Lacosamide - Lacosamide injection (Lacosamide)

Lacosamide Injection is indicated for:

• Treatment of partial-onset seizures in patients 4 years of age and older (
  
  
  1.1 Partial-Onset Seizures

  Lacosamide Injection is indicated for the treatment of partial-onset seizures in patients 4 years of age and older.

  Pediatric use information is approved for UCB, Inc.'s VIMPAT® (lacosamide) injection. However, due to UCB, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.
  )
  
• Adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in patients 4 years of age and older (1.2)

• 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 4 years 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 4 Years and Older, and for Primary Generalized Tonic-Clonic Seizures (Adjunctive Therapy) in Patients 4 Years of Age and Older*

    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 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)
    *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

    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 (6.1)and Clinical Studies (14.2)]

    .

    Lacosamide Injection Dosage

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

    [see Dosage and Administration (2.6)and Warnings and Precautions (5.3)].

    Lacosamide injection can be administered intravenously to adult patients with the same dosing regimens described for oral dosing.

    The clinical study experience of intravenous Lacosamide Injection is limited to 5 days of consecutive treatment.

    Pediatric use information is approved for UCB, Inc.'s VIMPAT^®(lacosamide) injection. However, due to UCB, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

    2.2 Alternate Initial Dosage Information to Achieve the Maintenance Dosage in a Shorter Timeframe

    For monotherapy and adjunctive therapy for partial-onset seizures in patients 17 years of age and older and for adjunctive therapy for primary generalized tonic-clonic seizures in patients 17 years of age and older, an alternate initial dosing regimen for week 1 (e.g., including a loading dose and/or a higher initial dosage) may be administered in patients for whom achieving the recommended maintenance dosage in a shorter timeframe is clinically indicated (see Table 2). The alternate initial dosage regimen should be continued for one week. Lacosamide may then be titrated based on clinical response and tolerability, no more frequently than once per week, if needed. The loading dose should be administered with medical supervision because of the possibility of increased incidence of adverse reactions, including central nervous system (CNS) and cardiovascular adverse reactions [

    see Warnings and Precautions (5.2, 5.3), Adverse Reactions (6.1), and Clinical Pharmacology (12.3)

    ]. Titration increments should not exceed those shown in Table 2.

    Table 2: Alternate Initial Dosing Regimen to Achieve the Maintenance Dosage in a Shorter Timeframe if Clinically Indicated*

    Age and Body Weight	Alternate Initial Dosage	Titration Regimen	Maintenance Dosage
    Adults (17 years and older)	Single loading dose: 200 mg 12 hours later initiate: 100 mg twice daily (200 mg per day)	Increase by 50 mg twice daily (100 mg per day) at weekly intervals, if needed	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)
    *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.

    Pediatric use information is approved for UCB, Inc.'s VIMPAT^®(lacosamide) injection. However, due to UCB, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.
    )
    
  • Initial dosage for adjunctive therapy for the treatment of partial-onset seizures or primary geeneralized 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 4 years 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 4 Years and Older, and for Primary Generalized Tonic-Clonic Seizures (Adjunctive Therapy) in Patients 4 Years of Age and Older*

    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 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)
    *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

    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 (6.1)and Clinical Studies (14.2)]

    .

    Lacosamide Injection Dosage

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

    [see Dosage and Administration (2.6)and Warnings and Precautions (5.3)].

    Lacosamide injection can be administered intravenously to adult patients with the same dosing regimens described for oral dosing.

    The clinical study experience of intravenous Lacosamide Injection is limited to 5 days of consecutive treatment.

