Epitech

Epitech

levetiracetam

Manufacturer:

Global Pharmatech

Distributor:

Averroes Pharma
Full Prescribing Info
Contents
Levetiracetam.
Description
Each mL concentrate for solution for infusion contains: Levetiracetam Ph. Eur. 500mg, Water for injections q.s to 5mL.
Action
Therapeutic category: Anticonvulsant. ATC Code: N03AX14.
Pharmacology:
Pharmacodynamics: The drug binds to a synaptic vesicle glycoprotein, and inhibits presynaptic calcium channels reducing neurotransmitter release and acting as a neuromodulator. This is believed to impede impulse conduction across synapses.
Pharmacokinetics: Absorption: Levetiracetam is rapidly and almost completely absorbed after oral administration. Levetiracetam injection and tablets are bioequivalent. The pharmacokinetics of levetiracetam are linear and time-invariant, with low intra-and inter-subject variability.
Distribution: 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.
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. Two minor metabolites were identified as the product of hydroxylation of the 2-oxo-pyrrolidine ring (2% of dose) and opening of the 2-oxo-pyrrolidine ring in position 5 (1% of dose). There is no enantiomeric interconversion of levetiracetam or its major metabolite.
Excretion: Levetiracetam is eliminated from the body primarily by the kidneys with about 66 percent of the original drug passed unchanged into urine. The plasma half-life of levetiracetam in adults is about 6 to 8 hours.
Toxicology: Preclinical Safety Data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenicity.
Adverse effects not observed in clinical studies but seen in the rat and to a lesser extent in the mouse at exposure levels similar to human exposure levels and with possible relevance for clinical use were liver changes, indicating an adaptive response such as increased weight and centrilobular hypertrophy, fatty infiltration and increased liver enzymes in plasma.
No adverse effects on male or female fertility or reproduction performance were observed in rats at doses up to 1800 mg/kg/day (x 6 the MRHD on a mg/m2 or exposure basis) in parents and F1 generation.
Two embryo-fetal development (EFD) studies were performed in rats at 400, 1200 and 3600 mg/kg/day. At 3600 mg/kg/day, in only one of the 2 EFD studies, there was a slight decrease in fetal weight associated with a marginal increase in skeletal variations/minor anomalies. There was no effect on embryomortality and no increased incidence of malformations. The NOAEL (No Observed Adverse Effect Level) was 3600 mg/kg/day for pregnant female rats (x 12 the MRHD on a mg/m2 basis) and 1200 mg/kg/day for fetuses.
Four embryo-fetal development studies were performed in rabbits covering doses of 200, 600, 800, 1200 and 1800 mg/kg/day. The dose level of 1800 mg/kg/day induced a marked maternal toxicity and a decrease in fetal weight associated with increased incidence of fetuses with cardiovascular/skeletal anomalies. The NOAEL was <200 mg/kg/day for the dams and 200 mg/kg/day for the fetuses (equal to the MRHD on a mg/m2 basis).
A peri- and post-natal development study was performed in rats with levetiracetam doses of 70, 350 and 1800 mg/kg/day. The NOAEL was ≥ 1800 mg/kg/day for the F0 females, and for the survival, growth and development of the F1 offspring up to weaning (x 6 the MRHD on a mg/m2 basis).
Neonatal and juvenile animal studies in rats and dogs demonstrated that there were no adverse effects seen in any of the standard developmental or maturation endpoints at doses up to 1800 mg/kg/day (x 6-17 the MRHD on a mg/m2 basis).
Indications/Uses
Levetiracetam Injection is indicated as monotherapy in the treatment of partial onset seizures with or without secondary generalisation and adolescents from 16 years of age with newly diagnosed epilepsy. Levetiracetam injection is indicated as adjunctive therapy: a) In the treatment of partial onset seizures with or without secondary generalisation in adults, adolescents and children from 4 years of age with epilepsy.
b) In the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy.
c) In the treatment of primary generalised tonic-clonic seizures in adults and adolescents from 12 years of age with Idiopathic Generalised Epilepsy.
d) Levetiracetam injection concentrate is an alternative for patients (adults and children from 4 years of age) when oral administration is temporarily not feasible.
Dosage/Direction for Use
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 should be maintained.
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.
Duration of treatment: There is no experience with administration of intravenous levetiracetam for longer period than 4 days.
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 weighting less than 50 kg: dose decrease should not exceed 10 mg/kg twice daily every two weeks).
Special populations: Elderly (65 years and older): Adjustment of the dose is recommended in elderly patients with compromised renal function (see "Renal impairment" as follows).
Renal impairment: The daily dose must be individualised according to renal function.
For adult patients, refer to the table as follows 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 adolescents patients weighing more than 50 kg with impaired renal function: (see Table 1).

