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.

2.1 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 evaluated. 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)].

5.1 Suicidal Behavior and Ideation

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

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

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

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

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

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

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.

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of VIMPAT. 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.

Cardiac disorders: Atrioventricular block, atrial fibrillation, atrial flutter, bradycardia

Immune system disorders: Drug hypersensitivity reactions

Psychiatric disorders: Aggression, agitation, insomnia, psychotic disorder

Skin and subcutaneous tissue disorders: Angioedema, rash, urticaria

8.1 Pregnancy

8.2 Labor and Delivery

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

8.3 Nursing Mothers

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

8.4 Pediatric Use

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

Lacosamide has been shown in vitro to interfere with the activity of CRMP-2, a protein involved in neuronal differentiation and control of axonal outgrowth. Potential adverse effects on CNS development can not be ruled out. Administration of lacosamide to rats during the neonatal and juvenile periods of postnatal development resulted in decreased brain weights and long-term neurobehavioral changes (altered open field performance, deficits in learning and memory). The no-effect dose for developmental neurotoxicity in rats was associated with a plasma lacosamide exposure (AUC) approximately 0.5 times the human plasma AUC at the maximum recommended human dose of 400 mg/day.

8.5 Geriatric Use

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

In healthy subjects, the dose and body weight normalized pharmacokinetic parameters AUC and Cmax were approximately 20% higher in elderly subjects compared to young subjects. The slightly higher lacosamide plasma concentrations in elderly subjects are possibly caused by differences in total body water (lean body weight) and age-associated decreased renal clearance. No VIMPAT dose adjustment based on age is considered necessary. Caution should be exercised for dose titration in elderly patients.

8.6 Patients with Renal Impairment

A maximum dose of 300 mg/day is recommended for patients with severe renal impairment (CLCR≤30mL/min) and in patients with endstage renal disease. VIMPAT is effectively removed from plasma by hemodialysis. Following a 4-hour hemodialysis treatment, AUC of VIMPAT is reduced by approximately 50%. Therefore dosage supplementation of up to 50% following hemodialysis should be considered. In all renal impaired patients, the dose titration should be performed with caution. [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]

8.7 Patients with Hepatic Impairment

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

9.1 Controlled Substance

VIMPAT is a Schedule V controlled substance.

9.2 Abuse

In a human abuse potential study, single doses of 200 mg and 800 mg lacosamide produced euphoria-type subjective responses that differentiated statistically from placebo; at 800 mg, these euphoria-type responses were statistically indistinguishable from those produced by alprazolam, a Schedule IV drug. The duration of the euphoria-type responses following lacosamide was less than that following alprazolam. A high rate of euphoria was also reported as an adverse event in the human abuse potential study following single doses of 800 mg lacosamide (15% [5/34]) compared to placebo (0%) and in two pharmacokinetic studies following single and multiple doses of 300-800 mg lacosamide (ranging from 6% [2/33] to 25% [3/12]) compared to placebo (0%). However, the rate of euphoria reported as an adverse event in the VIMPAT development program at therapeutic doses was less than 1%.

9.3 Dependence

Abrupt termination of lacosamide in clinical trials with diabetic neuropathic pain patients produced no signs or symptoms that are associated with a withdrawal syndrome indicative of physical dependence. However, psychological dependence cannot be excluded due to the ability of lacosamide to produce euphoria-type adverse events in humans.

10.1 Signs, Symptoms, and Laboratory Findings of Acute Overdose in Humans

There is limited clinical experience with VIMPAT overdose in humans. The highest reported accidental overdose of VIMPAT during clinical development was 1200 mg/day which was non-fatal. The types of adverse events experienced by patients exposed to supratherapeutic doses during the trials were not clinically different from those of patients administered recommended doses of VIMPAT.

