Lacosamide for Partial-Onset Seizures in Epilepsy

Overview

The drug is indicated for treating partial-onset seizures (an uncontrollable electrical activity in the brain cells) in epilepsy (disrupted brain nerve cell activity), a condition that affects only one part of the brain in adults and children of one year of age or older. Lacosamide is an anticonvulsant class of drugs that helps relieve abnormal electrical activity in the brain (seizures). The drug was approved by the United States Food and Drug Administration (US FDA) in October 2008 for treating partial-onset seizures in epilepsy. The drug can also be used along with other medications to treat various types of seizures.

Indications

• Partial-onset seizures.

• Grand mal or generalized tonic-clonic seizures.

Dose Form and Strength

• Tablets - 50 mg (milligrams), 100 mg, 150 mg, and 200 mg.

• Injections - 200 mg per 100 mL (milliliters).

• Oral Solution - 10 mg per mL.

For Patients:

What Is Lacosamide Prescribed For?

Lacosamide is prescribed for the treatment of partial-onset seizures (that affect only one part of the brain) in adults and children one month and older. The medication is also prescribed in combination with other drugs for treating grand mal or generalized tonic-clonic seizures (that affect the entire body) in adults and children four years and older.

How Should the Drug Be Used?

Lacosamide is available in table form or as an oral solution (liquid) to be taken through the mouth two times a day with or without food. The medication should be taken at fixed times every day. Also, one must follow the label instructions and ask the doctor or pharmacist if they do not understand any part of the prescription.

The drug should be taken exactly as prescribed by the doctor. The drug dosage, frequency, and duration of the treatment should not be changed without consulting the doctor.

The medication must be swallowed whole and should not be crushed or split.

If a person takes an oral solution of Lacosamide, they must use an oral syringe or measuring spoon to correctly measure the amount of solution needed for each drug dosage. Household regular spoons should not be used. If a person uses a gastric or nasogastric tube, the pharmacist or the doctor will explain how to take the medication.

The patient is initially started with a low dose of the drug, and later, the dose is increased, but not more than once a week.

The drug does not cure the condition but can only control it. Therefore, it will take a few weeks or even more to see the effects of the medication. Thus, one should continue taking the drug even after feeling well. The medication should not be stopped without consulting the doctor and also if one experiences any symptoms of side effects, such as mood or behavior change. If one stops the drug suddenly, seizures may start occurring frequently, and the doctor may decrease the drug dosage gradually.

What Precautions Are Needed Before Taking Lacosamide?

• One must inform the doctor if they are allergic to Lacosamide, its ingredients, or any other medication.

• The doctor should also be informed about all the prescription and non-prescription drugs that one is taking, including nutritional supplements, herbal products, and vitamins. The doctor may need to adjust the drug dosage or monitor the patient for side effects.

• If one is pregnant, planning to conceive, or gets pregnant while taking this drug, the doctor must be informed.

• If one is breastfeeding, one must also inform the doctor, as Lacosamide can cause some side effects in breastfed babies, such as sleepiness, as it gets excreted in the breast milk. Also, report to the doctor immediately.

• The doctor must also be informed about any history of medical conditions, such as suicidal thoughts, mood-related problems, depression, irregular heartbeat, heart failure, heart attack, pacemaker, diabetic neuropathy (nerve damage due to diabetes), or liver and kidney disease. The doctor must also be informed if one has or ever has overconsumed alcohol, overused prescription drugs, or overused any street drug.

• The drug may also cause dizziness, drowsiness, problems with balance and coordination, and blurred vision; therefore, one must avoid driving vehicles and operating heavy machinery while taking this drug.

• The drug may also affect the person’s mental health or make them suicidal (thoughts of killing or harming oneself or planning such things). The risks are associated with both taking the drug and also stopping the drug without treating the condition. Therefore, one must discuss with the healthcare provider if the risks are more with taking the drug or not taking the medication. Also, the family members or caregivers must contact the doctor immediately if the person experiences any symptoms, such as agitation, panic attacks, or restlessness.

• Additionally, one must also know that phenylketonuria, an inherited condition affecting intellectual abilities, requires a special diet to prevent brain damage. The oral solution of Lacosamide contains aspartame, which leads to the formation of Phenylalanine, which causes phenylketonuria.

