Lacosamide

Lacosamide
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-in-Chief: Stefano Giannoni [3]

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Overview

Lacosamide is an anticonvulsant that is FDA approved for the treatment of partial-onset seizures. Common adverse reactions include diplopia, headache, dizziness, nausea.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

There is limited information regarding Lacosamide FDA-Labeled Indications and Dosage (Adult) in the drug label.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Lacosamide in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Lacosamide in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Lacosamide FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Lacosamide in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Lacosamide in pediatric patients.

Contraindications

• None

Warnings

5.1 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including VIMPAT, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number of events is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed.

Table 1 shows absolute and relative risk by indication for all evaluated AEDs.

Adverse Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In the premarketing development of adjunctive therapy for partial onset seizures, 1327 patients received lacosamide in controlled and uncontrolled trials, of whom 1000 were treated for longer than 6 months, and 852 for longer than 12 months. The monotherapy development program included 425 patients, 310 of whom were treated for longer than 6 months, and 254 for longer than 12 months.

lacosamide Tablet and Oral solution

Monotherapy Historical-Control Trial (Study 1)

In the monotherapy trial, 16% of patients randomized to receive lacosamide at the recommended doses of 300 and 400 mg/day discontinued from the trial as a result of an adverse event. The adverse reaction most commonly (≥1% on lacosamide) leading to discontinuation was dizziness.

Adverse reactions observed in this study were generally similar to those observed and attributed to drug in adjunctive placebo-controlled studies. One adverse reaction, insomnia, was observed at a rate of ≥2% and was not reported at a similar rate in previous studies. This adverse reaction has also been observed in postmarketing experience [see ADVERSE REACTIONS (6.2)]. Because this study did not include a placebo control group, causality could not be established.

Dizziness, headache, nausea, somnolence, and fatigue were all reported at lower incidences during the AED Withdrawal Phase and Monotherapy Phase, compared with the Titration Phase [see CLINICAL STUDIES (14.1)].

Adjunctive Therapy Controlled Trials (Studies 2, 3, and 4)

In adjunctive therapy controlled clinical trials, the rate of discontinuation as a result of an adverse event was 8% and 17% in patients randomized to receive lacosamide at the recommended doses of 200 and 400 mg/day, respectively, 29% at 600 mg/day, and 5% in patients randomized to receive placebo. The adverse events most commonly (>1% on lacosamide and greater than placebo) leading to discontinuation were dizziness, ataxia, vomiting, diplopia, nausea, vertigo, and vision blurred.

Table 2 gives the incidence of treatment-emergent adverse events that occurred in ≥2% of adult patients with partial-onset seizures in the lacosamide total group and for which the incidence was greater than placebo. The majority of adverse events in the lacosamide patients were reported with a maximum intensity of 'mild' or 'moderate'.

The overall adverse event rate was similar in male and female patients. Although there were few non-Caucasian patients, no differences in the incidences of adverse events compared to Caucasian patients were observed.

Laboratory Abnormalities

Abnormalities in liver function tests have been observed in controlled trials with VIMPAT in adult patients with partial-onset seizures who were taking 1 to 3 concomitant anti-epileptic drugs. Elevations of ALT to ≥3× ULN occurred in 0.7% (7/935) of VIMPAT patients and 0% (0/356) of placebo patients. One case of hepatitis with transaminases >20× ULN was observed in one healthy subject 10 days after VIMPAT treatment completion, along with nephritis (proteinuria and urine casts). Serologic studies were negative for viral hepatitis. Transaminases returned to normal within one month without specific treatment. At the time of this event, bilirubin was normal. The hepatitis/nephritis was interpreted as a delayed hypersensitivity reaction to VIMPAT.

Other Adverse Reactions

The following is a list of treatment-emergent adverse reactions reported by patients treated with VIMPAT in all clinical trials in patients with partial-onset seizures, including controlled trials and long-term open-label extension trials. Events addressed in other tables or sections are not listed here. Events included in this list from the controlled trials occurred more frequently on drug than on placebo and were based on consideration of VIMPAT pharmacology, frequency above that expected in the population, seriousness, and likelihood of a relationship to VIMPAT. Events are further classified within system organ class.

