Lacosamide

Registered South African indications:

• As monotherapy in the treatment of partial-onset seizures with or without secondary generalisation in adults, adolescents and children from 2 years of age with epilepsy
• As adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalisation in adults, adolescents and children from 2 years of age with epilepsy
• As adjunctive therapy in the treatment of primary generalised tonic-clonic seizures in adults, adolescents and children from 4 years of age with idiopathic generalised epilepsy

Contraindications

Registered contraindications in South Africa & other jurisdictions

• Patients with a history of hypersensitivity to the active substance or to any of the excipients
• Known second- or third-degree atrioventricular (AV) block

Cautions

Recommendations in South Africa & other jurisdictions

Caution in the following patient groups

• Pregnancy
• Breastfeeding
• Severe renal impairment (CrCl≤30ml/min)
• Hepatic impairment
• Elderly

Suicidal ideation and behaviour

• Suicidal ideation and behaviour have been reported in patients treated with antiepileptic medicinal products
• A meta-analysis of randomised placebo-controlled clinical studies showed a small increased risk of suicidal ideation and behaviour
• The mechanism of this risk is unknown, and the data do not exclude an increased risk for lacosamide
• Patients should be monitored for signs of suicidal ideation and behaviours, and appropriate treatment should be considered
• Patients and caregivers should be advised to seek medical advice if signs of suicidal ideation or behaviour emerge

Cardiac rhythm and conduction

• Dose-related prolongations in PR interval have been observed with lacosamide in clinical studies
• Lacosamide should be used with caution in patients with underlying proarrhythmic conditions, severe cardiac disease (e.g. myocardial ischaemia/infarction, heart failure, structural heart disease or cardiac sodium channelopathies), or those taking medications affecting cardiac conduction
• An ECG should be considered before increasing the dose above 400 mg/day and after titration to steady-state
• In post-marketing experience, AV block and ventricular tachyarrhythmia have been reported, potentially leading to asystole, cardiac arrest, and death in patients with proarrhythmic conditions
• Patients should be informed about symptoms of cardiac arrhythmia (e.g. slow, rapid or irregular pulse, palpitations,
  shortness of breath, feeling lightheaded, fainting) and advised to seek immediate medical advice if symptoms occur

Dizziness

• Lacosamide treatment is associated with dizziness, which may increase the risk of accidental injury or falls
• Patients should exercise caution until they are familiar with the effects of the medication

Potential for new onset or worsening of myoclonic seizures

• New onset or worsening of myoclonic seizures has been reported, especially during titration, in both adult and paediatric patients with PGTCS (primary generalised tonic-clonic seizures)
• The benefit of controlling one seizure type should be weighed against any worsening of another seizure type

Potential for electro-clinical worsening in specific paediatric epilepsy syndromes

• The safety and efficacy of lacosamide in paediatric patients with epilepsy syndromes, where focal and generalised seizures may coexist, have not been determined

Ability to drive and use machines

• Lacosamide has a minor to moderate influence on the ability to drive and use machines
• Treatment with lacosamide has been associated with dizziness or blurred vision
• Patients should be advised not to drive or operate potentially hazardous machinery until they are familiar with how lacosamide affects their ability to perform these activities

Forms avail. in SA and covered in this monograph: fct

South African registered indications and dosages

Summarised dose recommendations

As monotherapy in the treatment of partial-onset seizures with or without secondary generalisation in those with epilepsy

• Oral (fct): Initial: 50-100mg, twice a day (approx. 12hrs apart) (100-200mg/day); Titrate by 50mg, twice a day (100mg/day) at weekly intervals; Max: Up to 300mg, twice a day (600mg/day)

Alternate initial dosage (if applicable)*

• Oral (fct): 200mg single loading dose; Followed by 100mg, twice a day (200 mg/day)

As adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalisation in those with epilepsy
As adjunctive therapy in the treatment of primary generalised tonic-clonic seizures in those with idiopathic generalised epilepsy

• Oral (fct): Initial: 50mg, twice a day (approx. 12hrs apart) (100mg/day); Titrate by 50mg, twice a day (100mg/day) at weekly intervals; Max: Up to 200mg, twice a day (400mg/day)

