Levisat

Levetiracetam.

LEVISAT 500 mg Film Coated Tablet: Yellow colored, oblong-shaped biconvex film coated tablet, debossed with "L" and "U" on either side of break line on one side and "X02" on the other side.
Each film coated tablet contains: Levetiracetam 500 mg.
LEVISAT 500 mg/5 mL Concentrate for solution for infusion: clear colorless sterile solution free from visible particulate matter.
Each 5 ml vial contains Levetiracetam 500 mg.
After dilution, the solution remains clear and colorless without any visible foreign matter.
Before administration, Levisat concentrate for solution for infusion can be diluted with the following diluents; 5% Dextrose Injection; 0.9% Sodium chloride injection.
Note: No diluent is provided along with Levisat concentrate for solution for infusion.

Pharmacotherapeutic group: Antiepileptics, other antiepileptics.
Therapeutic code: N03AX14.
Pharmacology: Pharmacodynamics: Mechanism of action: 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.
The mechanism of action of levetiracetam still remains to be fully elucidated.
FC tab: Clinical efficacy and safety: Adjunctive therapy in the treatment of partial onset seizures with or without secondary generalization in adults, adolescents and children from 4 years of age with epilepsy.
Infusion conc: Pharmacodynamics effects: In man, an activity in both partial and generalized epilepsy conditions (epileptiform discharge/photo paroxysmal response) has confirmed the broad spectrum pharmacological profile of levetiracetam.
Pharmacokinetics: Levetiracetam is a highly soluble and permeable compound. The pharmacokinetic profile is linear with low intra- and inter-subject variability. There is no modification of the clearance after repeated administration.
Absorption: FC tab: Levetiracetam is rapidly absorbed after oral administration. Oral absolute bioavailability is close to 100%. Peak plasma concentrations (C_max) are achieved at 1.3 hours after dosing. Steady-state is achieved after two days of a twice daily administration schedule. The extent of absorption is dose-independent and is not altered by food.
Distribution: Neither levetiracetam nor its primary metabolite are significantly bound to plasma proteins (<10%).
Infusion conc: The volume of distribution of levetiracetam is approximately 0.5 to 0.7 l/kg, a value close to total body water volume.
Metabolism: Levetiracetam is not extensively metabolized 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.
Elimination: Infusion conc: 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. It is therefore recommended to adjust the maintenance daily dose of levetiracetam, based on creatinine clearance in patients with moderate and severe renal impairment.
Renal impairment: The apparent body clearance of both Levetiracetam and of its primary metabolite is correlated to the creatinine clearance.

Levisat is indicated as monotherapy in the treatment of partial onset seizures with or without secondary generalization in patients from 16 years of age with newly diagnosed epilepsy.
Levisat is indicated as adjunctive therapy for the following: In the treatment of partial onset seizures with or without secondary generalisation in adults and children from 4 years of age with epilepsy; In the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy; In the treatment of primary generalized tonic-clonic seizures in adults and children from 12 years of age with Idiopathic Generalized Epilepsy.
Infusion conc: Levisat Concentrate is an alternative for patients (adults and children from 4 years of age) when oral administration is not feasible.

