Clinical Applications

Acetazolamide is effective as an adjunctive therapy for a variety of seizures, but mainly absences.^1;3;4 However, it also controls myoclonic jerks, GTCS and focal seizures. It is particularly used for intermittent administration in catamenial epilepsy (8 days before the expected onset of menses and continued until termination of bleeding); it is not recommended if there is a likelihood of pregnancy.

Dosage and Titration

Adults: start treatment with 250 mg and increase to 500–750 mg.

Children: 10–20 mg/day.

Dosing: two or three times daily.

Therapeutic range: 40–100 mg/L (300–700 μmol/L).

Therapeutic drug monitoring: not needed.

Main Adverse Reactions

Common: flushing, lethargy, anorexia, paraesthesia and increased diuresis.

Serious: idiosyncratic reactions as for other sulfonamides (rash, aplastic anaemia, Stevens-Johnson syndrome), renal failure, nephrolithiasis in chronic treatment and metabolic acidosis (see also topiramate page 513).

Mechanism of Action

Acetazolamide is a carbonic anhydrase inhibiting drug and reversibly catalyses the hydration of CO₂ and the dehydration of carbonic acid. It blocks the action of brain carbonic anhydrase resulting in elevation of intracellular CO₂, decrease of intracellular pH and depression of neuronal activity.

Pharmacokinetics

Oral bioavailability: > 90%.

Protein binding: 90–95%.

Metabolism: does not undergo metabolic alteration.

Excretion: renal.

Elimination half-life: 12–14 hours.

Drug Interactions

Not significant. Reduces carbamazepine levels. Salicylates increase levels of acetazolamide.

Main Disadvantages

Unpredictable seizure efficacy, development of tolerance and idiosyncratic reactions that exceptionally may be fatal.

Useful Note

Risk of withdrawal seizures. Combination with carbamazepine or oxcarbazepine increases the risk of hyponatraemia. It should be withdrawn prior to starting a ketogenic diet.

Clinical Applications

Carbamazepine is the superior drug for the treatment of focal epilepsies of any type (idiopathic or symptomatic) with or without secondarily GTCS. It is also effective in primarily GTCS. In numerous comparative studies, no other drug showed better efficacy than carbamazepine in focal seizures though some of the new AEDs are better tolerated. Other AEDs are only used to treat these conditions when carbamazepine fails, either because of adverse reactions or ineffectiveness.

However, carbamazepine is ineffective and often contraindicated in generalised epilepsies, such as juvenile myoclonic epilepsy, juvenile absence epilepsy and epileptic encephalopathies (e.g. Lennox-Gastaut syndrome). It exaggerates myoclonic jerks, absences and atonic seizures.^3;5 It is ineffective in neonatal and febrile seizures.

Dosage and Titration

‘Start low and go slow’ is important when initiating carbamazepine treatment in order to minimise adverse reactions.

Adults and children over 12 years of age: start treatment with 200 mg/day in two equally divided doses and increase at weekly intervals in increments of 200 mg/day up to 800–1200 mg/day. Rarely, higher doses of up to 1800 mg/day are needed.

Children 6–12 years old: start treatment with 100 mg/day in two equally divided doses and increase at weekly intervals in increments of 100 mg/day up to 600–1000 mg/day.

Children under 6 years: start treatment with 5–10 mg/kg/day in two or three divided doses and increase at weekly intervals in increments of 5–10 mg/kg/day up to a maintenance dose of no more than 35 mg/kg/day.

Dosing: two or three times daily. Four times daily dosing may be needed for children receiving a high dosage.

There is a significant difference in the dose of carbamazepine given as monotherapy and that used in combination with other AEDs. Higher doses may be necessary in polytherapy with enzyme-inducing AEDs, which increase the metabolism of carbamazepine.

Fluctuations in the levels of carbamazepine can be reduced by the use of sustained-release preparations.

The clearance of carbamazepine in children is faster than in adults and therefore three times daily dosing may be required.

Therapeutic drug monitoring: useful, but substantial diurnal variation in plasma concentration are common and symptoms of toxicity due to carbamazepine epoxide may occur without increases in carbamazepine levels.

Therapeutic range: 3–12 mg/L (12–50 μmol/L). Carbamazepine epoxide: up to 9 μmol/L.

Important note

Developing diplopia may be a good indicator of maximum tolerated carbamazepine levels or epoxide toxicity when carbamazepine levels are within the target range.

Main Adverse Reactions

Common: sedation, headache, diplopia, blurred vision, rash, gastrointestinal disturbances, ataxia, tremor, impotence, hyponatraemia and neutropenia. CNS-related adverse reactions are usually dose-related and appear on initiation of treatment. These are primarily reversible and can be prevented by slow and careful upward titration following initiation of treatment.

Carbamazepine causes a dose-related reduction in the neutrophil count in 10–20% of patients, but it rarely drops below 1.2 × 10⁹ and is seldom of any clinical significance. Hyponatraemia occurs in around 5% of treated patients. Most physicians advise obtaining blood counts at baseline and every 6–8 weeks for the first 6 months of carbamazepine treatment.

Serious: rash, hepatic dysfunction, haematological toxicity and cardiac arrhythmias. Allergic skin rash is the commonest idiosyncratic adverse reaction that occurs in 5–10% of patients. This is usually mild and develops within the first 2–6 weeks of treatment. Carbamazepine should be withdrawn immediately a skin rash develops in order to prevent serious and sometimes life-threatening conditions, such as anticonvulsant hypersensitivity syndrome. Hepatotoxicity usually occurs in the setting of a generalised hypersensitivity response.

There are exceptional instances of aplastic anaemia, agranulocytosis, thrombocytopenia and cardiac conduction disturbances.

Considerations in Women

Pregnancy: category D. Contrary to previous studies, a recent pregnancy registry study found that the risk of teratogenicity is small.⁶ In a UK Epilepsy and Pregnancy Register, serious malformation rates for monotherapy were 2.3% for carbamazepine as opposed to 2.4% with no AED, 2.1% for lamotrigine and 5.9% for valproate.⁷

Main Mechanisms of Action

Carbamazepine inhibits sustained, repetitive high-frequency firing of cortical neurons via use- and frequency-dependent blockade of voltage-gated sodium channels. Other mechanisms may include inhibition of L-type calcium channels and modulations of neurotransmission.

