Lacosamide - Lacosamide injection (Lacosamide)

Lacosamide is indicated for:

• Treatment of partial-onset seizures in patients 1 month of age and older (
  1.1 Partial-Onset Seizures

  Lacosamide is indicated for the treatment of partial-onset seizures in patients 1 month of age and older.
  )
• Adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in patients 4 years of age and older (
  1.2 Primary Generalized Tonic-Clonic Seizures

  Lacosamide is indicated as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in patients 4 years of age and older.
  )

• Adults (17 years and older):
  • Initial dosage for monotherapy for the treatment of partial-onset seizures is 100 mg twice daily (
    2.1 Dosage Information

    The recommended dosage for monotherapy and adjunctive therapy for partial-onset seizures in patients 1 month of age and older and for adjunctive therapy for primary generalized tonic-clonic seizures in patients 4 years of age and older is included in Table 1. In pediatric patients, the recommended dosing regimen is dependent upon body weight. Dosage should be increased based on clinical response and tolerability, no more frequently than once per week. Titration increments should not exceed those shown in Table 1.

    Table 1: Recommended Dosages for Partial-Onset Seizures (Monotherapy or Adjunctive Therapy) in Patients 1 Month and Older, and for Primary Generalized Tonic-Clonic Seizures (Adjunctive Therapy) in Patients 4 Years of Age and Older *

    *when not specified, the dosage is the same for monotherapy for partial-onset seizures and adjunctive therapy for partial-onset seizures or primary generalized tonic-clonic seizures.
    **Monotherapy for partial-onset seizures only
    ± indicated only for partial-onset seizures
    Age and Body Weight	Initial Dosage	Titration Regimen	Maintenance Dosage
    Adults (17 years and older)	Monotherapy**: 100 mg twice daily (200 mg per day) Adjunctive Therapy: 50 mg twice daily (100 mg per day)	Increase by 50 mg twice daily (100 mg per day) every week	Monotherapy**: 150 mg to 200 mg twice daily (300 mg to 400 mg per day) Adjunctive Therapy: 100 mg to 200 mg twice daily (200 mg to 400 mg per day)
    Pediatric patients weighing at least 50 kg	50 mg twice daily (100 mg per day)	Increase by 50 mg twice daily (100 mg per day) every week	Monotherapy**: 150 mg to 200 mg twice daily (300 mg to 400 mg per day) Adjunctive Therapy: 100 mg to 200 mg twice daily (200 mg to 400 mg per day)
    Pediatric patients weighing 30 kg to less than 50 kg	1 mg/kg twice daily (2 mg/kg/day)	Increase by 1 mg/kg twice daily (2 mg/kg/day) every week	2 mg/kg to 4 mg/kg twice daily (4 mg/kg/day to 8 mg/kg/day)
    Pediatric patients weighing 11 kg to less than 30 kg	1 mg/kg twice daily (2 mg/kg/day)	Increase by 1 mg/kg twice daily (2 mg/kg/day) every week	3 mg/kg to 6 mg/kg twice daily (6 mg/kg/day to 12 mg/kg/day)
    Pediatric patients weighing 6 kg to less than 11 kg ±
    Pediatric patients weighing less than 6kg ±	Intravenous: 0.66 mg/kg three times daily (2 mg/kg/day)	Intravenous: Increase by 0.66 mg/kg three times daily (2 mg/kg/day) every week	Intravenous: 2.5 mg/kg to 5 mg/kg three times daily (7.5 mg/kg/day to 15 mg/kg/day)

    In adjunctive clinical trials in adult patients with partial-onset seizures, a dosage higher than 200 mg twice daily (400 mg per day) was not more effective and was associated with a substantially higher rate of adverse reactions

    [see Adverse Reactions and Clinical Studies ]

    .

    Lacosamide Injection Dosage

    Lacosamide injection may be used when oral administration is temporarily not feasible

    [see Warnings and Precautions ].

    Lacosamide injection can be administered intravenously to adult and pediatric patients weighing 6 kg or more with the same dosing regimens described for oral dosing. For pediatric patients weighing less than 6 kg, lacosamide injection may be initiated with a dose of 0.66 mg/kg three times daily (see Table 1).

    The clinical study experience of intravenous lacosamide is limited to 5 days of consecutive treatment.
    )
  • Initial dosage for adjunctive therapy for the treatment of partial-onset seizures or primary generalized tonic-clonic seizures is 50 mg twice daily (
    2.1 Dosage Information

    The recommended dosage for monotherapy and adjunctive therapy for partial-onset seizures in patients 1 month of age and older and for adjunctive therapy for primary generalized tonic-clonic seizures in patients 4 years of age and older is included in Table 1. In pediatric patients, the recommended dosing regimen is dependent upon body weight. Dosage should be increased based on clinical response and tolerability, no more frequently than once per week. Titration increments should not exceed those shown in Table 1.

