LACOSAMIDE

66 mg/kg three times daily (see Table 1). The clinical study experience of intravenous L acosamide is limited to 5 days of consecutive treatment. 's VIMPAT® (lacosamide) injection. 's marketing exclusivity rights, this drug product is not labeled with that information.

, 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 injection may then be titrated based on clinical response and tolerability, no more frequently than once per week, if needed. 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.

Oral and intravenous dosages are the same unless specified. 's VIMPAT® (lacosamide) injection. 's marketing exclusivity rights, this drug product is not labeled with that information. 3 Converting From a Single Antiepileptic (AED) to Lacosamide Monotherapy for the Treatment of Partial-Onset Seizures For patients who are already on a single AED and will convert to lacosamide monotherapy, withdrawal of the concomitant AED should not occur until the therapeutic dosage of lacosamide is achieved and has been administered for at least 3 days.

A gradual withdrawal of the concomitant AED over at least 6 weeks is recommended. 4 Dosage Information for Patients with Renal Impairment For patients with mild to moderate renal impairment, no dosage adjustment is necessary. 73m 2 as 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.

3)] . 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. 3)] . 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. 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. 3)]. 1)]. 3)] . 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)] .

Patients had to have been maintained on a stable dose regimen of 1 to 2 marketed antiepileptics for at least 28 days prior to treatment assignment.

Treatment groups were as follows:

Single dose of intravenous lacosamide Injection 200 mg followed by oral lacosamide 200 mg/day (100 mg every 12 hours) Single dose of intravenous lacosamide Injection 300 mg followed by oral lacosamide 300 mg/day (150 mg every 12 hours) Single dose of intravenous lacosamide Injection 400 mg followed by oral lacosamide 400 mg/day (200 mg every 12 hours).

Table 5 gives the incidence of adverse reactions that occurred in ≥5% of adult patients in any lacosamide dosing group.

Table 5:

Adverse Reactions in a 15-minute Infusion Study in Adult Patients with Partial-Onset Seizures Adverse Reaction Lacosamide 200 mg N=25 % Lacosamide 300 mg N=50 % Lacosamide 400 mg N=25 % Lacosamide Total N=100 % Eye disorders Diplopia 4 6 20 9 Blurred Vision 0 4 12 5 Gastrointestinal disorders Nausea 0 16 24 14 Dry mouth 0 6 12 6 Vomiting 0 4 12 5 Oral Paresthesia 4 4 8 5 Oral Hypoesthesia 0 6 8 5 Diarrhea 0 8 0 4 General disorders/ administration site conditions Fatigue 0 18 12 12 Gait disturbance 8 2 0 3 Chest pain 0 0 12 3 Nervous system disorders Dizziness 20 46 60 43 Somnolence 0 34 36 26 Headache 8 4 16 8 Paresthesia 8 6 4 6 Tremor 0 6 4 4 Abnormal Coordination 0 6 0 3 Skin & subcutaneous tissue disorders Pruritus 0 6 4 4 Hyperhidrosis 0 0 8 2 Adverse reactions that occurred with infusion of lacosamide 200 mg over 15-minutes followed by lacosamide 100 mg administered orally twice per day were similar in frequency to those that occurred in 3-month adjunctive therapy controlled trials.

Considering the difference in period of observations (1 week vs. 3 months), the incidence of CNS adverse reactions, such as dizziness, somnolence, and paresthesia may be higher with 15- minute administration of lacosamide Injection than with administration over a 30-to 60-minute period.

The adverse reactions associated with lacosamide injection in adult patients with primary generalized tonic-clonic seizures are expected to be similar to those seen in adults with partial-onset seizures. Pediatric Patients (4 years to less than 17 Years of Age) The safety of lacosamide injection was evaluated in a multicenter, open-label study of 77 pediatric patients 4 years to less than 17 years of age with epilepsy.

7)] . Although no serious or severe adverse reactions were noted at the time of infusion in this small study, the adverse reactions associated with lacosamide injection in pediatric patients are expected to be similar to those noted in adults.

's VIMPAT® (lacosamide) injection. 's marketing exclusivity rights, this drug product is not labeled with that information. 2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of lacosamide.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders:

Agranulocytosis Psychiatric disorders: Aggression, agitation, hallucination, insomnia, psychotic disorder Skin and subcutaneous tissue disorders: Angioedema, rash, urticaria, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Neurologic disorders:

Dyskinesia, new or worsening seizures

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. 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. 1)] .

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. 2)] . 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.

, Brugada Syndrome). 2)] . In such patients, obtaining an ECG before beginning lacosamide, and after lacosamide is titrated to steady-state maintenance dose, is recommended. 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. 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. 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.

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. 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.

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. , 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.