Blood and lymphatic system disorders: neutropenia, anemia

Cardiac disorders: palpitations

Ear and labyrinth disorders: tinnitus

Gastrointestinal disorders: constipation, dyspepsia, dry mouth, oral hypoaesthesia

General disorders and administration site conditions: irritability, pyrexia, feeling drunk

Injury, poisoning, and procedural complications: fall

Musculoskeletal and connective tissue disorders: muscle spasms

Nervous system disorders: paresthesia, cognitive disorder, hypoaesthesia, dysarthria, disturbance in attention, cerebellar syndrome

Psychiatric disorders: confusional state, mood altered, depressed mood

VIMPAT Injection

Adverse reactions with intravenous administration generally were similar to those observed with the oral formulation, although intravenous administration was associated with local adverse events such as injection site pain or discomfort (2.5%), irritation (1%), and erythema (0.5%). One case of profound bradycardia (26 bpm: BP 100/60 mmHg) was observed in a patient during a 15-minute infusion of 150 mg VIMPAT. This patient was on a beta-blocker. Infusion was discontinued and the patient experienced a rapid recovery.

The safety of a 15-minute loading dose administration of VIMPAT Injection 200 mg to 400 mg followed by oral administration of VIMPAT given twice daily at the same total daily dose as the initial intravenous infusion was assessed in an open-label study in patients with partial onset seizures. Patients had to have been maintained on a stable dose regimen of 1 to 2 marketed antiepileptics for at least 28 days prior to treatment assignment. Treatment groups were as follows:

Single dose of intravenous VIMPAT Injection 200 mg followed by oral VIMPAT 200 mg/day (100 mg every 12 hours) Single dose of intravenous VIMPAT Injection 300 mg followed by oral VIMPAT 300 mg/day (150 mg every 12 hours) Single dose of intravenous VIMPAT Injection 400 mg followed by oral VIMPAT 400 mg/day (200 mg every 12 hours). Table 3 gives the incidence of adverse events that occurred in ≥5% of adult patients in any VIMPAT dosing group.

Adverse events observed with infusion of VIMPAT 200 mg over 15-minutes followed by VIMPAT 100 mg administered orally twice day were similar in frequency to those observed in 3-month adjunctive therapy controlled trials. Considering the difference in period of observations (1 week vs. 3 months), the incidence of CNS adverse reactions, such as dizziness, somnolence, and paresthesia may be higher with 15-minute administration of VIMPAT Injection than with administration over a 30-to 60-minute period.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of lacosamide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: Agranulocytosis

Psychiatric disorders: Aggression, agitation, hallucination, insomnia, psychotic disorder

Skin and subcutaneous tissue disorders: Angioedema, rash, urticaria, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Drug Interactions

Pharmacokinetic Interactions Drug-drug interaction studies in healthy subjects showed no pharmacokinetic interactions between VIMPAT and carbamazepine, valproate, digoxin, metformin, omeprazole, midazolam, oral contraceptives containing ethinylestradiol and levonorgestrel, or warfarin. There was no evidence for any relevant drug-drug interaction of VIMPAT with the AEDs used most commonly in the placebo-controlled clinical trials in patients with partial-onset seizures [see CLINICAL PHARMACOLOGY (12.3)]. The lack of pharmacokinetic interaction does not rule out the possibility of pharmacodynamic interactions, particularly among drugs that affect the heart conduction system.

7.2 Strong CYP3A4 or CYP2C9 Inhibitors Patients with renal or hepatic impairment who are taking strong inhibitors of CYP3A4 and CYP2C9 may have a significant increase in exposure to VIMPAT. Dose reduction may be necessary in these patients.

7.3 Concomitant Medications that Prolong PR Interval VIMPAT should be used with caution in patients on concomitant medications that prolong PR interval, because of a risk of AV block or bradycardia, e.g., beta-blockers and calcium channel blockers. In such patients, obtaining an ECG before beginning VIMPAT, and after VIMPAT is titrated to steady-state, is recommended. In addition, these patients should be closely monitored if they are administered VIMPAT through the intravenous route [see WARNINGS AND PRECAUTIONS (5.3)].

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): C Pregnancy Pregnancy Category C

Lacosamide produced developmental toxicity (increased embryofetal and perinatal mortality, growth deficit) in rats following administration during pregnancy. Developmental neurotoxicity was observed in rats following administration during a period of postnatal development corresponding to the third trimester of human pregnancy. These effects were observed at doses associated with clinically relevant plasma exposures.

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 related adverse effects on CNS development cannot be ruled out.

There are no adequate and well-controlled studies in pregnant women. VIMPAT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Oral administration of lacosamide to pregnant rats (20, 75, or 200 mg/kg/day) and rabbits (6.25, 12.5, or 25 mg/kg/day) during the period of organogenesis did not produce any teratogenic effects. However, the maximum doses evaluated were limited by maternal toxicity in both species and embryofetal death in rats. These doses were associated with maternal plasma lacosamide exposures [area under the plasma-time concentration curve; (AUC)] ≈2 and 1 times (rat and rabbit, respectively) that in humans at the maximum recommended human dose (MRHD) of 400 mg/day.

