use machines have been performed. Due to possible different individual sensitivity, some patients might experience somnolence or other central nervous system related symptoms, especially at the beginning of treatment or following a dose increase. Therefore, caution is recommended in those patients when performing skilled tasks, e.g. driving vehicles or operating machinery. Patients are advised not to drive or use machines until it is established that their ability to perform such activities is not affected.
Oral solution: 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 (≤1.0 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 (3.0% levetiracetam-treated versus 0% placebo), however, there was no apparent difference between treatment groups with respect to neutrophil count (5.0% 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.
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. UCB, Inc. has established the UCB AED Pregnancy Registry to advance scientific knowledge about safety and outcomes associated with pregnant women being treated with all UCB antiepileptic drugs, including levetiracetam.
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.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: Rats were dosed with levetiracetam in the diet for 104 weeks at doses of 50, 300 and 1800 mg/kg/day. The highest dose corresponds to 6 times the maximum recommended daily human dose (MRHD) of 3000 mg on a mg/m² basis and it also provided systemic exposure (AUC) approximately 6 times that achieved in humans receiving the MRHD. There was no evidence of carcinogenicity. A study was conducted in which mice received levetiracetam in the diet for 80 weeks at doses of 60, 240 and 960 mg/kg/day (high dose is equivalent to 2 times the MRHD on a mg/m² or exposure basis). Although no evidence for carcinogenicity was seen, the potential for a carcinogenic response has not been fully evaluated in that species because adequate doses have not been studied.
Mutagenesis: Levetiracetam was not mutagenic in the Ames test or in mammalian cells in vitro in the Chinese hamster ovary/HGPRT locus assay. It was not clastogenic in an in vitro analysis of metaphase chromosomes obtained from Chinese hamster ovary cells or in an in vivo mouse micronucleus assay. The hydrolysis product and major human metabolite of levetiracetam (ucb L057) was not mutagenic in the Ames test or the in vitro mouse lymphoma assay.
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 levetiracetam and supplemental doses should be given to patients after dialysis.
Julitam I.V.: The recommendation in accordance with the current clinical experience is the termination of JULITAM I.V. treatment with a gradual dose reduction. (For example: in adults and adolescents over 50 kg, reducing 2 x 500 mg/day every 2-4 weeks; in children and adolescents under 50 kg; 2 x 10 mg/kg/day dose every 2 weeks. Not to exceed the condition).
Acute kidney injury: Levetiracetam use is rarely associated with acute renal injury, and the onset time ranges from several days to several months.
Renal impairment: Dose adjustment may be required in patient with renal impairment. Therefore, in patients with severe hepatic impairment, assessment of renal function is recommended before dose selection (see Dosage & Administration).
Blood cell counts: Sparse cases with a decrease in blood cell counts (neutropenia, agranulocytosis, leukopenia, thrombocytopenia and pancytopenia) have been generally described in connection with levetiracetam administration at the beginning of treatment. Whole blood cell count is recommended in patients experiencing significant weakness, pyrexia, recurrent infections and coagulation disorders.
Suicide: Suicide, suicide attempt, suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents (including levetiracetam). A meta-analysis of randomized placebo-controlled trials of anti-epileptic medicinal products has shown a small increased risk of suicidal thoughts and behaviour. The mechanism of this 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.
Excipients: This medicinal product contains 2.5 mmol (or 57 mg) sodium per maximum single dose [or 0.8 mmol (or 19 mg) per vial]. The sodium content should be taken into account in patients on a controlled sodium diet.
Effects on Ability to Drive and Use Machines: Levetiracetam has a minor or moderate effect on vehicle and machine use. Thus, drowsiness or other central nervous system-related symptoms may occur due to different individual sensitivities, especially at the beginning of treatment or in dose increases. For this reason, it is necessary for people to perform tasks requiring skills eg, it is recommended that vehicle drivers and machine operators be careful. It is not recommended to use tools or machinery until it is determined that the skills of the patients performing such activities are not affected.
Use in Pregnancy & Lactation: See Use in Pregnancy & Lactation for further information.
Use in Children: Julitam: Tablet: The tablet formulation is not adapted for use in infants and 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.
Oral solution: 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.
Julitam I.V.: 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.
As in adults, there is no clinically significant evidence of drug interaction in pediatric patients treated with doses up to 60 mg/kg/day.
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 valproic acid. However, data suggested a 20% higher levetiracetam clearance in children taking enzyme-inducing antiepileptic medicinal products. Dosage adjustment is not required.
Use in the Elderly: Julitam: Oral solution: 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 levetiracetam in these patients.
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.