What Are the Side Effects of Lacosamide?

Common Side Effects:

• Diarrhea.

• Headache.

• Nausea.

• Dizziness.

• Weakness.

• Vomiting.

• Blurred vision.

• Double visible.

• Drowsiness.

• Itching.

• Uncontrolled eye movements.

• Problems with balance, coordination, and walking.

Serious Side Effects:

• Shortness of breath.

• Fainting.

• Rash.

• Fever.

• Dark urine.

• Tiredness.

• Chest pain.

• Slow heartbeat.

• Tiredness.

• Fast heartbeat or pulse.

• Skin or eye yellowing.

• Swelling in the throat, tongue, eyes, lips, and face.

Dosage and Administration

1. For Partial-Onset Seizures: Adults (17 Years and Older)

Initial Dosage:

• Monotherapy: 100 mg (milligrams) twice daily (200 mg per day).

• Adjunctive Therapy: 50 mg twice daily (100 mg per day).

Titration Regime: Increase by 50 mg twice daily (100 mg daily) weekly.

Maintenance Dose:

• Monotherapy: 150 to 200 mg twice daily (300 to 400 mg daily).

• Adjunctive Therapy: 100 to 200 mg twice daily (200 to 400 mg daily).

2. For Pediatric Patients Weighing at Least 50 KG or Kilograms (110.23 Pounds):

Initial Dose: 50 mg (milligrams) twice daily (100 mg daily).

Titration Regime: Increase by 50 mg twice daily (100 mg daily) weekly.

Maintenance Dose:

• Monotherapy: 150 to 200 mg twice daily (300 to 400 mg daily).

• Adjunctive Therapy: 100 to 200 mg twice daily (200 to 400 mg daily).

3. Pediatric Patients Weighing 30 KG (66.1 Pounds) to Less Than 50 KG (110.23 Pounds):

Initial Dose: 1 mg/kg (milligrams per kilogram) twice daily (2 mg/kg/day).

Titration Regime: Increase by 1 mg/kg twice daily (2 mg/kg/day) weekly.

Maintenance Dose: 2 mg/kg to 4 mg/kg twice daily (4 to 8 mg/kg/day).

4. Pediatric Patients Weighing 11 KG to Less Than 30 KG and Pediatric Patients Weighing 6 KG to Less Than 11 KG:

Initial Dose: 1 mg/kg (milligrams per kilogram) twice daily (2 mg/kg/day).

Titration Regime: Increase by 1 mg/kg twice daily (2 mg/kg/day) weekly.

Maintenance Dose: 3 mg/kg to 6 mg/kg twice daily (6 to 12 mg/kg/day).

5. Pediatric Patients Weighing Less Than 6 KG

Initial Dose:

• Intravenous: 0.66 mg/kg (milligrams per kilogram) thrice daily (2 mg/kg/day).

• Oral: 1 mg/kg twice daily (2 mg/kg/day).

Titration Regime:

• Intravenous: Increase by 0.66 mg/kg (milligrams per kilogram) three times daily (2 mg/kg/day) weekly.

• Oral: Increase by 1 mg/kg twice daily (2 mg/kg/day) weekly.

Maintenance Dose:

• Intravenous: 2.5 mg/kg (milligrams per kilogram) to 5 mg/kg three times daily (7.5 to 15 mg/kg/day).

• Oral: 3.75 to 7.5 mg/kg twice daily (7.5 to 15 mg/kg/day).

Missed Dose:

In case one misses the drug dosage, it should be taken as soon as one remembers it. However, if it is already time to take the following regular drug dosage, then one must skip the missed dose and continue with the next one. Do not take a double drug dosage to compensate for the missed one.

Overdose

In case of an overdose of the drug, the nearest poison control department must be contacted. If the person collapses, has seizures, or has trouble breathing, emergency medical help must be called.

Storage and Disposal

The drug must be kept away from children in an airtight container. It should be stored at a room temperature of 20 to 25 degrees Celsius (68 to 77 degrees Fahrenheit), with excursions permitted between 15 and 30 degrees Celsius (59 to 86 degrees Fahrenheit).