Alternate initial dosage (if applicable)*

• Oral (fct): 200mg single loading dose; Followed by 100mg, twice a day (200 mg/day)

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*A loading dose may be initiated in patients in situations when the medical practitioner determines that rapid attainment of lacosamide steady state plasma concentration and therapeutic effect is warranted. It should be administered under medical supervision with consideration of the potential for increased incidence of serious cardiac arrhythmia and central nervous system adverse reactions. Administration of a loading dose has not been studied in acute conditions such as status epilepticus

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Detailed dose recommendations

Monotherapy (in the treatment of partial-onset seizures)

• Oral (fct): Initial: 50mg, twice a day (approx. 12hrs apart) (100mg/day); Increase to initial therapeutic dose of 100mg, twice a day (200mg/day) after one week; Alternative initiation: 100mg, twice a day (200mg/day) based on the medical practitioner’s assessment of required seizure reduction versus potential side effects; Maintenance dose: Depending on response and tolerability, the maintenance dose can be further increased by 50mg, twice a day (100mg/day) at weekly intervals; Max: Up to 300mg, twice a day (600mg/day); In patients having reached a dose >200mg, twice a day (400mg/day) and who need an additional antiepileptic medicinal product, the posology that is recommended for adjunctive therapy below should be followed

Adjunctive therapy (in the treatment of partial-onset seizures or in the treatment of primary generalised tonic-clonic seizures)

• Oral (fct): Initial: 50mg, twice a day (approx. 12hrs apart) (100mg/day); Increase to initial therapeutic dose of 100mg, twice a day (200mg/day) after one week; Maintenance dose: Depending on response and tolerability, the maintenance dose can be further increased by 50mg, twice a day (100mg/day) at weekly intervals; Max: Up to 200mg, twice a day (400mg/day)

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The medical practitioner should prescribe the most appropriate formulation and strength according to weight and dose

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Lacosamide treatment may also be initiated with a single loading dose of 200mg, followed approximately 12 hours later by a 100mg twice a day (200mg/day) maintenance dose regimen. Subsequent dose adjustments should be performed according to individual response and tolerability as described above. A loading dose may be initiated in patients in situations when the medical practitioner determines that rapid attainment of lacosamide steady state plasma concentration and therapeutic effect is warranted. It should be administered under medical supervision with consideration of the potential for increased incidence of serious cardiac arrhythmia and central nervous system adverse reactions. Administration of a loading dose has not been studied in acute conditions such as status epilepticus

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Missed doses
If a dose is missed, the patient should be instructed to take the missed dose immediately, and then to take the next dose of lacosamide at the regularly scheduled time. If the patient notices the missed dose within 6 hours of the next one, he/she should be instructed to wait to take the next dose of lacosamide at the regularly scheduled time. Patient’s should not take a double dose

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Discontinuation
If lacosamide has to be discontinued, it is recommended that the dose is reduced gradually in weekly decrements of 4mg/kg/day (for patients with a body weight less than 50 kg) or 200 mg/day (for patients with a body weight of 50 kg or more) for patients who have achieved a dose of lacosamide ≥6mg/kg/day or ≥300mg/day, respectively. A slower taper in weekly decrements of 2mg/kg/day or 100mg/day can be considered, if medically necessary. In patients who develop serious cardiac arrhythmia, clinical benefit/risk assessment should be performed and if needed lacosamide should be discontinued

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For oral use. Lacosamide may be taken with or without food, twice a day, approximately 12 hours apart

Forms avail. in SA and covered in this monograph: fct

South African registered indications and dosages

Summarised dose recommendations

As monotherapy in the treatment of partial-onset seizures with or without secondary generalisation in adolescents and children from 2 years of age with epilepsy

Younger than 2 years

• Not established for use

2 years and older

• ≥10-<40kg: Initial: 1mg/kg, twice a day (2mg/kg/day); Titrate by 1mg/kg, twice a day (2mg/kg/day) at weekly intervals; Max: Up to 6mg/kg, twice a day (12mg/kg/day)
• ≥40-<50kg: Initial: 1mg/kg, twice a day (2mg/kg/day); Titrate by 1mg/kg, twice a day (2mg/kg/day) at weekly intervals; Max: Up to 5mg/kg, twice a day (10 mg/kg/day)
• ≥50kg: See adult dosages

As adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalisation in adolescents and children from 2 years of age with epilepsy

Younger than 2 years

• Not established for use

2 years and older

• ≥10-<20kg: Initial: 1mg/kg, twice a day (2mg/kg/day); Titrate by 1mg/kg, twice a day (2mg/kg/day) at weekly intervals; Max: Up to 6mg/kg, twice a day (12mg/kg/day)
• ≥20-<30kg: Initial: 1mg/kg, twice a day (2mg/kg/day); Titrate by 1mg/kg, twice a day (2mg/kg/day) at weekly intervals; Max: Up to 5mg/kg, twice a day (10mg/kg/day)
• ≥30-<50kg: Initial: 1mg/kg, twice a day (2mg/kg/day); Titrate by 1mg/kg, twice a day (2mg/kg/day) at weekly intervals; Max: Up to 4mg/kg twice a day (8mg/kg/day)
• ≥50kg: See adult dosages

As adjunctive therapy in the treatment of primary generalised tonic-clonic seizures in adolescents and children from 4 years of age with idiopathic generalised epilepsy

Younger than 4 years

• Not established for use

4 years and older

• ≥10-<20kg: Initial: 1mg/kg, twice a day (2mg/kg/day); Titrate by 1mg/kg, twice a day (2mg/kg/day) at weekly intervals; Max: Up to 6mg/kg, twice a day (12mg/kg/day)
• ≥20-<30kg: Initial: 1mg/kg, twice a day (2mg/kg/day); Titrate by 1mg/kg, twice a day (2mg/kg/day) at weekly intervals; Max: Up to 5mg/kg, twice a day (10mg/kg/day)
• ≥30-<50kg: Initial: 1mg/kg, twice a day (2mg/kg/day); Titrate by 1mg/kg, twice a day (2mg/kg/day) at weekly intervals; Max: Up to 4mg/kg twice a day (8mg/kg/day)
• ≥50kg: See adult dosages

Detailed dose recommendations

Monotherapy (in the treatment of partial-onset seizures)

Younger than 2 years

• Not established for use

2 years and older

• ≥10-<40kg: Initial: 1mg/kg, twice a day (2mg/kg/day); Increase to an initial therapeutic dose of 2mg/kg, twice a day (4mg/kg/day) after one week; Maintenance: Depending on response and tolerability, the maintenance dose can be further increased by 1mg/kg, twice a day (2mg/kg/day) every week. The dose should be gradually increased until the optimum response is obtained; Max: Up to 6mg/kg, twice a day (12mg/kg/day)
• ≥40-<50kg: Initial: 1mg/kg, twice a day (2mg/kg/day); Increase to an initial therapeutic dose of 2mg/kg, twice a day (4mg/kg/day) after one week; Maintenance: Depending on response and tolerability, the maintenance dose can be further increased by 1mg/kg, twice a day (2mg/kg/day) every week. The dose should be gradually increased until the optimum response is obtained; Max: Up to 5mg/kg, twice a day (10mg/kg/day)
• ≥50kg: See adult dosage

Adjunctive therapy (in the treatment of partial-onset seizures)

Younger than 2 years

• Not established for use

2 years and older

• ≥10-<20kg: Initial: 1mg/kg, twice a day (2mg/kg/day); Increase to an initial therapeutic dose of 2mg/kg, twice a day (4mg/kg/day) after one week; Maintenance: Depending on response and tolerability, the maintenance dose can be further increased by 1mg/kg, twice a day (2mg/kg/day) every week. The dose should be gradually increased until the optimum response is obtained; Max: Up to 6mg/kg, twice a day (12mg/kg/day)
• ≥20-<30kg: Initial: 1mg/kg, twice a day (2mg/kg/day); Increase to an initial therapeutic dose of 2mg/kg, twice a day (4mg/kg/day) after one week; Maintenance: Depending on response and tolerability, the maintenance dose can be further increased by 1mg/kg, twice a day (2mg/kg/day) every week. The dose should be gradually increased until the optimum response is obtained; Max: Up to 5mg/kg, twice a day (10mg/kg/day)
• ≥30-<50kg: Initial: 1mg/kg, twice a day (2mg/kg/day); Increase to an initial therapeutic dose of 2mg/kg, twice a day (4mg/kg/day) after one week; Maintenance: Depending on response and tolerability, the maintenance dose can be further increased by 1mg/kg, twice a day (2mg/kg/day) every week. The dose should be gradually increased until the optimum response is obtained; Max: Up to 4mg/kg twice a day (8mg/kg/day); A dose up to 6mg/kg twice a day (12mg/kg/day) has been used by a small number of children from this latter group
• ≥50kg: See adult dosages

