Lacosamide

Lacosamide is an Antiseizure Agent belonging to Sodium channels inhibitor class.

Lacosamide is an antiepileptic drug used to treat partial onset seizures in adults.

Lacosamide is Rapidly and completely absorbed (oral). Its Bioavailability is Approximately 100% (oral). Time taken to reach peak plasma concentration: 1-4 hours (oral). Lacosamide has Volume of distribution of Approximately 0.6 L/kg. The Plasma protein binding is about <15%. Lacosamide is metabolized in the liver by the CYP3A4, CYP2C9, and CYP2C19 isoenzymes to form its inactive metabolite, O-desmethyl-lacosamide.It is Mainly excreted via urine 95% and approximately 40% as unchanged drug, <30% as O-desmethyl-lacosamide, and approximately 20% as uncharacterized metabolites); faeces (<0.5%).

Lacosamide shows side effects like Nausea, vomiting, diarrhea, blurred or double vision, uncontrollable eye movements, dizziness, headache, etc.

Lacosamide is available in the form of Oral Tablet, Oral capsule, Injectable solution and oral solution.

Lacosamide is available in India, US, Germany, Spain, Italy, France, Japan, China, Singapore and Australia.

Lacosamide belongs to Sodium channels inhibitor class and acts as Antiseizure Agent.

It is proposed that lacosamide's inhibition of sodium channels is responsible for analgesia. Lacosamide may be selective for inhibiting depolarized neurons rather than neurons with normal resting potentials. Pain and nociceptor hyperexcitability are associated with neural membrane depolarization. Lacosamide binds to collapsin response mediator protein-2 (CRMP-2), a phosphoprotein which is expressed primarily in the nervous system and is involved in neuronal differentiation and control of axonal outgrowth. The role CRMP-2 of binding in seizure control is hasn't been elucidated.

The Onset and Duration of action of Lacosamide is not clinically established.

The Time to peak plasma concentration of Lacosamide is approximately 1-4 hours.

Lacosamide is available in the form of Oral Tablet, Oral capsule, Injectable solution and oral solution.

Lacosamide Tablet, capsule, oral solution are taken orally usually in divided dose while Injectable solution is given via intravenous route.

Lacosamide is an anticonvulsant used either alone or in combination with other medicines for the treatment of seizures. The oral forms of Lacosamide are not recommended for use in patients less than 4 years of age. The injectable form of Lacosamide is not recommended for use in patients less than 17 years of age.

Lacosamide is an Antiseizure Agent belonging to Sodium channels inhibitor class.

Lacosamide, a functionalized amino acid, selectively enhances the slow inactivation of voltage-gated Na channels, resulting in the stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing. It binds to collapsin response mediator protein-2 (CMRP-2), a phosphoprotein involved in neuronal differentiation, polarisation, gene expression, and control of axonal outgrowth.

Lacosamide is approved for use in the following clinical indications

• Focal onset seizures

Oral, IV:

Initial: 50 to 100 mg twice daily; may be increased at weekly intervals by 50 mg twice daily based on response and tolerability. Alternatively, may give 200 mg loading dose followed 12 hours later by 100 mg twice daily with same titration schedule. Administer loading doses under medical supervision due to increased incidence of CNS adverse reactions.

Maintenance: 150 to 200 mg twice daily. Doses up to 600 mg/day may provide additional benefit in some patients.

• Primary generalized tonic-clonic seizures

Oral, IV:

Initial: 50 mg twice daily; may be increased at weekly intervals by 50 mg twice daily based on response and tolerability. Alternatively, may give 200 mg loading dose followed 12 hours later by 100 mg twice daily with same titration schedule. Administer loading doses under medical supervision due to increased incidence of CNS adverse reactions.

Maintenance dose: 100 to 200 mg twice daily.

• Status epilepticus

IV: Initial: 200 to 400 mg as a single dose followed by a maintenance dose of 200 to 400 mg/day in 2 divided doses; some patients may require up to 600 mg/day.

• Focal onset seizures
• Primary generalized tonic-clonic seizures
• Status epilepticus

Lacosamide is available in various strengths as 50mg,100mg,150mg,200mg, 200mg/20mL, 10mg/mL.

Lacosamide is available in the form of Oral Tablet, Oral capsule, Injectable solution and oral solution.

• Dosage Adjustment in Kidney Patient

CrCl ≥30 mL/minute: Initial and maintenance: No dosage adjustment necessary.

CrCl <30 mL/minute:

Initial: No dosage adjustment necessary; base initiation and titration schedule on clinical response and tolerability.

