AHFS Class:

• Ion Channel Inhibition Agents 28:12.24

Generic Name(s):

• Lacosamide

Lacosamide, a functionalized amino acid, is an anticonvulsant.1,4,5,6,22,23,34

Seizure Disorders

Partial Seizures

Lacosamide is used orally as monotherapy or adjunctive therapy (i.e., in combination with other anticonvulsants) in the management of partial-onset seizures in adults and pediatric patients 4 years of age or older.1,2,3,4,20,24,36,49,51,53,54,55,56 IV lacosamide is used in adults with partial-onset seizures when oral administration is temporarily not feasible; use of the IV formulation has not been evaluated in pediatric patients.1,20,24,36

Efficacy of lacosamide monotherapy in the treatment of partial-onset seizures has been established in a historically controlled, conversion-to-monotherapy study.1,49 Patients 16-70 years of age who were receiving stable dosages of 1 or 2 anticonvulsant drugs and experienced at least 2 partial-onset seizures every 28 days during an initial 8-week baseline period were transferred to lacosamide monotherapy and compared with a historical control group derived from the low-dose active control groups of 8 similarly designed conversion-to-monotherapy studies.1,49,50 The study design required the inclusion of 2 effective dosage groups; however, the primary analysis was based on an oral lacosamide dosage of 400 mg daily.1,49,50 Following randomization, lacosamide was added to the baseline anticonvulsant regimen over a 3-week titration period and then continued for an additional 16 weeks while background anticonvulsant drugs were withdrawn.1 The primary efficacy end point was the proportion of lacosamide-treated patients who met a predefined “exit” criteria (defined as doubling of the mean monthly seizure count; doubling of the highest consecutive 2-day seizure frequency; occurrence of a single generalized tonic-clinic seizure; clinically important prolongation or worsening of overall seizure duration, frequency, type, or pattern requiring discontinuance from the study; or status epilepticus or new onset of serial or cluster seizures) during the maintenance period compared with historical controls.1 Among patients receiving lacosamide 400 mg daily, the estimated percentage of patients meeting at least one exit criterion (30%) was lower than the expected rate in historical controls (65%), which met the statistical criteria for efficacy.1,49

Efficacy of lacosamide as adjunctive therapy of partial-onset seizures has been established in three 12-week, randomized, double-blind, placebo-controlled clinical studies in adults.1,2,3,4,56 Patients enrolled in these trials had refractory partial-onset seizures with or without secondary generalization while receiving a regimen of 1-3 concomitant anticonvulsants and had experienced at least 4 partial-onset seizures every 28 days (with no seizure-free period exceeding 21 days) during an 8-week baseline period.1,2,3,4 In these 3 studies, which included a total of 1294 evaluable patients, patients had epilepsy for an average of 24 years and a median baseline seizure frequency ranging from 10 to 17 seizures over a 28-day period; 84% of the patients were concurrently receiving 2 or 3 anticonvulsants with or without concurrent vagal nerve stimulation.1,2,3,4 The studies compared oral lacosamide dosages of 200, 400, or 600 mg daily with placebo.1,4 Following an initial 4- to 6-week titration phase, patients were maintained on stable dosages of lacosamide for 12 weeks.1

In these studies, patients receiving lacosamide 400 or 600 mg daily experienced substantially greater percent reduction in 28-day seizure frequency from baseline compared with those receiving placebo.1,2,3,4 A statistically significant effect was observed with lacosamide 200 mg daily in only one of the studies that evaluated this dosage.1 Across all 3 studies, lacosamide demonstrated consistently higher 50% responder rates (defined as the proportion of patients experiencing a reduction in seizure frequency of 50% or greater) relative to placebo.1,51 Subset evaluations did not demonstrate important differences in response based on gender or race in these studies; however, data on race were limited (about 10% of patients were non-Caucasian).1 In long-term, open-label extensions of the placebo-controlled studies, lacosamide (100-800 mg daily based on individual tolerability and response) was generally well tolerated and effective in maintaining seizure reduction in patients receiving the drug for periods of up to 8 years.2,3,4,5,13,53,54,55

The safety and tolerability of IV lacosamide (200-600 mg daily for 2 days) as a temporary replacement for oral lacosamide have been demonstrated in a randomized, double-blind, multicenter study in patients with partial-onset seizures.24 In addition, the safety and tolerability of IV lacosamide (200-800 mg daily for 2-5 days) as a short-term replacement for oral lacosamide in hospitalized patients with partial-onset seizures have been demonstrated in a larger, open-label, multicenter study.36

Neuropathic Pain

Lacosamide has been used orally in the management of pain associated with diabetic peripheral neuropathy (DPN)† and has been evaluated for this use in adults in several short-term and long-term (up to approximately 2.5 years) clinical trials; however, additional controlled trials are needed to confirm the drug's efficacy and safety in this condition.14,15,16,17,18,38,43