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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 2).

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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.
Paediatric population: The physician should prescribe the most appropriate pharmaceutical form, presentation and strength according to age, weight and dose.
Monotherapy: The safety and efficacy of Levetiracetam in children below and adolescents 16 years as monotherapy treatment have not been established.
No data are available.
Add-on therapy for children aged 4 to 11 years and adolescents (12 to 17 years) weighing less than 50 kg: The initial therapeutic dose is 10 mg/kg twice daily.
Depending upon the clinical response and tolerability, the dose can be increased up to 30 mg/kg twice daily. Dose changes should not exceed increases or decreases of 10 mg/kg twice daily every two weeks. The lowest effective dose should be used.
Dose in children 50 kg or greater is the same as in adults: Dose recommendations for children and adolescents: (see Table 3.)

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Add-on therapy for infants and children less than 4 years: The safety and efficacy of Levetiracetam concentrate for solution for infusion in infants and children less than 4 years have not been established.
Route of Administration: Levetiracetam concentrate is for intravenous use only and the recommended dose must be diluted in at least 100 ml of a compatible diluent and administered intravenously as a 15-minute intravenous infusion.
Overdosage
Symptoms: Somnolence, agitation, aggression, depressed level of consciousness; respiratory depression and coma were observed with levetiracetam overdoses.
Management of Overdose: 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.
Contraindications
Hypersensitivity to levetiracetam, other pyrrolidone derivative or any other excipient of the formulation.
Special Precautions
Behavioral Abnormalities and Psychotic Symptoms: Levetiracetam may cause behavioural abnormalities and psychotic symptoms and should be monitored for psychiatric signs and symptoms.
Behavioral abnormalities: Studies showed that levetiracetam-treated patients experienced non-psychotic behavioral symptoms like aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, hyperkinesia, irritability, nervousness, neurosis, and personality disorder. The result of a randomized, double-blind, placebo-controlled study using Levetiracetam in paediatric patients of 4 to 16 years of age indicated a worsening of the aggressive behaviour. In clinical studies in paediatric patients 1 month to < 4 years of age, irritability was reported.
Psychotic Symptoms: Studies indicate 1% of levetiracetam-treated adult patients, 2% of levetiracetam-treated paediatric patients 4 to 16 years of age, and 17% of levetiracetam-treated pediatric patients 1 month to <4 years of age experienced psychotic symptoms. Patients also experienced paranoia and confusional state. Adult patients were hospitalized, and their treatment was discontinued due to psychosis.
Acute Kidney Injury: The use of Levetiracetam has been rarely associated with acute kidney injury, with a time to onset ranging from a few days to several months.
Somnolence and Fatigue and Coordination Difficulties: Levetiracetam may cause somnolence and fatigue most frequently within the first 4 weeks of treatment. Patients should be monitored for signs and symptoms of coordination difficulties. In such cases, the patient should be advised not to drive or operate machinery when under treatment.
Serious Dermatological Reactions: Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in both pediatric and adult patients treated with levetiracetam. The median time of onset is reported to be 14 to 17 days, but cases have been reported at least four months after initiation of treatment. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.
Withdrawal Seizures: Antiepileptic drugs, including levetiracetam, should be withdrawn gradually to minimize the potential of increased seizure frequency.
Hematologic Abnormalities: Levetiracetam can cause hematologic abnormalities which includes decreases in red blood cells count (RBC), haemoglobin, and haematocrit, and increases in eosinophil counts. Decreased white blood cells count (WBC) and neutrophil counts also occurred and cases of agranulocytosis have been reported.
Increase in Blood Pressure: Studies in levetiracetam treated patients 1 month to <4 years of age a significantly higher risk of increased diastolic blood pressure was observed (17%), compared to placebo-treated patients (2%). This disparity between the levetiracetam and placebo treatment groups was not observed in the studies of older children or in adults. Hence it is necessary to monitor patients 1 month to <4 years of age for increases in diastolic blood pressure.
Seizure Control During Pregnancy: Physiological changes may gradually decrease plasma levels of levetiracetam throughout pregnancy. This decrease is more pronounced during the third trimester. It is recommended that patients be monitored carefully during pregnancy and continue through the postpartum period especially if the dose was changed during pregnancy.
Effects on Ability to Drive and Use Machine: 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.
Use In Pregnancy & Lactation
Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. In animal studies, levetiracetam produced evidence of developmental toxicity, including teratogenic effects, at doses similar to or greater than human therapeutic doses. Hence levetiracetam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery: The effect of levetiracetam on labor and delivery in humans is unknown.
Nursing Mothers: Levetiracetam is excreted in human 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.
Side Effects
The most frequently reported adverse reactions were nasopharyngitis, somnolence, headache, fatigue and dizziness.
Tabulated list of adverse reactions: Adverse reactions reported in clinical studies (adults, adolescents, children and infants > 1 month) and from post-marketing experience are listed in the following table per System Organ Class and per frequency. Adverse reactions are presented in the order of decreasing seriousness and their frequency is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000). (See Table 4).