The oral solution of Lacosamide must not be frozen, and the unused solution should be discarded six months after opening the bottle.

Unneeded or expired medication should be discarded safely to prevent accidental consumption by the children or pets, but it should be flushed down into the toilets. The drug should be disposed of by contacting the nearest local garbage or recycling authority or by contacting the local pharmacist to discard the drug through a take-back program. However, if one cannot access the take-back program, they can discard the drug by following FDA protocols and guidelines for safe drug disposal.

For Doctors:

Clinical Pharmacology

Mechanism of Action

The mechanism by which Lacosamide exerts antiepileptic effects in humans remains to be fully elucidated. The drug also binds to CRMP-2 (collapsin response mediator protein-2), a phosphoprotein primarily expressed in the nervous system and involved in controlling axonal outgrowth and neuronal differentiation. However, the role of CRMP-2 binding is unknown in seizure control.

Pharmacodynamics

A pharmacokinetic-pharmacodynamic (efficacy) analysis was performed based on the pooled data from the three efficacy trials for partial-onset seizures. Drug exposure is correlated with a reduction in seizure frequency. However, drug dosages above 400 mg/day (milligrams per day) do not grant any additional benefit in group analyses.

Pharmacokinetics

• Absorption—Following oral administration, the drug is completely absorbed in the negligible first-pass effect, showing an absolute bioavailability of about 100 percent. The extent and rate of absorption do not affect the drug.

The maximum serum concentration is reached at the end of the infusion following intravenous or into-the-vein (IV) administration. An infusion of 30 to 60 minutes is bioequivalent to tablets (oral).

• Distribution - The drug's distribution volume is 0.6 liters per kilogram (L/kg), and it is less than 15 percent bound to plasma protein.

• Metabolism - The drug gets metabolized by CYP3A4, CYP2C9, and CYP2C19 to form O-desmethyl lacosamide, an inactive metabolite in humans. There is no enantiomeric interconversion of the drug.

• Elimination - The drug gets excreted from the systemic circulation by biotransformation or renal excretion. Following oral and intravenous administration of approximately 100 mg (milligrams) of radiolabeled drug, around 95 percent of the radioactivity was found in the urine and less than 0.5 percent in the feces. The major part of the excreted compounds, approximately 40 percent of the dose, were unchanged Lacosamide, and around 30 percent was its O-desmethyl metabolite. Almost 20 percent was a structurally unknown polar fraction.

Ingredients:

Active Ingredients: Lacosamide.

Inactive Ingredients: Crospovidone, colloidal silicon dioxide, hydroxypropyl cellulose, Lecithin, hypromellose, low substituted hydroxypropyl cellulose, microcrystalline cellulose, magnesium stearate, polyethylene glycol, polyvinyl alcohol, talc, polyvinyl alcohol, and titanium dioxide.

Contraindications

None.

Warning and Precautions

• Suicidal Behavior and Ideation

AEDs or antiepileptic drugs, such as Lacosamide, are known to increase the risk of suicidal behavior or thoughts in patients using these medications for any indication. Therefore, a person treated with such drugs for any condition should be carefully monitored.

• Cardiac Rhythm and Conduction Abnormalities

  • Atrial Fibrillation and Atrial Flutter - Lacosamide in adult patients with partial-onset seizures showed no cases of atrial fibrillation or flutter during clinical studies. The drug is not recommended in elderly patients with diabetic neuropathy. The drug administration may predispose to atrial fibrillation or flutter (atrial arrhythmias), especially in patients with cardiovascular disease and diabetic neuropathy.

  • PR interval Prolongation, Atrioventricular Block, and Ventricular Tachyarrhythmia - Lacosamide should be cautiously used in patients with underlying cardiac conduction problems, including marked first-degree AV (atrioventricular) block, second-degree, or higher AV block, severe cardiac disease, such as myocardial ischemia or heart failure, or structural heart disease, and cardiac sodium channelopathies (Brugada Syndrome). Also, the drug should be cautiously used with medications, such as beta-blockers, sodium channel blockers, calcium channel blockers, potassium channel blockers, and drugs that prolong the PR interval. In such cases, it is recommended that the patient obtain the ECG (electrocardiogram) before starting Lacosamide and after the drug is titrated to the steady-state maintenance dose. Additionally, the patients administered an intravenous dosage of Lacosamide should be closely monitored.