    Table 1: Recommended Dosages for Partial-Onset Seizures (Monotherapy or Adjunctive Therapy) in Patients 1 Month and Older, and for Primary Generalized Tonic-Clonic Seizures (Adjunctive Therapy) in Patients 4 Years of Age and Older *

    *when not specified, the dosage is the same for monotherapy for partial-onset seizures and adjunctive therapy for partial-onset seizures or primary generalized tonic-clonic seizures.
    **Monotherapy for partial-onset seizures only
    ± indicated only for partial-onset seizures
    Age and Body Weight	Initial Dosage	Titration Regimen	Maintenance Dosage
    Adults (17 years and older)	Monotherapy**: 100 mg twice daily (200 mg per day) Adjunctive Therapy: 50 mg twice daily (100 mg per day)	Increase by 50 mg twice daily (100 mg per day) every week	Monotherapy**: 150 mg to 200 mg twice daily (300 mg to 400 mg per day) Adjunctive Therapy: 100 mg to 200 mg twice daily (200 mg to 400 mg per day)
    Pediatric patients weighing at least 50 kg	50 mg twice daily (100 mg per day)	Increase by 50 mg twice daily (100 mg per day) every week	Monotherapy**: 150 mg to 200 mg twice daily (300 mg to 400 mg per day) Adjunctive Therapy: 100 mg to 200 mg twice daily (200 mg to 400 mg per day)
    Pediatric patients weighing 30 kg to less than 50 kg	1 mg/kg twice daily (2 mg/kg/day)	Increase by 1 mg/kg twice daily (2 mg/kg/day) every week	2 mg/kg to 4 mg/kg twice daily (4 mg/kg/day to 8 mg/kg/day)
    Pediatric patients weighing 11 kg to less than 30 kg	1 mg/kg twice daily (2 mg/kg/day)	Increase by 1 mg/kg twice daily (2 mg/kg/day) every week	3 mg/kg to 6 mg/kg twice daily (6 mg/kg/day to 12 mg/kg/day)
    Pediatric patients weighing 6 kg to less than 11 kg ±
    Pediatric patients weighing less than 6kg ±	Intravenous: 0.66 mg/kg three times daily (2 mg/kg/day)	Intravenous: Increase by 0.66 mg/kg three times daily (2 mg/kg/day) every week	Intravenous: 2.5 mg/kg to 5 mg/kg three times daily (7.5 mg/kg/day to 15 mg/kg/day)

    In adjunctive clinical trials in adult patients with partial-onset seizures, a dosage higher than 200 mg twice daily (400 mg per day) was not more effective and was associated with a substantially higher rate of adverse reactions

    [see Adverse Reactions and Clinical Studies ]

    .

    Lacosamide Injection Dosage

    Lacosamide injection may be used when oral administration is temporarily not feasible

    [see Warnings and Precautions ].

    Lacosamide injection can be administered intravenously to adult and pediatric patients weighing 6 kg or more with the same dosing regimens described for oral dosing. For pediatric patients weighing less than 6 kg, lacosamide injection may be initiated with a dose of 0.66 mg/kg three times daily (see Table 1).

    The clinical study experience of intravenous lacosamide is limited to 5 days of consecutive treatment.
    )
  • Maximum recommended dosage for monotherapy and adjunctive therapy is 200 mg twice daily (
    2.1 Dosage Information

    The recommended dosage for monotherapy and adjunctive therapy for partial-onset seizures in patients 1 month of age and older and for adjunctive therapy for primary generalized tonic-clonic seizures in patients 4 years of age and older is included in Table 1. In pediatric patients, the recommended dosing regimen is dependent upon body weight. Dosage should be increased based on clinical response and tolerability, no more frequently than once per week. Titration increments should not exceed those shown in Table 1.

    Table 1: Recommended Dosages for Partial-Onset Seizures (Monotherapy or Adjunctive Therapy) in Patients 1 Month and Older, and for Primary Generalized Tonic-Clonic Seizures (Adjunctive Therapy) in Patients 4 Years of Age and Older *

    *when not specified, the dosage is the same for monotherapy for partial-onset seizures and adjunctive therapy for partial-onset seizures or primary generalized tonic-clonic seizures.
    **Monotherapy for partial-onset seizures only
    ± indicated only for partial-onset seizures
    Age and Body Weight	Initial Dosage	Titration Regimen	Maintenance Dosage
    Adults (17 years and older)	Monotherapy**: 100 mg twice daily (200 mg per day) Adjunctive Therapy: 50 mg twice daily (100 mg per day)	Increase by 50 mg twice daily (100 mg per day) every week	Monotherapy**: 150 mg to 200 mg twice daily (300 mg to 400 mg per day) Adjunctive Therapy: 100 mg to 200 mg twice daily (200 mg to 400 mg per day)
    Pediatric patients weighing at least 50 kg	50 mg twice daily (100 mg per day)	Increase by 50 mg twice daily (100 mg per day) every week	Monotherapy**: 150 mg to 200 mg twice daily (300 mg to 400 mg per day) Adjunctive Therapy: 100 mg to 200 mg twice daily (200 mg to 400 mg per day)
    Pediatric patients weighing 30 kg to less than 50 kg	1 mg/kg twice daily (2 mg/kg/day)	Increase by 1 mg/kg twice daily (2 mg/kg/day) every week	2 mg/kg to 4 mg/kg twice daily (4 mg/kg/day to 8 mg/kg/day)
    Pediatric patients weighing 11 kg to less than 30 kg	1 mg/kg twice daily (2 mg/kg/day)	Increase by 1 mg/kg twice daily (2 mg/kg/day) every week	3 mg/kg to 6 mg/kg twice daily (6 mg/kg/day to 12 mg/kg/day)
    Pediatric patients weighing 6 kg to less than 11 kg ±
    Pediatric patients weighing less than 6kg ±	Intravenous: 0.66 mg/kg three times daily (2 mg/kg/day)	Intravenous: Increase by 0.66 mg/kg three times daily (2 mg/kg/day) every week	Intravenous: 2.5 mg/kg to 5 mg/kg three times daily (7.5 mg/kg/day to 15 mg/kg/day)