Posology: Levetiracetam therapy can be initiated with either intravenous or oral administration. Conversion to or from oral to intravenous administration can be done directly without titration. The total daily dose and frequency of administration must be maintained.
FC tab: The film-coated tablets must be taken orally, swallowed with a sufficient quantity of liquid and may be taken with or without food. After oral administration the bitter taste of levetiracetam may be experienced. The daily dose is administered in two equally divided doses.
Infusion conc: Levetiracetam concentrate is for intravenous use only and the recommended dose must be diluted in at least 100 ml of compatible diluent and administered intravenously as a 15-minute intravenous infusion.
Levetiracetam concentrate is an alternative for patients (adults and children from 4 years of age) when oral administration is temporarily not feasible.
Adults: 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 1500 mg twice daily. Dose changes can be made in 500 mg twice daily increases or decreases every two to four weeks.
Children: The physician should prescribe the most appropriate pharmaceutical form, presentation and strength according to age, weight and dose.
FC tab: The tablet formulation is not adapted for use in children under the age of 6 years. In addition, the available dose strengths of the tablets are not appropriate for initial treatment in children weighing less than 25 kg, for patients unable to swallow tablets or for the administration of doses below 250 mg.
Monotherapy: The safety and efficacy of levetiracetam in children and adolescents below 16 years as monotherapy treatment have not been established. There are no data available.
Add-on therapy for children (4 to 11 years) and adolescents (12 to 17 years) weighing less than 50 kg: The initial therapeutic dose is 10 mg/kg twice daily.
Depending upon the clinical response and tolerability, the dose can be increased up to 30 mg/kg twice daily. Dose changes should not exceed increases or decreases of 10 mg/kg twice daily every two weeks.
The lowest effective dose should be used.
Dose in children 50 kg or greater is the same as in adults.
Dose recommendations for children and adolescents: (see Tables 1 and 2.)

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FC tab: Add-on therapy for children (4 to 11 years) and adolescents (12 to 17 years) weighing between 25 to 50 kg: For children 6 years and above, levetiracetam tablet formulation is not adapted to be used for doses under 250 mg, for doses not multiple of 250 mg when dosing recommendation is not achievable by taking multiple tablets and for patients unable to swallow tablets.
Special populations: Elderly (65 years and older): Adjustment of the dose is recommended in elderly patients with compromised renal function.
Renal impairment: 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 weighing 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 3.)

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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 using, for young adolescents and children using the following (Schwartz formula): (see Equation 3.)

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Dosing adjustment for children and adolescent patients weighing between 25 to 50 kg with impaired renal function: (see Table 4.)

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Dosing adjustment for children and adolescent patients weighing less than 50 kg with impaired renal function: (see Table 5.)

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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.

Symptoms: Somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with Levisat overdoses.
Management of overdose: There is no specific antidote for levetiracetam. Treatment of an overdose will be symptomatic and may include haemodialysis. The dialyzer 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.

Discontinuation: If levetiracetam 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 weighing less than 50 kg: dose decrease should not exceed 10 mg/kg twice daily every two weeks).
Acute Kidney Injury: The use of Levetiracetam has been very rarely associated with acute kidney injury, with a time to onset ranging from a few days to several months.
Blood cell counts: Rare cases of decreased blood cell counts (neutropenia, agranulocytosis, leucopenia, thrombocytopenia and pancytopenia) have been described in association with levetiracetam administration, generally at the beginning of the treatment. Complete blood cell counts are advised in patients experiencing important weakness, pyrexia, recurrent infections or coagulation disorders.
Depression and/or suicidal ideation: 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 sign of depression and/or suicidal ideation or behaviour emerge.
Infusion conc: Potential for an increase in risk of suicidal thoughts or behaviours.
Abnormal and aggressive behaviours: Levetiracetam may cause psychotic symptoms and behavioural abnormalities including irritability and aggressiveness. Patients treated with levetiracetam should be monitored for developing psychiatric signs suggesting important mood and/or personality changes. If such behaviours are noticed, treatment adaptation or gradual discontinuation should be considered.
FC tab: If discontinuation is considered, see Discontinuation as previously mentioned.
Excipients: Infusion conc: This medicinal product contains 2.5 mmol (or 57 mg) sodium per maximum single dose (0.8 mmol (or 19 mg) per vial). To be taken into consideration by patients on a controlled sodium diet.
Effects on Ability to Drive and Use Machines: Levetiracetam has minor or moderate influence on the ability to drive and use machines. 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.
Renal or hepatic impairment: The administration of Levetiracetam to patients with renal impairment may require dose adjustment.
In patients with severely impaired hepatic function, assessment of renal function is recommended before dose selection.
Use in Children: FC tab: The tablet formulation is not adapted for use in children under the age of 6 years. Available data in children did not suggest impact on growth and puberty. However, long term effects on learning, intelligence, growth, endocrine function, puberty and childbearing potential in children remain unknown.
Infusion conc: Long term effects on learning, intelligence, growth, endocrine function, puberty and childbearing potential in children remain unknown.