    Pediatric use information is approved for UCB, Inc.'s VIMPAT^®(lacosamide) injection. However, due to UCB, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

    2.2 Alternate Initial Dosage Information to Achieve the Maintenance Dosage in a Shorter Timeframe

    For monotherapy and adjunctive therapy for partial-onset seizures in patients 17 years of age and older and for adjunctive therapy for primary generalized tonic-clonic seizures in patients 17 years of age and older, an alternate initial dosing regimen for week 1 (e.g., including a loading dose and/or a higher initial dosage) may be administered in patients for whom achieving the recommended maintenance dosage in a shorter timeframe is clinically indicated (see Table 2). The alternate initial dosage regimen should be continued for one week. Lacosamide may then be titrated based on clinical response and tolerability, no more frequently than once per week, if needed. The loading dose should be administered with medical supervision because of the possibility of increased incidence of adverse reactions, including central nervous system (CNS) and cardiovascular adverse reactions [

    see Warnings and Precautions (5.2, 5.3), Adverse Reactions (6.1), and Clinical Pharmacology (12.3)

    ]. Titration increments should not exceed those shown in Table 2.

    Table 2: Alternate Initial Dosing Regimen to Achieve the Maintenance Dosage in a Shorter Timeframe if Clinically Indicated*

    Age and Body Weight	Alternate Initial Dosage	Titration Regimen	Maintenance Dosage
    Adults (17 years and older)	Single loading dose: 200 mg 12 hours later initiate: 100 mg twice daily (200 mg per day)	Increase by 50 mg twice daily (100 mg per day) at weekly intervals, if needed	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)
    *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.

    Pediatric use information is approved for UCB, Inc.'s VIMPAT^®(lacosamide) injection. However, due to UCB, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.
    )
    
  • 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 4 years 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 4 Years and Older, and for Primary Generalized Tonic-Clonic Seizures (Adjunctive Therapy) in Patients 4 Years of Age and Older*

    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 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)
    *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

    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 (6.1)and Clinical Studies (14.2)]

    .

    Lacosamide Injection Dosage

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

    [see Dosage and Administration (2.6)and Warnings and Precautions (5.3)].

    Lacosamide injection can be administered intravenously to adult patients with the same dosing regimens described for oral dosing.

    The clinical study experience of intravenous Lacosamide Injection is limited to 5 days of consecutive treatment.

    Pediatric use information is approved for UCB, Inc.'s VIMPAT^®(lacosamide) injection. However, due to UCB, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

    2.2 Alternate Initial Dosage Information to Achieve the Maintenance Dosage in a Shorter Timeframe

    For monotherapy and adjunctive therapy for partial-onset seizures in patients 17 years of age and older and for adjunctive therapy for primary generalized tonic-clonic seizures in patients 17 years of age and older, an alternate initial dosing regimen for week 1 (e.g., including a loading dose and/or a higher initial dosage) may be administered in patients for whom achieving the recommended maintenance dosage in a shorter timeframe is clinically indicated (see Table 2). The alternate initial dosage regimen should be continued for one week. Lacosamide may then be titrated based on clinical response and tolerability, no more frequently than once per week, if needed. The loading dose should be administered with medical supervision because of the possibility of increased incidence of adverse reactions, including central nervous system (CNS) and cardiovascular adverse reactions [

    see Warnings and Precautions (5.2, 5.3), Adverse Reactions (6.1), and Clinical Pharmacology (12.3)

    ]. Titration increments should not exceed those shown in Table 2.

    Table 2: Alternate Initial Dosing Regimen to Achieve the Maintenance Dosage in a Shorter Timeframe if Clinically Indicated*

    Age and Body Weight	Alternate Initial Dosage	Titration Regimen	Maintenance Dosage
    Adults (17 years and older)	Single loading dose: 200 mg 12 hours later initiate: 100 mg twice daily (200 mg per day)	Increase by 50 mg twice daily (100 mg per day) at weekly intervals, if needed	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)
    *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.

    Pediatric use information is approved for UCB, Inc.'s VIMPAT^®(lacosamide) injection. However, due to UCB, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.
    )
    
• Pedeatric Patients 4 years to less than 17 years. The recommended dosage is based on body weight and is administered orally twice daily(2.1)
• 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 4 years 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 4 Years and Older, and for Primary Generalized Tonic-Clonic Seizures (Adjunctive Therapy) in Patients 4 Years of Age and Older*

  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 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)
  *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

  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 (6.1)and Clinical Studies (14.2)]

  .