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Cases of encephalopathy have been rarely observed after levetiracetam administration. These undesirable effects generally occurred at the beginning of the treatment (few days to a few months) and were reversible after treatment discontinuation.
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.
Drug Interactions
Levetiracetam circulates largely unbound (<10% bound) to plasma proteins; clinically significant interactions with other drugs through competition for protein binding sites are therefore unlikely. Potential pharmacokinetic interactions were assessed with phenytoin, valproate, oral contraceptive, digoxin, warfarin, probenecid.
Phenytoin: Levetiracetam (3000 mg daily) had no effect on the pharmacokinetic disposition of phenytoin in patients with refractory epilepsy. Pharmacokinetics of levetiracetam was also not affected by phenytoin.
Valproate: Levetiracetam (1500 mg twice daily) did not alter the pharmacokinetics of valproate in healthy volunteers. Valproate 500 mg twice daily did not modify the rate or extent of levetiracetam absorption or its plasma clearance or urinary excretion.
Other Antiepileptic Drugs: Potential drug interactions between Levetiracetam and other AEDs (carbamazepine, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone and valproate) were studied and found that levetiracetam does not influence the plasma concentration of other AEDs and that these AEDs do not influence the pharmacokinetics of levetiracetam.
Oral Contraceptives: Levetiracetam (500 mg twice daily) did not influence the pharmacokinetics of an oral contraceptive containing 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel, or of the luteinizing hormone and progesterone levels, indicating that impairment of contraceptive efficacy is unlikely. Coadministration of this oral contraceptive did not influence the pharmacokinetics of levetiracetam.
Digoxin: Levetiracetam (1000 mg twice daily) did not influence the pharmacokinetics and pharmacodynamics (ECG) of digoxin given as a 0.25 mg dose every day. Coadministration of digoxin did not influence the pharmacokinetics of levetiracetam.
Warfarin: Levetiracetam (1000 mg twice daily) did not influence the pharmacokinetics of R and S warfarin. Prothrombin time was not affected by levetiracetam. Coadministration of warfarin did not affect the pharmacokinetics of levetiracetam.
Probenecid: Probenecid administered at a dose of 500 mg four times a day, did not change the pharmacokinetics of levetiracetam 1000 mg twice daily.
Caution For Usage
Instructions for Use: 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 should be maintained.
Levetiracetam injection concentrate is for intravenous use only and the recommended dose must be diluted in at least 100 ml of a compatible diluent and administered intravenously as a 15-minute intravenous infusion.
Compatibility and Stability: From a microbiological point of view, the product should be used immediately after dilution. If not used immediately, in-use storage time and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions
Chemical and physical in-use stability and compatibility of Levetiracetam 100mg/ml concentrate for solution for infusion when diluted with 0.9% sodium chloride, 5% dextrose or Hartmann's (Ringer's lactate) solution has been demonstrated for 24h at 25°C when stored in PVC bags or PP bottles. Do not use if the product shows signs of deterioration such as discolouration.
Storage
Store below 30 C. Do not freeze. For single use only. Discard unused portion. Product with particulate matter or discoloration should not be used.
Shelf-Life: 24 Months from the date of manufacturing.
MIMS Class
ATC Classification
N03AX14 - levetiracetam ; Belongs to the class of other antiepileptics.
Presentation/Packing
Infusion conc (vial) 100 mg/mL (clear colourless transparent solution) x 5 mL.
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