Administration

Lacosamide is administered orally (as tablets or oral solution).1 The drug may be administered by IV infusion in adults when oral administration is temporarily not feasible (e.g., after surgery or in patients with dysphagia or acute GI disorders); safety of the IV formulation has not been established in pediatric patients.1,20,24,36,57

Bioequivalence has been demonstrated between the oral tablets and the 30- and 60-minute IV infusions (but not the 15-minute IV infusion) of lacosamide.1 The commercially available oral solution containing 50 mg/5 mL of lacosamide is bioequivalent to the tablets.1

Cardiac conduction abnormalities and arrhythmias have been observed in patients receiving lacosamide orally or by IV infusion; the manufacturer recommends ECG monitoring prior to initiating therapy and after reaching steady-state maintenance dosage in patients who may be at risk.1 In addition, the manufacturer recommends close monitoring in patients receiving lacosamide by IV infusion.1 (See Cardiac Effects under Cautions: Warnings/Precautions.)

Lacosamide therapy should be withdrawn gradually (e.g., by discontinuing therapy over at least one week) to minimize the potential for increased seizure frequency in patients with seizure disorders.1

Patients currently receiving or beginning therapy with lacosamide and/or any other anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior.1,9,10,12 (See Suicidality Risk under Cautions: Warnings/Precautions.)

Oral Administration

Lacosamide tablets and oral solution are administered orally (usually twice daily) without regard to food.1

The tablets should be swallowed whole with liquid and should not be divided.1

A calibrated dosing device should be used to measure and administer the oral solution; a household teaspoon or tablespoon is not an adequate measuring device.1 Any unused portions of the oral solution should be discarded after 7 weeks of first opening the bottle.1 Lacosamide oral solution may be administered through a nasogastric or gastrostomy tube.1

IV Administration

Lacosamide injection may be administered IV without further dilution or may be mixed with a compatible diluent (5% dextrose injection, lactated Ringer's injection, or 0.9% sodium chloride injection).1,24,36 Following dilution, the infusion solution may be stored for up to 4 hours at room temperature.1

Lacosamide injection should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit; the drug should not be used if discoloration or particulate matter is observed.1 Vials are for single use only; unused portions should be discarded.1

Rate of Administration

IV infusions of lacosamide are usually administered over 30-60 minutes.1 Because shorter infusion times have been used safely in clinical trials, the manufacturer states that the drug may be administered as rapidly as over 15 minutes if necessary.1,24,36,40,41,57 The risk of adverse CNS effects may be increased with shorter durations of infusion.1,57

Dosage

Partial Seizures

Patients being transferred from monotherapy with another anticonvulsant to lacosamide should receive both anticonvulsant agents concomitantly until the therapeutic dosage of lacosamide is reached and has been administered for at least 3 days.1 Withdrawal of the concomitant anticonvulsant should then be done gradually over at least 6 weeks.1

Adult Dosage

In adults 17 years of age or older, the recommended initial oral dosage of lacosamide for the management of partial-onset seizures is 200 mg daily (administered as 100 mg twice daily) as monotherapy or 100 mg daily (administered as 50 mg twice daily) as adjunctive therapy .1 Dosage should be increased by 100 mg daily (50 mg twice daily) based on individual patient response and tolerability, no more frequently than once a week, up to the recommended maintenance dosage of 300-400 mg daily (150-200 mg twice daily) as monotherapy or 200-400 mg daily (100-200 mg twice daily) as adjunctive therapy .1

Alternatively, lacosamide therapy may be initiated with a single oral loading dose of 200 mg in adults, followed 12 hours later by a dosage of 100 mg twice daily for 1 week; subsequent dosage may be increased by 100 mg daily (50 mg twice daily) based on individual patient response and tolerability, no more frequently than once a week, up to the recommended maintenance dosage of 300-400 mg daily (150-200 mg twice daily) as monotherapy or 200-400 mg daily (100-200 mg twice daily) as adjunctive therapy .1 Steady-state concentrations produced by a single lacosamide loading dose of 200 mg are comparable to those produced by an oral dosage of 100 mg twice daily.1 The loading dose should be administered under medical supervision because of an increased risk of adverse CNS effects.1

When oral therapy is temporarily not feasible, lacosamide may be administered by IV infusion in adults at the same dosages recommended for oral administration, including the alternative loading dosage.1,57 The manufacturer states that clinical experience with IV dosing of lacosamide is limited to 5 consecutive days.1,24,36

