Brand Name: Vimpat

Generic Name: Lacosamide

Manufacturer ³: UCB Pharmaceuticals, Inc

Drug Class ³: Anticonvulsant

Uses ³: Adjunctive therapy in the treatment of partial-onset seizures

Mechanism of Action ^1,2,3,4:
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).

Pharmacokinetics: ^1,2,3,4

Metabolism ^3,6: 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 administrations.

Elimination ^3,6: 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.

Efficacy ^1,2,4:

Ben-Menachem E, Biton V, Jatuzis D, et al, “Efficacy and Safety of Oral Lacosamide as Adjunctive Therapy in Adults With Partial-Onset Seizures,” Epilepsia, 2007, 48(7):1308-17.

Study design: multicenter, double-blind, placebo-controlled trial.

Description of study: This trial was conducted between February 2002 and May 2004 at 68 centers in Germany, Hungary, Lithuania, Poland, Sweden, Switzerland, U.K., and the USA. 418 subjects were randomly assigned to one of the four treatment groups: placebo (97), lacosamide 200 mg/day (107), 400 mg/day (108), or 600 (106) mg/day after an 8-week baseline period. Lacosamide was titrated in weekly increments of 100 mg/day over 6 weeks and maintained for 12 weeks. Results were analyzed on an intention-to-treat basis. The primary assessment of efficacy was based on the change in seizure frequency. Seizure counts were analyzed in two ways: reduction in seizure frequency per 28 days from baseline to maintenance; and responder rate, defined as a reduction of at least 50% in seizure frequency from baseline to maintenance. Secondary efficacy parameters included percent change in seizure frequency, achievement of seizure-free status, proportion of seizure-free days, clinical Global Impression of Change (CGIC) score, and Quality of Life in Epilepsy (QOLIE-31) questionnaire score. Results: Of the 418 patients, 312 completed the trial. The median percent reduction in seizure frequency per 28 days was 10%, 26%, 39%, and 40% in the placebo, lacosamide 200, 400, and 600 mg/day treatment groups, respectively. The median reduction in seizure frequency over placebo was significant for lacosamide 400 mg/day (p=0.0023) and 600 mg/day (p=0.0084). The 50% responder rates were 22%, 33%, 41%, and 38% for placebo, lacosamide 200,400, and 600 mg/day, respectively. The 50% responder rate over placebo was significant for lacosamide 400mg/day (p=0.0038) and 600 mg/day (p=0.0141). The most commonly reported AEs occurred in the CNS and gastrointestinal system. Adverse events that appeared dose-related included dizziness, nausea, fatigue, ataxia, vision abnormal, diplopia, and nystagmus. The 600 mg/day and 400 mg/day doses of lacosamide showed similar efficacy. However, the 400 mg/day dose appeared to be better tolerated in this trial.

Limitations: Most of the study subjects were Caucasian (93%); thus, the study was limited to this ethnicity. Medications other than antiepileptic drugs taken concomitantly with lacosamide were not reported.

Conclusion: Twice-daily dosing of lacosamide produced statistically significantly reductions in seizure frequency at doses of 400 mg/day and 600 mg/day in patients with uncontrolled partial-onset seizures. Further investigation is needed to determine the efficacy of the 200 mg/day lacosamide dose.

Biton V, Rosenfeld WE, Whitesides J, et al, “Intravenous Lacosamide as Replacement for Oral Lacosamide in Patients With Partial-Onset Seizures,” Epilepsia, 2008, 49(3):418-24.

Study design: Multicenter, double-blind, double-dummy, randomized, inpatient trial.

Description of the study: The objective of this study was to evaluate the safety, tolerability, and pharmacokinetics of intravenous lacosamide as replacement for oral lacosamide in patients with partial-onset seizures. 60 patients were enrolled from an ongoing open-label extension trial of oral lacosamide and randomized to either intravenous lacosamide and oral placebo or and intravenous placebo and oral lacosamide. During the 2-day inpatient treatment period, patients received twice-daily doses of lacosamide equivalent to their current daily dose of oral lacosamide (200-600 mg/day). The first 30 patients enrolled received infusion within 60-min durations and the next 30received infusions with 30-min durations. Results: Of 60 patients randomized, 50 completed the trial. Treatment-emergent adverse events were reported by 16 patients and included dizziness, headache, back pain, somnolence, and injectable site pain. The tolerability profile of intravenous lacosamide was consistent with that of oral lacosamide. All AEs were considered mild or moderate in intensity, and no serious AEs leading to discontinuation were reported. Intravenous lacosamide, administered as 60- or 30- min twice daily infusions, showed a similar safety and tolerability profile to oral lacosamide when used as replacement therapy.