Adjunctive therapy (in the treatment of primary generalised tonic-clonic seizures)

Younger than 4 years

• Not established for use

4 years and older

• ≥10-<20kg: Initial: 1mg/kg, twice a day (2mg/kg/day); Increase to an initial therapeutic dose of 2mg/kg, twice a day (4mg/kg/day) after one week; Maintenance: Depending on response and tolerability, the maintenance dose can be further increased by 1mg/kg, twice a day (2mg/kg/day) every week. The dose should be gradually increased until the optimum response is obtained; Max: Up to 6mg/kg, twice a day (12mg/kg/day)
• ≥20-<30kg: Initial: 1mg/kg, twice a day (2mg/kg/day); Increase to an initial therapeutic dose of 2mg/kg, twice a day (4mg/kg/day) after one week; Maintenance: Depending on response and tolerability, the maintenance dose can be further increased by 1mg/kg, twice a day (2mg/kg/day) every week. The dose should be gradually increased until the optimum response is obtained; Max: Up to 5mg/kg, twice a day (10mg/kg/day)
• ≥30-<50kg: Initial: an 1mg/kg, twice a day (2mg/kg/day); Increase to initial therapeutic dose of 2mg/kg, twice a day (4mg/kg/day) after one week; Maintenance: Depending on response and tolerability, the maintenance dose can be further increased by 1mg/kg, twice a day (2mg/kg/day) every week. The dose should be gradually increased until the optimum response is obtained; Max: Up to 4mg/kg twice a day (8mg/kg/day); A dose up to 6mg/kg twice a day (12mg/kg/day) has been used by a small number of children from this latter group
• ≥50kg: See adult dosage

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The medical practitioner should prescribe the most appropriate formulation and strength according to weight and dose

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For children from 2 years of age and adolescents weighing less than 50kg, the dose is determined based on body weight

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The lowest effective dose should be used

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Administration of a loading dose has not been studied in children. Use of a loading dose is not recommended in adolescents and children weighing less than 50kg

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In adolescents and children weighing 50 kg or more, lacosamide treatment may also be initiated with a single loading dose of 200mg, followed approximately 12 hours later by a 100mg twice a day (200mg/day) maintenance dose regimen. Subsequent dose adjustments should be performed according to individual response and tolerability as described above. A loading dose may be initiated in patients in situations when the medical practitioner determines that rapid attainment of lacosamide steady state plasma concentration and therapeutic effect is warranted. It should be administered under medical supervision with consideration of the potential for increased incidence of serious cardiac arrhythmia and central nervous system adverse reactions. Administration of a loading dose has not been studied in acute conditions such as status epilepticus

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Missed doses
If a dose is missed, the patient should be instructed to take the missed dose immediately, and then to take the next dose of lacosamide at the regularly scheduled time. If the patient notices the missed dose within 6 hours of the next one, he/she should be instructed to wait to take the next dose of lacosamide at the regularly scheduled time. Patient’s should not take a double dose

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Discontinuation
If lacosamide has to be discontinued, it is recommended that the dose is reduced gradually in weekly decrements of 4mg/kg/day (for patients with a body weight less than 50 kg) or 200 mg/day (for patients with a body weight of 50 kg or more) for patients who have achieved a dose of lacosamide ≥6mg/kg/day or ≥300mg/day, respectively. A slower taper in weekly decrements of 2mg/kg/day or 100mg/day can be considered, if medically necessary. In patients who develop serious cardiac arrhythmia, clinical benefit/risk assessment should be performed and if needed lacosamide should be discontinued