    In adjunctive clinical trials in adult patients with partial-onset seizures, a dosage higher than 200 mg twice daily (400 mg per day) was not more effective and was associated with a substantially higher rate of adverse reactions

    [see Adverse Reactions and Clinical Studies ]

    .

    Lacosamide Injection Dosage

    Lacosamide injection may be used when oral administration is temporarily not feasible

    [see Warnings and Precautions ].

    Lacosamide injection can be administered intravenously to adult and pediatric patients weighing 6 kg or more with the same dosing regimens described for oral dosing. For pediatric patients weighing less than 6 kg, lacosamide injection may be initiated with a dose of 0.66 mg/kg three times daily (see Table 1).

    The clinical study experience of intravenous lacosamide is limited to 5 days of consecutive treatment.
    )
  • Pediatric Patients 1 month to less than 17 years: The recommended dosage is based on body weight and is administered orally twice daily (
    2.1 Dosage Information

    The recommended dosage for monotherapy and adjunctive therapy for partial-onset seizures in patients 1 month of age and older and for adjunctive therapy for primary generalized tonic-clonic seizures in patients 4 years of age and older is included in Table 1. In pediatric patients, the recommended dosing regimen is dependent upon body weight. Dosage should be increased based on clinical response and tolerability, no more frequently than once per week. Titration increments should not exceed those shown in Table 1.

    Table 1: Recommended Dosages for Partial-Onset Seizures (Monotherapy or Adjunctive Therapy) in Patients 1 Month and Older, and for Primary Generalized Tonic-Clonic Seizures (Adjunctive Therapy) in Patients 4 Years of Age and Older *

    *when not specified, the dosage is the same for monotherapy for partial-onset seizures and adjunctive therapy for partial-onset seizures or primary generalized tonic-clonic seizures.
    **Monotherapy for partial-onset seizures only
    ± indicated only for partial-onset seizures
    Age and Body Weight	Initial Dosage	Titration Regimen	Maintenance Dosage
    Adults (17 years and older)	Monotherapy**: 100 mg twice daily (200 mg per day) Adjunctive Therapy: 50 mg twice daily (100 mg per day)	Increase by 50 mg twice daily (100 mg per day) every week	Monotherapy**: 150 mg to 200 mg twice daily (300 mg to 400 mg per day) Adjunctive Therapy: 100 mg to 200 mg twice daily (200 mg to 400 mg per day)
    Pediatric patients weighing at least 50 kg	50 mg twice daily (100 mg per day)	Increase by 50 mg twice daily (100 mg per day) every week	Monotherapy**: 150 mg to 200 mg twice daily (300 mg to 400 mg per day) Adjunctive Therapy: 100 mg to 200 mg twice daily (200 mg to 400 mg per day)
    Pediatric patients weighing 30 kg to less than 50 kg	1 mg/kg twice daily (2 mg/kg/day)	Increase by 1 mg/kg twice daily (2 mg/kg/day) every week	2 mg/kg to 4 mg/kg twice daily (4 mg/kg/day to 8 mg/kg/day)
    Pediatric patients weighing 11 kg to less than 30 kg	1 mg/kg twice daily (2 mg/kg/day)	Increase by 1 mg/kg twice daily (2 mg/kg/day) every week	3 mg/kg to 6 mg/kg twice daily (6 mg/kg/day to 12 mg/kg/day)
    Pediatric patients weighing 6 kg to less than 11 kg ±
    Pediatric patients weighing less than 6kg ±	Intravenous: 0.66 mg/kg three times daily (2 mg/kg/day)	Intravenous: Increase by 0.66 mg/kg three times daily (2 mg/kg/day) every week	Intravenous: 2.5 mg/kg to 5 mg/kg three times daily (7.5 mg/kg/day to 15 mg/kg/day)

    In adjunctive clinical trials in adult patients with partial-onset seizures, a dosage higher than 200 mg twice daily (400 mg per day) was not more effective and was associated with a substantially higher rate of adverse reactions

    [see Adverse Reactions and Clinical Studies ]

    .

    Lacosamide Injection Dosage

    Lacosamide injection may be used when oral administration is temporarily not feasible

    [see Warnings and Precautions ].

    Lacosamide injection can be administered intravenously to adult and pediatric patients weighing 6 kg or more with the same dosing regimens described for oral dosing. For pediatric patients weighing less than 6 kg, lacosamide injection may be initiated with a dose of 0.66 mg/kg three times daily (see Table 1).