Like other tricyclic compounds, carbamazepine has a moderate anticholinergic action, which is responsible for some of its adverse reactions.

Pharmacokinetics

Oral bioavailability: 75–85% and unaffected by food intake. Bioavailability may be reduced by up to 50% when stored in hot humid conditions. After oral administration, absorption is relatively slow and often erratic reaching peak plasma concentrations within 4–24 hours; 75–85% of orally ingested carbamazepine is absorbed. Absorption and bioavailability vary among different carbamazepine formulations. Slow-release formulations have a prolonged absorption phase. Syrup formulations reach maximum plasma concentration faster than chewable or plain tablets.

There are significant diurnal variations in plasma concentrations of carbamazepine. This is greater in children than in adults, which can result in intermittent side effects that demand adjustments to the daily dose.

Protein binding: 66–89%.

Metabolism: carbamazepine is extensively metabolised in the liver. The predominant elimination pathway results in the formation of carbamazepine 10,11-epoxide, which is a stable and pharmacologically active agent with its own antiepileptic activity and adverse reactions.

Carbamazepine-epoxide makes a greater contribution to the pharmacological effects (both beneficial and toxic) of carbamazepine in children than in adults. This is because children metabolise carbamazepine more rapidly than adults and this results in carbamazepine-epoxide concentrations approaching those of carbamazepine.

Carbamazepine is a potent enzyme inducer. It also induces its own metabolism (autoinduction) by simulating the activity of the CYP3A4 component of cytochrome P450. Autoinduction is usually completed within 3–5 weeks. The half-life of carbamazepine decreases considerably from 18–55 hours to 6–18 hours as autoinduction takes place. In practical terms, this means that carbamazepine levels fall significantly (by about 50%) after several weeks of treatment, which may result in seizure recurrence within this period of autoinduction.

Elimination half-life: 5–26 hours. In combination treatment, the elimination half-life of carbamazepine is reduced by enzyme-inducers and increased by enzyme-inhibitors.

Drug Interactions^19;20

Main Disadvantages

Idiosyncratic and other adverse reactions, drug–drug interactions, need for laboratory testing and relatively narrow spectrum of antiepileptic efficacy.

Although carbamazepine is by far the best AED in the treatment of focal and secondarily GTCS, it offers no benefit in most other epilepsies, because of ineffectiveness or seizure exacerbation; these include absences and myoclonic jerks of IGE, non-convulsive generalised seizures in Lennox-Gastaut syndrome and epileptic encephalopathies. Exceptionally carbamazepine may exaggerate seizures in Rolandic epilepsy and may induce non-convulsive status and features of serious atypical evolutions.

Clinical Applications

Based on recent evidence, clobazam is a very useful AED, both as polytherapy and monotherapy.^21–31 It is neglected in current clinical practice mainly because it is considered to induce high dependence/tolerance, it is of similar effectiveness regarding seizure type to clonazepam and it is a benzodiazepine. It is not licensed in the USA.

The main clinical applications of clobazam are as follows.

1. It is used as adjunctive medication in all forms of drug-resistant epilepsy in adults and children.^21–29 It is particularly effective in focal rather than generalised seizures. Clobazam was found to be of equivalent efficacy to carbamazepine and phenytoin as monotherapy in childhood epilepsy.^30;31
2. Intermittent clobazam administration 5 days prior and during the menses in catamenial epilepsy³² is the most popular textbook recommendation.

Dosage and Titration

Adults and children over 12 years: start treatment with 5–10 mg/day at night and increase at weekly intervals in increments of 5 mg/day up to 40 mg/day. In my experience 10 mg taken before sleep is often therapeutic in focal seizures. I do not use dose of more than 20 mg in children.

Children under 12 years: start with 0.1–0.2 mg/kg/day and slowly increase at weekly intervals in increments of 0.1mg/kg/day up to 0.8 mg/kg/day.

Dosing: once or twice daily; a smaller dose in the day time and a larger dose prior to going to sleep.

Therapeutic range: norclobazam (active metabolite) 60–200 μg/L (200–670 nmol/L).

Therapeutic drug monitoring: not useful except when unusual side effects appear.³⁴

Main Adverse Reactions

As for all the benzodiazepines, but much milder than with most of them.^22;29 Somnolence may be partly prevented by administering the drug in small doses 1 hour prior to going to sleep. The cognitive and behavioural effects of clobazam appear to be similar to those of standard monotherapy with carbamazepine or phenytoin.³¹

Severe aggressive outbursts, hyperactivity, insomnia and depression with suicidal ideation may occur, particularly in children.

Tolerance may develop, but this aspect has been largely overemphasised as documented in many recent studies.^22;30 More than one-third of patients do not develop tolerance.²⁵ When clobazam is effective, most patients continue to benefit for years without drug dependence or unwanted side effects.²⁵

Main Mechanism of Action

GABA_A receptor agonist.

Pharmacokinetics

Oral bioavailability: 90%.

Protein binding: 85%.

Metabolism: hepatic oxidation and then conjugation.

Elimination half-life: 20 hours, but that of its principal metabolite, norclobazam, is about 50 hours.

Drug Interactions

Minor and not clinically significant. Potentiates the effect of CNS depressants such as alcohol, barbiturates and neuroleptics.

Main Disadvantages

Sedation and development of tolerance.

Useful Clinical Note

1. Clobazam should be tried as adjunctive medication in all drug-resistant epilepsies at a dose of 10–30 mg nocte (half this dose in children > 3 years old). It is more effective in focal than symptomatic epilepsies and can also be used as monotherapy. Probably only 1 out of 10 patients will have a clinically significant improvement, but this may be very dramatic and render the patient seizure-free.
2. Unlike clonazepam, clobazam is much less effective in myoclonic jerks and absences.
3. Avoid overmedication. Small doses of 10–20 mg given 1 hour prior to going to sleep may be therapeutic and well tolerated.
4. Withdrawal should be very slow (months). Rapid discontinuation often leads to withdrawal symptoms, seizures and status epilepticus.

