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Other antiepileptic drugs: rufinamide, lacosamide, perampanel 

Other antiepileptic drugs: rufinamide, lacosamide, perampanel
Chapter:
Other antiepileptic drugs: rufinamide, lacosamide, perampanel
Author(s):

Andrea E. Cavanna

DOI:
10.1093/med/9780198791577.003.0017
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Rufinamide (licensed in 2007) is a third-generation AED known with the proprietary brand name of Invelon® (Eisai, Hatfield) in the UK and USA (Fig. 17.1). Lacosamide (licensed in 2008) is a third-generation AED known with the proprietary brand name of Vimpat® (UCB Pharma, Slough) in the UK and USA (Fig. 17.2). Perampanel (licensed in 2012) is a third-generation AED known with the proprietary brand name of Fycompa® (Eisai, Hatfield) in the UK and Banzel® (Eisai, Hatfield) in the USA (Fig. 17.3).

Fig. 17.1 Chronology of the clinical use of rufinamide

Fig. 17.1 Chronology of the clinical use of rufinamide

Fig. 17.2 Chronology of the clinical use of lacosamide

Fig. 17.2 Chronology of the clinical use of lacosamide

Fig. 17.3 Chronology of the clinical use of perampanel

Fig. 17.3 Chronology of the clinical use of perampanel

Preparations

Rufinamide

Tablets

  • Rufinamide 100 mg (10-tab pack).

  • Rufinamide 200 mg (60-tab pack).

  • Rufinamide 400 mg (60-tab pack).

Oral suspension

Rufinamide 40 mg/mL (460 mL).

Lacosamide

Tablets

  • Lacosamide 50 mg (14-tab pack).

  • Lacosamide 100 mg (14-tab pack).

  • Lacosamide 150 mg (14-tab pack).

  • Lacosamide 200 mg (56-tab pack).

Oral solution

Lacosamide 10mg/mL (200mL)

Perampanel

Tablets

  • Perampanel 2 mg (7-tab pack).

  • Perampanel 4 mg (28-tab pack).

  • Perampanel 6 mg (28-tab pack).

  • Perampanel 8 mg (28-tab pack).

  • Perampanel 10 mg (28-tab pack).

  • Perampanel 12 mg (28-tab pack).

Generic formulation

Rufinamide, perampanel

MHRA/CHM advice to minimize risk when switching patients with epilepsy between different manufacturers’ products (including generic products):

  • Category 2: the need for continued supply of a particular manufacturer’s product should be based on clinical judgment and consultation with the patient and/or carer taking into account factors such as seizure frequency and treatment history.

Lacosamide

MHRA/CHM advice to minimize risk when switching patients with epilepsy between different manufacturers’ products (incl. generic products):

  • Category 3: it is usually unnecessary to ensure that patients are maintained on a specific manufacturer’s product unless there are specific concerns, such as patient anxiety and risk of confusion/dosing error.

Indications

Rufinamide

Epilepsy: Adjunctive treatment of Lennox–Gastaut syndrome; refractory tonic/atonic seizures (unlicensed).

Lacosamide

Epilepsy: Adjunctive treatment of focal seizures with or without secondary generalization.

Perampanel

Epilepsy: Adjunctive treatment of focal seizures with or without secondary generalization and primary generalized tonic-clonic seizures.

Dose titration

Rufinamide

  • Epilepsy—adjunctive therapy (adults with body weight 30–50 kg): 200 mg bd for at least 2 days, then increased by 200 mg bd every 2 or more days (max. 900 mg bd).

  • Epilepsy—adjunctive therapy (adults with body weight 50–70 kg): 200 mg bd for at least 2 days, then increased by 200 mg bd every 2 or more days (max. 1200 mg bd).

  • Epilepsy—adjunctive therapy (adults with body weight above 70 kg): 200 mg bd for at least 2 days, then increased by 200 mg bd every 2 or more days (max. 1600 mg bd).

Lacosamide

  • Epilepsy—adjunctive therapy: 50 mg bd for 7 days, then increased by 50 mg bd every 7 days; usual maintenance 100 mg bd (max. 200 mg bd).

  • Epilepsy—adjunctive therapy (loading dose regimen when it is necessary to rapidly attain therapeutic plasma concentrations, under close medical supervision): 200 mg bd for 1 day, followed by maintenance dose of 100 mg bd after 1 day, then increased if needed by 50 mg bd every 7 days (max. 200 mg bd).

Perampanel

  • Epilepsy—adjunctive therapy: 2 mg nocte for at least 14 days, then increased by 2 mg every 14 or more days; usual maintenance 4–8 mg nocte (max. 12 mg nocte).

Cautions

Rufinamide

Nil

Lacosamide

  • Patients with conduction problems (contraindicated in patients with second- or third-degree A–V block).

  • Patients with severe cardiac disease.

  • Patients at risk of PR-interval prolongation.

  • Elderly patients.

Perampanel

Nil

Adverse effects

Rufinamide

Rufinamide can be associated with adverse effects at the level the nervous system and other systems (Table 17.1).