The maximum recommended dosage of lacosamide for the management of partial-onset seizures is 400 mg daily (200 mg twice daily).1 In clinical studies evaluating adjunctive therapy, lacosamide dosages exceeding 400 mg daily were not more effective than lower dosages and were associated with a substantially higher incidence of adverse effects.1

Pediatric Dosage

Dosage of lacosamide in pediatric patients is based on weight.1

In pediatric patients 4 years of age or older weighing at least 50 kg, the recommended initial oral dosage of lacosamide for monotherapy or adjunctive therapy of partial-onset seizures is 100 mg daily (administered as 50 mg twice daily).1 Dosage should be increased by 100 mg daily (50 mg twice daily) based on individual patient response and tolerability, no more frequently than once a week, up to the recommended maintenance dosage of 300-400 mg daily (150-200 mg twice daily) as monotherapy or 200-400 mg daily (100-200 mg twice daily) as adjunctive therapy .1

In pediatric patients 4 years of age or older weighing 30 kg to less than 50 kg, the recommended initial oral dosage of lacosamide for monotherapy or adjunctive therapy of partial-onset seizures is 2 mg/kg daily (administered as 1 mg/kg twice daily).1 Dosage should be increased by 2 mg/kg daily (1 mg/kg twice daily) based on individual patient response and tolerability, no more frequently than once a week, up to the recommended maintenance dosage of 4-8 mg/kg daily (2-4 mg/kg twice daily) as monotherapy or adjunctive therapy.1

In pediatric patients 4 years of age or older weighing 11 kg to less than 30 kg, the recommended initial oral dosage of lacosamide for monotherapy or adjunctive therapy of partial-onset seizures is 2 mg/kg daily (administered as 1 mg/kg twice daily).1 Dosage should be increased by 2 mg/kg daily (1 mg/kg twice daily) based on individual patient response and tolerability, no more frequently than once a week, up to the recommended maintenance dosage of 6-12 mg/kg daily (3-6 mg/kg twice daily) as monotherapy or adjunctive therapy.1

The maximum recommended dosage of lacosamide for the management of partial-onset seizures is 400 mg daily (200 mg twice daily).1 In clinical studies evaluating adjunctive therapy, lacosamide dosages exceeding 400 mg daily were not more effective than lower dosages and were associated with a substantially higher incidence of adverse effects.1

Neuropathic Pain

For the management of pain associated with diabetic peripheral neuropathy† in adults, lacosamide usually has been given in an initial oral dosage of 100 mg daily (given as 50 mg twice daily) in clinical trials, with subsequent weekly increases to reach maintenance dosages of 400-600 mg daily (given as 200-300 mg twice daily) based on individual patient response and tolerability.14,15,16,17,18,38

Special Populations

Dosage adjustment of lacosamide is not necessary in patients with mild to moderate renal impairment.1 In patients with severe renal impairment (creatinine clearance of 30 mL/minute or less) or end-stage renal disease, the maximum dosage of lacosamide should be reduced by 25%.1 Dosage titration should be undertaken with caution in patients with any degree of renal impairment.1 In patients undergoing hemodialysis, dosage supplementation of up to 50% following hemodialysis should be considered.1

In patients with mild or moderate hepatic impairment, the maximum dosage of lacosamide should be reduced by 25% and dosage titration should be undertaken with caution.1 Use of lacosamide is not recommended in patients with severe hepatic impairment.1

Patients with renal or hepatic impairment who are taking potent inhibitors of cytochrome P-450 (CYP) 3A4 and/or CYP2C9 may require dosage reduction of lacosamide.1 (See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.)

Dosage adjustment based solely on age is not considered necessary in geriatric patients; however, the manufacturer recommends cautious dosage titration in such patients, usually starting at the low end of the dosing range because of the greater frequency of decreased hepatic and renal function in this age group.1

Contraindications

The manufacturer states that there are no known contraindications to the use of lacosamide.1

Warnings/Precautions

Suicidality Risk

An increased risk of suicidality (suicidal behavior or ideation) was observed in an analysis of 199 studies using various anticonvulsants compared with placebo.1,9,10,12 The analysis of suicidality reports from placebo-controlled studies involving 11 anticonvulsants (carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide) in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain) found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.24%).1,9,10,12 This increased suicidality risk was observed as early as one week after beginning therapy and continued through 24 weeks.1,9,10 Although patients treated with an anticonvulsant for epilepsy, psychiatric disorders, and other conditions were all found to have an increased suicidality risk compared with those receiving placebo, the relative suicidality risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.1,9,10

Clinicians should inform patients, their families, and caregivers of the potential for an increased risk of suicidality with anticonvulsant therapy; all patients currently receiving or beginning therapy with any anticonvulsant should be closely monitored for the emergence or worsening of suicidal thoughts or behavior or depression.1,9,10,12

Clinicians who prescribe lacosamide or any other anticonvulsant should balance the risk of suicidality with the risk of untreated illness.1,10 Epilepsy and many other illnesses for which anticonvulsants are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.1,12 If suicidal thoughts or behavior emerge during anticonvulsant therapy, the clinician should consider whether these symptoms may be related to the illness being treated.1,12 (See Advice to Patients.)

