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Lacosamide

Pronunciation

Pronunciation

(la KOE sa mide)

Index Terms

  • ADD 234037
  • Harkoseride
  • LCM
  • SPM 927

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous:

Vimpat: 200 mg/20 mL (20 mL)

Solution, Oral:

Vimpat: 10 mg/mL (200 mL, 465 mL) [contains aspartame, methylparaben, polyethylene glycol, propylene glycol; strawberry flavor]

Tablet, Oral:

Vimpat: 50 mg [contains fd&c blue #2 aluminum lake]

Vimpat: 100 mg, 150 mg

Vimpat: 200 mg [contains fd&c blue #2 aluminum lake]

Brand Names: U.S.

  • Vimpat

Pharmacologic Category

  • Anticonvulsant, Miscellaneous

Pharmacology

In vitro studies have shown that lacosamide stabilizes hyperexcitable neuronal membranes and inhibits repetitive neuronal firing by enhancing the slow inactivation of sodium channels (with no effects on fast inactivation of sodium channels).

Absorption

Oral: Completely

Distribution

Vd: ~0.6 L/kg

Metabolism

Hepatic via CYP3A4, CYP2C9, and CYP2C19; forms metabolite, O-desmethyl-lacosamide (inactive)

Excretion

Urine (95%; 40% as unchanged drug, 30% as inactive metabolite, 20% as uncharacterized metabolite); feces (<0.5%)

Time to Peak

Oral: 1-4 hours

Half-Life Elimination

~13 hours

Protein Binding

<15%

Special Populations: Renal Function Impairment

AUC is increased ~25% in patients with mild or moderate renal impairment (CrCl >30 to 80 mL/minute) and 60% in patients with severe renal impairment (CrCl ≤30 mL/minute). Following a 4-hour hemodialysis treatment, AUC is reduced by ~50%.

Special Populations: Hepatic Function Impairment

AUC is increased by ~50% to 60% in patients with moderate hepatic impairment (Child-Pugh class B).

Special Populations: Elderly

In patients >65 years of age, AUC and Cmax are increased ~20% compared with younger subjects.

Use: Labeled Indications

Partial-onset seizures:

US labeling: Monotherapy or adjunctive therapy in the treatment of partial-onset seizures in patients ≥17 years.

Canadian labeling: Adjunctive therapy in the treatment of partial-onset seizures in adults who are not satisfactorily controlled with conventional therapy.

Contraindications

U.S. labeling: There are no contraindications listed in manufacturer's labeling.

Canadian labeling: Hypersensitivity to lacosamide or any component of the formulation; second- or third-degree atrioventricular (AV) block (current or history of).

Dosage

Partial onset seizure:

Monotherapy: Adolescents ≥17 years and Adults: Oral, IV:

Initial: 100 mg twice daily; may be increased at weekly intervals by 50 mg twice daily based on response and tolerability.

Alternative initial dosage: Loading dose: 200 mg followed approximately 12 hours later by 100 mg twice daily for 1 week; may be increased at weekly intervals by 50 mg twice daily based on response and tolerability. Note: Administer loading doses under medical supervision because of the increased incidence of CNS adverse reactions.

Maintenance: 150 to 200 mg twice daily. Note: For patients already on a single antiepileptic and converting to lacosamide monotherapy, maintain the maintenance dose for 3 days before beginning withdrawal of the concomitant antiepileptic drug. Gradually taper the concomitant antiepileptic drug over ≥6 weeks.

Adjunctive therapy: Adolescents ≥17 years and Adults (US labeling) or Adults (Canadian labeling): Oral, IV:

Initial: 50 mg twice daily; may be increased at weekly intervals by 50 mg twice daily based on response and tolerability.

Alternative initial dosage: Loading dose of 200 mg followed approximately 12 hours later by 100 mg twice daily for 1 week; may be increased at weekly intervals by 50 mg twice daily based on response and tolerability. Note: Administer loading doses under medical supervision because of the increased incidence of CNS adverse reactions.

Maintenance dose: 100 to 200 mg twice daily (maximum: 400 mg daily)

Status epilepticus, refractory (off-label use): Adults: IV: 200 to 400 mg followed by a daily maintenance dose of 200 to 600 mg daily in 2 divided doses (Albers, 2011; Goodwin, 2011; Kellinghaus, 2011; NCS [Brophy, 2012]). Note: Although the Neurocritical Care Society recommends administration of the initial dose at a rate of 200 mg over 15 minutes, others have administered doses up to 400 mg IV push over ≤5 minutes without apparent harm (Goodwin, 2011; Kellinghaus, 2011; NCS [Brophy, 2012]).

Switching from oral to IV dosing: When switching from oral to IV formulations, the total daily dose and frequency should be the same; IV therapy should only be used temporarily. Clinical study experience of IV lacosamide is limited to 5 days of consecutive treatment.

Dosage adjustment in renal impairment: Use caution when titrating dose.