• Dizziness and Ataxia

The drug may cause ataxia and dizziness in adult and pediatric patients. The onset of these two conditions was most commonly noticed during titration. Therefore, it is recommended to administer the clinically indicated loading dose under medical supervision because of the possibility of increased incidence of adverse reactions, including central nervous system-related adverse reactions, such as dizziness and ataxia.

• Withdrawal of Antiepileptic Drugs

Lacosamide, like any other antiepileptic drug, should be withdrawn slowly, over a minimum of one week, to minimize the potential for increased seizure frequency in patients with seizure disorders.

• Syncope

There was no increase in syncope compared to placebo during the short-term controlled trials of Lacosamide in adult patients with partial-onset seizures with no significant system conditions. Also, the cause of syncope was not determined in most cases. However, in some cases, changes in orthostatic blood pressure, bradycardia, atrial flutter, or fibrillation (and associated tachycardia) were observed in patients receiving doses above 400 milligrams per day.

• Risks in Patients with Phenylketonuria

Lacosamide oral solution contains aspartame, a source of phenylalanine, which is harmful for patients suffering from phenylketonuria. Thus, before prescribing the drug’s oral solution to such patients, the doctor must consider the combined daily amount of Phenylalanine from all sources, including the drug itself.

• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity

DRESS, also known as multi-organ hypersensitivity, has previously been reported in patients taking antiepileptic drugs, such as Lacosamide. The events have also been fatal or life-threatening in some cases. The condition is often characterized by rash, fever, lymphadenopathy, or facial swelling in association with other organ system involvement, such as nephritis, hepatitis, hematologic abnormalities, myositis, myocarditis, or sometimes resembling an acute viral infection. Therefore, in such cases, the patient must be cautiously evaluated, and Lacosamide should be discontinued if any other cause cannot be established for the signs or symptoms.

Drug Interactions:

Some serious drug reactions occur with the following drugs:

• Abametapir.

• Fexinidazole.

• Ivosidenib.

• Tucatinib.

• Apalutamide.

• Idelalisib.

• Metoclopramide intranasal.

• Voxelotor.

Uses in Specific Populations

Pregnancy

It is recommended to maintain a pregnancy exposure registry that monitors pregnancy outcomes in females exposed to antiepileptic drugs, such as Lacosamide, during pregnancy.

The background risk of miscarriage and major birth defects for this population group is not known. However, all pregnancies carry a risk of birth loss, defect, or other adverse outcomes. Also, during animal studies, the drug has shown birth defects, neurobehavioral changes, and decreased brain weight in the juvenile and neonatal phases. Therefore, the drug should be cautiously prescribed to this population group only after evaluating the potential risks and benefits of the drug to the pregnant women and the fetus.

Breastfeeding

The drug gets excreted in human milk and is also known to cause sleepiness in breastfed infants due to Lacosamide exposure. The effects of the drug on milk production are not known clearly. Therefore, the drug must be cautiously prescribed to breastfeeding females. Also, the health and developmental effects of the fetus, along with the drug’s need for the mother, and the adverse effects of the drug on the fetus and mother, must be cautiously evaluated.

Pediatric Use

The safety and effectiveness of the drug in the pediatric population of less than one month of age is not yet established. However, the drug is safe to be used in children of one month of age and older.

Geriatric Use

The safety and effectiveness of the drug is not known in this population. However, dose titration should be done cautiously, usually starting at the lower end of the dosing range.

Hepatic Impairment

For pediatric and adult patients with mild to moderate hepatic impairment, an approximately 25 percent reduction of the maximum dosage is recommended. Close observation, dose initiation, and titration are advised for mild to moderate cases. The drug is not recommended for severe cases.

Renal Impairment

Dose adjustment is not needed in patients with mild to moderate renal impairment. However, in patients with severe renal impairment and those with end-stage renal disease, a reduction of 25 percent of the maximum dosage is recommended.