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Lacosamide - An Anti Seizure Drug

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In 2009 the U.S. FDA (Federal Drug Administration) approved the use of lacosamide (Vimpat) for adjunctive therapy for partial-onset seizures in patients 17 years of age and older. Moreover, it approved an intravenous (IV) version of the drug when oral administration is not feasible in these same patients. It does not have an approval for its use in status epilepticus, seizure clusters or seizure emergencies. The drug was reviewed by the FDA for its use in diabetic neuropathic pain, but was not approved for this indication. Since that time, lacosamide has rapidly ascended the prescription drug market as a popular choice of medication for epilepsy. In this month’s column we explore this drug lacosamide (Vimpat).

Mechanisms
Similar to almost every other seizure medication currently approved, the mechanism of the antiseizure effect of lacosamide is not fully understood. It is believed that lacosamide impacts its antiseizure effect by enhancing sodium channel slow inactivation. Lacosamide reduces voltage gated sodium channel availability by selective enhancement of slow inactivation without interacting with fast inactivation of the same channel. Slow inactivation of sodium channels is a mechanism by which nerve cells (neurons) reduce electrical stimulation. Therefore, it helps to calm down abnormal excitability of nerve cells. Thus, lacosamide would have a similar yet distinct mechanism to other seizure medications, such as phenytoin, carbamazepine. It does not bind GABA or glutamate or calcium or potassium currents similar to other medications. It also does not have any special receptor binding that has been identified so this makes this agent a chemically different drug. In animal studies the use of lacosamide revealed protection against partial and generalized seizures in several animal models, particularly maximal electroshock induced seizures in mice and rats and hippocampal kindling models.

Pharmacokinetics
Oral lacosamide is bioavailable at 100%. Peak serum levels of the drug are reached one to five hours after oral administration and at the end of an IV dose. Food does not alter the rate or extent of Vimpat absorption. There is bioequivalence between a 200 mg oral version of the medication, as well as IV versions of medications given over 30 to 60 minutes. Lacosamide has low protein binding which has implications for patients on dialysis treatment. After a four hour dialysis session, 50% of the dose must be supplemented following hemodialysis. Lacosamide’s pharmacokinetic profile is linear from 100 to 800 mg dose, which means that as one increases the dose there is a proportional increase in the serum level of the drug in one’s system.
The half life of lacosamide is approximately 13 hours. Steady serum concentrations are reached after three days of twice daily dosing. The drug is eliminated by renal excretion. Forty percent (40%) of this drug is excreted renally as unchanged drug, and about 30% is excreted as a metabolite, and about 20% as an unknown metabolite as well. Its major breakdown product is chemically inactive.

Lacosamide levels increase in patients with mild or moderate renal impairment and in patients with severe renal impairment, one need to adjust the dose appropriately. In patients with liver disease, Vimpat levels may increase from 50 to 60% and therefore doses should be adjusted downward for individuals with mild or moderate liver impairment. In patients age 65 years and older there may be a slight increase in levels by 20% compared to younger patients, This means that lower doses of the medication are needed as compared to a younger aged adult.

Efficacy
The efficacy of lacosamide was established in three 12-week randomized, double-blind, multi-center studied enrolling adult patients. Patients enrolled in these studies exclusively had partial-onset seizures with or without secondary generalization that were not adequately controlled on one to three other antiepileptic drugs. The patient that would typically enroll in these trials tended to have somewhat severe epilepsy, with an average of four or more partial-onset seizures every 28 days, and no seizure-free period exceeding more than 21 days. The studies found that at its best, the median percentage reduction of seizure frequency was 35%; 37.3%; and 39% in the 3 studies. Fifty percent (50%) reduction seizure frequency was achieved in 33%-35% who received 200 mg of the pill; 38.3%-41% with those taking 400 mg. Although lacosamide was tested at doses higher than 400 mg, the FDA approved the drug up to a dose of 400 mg, due to the fact that higher doses produced more side effects than benefits.

IV lacosamide was also trialed in a randomized, double-blind study with 60 patients. The IV version of the drug was consistent with the oral drug and seizure rates were similar to what was observed with the oral form. The drug was infused over 30 minutes in 40 patients; 50 minutes in 100 patients; and 10 minute in 20 patients. Adverse reactions did not differ with varying administration times; however, the drug was approved to a maximum drug infusion of 300 mg over 30-60 minutes.

Side Effects
Lacosamide’s most common adverse effects include dizziness, ataxia or syncope. Dizziness occurred in 25% of patients receiving lacosamide as add-on therapy. Ataxia, or gait disturbance, was experienced by 6% who were receiving lacosamide. Dizziness and ataxia were observed while the drug was being initiated. Episodes of syncope were reported in individuals with diabetic neuropathy. There also appears to be no clear abnormalities related to psychiatric , mood or behavioral issues related to use of the medicationsThere is a small but measurable cardiac effect with the use of lacosamide. A dose-dependent PR interval prolongation has been observed in association with lacosamide. Caution is advised for patients who have a known cardiac conduction problem, such as first degree AV block, second degree or higher AV block, or sick sinus syndrome without a pacemaker. Patients with myocardial disease or heart failure and patients taking other drugs known to impact PR interval should obtain an EKG while taking this drug.

Lacosamide is considered a pregnancy category C drug. Teratogenic effects have not been observed in humans, however, lacosamide was associated with increased embryo, fetal, and perinatal mortality in growth, of rats following administration during pregnancy. Developmental neural toxicity was also observed following exposure during a period of postnatal development corresponding to a third trimester of a human pregnancy. Because Vimpat may have some impact on the CRNP- 2 receptor- an important receptor for fetal central nervous system development, potential adverse reactions on central nervous system development have not been ruled out. Lacosamide should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.
Lacosamide and its metabolites are excreted in the milk of lactating rats. It is not known whether lacosamide is excreted in human milk. Thus, lacosamide should not be used in mothers who are breastfeeding.

Drug Interactions
Lacosamide does not induce hepatic enzymes. Therefore, lacosamide does not have any drug interactions associated with the use of other seizure medications. It does also not have any interactions with oral contraceptives, cardiac, antihypertensives, or antibiotics.

Dosing
Lacosamide therapy can be started orally at an initial dose of 50 mg twice daily. This can be increased based on tolerability by up to 100 mg per day in two divided doses on a daily basis. It is important to note that with lacosamide, the faster that one increases the dose of the drug the more likely one is to encounter side effects. This is important in older adults and other individuals who are sensitive to medication. Thus the adage of going “slow and low” when dosing the older adults is vital in order to maximize tolerability.
Lacosamide can be taken with or without food. Its maximum dosage should be 400 mg, although higher than 400 mg can be used if the physician feels that the benefits of the increased dose outweigh the risks of side effects.

Summary
Lacosamide is a unique medication for individuals with uncontrolled partial seizures. Its primary advantages include the fact that it has no drug interactions, is dosed twice a day, and it effective. The drug appears to work in a manner similar yet distinct to phenytoin and carbamazepine. The drug has an IV formulation, therefore it might be useful in emergency situations; but again, it has not been approved for use in this condition.


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