When lacosamide (25, 70, or 200 mg/kg/day) was orally administered to rats throughout gestation, parturition, and lactation, increased perinatal mortality and decreased body weights were observed in the offspring at the highest dose. The no-effect dose for pre- and post-natal developmental toxicity in rats (70 mg/kg/day) was associated with a maternal plasma lacosamide AUC approximately equal to that in humans at the MRHD.

Oral administration of lacosamide (30, 90, or 180 mg/kg/day) to rats during the neonatal and juvenile periods of postnatal development resulted in decreased brain weights and long-term neurobehavioral changes (altered open field performance, deficits in learning and memory). The early postnatal period in rats is generally thought to correspond to late pregnancy in humans in terms of brain development. The no-effect dose for developmental neurotoxicity in rats was associated with a plasma lacosamide AUC approximately 0.5 times that in humans at the MRHD.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lacosamide in women who are pregnant.

Labor and Delivery

The effects of VIMPAT on labor and delivery in pregnant women are unknown. In a pre- and post-natal study in rats, there was a tendency for prolonged gestation in all lacosamide treated groups at plasma exposures (AUC) at or below the plasma AUC in humans at the maximum recommended human dose of 400 mg/day.

Nursing Mothers

Studies in lactating rats have shown that lacosamide and/or its metabolites are excreted in milk. It is not known whether VIMPAT is excreted in human milk. Because many drugs are excreted into human milk, a decision should be made whether to discontinue nursing or to discontinue VIMPAT, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of VIMPAT in pediatric patients <17 years have not been established.

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 related adverse effects on CNS development cannot be ruled out. Administration of lacosamide to rats during the neonatal and juvenile periods of postnatal development resulted in decreased brain weights and long-term neurobehavioral changes (altered open field performance, deficits in learning and memory). The no-effect dose for developmental neurotoxicity in rats was associated with a plasma lacosamide exposure (AUC) approximately 0.5 times the human plasma AUC at the maximum recommended human dose of 400 mg/day.

Geriatic Use

There were insufficient numbers of elderly patients enrolled in partial-onset seizure trials (n=18) to adequately assess the effectiveness of VIMPAT in this population.

No VIMPAT dose adjustment based on age is necessary. In elderly patients, dose titration should be performed with caution

Gender

There is no FDA guidance on the use of Lacosamide with respect to specific gender populations.

Race

• There are no clinically relevant differences in the pharmacokinetics of VIMPAT between Asian, Black, and Caucasian subjects.

Renal Impairment

A maximum dose of 300 mg/day is recommended for patients with severe renal impairment (CLCR≤30 mL/min) and in patients with endstage renal disease. VIMPAT is effectively removed from plasma by hemodialysis. Dosage supplementation of up to 50% following hemodialysis should be considered. In all renally impaired patients, dose titration should be performed with caution

Hepatic Impairment

Patients with mild to moderate hepatic impairment should be observed closely during dose titration. A maximum dose of 300 mg/day is recommended for patients with mild to moderate hepatic impairment. The pharmacokinetics of lacosamide has not been evaluated in severe hepatic impairment. VIMPAT use is not recommended in patients with severe hepatic impairment [see DOSAGE AND ADMINISTRATION (2.3) and CLINICAL PHARMACOLOGY (12.3)]. Patients with co-existing hepatic and renal impairment should be monitored closely during dose titration.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Lacosamide in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Lacosamide in patients who are immunocompromised.

CYP2C19 Polymorphism

There are no clinically relevant differences in the pharmacokinetics of VIMPAT between CYP2C19 poor metabolizers and extensive metabolizers. Results from a trial in poor metabolizers (PM) (N=4) and extensive metabolizers (EM) (N=8) of cytochrome P450 (CYP) 2C19 showed that lacosamide plasma concentrations were similar in PMs and EMs, but plasma concentrations and the amount excreted into urine of the O-desmethyl metabolite were about 70% reduced in PMs compared to EMs.

Administration and Monitoring

Administration

There is limited information regarding Lacosamide Administration in the drug label.

Monitoring

There is limited information regarding Lacosamide Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Lacosamide and IV administrations.

Overdosage

Signs, Symptoms, and Laboratory Findings of Acute Overdose in Humans The types of adverse events experienced by patients exposed to supratherapeutic VIMPAT doses during clinical trials were not clinically different from those of patients administered recommended doses of VIMPAT. The highest reported accidental overdose of VIMPAT during clinical development was 1200 mg/day which was non-fatal.

There has been a single case of intentional overdose in a clinical trial by a patient who self-administered 12,000 mg VIMPAT along with large doses of zonisamide, topiramate, and gabapentin. The patient presented in a coma with AV block and was hospitalized. An EEG revealed epileptic waveforms. The patient recovered 2 days later.