Limitations: This study lacks of p values.

Conclusion: Results from this trial support the safety of intravenous lacosamide as a short-term (up to 2 days) replacement for oral lacosamide in patients with partial-onset seizures. The safety and tolerability profile for intravenous lacosamide was similar to oral lacosamide based on analyses of AEs, ECGs, vital signs, and seizure counts. Based on limited exposure to higher doses in this trial, additional research is needed to determine the safety and tolerability profile of the 500 and 600 mg/day doses of lacosamide with 30-min infusion duration. In addition, a clearer understanding of the full safety profile of the intravenous formulation of lacosamide will require additional patient exposures and examination of the potential effects of even shorter infusion durations.

Rauck RL, Shaibani A, Biton V, et al: Lacosamide in painful diabetic peripheral neuropathy: a phase 2 double-blind placebo-controlled study. Clin J Pain 2007; 23(2):150-158.

Study design: Multicenter, randomized, double-blind, placebo-controlled trial.

Description of study: The objective of the study was to ascertain the effect of lacosamide on pain associated with peripheral diabetic neuropathy. 119 patients with a 1 to 5 year history of pain attributed to diabetic neuropathy and a score of > 4 on the Likert pain scale entered trial. Lacosamide (n=60) titrated from 100 to 400 mg/day or maximum tolerated dose and placebo (n=59) were the trial interventions. Results: 94 patients (lacosamide 46, placebo 48) completed the trial. Lacosamide had significantly (p=0.039) better pain relief versus placebo (primary outcome). Improvements were also seen in secondary outcome measures. Adverse events occurred in 52 lacosamide and 44 placebo patients. Common adverse events, occurring in more than 5% of patients, were headache (lacosamide 18%, placebo 22%), dizziness (lacosamide 15%, placebo 8%), and nausea (lacosamide 12%, placebo 7%). 5 lacosamide and 3 placebo patients withdrew because of AEs.

Limitations: Variability in outcome measures across clinical trials generally makes it difficult to evaluate objectively the effectiveness of treatments for chronic pain. In addition, the diagnosis of diabetic neuropathy was made on clinical examination alone without use of nerve electrophysiology studies. Analgesic use may have contributed to the higher than expected placebo response. There was also higher rate of adverse events in placebo group. The sample size was small that could increase the risk of making type II error.

Conclusion: Further studies need to be done to ascertain that lacosamide attenuate pain in diabetic neuropathy and improves quality of life issues.

Contraindications:
specific contraindications have not been determined

Precautions ^1,2,3,4,6:

• Altered cardiac conduction: Lacosamide may prolong PR interval; ECG is recommended prior to initiating therapy and when at steady state.
• 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.
• Suicidal ideation: Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression.

Adverse effects ^1,2,3,4:

>10%:

• Central nervous system: Dizziness (31%), headache (13%)
• Gastrointestinal: Nausea (11%)
• Ocular: Diplopia (11%)

1% to 10%:

• Cardiovascular: Syncope (1%; dose-related: >400 mg/day)
• Central nervous system: Fatigue (9%), ataxia (8%), somnolence (7%), coordination impaired (4%), vertigo (4%), depression (2%), memory impairment (2%)
• Dermatologic: Pruritus (2%)
• Gastrointestinal: Vomiting (9%), diarrhea (4%)
• Local: Contusion (3%), skin laceration (3%), injection site pain/discomfort (2.5%), irritation (1%)
• Neuromuscular & skeletal: Tremor (7%), weakness (2%)
• Ocular: Blurred vision (8%), nystagmus (5%)

Drug Interactions ³:

Ethanol: taking ethanol with lacosamide may increase CNS depression.

Dosing/Administration ³:

Oral: Initial: 50 mg twice daily; may be increased at weekly intervals by 100 mg/day.