Maintenance: Administer up to 75% of the indication-specific maximum dose.

• Dosage Adjustment in Hepatic impairment Patient

Mild to moderate hepatic impairment: Reduce dose to 75% of the maximum dose; base initiation and titration schedule on clinical response and tolerability.

Severe hepatic impairment: Use is not recommended.

• Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including Lacosamide, 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.

• Dizziness and Ataxia

Lacosamide may cause dizziness and ataxia. In adult 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 Lacosamide (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 Lacosamide (compared to 2% of placebo patients). The onset of dizziness and ataxia was most observed during titration. There was a substantial increase in these adverse events at doses higher than 400 mg/day. Dizziness and ataxia were also observed in pediatric clinical trials.

• Cardiac Rhythm and Conduction Abnormalities

PR Interval Prolongation, Atrioventricular Block, and Ventricular Tachyarrhythmia Dose-dependent prolongations in PR interval with Lacosamide have been observed in clinical studies in adult patients and in healthy volunteers. In adjunctive clinical trials in adult patients with partial-onset seizures, asymptomatic first-degree atrioventricular (AV)block was observed as an adverse reaction in 0.4% (4/944) of patients randomized to receive Lacosamide and 0% (0/364) of patients randomized to receive placebo. One case of profound bradycardia was observed in a patient during a 15-minute infusion of 150 mg Lacosamide. When Lacosamide is given with other drugs that prolong the PR interval, further PR prolongation is possible.

Vimpat should be used with caution in patients with underlying proarrhythmic conditions such as known cardiac conduction problems (e.g., marked first-degree AV block, second-degree or higher AV block and sick sinus syndrome without pacemaker), severe cardiac disease (such as myocardial ischemia or heart failure, or structural heart disease), and cardiac sodium channelopathies (e.g., Brugada Syndrome). Lacosamide should also be used with caution in patients on concomitant medications that affect cardiac conduction, including sodium channel blockers, beta-blockers, calcium channel blockers, potassium channel blockers, and medications that prolong the PR interval. In such patients, obtaining an ECG before beginning Lacosamide, and after Lacosamide is titrated to steady-state maintenance dose, is recommended. In addition, these patients should be closely monitored if they are administered Lacosamide through the intravenous route.

• Withdrawal of Antiepileptic Drugs (AEDs)

As with all AEDs, Lacosamide should be withdrawn gradually (over a minimum of 1 week) to minimize the potential of increased seizure frequency in patients with seizure disorders.

• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multi-organ hypersensitivity, has been reported in patients taking antiepileptic drugs, including Lacosamide. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Lacosamide should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

There are no data on the presence of lacosamide in human milk, the effects on the breastfed infant, or the effects on milk production. Studies in lactating rats have shown excretion of lacosamide and/or its metabolites in milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Lacosamide and any potential adverse effects on the breast-fed infant from Lacosamide or from the underlying maternal condition.

There are no adequate data on the developmental risks associated with the use of Lacosamide in pregnant women. Lacosamide produced developmental toxicity (increased embryofetal and perinatal mortality, growth deficit) in rats following administration during pregnancy. Developmental neurotoxicity was observed in rats following administration during a period of postnatal development corresponding to the third trimester of human pregnancy. These effects were observed at doses associated with clinically relevant plasma exposures (see Data). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Common

Nausea, Dizziness, drowsiness, headache, Pruritus, Diarrhea, vomiting, Bruise , Local irritation, pain at injection site, Abnormal gait, asthenia, ataxia, balance impairment, depression, fatigue, tremor, vertigo, Blurred vision, diplopia, nystagmus disorder Laceration, Bradycardia, first-degree atrioventricular block, Abnormal hepatic function tests, hepatitis, Erythema at injection site, Nephritis, Constipation, oral hypoesthesia, xerostomia, Anemia, Cerebellar syndrome, dysarthria, euphoria, falling, hypoesthesia, intoxicated feeling, Muscle spasm, Tinnitus, Fever.

Rare

Angina pectoris, atrial fibrillation, atrial flutter, atrioventricular block, cardiac arrhythmia, complete atrioventricular block, palpitations, prolongation P-R interval on ECG, prolonged QT interval on ECG, syncope, ventricular tachycardia, Skin rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria, Hyponatremia, Dyspepsia, Agranulocytosis, neutropenia, Angioedema, drug reaction with eosinophilia and systemic symptoms, Acute psychosis, aggressive behavior, agitation, amnesia, cognitive dysfunction, confusion, depressed mood, disturbance in attention, hallucination, irritability, memory impairment, mood changes, paresthesia, sleep disturbance, suicidal ideation, suicidal tendencies, Dyskinesia, panniculitis.