In postmarketing experience, cardiac conduction disorders and fatal cardiac arrest were reported following an acute overdose of 7,000 mg of VIMPAT in a patient with cardiovascular risk factors.

10.2 Treatment or Management of Overdose There is no specific antidote for overdose with VIMPAT. Standard decontamination procedures should be followed. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of patient. A Certified Poison Control Center should be contacted for up to date information on the management of overdose with VIMPAT.

Standard hemodialysis procedures result in significant clearance of VIMPAT (reduction of systemic exposure by 50% in 4 hours). Hemodialysis has not been performed in the few known cases of overdose, but may be indicated based on the patient's clinical state or in patients with significant renal impairment.

Pharmacology

There is limited information regarding Lacosamide Pharmacology in the drug label.

Mechanism of Action

The precise mechanism by which VIMPAT exerts its antiepileptic effects in humans remains to be fully elucidated. In vitro electrophysiological studies have shown that lacosamide selectively enhances slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing.

Structure

The chemical name of lacosamide, the single (R)-enantiomer, is (R)-2-acetamido-N-benzyl-3-methoxypropionamide (IUPAC). Lacosamide is a functionalized amino acid. Its molecular formula is C13H18N2O3 and its molecular weight is 250.30. The chemical structure is:

Pharmacodynamics

A pharmacokinetic-pharmacodynamic (efficacy) analysis was performed based on the pooled data from the 3 efficacy trials for partial-onset seizures. Lacosamide exposure is correlated with the reduction in seizure frequency. However, doses above 400 mg/day do not appear to confer additional benefit in group analyses.

Cardiac Electrophysiology

Electrocardiographic effects of VIMPAT were determined in a double-blind, randomized clinical pharmacology trial of 247 healthy subjects. Chronic oral doses of 400 and 800 mg/day were compared with placebo and a positive control (400 mg moxifloxacin). VIMPAT did not prolong QTc interval and did not have a dose-related or clinically important effect on QRS duration. VIMPAT produced a small, dose-related increase in mean PR interval. At steady-state, the time of the maximum observed mean PR interval corresponded with tmax. The placebo-subtracted maximum increase in PR interval (at tmax) was 7.3 ms for the 400 mg/day group and 11.9 ms for the 800 mg/day group. For patients who participated in the controlled trials, the placebo-subtracted mean maximum increase in PR interval for a 400 mg/day VIMPAT dose was 3.1 ms in patients with partial-onset seizures and 9.4 ms for patients with diabetic neuropathy.

Pharmacokinetics

The pharmacokinetics of VIMPAT have been studied in healthy adult subjects (age range 18 to 87), adults with partial-onset seizures, adults with diabetic neuropathy, and subjects with renal and hepatic impairment.

VIMPAT is completely absorbed after oral administration with negligible first-pass effect with a high absolute bioavailability of approximately 100%. The maximum lacosamide plasma concentrations occur approximately 1 to 4 hour post-dose after oral dosing, and elimination half-life is approximately 13 hours. Steady state plasma concentrations are achieved after 3 days of twice daily repeated administration. Pharmacokinetics of VIMPAT are dose proportional (100-800 mg) and time invariant, with low inter- and intra-subject variability. Compared to lacosamide the major metabolite, O-desmethyl metabolite, has a longer Tmax (0.5 to 12 hours) and elimination half-life (15-23 hours).

Absorption and Bioavailability

VIMPAT is completely absorbed after oral administration. The oral bioavailability of VIMPAT tablets is approximately 100%. Food does not affect the rate and extent of absorption.

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 AUC(0-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.

Distribution

The volume of distribution is approximately 0.6 L/kg and thus close to the volume of total body water. VIMPAT is less than 15% bound to plasma proteins.

Metabolism and Elimination

VIMPAT is primarily eliminated from the systemic circulation by renal excretion and biotransformation.

After oral and intravenous administration of 100 mg [14C]-lacosamide approximately 95% of radioactivity administered 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 plasma exposure of the major human metabolite, O-desmethyl-lacosamide, is approximately 10% of that of lacosamide. This metabolite has no known pharmacological activity.

The CYP isoforms mainly responsible for the formation of the major metabolite (O-desmethyl) are CYP3A4, CYP2C9, and CYP2C19. The elimination half-life of the unchanged drug is approximately 13 hours and is not altered by different doses, multiple dosing or intravenous administration.

There is no enantiomeric interconversion of lacosamide.

Special Populations

Renal impairment

Lacosamide and its major metabolite are eliminated from the systemic circulation primarily by renal excretion.