Dizziness and Ataxia

Dizziness and ataxia were reported in 25 and 6%, respectively, of patients with partial-onset seizures receiving lacosamide dosages of 200-400 mg daily and 1-3 concomitant anticonvulsants in clinical studies compared with 8 and 2% of placebo recipients, respectively; dizziness was the adverse effect most frequently leading to drug discontinuance (3%).1 The onset of dizziness and ataxia was most commonly observed during dosage titration.1 A substantial increase in these adverse effects was reported with lacosamide dosages exceeding 400 mg daily.1 (See Advice to Patients.)

Cardiac Effects

Like some other anticonvulsants (e.g., carbamazepine, lamotrigine, pregabalin), lacosamide can cause PR-interval prolongation.1,2,4,5,13,19,20,24,43 Dose-dependent increases in the PR interval have been observed in patients and healthy individuals receiving lacosamide in clinical studies.1,2,4,5,13,19,20,24,42 At steady state, the timing of the maximum observed mean PR interval coincided with the peak plasma lacosamide concentration.1 In adjunctive clinical trials in adults with partial-onset seizures, asymptomatic first-degree AV block was observed in 0.4% of patients receiving oral lacosamide compared with none of the patients receiving placebo.1,2,20 Profound bradycardia was reported in a patient who received lacosamide 150 mg by IV infusion over 15 minutes.1

During postmarketing experience, additional cases of cardiac arrhythmias (e.g., bradycardia, AV block, ventricular tachyarrhythmias), which rarely resulted in asystole, cardiac arrest, or death, have been reported in patients receiving IV or oral lacosamide at recommended dosages as well as in the setting of overdosage.1 In most cases, patients had underlying proarrhythmic conditions or were taking concomitant drugs that affect cardiac conduction or prolong the PR interval.1

Lacosamide should be used with caution in patients with underlying proarrhythmic conditions such as known cardiac conduction abnormalities (e.g., marked first-degree AV block, second- or third-degree AV block, sick sinus syndrome without a pacemaker), cardiac sodium channelopathies (e.g., Brugada syndrome), or severe cardiovascular disease (e.g., myocardial ischemia, heart failure, structural heart disease) and in patients receiving concomitant drugs that affect cardiac conduction, including drugs that prolong the PR interval (e.g., sodium channel blockers, β-adrenergic blocking agents, calcium-channel blocking agents, potassium channel blockers).1,23 When lacosamide is given concomitantly with other drugs that prolong the PR interval, further PR prolongation is possible.1,23 (See Drug Interactions: Drugs that Affect Cardiac Conduction.) The manufacturer recommends obtaining an ECG before initiating lacosamide therapy and after the drug is titrated to steady state in such patients.1 In addition, such patients who are receiving lacosamide by the IV route should be closely monitored.1

Atrial Fibrillation and Atrial Flutter

In short-term trials of lacosamide in patients with partial-onset seizures, there were no cases of atrial fibrillation or flutter.1 In patients with diabetic neuropathy, 0.5% of lacosamide-treated patients experienced atrial fibrillation or flutter compared with none of the placebo recipients.1 Lacosamide may predispose patients to develop atrial arrhythmias (i.e., atrial fibrillation or flutter), particularly in patients with diabetic neuropathy and/or cardiovascular disease.1 Patients should therefore be made aware of the symptoms of atrial fibrillation and flutter (e.g., palpitations, rapid pulse, shortness of breath).1 (See Advice to Patients.)

Syncope

In short-term controlled trials in patients with partial-onset seizures without significant systemic illness, there was no increase in syncope with lacosamide compared with placebo; however, cases of syncope have been reported in open-label partial-onset seizure studies in adults and pediatric patients with preexisting cardiac risk factors.1 In short-term controlled trials of lacosamide in patients with diabetic neuropathy, syncope or loss of consciousness was reported in 1.2% of patients receiving the drug compared with none of the placebo recipients.1 Most of the syncope cases were observed in patients receiving lacosamide dosages exceeding 400 mg daily.1 Although the cause of syncope was not determined in most cases, several cases were associated with orthostatic changes in blood pressure, atrial fibrillation/flutter (and associated tachycardia), or bradycardia.1 (See Advice to Patients.)