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

10.2 Treatment or Management of Overdose

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

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

11.1 VIMPAT Tablets

VIMPAT tablets contain the following inactive ingredients: colloidal silicon dioxide, crospovidone, hydroxypropylcellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and dye pigments as specified below:

VIMPAT tablets are supplied as debossed tablets and contain the following coloring agents:

50 mg tablets: red iron oxide, black iron oxide, FD&C Blue #2/indigo carmine aluminum lake
100 mg tablets: yellow iron oxide
150 mg tablets: yellow iron oxide, red iron oxide, black iron oxide
200 mg tablets: FD&C Blue #2/indigo carmine aluminum lake

11.2 VIMPAT Injection

VIMPAT injection is a clear, colorless, sterile solution containing 10 mg lacosamide per mL for intravenous infusion. One 20-mL vial contains 200 mg of lacosamide drug substance. The inactive ingredients are sodium chloride and water for injection. Hydrochloric acid is used for pH adjustment. VIMPAT injection has a pH of 3.5 to 5.0.

11.3 VIMPAT Oral Solution

VIMPAT oral solution contains 10 mg of lacosamide per mL. The inactive ingredients are purified water, sorbitol solution, glycerin, polyethylene glycol, carboxymethylcellulose sodium, acesulfame potassium, methylparaben, flavoring (including natural and artificial flavors, propylene glycol, aspartame, and maltol), anhydrous citric acid and sodium chloride.

12.1 Mechanism of Action

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

Lacosamide binds to collapsin response mediator protein-2 (CRMP-2), a phosphoprotein which is mainly expressed in the nervous system and is involved in neuronal differentiation and control of axonal outgrowth. The role of CRMP-2 binding in seizure control is unknown.

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

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

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

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

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

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

14.1 Effectiveness in Partial-Onset Seizures

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

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

A reduction in 28 day seizure frequency (Baseline to Maintenance Phase) as compared to the placebo group was the primary variable in all three trials. The criteria for statistical significance was p<0.05. A statistically significant effect was observed with VIMPAT treatment (Figure 1) at doses of 200 mg/day (Study 3), 400 mg/day (Studies 1, 2, and 3), and 600 mg/day (Studies 1 and 2).

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

Figure 2 presents the percentage of patients (X-axis) with a percent reduction in partial seizure frequency (responder rate) from Baseline to the Maintenance phase at least as great as that represented on the Y-axis. A positive value on the Y-axis indicates an improvement from Baseline (i.e., a decrease in seizure frequency), while a negative value indicates a worsening from Baseline (ie., an increase in seizure frequency). Thus, in a display of this type, a curve for an effective treatment is shifted to the left of the curve for placebo. The proportion of patients achieving any particular level of reduction in seizure frequency was consistently higher for the VIMPAT groups compared to the placebo group. For example, 40% of patients randomized to VIMPAT (400 mg/day) experienced a 50% or greater reduction in seizure frequency, compared to 23% of patients randomized to placebo. Patients with an increase in seizure frequency >100% are represented on the Y-axis as equal to or greater than -100%.

16.1 Storage

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature].

Do not freeze Vimpat injection or oral solution. Discard any unused Vimpat oral solution remaining after seven (7) weeks of first opening the bottle.

17.1 Suicidal Thinking and Behavior

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

17.2 Dizziness and Ataxia

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

17.3 Cardiac Rhythm and Conduction Abnormalities

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

17.4 Multiorgan Hypersensitivity Reactions

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

17.5 Pregnancy Registry

UCB, Inc. has established the UCB AED Pregnancy Registry to advance scientific knowledge about safety and outcomes in pregnant women being treated with VIMPAT. To ensure broad program access and reach, either a healthcare provider or the patient can initiate enrollment in the UCB AED Pregnancy Registry by calling 1-888-537-7734 (toll free).

Patients should also be encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry if they become pregnant. This Registry is collecting information about the safety of AEDs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 [see Use in Specific Populations (8.1)].

Additional barcode labeling by:
Physicians Total Care, Inc.
Tulsa, Oklahoma      74146