Clinical Applications

Clonazepam^33;35 is the most potent AED in the treatment of myoclonic jerks (superior to valproate), and is also effective in absences (though much inferior to valproate and ethosuximide)³ and focal seizures (much inferior to carbamazepine and any other appropriate drug for this type of seizure). Opinions about its effectiveness in GTCS are conflicting and range from beneficial³⁶ to exaggeration.^36;37

Clonazepam is the main AED for myoclonic jerks in all forms of idiopathic or symptomatic and progressive epilepsies (monotherapy, but mainly adjunctive therapy). Clonazepam monotherapy is probably the first choice in reading epilepsy (better than valproate). It is particularly effective in JME if myoclonic jerks are not controlled by other drugs. Adding small doses of clonazepam (0.5–1 mg prior to going to sleep) to valproate, levetiracetam or lamotrigine is highly beneficial and may prevent an unnecessary increase in the main concomitant drug. It is widely used in epileptic encephalopathies.

Dosage and Titration

‘Start low and go slow’ is essential, both in adults and children.

Adults: initiate treatment with 0.25–8 mg/day. Start treatment with 0.25 mg/day at night and increase at weekly intervals in increments of 0.25 mg/day up to 8–10 mg/day. In my experience 0.5–1 mg of clonazepam taken before sleep is often highly effective in controlling myoclonic jerks either as monotherapy or as adjunctive therapy.

Children: start with 0.01–0.02 mg/kg/day and slowly increase up to 0.1–0.2 mg/kg/day.

Dosing: once or twice daily; a smaller dose in the day time and a larger dose prior to going to sleep.

Therapeutic range: 20–80 μg/L (80–250 nmol/L).

Therapeutic drug monitoring: not needed.

Main Adverse Reactions

Common: sedation, drowsiness, hypersalivation, hyperactivity, lack of concentration and incoordination. Sedation is more serious than with clobazam. This may be partly prevented by administering the drug in small doses 1 hour prior to going to sleep.

Serious: withdrawal syndrome in chronic use.

Main Mechanism of Action

GABA_A receptor agonist.

Pharmacokinetics

Oral bioavailability: > 80%.

Protein binding: 85%.

Metabolism: hepatic.

Elimination half-life: 20–80 hours.

Drug Interactions

Minor and not clinically significant. Potentiates the effect of CNS depressants such as alcohol, barbiturates and neuroleptics.

Main Disadvantages

Sedation and development of tolerance.

Useful Note

1. Clonazepam is the drug of first choice for the control of myoclonic jerks (either as monotherapy if this is the only seizure type as in reading epilepsy or mainly as adjunctive medication).
2. Avoid overmedication. Small doses 1 hour prior to going to sleep may be effective and well tolerated.
3. Withdrawal should be very slow in months. Rapid discontinuation often leads to withdrawal symptoms, seizures and status epilepticus.

Clinical Applications

Ethosuximide is still a valuable AED for the treatment of typical absence seizures and has a 70% seizure-free success rate as monotherapy.³ It does not control GTCS, which on an anecdotal basis may become worse. It is recommended in childhood absence epilepsy (monotherapy) and IGE with intractable absence seizures (adjunctive therapy).

Ethosuximide is also useful as adjunctive treatment in negative myoclonus,⁴² drop attacks⁴³ and certain types of myoclonic epilepsy.⁴⁴

Dosage and Titration

Titrate slowly to avoid adverse reactions and mainly gastrointestinal disturbances.

Adults and children over 12 years: start treatment with 250 mg/day and increase slowly in 250 mg increments every 4–7 days to 750–1500 mg.

Children under 12 years: start with 5–10 mg/kg/day increase slowly to 20–35 mg/kg/day.

Dosing: two or three times daily.

Therapeutic range: 40–100 mg/L (300–700 μmol/L).

Therapeutic drug monitoring: mostly not needed.

Main Adverse Reactions

Common: gastrointestinal symptoms include anorexia, vague gastric upset, nausea and vomiting, cramps, epigastric and abdominal pain, weight loss and diarrhoea. Drowsiness, photophobia, euphoria, hiccups, headache and less often behaviour and psychotic disturbances may occur.

Severe: haemopoietic complications (aplastic anaemia), Stevens-Johnson syndrome, renal and hepatic impairment, and systemic lupus erhythematosus.

Considerations in Women

Pregnancy: category C.

Interaction with hormonal contraception: none.

Main Mechanisms of Action

Ethosuximide exerts its anti-absence effect by either reducing thalamic low threshold calcium currents, probably by a direct channel blocking action that is voltage dependent,⁴⁵ or through a potent inhibitory effect in the perioral region of the primary somatosensory cortex.^46;47

Pharmacokinetics

Oral bioavailability: 90–100%.

Protein binding: 85%.

Metabolism: hepatic oxidation and then conjugation.

Elimination half-life: 30–60 hours.

Drug Interactions

Commonly, there are no clinically significant drug–drug interactions. Ethosuximide may raise the plasma concentration of phenytoin. Valproate has been reported to both increase and decrease ethosuximide levels.

Main Disadvantages

Narrow spectrum of antiepileptic activity limited to absence seizures and certain types of myoclonus (mainly negative myoclonus). It may aggravate GTCS.

It sometimes exhibits severe adverse idiosyncratic reactions.

Abrupt withdrawal in patients with absences may precipitate absence status epilepticus

Other Available Succinimides

1. Methsuximide is a broader spectrum drug than ethosuximide (but with a weaker action) that is also effective in focal seizures. Adverse reactions are more frequent and may be more serious than with ethosuximide.
2. Phensuximide is rarely used because its effect is inferior to other succinimides.

Clinical Applications

Recommendations of gabapentin as an AED are limited to focal seizures. It is the least effective of all other new AEDs even at higher doses of around 3000 mg/day.⁵⁴ It has no effect in generalised seizures of any type and may exaggerate them.⁵⁵ However, it is considered relatively safe with few side effects. It is mainly used for non-epileptic disorders such as neuropathic pain.