Julitam: Pregnancy: Tablet: There are no adequate data available from the use of Levetiracetam in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for human is unknown.
Levetiracetam is not recommended during pregnancy and in women of childbearing potential not using contraception unless clearly necessary.
As with other antiepileptic medicinal products, 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. Appropriate clinical management of pregnant women treated with levetiracetam should be ensured. Discontinuation of antiepileptic treatments may result in exacerbation of the disease which could be harmful to the mother and the foetus.
Oral solution Pregnancy Category C.
In animal studies, levetiracetam produced evidence of developmental toxicity at doses similar to or greater than human therapeutic doses.
Administration to female rats throughout pregnancy and lactation was associated with increased incidences of minor fetal skeletal abnormalities and retarded offspring growth pre- and/or postnatally at doses ≥350 mg/kg/day (approximately equivalent to the maximum recommended human dose of 3000 mg [MRHD] on a mg/m² basis) and with increased pup mortality and offspring behavioral alterations at a dose of 1800 mg/kg/day (6 times the MRHD on a mg/m² basis). The developmental no effect dose was 70 mg/kg/day (0.2 times the MRHD on a mg/m² basis). There was no overt maternal toxicity at the doses used in this study.
Treatment of pregnant rabbits during the period of organogenesis resulted in increased embryofetal mortality and increased incidences of minor fetal skeletal abnormalities at doses ≥600 mg/kg/day (approximately 4 times MRHD on a mg/m² basis) and in decreased fetal weights and increased incidences of fetal malformations at a dose of 1800 mg/kg/day (12 times the MRHD on a mg/m² basis). The developmental no effect dose was 200 mg/kg/day (1.3 times the MRHD on a mg/m² basis). Maternal toxicity was also observed at 1800 mg/kg/day.
When pregnant rats were treated during the period of organogenesis, fetal weights were decreased and the incidence of fetal skeletal variations was increased at a do se of 3600 mg/kg/day (12 times the MRHD). 1200 mg/kg/day (4 times the MRHD) was a developmental no effect dose. There was no evidence of maternal toxicity in this study.
Treatment of rats during the last third of gestation and throughout lactation produced no adverse developmental or maternal effects at doses of up to 1800 mg/kg/day (6 times the MRHD on a mg/m² basis).
There are no adequate and well-controlled studies in pregnant women. Levetiracetam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Registries: To provide information regarding the effects of in utero exposure to levetiracetam, physicians are advised to recommend that pregnant patients taking levetiracetam enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry.
The effect of levetiracetam on labor and delivery in humans is unknown.
Breastfeeding: Tablet: Levetiracetam is excreted in human breast milk. Therefore, breastfeeding 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.
Oral solution: Levetiracetam is excreted in breast milk. Because of the potential for serious adverse reactions in nursing infants from levetiracetam, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Impairment of Fertility: Tablet: No impact on fertility was detected in animal studies. No clinical data are available, potential risk for human is unknown.
Oral solution: No adverse effects on male or female fertility or reproductive performance were observed in rats at doses up to 1800 mg/kg/day (approximately 6 times the maximum recommended human dose on a mg/m² or exposure basis).
Julitam I.V.: Women with childbearing potential/Contraception: Not recommended unless clinically necessary in women with childbearing potential and who do not undergo contraception.
Women with childbearing potential should seek expert medical advice. Levetiracetam should be re-evaluated in women planning pregnancy. As with all antiepileptic drugs, sudden discontinuation of treatment with levetiracetam should be avoided because this can lead to sudden seizures that can have serious consequences for the mother and her unborn child. Where possible, monotherapy should be preferred because treatment with multiple antiepileptic drugs has been associated with a higher risk of congenital malformation than monotherapy due to concomitant antiepileptics.
Pregnancy: Category C: Should not be used in pregnancy unless clearly necessary. Studies in animals have shown reproductive toxicity. Potential risk for human is unknown.
Should not be used in pregnancy unless clearly necessary. Studies in animals have shown reproductive toxicity. Potential risk for human is unknown.
As with other antiepileptic drugs, 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 JULITAM IV should be ensured. Discontinuation of antiepileptic treatments may result in exacerbation of the disease which could be harmful to the mother and the foetus.
Lactation: Levetiracetam is excreted in human breast milk. Therefore, breast-feeding is not recommended during treatment with JULITAM IV.
However, a decision on whether to discontinue breast-feeding or to discontinue/abstain from JULITAM IV therapy should take into account the benefit of breast-feeding for the child, and the benefit of JULITAM IV therapy for the breastfeeding mother.
Fertility: No impact on fertility was detected in animal studies. No clinical data are available, potential risk for human is unknown.