  Lacosamide Injection Dosage

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

  [see Dosage and Administration (2.6)and Warnings and Precautions (5.3)].

  Lacosamide injection can be administered intravenously to adult patients with the same dosing regimens described for oral dosing.

  The clinical study experience of intravenous Lacosamide Injection is limited to 5 days of consecutive treatment.

  Pediatric use information is approved for UCB, Inc.'s VIMPAT^®(lacosamide) injection. However, due to UCB, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

  2.2 Alternate Initial Dosage Information to Achieve the Maintenance Dosage in a Shorter Timeframe

  For monotherapy and adjunctive therapy for partial-onset seizures in patients 17 years of age and older and for adjunctive therapy for primary generalized tonic-clonic seizures in patients 17 years of age and older, an alternate initial dosing regimen for week 1 (e.g., including a loading dose and/or a higher initial dosage) may be administered in patients for whom achieving the recommended maintenance dosage in a shorter timeframe is clinically indicated (see Table 2). The alternate initial dosage regimen should be continued for one week. Lacosamide may then be titrated based on clinical response and tolerability, no more frequently than once per week, if needed. The loading dose should be administered with medical supervision because of the possibility of increased incidence of adverse reactions, including central nervous system (CNS) and cardiovascular adverse reactions [

  see Warnings and Precautions (5.2, 5.3), Adverse Reactions (6.1), and Clinical Pharmacology (12.3)

  ]. Titration increments should not exceed those shown in Table 2.

  Table 2: Alternate Initial Dosing Regimen to Achieve the Maintenance Dosage in a Shorter Timeframe if Clinically Indicated*

  Age and Body Weight	Alternate Initial Dosage	Titration Regimen	Maintenance Dosage
  Adults (17 years and older)	Single loading dose: 200 mg 12 hours later initiate: 100 mg twice daily (200 mg per day)	Increase by 50 mg twice daily (100 mg per day) at weekly intervals, if needed	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)
  *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.

  Pediatric use information is approved for UCB, Inc.'s VIMPAT^®(lacosamide) injection. However, due to UCB, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.
  )
  
• Injection: for intravenous use only when oral administration is temporarily not feasible; the recommended dosage is based on weight and is administered two or three times daily over 15 to 60 minutes; obtaining ECG before initiation is recommended in certain patients (
  
  2.7 Preparation and Administration Information for Lacosamide Injection

  Preparation

  Lacosamide injection can be administered intravenously without further dilution or may be mixed with diluents listed below. The diluted solution should not be stored for more than 4 hours at room temperature.

  Diluents:

  Sodium Chloride Injection 0.9% (w/v)
  
  Dextrose Injection 5% (w/v)
  
  Lactated Ringer's Injection

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Product with particulate matter or discoloration should not be used.

  Lacosamide injection is for single-dose only. Any unused portion of Lacosamide injection should be discarded.

  Administration

  The recommended infusion duration is 30 to 60 minutes; however, infusions as rapid as 15 minutes can be administered in adults if required

  [see Adverse Reactions (6.1)and Clinical Pharmacology (12.3)].

  Infusion durations less than 30 minutes are generally not recommended in pediatric patients

  [see Adverse Reactions (6.1)].

  Intravenous infusion of Lacosamide may cause bradycardia, AV blocks, and ventricular tachyarrhythmia

  [see Warnings and Precautions (5.3)]

  . Obtaining an ECG before beginning Lacosamide and after Lacosamide is titrated to steady-state maintenance dose is recommended in patients with underlying proarrhythmic conditions or on concomitant medications that affect cardiac conduction

  [see Drug Interactions (7.2)]

  .

  Storage and Stability

  The diluted solution should not be stored for more than 4 hours at room temperature. Any unused portion of Lacosamide injection should be discarded.
  ,
  
  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 (12.2)]

  . 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 (10)]

  . 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 (7.2)]

  . 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 (6.1)and Drug Interactions (7.2)].