Dosage and Titration

Adults: the starting dose is 300mg/day, which can be increased rapidly in increments of 300 mg/day to a typical adult maintenance dose of 900–1800 mg/day given in three divided doses. Doses of up to 3600 mg/day have been used.

Children: start treatment with 15/mg/kg/day and increase to 30 mg/kg/day within a few days. Recommended maintenance dose is 50–100 mg/day. Children require relatively higher doses than adults, because clearance of gabapentin is greater in children than in adults.

Dosing: three times daily.

Therapeutic range: 2–20 mg/L (12–120 μmol/L).

Therapeutic drug monitoring: unnecessary.

Main Adverse Reactions

Gabapentin has a relatively good adverse reaction profile.

Common: increased appetite and weight gain is a problem. Other reactions include dizziness, ataxia, nystagmus, headache, tremor, fatigue, diplopia, rhinitis and nausea. Significant behavioural disturbances, such as aggression, hyperexcitabilty and tantrums, have been reported mainly in children.⁵⁶ Caution is recommended in patients with a history of psychotic illness.

Potentially serious adverse reactions: rarely, rash (0.5%), leucopenia (0.2%), and electrocardiographic changes and angina (0.05%).

Gabapentin may unmask myasthenia gravis and should be used with caution in this disease.⁵⁷

Seizure exacerbation: treatment emergent exaggeration of seizures occurs particularly in patients with generalised epilepsies.

Considerations in Women

Pregnancy: category C.

Breastfeeding: it is excreted in human milk, but the effect on the nursing infant is unknown.

Interaction with hormonal contraception: none.

Others: Weight gain may be of particular importance to women because of the associated risk for polycystic ovary syndrome.*

Main Mechanisms of Action

The mechanism of action is uncertain. Gabapentin was developed because of its structural similarity to GABA and its ability to cross the blood-brain barrier. However, it does not appear to be a GABA-agonist.

The mechanism responsible for its antiepileptic activity and the relief of neuropathic pain is probably due to a modulating action of gabapentin on voltage-gated calcium channels and neurotransmitter release.

Pharmacokinetics

Oral bioavailability: low < 60%. Gabapentin is rapidly absorbed reaching peak plasma levels within 2–4 hours after oral ingestion. Bioavailability is less than 60%, but is dose-dependent; absorption is progressively reduced with increasing dosage. Food intake does not influence absorption.

Protein binding: none.

Metabolism: gabapentin is not metabolised and is excreted by the kidneys. Renal impairment reduces drug clearance and raises plasma gabapentin concentrations.

Elimination half-life: 5–9 hours.

Drug Interactions

There are no significant interactions with other AEDs.

However, cimetidine reduces the renal clearance of gabapentin and antacids reduce the absorption of gabapentin by 20%.

Main Disadvantages

Narrow-spectrum AED limited to the treatment of focal seizures only and with low efficacy.

Patient note

Therapeutic efficacy is weak in relation to other AEDs, the number of responders is disappointingly low even when higher doses are used and it is unusual for patients with severe focal epilepsies to derive much benefit.^54;58

It is ineffective and may exaggerate generalised seizures of any type.

Clinical Applications

Lamotrigine is an effective broad-spectrum AED for the treatment of all types of seizure except myoclonic jerks.^60–67 It has been recommended for all focal or generalised, idiopathic or symptomatic epileptic syndromes of adults,^63–65 children^60;61 and neonates.⁶⁸ Exception to this are syndromes with predominantly myoclonic jerks.

In polytherapy, lamotrigine is at its best when combined with valproate, because of very efficacious pharmacodynamic interactions.⁶⁹ This combination may be ideal for drug-resistant generalised epilepsies including those with myoclonic seizures.⁷⁰ Usually, small doses of lamotrigine added to valproate may render previously uncontrolled patients seizure-free.^3;69;71;72

Other major advantages of lamotrigine are that it lacks cognitive and behavioural adverse reactions and it is non-sedating with improved global functioning, which includes increased attention and alertness reported in both paediatric and adult trials.⁶² Idiosyncratic reactions and mainly rash that can become very serious are a significant disadvantage.^73;74

Dosage and Titration

Slow titration and in small doses is essential in both adults and children.

Dosage and titration vary considerably between monotherapy, co-medication with valproate and comedication with enzyme-inducing AEDs. For this reason the manufacturers have provided detailed tables to be followed in each of these circumstances in children and adults. The following are some examples of these:

Adults and children over 12 years (monotherapy): start with 25 mg once a day for 2 weeks, followed by 50 mg once daily for 2 weeks. Thereafter, the dose should be increased by a maximum of 50–100 mg every 1–2 weeks until the optimal response is achieved. The usual maintenance dose to achieve optimal response is 100–200mg/day given once daily or as two divided doses. Some patients have required 500 mg/day to achieve the desired response.

Adults and children over 12 years (add-on therapy with valproate): start with 25 mg every alternate day for 2 weeks, followed by 25 mg once daily for 2 weeks. Thereafter, the dose should be increased by a maximum of 25–50 mg every 1–2 weeks until the optimal response is achieved. The usual maintenance dose to achieve optimal response is 100–200 mg/day given once daily or in two divided doses.

Adults and children over 12 years (add-on therapy with enzyme inducing AEDs): start with 50 mg once daily for 2 weeks, followed by 100 mg/day given in two divided doses for 2 weeks. Thereafter, the dose should be increased by a maximum of 100 mg every 1–2 weeks until the optimal response is achieved. The usual maintenance dose to achieve optimal response is 200–400 mg/day given in two divided doses. Some patients have required 700 mg/day to achieve the desired response.

Children aged 2–12 years (with valproate comedication):* start with 0.15 mg/kg/day given once daily for 2 weeks, followed by 0.3 mg/kg/day given once daily for 2 weeks. Thereafter, the dose should be increased by a maximum of 0.3 mg/kg every 1–2 weeks until the optimal response is achieved. The usual maintenance dose to achieve optimal response is 1–5 mg/kg/day given once daily or in two divided doses.