Mild-to-moderate renal impairment (CrCl >30 mL/minute): No dosage adjustment necessary. However, in patients with renal impairment taking concomitant strong CYP3A4 and/or CYP2C9 inhibitors, dosage reduction may be necessary.

Severe renal impairment (CrCl ≤30 mL/minute): Maximum dose: 300 mg daily. Further dosage reduction/limitation may be necessary with concomitant use of strong CYP3A4 and/or CYP2C9 inhibitors.

End-stage renal disease (ESRD) requiring hemodialysis: Maximum dose: 300 mg daily. Further dosage reduction/limitation may be necessary with concomitant use of strong CYP3A4 and/or CYP2C9 inhibitors. Removed by hemodialysis; after 4-hour hemodialysis treatment, a supplemental dose of up to 50% should be considered.

Dosage adjustment in hepatic impairment: Use caution when titrating dose.

Mild-to-moderate hepatic impairment: Maximum dose: 300 mg daily. Further dosage reduction/limitation may be necessary in patients taking concomitant strong CYP3A4 and/or CYP2C9 inhibitors.

Severe hepatic impairment: Use is not recommended.

Reconstitution

Injection: May be mixed with compatible diluents (NS, LR, D5W) in glass or PVC.

Administration

Injection: Administer over 15 to 60 minutes (US labeling) or 30 to 60 minutes (Canadian labeling); infusions over 30 to 60 minutes are preferred to minimize adverse effects. IV administration has been used for up to 5 days. Can be administered without further dilution or may be mixed with compatible diluents (NS, LR, D5W).

Oral solution, tablets: May be administered with or without food. Oral solution should be administered with a calibrated measuring device (not a household teaspoon or tablespoon).

Dietary Considerations

Some products may contain phenylalanine.

Compatibility

Stable in NS, LR, D5W.

Storage

Injection: Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Do not freeze. Stable when mixed with compatible diluents (NS, LR, D5W) for up to 4 hours at room temperature [Canadian labeling indicates the admixture in glass or polyvinyl chloride (PVC) bags is stable for at least 24 hours at 15°C to 30°C]. Discard any unused portion.

Oral solution, tablets: Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Do not freeze oral solution. Discard any unused portion of oral solution after 7 weeks.

Drug Interactions

Bradycardia-Causing Agents: May enhance the AV-blocking effect of Lacosamide. Monitor therapy

CarBAMazepine: May enhance the AV-blocking effect of Lacosamide. CarBAMazepine may decrease the serum concentration of Lacosamide. Monitor therapy

CYP2C9 Inhibitors (Strong): May increase the serum concentration of Lacosamide. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Lacosamide. Monitor therapy

Delavirdine: May increase the serum concentration of Lacosamide. Management: Lacosamide prescribing information cautions that a lacosamide dose reduction may be warranted in patients with renal dysfunction or mild-moderate hepatic impairment who are also using a strong inhibitor of CYP2C9 and CYP3A4, such as delavirdine. Consider therapy modification

Fosphenytoin: May decrease the serum concentration of Lacosamide. Monitor therapy

Mefloquine: May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of convulsions. Monitor anticonvulsant concentrations and treatment response closely with concurrent use. Consider therapy modification

Mianserin: May diminish the therapeutic effect of Anticonvulsants. Monitor therapy

NiCARdipine: May increase the serum concentration of Lacosamide. Management: Lacosamide prescribing information cautions that a lacosamide dose reduction may be warranted in patients with renal dysfunction or mild-moderate hepatic impairment who are also using a strong inhibitor of CYP2C9 and CYP3A4, such as delavirdine. Consider therapy modification

Orlistat: May decrease the serum concentration of Anticonvulsants. Monitor therapy

PHENobarbital: May decrease the serum concentration of Lacosamide. Monitor therapy

Phenytoin: May decrease the serum concentration of Lacosamide. Monitor therapy

Adverse Reactions

The majority of adverse events are dose-dependent.

>10%:

Central nervous system: Dizziness (16% to 53%), fatigue (7% to 15%), ataxia (4% to 15%), headache (11% to 14%)

Gastrointestinal: Nausea (7% to 17%), vomiting (6% to 16%)

Neuromuscular & skeletal: Tremor (4% to 12%)

Ophthalmic: Diplopia (6% to 16%), blurred vision (2% to 16%)

1% to 10%:

Cardiovascular: Syncope (adults 1%; dose-related: >400 mg/day)

Central nervous system: Drowsiness (5% to 8%), memory impairment (2% to 6%), equilibrium disturbance (1% to 6%), vertigo (3% to 5%), abnormal gait (2% to 4%), depression (2%)

Dermatologic: Pruritus (2% to 3%)

Gastrointestinal: Diarrhea (3% to 5%)

Hematologic & oncologic: Bruise (2% to 4%)

Hepatic: Increased serum ALT (1%)

Local: Pain at injection site (3%), local irritation (1%)