Discontinuance of Anticonvulsants

To minimize the risk of increased seizure frequency in patients with seizure disorders, anticonvulsant drugs, including lacosamide, should not be abruptly discontinued.1 The manufacturer recommends that oral lacosamide therapy be withdrawn gradually (e.g., over at least 1 week).1 (See Dosage and Administration: Administration.)

Phenylketonuria

Individuals with phenylketonuria (i.e., homozygous genetic deficiency of phenylalanine hydroxylase) and other individuals who must restrict their intake of phenylalanine should be warned that lacosamide oral solution contains aspartame, which is metabolized in the GI tract following oral administration to provide 0.32 mg of phenylalanine per 20 mL of solution.1,44,45,46,47,48 The combined daily amount of phenylalanine from all sources, including from lacosamide oral solution, should be considered in patients with phenylketonuria.1

Sensitivity Reactions

Multi-organ Hypersensitivity

Multi-organ hypersensitivity (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]), a potentially fatal or life-threatening reaction, has been reported with some anticonvulsant drugs.1 The clinical presentation is variable, but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling associated with other organ system involvement such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis.1 However, signs and symptoms associated with other organ systems also may occur.1

One case of symptomatic hepatitis and nephritis, which was consistent with a delayed multi-organ hypersensitivity reaction, was reported in a healthy individual 10 days after discontinuing lacosamide.1 Full recovery occurred within 1 month without specific treatment; potential known viral etiologies for hepatitis were ruled out and the individual was not receiving any concomitant therapy.1 Additional cases of possible multi-organ hypersensitivity with lacosamide include 2 patients with rash and elevated hepatic enzyme concentrations and one patient with myocarditis and hepatitis of uncertain etiology.1

If manifestations of a multi-organ hypersensitivity reaction occur, patients should be evaluated immediately; if an alternative cause cannot be identified, lacosamide should be discontinued.1

Specific Populations

Pregnancy

There are no adequate data in humans to determine if there is any risk associated with the use of lacosamide during pregnancy.1 In animal studies, lacosamide produced developmental toxicity (i.e., increased embryofetal and perinatal mortality, growth deficit) when given orally to pregnant rats.1 Developmental neurotoxicity was observed in animals given lacosamide during a period of postnatal development corresponding to the third trimester of human pregnancy.1 These effects were observed at dosages associated with clinically relevant plasma exposures.1

Women who are pregnant while receiving lacosamide should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry; patients can enroll by calling 888-233-2334.1 Information on the registry also can be found on the website [Web].1

Lactation

Lacosamide and/or its metabolites are distributed into milk of lactating rats.1 It is not known if lacosamide is distributed into human milk.1 The effects of lacosamide on the nursing infant or on milk production also are not known.1 The known benefits of breast-feeding should be considered along with the mother's clinical need for lacosamide and any potential adverse effects on the infant from the drug or underlying maternal condition.1

Pediatric Use

Safety and efficacy of lacosamide in pediatric patients younger than 4 years of age have not been established.1 Use of lacosamide tablets and oral solution in pediatric patients 4 years of age and older is supported by data from partial-onset seizure studies in adults, pharmacokinetic studies in adults and pediatric patients, and safety data in pediatric patients.1 Safety of lacosamide injection has not been established in pediatric patients.1

Lacosamide has been shown in vitro to interfere with the activity of collapsin response mediator protein-2 (CRMP-2), a protein involved in neuronal differentiation and control of axonal outgrowth; potential adverse effects on CNS development cannot be ruled out.1 (See Description.) Administration of lacosamide to rats during the neonatal and juvenile periods of postnatal development resulted in decreased brain weights and long-term neurobehavioral changes (e.g., altered open field performance, deficits in learning and memory).1 The no-effect dosage for developmental neurotoxicity in rats was associated with an area under the plasma concentration-time curve (AUC) less than that in humans at the maximum recommended dosage of 400 mg daily.1

Geriatric Use

Clinical studies of lacosamide did not include sufficient numbers of geriatric patients to determine whether they respond differently than younger patients.1 Systemic exposure and peak plasma concentrations of lacosamide (normalized for dosage and body weight) were approximately 20% higher in geriatric individuals compared with younger individuals, which may be related to differences in body weight and renal clearance.1 (See Dosage and Administration: Special Populations.)

Renal Impairment

Lacosamide and its principal metabolite are eliminated from the systemic circulation mainly by renal excretion.1 Systemic exposure of lacosamide was increased by approximately 25% in individuals with mild or moderate renal impairment and by 60% in individuals with severe renal impairment compared with individuals with normal renal function; however, peak plasma concentrations of the drug were unaffected.1,41 Dosage adjustments may be required in some patients with renal impairment.1 (See Dosage and Administration: Special Populations.)

