Vimpat® – Lacosamide

VIMPAT® (lacosamide) Injection for Intravenous use

Usual Diluents

Standard Dilution [Amount of drug] [Infusion volume] [Infusion rate]

Stability / Miscellaneous

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.

Storage (vials):
Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F).

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

CLINICAL PHARMACOLOGY
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.

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).

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

After intravenous administration, Cmax is reached at the end of infusion. The 30- and 60-minute intravenous infusions are bioequivalent to the oral tablet.

In a trial comparing the oral tablet with and an oral solution containing 10 mg/mL lacosamide, bioequivalence between both formulations was shown.

Distribution
The volume of distribution is approximately 0.6 L/kg and thus close to the volume of total body water. VIMPAT is less than 15% bound to plasma proteins.

Metabolism and Elimination
VIMPAT 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.

Lacosamide is a CYP2C19 substrate. The relative contribution of other CYP isoforms or non-CYP enzymes in the metabolism of lacosamide is not clear. 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.

INDICATIONS AND USAGE
VIMPAT is indicated for:
Partial-onset seizures: Tablets and oral solution are indicated for adjunctive therapy in patients ≥17 years. Injection is indicated as short term replacement when oral administration is not feasible in these patients.

DOSAGE AND ADMINISTRATION
Partial-onset seizures: Initially, give 50 mg twice daily (100 mg/day). The dose may be increased, based on clinical response and tolerability, at weekly intervals by 100 mg/day given as two divided doses to a daily dose of 200 to 400 mg/day. VIMPAT injection may be given without further dilution or mixed in compatible diluent and should be administered intravenously over a period of 30 to 60 minutes.

Oral-Intravenous Replacement therapy: 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. 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.

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.

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 4 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.

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.

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.

DOSAGE FORMS AND STRENGTHS:

• 50 mg (pink), 100 mg (dark yellow), 150 mg (salmon), 200 mg (blue) film-coated tablets
• 200 mg/20 mL single-use vial for intravenous use.
• 10 mg/mL oral solution.

CONTRAINDICATIONS:
None

WARNINGS AND PRECAUTIONS:

• Suicidal Behavior and Ideation
• Patients should be advised that VIMPAT may cause dizziness and ataxia.
• Caution is advised for patients with known cardiac conduction problems [e.g., second-degree atrioventricular (AV) block], who are taking drugs known to induce PR interval prolongation, or with severe cardiac disease such as myocardial ischemia or heart failure.
• Patients should be advised that VIMPAT may cause syncope.
• In patients with seizure disorders, VIMPAT should be gradually withdrawn to minimize the potential of increased seizure frequency.
• Multiorgan Hypersensitivity Reactions
• Phenylketonurics

ADVERSE REACTIONS
Most common adverse reactions (≥10% and greater than placebo) are diplopia, headache, dizziness, nausea.

To report SUSPECTED ADVERSE REACTIONS, contact UCB, Inc. at 1-800-477-7877 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

USE IN SPECIFIC POPULATIONS

• To enroll in the UCB AED Pregnancy Registry call 1-888-537-7734 (toll free).To enroll in the North American Antiepileptic Drug Pregnancy Registry call 1-888-233-2334 (toll free).
• Renal impairment: Dose adjustment is recommended for patients with severe renal impairment (creatinine clearance ≤ 30 mL/min). Dose supplementation should be considered following hemodialysis.
• Hepatic impairment: Dose adjustment is recommended for patients with mild or moderate hepatic impairment. Use in severe hepatic impairment patients is not recommended. Patients with co-existing hepatic and renal impairment should be monitored closely during dose titration.

Storage (vials):
Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F).

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

Reference(s)

NDC 0131-1810-67
Single Use Vial

VIMPAT®
(lacosamide) injection

200 mg /20 mL (10 mg/mL)
For Intravenous Use Only
Rx only
20 mL