Julitam/Julitam I.V.

Levetiracetam.

Julitam: Each film-coated tablet contains: Levetiracetam USP 500 mg or 1 g.
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.

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: 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.
Pharmacodynamics: 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: 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.
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: 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.
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: 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.
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 1.

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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 2.

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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 3.

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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: 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.
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 Children: Julitam: 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.
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.

Julitam: Pregnancy: 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.
Breastfeeding: 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.
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.
Julitam/Julitam I.V.: Fertility: No impact on fertility was detected in animal studies. No clinical data are available, potential risk for human is unknown.

Julitam: 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 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: 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.

Julitam: 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.
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 4.

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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