Table 17.1 Estimated frequency of adverse effects of rufinamide

Very common (>1 in 10 patients on rufinamide)

Nervous system

  • dizziness

  • drowsiness

  • fatigue

  • headache

Other systems

  • nausea and vomiting

Common (>1 in 100 patients on rufinamide)

nervous system

  • anxiety

  • ataxia

  • blurred vision

  • convulsions

  • diplopia

  • gait disturbance

  • hyperactivity

  • insomnia

  • nystagmus

  • tremor

Other systems

  • dyspepsia, constipation, abdominal pain

  • acne

  • anorexia

  • back pain

  • diarrhoea

  • epistaxia

  • influenza-like symptoms

  • oligomenorrhoea

  • skin rash

  • rhinitis

  • weight loss

Uncommon (>1 in 1000 patients on rufinamide)

Nervous system

Other systems

  • Hypersensitivity syndromes including DRESS and Stevens–Johnson syndrome

Rare (>1 in 10,000 patients on rufinamide)

Nervous system

Other systems

Very rare (<1 in 10,000 patients on rufinamide)

Nervous system

Other systems

Lacosamide

Lacosamide can be associated with adverse effects at the level the nervous system and other systems (Table 17.2).

Table 17.2 Estimated frequency of adverse effects of lacosamide

Very common (>1 in 10 patients on lacosamide)

Nervous system

  • diplopia

  • dizziness

  • headache

Other systems

  • nausea

Common (>1 in 100 patients on lacosamide)

Nervous system

  • abnormal gait

  • amnesia

  • ataxia

  • blurred vision

  • confusion

  • depression

  • diplopia

  • drowsiness

  • fatigue

  • hypoaesthesia

  • irritability

  • nystagmus

  • tinnitus

  • tremor

Other systems

  • dry mouth

  • dyspepsia, constipation, flatulence

  • muscle spasms

  • pruritus

  • skin rash

  • vomiting

Uncommon (>1 in 1000 patients on lacosamide)

Nervous system

  • aggression

  • agitation

  • psychosis

  • suicidal ideation

Other systems

  • atrial fibrillation, atrial flutter, AV block, PR interval prolongation

  • bradycardia

Rare (>1 in 10,000 patients on lacosamide)

Nervous system

Other systems

  • multi-organ hypersensitivity reaction

Very rare (<1 in 10,000 patients on lacosamide)

Nervous system

Other systems

Perampanel

Perampanel can be associated with adverse effects at the level the nervous system and other systems (Table 17.3).

Table 17.3 Estimated frequency of adverse effects of perampanel

Very common (>1 in 10 patients on perampanel)

Nervous system

  • dizziness

  • drowsiness

Other systems

Common (>1 in 100 patients on perampanel)

Nervous system

  • aggression

  • anxiety

  • ataxia

  • blurred vision

  • confusion

  • diplopia

  • dysarthria

  • gait disturbance

  • irritability

  • vertigo

Other systems

  • back pain

  • changes in appetite and weight gain

  • malaise

  • nausea

Uncommon (>1 in 1000 patients on perampanel)

Nervous system

  • suicidal ideation and behaviour

Other systems

Rare (>1 in 10,000 patients on perampanel)

Nervous system

Other systems

Very rare (<1 in 10,000 patients on perampanel)

Nervous system

Other systems

Interactions

Rufinamide

With AEDs

Significant increases in rufinamide plasma concentrations may occur with co-administration of valproate.

With other drugs

  • Women of child-bearing age using hormonal contraceptives are advised to use an additional safe and effective contraceptive method as co-administration of rufinamide has been shown to decrease exposure to a combined oral contraceptives.

  • Rufinamide has been shown to induce the cytochrome P450 enzyme CYP3A4 and may, therefore, reduce the plasma concentrations of substances, which are metabolized by this enzyme (modest-to-moderate effect). It is therefore recommended that patients treated with substances that are metabolized by the CYP3A4 enzyme system are to be carefully monitored for 2 weeks at the start of or after the end of treatment with rufinamide, or after any marked change in the dose (a dose adjustment of the concomitantly administered medicinal product may need to be considered). These recommendations should also be considered when rufinamide is used concomitantly with substances with a narrow therapeutic window, such as warfarin and digoxin.

With alcohol/food

  • No data on the interaction of rufinamide with alcohol are available

  • As a food effect was observed, rufinamide should be administered with food

Lacosamide

With AEDs

Concomitant treatment with other AEDs known to be enzyme inducers (such as carbamazepine, phenobarbital, phenytoin) decreases the overall systemic exposure of lacosamide by 25%.

With other drugs

Nil.

With alcohol/food

  • Although no pharmacokinetic data on the interaction of lacosamide with alcohol are available, a pharmacodynamic effect cannot be excluded.

  • There are no specific foods that must be excluded from diet when taking lamotrigine.