    The clinical study experience of intravenous lacosamide is limited to 5 days of consecutive treatment.
    )
• Increase dosage based on clinical response and tolerability, no more frequently than once per week (
  2.1 Dosage Information

  The recommended dosage for monotherapy and adjunctive therapy for partial-onset seizures in patients 1 month of age and older and for adjunctive therapy for primary generalized tonic-clonic seizures in patients 4 years of age and older is included in Table 1. In pediatric patients, the recommended dosing regimen is dependent upon body weight. Dosage should be increased based on clinical response and tolerability, no more frequently than once per week. Titration increments should not exceed those shown in Table 1.

  Table 1: Recommended Dosages for Partial-Onset Seizures (Monotherapy or Adjunctive Therapy) in Patients 1 Month and Older, and for Primary Generalized Tonic-Clonic Seizures (Adjunctive Therapy) in Patients 4 Years of Age and Older *

  *when not specified, the dosage is the same for monotherapy for partial-onset seizures and adjunctive therapy for partial-onset seizures or primary generalized tonic-clonic seizures.
  **Monotherapy for partial-onset seizures only
  ± indicated only for partial-onset seizures
  Age and Body Weight	Initial Dosage	Titration Regimen	Maintenance Dosage
  Adults (17 years and older)	Monotherapy**: 100 mg twice daily (200 mg per day) Adjunctive Therapy: 50 mg twice daily (100 mg per day)	Increase by 50 mg twice daily (100 mg per day) every week	Monotherapy**: 150 mg to 200 mg twice daily (300 mg to 400 mg per day) Adjunctive Therapy: 100 mg to 200 mg twice daily (200 mg to 400 mg per day)
  Pediatric patients weighing at least 50 kg	50 mg twice daily (100 mg per day)	Increase by 50 mg twice daily (100 mg per day) every week	Monotherapy**: 150 mg to 200 mg twice daily (300 mg to 400 mg per day) Adjunctive Therapy: 100 mg to 200 mg twice daily (200 mg to 400 mg per day)
  Pediatric patients weighing 30 kg to less than 50 kg	1 mg/kg twice daily (2 mg/kg/day)	Increase by 1 mg/kg twice daily (2 mg/kg/day) every week	2 mg/kg to 4 mg/kg twice daily (4 mg/kg/day to 8 mg/kg/day)
  Pediatric patients weighing 11 kg to less than 30 kg	1 mg/kg twice daily (2 mg/kg/day)	Increase by 1 mg/kg twice daily (2 mg/kg/day) every week	3 mg/kg to 6 mg/kg twice daily (6 mg/kg/day to 12 mg/kg/day)
  Pediatric patients weighing 6 kg to less than 11 kg ±
  Pediatric patients weighing less than 6kg ±	Intravenous: 0.66 mg/kg three times daily (2 mg/kg/day)	Intravenous: Increase by 0.66 mg/kg three times daily (2 mg/kg/day) every week	Intravenous: 2.5 mg/kg to 5 mg/kg three times daily (7.5 mg/kg/day to 15 mg/kg/day)

  In adjunctive clinical trials in adult patients with partial-onset seizures, a dosage higher than 200 mg twice daily (400 mg per day) was not more effective and was associated with a substantially higher rate of adverse reactions

  [see Adverse Reactions and Clinical Studies ]

  .

  Lacosamide Injection Dosage

  Lacosamide injection may be used when oral administration is temporarily not feasible

  [see Warnings and Precautions ].

  Lacosamide injection can be administered intravenously to adult and pediatric patients weighing 6 kg or more with the same dosing regimens described for oral dosing. For pediatric patients weighing less than 6 kg, lacosamide injection may be initiated with a dose of 0.66 mg/kg three times daily (see Table 1).

  The clinical study experience of intravenous lacosamide is limited to 5 days of consecutive treatment.
  )
• Injection: for intravenous use only when oral administration is temporarily not feasible; the recommended dosage is based on body weight and is administered two or three times daily over 15 to 60 minutes; obtaining ECG before initiation is recommended in certain patients (
  2.8 Discontinuation of Lacosamide

  When discontinuing lacosamide, a gradual withdrawal over at least 1 week is recommended

  [see Warnings and Precautions ]

  .
  ,
  5.3 Cardiac Rhythm and Conduction Abnormalities

  PR Interval Prolongation, Atrioventricular Block, and Ventricular Tachyarrhythmia

  Dose-dependent prolongations in PR interval with lacosamide have been observed in clinical studies in adult patients and in healthy volunteers

  [see Clinical Pharmacology ]

  . In adjunctive clinical trials in adult patients with partial-onset seizures, asymptomatic first-degree atrioventricular (AV) block was observed as an adverse reaction in 0.4% (4/944) of patients randomized to receive lacosamide and 0% (0/364) of patients randomized to receive placebo. One case of profound bradycardia was observed in a patient during a 15-minute infusion of 150 mg lacosamide. When lacosamide is given with other drugs that prolong the PR interval, further PR prolongation is possible.

  In the postmarketing setting, there have been reports of cardiac arrhythmias in patients treated with lacosamide, including bradycardia, AV block, and ventricular tachyarrhythmia, which have rarely resulted in asystole, cardiac arrest, and death. Most, although not all, cases have occurred in patients with underlying proarrhythmic conditions, or in those taking concomitant medications that affect cardiac conduction or prolong the PR interval. These events have occurred with both oral and intravenous routes of administration and at prescribed doses as well as in the setting of overdose

  [see Overdosage ]

  . In all patients for whom a loading dose is clinically indicated, administer the loading dose with medical supervision because of the possibility of increased incidence of adverse reactions, including cardiovascular adverse reactions.