Children aged 2–12 years (with co-medication with enzyme inducing AED):* start with 0.6 mg/kg/day given in two divided doses for 2 weeks, followed by 1.2mg/kg/day for 2 weeks. Thereafter, the dose should be increased by a maximum of 1.2 mg/kg every 1–2 weeks until the optimal response is achieved. The usual maintenance dose to achieve optimal response is 5–15mg/kg/day given in two divided doses.

Important note

* Doses should be rounded down to the nearest whole tablet. Only whole tablets should be used for dosing.

Important note

Caution: probably, slower dosage titration reduces the risk of skin rash and possibly generalised hypersensitive reaction.⁷⁴ Therefore, it is mandatory to follow the recommendations of the manufacturers regarding initial dose and subsequent slow-dose escalation of lamotrigine.

Conversion to monotherapy from polytherapy with valproate or with enzyme-inducing AEDs should follow appropriate guidelines provided by the manufacturers of lamotrigine.

Therapeutic range: 1–15 mg/L (10–60 μmol/L).

Therapeutic drug monitoring: though therapeutic drug monitoring was not recommended initially for lamotrigine, it has recently been recognised that this is particularly useful in pregnancy^75–77 and in conjunction with hormonal contraception.⁷⁸

Main Adverse Reactions

Common: skin rash, headache, nausea, diplopia, dizziness, ataxia, tremor, asthenia and anxiety.

Severe: an allergic skin rash is the commonest and probably the most dangerous adverse effect prompting withdrawal of lamotrigine.⁷⁴ Skin rash occurs in approximately 10% of patients, but serious rashes leading to hospitalisation, including Stevens-Johnson syndrome and anticonvulsant hypersensitivity syndrome, occur in approximately 1 out of 300 adults (0.3%) and 1 out of 100 children (< 16 years of age) treated with lamotrigine.⁷⁴

Nearly all cases of life-threatening rashes associated with lamotrigine have occurred within 2–8 weeks of treatment initiation. However, isolated cases have been reported after prolonged treatment (e.g. 6 months). Accordingly, duration of therapy cannot be relied on as a means to predict the potential risk heralded by the first appearance of a rash.

There are suggestions, yet to be proven, that the risk of rash may also be increased by: (1) co-administration of lamotrigine with valproate; (2) exceeding the recommended initial dose of lamotrigine; or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have been reported in the absence of these factors. The incidence of skin rash can probably be reduced by starting treatment with a low dose spread over longer intervals, particularly in patients receiving concomitant valproate, which inhibits lamotrigine metabolism.

Although benign rashes also occur with lamotrigine, it is not possible to predict reliably which rashes will prove to be serious or life threatening. Accordingly, lamotrigine should ordinarily be discontinued at the first sign of rash, unless the rash is clearly not drug related. Discontinuation of treatment may not prevent a rash from becoming life threatening, or permanently disabling or disfiguring.

Important note

Patients should be advised to report immediately any symptoms of skin rash, hives, fever, swollen lymph glands, painful sores in the mouth or around the eyes, or swelling of lips or tongue, because these symptoms may be the first signs of a serious reaction.

Other: other adverse experiences have included gastrointestinal disturbance (including vomiting and diarrhoea), irritability/aggression, agitation, confusion and hallucinations. Very rarely, lupus-like reactions have been reported.

There have been reports of haematological abnormalities, which may or may not be associated with the anticonvulsant hypersensitivity syndrome. These have included neutropenia, leucopenia, anaemia, thrombocytopenia, pancytopenia, and very rarely aplastic anaemia and agranulocytosis. Elevations of liver function tests and rare reports of hepatic dysfunction, including hepatic failure, have been reported. Hepatic dysfunction usually occurs in association with hypersensitivity reactions, but isolated cases have been reported without overt signs of hypersensitivity.

Movement disorders such as tics, unsteadiness, ataxia, nystagmus and tremor have also been reported.

Exacerbation of seizures: increase in seizure frequency, mainly myoclonic jerks, has been reported in juvenile myoclonic epilepsy and Dravet syndrome.

Considerations in Women

Pregnancy: category C.

Breastfeeding: significant amounts of lamotrigine (40%–60%) are excreted in human milk. In breastfed infants, serum concentrations of lamotrigine reached levels at which pharmacological effects may occur.

Interactions with oral hormonal contraception and pregnancy: oral contraceptives are not affected by lamotrigine. However, pregnancy^75–77 and hormonal contraception⁷⁸ significantly lower lamotrigine levels (by more than half). Patients may suffer breakthrough seizures, mainly during the first trimester of pregnancy (if lamotrigine levels are not corrected) or toxic effects postpartum (if lamotrigine levels had been adjusted during pregnancy, but not after delivery). Gradual transient increases in lamotrigine levels will occur during the week of no active hormone preparation (pill-free week).

Main Mechanisms of Action

The precise mechanisms by which lamotrigine exerts its antiepileptic action are unknown. The most likely mechanism is inhibition of voltage-gated sodium channels, thereby stabilising neuronal membranes and consequently modulating presynaptic transmitter release of excitatory amino acids (e.g. glutamate and aspartate).

Pharmacokinetics

Oral bioavailability: < 100%. Lamotrigine is rapidly and completely absorbed from the gut with no significant first-pass metabolism.

Protein binding: 55%.

Metabolism: hepatic. Uridine diphosphate glucuronosyltransferases (UGT) have been identified as the enzymes responsible for the metabolism of lamotrigine.

Elimination half-life: 29 hours, but this is greatly affected by concomitant medication. Mean half-life is reduced to approximately 14 hours when given with enzyme-inducing drugs and is increased to a mean of approximately 70 hours when co-administered with valproate alone. Valproate is a potent inhibitor of UGT-dependent metabolism of lamotrigine, while enzyme-inducer AEDs are potent inducers of UGT-dependent metabolism of lamotrigine, which is the reason for different schemes of lamotrigine dosage and titration when combined with these AEDS.

Also, the half-life of lamotrigine is generally shorter in children than in adults with a mean value of approximately 7 hours when given with enzyme-inducing drugs and increasing to mean values of 45–50 hours when co-administered with valproate alone.