Antiarrhythmic Agents (Class III)

May enhance the adverse/toxic effect of Lacosamide. Specifically, the risk for bradycardia, ventricular tachyarrhythmias, or a prolonged PR interval may be increased.

Blonanserin

CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin.

Mefloquine

May diminish the therapeutic effect of Antiseizure Agents. Mefloquine may decrease the serum concentration of Antiseizure Agents. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of seizures. If antiseizure drugs are being used for another indication, monitor antiseizure drug concentrations and treatment response closely with concurrent use.

Methotrimeprazine

CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patients closely for evidence of CNS depression.

QT-prolonging Class IA Antiarrhythmics (Highest Risk)

May enhance the adverse/toxic effect of Lacosamide. Specifically, the risk for bradycardia, ventricular tachyarrhythmias, or a prolonged PR interval may be increased. Risk C: Monitor therapy

QT-prolonging Class IC Antiarrhythmics (Moderate Risk)

May enhance the adverse/toxic effect of Lacosamide. Specifically, the risk for bradycardia, ventricular tachyarrhythmias, or a prolonged PR interval may be increased.

The common side effects of Lacosamide include the following

Common side effects

Nausea, vomiting, diarrhoea, blurred or double vision, uncontrollable eye movements, dizziness, headache, drowsiness, uncontrollable shaking of a part of the body, problems with coordination, balance, or walking, weakness, itching.

Rare side effects

Fast or pounding heartbeat or pulse, shortness of breath, slow heartbeat, chest pain, fainting, swelling of the face, throat, tongue, lips, and eyes, fever, rash, tiredness, yellowing of the skin or eyes, dark urine.

• Pregnancy

Pregnancy Category

There are no adequate data on the developmental risks associated with the use of Lacosamide in pregnant women. Lacosamide produced developmental toxicity (increased embryofetal and perinatal mortality, growth deficit) in rats following administration during pregnancy. Developmental neurotoxicity was observed in rats following administration during a period of postnatal development corresponding to the third trimester of human pregnancy. These effects were observed at doses associated with clinically relevant plasma exposures (see Data). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

• Nursing Mothers

There are no data on the presence of lacosamide in human milk, the effects on the breastfed infant, or the effects on milk production. Studies in lactating rats have shown excretion of lacosamide and/or its metabolites in milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Lacosamide and any potential adverse effects on the breast-fed infant from Lacosamide or from the underlying maternal condition.

• Pediatric Use

Safety of Lacosamide injection in pediatric patients has not been established. Safety and effectiveness in pediatric patients below the age of 4 years have not been established.

• Geriatric Use

There were insufficient numbers of elderly patients enrolled in partial-onset seizure trials (n=18) to adequately determine whether they respond differently from younger patients. No Lacosamide dose adjustment based on age is necessary.

Symptoms: Dizziness, nausea, vomiting, seizures (e.g. generalized tonic-clonic seizures, status epilepticus), cardiac conduction disorders, shock and coma.

Management: Symptomatic and supportive treatment. May consider hemodialysis if necessary.

• Pharmacodynamic

Lacosamide therapy is correlated with a decrease in seizure frequency. It should be noted that in group analyses, dosages above 400 mg/day do not appear to result in additional benefit.

• Pharmacokinetics

Absorption

Lacosamide is Rapidly and completely absorbed (oral). Its Bioavailability is Approximately 100% (oral). Time taken to reach peak plasma concentration: 1-4 hours (oral).

Distribution

Lacosamide has Volume of distribution of Approximately 0.6 L/kg. The Plasma protein binding is about <15%.

Metabolism and Excretion

Lacosamide is metabolized in the liver by the CYP3A4, CYP2C9, and CYP2C19 isoenzymes to form its inactive metabolite, O-desmethyl-lacosamide.It is Mainly excreted via urine 95% and approximately 40% as unchanged drug, <30% as O-desmethyl-lacosamide, and approximately 20% as uncharacterized metabolites); faeces (<0.5%).

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022253s042lbl.pdf
• https://go.drugbank.com/drugs/DB06218
• https://www.drugs.com/vimpat.html
• https://medlineplus.gov/druginfo/meds/a609028.html
• https://www.uptodate.com/contents/lacosamide-drug-information?search=lacosamide&source=panel_search_result&selectedTitle=1~33&usage_type=panel&kp_tab=drug_general&display_rank=1
• https://reference.medscape.com/drug/vimpat-motpoly-xr-lacosamide-343026