Julitam: Tablet: Adverse effects reported in clinical studies and from post marketing survey are listed followings: CNS: Somnolence (23%); headache (14%); hostility (12%); fatigue, nervousness (10%); dizziness (9%); personality disorder (8%); agitation, emotional lability, irritability (6%); depression, mood swings, vertigo (5%); ataxia, seizures (3%); amnesia, anxiety, confusion, hypersomnia, increased reflexes, insomnia, irritability, paresthesia (2%); suicidal behavior.
Dermatologic: Pruritus, skin discoloration, vesiculobullous rash (2%); alopecia.
ENT: Nasopharyngitis (14%); rhinitis (13%); pharyngitis (10%); conjunctivitis (3%); amblyopia, diplopia, ear pain (2%).
GI: Vomiting (15%); anorexia (13%); diarrhea (8%); gastroenteritis (4%); constipation (3%); pancreatitis.
Genitourinary: Albuminuria (4%); urine abnormality (2%).
Hematologic-Lymphatic: Ecchymosis (4%); leukopenia, neutropenia, pancytopenia, thrombocytopenia.
Hepatic: Hepatic failure, hepatitis.
Metabolic-Nutritional: Dehydration (2%); weight loss.
Musculoskeletal: Neck pain (8%).
Respiratory: Increased cough (11%); asthma, sinusitis (2%).
Miscellaneous: Accidental injury (17%); asthenia (15%); infection (13%); pain (7%); influenza (5%); flu syndrome (3%); face edema, viral infection (2%).
Summary of the safety profile: Julitam: Oral solution: Pooled safety data from clinical studies conducted with Levetiracetam Oral Solution oral formulations in adult patients with partial onset seizures showed that 46.4% of the patients in the Levetiracetam Oral Solution group and 42.2% of the patients in the placebo group experienced adverse reactions. Serious adverse reactions were experienced in 2.4% of the patients in the Levetiracetam Oral Solution and 2.0% of the patients in the placebo groups.
The most commonly reported adverse reactions were somnolence, asthenia and dizziness. In the pooled safety analysis, there was no clear dose-response relationship but incidence and severity of the central nervous system related adverse reactions decreased over time.
In monotherapy 49.8% of the subjects experienced at least one drug related adverse reaction. The most frequently reported adverse reactions were fatigue and somnolence.
A study conducted in adults and adolescents with myoclonic seizures (12 to 65 years) showed that 33.3% of the patients in the Levetiracetam Oral Solution group and 30.0% of the patients in the placebo group experienced adverse reactions that were judged to be related to treatment. The most commonly reported adverse reactions were headache and somnolence. The incidence of adverse reactions in patients with myoclonic seizures was lower than that in adult patients with partial onset seizures (33.3% versus 46.4%).
A study conducted in adults and children (4 to 65 years) with idiopathic generalised epilepsy with primary generalised tonic-clonic seizures showed that 39.2% of the patients in the Levetiracetam Oral Solution group and 29.% of the patients in the placebo group experienced undesirable effects that were judged to be related to treatment. The most commonly reported adverse reaction was fatigue.
An increase in seizure frequency of more than 25% was reported in 14% of levetiracetam treated adult and paediatric patients (4 to 16 years of age) with partial onset seizures, whereas it was reported in 26% and 21% of placebo treated adult and paediatric patients, respectively.
When Levetiracetam Oral Solution was used to treat primary generalised tonic clonic seizures in adults and adolescents with idiopathic generalised epilepsy, there was no effect on the frequency of absences.
Adverse reactions that resulted from Levetiracetam Oral Solution intravenous use are similar to those associated with Levetiracetam Oral Solution oral use. The most frequently reported adverse reactions were dizziness, somnolence, headache and postural dizziness. Since there was limited exposure for Levetiracetam Oral Solution intravenous use and since oral and intravenous formulations are bioequivalent, the safety information of Levetiracetam Oral Solution intravenous will rely on Levetiracetam Oral Solution oral use.
Julitam I.V.: The adverse reaction profile presented as follows is based on the analysis of pooled placebo-controlled clinical trials with all indications studied, with a total of 3,416 patients treated with levetiracetam. These data are supplemented with the use of levetiracetam in corresponding open-label extension studies, as well as post-marketing experience. 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 pediatric patients) and across the approved epilepsy indications.
Adverse reactions reported in clinical studies (adults, adolescents and children >1 month) and from postmarketing experience are listed in the following table per System and per Frequency.
Very common (≥ 1/10); Common (≥1/100, <1/10); Uncommon (≥1/1000; <1/100); Rare (≥1/10000, <1/1000); Very rare (<1/10000); Not known (cannot be estimated from the available data).
Infections and Infestations: Very common: Nasopharyngitis. Rare: Infection.
Blood and lymphatic system disorders: Uncommon: Thrombocytopenia, leukopenia. Rare: Neutropenia, pancytopenia.
Diseases of the immune system: Infrequent: Drug reaction (DRESS), hypersensitivity (including angioedema and anaphylaxis) with eosinophilia and systemic symptoms.
Metabolism and nutrition disorders: Common: Anorexia. Uncommon: Weight increase, weight decrease, agranulocytosis. Rare: Hyponatremia.
Psychiatric disorders: Common: Depression, hostility/aggression, anxiety, insomnia, nervousness/irritability. Uncommon: Suicide attempt, suicidal ideation, psychotic disorder, abnormal behaviour, hallucination, anger, confusional state, panic attack, affect lability/mood swings, agitation. Rare: Completed suicide, personality disorder, thinking abnormal.