  Lacosamide should be used with caution in patients with underlying proarrhythmic conditions such as known cardiac conduction problems (e.g., marked first-degree AV block, second-degree or higher AV block and sick sinus syndrome without pacemaker), severe cardiac disease (such as myocardial ischemia or heart failure, or structural heart disease), and cardiac sodium channelopathies (e.g., Brugada Syndrome). Lacosamide should also be used with caution in patients on concomitant medications that affect cardiac conduction, including sodium channel blockers, beta-blockers, calcium channel blockers, potassium channel blockers, and medications that prolong the PR interval

  [see Drug Interactions ]

  . In such patients, obtaining an ECG before beginning lacosamide, and after lacosamide is titrated to steady-state maintenance dose, is recommended. In addition, these patients should be closely monitored if they are administered lacosamide through the intravenous route

  [see Adverse Reactions and Drug Interactions ]

  .

  Atrial Fibrillation and Atrial Flutter

  In the short-term investigational trials of lacosamide in adult patients with partial-onset seizures there were no cases of atrial fibrillation or flutter. Both atrial fibrillation and atrial flutter have been reported in open label partial-onset seizure trials and in postmarketing experience. In adult patients with diabetic neuropathy, for which lacosamide is not indicated, 0.5% of patients treated with lacosamide experienced an adverse reaction of atrial fibrillation or atrial flutter, compared to 0% of placebo-treated patients. Lacosamide administration may predispose to atrial arrhythmias (atrial fibrillation or flutter), especially in patients with diabetic neuropathy and/or cardiovascular disease.
  )
• Dose adjustment is recommended for severe renal impairment (
  2.4 Dosage Information for Patients with Renal Impairment

  For patients with mild to moderate renal impairment, no dosage adjustment is necessary.

  For patients with severe renal impairment [creatinine clearance (CL_CR) less than 30 mL/min as estimated by the Cockcroft-Gault equation for adults; CL_CRless than 30 mL/min/1.73m²as estimated by the Schwartz equation for pediatric patients] or end-stage renal disease, a reduction of 25% of the maximum dosage is recommended.

  In all patients with renal impairment, dose initiation and titration should be based on clinical response and tolerability.

  Hemodialysis

  Lacosamide is effectively removed from plasma by hemodialysis. Following a 4-hour hemodialysis treatment, dosage supplementation of up to 50% should be considered.

  Concomitant Strong CYP3A4 or CYP2C9 Inhibitors

  Dose reduction may be necessary in patients with renal impairment who are taking strong inhibitors of CYP3A4 and CYP2C9

  [see Drug Interactions , Use in Specific Populations and Clinical Pharmacology ]

  .
  ,
  12.3 Pharmacokinetics

  The pharmacokinetics of lacosamide 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. The pharmacokinetics of lacosamide are similar in healthy subjects, patients with partial-onset seizures, and patients with primary generalized tonic-clonic seizures.

  Lacosamide 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 lacosamide are dose proportional (100 to 800 mg) and time invariant, with low inter- and intra-subject variability. Compared to lacosamide the major metabolite, O-desmethyl metabolite, has a longer T_max(0.5 to 12 hours) and elimination half-life (15 to 23 hours).

  Absorption and Bioavailability

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

  After intravenous administration, C_maxis 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 C_max. The point estimate of C_maxwas 20% higher than C_maxfor oral tablet and the 90% CI for C_maxexceeded 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. Lacosamide is less than 15% bound to plasma proteins.

  Metabolism and Elimination

  Lacosamide 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.

  Specific Populations

  Renal Impairment

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

  The AUC of lacosamide was increased approximately 25% in mildly (CL_CR50 to 80 mL/min) and moderately (CL_CR30 to 50 mL/min) and 60% in severely (CL_CR≤30 mL/min) renally impaired patients compared to subjects with normal renal function (CL_CR>80 mL/min), whereas C_maxwas unaffected. Lacosamide is effectively removed from plasma by hemodialysis. Following a 4-hour hemodialysis treatment, AUC of lacosamide is reduced by approximately 50% [

  see Dosage and Administration

  ].

  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 pharmacokinetics of lacosamide have not been evaluated in severe hepatic impairment [

  see Dosage and Administration

  ].

  Pediatric Patients (1 month to less than 17 Years of Age)

  A multicenter, double-blind, randomized, placebo-controlled, parallel-group study with a 20-day titration period and 7-day maintenance period using lacosamide oral solution (8mg/kg/day to 12mg/kg/day) was conducted in 255 (128 were randomized to lacosamide and 127 were randomized to placebo) pediatric patients with epilepsy 1 month to less than 4 years of age with uncontrolled partial-onset seizures. The pediatric pharmacokinetic profile of lacosamide was determined in a population pharmacokinetic analysis using sparse plasma concentration data obtained in six placebo-controlled studies and five open-label studies in 1,655 adult and pediatric patients with epilepsy aged 1 month to less than 17 years who received intravenous, oral solution, or oral tablet formulations.

