1 INDICATIONS AND USAGE

1.1 Partial-Onset Seizures

VIMPAT (lacosamide) tablets and oral solution are indicated as adjunctive therapy in the treatment of partial-onset seizures in patients with epilepsy aged 17 years and older.

VIMPAT (lacosamide) injection for intravenous use is indicated as adjunctive therapy in the treatment of partial-onset seizures in patients with epilepsy aged 17 years and older when oral administration is temporarily not feasible.

2 DOSAGE AND ADMINISTRATION

VIMPAT may be taken with or without food.

When using VIMPAT oral solution, it is recommended that a calibrated measuring device be obtained and used. A household teaspoon or tablespoon is not an adequate measuring device. Healthcare providers should recommend a device that can measure and deliver the prescribed dose accurately, and provide instructions for measuring the dosage.

2.1 Partial-Onset Seizures

VIMPAT can be initiated with either oral or intravenous administration. The initial dose should be 50 mg twice daily (100 mg per day). VIMPAT can be increased at weekly intervals by 100 mg/day given as two divided doses up to the recommended maintenance dose of 200 to 400 mg/day, based on individual patient response and tolerability. In clinical trials, the 600 mg daily dose was not more effective than the 400 mg daily dose, and was associated with a substantially higher rate of adverse reactions. [see Clinical Studies (14.1)]

Switching from Oral to Intravenous Dosing

When switching from oral VIMPAT, the initial total daily intravenous dosage of VIMPAT should be equivalent to the total daily dosage and frequency of oral VIMPAT and should be infused intravenously over a period of 30 to 60 minutes. There is experience with twice daily intravenous infusion for up to 5 days.

Switching from Intravenous to Oral Dosing

At the end of the intravenous treatment period, the patient may be switched to VIMPAT oral administration at the equivalent daily dosage and frequency of the intravenous administration.

Compatibility and Stability

VIMPAT injection can be administered intravenously without further dilution or may be mixed with diluents. VIMPAT injection was found to be physically compatible and chemically stable when mixed with the following diluents for at least 24 hours and stored in glass or polyvinyl chloride (PVC) bags at ambient room temperature 15-30°C (59-86°F).

Diluents:

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

The stability of VIMPAT injection in other infusion solutions has not been eva luated. Product with particulate matter or discoloration should not be used.

Any unused portion of VIMPAT injection should be discarded.

2.2 Patients with Renal Impairment

No dose adjustment is necessary in patients with mild to moderate renal impairment. A maximum dose of 300 mg/day VIMPAT is recommended for patients with severe renal impairment [creatinine clearance (CLCR) ≤30mL/min] and in patients with endstage renal disease. VIMPAT is effectively removed from plasma by hemodialysis. Following a 4-hour hemodialysis treatment, dosage supplementation of up to 50% should be considered. In all renally impaired patients, the dose titration should be performed with caution. [see Use in Specific Populations (8.6)]

2.3 Patients with Hepatic Impairment

The dose titration should be performed with caution in patients with hepatic impairment. A maximum dose of 300 mg/day is recommended for patients with mild or moderate hepatic impairment.

VIMPAT use is not recommended in patients with severe hepatic impairment [see Use in Specific Populations (8.7)].

3 DOSAGE FORMS AND STRENGTHS

50 mg (pink), 100 mg (dark yellow), 150 mg (salmon), and 200 mg (blue) film-coated tablets

200 mg/20mL injection

10 mg/mL oral solution

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Suicidal Behavior and Ideation

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

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

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

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

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

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 VIMPAT 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.

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

5.2 Dizziness and Ataxia

Patients should be advised that VIMPAT may cause dizziness and ataxia. Accordingly, they should be advised not to drive a car or to operate other complex machinery until they are familiar with the effects of VIMPAT on their ability to perform such activities.

