라코사미드

DEA Schedule V Controlled Substance -> Depressants

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Used in Switzerland

Pharmaceuticals -> Synthetic Cannabinoids or Psychoactive Compounds

Pharmaceuticals -> Antiepileptic

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

This chemical does not meet GHS hazard criteria for 1.5% (1 of 66) of reports.

Danger

H301 (93.9%): Toxic if swallowed [Danger Acute toxicity, oral]

P264, P264+P265, P270, P280, P301+P316, P305+P351+P338, P321, P330, P337+P317, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 66 reports by companies from 8 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

In prelicensure clinical trials, addition of lacosamide to standard anticonvulsant therapy was reported to be associated with ALT elevations above 3 times the upper limit of normal (ULN) in 7 of 935 patients (0.7%) compared to none of 356 treated with placebo. A single case of hepatitis with jaundice during lacosamide therapy was also reported. Since approval, there have been rare isolated reports of clinically apparent liver injury associated with lacosamide used, but the clinical features suggested that hepatic ischemia or other anticonvulsants combined with lacosamide may have been responsible. The onset was within a few days to several months after starting and the presentation was with a hepatocellular pattern of serum enzyme elevations, one case being asymptomatic and mild and the other severe. In both instances, there was rapid recovery.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Lacosamide

Ambiguous-DILI-concern

3

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

N03AX18

N - Nervous system

QN - Nervous system

Lacosamide is an antiepileptic drug with high oral potency, stereoselectivity, and anticonvulsant effects. By blocking sensory neuronal voltage-gated sodium channels that mediate neuropathic pain responses, lacosamide was shown to possess analgesic activity. Lacosamide is a chiral functionalized amino acid. The S-stereoisomer does not exhibit antiepileptic activity.

Caused by neuronal hyperexcitability, seizures in epilepsy involve sustained firing of sodium-dependent action potentials. The slow inactivation process, intrinsic to voltage-gated sodium channel functioning, has been implicated in the paroxysmal depolarizing shifts associated with epileptic activity. The exact mechanism of action of lacosamide is not fully known; however, in vitro electrophysiological studies have shown that lacosamide selectively enhances the slow inactivation of voltage-gated sodium channels, shifting the slow inactivation curve to more hyperpolarized potentials and augmenting the maximal fraction of channels in the slow inactivated state. This results in the stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing. Lacosamide does not affect the fast component of voltage-gated sodium currents, unlike traditional sodium channel blockers.

The elimination half-life of the unchanged drug is approximately 13 hours and is not altered by different doses, multiple dosing or intravenous administration. The major O-desmethyl metabolite of lacosamide has an elimination half-life ranging from 15 to 23 hours).

563KS2PQY5

LACOSAMIDE

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

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

LACOSAMIDE

Decreased Central Nervous System Disorganized Electrical Activity [PE]

Drugs used to prevent SEIZURES or reduce their severity.

A class of drugs that inhibit the activation of VOLTAGE-GATED SODIUM CHANNELS.

Lacosamide is completely absorbed after oral administration with negligible first-pass effect. It has a high absolute bioavailability of approximately 100%. Food does not affect the rate and extent of absorption. The Tmax ranges from one to four hours. Steady-state plasma concentrations are achieved after three days of twice-daily repeated administration. The pharmacokinetics of lacosamide are dose-proportional over the dose range between 100 and 800 mg, and time-invariant, with low inter- and intra-subject variability. The major O-desmethyl metabolite of lacosamide has a longer Tmax that ranges from 0.5 to 12 hours. After intravenous administration, Cmax is reached at the end of infusion. The 30- and 60-minute intravenous infusions are bioequivalent to the oral tablet. For the 15-minute intravenous infusion, bioequivalence was met for AUC0-tz but not for Cmax. The point estimate of Cmax was 20% higher than Cmax for oral tablet and the 90% CI for Cmax exceeded the upper boundary of the bioequivalence range. In a trial comparing the oral tablet with an oral solution containing 10 mg/mL lacosamide, bioequivalence between both formulations was shown. A single loading dose of 200 mg approximates steady-state concentrations comparable to the 100 mg twice-daily oral administration.

Lacosamide is primarily eliminated from the systemic circulation by renal excretion and biotransformation. After oral and intravenous administration of 100 mg radiolabeled lacosamide, approximately 95% of the radioactivity was recovered in the urine and less than 0.5 % in the feces. The major compounds excreted were unchanged lacosamide (approximately 40% of the dose), its O-desmethyl metabolite (approximately 30%), and a structurally unknown polar fraction (~20%).

The volume of distribution is approximately 0.6 L/kg and thus close to the volume of total body water.