  A weight based dosing regimen is necessary to achieve lacosamide exposures in pediatric patients 1 month to less than 17 years of age similar to those observed in adults treated at effective doses of lacosamide

  [see Dosage and Administration ].

  For patients weighing 10 kg, 28.9 kg (the mean population body weight), and 70 kg, the typical plasma half-life (t_1/2) is 7.2 hours, 10.6 hours, and 14.8 hours, respectively. Steady state plasma concentrations are achieved after 3 days of twice daily repeated administration.

  The pharmacokinetics of lacosamide in pediatric patients are similar when used as monotherapy or as adjunctive therapy for the treatment of partial-onset seizures and as adjunctive therapy for the treatment of primary generalized tonic-clonic seizures.

  Geriatric Patients

  In the elderly (>65 years), dose and body-weight normalized AUC and C_maxis about 20% increased compared to young subjects (18 to 64 years). This may be related to body weight and decreased renal function in elderly subjects.

  Gender

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

  Race

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

  CYP2C19 Polymorphism

  There are no clinically relevant differences in the pharmacokinetics of lacosamide 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 lacosamide on concomitant AEDs

  Lacosamide 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 lacosamide at any dose.

  ○

  Effect of concomitant AEDs on lacosamide

  Drug-drug interaction studies in healthy subjects showed that 600 mg/day valproic acid had no influence on the pharmacokinetics of 400 mg/day lacosamide. Likewise, 400 mg/day carbamazepine had no influence on the pharmacokinetics of lacosamide 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 lacosamide was coadministered with carbamazepine, phenobarbital or phenytoin.

  • Drug-drug interaction studies with other drugs

  ○    Digoxin

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

  ○

  Omeprazole

  Omeprazole is a CYP2C19 substrate and inhibitor. There was no effect of lacosamide (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 lacosamide (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 lacosamide (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 lacosamide (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 C_maxwas observed.

  ○

  Warfarin

  Coadministration of lacosamide (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.
  )
• Dose adjustment is recommended for mild or moderate hepatic impairment; use in patients with severe hepatic impairment is not recommended (
  2.5 Dosage Information for Patients with Hepatic Impairment

  For patients with mild or moderate hepatic impairment, a reduction of 25% of the maximum dosage is recommended. The dose initiation and titration should be based on clinical response and tolerability in patients with hepatic impairment.

  Lacosamide use is not recommended in patients with severe hepatic impairment.

  Concomitant Strong CYP3A4 and CYP2C9 Inhibitors

  Dose reduction may be necessary in patients with hepatic impairment who are taking strong inhibitors of CYP3A4 and CYP2C9

  [see Drug Interactions , Use in Specific Populations and Clinical Pharmacology ]

  .
  ,
  12.3 Pharmacokinetics

  The pharmacokinetics of lacosamide 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. The pharmacokinetics of lacosamide are similar in healthy subjects, patients with partial-onset seizures, and patients with primary generalized tonic-clonic seizures.

  Lacosamide 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 lacosamide are dose proportional (100 to 800 mg) and time invariant, with low inter- and intra-subject variability. Compared to lacosamide the major metabolite, O-desmethyl metabolite, has a longer T_max(0.5 to 12 hours) and elimination half-life (15 to 23 hours).

  Absorption and Bioavailability

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

  After intravenous administration, C_maxis 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 C_max. The point estimate of C_maxwas 20% higher than C_maxfor oral tablet and the 90% CI for C_maxexceeded 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. Lacosamide is less than 15% bound to plasma proteins.

  Metabolism and Elimination

  Lacosamide 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.

  Specific Populations

  Renal Impairment

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

  The AUC of lacosamide was increased approximately 25% in mildly (CL_CR50 to 80 mL/min) and moderately (CL_CR30 to 50 mL/min) and 60% in severely (CL_CR≤30 mL/min) renally impaired patients compared to subjects with normal renal function (CL_CR>80 mL/min), whereas C_maxwas unaffected. Lacosamide is effectively removed from plasma by hemodialysis. Following a 4-hour hemodialysis treatment, AUC of lacosamide is reduced by approximately 50% [

  see Dosage and Administration

  ].

  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 pharmacokinetics of lacosamide have not been evaluated in severe hepatic impairment [

  see Dosage and Administration

  ].

  Pediatric Patients (1 month to less than 17 Years of Age)

  A multicenter, double-blind, randomized, placebo-controlled, parallel-group study with a 20-day titration period and 7-day maintenance period using lacosamide oral solution (8mg/kg/day to 12mg/kg/day) was conducted in 255 (128 were randomized to lacosamide and 127 were randomized to placebo) pediatric patients with epilepsy 1 month to less than 4 years of age with uncontrolled partial-onset seizures. The pediatric pharmacokinetic profile of lacosamide was determined in a population pharmacokinetic analysis using sparse plasma concentration data obtained in six placebo-controlled studies and five open-label studies in 1,655 adult and pediatric patients with epilepsy aged 1 month to less than 17 years who received intravenous, oral solution, or oral tablet formulations.

