Adult: With or without secondary generalisation: Monotherapy: Initially, 50 mg bid, increased to 100 mg bid after 1 week; or 100 mg bid based on required seizure reduction versus potential side effects. Maintenance dose may be further increased in 50 mg bid increments at weekly intervals according to patient response and tolerability. Max: 300 mg bid. Adjunctive therapy: Initially, 50 mg bid, increased to 100 mg bid after 1 week. Maintenance dose may be further increased in 50 mg bid increments at weekly intervals according to patient response and tolerability. Max: 200 mg bid. Treatment with loading dose: Initially, 200 mg as a single dose, followed by 100 mg bid after approx 12 hours, then adjust subsequent doses according to patient response and tolerability. Infusion duration: 15-60 minutes bid. Child: With or without secondary generalisation: ≥4 years <50 kg: Monotherapy: Initially, 2 mg/kg daily, increased to 4 mg/kg daily after 1 week. Maintenance dose may be further increased in 2 mg/kg daily increments at weekly intervals according to patient response and tolerability. <40 kg: Max: 12 mg/kg daily. ≥40 kg to <50 kg: Max: 10 mg/kg daily. Adjunctive therapy: Initially, 2 mg/kg daily, increased to 4 mg/kg daily after 1 week. Maintenance dose may be further increased in 2 mg/kg daily increments at weekly intervals according to patient response and tolerability. <20 kg: Max: 12 mg/kg daily. ≥20 kg to <30 kg: Max: 10 mg/kg daily. ≥30 kg to <50 kg: Max: 8 mg/kg daily. ≥50 kg: Same as adult dose. Infusion duration: 15-60 minutes bid.
Oral Partial seizures
Adult: With or without secondary generalisation: Monotherapy: Initially, 50 mg bid, increased to 100 mg bid after 1 week; or 100 mg bid based on required seizure reduction versus potential side effects. Maintenance dose may be further increased in 50 mg bid increments at weekly intervals according to patient response and tolerability. Max: 300 mg bid. Adjunctive therapy: Initially, 50 mg bid, increased to 100 mg bid after 1 week. Maintenance dose may be further increased in 50 mg bid increments at weekly intervals according to patient response and tolerability. Max: 200 mg bid. Treatment with loading dose: Initially, 200 mg as a single dose, followed by 100 mg bid after approx 12 hours, then adjust subsequent doses according to patient response and tolerability. Child: With or without secondary generalisation: ≥4 years <50 kg: Monotherapy: Initially, 2 mg/kg daily, increased to 4 mg/kg daily after 1 week. Maintenance dose may be further increased in 2 mg/kg daily increments at weekly intervals according to patient response and tolerability. <40 kg: Max: 12 mg/kg daily. ≥40 kg to <50 kg: Max: 10 mg/kg daily. Adjunctive therapy: Initially, 2 mg/kg daily, increased to 4 mg/kg daily after 1 week. Maintenance dose may be further increased in 2 mg/kg daily increments at weekly intervals according to patient response and tolerability. <20 kg: Max: 12 mg/kg daily. ≥20 kg to <30 kg: Max: 10 mg/kg daily. ≥30 kg to <50 kg: Max: 8 mg/kg daily. ≥50 kg: Same as adult dose.
Special Patient Group
Lacosamide is metabolised to its major inactive O-desmethyl metabolite mainly by CYP2C19, CYP2C9, and CYP3A4 isoenzymes.
Individuals who have no CYP2C19 enzyme activity are known as CYP2C19 poor metabolisers. CYP2C19 poor metabolisers are carriers of 2 nonfunctional CYP2C19 variant alleles and extensive metabolisers are carriers of 2 functional CYP2C19 alleles.
FDA-approved 2016 drug label for lacosamide cites that results from a small study in CYP2C19 poor metabolisers (n=4) and extensive metabolisers (n=8) showed that there are no clinically relevant differences in the pharmacokinetics of lacosamide between CYP2C19 poor metabolisers and extensive metabolisers, but plasma concentrations and the amount of the inactive O-desmethyl metabolite excreted into urine were about 70% reduced in poor metabolisers as compared to extensive metabolisers. The recommended standard doses of lacosamide may be used for CYP2C19 poor metabolisers.
There is no evidence supporting clinical CYP2C19 pharmacogenetic testing prior to initiating lacosamide treatment, and testing has not yet been addressed by currently available professional society practice guidelines.
Renal Impairment
Patient with ESRD: Treatment with loading dose: Initially, 100 mg, followed by 50 mg bid for the first week. Max: 250 mg daily. Titrate dose with caution. Patient undergoing haemodialysis: Supplement dose of up to 50% of the divided daily dose directly after the end of each session.
CrCl (mL/min)
Dosage
≤30
Treatment with loading dose: Initially, 100 mg,
followed by 50 mg bid for the first week. Max: 250 mg daily. Titrate dose
with caution.
>30
May consider loading dose of 200 mg, further
dose titration
(>200 mg daily) should be performed with caution.
Hepatic Impairment
Mild to moderate: May consider loading dose of 200 mg, further dose titration (>200 mg daily) should be performed with caution. Max: 300 mg daily. Severe: Not recommended.
Administration
FC tab & oral soln: May be taken with or without food. FC tab: Swallow whole w/ liqd, do not divide. Oral soln: May be administered via nasogastric or gastrostomy tube.