Drug Interactions

The metabolism of lamotrigine is badly affected by concomitant AEDs, which makes its use in polytherapy problematic.

1. Valproate inhibits lamotrigine metabolism, doubling or tripling its half life,⁷³ whether given with or without carbamazepine, phenytoin, phenobarbitone or primidone.
2. Enzyme inducers, such as carbamazepine, phenytoin and phenobarbitone, accelerate its elimination, but lamotrigine itself has no effect on hepatic metabolic processes.⁷⁹

With lamotrigine added to carbamazepine, symptoms of carbamazepine neurotoxicity (headache, diplopia, ataxia) may occur (probably because of pharmacodynamic interactions rather than elevated carbamazepine epoxide levels); this necessitates a reduction in the carbamazepine dose when lamotrigine is introduced.

Oxcarbazepine and levetiracetam do not affect the clearance of lamotrigine

Main Disadvantages

1. High incidence of idiosyncratic adverse reactions, which exceptionally may be fatal.
2. Slow titration in months.
3. Significant interactions with other AEDs requiring complex schemes of dosage and titration.
4. Pregnancy^75–77 and hormonal contraception⁷⁸ significantly lower lamotrigine levels (by more than half). This necessitates frequent adjustments of lamotrigine dosage before, during and after pregnancy and hormonal contraception. (d). Pro-myoclonic effect in syndromes with predominant myoclonic jerks,^80–83 such as juvenile myoclonic epilepsy and Dravet syndrome.

The use of lamotrigine should follow the manufacturer’s recommendations regarding titration and include a proper warning to the patient or guardians that immediate withdrawal of the drug is necessary if suspicious rashes appear, unless the rash is clearly not drug-related.

Clinical Applications

Levetiracetam is probably the major breakthrough in the treatment of epilepsies similar to that of carbamazepine and valproate in the 1960s. It is a highly effective, broad-spectrum, new class of AED with a unique mechanism of action and can be used to treat all focal or generalised, idiopathic or symptomatic epileptic syndromes in all age groups.

Levetiracetam is the first choice AED in polytherapy of focal epilepsies (page 436) and it is the likely candidate to replace valproate in the treatment of JME and IGEs in general (page 317 and 335). Levetiracetam has a significant proven efficacy for intractable focal seizures with or without secondary generalisation.^93;94 Addition of levetiracetam to standard medication seems to have a positive impact on health-related quality of life.⁹⁵

Its effectiveness in generalised seizures of any type and at any age is promising, because of its profile in experimental and observational studies, and vast postmarketing experience (see treatment of IGE page 335). This includes IGE,^96–98 JME,^99–101 myoclonus^102–105 and photosensitivity.^97;106

Levetiracetam also appears effective in epileptic encephalopathies, such as Lennox-Gastaut¹⁰⁷ and Landau-Kleffner syndrome.¹⁰⁸

That levetiracetam is considered as one of drugs most free from adverse reactions^95;109 makes it the most useful of all the new AEDs.¹¹⁰ Other significant advantages of levetiracetam are:

1. the starting dose is often therapeutic for all forms of seizures and epilepsies (including the difficult to treat myoclonic seizures)
2. there are no clinically significant drug–drug interactions. Levetiracetam does not influence other AEDs in a clinically meaningful way and conversely other AEDs do not interfere with the pharmacokinetics of levetiracetam.^111;112 This profile provides a safer and less-complicated therapeutic strategy
3. it has a wide margin of safety and patient-friendly pharmacokinetics that distinguish it from other currently available AEDs¹¹³
4. it does not interfere with liver function (a major problem with most other AEDs that are metabolised in the liver).

Dosage and Titration

Adults: start treatment with 1000 mg/day (twice daily dosing), which may be sufficient for seizure control. If needed, levetiracetam can be titrated in steps of 500 mg/week to a maximum of 3000 mg/day. Personally, I recommend starting with 250 mg twice daily and titrate according to the response.

Children: start treatment with 5–10 mg/kg/day, which may be sufficient for seizure control. If needed, levetiracetam can be titrated in steps of 5–10 mg/kg/week to a usual maintenance dose of 20–40 mg/kg/day (a maximum of 60 mg/kg/day has been used) given in two equally divided doses.^85;114–117

Based on weight, the maintenance dose for children should be 30–40% higher than that for adults. The reason for this is that levetiracetam clearance in children is 30–40% higher than in adults.^118;119 However, it is likely that the increase, compared with adults, is even higher in infants, for whom the data remain insufficient.¹²⁰

The drug is available as 250 mg (blue), 500 mg (yellow) and 750 mg (orange) tablets and as a clear, colourless, grape-flavoured liquid (100 mg/mL) for oral administration. If needed the tablets can be crushed and dissolved in water. The corresponding volume of suspension would then be administered using either a syringe or a 5-mL measuring spoon, often in conjunction with the child’s preferred juice or semi-solid food such as yoghurt.

Dosing: twice daily.

Dose adjustment is required for patients with renal dysfunction, but not for patients with liver disease.

Therapeutic range: 6–20 mg/L (35–120 μmol/L).

Therapeutic drug monitoring: not needed.

Levetiracetam can be efficacious from the starting dose.

Main Adverse Reactions

Levetiracetam is probably the AED that is most free from adverse reactions. Few major adverse effects were reported in the clinical trials and, overall, their incidence in the levetiracetam groups was little higher than that in the placebo groups.¹²¹

Common: the most common adverse effects are somnolence, asthenia and dizziness, which are dose-dependent and reversible. Others include headache, infection (common cold, upper respiratory infection which were not preceded by low neutrophil counts that might suggest impaired immunological status), anorexia, pharyngitis and pain. No withdrawal-related adverse events were reported during the cross-titration period.^84;85 Levetiracetam interferes with rapid motor learning in humans due to suppression of excitatory activity in the motor cortex.¹²²

Caution should be exercised when administering levetiracetam to individuals who may be prone to psychotic or psychiatric reactions.⁸⁷

In an uncontrolled study, add-on levetiracetam was associated with a paradoxical increase in seizure frequency, particularly in mentally retarded patients and those with difficult-to-treat partial onset seizures treated with high doses of levetiracetam.¹²³ This may be avoided by using a lower initial dose and a slower dose escalation than that recommended.