Perampanel

With AEDs

  • Some AEDs known as CYP450 3A enzyme inducers (carbamazepine, oxcarbazepine, phenytoin) have been shown to increase perampanel clearance and consequently to decrease plasma concentrations of perampanel. Carbamazepine, a known potent enzyme inducer, reduced perampanel levels by two-thirds in a study performed on healthy subjects

  • In the epilepsy population pharmacokinetic analysis, perampanel was found to decrease the clearance of oxcarbazepine by 26%. Oxcarbazepine is rapidly metabolized by cytosolic reductase enzyme to the active metabolite, monohydroxycarbazepine. The effect of perampanel on monohydroxycarbazepine concentrations is not known

With other drugs

  • Strong inducers of cytochrome P450, such as rifampicin and St John’s wort (Hypericum perforatum), are expected to decrease perampanel concentrations.

  • In healthy subjects, the CYP3A4 inhibitor ketoconazole increases perampanel exposure.

  • Perampanel can make certain hormonal contraceptives such as levonorgestrel less effective.

  • Decrease in exposure of midazolam may be caused by perampanel.

With alcohol/food

  • Drinking alcohol while taking perampanel can affect a patients’ alertness and ability to drive or use tools or machines. It can also aggravate irritability, confusion, and depression.

  • There are no specific foods that must be excluded from diet when taking perampanel

Special populations

Rufinamide

Hepatic impairment

  • Caution and careful dose titration in mild-to-moderate impairment

  • Avoid in severe impairment

Renal impairment

The pharmacokinetics of rufinamide does not appear to be altered in subjects with chronic and severe renal failure compared to healthy volunteers

Pregnancy

  • No clinical data are available on pregnancies exposed to rufinamide. Therefore, rufinamide should not be used during pregnancy or in women of childbearing age who are not using contraceptive measures, unless clearly necessary. Women of childbearing age must use contraceptive measures during treatment with rufinamide.

  • If women treated with rufinamide plan to become pregnant, the continued use of this product should be carefully weighed. In case of treatment with rufinamide, the dose should be monitored carefully during pregnancy and after birth, and adjustments made on a clinical basis.

  • It is not known if rufinamide is excreted in human breastmilk. Due to the potential harmful effects for the breastfed infant, breastfeeding should be avoided during maternal treatment with rufinamide.

Lacosamide

Hepatic impairment

  • Titrate with caution in mild-to-moderate impairment if co-existing renal impairment.

  • Caution in severe impairment.

Renal impairment

  • Loading dose regimen can be considered in mild-to-moderate impairment (titrate above 200 mg with caution).

  • Titrate with caution in severe impairment (max. 250 mg daily).

Pregnancy

  • There are no adequate data from the use of lacosamide in pregnant women and 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 a woman decides to become pregnant, the use of lacosamide should be carefully re-evaluated. In case of treatment with lacosamide, the dose should be monitored carefully during pregnancy and after birth, and adjustments made on a clinical basis.

  • Lacosamide has been found to be present in milk in animal studies and it is recommended that it should be avoided during breastfeeding

Perampanel

Hepatic impairment

  • Increase at intervals of at least 2 weeks, up to a maximum of 8 mg daily, in mild-to-moderate impairment.

  • Avoid in severe impairment.

Renal impairment

Avoid in moderate or severe impairment.

Pregnancy

  • There are limited amount of data available on the use of perampanel in pregnant women and the potential risk for humans is unknown.

  • Perampanel is not recommended in pregnancy and female patients must use a reliable method of contraception to avoid becoming pregnant while being treated with perampanel (this should be continued for 1 month after stopping treatment).

  • As perampanel can make certain hormonal contraceptives such as levonorgestrel less effective, other forms of safe and effective contraception (such as a condom or coil) should be used when taking perampanel (this should be continued for 1 month after stopping treatment).

  • Perampanel has been found to be present in milk in animal studies and it is recommended that breastfeeding should be avoided.

Behavioural and cognitive effects in patients with epilepsy

Rufinamide

For this third-generation agent, clinical experience is still limited, and little is known about its positive and negative psychotropic properties, and their implications for the management of behavioural symptoms in patients with epilepsy. There are initial reports of anxiety, depression, irritability, and agitation. Reports of cognitive effects are rare.

Lacosamide

For this third-generation agent, clinical experience is still limited and little is known about its positive and negative psychotropic properties and their implications for the management of behavioural symptoms in patients with epilepsy. There are initial reports of depression, irritability and agitation, and psychotic symptoms. Reports of cognitive effects (mainly affecting attention and memory) are rare and usually not severe.

Perampanel

For this third-generation agent, clinical experience is still limited, and little is known about its positive and negative psychotropic properties, and their implications for the management of behavioural symptoms in patients with epilepsy. There are initial reports of behavioural disturbances (especially depression, anxiety, irritability, and psychosis), which seem to be dose-related and tend to appear within the first weeks of treatment. Reports of cognitive effects (mainly affecting memory) are relatively rare.

Psychiatric use

Rufinamide

Rufinamide has no indications for the treatment of psychiatric disorders. There is insufficient experience with rufinamide to draw any conclusion regarding its psychotropic profile.

Lacosamide

Lacosamide has no indications for the treatment of psychiatric disorders. There is insufficient experience with lacosamide to draw any conclusion regarding its psychotropic profile.

Perampanel

Perampanel has no indications for the treatment of psychiatric disorders. There is insufficient experience with perampanel to draw any conclusion regarding its psychotropic profile.