The AUC of VIMPAT was increased approximately 25% in mildly (CLCR 50-80 mL/min) and moderately (CLCR 30-50 mL/min) and 60% in severely (CLCR≤30 mL/min) renally impaired patients compared to subjects with normal renal function (CLCR>80 mL/min), whereas Cmax was unaffected. No dose adjustment is considered necessary in mildly and moderately renal impaired subjects. A maximum dose of 300 mg/day is recommended for patients with severe renal impairment (CLCR≤30 mL/min) and in patients with endstage renal disease. VIMPAT is effectively removed from plasma by hemodialysis. Following a 4-hour hemodialysis treatment, AUC of VIMPAT is reduced by approximately 50%. Therefore dosage supplementation of up to 50% following hemodialysis should be considered. In all renally impaired patients, the dose titration should be performed with caution [see DOSAGE AND ADMINISTRATION (2.3)].

Hepatic impairment

Lacosamide undergoes metabolism. Subjects with moderate hepatic impairment (Child-Pugh B) showed higher plasma concentrations of lacosamide (approximately 50-60% higher AUC compared to healthy subjects). The dose titration should be performed with caution in patients with hepatic impairment. A maximum dose of 300 mg/day is recommended for patients with mild or moderate hepatic impairment.

Patients with mild to moderate hepatic impairment should be observed closely during dose titration. A maximum dose of 300 mg/day is recommended for patients with mild to moderate hepatic impairment. The pharmacokinetics of lacosamide have not been evaluated in severe hepatic impairment. VIMPAT use is not recommended in patients with severe hepatic impairment [see DOSAGE AND ADMINISTRATION (2.4)]. Patients with co-existing hepatic and renal impairment should be monitored closely during dose titration.

Geriatric

In the elderly (>65 years), dose and body-weight normalized AUC and Cmax is about 20% increased compared to young subjects (18-64 years). This may be related to body weight and decreased renal function in elderly subjects. Dose reduction is not considered to be necessary.

Pediatric Patients

Pharmacokinetics of VIMPAT have not been studied in pediatric patients.

Gender

VIMPAT clinical trials indicate that gender does not have a clinically relevant influence on the pharmacokinetics of VIMPAT.

Race

There are no clinically relevant differences in the pharmacokinetics of VIMPAT between Asian, Black, and Caucasian subjects.

CYP2C19 Polymorphism

There are no clinically relevant differences in the pharmacokinetics of VIMPAT between CYP2C19 poor metabolizers and extensive metabolizers. Results from a trial in poor metabolizers (PM) (N=4) and extensive metabolizers (EM) (N=8) of cytochrome P450 (CYP) 2C19 showed that lacosamide plasma concentrations were similar in PMs and EMs, but plasma concentrations and the amount excreted into urine of the O-desmethyl metabolite were about 70% reduced in PMs compared to EMs.

Drug interactions

In Vitro Assessment of Drug Interactions

In vitro metabolism studies indicate that lacosamide does not induce the enzyme activity of drug metabolizing cytochrome P450 isoforms CYP1A2, 2B6, 2C9, 2C19 and 3A4. Lacosamide did not inhibit CYP 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4/5 at plasma concentrations observed in clinical studies.

In vitro data suggest that lacosamide has the potential to inhibit CYP2C19 at therapeutic concentrations. However, an in vivo study with omeprazole did not show an inhibitory effect on omeprazole pharmacokinetics.

Lacosamide was not a substrate or inhibitor for P-glycoprotein.

Lacosamide is a substrate of CYP3A4, CYP2C9, and CYP2C19. Patients with renal or hepatic impairment who are taking strong inhibitors of CYP3A4 and CYP2C9 may have increased exposure to lacosamide.

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

In Vivo Assessment of Drug Interactions

Drug interaction studies with AEDs Effect of VIMPAT on concomitant AEDs VIMPAT 400 mg/day had no influence on the pharmacokinetics of 600 mg/day valproic acid and 400 mg/day carbamazepine in healthy subjects.

The placebo-controlled clinical studies in patients with partial-onset seizures showed that steady-state plasma concentrations of levetiracetam, carbamazepine, carbamazepine epoxide, lamotrigine, topiramate, oxcarbazepine monohydroxy derivative (MHD), phenytoin, valproic acid, phenobarbital, gabapentin, clonazepam, and zonisamide were not affected by concomitant intake of VIMPAT at any dose.

Effect of concomitant AEDs on VIMPAT Drug-drug interaction studies in healthy subjects showed that 600 mg/day valproic acid had no influence on the pharmacokinetics of 400 mg/day VIMPAT. Likewise, 400 mg/day carbamazepine had no influence on the pharmacokinetics of VIMPAT in a healthy subject study. Population pharmacokinetics results in patients with partial-onset seizures showed small reductions (15% to 20% lower) in lacosamide plasma concentrations when VIMPAT was coadministered with carbamazepine, phenobarbital or phenytoin.