Lacosamide is removed by hemodialysis.1 Following a 4-hour hemodialysis session, systemic exposure of lacosamide is reduced by approximately 50%.1 (See Dosage and Administration: Special Populations.)

Hepatic Impairment

Lacosamide undergoes hepatic metabolism.1 Individuals with moderate hepatic impairment (Child-Pugh class B) had approximately 50-60% higher systemic exposure of lacosamide compared with healthy individuals.1 The pharmacokinetics of lacosamide have not been specifically studied in individuals with severe hepatic impairment, and use of the drug in patients with severe hepatic impairment is not recommended.1,21

Dosage adjustments may be required in some patients with hepatic impairment.1 (See Dosage and Administration: Special Populations.)

Common Adverse Effects

Adverse reactions occurring in 5% or more of patients receiving oral lacosamide as adjunctive therapy in controlled clinical trials for partial-onset seizures and reported more frequently than with placebo include dizziness,1,2,3,4,13,14,15,16,52 headache,1,4,13,14,15,16,52 diplopia,1,3,4,13,52 nausea,1,2,3,4,14,16,52 vomiting,1,2,3,4,13 fatigue,1,4,13,15,16 blurred vision,1,3,13 ataxia,1,2 somnolence,1 tremor,1,3,15,16 nystagmus,1,2,3 memory impairment,1 balance disorder,1 vertigo,1,4 and diarrhea.1,14

Adverse effects reported in the study evaluating lacosamide monotherapy generally were similar to those reported in the adjunctive placebo-controlled studies with the exception of insomnia (occurring in 2% or more of patients receiving lacosamide monotherapy).1

Systemic adverse effects associated with short-term IV lacosamide therapy in patients with partial-onset seizures generally appear to be consistent with those associated with oral administration of the drug; local adverse effects include injection site pain or discomfort, irritation, and erythema.1,8,24,36

Lacosamide generally appears to have a low potential for pharmacokinetic drug interactions with other anticonvulsants or other drugs.1,4,19,26

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Lacosamide is metabolized by cytochrome P-450 (CYP) isoenzymes 3A4, 2C9, and 2C19.1 Increased exposure to lacosamide is possible in patients with renal or hepatic impairment receiving potent inhibitors of CYP3A4 and/or CYP2C9.1

Lacosamide does not substantially induce CYP 1A2, 2B6, 2C9, 2C19, or 3A4 in vitro; pharmacokinetic interaction is unlikely.1,19

Lacosamide does not substantially inhibit CYP isoenzymes 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4, or 3A5 at plasma concentrations observed in clinical studies; pharmacokinetic interaction is unlikely.1,19

In vitro data suggest that lacosamide may inhibit CYP 2C19 at therapeutic concentrations; however, an in vivo study with omeprazole suggested minimal or no inhibitory effect (see Drug Interactions: Omeprazole).1,19

Drugs Affecting or Affected by P-glycoprotein Transport

Lacosamide is not an inhibitor or substrate of the P-glycoprotein transport system; pharmacokinetic interactions are unlikely.1

Drugs that Affect Cardiac Conduction

The risk of AV block, bradycardia, and ventricular tachyarrhythmias may be increased when lacosamide is administered concomitantly with other drugs that affect cardiac conduction, including those that prolong the PR interval (e.g., β-adrenergic blocking agents, calcium-channel blocking agents, sodium channel blockers [including carbamazepine, eslicarbazepine, oxcarbazepine, phenytoin, rufinamide, and zonisamide], potassium channel blockers, digoxin, pregabalin).1,23,39,42,43,59 These drugs should be used concomitantly with caution.1 (See Cardiac Effects under Cautions: Warnings/Precautions.) The manufacturer recommends ECG monitoring prior to initiating lacosamide therapy and after the drug is titrated to steady state in patients receiving concomitant drugs that prolong the PR interval.1 In addition, such patients who are receiving lacosamide by the IV route should be closely monitored.1

Alcohol

No data are currently available concerning an interaction between lacosamide and alcohol.41

Anticonvulsants

Carbamazepine

Concomitant administration of lacosamide and carbamazepine did not alter the pharmacokinetics of either drug in healthy individuals.1 In placebo-controlled studies in patients with partial-onset seizures, steady-state plasma concentrations of carbamazepine and its epoxide metabolite were not affected by concurrent lacosamide administered at any dosage.1 Population pharmacokinetic studies in patients with partial-onset seizures demonstrated small reductions (15-20% lower) in plasma lacosamide concentrations during concurrent administration of the enzyme-inducing anticonvulsants carbamazepine, phenobarbital, or phenytoin.1,19,20