Neuromuscular & skeletal: Weakness (2% to 4%)

Ophthalmic: Nystagmus (2% to 10%)

Miscellaneous: Laceration (2% to 3%)

<1% (Limited to important or life-threatening): Abnormal hepatic function tests, acute psychosis, aggressive behavior, agitation, agranulocytosis, anemia, angioedema, atrial fibrillation, atrial flutter, atrioventricular block, bradycardia, cerebellar syndrome, cognitive dysfunction, disturbance in attention, DRESS syndrome, euphoria, falling, hallucination, hepatitis, insomnia, nephritis, neutropenia, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria

Warnings/Precautions

Concerns related to adverse effects:

• Cardiovascular effects: Lacosamide may prolong PR interval; second degree and complete AV block has also been reported. Use caution in patients with conduction problems (eg, first/second degree atrioventricular block and sick sinus syndrome without pacemaker), sodium channelopathies (eg, Brugada syndrome), myocardial ischemia, heart failure, structural heart disease, or if concurrent use with other drugs that prolong the PR interval; ECG is recommended prior to initiating therapy and when at the steady state maintenance dose. Monitor closely with IV lacosamide administration; bradycardia and AV block have occurred during infusions. Instruct patients to contact their healthcare provider if signs or symptoms of conduction problems occur (eg, low or irregular pulse, feeling of lightheadedness and fainting). During short-term trials, atrial fibrillation/flutter, or syncope occurred slightly more often in patients with diabetic neuropathy and/or cardiovascular disease. In addition, in open-label studies, syncope has been associated with a history of cardiac disease risk factors and use of drugs that slow AV conduction.

• CNS effects: Dizziness and ataxia may occur during therapy; patients should be cautioned about performing tasks which require alertness (eg, operating machinery or driving).

• Multiorgan hypersensitivity reactions (drug reaction with eosinophilia and systemic symptoms [DRESS]): Potentially serious (sometimes fatal, possibly delayed) multiorgan hypersensitivity reactions have been reported with some antiepileptic drugs (rare); monitor for signs and symptoms of possible disparate manifestations associated with lymphatic, hepatic, renal, and/or hematologic organ systems; gradual discontinuation and conversion to alternate therapy may be required.

• Ophthalmic effects: Blurred vision and diplopia may occur during therapy. Patients with persistent visual disturbances may need further assessment. Consider increased monitoring in patients with preexisting ocular conditions or vision-related issues.

• Suicidal ideation: Pooled analysis of trials involving various antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify healthcare provider immediately if symptoms occur.

Disease-related concerns:

• Hepatic impairment: Not recommended for use in patients with severe hepatic impairment; dosage adjustment required for mild-to-moderate hepatic impairment. Further dosage adjustment may be necessary in patients with hepatic impairment taking concomitant strong CYP3A4 and/or CYP2C9 inhibitors.

• Renal impairment: Use caution in patients with renal impairment; dosage adjustment required for severe renal impairment (CrCl ≤30 mL/minute) and supplementation may be necessary in hemodialysis. Patients with any degree of renal impairment taking concomitant strong CYP3A4 and/or CYP2C9 inhibitors may require dosage adjustment.

Concurrent drug therapy issues:

• Ethanol: Avoid ethanol (may increase CNS depression).

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Phenylalanine: Some products may contain phenylalanine.

• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures and respiratory depression; use caution (AAP, 1997; Zar, 2007).

Other warnings/precautions:

• Withdrawal: Anticonvulsants should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually (≥1 week) to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal.

Monitoring Parameters

Patients with conduction problems, sodium channelopathies, concomitant medications that prolong PR interval or severe cardiac disease should have ECG tracing prior to start of therapy and when at steady-state. Monitor these patients closely during IV infusions (cases of bradycardia and AV block have occurred during infusions). Monitor for suicidality (eg, suicidal thoughts, depression, behavioral changes).

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Information related to pregnancy outcomes following maternal use of lacosamide is limited (Hoeltzenbein 2011). In general, maternal polytherapy with antiepileptic drugs may increase the risk of congenital malformations; monotherapy with the lowest effective dose is recommended. Newborns of women taking antiepileptic medications may be at an increased risk of adverse events (Harden and Meader 2009).

Patients exposed to lacosamide during pregnancy are encouraged to enroll themselves into the NAAED Pregnancy Registry by calling 1-888-233-2334. Additional information is available at http://www.aedpregnancyregistry.org.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience fatigue, headache, blurred vision, nausea, or injection site irritation. Have patient report immediately to prescriber change in balance, memory impairment, severe dizziness, syncope, considerable asthenia, bradycardia, tachycardia, arrhythmia, tremors, significant nausea, vision changes, dyspnea, suicidal ideation, depression, anxiety, akathisia, irritability, panic attacks, mood changes, enlarged lymph nodes, fever, rash, angina, urinary retention, oliguria, or signs of hepatic impairment (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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