Nervous system disorders: Very common: Somnolence, headache. Common: Convulsion, balance disorder, dizziness, lethargy, tremor. Uncommon: Amnesia, memory impairment, coordination abnormal/ataxia, paraesthesia, disturbance in attention. Rare: Choreoathetosis, dyskinesia, hyperkinesia, difficulty in walking.
Eye disorders: Uncommon: Diplopia, vision blurred.
Ear and Labyrinth Disorders: Common: Vertigo.
Respiratory, thoracic and mediastinal disorders: Common: Cough.
Gastrointestinal disorders: Common: Abdominal pain, diarrhoea, dyspepsia, vomiting, nausea. Rare: Pancreatitis.
Hepatobiliary disorders: Uncommon: Liver function test abnormal. Rare: Hepatic failure, hepatitis.
Kidney and urinary tract diseases: Rare: Acute kidney injury.
Skin and subcutaneous tissue disorders: Common: Rash. Uncommon: Alopecia, eczema, pruritus. Rare: Toxic epidermal necrolysis, Stevens Johnson syndrome, erythema multiforme.
Musculoskeletal and connective tissue disorders: Uncommon: Muscular weakness, myalgia.
General disorders and administration site disorders: Common: Asthenia/fatigue.
Injury, poisoning and procedural complications: Uncommon: Injury.
Encephalopathy has rarely been seen after levetiracetam administration. These undesirable effects usually occur at the beginning of treatment (several days to several months) and resolve after discontinuation of treatment.
* In Japanese patients, the prevalence is significantly higher than in non-Japanese patients.
Description of selected adverse reactions: Julitam: Oral solution: The risk of anorexia is higher when topiramate is coadministered with levetiracetam. In several cases of alopecia, recovery was observed when levetiracetam was discontinued.
Julitam I.V.: The risk of anorexia is higher when levetiracetam is co-administered with topiramate. In several cases of alopecia, recovery was observed when levetiracetam was discontinued.
Bone marrow suppression was identified in some of the cases of pancytopenia.
Pediatric population: In patients aged 1 month to less than 4 years, a total of 190 patients have been treated with levetiracetam in placebo-controlled and open label extension studies. Sixty of these patients were treated with levetiracetam in placebo-controlled studies. In patients aged 4-16 years, a total of 645 patients have been treated with levetiracetam in placebo-controlled and open label extension studies. 233 of these patients were treated with levetiracetam in placebo-controlled studies. In both these paediatric age groups, these data are supplemented with the post-marketing experience.
In addition, 101 infants under 12 months of age were included in the post-registration safety study. No new safety concerns were found in infants with epilepsy younger than 12 months.
The adverse reaction profile of levetiracetam is generally similar across age groups and across the approved epilepsy indications. Safety results in pediatric patients in placebo-controlled clinical studies were consistent with the safety profile of levetiracetam in adults except for behavioural and psychiatric adverse reactions which were more common in children than in adults. In children and adolescents aged 4 to 16 years, vomiting (very common, 11.2%), agitation (common, 3.4%), mood swings (common, 2.1%), affect lability (common, 1.7%), aggression (common, 8.2%), abnormal behaviour (common, 5.6%), and lethargy (common, 3.9%) were reported more frequently than in other age ranges or in the overall safety profile. In infants and children aged 1 month to less than 4 years, irritability (very common, 11.7%) and coordination abnormal (common, 3.3%) were reported more frequently than in other age groups or in the overall safety profile.
A double-blind, placebo-controlled pediatric safety study with a non-inferiority design has assessed the cognitive and neuropsychological effects of levetiracetam in children 4 to 16 years of age with partial onset seizures. It was concluded that levetiracetam was not different (non-inferior) from placebo with regard to the change from baseline of the Leiter-R Attention and Memory, Memory Screen Composite score in the per-protocol population. Results related to behavioural and emotional functioning indicated a worsening in levetiracetam treated patients on aggressive behaviour as measured in a standardized and systematic way using a validated instrument (CBCL-Achenbach Child Behavior Checklist). However, subjects who took levetiracetam in the long-term open label follow-up study, did not experience a worsening, on average, in their behavioural and emotional functioning; in particular measures of aggressive behaviour were not worse than baseline.
Paediatric population: Julitam: Oral solution: A study conducted in paediatric patients (4 to 16 years) with partial onset seizures showed that 55.4% of the patients in the Levetiracetam Oral Solution group and 40.2% of the patients in the placebo group experienced adverse reactions. Serious adverse reactions were experienced in none of the patients in the Levetiracetam Oral Solution group and 1.0% of the patients in the placebo group. The most commonly reported adverse reactions were somnolence, hostility, nervousness, emotional lability, agitation, anorexia, asthenia and headache in the paediatric population. Safety results in paediatric patients were consistent with the safety profile of levetiracetam in adults except for behavioural and psychiatric adverse reactions which were more common in children than in adults (38.6% versus 18.6%). However, the relative risk was similar in children as compared to adults.

