レベチラセタム

Pharmaceuticals -> Used in Switzerland

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Antiepileptic

Crystals from ethyl acetate

White to off-white crystalline powder

104g/100mL

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/mL), soluble in ethanol (16.5 g/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)

Breast Feeding; Lactation; Milk, Human; Anticonvulsants

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

115-119C

117 °C

This chemical does not meet GHS hazard criteria for 1.7% (2 of 119) of reports.

Warning

H302 (89.1%): Harmful if swallowed [Warning Acute toxicity, oral]

P264, P264+P265, P270, P280, P301+P317, P305+P351+P338, P330, P337+P317, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 119 reports by companies from 12 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl levetiracetam, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

There is no specific antidote for overdose with Levetiracetam. If indicated, elimination of unabsorbed drug should be attempted by emesis or gastric lavage; usual precautions should be observed to maintain airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the patient's clinical status.

No interaction between probenecid and levetiracetam was observed; however, probenecid decreased the renal clearance of ucb L057 (inactive metabolite of levetiracetam) by 60%.

/Levetiracetam/ had no effect on the pharmacokinetic disposition of phenytoin in patients with refractory epilepsy. Pharmacokinetics of levetiracetam were also not affected by phenytoin.

Levetiracetam 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. There also was no effect on exposure to and the excretion of the primary metabolite, ucb L057. Potential drug interactions between /levetiracetam/ and other Antiepileptic Drugs (AEDs) (carbamazepine, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone and valproate) were also assessed by evaluating the serum concentrations of levetiracetam and these AEDs during placebo-controlled clinical studies. These data indicate that levetiracetam does not influence the plasma concentration of other AEDs and that these AEDs do not influence the pharmacokinetics of levetiracetam.

/Levetiracetam/ 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.

For more Interactions (Complete) data for LEVETIRACETAM (7 total), please visit the HSDB record page.

Prospective studies reported that chronic levetiracetam therapy was not accompanied by significant elevations in serum aminotransferase levels and clinically apparent liver injury was not observed. Since its approval for use and wide spread availability, however, levetiracetam has been linked to rare instances of serum enzyme elevations and occasional cases of clinically apparent liver injury. The time to onset of liver injury after starting levetiracetam has ranged from 1 week to 5 months and the usual pattern of injury has been hepatocellular. Immunoallergic features and autoantibodies were rare. At least one case of acute liver failure attributed to levetiracetam has been published, but the number of reported cases clinically apparent cases of liver injury has been few. In addition, levetiracetam is usually considered a reasonable alternative therapy in patients who develop anticonvulsant hypersensitivity (DRESS) syndrome after aromatic anticonvulsant use despite the fact that it has been implicated in rare instances of DRESS and Stevens Johnson syndrome.

Central nervous system (CNS): Most common adverse effects are neurobehavioral, like sedation, fatigue, mood swings, headache, agitation, irritability, aggression, depression, memory loss, confusion, paresthesia, a decline in cognition, and increased suicide risk. Most of the time, the side effects are mild. About 1% of patients experience serious side effects like psychosis, hallucinations, and suicidal thoughts. These side effects are more common in the first month of treatment but can develop during treatment and improve once the drug is discontinued. Dose reduction is associated with improvement in behavioral problems. A systematic review suggests that pyridoxine supplementation might be of benefit in relieving levetiracetam-induced neuropsychiatric adverse events.

To study the pharmacokinetics of levetiracetam (LEV) at birth, during lactation, and in the nursed infant. Eight consecutive breast-feeding women with epilepsy treated with LEV twice daily and their infants were studied. The mean umbilical cord serum/maternal serum ratio was 1.14 (range, 0.97-1.45) (n = 4). The mean milk/maternal serum concentration ratio was 1.00 (range, 0.76-1.33) at 3 to 5 days after delivery (n = 7). At sampling 2 weeks to 10 months after delivery (n = 5), it was similar (range, 0.85-1.38). At 3 to 5 days after delivery, the infants had very low LEV serum concentrations (<10-15 microM), a finding that persisted during continued breast-feeding. ...