In 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 VIMPAT (compared with 8% of placebo patients) and was the adverse event most frequently leading to discontinuation (3%). Ataxia was experienced by 6% of patients randomized to the recommended doses (200 to 400 mg/day) of VIMPAT (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 events at doses higher than 400 mg/day. [see Adverse Reactions/Table 2 (6.1)]

5.3 Cardiac Rhythm and Conduction Abnormalities

PR interval prolongation

Dose-dependent prolongations in PR interval with VIMPAT have been observed in clinical studies in patients and in healthy volunteers. [see Clinical Pharmacology (12.2)] In clinical trials in patients with partial-onset epilepsy, asymptomatic first-degree atrioventricular (AV) block was observed as an adverse reaction in 0.4% (4/944) of patients randomized to receive VIMPAT and 0% (0/364) of patients randomized to receive placebo. In clinical trials in patients with diabetic neuropathy, asymptomatic first-degree AV block was observed as an adverse reaction in 0.5% (5/1023) of patients receiving VIMPAT and 0% (0/291) of patients receiving placebo. Second degree or higher AV block has been reported in postmarketing experience in epilepsy patients. When VIMPAT is given with other drugs that prolong the PR interval, further PR prolongation is possible. Patients should be made aware of the symptoms of second-degree or higher AV block (e.g. slow or irregular pulse, feeling of lightheadedness and fainting) and told to contact their physician should any of these occur.

VIMPAT should be used with caution in patients with known conduction problems (e.g. marked first-degree AV block, second-degree or higher AV block and sick sinus syndrome without pacemaker), or with severe cardiac disease such as myocardial ischemia or heart failure. In such patients, obtaining an ECG before beginning VIMPAT, and after VIMPAT is titrated to steady-state, is recommended.

Atrial fibrillation and Atrial flutter

In the short-term investigational trials of VIMPAT in epilepsy patients, there were no cases of atrial fibrillation or flutter, however, both have been reported in open label epilepsy trials and in postmarketing experience. In patients with diabetic neuropathy, 0.5% of patients treated with VIMPAT experienced an adverse reaction of atrial fibrillation or atrial flutter, compared to 0% of placebo-treated patients. VIMPAT administration may predispose to atrial arrhythmias (atrial fibrillation or flutter), especially in patients with diabetic neuropathy and/or cardiovascular disease. Patients should be made aware of the symptoms of atrial fibrillation and flutter (e.g., palpitations, rapid pulse, shortness of breath) and told to contact their physician should any of these symptoms occur.

5.4 Syncope

In the short-term controlled trials of VIMPAT in epilepsy patients with no significant system illnesses, there was no increase in syncope compared to placebo. In the short-term controlled trials of VIMPAT in patients with diabetic neuropathy, 1.2% of patients who were treated with VIMPAT reported an adverse reaction of syncope or loss of consciousness, compared to 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.

5.5 Withdrawal of Antiepileptic Drugs (AEDs)

As with all AEDs, VIMPAT should be withdrawn gradually (over a minimum of 1 week) to minimize the potential of increased seizure frequency in patients with seizure disorders.

5.6 Multiorgan Hypersensitivity Reactions

One case of symptomatic hepatitis and nephritis was observed among 4011 subjects exposed to VIMPAT during clinical development. The event occurred in a healthy volunteer, 10 days after stopping VIMPAT treatment. The subject was not taking any concomitant medication and potential known viral etiologies for hepatitis were ruled out. The subject fully recovered within a month, without specific treatment. The case is consistent with a delayed multiorgan hypersensitivity reaction. Additional potential cases included 2 with rash and elevated liver enzymes and 1 with myocarditis and hepatitis of uncertain etiology.

Multiorgan hypersensitivity reactions (also known as Drug Reaction with Eosinophilia and Systemic Symptoms, or DRESS) have been reported with other anticonvulsants and typically, although not exclusively, present with fever and rash associated with other organ system involvement, that may or may not include eosinophilia, hepatitis, nephritis, lymphadenopathy, and/or myocarditis. Because this disorder is variable in its expression, other organ system signs and symptoms not noted here may occur. If this reaction is suspected, VIMPAT should be discontinued and alternative treatment started.

5.7 Phenylketonurics

VIMPAT oral solution contains aspartame, a source of phenylalanine. A 200 mg dose of VIMPAT oral solution (equivalent to 20 mL) contains 0.32 mg of phenylalanine.

6 ADVERSE REACTIONS

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

In all controlled and uncontrolled trials in patients with partial-onset seizures, 1327 patients have received VIMPAT of whom 1000 have been treated for longer than 6 months and 852 for longer than 12 months.

6.1 Clinical Trials Experience

Controlled Trials

Adverse reactions leading to discontinuation

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

Most common adverse reactions

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