Considerations in Women

Pregnancy: category C. In a small series, three women receiving levetiracetam monotherapy during pregnancy gave birth to normal babies.¹⁸

Breastfeeding: unknown.

Interaction with hormonal contraception: none.

Main Mechanisms of Action

Levetiracetam has a novel mechanism of action that is distinct from that of other AEDs by targeting a synaptic vesicle protein in presynaptic terminals.^124–126 Its antiepileptic activity does not involve a direct interaction with any of the three main mechanisms of the other AEDs. Thus, levetiracetam does not modulate Na⁺ and low voltage-gated (T-type) Ca²⁺ currents, and does not induce any conventional facilitation of the GABAergic system. In contrast, levetiracetam has been observed to exert several atypical electrophysiological actions including a moderate inhibition of high voltage-gated N-type Ca²⁺ currents, reduction of intracellular Ca²⁺ release from the endoplasmic reticulum, as well as suppression of the inhibitory effect of zinc and other negative allosteric modulators of both GABA- and glycine-gated currents.

The apparent absence of any direct interaction with conventional mechanisms involved in the action of other AEDs parallels the discovery of a specific binding site for levetiracetam. Recent experiments have shown that the synaptic vesicle protein 2A (SV2A) is the binding site (Figure 12.21).¹²⁷

Studies in mice lacking SV2A indicate that this protein has a crucial role in the regulation of vesicle function, probably involving a modulation of vesicle fusion. These mice seem normal at birth, but develop unusually severe seizures by 1–2 weeks of age and die within 3 weeks after birth.¹²⁷

Brain membranes and purified synaptic vesicles from mice lacking SV2A did not bind a tritiated derivative of levetiracetam, indicating that SV2A is necessary for levetiracetam binding. Levetiracetam and related derivatives bind to SV2A, but not to the related isoforms, SV2B and SV2C, expressed in fibroblasts, indicating that SV2A is sufficient for levetiracetam binding. In contrast, none of the other AEDs tested revealed any binding to SV2A.¹²⁷

The severe seizures observed in mice lacking SV2A support the interpretation that this protein influences mechanisms of seizure generation or propagation. Furthermore, there is a strong correlation between the binding affinity of a series of levetiracetam derivatives and their anticonvulsant potency in the audiogenic seizure mice model. These results suggest that levetiracetam’s interaction with SV2A provides a significant contribution to its antiepileptic activity.

Pharmacokinetics

Patient note

“The pharmacokinetic profile of levetiracetam closely approximates the ideal characteristics expected of an antiepileptic drug, with good bioavailability, rapid achievement of steady-state concentrations, linear and time-invariant kinetics, minimal protein binding, and minimal metabolism.”¹¹³

“Levetiracetam, comes especially close to fulfilling the desirable pharmacokinetic characteristics for an AED: (1) it has a high oral bioavailability, which is unaffected by food; (2) it is not significantly bound to plasma proteins; (3) it is eliminated partly in unchanged form by the kidneys and partly by hydrolysis to an inactive metabolite, without involvement of oxidative and conjugative enzymes; (4) it has linear kinetics; and (5) it is not vulnerable to important drug interactions, nor does it cause clinically significant alterations in the kinetics of concomitantly administered drugs. Although its half-life is relatively short (6 to 8 hours), its duration of action is longer than anticipated from its pharmacokinetics in plasma, and a twice-daily dosing regimen is adequate to produce the desired response.”¹¹²

Oral bioavailability: 100% and it is unaffected by food. Levetiracetam is rapidly and almost completely absorbed after oral administration with peak plasma concentrations occurring in about 1 hour. The pharmacokinetics are linear and time-invariant, with low intra- and inter-subject variability.

Protein binding: < 10%. Levetiracetam is not appreciably protein-bound nor does it affect the protein binding of other drugs. Its volume of distribution is close to the volume of intracellular and extracellular water.

Metabolism/elimination: the major metabolic pathway of levetiracetam (24% of dose) is an enzymatic hydrolysis of the acetamide group. This is not dependent on the hepatic cytochrome P450 system. Further, levetiracetam does not inhibit or induce hepatic enzymes to produce clinically relevant interactions. Levetiracetam is eliminated from the systemic circulation by renal excretion as unchanged drug, which represents 66% of the administered dose. The mechanism of excretion is glomerular filtration with subsequent partial tubular reabsorption. The metabolites have no known pharmacological activity and are also renally excreted.

Elimination half-life: 6–8 hours. It is shorter in children and longer in the elderly and in subjects with renal impairment.

Drug Interactions

Unlike the majority of other AEDs, levetiracetam has no clinically meaningful drug–drug interactions.

Other AEDs: levetiracetam does not influence the plasma concentration of existing AEDs and conversely other AEDs do not influence the pharmacokinetics of levetiracetam. In addition, levetiracetam does not affect the in-vitro glucuronidation of valproate.

Other non-AEDs: levetiracetam has no known interactions with other drugs such as oral contraceptives, warfarin and digoxin. It does not reduce the effectiveness of oral contraceptives.

Main Disadvantages

There are some post-marketing reports of increased behavioural abnormalities in children treated with levetiracetam. Though this is not confirmed, one explanation may be fast titration recommended by the manufacturers.

Clinical Applications

Oxcarbazepine is a first class AED for monotherapy, conversion to monotherapy or adjunctive therapy for all types of focal seizures with or without secondarily generalised convulsions in adults and children over the age of 4 years. This has been documented in a series of clinical trials and extensive clinical use from 1980 when it was first licensed in Europe. It is the first AED in 25 years to be approved by the FDA in 2003 for use as monotherapy in children aged 4 years or older with focal epilepsy.

Dosage and Titration

Adults: start treatment with 150 mg/day and increase by 150 mg/day every second day until a target dose of 900–1200 mg/day is reached. Others start with 600 mg/day and increase weekly in 600 mg increments until a maintenance dose of between 900–2400 mg/day is reached.