Maintenance dose: 200-400 mg/day

IV: When oral lacosamide therapy is not feasible, the recommended initial dose of lacosamide injection for the adjunctive treatment of partial-onset seizures is 50 milligrams (mg) infused intravenously (IV) over 30 to 60 minutes twice daily.

Note: When switching from oral to I.V. formulations, the total daily dose and frequency should be the same; I.V. therapy should only be used temporarily.

Geriatric dose: Refer to adult dose

Pediatric dose: Adolescents ≥17 years: Refer to adult dosing. The safety and efficacy of lacosamide has not been established in pediatric patients aged less than 17 years.

Renal impairment dose: Mild-to-moderate renal impairment: No dose adjustment necessary. Severe renal impairment (Cl_cr ≤30 mL/minute): Maximum dose: 300 mg/day.

Hemodialysis: Removed by hemodialysis; after 4-hour HD treatment, a supplemental dose of up to 50% should be considered.

Hepatic impairment dose:  Mild-to-moderate hepatic impairment: Maximum dose: 300 mg/day.

Severe hepatic impairment: Use is not recommended.

Use in special circumstances ³:

Pregnancy Risk Factor: C

Pregnancy Considerations: Developmental toxicities were observed in animal studies. There are no adequate and well-controlled studies in pregnant women; only use during pregnancy if potential benefit justifies the potential risk to the fetus

Lactation: Excretion in breast milk is unknown

Breast Feeding Considerations: It is unknown if lacosamide is excreted in human milk. Use during lactation only if the potential benefits to the mother outweigh the potential risks to the infant.

Conclusion:

Lacosamide is indicated for adjunctive therapy in the treatment of partial-onset seizures in epileptic patients aged 17 years and older; intravenous use is indicated as short-term replacement when oral administration is not feasible. Efficacy of lacosamide was established in three randomized, double-blind, placebo-controlled trials involving adult patients with partial-onset seizures with or without secondary generalization who were not adequately controlled with 1 to 3 concomitant antiepileptic drugs. The adverse event profile of lacosamide is similar across trials. For patients who are temporarily unable to take oral lacosamide, the equivalent safety and efficacy of intravenous lacosamide may provide an added benefit. There is also early evidence of efficacy in pain relief with lacosamide monotherapy in the treatment of diabetic neuropathy. Recently, The U.S. Food and Drug Administration (FDA) alerts healthcare professionals of an increased risk of suicidality (suicidal behavior or ideation) observed from analysis of clinical studies using various antiepileptic medications compared to placebo. Most lacosamide trials were less than 24 week duration and the risk of suicide extending beyond 24 weeks is currently unknown. Healthcare professionals and family members or caregivers are encouraged to monitor patients receiving any antiepileptic medication for signs and symptoms of suicidality (eg, anxiety, depression, behavior changes). Patients should not stop taking their antiepileptic therapy unless advised by a healthcare professional.

Recommended References:

1.Ben-Menachem E, Biton V, Jatuzis D, et al, “Efficacy and Safety of Oral Lacosamide as Adjunctive Therapy in Adults With Partial-Onset Seizures,” Epilepsia, 2007, 48(7):1308-17.

2. Biton V, Rosenfeld WE, Whitesides J, et al, “Intravenous Lacosamide as Replacement for Oral Lacosamide in Patients With Partial-Onset Seizures,” Epilepsia, 2008, 49(3):418-24.

3. Product Information: VIMPAT(R) oral tablets, IV injection, lacosamide oral tablets, IV injection. UCB,Inc, Smyrna, GA, 2008.

4. Rauck RL, Shaibani A, Biton V, et al: Lacosamide in painful diabetic peripheral neuropathy: a phase 2 double-blind placebo-controlled study. Clin J Pain 2007; 23(2):150-158.

5. Beyreuther BK, Freitag J, Heers C, et al, “Lacosamide: A Review of Preclinical Properties,” CNS Drug Rev, 2007, 13(1):21-42.

6. Doty P, Rudd GD, Stoehr T, et al, “Lacosamide,” Neurotherapeutics, 2007, 4(1):145-8.

Prepared by: Khanh-Ha Nguyen, Doctor of Pharmacy Candidate