  A weight based dosing regimen is necessary to achieve lacosamide exposures in pediatric patients 1 month to less than 17 years of age similar to those observed in adults treated at effective doses of lacosamide

  [see Dosage and Administration ].

  For patients weighing 10 kg, 28.9 kg (the mean population body weight), and 70 kg, the typical plasma half-life (t_1/2) is 7.2 hours, 10.6 hours, and 14.8 hours, respectively. Steady state plasma concentrations are achieved after 3 days of twice daily repeated administration.

  The pharmacokinetics of lacosamide in pediatric patients are similar when used as monotherapy or as adjunctive therapy for the treatment of partial-onset seizures and as adjunctive therapy for the treatment of primary generalized tonic-clonic seizures.

  Geriatric Patients

  In the elderly (>65 years), dose and body-weight normalized AUC and C_maxis about 20% increased compared to young subjects (18 to 64 years). This may be related to body weight and decreased renal function in elderly subjects.

  Gender

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

  Race

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

  CYP2C19 Polymorphism

  There are no clinically relevant differences in the pharmacokinetics of lacosamide 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 lacosamide on concomitant AEDs

  Lacosamide 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 lacosamide at any dose.

  ○

  Effect of concomitant AEDs on lacosamide

  Drug-drug interaction studies in healthy subjects showed that 600 mg/day valproic acid had no influence on the pharmacokinetics of 400 mg/day lacosamide. Likewise, 400 mg/day carbamazepine had no influence on the pharmacokinetics of lacosamide 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 lacosamide was coadministered with carbamazepine, phenobarbital or phenytoin.

  • Drug-drug interaction studies with other drugs

  ○    Digoxin

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

  ○

  Omeprazole

  Omeprazole is a CYP2C19 substrate and inhibitor. There was no effect of lacosamide (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 lacosamide (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 lacosamide (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 lacosamide (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 C_maxwas observed.

  ○

  Warfarin

  Coadministration of lacosamide (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.
  )

• 200 mg/20 mL injection: clear, colorless sterile solution in single-dose vials

• Pregnancy: Based on animal data, may cause fetal harm (
  8.1 Pregnancy

  Pregnancy Exposure Registry

  There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as lacosamide, during pregnancy. Encourage women who are taking lacosamide during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/.

  Risk Summary

  Available data from the North American Antiepileptic Drug (NAAED) pregnancy registry, a prospective cohort study, case reports, and a case series with lacosamide use in pregnant women are insufficient to identify a drug associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. 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

  (see Data)

  .

  The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

  Data

  Animal Data

  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 effects on the incidences of fetal structural abnormalities. 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 (AUC) approximately 2 and 1 times (rat and rabbit, respectively) that in humans at the maximum recommended human dose (MRHD) of 400 mg/day.

  In two studies in which lacosamide (25, 70, or 200 mg/kg/day and 50, 100, or 200 mg/kg/day) was orally administered to rats throughout pregnancy and lactation, increased perinatal mortality and decreased body weights in the offspring were observed at the highest dose tested. The no-effect dose for pre- and postnatal developmental toxicity in rats (70 mg/kg/day) was associated with a maternal plasma lacosamide AUC similar 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 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 less than that in humans at the MRHD.

  In Vitro Data

  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 related to this activity cannot be ruled out.
  )

• Monitor patients for suicidal behavior and ideation (
  5.1 Suicidal Behavior and Ideation

  Antiepileptic drugs (AEDs), including lacosamide, 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 to 100 years) in the clinical trials analyzed.

  Table 3 shows absolute and relative risk by indication for all evaluated AEDs.

  Table 3: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis

  Indication	Placebo Patients with Events Per 1,000 Patients	Drug Patients with Events Per 1,000 Patients	Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients	Risk Difference: Additional Drug Patients with Events Per 1,000 Patients
  Epilepsy	1	3.4	3.5	2.4
  Psychiatric	5.7	8.5	1.5	2.9
  Other	1	1.8	1.9	0.9
  Total	2.4	4.3	1.8	1.9

  The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar.

  Anyone considering prescribing lacosamide or any other AED must balance this risk with the risk of untreated illness. Epilepsy and many other illnesses for which antiepileptics are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
  )
• Lacosamide may cause dizziness and ataxia (
  5.2 Dizziness and Ataxia

  Lacosamide may cause dizziness and ataxia in adult and pediatric patients. In adult patients with partial-onset seizures taking 1 to 3 concomitant AEDs, dizziness was experienced by 25% of patients randomized to the recommended doses (200 to 400 mg/day) of lacosamide (compared with 8% of placebo patients) and was the adverse reaction most frequently leading to discontinuation (3%). Ataxia was experienced by 6% of patients randomized to the recommended doses (200 to 400 mg/day) of lacosamide (compared to 2% of placebo patients). The onset of dizziness and ataxia was most commonly observed during titration. There was a substantial increase in these adverse reactions at doses higher than 400 mg/day

  [see Adverse Reactions ]

  . If a loading dose is clinically indicated, administer with medical supervision because of the possibility of increased incidence of adverse reactions, including CNS adverse reactions such as dizziness and ataxia.
  )
• Cardiac Rhythm and Conduction Abnormalities: Obtaining ECG before beginning and after titration to steady-state maintenance is recommended in patients with underlying proarrhythmic conditions or on concomitant medications that affect cardiac conduction; closely monitor these patients (
  5.3 Cardiac Rhythm and Conduction Abnormalities