Julitam: Tablet: Evidence of significant interactions between Levetiracetam and other epileptics is mostly lacking. However, for the effects of Levetiracetam on carbamazepine, there are symptoms of carbamazepine toxicity due to a pharmacodynamic mechanism as blood levels of carbamazepine and its epoxide metabolite were not affected.
Oral solution: Antiepileptic medicinal products: Pre-marketing data from clinical studies conducted in adults indicate that Levetiracetam Oral Solution 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 Oral Solution.
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. Dose 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. It is expected that other medicinal products excreted by active tubular secretion could also reduce the renal clearance of the metabolite. The effect of levetiracetam on probenecid was not studied and the effect of levetiracetam on other actively secreted medicinal products, e.g. NSAIDs, sulfonamides and methotrexate, is unknown.
Antacids: No data on the influence of antacids on the absorption of levetiracetam are available.
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.
Julitam I.V.: 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 medicinal products did not influence the pharmacokinetics of levetiracetam.
As in adults, there is no clinically significant evidence of drug interaction in pediatric patients treated with doses up to 60 mg/kg/day.
In a retrospective evaluation of pharmacokinetic interaction in children and adolescents (4 to 17 years) with epilepsy, it was confirmed that oral levetiracetam in additional treatment did not affect the steady-state concentration of carbamazepine and valproate. However, data suggest that 20% higher levetiracetam clearance is seen in children receiving enzyme-inducing antiepileptic drugs. No dose adjustment is required.
Probenecid: Probenecid (500 mg 4 times a day), a drug that blocks tubular secretion from the kidney, has been shown to inhibit renal clearance of the primary metabolite but not levetiracetam. However, the concentration of this metabolite remains low.
Methotrexate: It has been reported that co-administration of levetiracetam and methotrexate reduces methotrexate clearance, thereby increasing/prolonging the concentration of methotrexate in the blood to potentially toxic levels. Blood methotrexate and levetiracetam levels should be carefully monitored in patients taking these two drugs together.
Oral contraceptives and other pharmacokinetic interactions: Levetiracetam 1,000 mg daily did not influence the pharmacokinetics of oral contraceptives (ethinylestradiol 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.
Coadministration with digoxin, oral contraceptives and warfarin did not influence the pharmacokinetics of levetiracetam.
Alcohol: No data on the interaction of levetiracetam with alcohol are available.

Special precautions for disposal and other handling: Julitam I.V.: Administration: See Table 6.

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This medicinal product is for single use only, any unused solution should be discarded.
JULITAM IV concentrate for solution for infusion was found to be physically compatible and chemically stable for at least 24 hours when mixed with the following diluents and stored in PVC bags at controlled room temperature (15-25°C).
Diluents: Sodium chloride 9 mg/ml (0.9%) solution for injection; Lactated Ringer's solution for injection; Dextrose 5% solution for injection.
Medicinal product with particulate matter or discoloration should not be used.

Store at temperatures not exceeding 30°C.

Anticonvulsants

N03AX14 - levetiracetam ; Belongs to the class of other antiepileptics.

Rx