  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] 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 (7.1), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)]

  .
  ,
  
  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 Injection 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 T_max(0.5 to 12 hours) and elimination half-life (15-23 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_CR50-80 mL/min) and moderately (CL_CR30-50 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 (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 pharmacokinetics of lacosamide have not been evaluated in severe hepatic impairment

  [see Dosage and Administration (2.4)]

  .

  Pediatric Patients (4 to less than 17 Years of Age)

  The pediatric pharmacokinetic profile of Lacosamide was determined in a population pharmacokinetic analysis using sparse plasma concentration data obtained in two open-label studies in 79 pediatric patients with epilepsy aged 4 years to less than 17 years.

  A weight based dosing regimen is necessary to achieve lacosamide exposures in pediatric patients 4 years to less than 17 years of age similar to those observed in adults treated at effective doses of lacosamide [see Dosage and Administration (2.1)]. For patients weighing 11 kg, 28.9 kg (the mean population body weight), and 70 kg, the typical plasma half-life(t1/2) is 7.4 hours, 10.6 hours, and 14.8 hours, respectively. Steady state plasama concentrations are achieved after 3 days of twice daily repeated adminitration.

  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.

  Pediatric use information is approved for UCB, Inc.'s VIMPAT^®(lacosamide) injection. However, due to UCB, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

  Geriatric Patients

  In the elderly (>65 years), dose and body-weight normalized AUC and C_maxis about 20% increased compared to young subjects (18-64 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 Injection 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 Injection (400 mg/day).
      
      Metformin (500 mg three times a day) had no effect on the pharmacokinetics of Lacosamide Injection (400 mg/day).
    • Omeprazole
      
      
      Omeprazole is a CYP2C19 substrate and inhibitor.
      
      There was no effect of Lacosamide Injection (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
      
      
      Co-administration 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.

  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 (7.1), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)]

  .
  ,
  
  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 Injection 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 T_max(0.5 to 12 hours) and elimination half-life (15-23 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_CR50-80 mL/min) and moderately (CL_CR30-50 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 (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 pharmacokinetics of lacosamide have not been evaluated in severe hepatic impairment

  [see Dosage and Administration (2.4)]

  .

  Pediatric Patients (4 to less than 17 Years of Age)

  The pediatric pharmacokinetic profile of Lacosamide was determined in a population pharmacokinetic analysis using sparse plasma concentration data obtained in two open-label studies in 79 pediatric patients with epilepsy aged 4 years to less than 17 years.

  A weight based dosing regimen is necessary to achieve lacosamide exposures in pediatric patients 4 years to less than 17 years of age similar to those observed in adults treated at effective doses of lacosamide [see Dosage and Administration (2.1)]. For patients weighing 11 kg, 28.9 kg (the mean population body weight), and 70 kg, the typical plasma half-life(t1/2) is 7.4 hours, 10.6 hours, and 14.8 hours, respectively. Steady state plasama concentrations are achieved after 3 days of twice daily repeated adminitration.

  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.

  Pediatric use information is approved for UCB, Inc.'s VIMPAT^®(lacosamide) injection. However, due to UCB, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

  Geriatric Patients

  In the elderly (>65 years), dose and body-weight normalized AUC and C_maxis about 20% increased compared to young subjects (18-64 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 Injection 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 Injection (400 mg/day).
      
      Metformin (500 mg three times a day) had no effect on the pharmacokinetics of Lacosamide Injection (400 mg/day).
    • Omeprazole
      
      
      Omeprazole is a CYP2C19 substrate and inhibitor.
      
      There was no effect of Lacosamide Injection (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
      
      
      Co-administration 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 single-dose vial for intravenous use (
  
  
  3 DOSAGE FORMS AND STRENGTHS

  • 200 mg/20 mL single-dose vial for intravenous use

  Lacosamide Injection, USP

  • 200 mg/20 mL: 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 ourcomes. 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 2-4% and 15-20%, 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.
  )