Drug-drug interaction studies with other drugs Digoxin There was no effect of VIMPAT (400 mg/day) on the pharmacokinetics of digoxin (0.5 mg once daily) in a study in healthy subjects.

Metformin There were no clinically relevant changes in metformin levels following coadministration of VIMPAT (400 mg/day).

Metformin (500 mg three times a day) had no effect on the pharmacokinetics of VIMPAT (400 mg/day).

Omeprazole Omeprazole is a CYP2C19 substrate and inhibitor.

There was no effect of VIMPAT (600 mg/day) on the pharmacokinetics of omeprazole (40 mg single dose) in healthy subjects. The data indicated that lacosamide had little in vivo inhibitory or inducing effect on CYP2C19.

Omeprazole at a dose of 40 mg once daily had no effect on the pharmacokinetics of VIMPAT (300 mg single dose). However, plasma levels of the O-desmethyl metabolite were reduced about 60% in the presence of omeprazole.

Midazolam Midazolam is a 3A4 substrate.

There was no effect of VIMPAT (200 mg single dose or repeat doses of 400 mg/day given as 200 mg BID) on the pharmacokinetics of midazolam (single dose, 7.5 mg), indicating no inhibitory or inducing effects on CYP3A4.

Oral Contraceptives There was no influence of VIMPAT (400 mg/day) on the pharmacodynamics and pharmacokinetics of an oral contraceptive containing 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel in healthy subjects, except that a 20% increase in ethinylestradiol Cmax was observed.

Warfarin Co-administration of VIMPAT (400 mg/day) with warfarin (25 mg single dose) did not result in a clinically relevant change in the pharmacokinetic and pharmacodynamic effects of warfarin in a study in healthy male subjects.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility There was no evidence of drug related carcinogenicity in mice or rats. Mice and rats received lacosamide once daily by oral administration for 104 weeks at doses producing plasma exposures (AUC) up to approximately 1 and 3 times, respectively, the plasma AUC in humans at the maximum recommended human dose (MRHD) of 400 mg/day.

Lacosamide was negative in an in vitro Ames test and an in vivo mouse micronucleus assay. Lacosamide induced a positive response in the in vitro mouse lymphoma assay.

No adverse effects on male or female fertility or reproduction were observed in rats at doses producing plasma exposures (AUC) up to approximately 2 times the plasma AUC in humans at the MRHD.

Clinical Studies

Monotherapy in Patients with Partial Onset Seizures The efficacy of VIMPAT in monotherapy was established in a historical-control, multicenter, randomized trial that included 425 patients, age 16 to 70 years, with partial-onset seizures (Study 1). To be included in Study 1, patients were required to be taking stable doses of 1 or 2 marketed antiepileptic drugs. This treatment continued into the 8 week baseline period. To remain in the study, patients were required to have at least 2 partial onset seizures per 28 days during the 8 week baseline period. The baseline period was followed by a 3 week titration period, during which VIMPAT was added to the ongoing antiepileptic regimen. This was followed by a 16-week maintenance period (i.e., a 6-week withdrawal period for background antiepileptic drugs, followed by a 10-week monotherapy period). Patients were randomized 3 to 1 to receive VIMPAT 400 mg/day or VIMPAT 300 mg/day. Treatment assignments were blinded. Response to treatment was based upon a comparison of the number of patients who met exit criteria during the maintenance phase, compared to historical controls. The historical control consisted of a pooled analysis of the control groups from 8 studies of similar design, which utilized a sub-therapeutic dose of an antiepileptic drug. Statistical superiority to the historical control was considered to be demonstrated if the upper limit from a 2-sided 95% confidence interval for the percentage of patients meeting exit criteria in patients receiving VIMPAT remained below the lower 95% prediction limit of 65% derived from the historical control data.

The exit criteria were one or more of the following: (1) doubling of average monthly seizure frequency during any 28 consecutive days, (2) doubling of highest consecutive 2-day seizure frequency, (3) occurrence of a single generalized tonic-clonic seizure, (4) clinically significant prolongation or worsening of overall seizure duration, frequency, type or pattern considered by the investigator to require trial discontinuation, (5) status epilepticus or new onset of serial/cluster seizures. The study population profile appeared comparable to that of the historical control population.

For the VIMPAT 400 mg/day group, the estimate of the percentage of patients meeting at least 1 exit criterion was 30% (95% CI: 25%, 36%). The upper limit of the 2-sided 95% CI (36%) was below the threshold of 65% derived from the historical control data, meeting the pre-specified criteria for efficacy. VIMPAT 300 mg/day also met the pre-specified criteria for efficacy.