Phenobarbital

In placebo-controlled studies in patients with partial-onset seizures, steady-state plasma concentrations of phenobarbital were not affected by concurrent lacosamide administered at any dosage.1 Population pharmacokinetic studies in patients with partial-onset seizures demonstrated small reductions (15-20% lower) in plasma lacosamide concentrations during concurrent administration of the enzyme-inducing anticonvulsants carbamazepine, phenobarbital, or phenytoin.1,19,20

Phenytoin

In placebo-controlled studies in patients with partial-onset seizures, steady-state plasma concentrations of phenytoin were not affected by concurrent lacosamide administered at any dosage.1 Population pharmacokinetic studies in patients with partial-onset seizures demonstrated small reductions (15-20% lower) in plasma lacosamide concentrations during concurrent administration of the enzyme-inducing anticonvulsants carbamazepine, phenobarbital, or phenytoin.1,19,20

Valproic Acid

Concomitant administration of lacosamide and valproic acid did not alter the pharmacokinetics of either drug in healthy individuals.1,58 In placebo-controlled studies in patients with partial-onset seizures, steady-state plasma concentrations of valproic acid were not affected by concurrent lacosamide at any dosage.1

Other Anticonvulsants

Steady-state plasma concentrations of clonazepam, gabapentin, lamotrigine, levetiracetam, oxcarbazepine's active monohydroxy metabolite (MHD), topiramate, and zonisamide were not altered by concomitant lacosamide administration at any dosage.1,22

Digoxin

Lacosamide did not alter the pharmacokinetics of digoxin in a study in healthy individuals.1,22,59 A small increase in the PR interval was observed when the drugs were administered concomitantly compared with digoxin alone.59

Because of possible additive effects on PR-interval prolongation, lacosamide and digoxin should be administered concomitantly with caution.1,23,42,59 The manufacturer recommends ECG monitoring prior to initiating lacosamide therapy and after the drug is titrated to steady state in patients receiving lacosamide with drugs that prolong the PR interval.1 In addition, such patients who are receiving lacosamide by the IV route should be closely monitored.1 (See Drug Interactions: Drugs that Affect Cardiac Conduction.)

Metformin

Clinically important changes in metformin concentrations were not observed during concurrent administration of lacosamide.1,22 Metformin hydrochloride did not alter the pharmacokinetics of lacosamide.1

Midazolam

When lacosamide was co-administered with the CYP3A4 substrate midazolam, no changes in the pharmacokinetics of midazolam were observed.1

Omeprazole

Lacosamide did not alter the pharmacokinetics of omeprazole (a CYP2C19 substrate and inhibitor) in healthy individuals, suggesting that lacosamide has little in vivo inhibitory or inducing effect on CYP2C19.1,60 Omeprazole did not alter the pharmacokinetics of lacosamide; however, peak plasma concentrations of lacosamide's inactive O -desmethyl metabolite were reduced by about 60%.1,60

Oral Contraceptives

Lacosamide did not substantially affect the pharmacodynamics and pharmacokinetics of an oral contraceptive containing ethinyl estradiol and levonorgestrel in healthy individuals, with the exception of a 20% increase in peak plasma ethinyl estradiol concentrations.1,22,61

Protein-bound Drugs

Since less than 15% of lacosamide is bound to plasma proteins, a clinically relevant interaction with other drugs through competition for protein binding sites is considered unlikely.1,16

Warfarin

In healthy individuals, concomitant administration of lacosamide and warfarin did not result in any clinically relevant changes in the pharmacokinetics or pharmacodynamics of warfarin.1,62 These results suggest that dosage adjustments are not necessary when lacosamide and warfarin are used concomitantly.62

Description

Lacosamide, a functionalized amino acid structurally related to serine, is an anticonvulsant.1,4,5,6,22,23,26 Although the precise mechanism(s) of its anticonvulsant action remains to be fully elucidated, available data suggest that lacosamide may have a dual mechanism of action, including modulation of the slow inactivation of sodium channels and modulation of collapsin response mediator protein-2 (CRMP-2)-mediated enurotropic signals.1,2,4,5,7,8,14,15,16,19,21,22,25,26,27 In vitro electrophysiologic studies have shown that lacosamide selectively enhances the slow inactivation of voltage-gated sodium channels without affecting fast inactivation.1,2,4,5,7,8,16,19,22,25,27 This selective slow inactivation of sodium channels may result in stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing.1,2,5,7,8,16,19 In addition, in preclinical testing, lacosamide was found to bind to CRMP-2, a phosphoprotein expressed mainly in the nervous system that is involved in neuronal differentiation, polarization, gene expression, and control of axonal outgrowth.1,8,16,21,25,26,27 However, in subsequent testing, such binding was not confirmed.41