  PR Interval Prolongation, Atrioventricular Block, and Ventricular Tachyarrhythmia

  Dose-dependent prolongations in PR interval with lacosamide have been observed in clinical studies in adult patients and in healthy volunteers

  [see Clinical Pharmacology ]

  . In adjunctive clinical trials in adult patients with partial-onset seizures, asymptomatic first-degree atrioventricular (AV) block was observed as an adverse reaction in 0.4% (4/944) of patients randomized to receive lacosamide and 0% (0/364) of patients randomized to receive placebo. One case of profound bradycardia was observed in a patient during a 15-minute infusion of 150 mg lacosamide. When lacosamide is given with other drugs that prolong the PR interval, further PR prolongation is possible.

  In the postmarketing setting, there have been reports of cardiac arrhythmias in patients treated with lacosamide, including bradycardia, AV block, and ventricular tachyarrhythmia, which have rarely resulted in asystole, cardiac arrest, and death. Most, although not all, cases have occurred in patients with underlying proarrhythmic conditions, or in those taking concomitant medications that affect cardiac conduction or prolong the PR interval. These events have occurred with both oral and intravenous routes of administration and at prescribed doses as well as in the setting of overdose

  [see Overdosage ]

  . In all patients for whom a loading dose is clinically indicated, administer the loading dose with medical supervision because of the possibility of increased incidence of adverse reactions, including cardiovascular adverse reactions.

  Lacosamide should be used with caution in patients with underlying proarrhythmic conditions such as known cardiac conduction problems (e.g., marked first-degree AV block, second-degree or higher AV block and sick sinus syndrome without pacemaker), severe cardiac disease (such as myocardial ischemia or heart failure, or structural heart disease), and cardiac sodium channelopathies (e.g., Brugada Syndrome). Lacosamide should also be used with caution in patients on concomitant medications that affect cardiac conduction, including sodium channel blockers, beta-blockers, calcium channel blockers, potassium channel blockers, and medications that prolong the PR interval

  [see Drug Interactions ]

  . In such patients, obtaining an ECG before beginning lacosamide, and after lacosamide is titrated to steady-state maintenance dose, is recommended. In addition, these patients should be closely monitored if they are administered lacosamide through the intravenous route

  [see Adverse Reactions and Drug Interactions ]

  .

  Atrial Fibrillation and Atrial Flutter

  In the short-term investigational trials of lacosamide in adult patients with partial-onset seizures there were no cases of atrial fibrillation or flutter. Both atrial fibrillation and atrial flutter have been reported in open label partial-onset seizure trials and in postmarketing experience. In adult patients with diabetic neuropathy, for which lacosamide is not indicated, 0.5% of patients treated with lacosamide experienced an adverse reaction of atrial fibrillation or atrial flutter, compared to 0% of placebo-treated patients. Lacosamide administration may predispose to atrial arrhythmias (atrial fibrillation or flutter), especially in patients with diabetic neuropathy and/or cardiovascular disease.
  ,
  7.2 Concomitant Medications that Affect Cardiac Conduction

  Lacosamide should be used with caution in patients on concomitant medications that affect cardiac conduction (sodium channel blockers, beta-blockers, calcium channel blockers, potassium channel blockers) including those that prolong PR interval (including sodium channel blocking AEDs), because of a risk of AV block, bradycardia, or ventricular tachyarrhythmia. In such patients, obtaining an ECG before beginning lacosamide, and after lacosamide is titrated to steady-state, is recommended. In addition, these patients should be closely monitored if they are administered lacosamide through the intravenous route

  [see Warnings and Precautions ]

  .
  )
• Lacosamide may cause syncope (
  5.4 Syncope

  In the short-term controlled trials of lacosamide in adult patients with partial-onset seizures with no significant system illnesses, there was no increase in syncope compared to placebo. In the short-term controlled trials in adult patients with diabetic neuropathy, for which lacosamide is not indicated, 1.2% of patients who were treated with lacosamide reported an adverse reaction of syncope or loss of consciousness, compared with 0% of placebo-treated patients with diabetic neuropathy. Most of the cases of syncope were observed in patients receiving doses above 400 mg/day. The cause of syncope was not determined in most cases. However, several were associated with either changes in orthostatic blood pressure, atrial flutter/fibrillation (and associated tachycardia), or bradycardia. Cases of syncope have also been observed in open-label clinical partial-onset seizure studies in adult and pediatric patients. These cases were associated with a history of risk factors for cardiac disease and the use of drugs that slow AV conduction.
  )
• Lacosamide should be gradually withdrawn to minimize the potential of increased seizure frequency (
  5.5 Withdrawal of Antiepileptic Drugs (AEDs)

  As with all AEDs, lacosamide should be withdrawn gradually (over a minimum of 1 week) to minimize the potential of increased seizure frequency in patients with seizure disorders.
  )
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity: Discontinue if no alternate etiology (
  5.6 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity

  Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multi-organ hypersensitivity, has been reported in patients taking antiepileptic drugs, including lacosamide. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Lacosamide should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
  )