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For oral use. Lacosamide may be taken with or without food, twice a day, approximately 12 hours apart

Pregnancy

South African recommendations

• Caution; not recommended
• Lacosamide should not be used during pregnancy If women decide to become pregnant, the use of this product should be carefully re-evaluated

Recommendations in other jurisdictions

• Caution; not recommended

Risk related to epilepsy and antiepileptic medicinal products in general

• For all antiepileptic medicinal products, it has been shown that in the offspring of treated women with epilepsy, the prevalence of malformations is two to three times greater than the rate of approximately 3% in the general population
• In the treated population, an increase in malformations has been noted with polytherapy, however, the extent to which the treatment and/or the illness is responsible has not been elucidated 
• Moreover, effective antiepileptic therapy must not be interrupted, since the aggravation of the illness is detrimental to both the mother and the foetus

Risk related to lacosamide

• There are no adequate data from the use of lacosamide in pregnant women. Studies in animals did not indicate any teratogenic effects in rats or rabbits, but embryotoxicity was observed in rats and rabbits at maternal toxic doses. The potential risk for humans is unknown
• Lacosamide should not be used during pregnancy unless clearly necessary (if the benefit to the mother clearly outweighs the potential risk to the foetus). If women decide to become pregnant, the use of this product should be carefully re-evaluated

Women of childbearing potential

• Physicians should discuss family planning and contraception with women of childbearing potential taking lacosamide
• If a woman decides to become pregnant, the use of lacosamide should be carefully re-evaluated

Breastfeeding

South African recommendations

• Caution; not recommended
• Mothers should not breastfeed when taking lacosamide

Recommendations in other jurisdictions

• Caution; not recommended
• Lacosamide is excreted in human breast milk. A risk to the newborns/infants cannot be excluded. It is recommended that breastfeeding should be discontinued during treatment with lacosamide

Fertility

Recommendations below are applicable to South Africa and other jurisdictions

• No adverse reactions on male or female fertility or reproduction were observed in rats at doses producing plasma exposures (AUC) up to approximately 2 times the plasma AUC in humans at the maximum recommended human dose (MHRD)

Recommendations below are applicable to South Africa and other jurisdictions

• Mild to moderate (CrCl>30ml/min): No dose adjustment recommended
  No dose adjustment is necessary in mildly and moderately renal impaired adult and paediatric patients (CrCl>30ml/min)
  In paediatric patients weighing 50kg or more and in adult patients with mild or moderate renal impairment, a loading dose of 200mg may be considered, but further dose titration (>200mg daily) should be performed with caution
• Severe (CrCl≤30ml/min): Caution; dose adjustment recommended
  In paediatric patients weighing 50 kg or more and in adult patients with severe renal impairment (CrCl≤ 30 ml/min) or with end-stage renal disease, a maximum dose of 250mg/day is recommended, and dose titration should be performed with caution. If a loading dose is indicated, an initial dose of 100mg followed by a 50mg twice daily regimen for the first week should be used
  In paediatric patients weighing less than 50kg with severe renal impairment (CrCl≤30ml/min) and in those with end-stage renal disease, a reduction of 25% of the maximum dose is recommended
  For all patients requiring haemodialysis, a supplement of up to 50% of the divided daily dose directly after the end of haemodialysis is recommended
  Treatment of patients with end-stage renal disease should be made with caution as there is little clinical experience and accumulation of a metabolite (with no known pharmacological activity)

Recommendations below are applicable to South Africa and other jurisdictions

• Mild to moderate: Caution; dose adjustment recommended
  A maximum dose of 300mg/day is recommended for paediatric patients weighing 50kg or more and for adult patients with mild to moderate hepatic impairment. The dose titration in these patients should be performed with caution, considering co-existing renal impairment
  In adolescents and adults weighing 50kg or more, a loading dose of 200mg may be considered, but further dose titration (>200mg daily) should be performed with caution
  Based on data in adults, in paediatric patients weighing less than 50kg with mild to moderate hepatic impairment, a reduction of 25% of the maximum dose should be applied
• Severe: Caution; no information available
  The pharmacokinetics of lacosamide has not been evaluated in severely hepatic impaired patients
  Lacosamide should be administered to adult and paediatric patients with severe hepatic impairment only when the expected therapeutic benefits outweigh the possible risks
  The dose may need to be adjusted while carefully observing disease activity and potential side effects in the patient