Lacosamide has demonstrated analgesic,26 antinociceptive,16,34 and anxiolytic activity in preclinical studies.33 The drug does not exhibit binding affinity for γ-aminobutyric acid (GABA), N -methyl-d-aspartate (NMDA), adenosine, muscarinic, serotonin, histamine, dopamine, or other receptors.14,20,26 In addition, lacosamide does not affect the reuptake or metabolism of norepinephrine, dopamine, serotonin, or GABA.6,7,20,26 The drug does not affect voltage-activated calcium channels (L-, N-, P/Q-, or T-type) or voltage-activated potassium channels and does not modulate delayed-rectifier or A-type potassium currents.6,20,22,26

Lacosamide is rapidly and completely absorbed following oral administration.1,19,20,22 The oral bioavailability of lacosamide tablets is approximately 100%;1,19,22 food does not affect the rate and extent of absorption.1,19 Peak plasma concentrations of lacosamide occur approximately 0.5-4 hours following oral dosing and steady-state plasma concentrations are achieved after 3 days of twice-daily oral administration.1,8,19,20,22 Following IV administration, peak plasma lacosamide concentrations are reached at the end of the infusion.1,19 When infused IV over 30 or 60 minutes, the IV formulation is bioequivalent to the oral tablets.1 The pharmacokinetics of both oral and IV lacosamide are dose-proportional over a dosage range of 100-800 mg and exhibit low intra- and intersubject variability.1,19 Lacosamide is less than 15% bound to plasma proteins and has an elimination half-life of approximately 12-13 hours.1,19,22

Lacosamide is primarily eliminated by renal excretion and biotransformation.1,19 Following oral and IV administration of a 100-mg radiolabeled dose of lacosamide, approximately 95% of the dose was recovered in the urine and less than 0.5% in the feces; the principal compounds excreted were unchanged lacosamide (approximately 40%), O -desmethyl-lacosamide (approximately 30%; inactive metabolite), and a structurally unknown polar fraction (approximately 20%; possibly serine derivatives).1 Lacosamide is a substrate of the cytochrome P-450 (CYP) isoenzyme 2C19; the relative contribution of other CYP isoenzymes or non-CYP enzymes in the metabolism of the drug is unclear.1 No clinically relevant differences in the pharmacokinetics of lacosamide were observed between poor and extensive metabolizers of CYP2C19 substrates; however, plasma concentrations and the amount excreted in the urine of the O -desmethyl metabolite were reduced by about 70% in poor metabolizers compared with extensive metabolizers.1

Advice to Patients

Importance of advising patients or their caregivers to read the patient information (medication guide).1

Importance of patients, family members, and caregivers being aware that anticonvulsants, including lacosamide, may increase the risk of having suicidal thoughts or actions in a very small number of people (about 1 in 500).1,10,12 Advise patients, family members, and caregivers to pay close attention to any day-to-day changes in mood, behavior, and actions; these changes can happen very quickly.1,10 They should also be aware of common warning signs that may signal suicide risk (e.g., talking or thinking about wanting to hurt oneself or end one's life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions).1,10 Advise patients, family members, and caregivers to contact the responsible clinician immediately if these or any other new and worrisome behaviors occur.1,10

Importance of taking lacosamide only as prescribed.1

Importance of informing patients that lacosamide may cause dizziness, drowsiness, blurred vision, or problems with coordination and balance.1,6,35 Importance of advising patients not to drive, operate complex machinery, or engage in other hazardous activities until they have become accustomed to any such effects.1,35

Importance of informing patients that lacosamide may be associated with dizziness, lightheadedness, fainting, or irregular heart beat, particularly in patients with underlying cardiovascular disease, those with cardiac conduction abnormalities, and those who are taking other drugs that affect the heart.1,35 These symptoms are more likely to occur when rising too quickly from a recumbent position.35 Cardiac arrest has been reported rarely.1 Importance of advising patients who develop syncope to lie down with their legs raised until they feel better and to contact their clinician promptly.1,35

Serious hypersensitivity reactions affecting multiple organs (e.g., liver, kidney) may occur; lacosamide should be discontinued if serious hypersensitivity reactions are suspected.1 Importance of informing patients to contact their clinician promptly if symptoms suggestive of liver damage occur (e.g., fatigue, jaundice, dark urine).1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1,35 Importance of clinicians informing women about the existence of and encouraging enrollment in pregnancy registries (see Pregnancy under Warnings/Precautions: Specific Populations, in Cautions).1

Importance of informing patients not to stop taking lacosamide without first talking to their clinician since stopping the drug suddenly can cause serious problems, including seizures.1,35

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illness (e.g., heart disease, kidney disease, liver disease, depression, bipolar disorder) or family history of suicidality or bipolar disorder.1,35

Importance of informing patients of other important precautionary information.1,35 (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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