14.2 Adjunctive Therapy in Patients with Partial Onset Seizures The efficacy of VIMPAT as adjunctive therapy in partial-onset seizures was established in three 12-week, randomized, double-blind, placebo-controlled, multicenter trials in adult patients (Study 2, Study 3, and Study 4). Enrolled patients had partial-onset seizures with or without secondary generalization, and were not adequately controlled with 1 to 3 concomitant AEDs. During an 8-week baseline period, patients were required to have an average of ≥4 partial-onset seizures per 28 days with no seizure-free period exceeding 21 days. In these 3 trials, patients had a mean duration of epilepsy of 24 years and a median baseline seizure frequency ranging from 10 to 17 per 28 days. 84% of patients were taking 2 to 3 concomitant AEDs with or without concurrent vagal nerve stimulation.

Study 2 compared doses of VIMPAT 200, 400, and 600 mg/day with placebo. Study 3 compared doses of VIMPAT 400 and 600 mg/day with placebo. Study 4 compared doses of VIMPAT 200 and 400 mg/day with placebo. In all three trials, following an 8-week baseline phase to establish baseline seizure frequency prior to randomization, subjects were randomized and titrated to the randomized dose (a 1-step back-titration of VIMPAT 100 mg/day or placebo was allowed in the case of intolerable adverse events at the end of the titration phase). During the titration phase, in all 3 adjunctive therapy trials, treatment was initiated at 100 mg/day (50 mg twice daily), and increased in weekly increments of 100 mg/day to the target dose. The titration phase lasted 6 weeks in Study 2 and Study 3, and 4 weeks in Study 4. In all three trials, the titration phase was followed by a maintenance phase that lasted 12 weeks, during which patients were to remain on a stable dose of VIMPAT.

A reduction in 28 day seizure frequency (baseline to maintenance phase), as compared to the placebo group, was the primary variable in all three adjunctive therapy trials. A statistically significant effect was observed with VIMPAT treatment (Figure 1) at doses of 200 mg/day (Study 4), 400 mg/day (Studies 2, 3, and 4), and 600 mg/day (Studies 2 and 3).

Subset evaluations of VIMPAT demonstrate no important differences in seizure control as a function of gender or race, although data on race was limited (about 10% of patients were non-Caucasian).

How Supplied

Lacosamide Tablets 50 mg

• Are pink, oval, film-coated tablets debossed with "SP" on one side and "50" on the other. They are supplied as follows:

• Bottles of 60 NDC 0131-2477-35
• Unit Dose Carton of 60 tablets [6 cards, each card contains 10 tablets] NDC 0131-2477-60

Lacosamide Tablets 100 mg

• Are dark yellow, oval, film-coated tablets debossed with "SP" on one side and "100" on the other. They are supplied as follows:

• Bottles of 60 NDC 0131-2478-35
• Unit Dose Carton of 60 tablets [6 cards, each card contains 10 tablets] NDC 0131-2478-60

Lacosamide Tablets 150 mg

• Are salmon, oval, film-coated tablets debossed with "SP" on one side and "150" on the other. They are supplied as follows:

• Bottles of 60 NDC 0131-2479-35
• Unit Dose Carton of 60 tablets [6 cards, each card contains 10 tablets] NDC 0131-2479-60

Lacosamide Tablets 200 mg

• Are blue, oval, film-coated tablets debossed with "SP" on one side and "200" on the other. They are supplied as follows:

• Bottles of 60 NDC 0131-2480-35
• Unit Dose Carton of 60 tablets [6 cards, each card contains 10 tablets] NDC 0131-2480-60

Lacosamide injection 200 mg/20 m

• Is a clear, colorless sterile solution supplied in 20 mL colorless single-use glass vials.

• 200 mg/20 mL vial in cartons of 10 vials NDC 0131-1810-67

Lacosamide oral solution 10 mg/mL

• Is a clear, colorless to yellow or yellow-brown, strawberry-flavored liquid. It is supplied in PET bottles as follows:

• 200 mL bottles NDC 0131-5410-71
• 465 mL bottles NDC 0131-5410-70

Storage

There is limited information regarding Lacosamide Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Suicidal Thinking and Behavior

Patients, their caregivers, and families should be counseled that AEDs, including VIMPAT, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Dizziness and Ataxia

Patients should be counseled that VIMPAT use may cause dizziness, double vision, abnormal coordination and balance, and somnolence. Patients taking VIMPAT should be advised not to drive, operate complex machinery, or engage in other hazardous activities until they have become accustomed to any such effects associated with VIMPAT.

Cardiac Rhythm and Conduction Abnormalities

Patients should be counseled that VIMPAT is associated with electrocardiographic changes that may predispose to irregular beat and syncope, particularly in patients with underlying cardiovascular disease, with heart conduction problems or who are taking other medications that affect the heart. Patients who develop syncope should lay down with raised legs and contact their health care provider.