Levetiracetam is distributed into milk.

There are few known cases of overdose with levetiracetam in clinical trials. Drowsiness, somnolence, agitation, respiratory depression, and coma have been observed with levetiracetam overdose. There is no antidote for levetiracetam. General supportive measures, airway protection, and monitoring of vital signs are done on overdose patients. Clinicians should contact poison control. Hemodialysis may be needed in patients with significant renal impairment. A four-hour hemodialysis session can remove almost 50% of the drug.

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. Levetiracetam is thought to stimulate synaptic vesicle protein 2A (SV2A), inhibiting neurotransmitter release.

/SIGNS AND SYMPTOMS/ Other than drowsiness, there were no adverse events in the few known cases of overdose in clinical trials. Cases of somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with /levetiracetam/ overdoses in postmarketing use.

/CASE REPORTS/ A twelve year-old-girl with idiopathic partial epilepsy with secondary generalization, developed acute psychosis 10 days after the administration of levetiracetam. The patient was already on sodium valproate, and levetiracetam was given as add on therapy. A final dosage of 60 mg/kg was used. Complete seizure control was achieved but the patient developed hallucinations, agitation and self-harming behavior, as well as poor social contact. The psychotic behavior resolved completely soon after the discontinuation of levetiracetam.

/CASE REPORTS/ I In two patients Levetiracetam (LEV) was initiated to control refractory complex partial seizures (CPS). The first patient was treated with 1500 mg/day and complained of abdominal pain and weight loss 6 months later. Internal examination and colonoscopy revealed a punctate colitis. The second patient presented with bloody stool 1 month after LEV initiation. Colonoscopy showed punctate colitis. In both patients gastrointestinal symptoms disappeared following tapering of LEV. Three possible mechanisms of action are discussed. Colitis may be part of a hypersensitivity syndrome caused by LEV. Pharmacodynamic interactions with other anti-epileptic drugs, for example, carbamazepine may play a role. ...

/CASE REPORTS/ /Investigators/ report here the case of a 43-year-old woman who developed symptoms compatible with catatonia after being exposed to levetiracetam for the treatment of epilepsy. /Investigators/ review the difficulties that may be encountered in the differential diagnosis of medical catatonia.

For more Human Toxicity Excerpts (Complete) data for LEVETIRACETAM (8 total), please visit the HSDB record page.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Levetiracetam

vLess-DILI-concern

8

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl levetiracetam, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

N03AX14

N - Nervous system

QN - Nervous system

N03AX14

Levetiracetam appears to prevent seizure activity via the selective inhibition of hypersynchronized epileptiform burst firing without affecting normal neuronal transmission, though the exact mechanism through which this occurs is unclear. The therapeutic index of levetiracetam is wide, making it relatively unique amongst other anti-epileptic medications. Anti-epileptic drugs, including levetiracetam, may increase the risk of suicidal ideation or behaviour - patients taking levetiracetam should be monitored for the emergence or worsening of depressive symptoms, suicidal ideation, and behavioural abnormalities.

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 CNS - 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. Levetiracetam has also been shown to indirectly affect GABAergic neurotransmission (despite having no direct effect on GABAergic or glutamatergic receptors) and modulate ionic currents. Similarly, levetiracetam has been shown in vitro to inhibit N-type calcium channels. How, or even if, these actions are implicated in its anti-epileptic action have yet to be elucidated.

The precise mechanism 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 hypersynchronization of epileptiform burst firing and propagation of seizure activity.

Levetiracetam at concentrations of up to 10 muM did not demonstrate binding affinity for a variety of known receptors, such as those associated with benzodiazepines, GABA (gammaaminobutyric 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 levetiractem opposes the activity of negative modulators of GABA- and glycine-gated currents and partially inhibits N-type calcium currents in neuronal cells.