Women of childbearing potential: Advice should be given to women who are of childbearing potential. Treatment with levetiracetam should be reviewed when a woman is planning to become pregnant. As with all antiepileptic medicines, sudden discontinuation of levetiracetam should be avoided as this may lead to breakthrough seizures that could have serious consequences for the woman and the unborn child. Monotherapy should be preferred whenever possible because therapy with multiple antiepileptic medicines AEDs could be associated with a higher risk of congenital malformations than monotherapy, depending on the associated antiepileptics.
Pregnancy: Levetiracetam can be used during pregnancy, if after careful assessment it is considered clinically needed. In such case, the lowest effective dose is recommended.
Physiological changes during pregnancy may affect levetiracetam concentration. Decrease in levetiracetam plasma concentrations has been observed during pregnancy. Appropriate clinical management of pregnant women treated with levetiracetam should be ensured.
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.
Fertility: No impact on fertility was detected. No clinical data are available, potential risk for human is unknown.

Cases of encephalopathy generally occurred at the beginning of the treatment (few days to a few months) and were reversible after treatment discontinuation. (See Table 6.)

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Infusion conc: Eye disorders: Diplopia, vision blurred (frequency uncommon).
FC tab: Description of selected adverse reactions: The risk of anorexia is higher when Levetiracetam is coadministered 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.

Antiepileptic medicinal products: Levetiracetam did not influence the serum concentrations of existing antiepileptic medicinal products (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone) and that these antiepileptic medicinal products did not influence the pharmacokinetics of Levetiracetam.
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 levetiracetam. Nevertheless, the concentration of this metabolite remains low.
Methotrexate: Concomitant administration of Levetiracetam and methotrexate has been reported to decrease methotrexate clearance, resulting in increased/prolonged blood methotrexate concentration to potentially toxic levels. Blood methotrexate and Levetiracetam levels should be carefully monitored in patients treated concomitantly with the two drugs.
Oral contraceptives and other pharmacokinetics interactions: Levetiracetam 1,000 mg daily did not influence the pharmacokinetics of oral contraceptives (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. Co-administration 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.
FC tab: Laxatives: There have been isolated reports of decreased Levetiracetam efficacy when the osmotic laxative macrogol has been concomitantly administered with Levetiracetam. Therefore, macrogol should not be taken orally for one hour before and for one hour after taking levetiracetam.
Food: The extent of absorption of levetiracetam was not altered by food, but the rate of absorption was slightly reduced.

Incompatibilities: This medicinal product must not be mixed with other medicinal products.
Instruction for Use: FC tab The film-coated tablets must be taken orally, swallowed with a sufficient quantity of liquid and may be taken with or without food. After oral administration the bitter taste of Levetiracetam may be experienced. The daily dose is administered in two equally divided doses.
Infusion conc: Table presents the recommended preparation and administration of levetiracetam concentrate to achieve a total daily dose of 500 mg, 1,000 mg, 2,000 mg, or 3,000 mg in two divided doses. (See Table 7.)

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This medicinal product is for single use only; any unused solution should be discarded. This medicinal product must not be mixed with other medicinal products except those mentioned as follows. Levetiracetam concentrate was found to be physically compatible and chemically stable when mixed with the following diluents for at least 24 hours and stored at controlled room temperature 30°C.
Diluents: Sodium chloride (0.9%) injection; Dextrose 5% injection.
Medicinal products with particulate matter or discoloration should not be used.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Store below 30°C.
Shelf Life: FC tab: 3 years.
Infusion conc: 2 years.
Storage Condition After Dilution: Use within 24 hours, store below 30°C. Balance solution or unused solution should be discarded.

Anticonvulsants

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

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