Multiorgan Hypersensitivity Reactions

Patients should be aware that VIMPAT may cause serious hypersensitivity reactions affecting multiple organs such as the liver and kidney. VIMPAT should be discontinued if a serious hypersensitivity reaction is suspected. Patients should also be instructed to report promptly to their physicians any symptoms of liver toxicity (e.g. fatigue, jaundice, dark urine).

Pregnancy Registry

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during VIMPAT therapy. Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry if they become pregnant. This registry is collecting information about the safety of AEDs during pregnancy.

Precautions with Alcohol

Alcohol-Lacosamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Lacosamide Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Lacosamide Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

Lacosamide

File:Lacosamide.svg
Clinical data
Trade names	lacosamide
Synonyms	(2R)-2-(acetylamino)-N-benzyl-3-methoxypropanamide
AHFS/Drugs.com	Monograph
MedlinePlus	a609028
Routes of administration	Oral, intravenous
ATC code	N03AX18 (WHO)
Legal status
Legal status	Schedule V (U.S.)
Pharmacokinetic data
Bioavailability	High
Elimination half-life	13 hours
Identifiers
IUPAC name N2-acetyl-N-benzyl-D-homoserinamide
CAS Number	175481-36-4 N
PubChem CID	219078
ChemSpider	189902 Y
UNII	563KS2PQY5
KEGG	D07299 Y
ChEMBL	ChEMBL58323 Y
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C13H18N2O3
Molar mass	250.294 g/mol
3D model (JSmol)	Interactive image
SMILES O=C(N[C@@H](C(=O)NCc1ccccc1)COC)C
InChI InChI=1S/C13H18N2O3/c1-10(16)15-12(9-18-2)13(17)14-8-11-6-4-3-5-7-11/h3-7,12H,8-9H2,1-2H3,(H,14,17)(H,15,16)/t12-/m1/s1 Y Key:VPPJLAIAVCUEMN-GFCCVEGCSA-N Y
NY (what is this?)  (verify)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [4]

Overview

Lacosamide (INN, formerly known as erlosamide) is a medication developed by UCB for the adjunctive treatment of partial-onset seizures and diabetic neuropathic pain marketed under the trade name lacosamide.

The U.S. Food and Drug Administration accepted UCB's New Drug Application for lacosamide as of November 29, 2007, beginning the approval process for the drug. UCB also filed for marketing approval in the European Union; the European Medicines Agency accepted the marketing application for review in May 2007.

The drug was approved in the EU on September 3, 2008. It was approved in the US on October 29, 2008. Lacosamide release was delayed owing to an objection about its placement into schedule V of the Controlled Substances Act. The FDA issued their final rule of placement into Schedule V on June 22, 2009.

Mechanism of action

Lacosamide is a functionalized amino acid that has activity in the maximal electroshock seizure test, like antiepileptic drugs that are believed to act through voltage-gated sodium channels. However, lacosamide does not act in a conventional way to stabilize fast sodium channel inactivation. Rather, recent studies indicate that it enhances slow inactivation . During an action potential voltage gated sodium channels undergo fast inactivation. This inactivation prevents the channel from opening, and helps end the action potential. Many antiepileptic drugs, like carbamazepine or lamotrigine, slow the recovery from inactivation and hence reduce the ability of neurons to fire action potentials. Inactivation only occurs in neurons firing action potentials, this means that drugs that modulate fast inactivation selectively reduce the firing in active cells. Slow inactivation is similar but does not produce complete blockade of voltage gated sodium channels, with both activation and inactivation occurring over hundreds of milliseconds or more. Lacosamide makes this inactivation happen at less depolarized membrane potentials. This means that lacosamide only affects neurons which are depolarized or active for long periods of time, typical of neurons at the focus of an epileptic focus.

Lacosamide does not affect AMPA, kainate, NMDA, GABA_A, GABA_B or a variety of dopaminergic, serotonergic, adrenergic, muscarinic or cannabinoid receptors and does not block potassium or calcium currents

Clinical trials

In a large double-blind, randomized clinical trial of people with poorly controlled partial-onset seizures, lacosamide was found to significantly reduce seizure frequency when given in addition to other antiepileptics, at doses of 400 and 600 milligrams a day. In a smaller trial of people with diabetic neuropathy, lacosamide also provided significantly better pain relief when compared to placebo.

Tolerability

Lacosamide was generally well tolerated in adult patients with partial-onset seizures. Dizziness was the most common treatment-related adverse event.

Chemistry

File:Lacosamide.png

J.A. McIntyre, J. Castaner, Drugs Future 29, 992 (2004).