A saturable and stereoselective neuronal binding site in rat brain tissue has been described for levetiracetam. Experimental data indicate that this binding site is the synaptic vesicle protein SV2A, thought to be involved in the regulation of vesicle exocytosis. Although the molecular significance of levetiracetam binding to synaptic vesicle protein SV2A is not understood, levetiracetam and related analogs showed a rank order of affinity for SV2A which correlated with the potency of their antiseizure activity in audiogenic seizure-prone mice. These findings suggest that the interaction of levetiracetam with the SV2A protein may contribute to the antiepileptic mechanism of action of the drug.

For more Mechanism of Action (Complete) data for LEVETIRACETAM (6 total), please visit the HSDB record page.

The plasma half-life of levetiracetam is 6-8 hours and is not affected by dose or repeat administration. Half-life is increased in the elderly (by about 40%) and those with renal impairment.

... The plasma elimination half-life of the unchanged drug varied between 7.4 hr and 7.9 hr. ...

Levetiracetam plasma half-life in adults is 7 +/-1 hour and is unaffected by either dose or repeated administration.

Levetiracetam is minimally metabolized within the body - the major metabolic pathway appears to be the enzymatic hydrolysis of its acetamide group which produces an inactive carboxylic acid metabolite, L057, which accounts for approximately 24% of the total administered dose. The specific enzyme(s) responsible for this reaction are unclear, but this pathway is known to be independent of hepatic CYP enzymes and has been proposed to be driven primarily by type B esterases in the blood and other tissues. Two minor metabolites involving modifications to the pyrrolidone ring have been identified, one involving hydroxylation of the ring (constituting 1.6% of the total dose) and the other involving opening of the ring structure (constituting 0.9% of the total dose).

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-oxo-pyrrolidine ring in position 5 (1% of dose). There is no enantiomeric interconversion of levetiracetam or its major metabolite.

The major metabolic pathway of levetiracetam (24% of dose) is an enzymatic hydrolysis of the acetamide group. No CYP450 metabolism detected. Route of Elimination: Sixty-six percent (66%) of the dose is renally excreted unchanged. The metabolites have no known pharmacological activity and are renally excreted. The mechanism of excretion is glomerular filtration with subsequent partial tubular reabsorption. Half Life: 6-8 hours

44YRR34555

LEVETIRACETAM

Physiologic Effects [PE] - Decreased Central Nervous System Disorganized Electrical Activity

The physiologic effect of levetiracetam is by means of Decreased Central Nervous System Disorganized Electrical Activity.

LEVETIRACETAM

Decreased Central Nervous System Disorganized Electrical Activity [PE]

Drugs used to prevent SEIZURES or reduce their severity.

Drugs used to specifically facilitate learning or memory, particularly to prevent the cognitive deficits associated with dementias. These drugs act by a variety of mechanisms.

Levetiracetam is rapidly and nearly completely absorbed following oral administration, with a reported absolute oral bioavailability of essentially 100%. Tmax is approximately 1.3 hours after dosing, and Cmax is 31 μg/mL following a single 1000mg dose and 43 μg/mL following repeated dosing. Co-administration of levetiracetam with food delays Tmax by approximately 1.5 hours and decreases Cmax by 20%.

Approximately 66% of the administered dose of levetiracetam is excreted in the urine as unchanged drug, while only 0.3% of the total dose is excreted via the feces. The primary inactive metabolite of levetiracetam, L057, is also found in the urine as approximately 24% of the administered dose.

The volume of distribution of levetiracetam is approximately 0.5 to 0.7 L/kg.

The total plasma clearance of levetiracetam is 0.96 mL/min/kg, with renal clearance comprising 0.6 mL/min/kg. The primary inactive metabolite of levetiracetam, L057, has a renal clearance of 4 mL/min/kg. Given the relatively high proportion of drug undergoing renal clearance, overall clearance of levetiracetam is reduced in patients with renal impairment.

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 C max by 20% and delays T max 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.

MEDICATION

THERAP CAT: Anticonvulsant

Use (kg) in Switzerland (2009): >2500

Used as adjunctive therapy in the treatment of partial onset seizures in adults and children 4 years of age and older with epilepsy.