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no dose adjustment recommended
  No dose reduction is necessary in elderly patients. Age-associated decreased renal clearance with an increase in AUC levels should be considered in elderly patients
  There is limited clinical data in elderly patients with epilepsy, particularly at doses greater than 400mg/day

Blood and Lymphatic System Disorders

Not known

• Agranulocytosis

Immune System Disorders

Uncommon

• Drug hypersensitivity

Not known

• Drug reaction with eosinophilia and systemic symptoms (DRESS)

Psychiatric Disorders

Common

• Depression
• Confusional state
• Insomnia

Uncommon

• Aggression
• Agitation
• Euphoric mood
• Psychotic disorder
• Suicidal ideation
• Suicide attempt
• Hallucination

Nervous System Disorders

Very common

• Dizziness
• Headache

Common

• Myoclonic disorders
• Ataxia
• Balance disorder
• Memory impairment
• Cognitive disorder
• Somnolence
• Tremor
• Nystagmus
• Hypoesthesia
• Dysarthria
• Disturbance in attention
• Paraesthesia

Uncommon

• Syncope
• Abnormal coordination
• Dyskinesia

Not known

• Convulsion

Eye Disorders

Very common

• Diplopia

Common

• Blurred vision

Ear and Labyrinth Disorders

Common

• Vertigo
• Tinnitus

Cardiac Disorders

Uncommon

• Atrioventricular block
• Bradycardia
• Atrial fibrillation
• Atrial flutter

Not known

• Ventricular tachyarrhythmia

Gastrointestinal Disorders

Very common

• Nausea

Common

• Vomiting
• Constipation
• Flatulence
• Dyspepsia
• Dry mouth
• Diarrhoea

Hepatobiliary Disorders

Uncommon

• Abnormal liver function test
• Increased hepatic enzyme (> 2x ULN)

Skin and Subcutaneous Tissue Disorders

Common

• Pruritus
• Rash

Uncommon

• Angioedema
• Urticaria

Not known

• Stevens-Johnson syndrome
• Toxic epidermal necrolysis

Musculoskeletal and Connective Tissue Disorders

Common

• Muscle spasms

General Disorders and Administration Site Conditions

Common

• Gait disturbance
• Asthenia
• Fatigue
• Irritability
• Feeling drunk

Injury, Poisoning and Procedural Complications

Common

• Fall
• Skin laceration
• Contusion

• Medicinal products associated with PR prolongation
• Sodium channel blocking antiepileptic medicinal products
• Antiarrhythmics
• Carbamazepine
• Phenytoin
• Phenobarbital
• Lamotrigine
• Strong inhibitors of CYP2C9
• Fluconazole
• Strong inhibitors of CYP3A4
• Itraconazole
• Ketoconazole
• Ritonavir
• Clarithromycin
• Strong enzyme inducers
• Rifampicin

Other interactions

• St John's wort (Hypericum perforatum)
• Alcohol

Specific cases may require

• ECG tracing prior to initiating therapy and when at steady-state
  - For patients with conduction problems, sodium channelopathies, severe cardiac disease, or taking concomitant medications that affect cardiac conduction or prolong PR interval
  - Monitor these patients closely during IV infusions (bradycardia, AV block, or ventricular tachyarrhythmias may occur during infusions)

Additional observations

• Monitor for signs/symptoms of conduction problems (eg, low or irregular pulse, feeling of light-headedness and fainting)
• Monitor for suicidality (eg, suicidal thoughts, depression, behavioural changes)
• Monitor for mental alertness
• Signs/symptoms of DRESS (eg, disparate manifestations associated with lymphatic, hepatic, renal, and/or hematologic organ systems)

The active substance, lacosamide (R-2-acetamido-N-benzyl-3-methoxypropionamide) is a functionalised amino acid. The precise mechanism by which lacosamide exerts its antiepileptic effect 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 stabilisation of hyperexcitable neuronal membranes.