Reconstitution
IV infusion: May be administered without further dilution or may be mixed with compatible diluents (e.g. 0.9% NaCl inj, Lactated Ringer’s inj, 5% dextrose in water).
Contraindications
2nd- or 3rd- degree AV block.
Special Precautions
Patients with severe cardiac disease (e.g. history of MI, heart failure, ischaemia), conduction problems (e.g. 1st degree AV block, sick sinus syndrome without pacemaker), Na channelopathies (e.g. Brugada syndrome), structural heart disease. Concomitant use with drugs that affect cardiac conduction and prolong PR interval; strong CYP3A4 or CYP2C9 inhibitors. Renal and hepatic impairment. Children and elderly. Pregnancy and lactation.
Adverse Reactions
Significant: PR interval prolongation, suicidal ideation and behaviour, syncope, dizziness, ataxia, blurred vision, diplopia. Blood and lymphatic system disorders: Agranulocytosis. Ear and labyrinth disorders: Tinnitus. Eye disorders: Nystagmus. Gastrointestinal disorders: Nausea, vomiting, constipation, flatulence, diarrhoea, dyspepsia, xerostomia. General disorders and admin site conditions: Fatigue, asthenia, gait disturbance, irritability, feeling drunk, inj site reactions (e.g. pain, irritation, erythema). Injury, poisoning and procedural complications: Skin laceration, fall, contusion. Investigations: Abnormal LFT, increased hepatic enzyme. Musculoskeletal and connective tissue disorders: Muscle spasms. Nervous system disorders: Headache, vertigo, tremor, abnormal coordination, memory impairment, balance disorder, cognitive disorder, paraesthesia, dysarthria. Psychiatric disorders: Depression, confusion, insomnia, somnolence. Skin and subcutaneous tissue disorders: Pruritus, rash. Potentially Fatal: Rarely, cardiac arrhythmias including bradycardia, AV block and ventricular tachyarrhythmia resulting in asystole and cardiac arrest; multiorgan hypersensitivity reaction such as drug reaction with eosinophilia and systemic symptoms (DRESS).
This drug may cause dizziness, blurred vision or ataxia, if affected, do not drive or operate machinery.
Monitoring Parameters
Monitor signs of suicidality (e.g. suicidal thoughts, depression, behavioural changes). Perform ECG prior to treatment initiation in patients with severe cardiac disease, conduction problems and Na channelopathies.
Overdosage
Symptoms: Dizziness, nausea, vomiting, seizures (e.g. generalised tonic-clonic seizure, status epilepticus), cardiac conduction disorders, shock and coma. Management: Symptomatic and supportive treatment. May consider haemodialysis if necessary.
Drug Interactions
Increased systemic exposure with strong inhibitors of CYP2C9 (e.g. fluconazole) and CYP3A4 (e.g. itraconazole, ketoconazole, ritonavir, clarithromycin). Increased risk of PR interval prolongation with carbamazepine, lamotrigine, eslicarbazepine, pregabalin and class I antiarrhythmics. May reduce systemic exposure with rifampicin, carbamazepine, phenytoin and phenobarbital.
Food Interaction
May reduce systemic exposure with St. John's wort. May increase effects of alcohol.
Action
Description: Lacosamide, a functionalised amino acid, selectively enhances the slow inactivation of voltage-gated Na channels without affecting the fast inactivation, resulting in the stabilisation of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing. It may also affect collapsin response mediator protein-2 (CMRP-2) which is the protein involved in neuronal differentiation and axonal growth dysregulated in epilepsy. Pharmacokinetics: Absorption: Rapidly and completely absorbed from the gastrointestinal tract (oral). Bioavailability: Approx 100% (oral). Time to peak plasma concentration: 1-4 hours (oral). Distribution: Volume of distribution: Approx 0.6 L/kg. Plasma protein binding: <15%. Metabolism: Metabolised in the liver by CYP3A4, CYP2C9, and CYP2C19 isoenzymes to form its inactive metabolite, O-desmethyl-lacosamide. Excretion: Mainly via urine (95%; approx 40% as unchanged drug, <30% as inactive O-desmethyl-lacosamide, approx 20% as unknown metabolites); faeces (<0.5%). Elimination half-life: Approx 13 hours.
Chemical Structure
Source: National Center for Biotechnology Information. PubChem Database. Lacosamide, CID=219078, https://pubchem.ncbi.nlm.nih.gov/compound/Lacosamide (accessed on Jan. 22, 2020)
Storage
Tab, oral solution, IV: Store between 20-25°C. Oral solution, IV: Do not freeze.
N03AX18 - lacosamide ; Belongs to the class of other antiepileptics.
References
Dean, L. Lacosamide Therapy and CYP2C19 Genotype. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US). Accessed 02/07/2019. PMID: 29671994Annotation of EMA Label for Lacosamide and CYP2C19. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 02/07/2019.Annotation of FDA Label for Lacosamide and CYP2C19. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 02/07/2019.Anon. Lacosamide. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 02/07/2019.Buckingham R (ed). Lacosamide. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 02/07/2019.Trelema 10 mg/mL Syrup (G.L. Pharma GmBH). MHRA. https://products.mhra.gov.uk/. Accessed 02/07/2019.Vimpat Film-Coated Tablet, Injection, Solution (UCB Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 02/07/2019.
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