In patients with impaired renal function (creatinine clearance < 30 mL/min), oxcarbazepine should be initiated at one-half the usual starting dose and increased slowly until the desired clinical response is achieved or adverse reactions appear.

Children: start with 10 mg/kg/day in two or three divided doses. The dosage can be increased by 10 mg/kg/day at approximately weekly intervals to a maximum of 30–46 mg/kg/day.

Dosing: twice or three times daily.

Therapeutic range: MHD, 4–12 mg/L (50–140 μmol/L).

Therapeutic drug monitoring: probably not useful.

Main Adverse Reactions

Common: the most common CNS adverse events are headache, dizziness, fatigue, nausea, somnolence, ataxia and diplopia. Most of these are dose–related, they usually occur at the start of therapy and subside during the course of therapy.

Serious: the reported rate of skin rash with oxcarbazepine is around 5% as opposed to 10–15% with carbamazepine. Multiorgan hypersensitivity disorder and Stevens-Johnson syndrome have been reported.

Important note

Cross reactivity with carbamazepine is approximately 25% (i.e. of the patients who have skin rash with carbamazepine, 25% will also have skin rash with oxcarbazepine). Therefore, given the availability of other AEDs, oxcarbazepine may not be a good option for patients who developed idiosyncratic reactions with carbamazepine.

Hyponatraemia (serum sodium level < 125 mmol/L) occurs in 3% of patients on oxcarbazepine. This develops gradually during the first few months of treatment. It is usually benign and can be reversed by fluid restriction or a reduction in the dose of oxcarbazepine. Acute water intoxication is rare. Measurement of serum sodium levels are needed for patients with renal disease, those taking medication that may lower serum sodium levels (e.g. diuretics, oral contraceptives or non-steroidal anti-inflammatory drugs) or if clinical symptoms of hyponatraemia develop.

Consumption of large volumes of fluid (e.g. beer) should be discouraged.

Oxcarbazepine is contraindicated in patients with a history of atrioventricular block.

Considerations in Women

Pregnancy: category C.

Breastfeeding: should be avoided because oxcarbazepine and its active metabolite are secreted in significant amounts in breast milk.

Interaction with hormonal contraception: yes.

Main Mechanisms of Action

Oxcarbazepine exerts its antiepileptic activity primarily via MHD. Like carbamazepine, blockade of voltage-sensitive sodium channels is the main mechanism of action. Others include reduction of the release of excitatory amino acids, probably by inhibiting high voltage-activated calcium currents. An effect on potassium channels might be clinically important.

Pharmacokinetics

Oral bioavailability: > 95% and peak concentrations are reached within 4–6 hours. Absorption is unaffected by food.

Protein binding: only 38% of the MHD is bound to serum proteins compared with 67% for the parent compound.

Metabolism: oxcarbazepine is rapidly metabolised in the liver to form the pharmacologically active MHD. This is then conjugated to a glucuronide compound and excreted in the urine as a monohydroxy derivative.

Elimination half-life: 8–10 hours. This is shorter in children and longer in the elderly.

As a neutral lipophilic substance, the active metabolite MHD of oxcarbazepine is able to diffuse rapidly through the various membranes and the blood-brain barrier.

Drug Interactions

The oxcarbazepine-MHD complex lowers concentrations of some drugs, such as hormonal contraceptives and lamotrigine, and increases concentrations of others, such as phenytoin. Conversely, strong inducers of the cytochrome P450 enzyme system, such as carbamazepine and phenytoin, lower plasma levels of MHD by 29–40%.

Combination therapy with monoamine oxidase inhibitors should be avoided, because oxcarbazepine has structural similarities with tricyclic antidepressants.

Main Disadvantages

1. Oxcarbazepine is contraindicated in generalised seizures, such as absences or myoclonic jerks in syndromes of IGE.¹²⁸ It may not be effective in neonates and children younger than 2 years of age.
2. One out of four patients have cross sensitivity to idiosyncratic reactions with carbamazepine or other AEDs.
3. Though probably the first choice AED as monotherapy in focal epilepsies, its use as polytherapy is less satisfactory because of drug–drug interactions.

Useful Clinical Note

Conversion to oxcarbazepine from carbamazepine or phenytoin is complicated by the need for higher doses of oxcarbazepine initially than needed later as monotherapy.

A carbamazepine dose of 200 mg appears to be equivalent to 300 mg of oxcarbazepine.

On anecdotal evidence, it is possible to change from carbamazepine to oxcarbazepine abruptly, using a dose ratio of 200 mg carbamazepine to 300 mg oxcarbazepine, without the need for titration. A lower ratio of 1:1 or 1:1.25 is commonly better tolerated, especially if the conversion is from slow release preparations of carbamazepine.

Levels of concomitant medication may be affected by the removal of the enzyme-inducing effects of carbamazepine.

Clinical Applications

Post-marketing experience is still very limited and it appears that pregabalin is a narrow spectrum AED that exaggerates myoclonus. Therefore pregabalin should be used in rational polytherapy in adults with intractable focal seizures who had failed to respond in other AED combinations as detailed in Chapter 12 (page 433). For these patients, there are insufficient data about withdrawal of concomitant antiepileptic medication, once seizure control with adjunctive pregabalin has been reached, in order to establish monotherapy with pregabalin.

Treatment emergent myoclonic jerks, even in patients with focal seizures,^142;143 may be a warning sign against the use of pregabalin in generalised epilepsies, where myoclonus is often a prominent symptom to treat.

Dosage and Titration

Adults: start treatment with 150 mg/day and, based on individual patient response and tolerability, increase to 300 mg/day after an interval of 7 days, and to a maximum dose of 600 mg/day after an additional 7-day interval. The maintenance dose is 150–600/day in either two or three divided doses taken orally.

Dosage adjustments are necessary in patients with renal impairment and probably the elderly.

Therapeutic drug monitoring: probably not needed.

Therapeutic range: not determined.

Main Adverse Reactions

Significant weight gain was noted in 5.6% of pregabalin-treated patients in all trials.

The most commonly (> 10%) reported side effects in placebo-controlled, double-blind studies were somnolence and dizziness. Other commonly (>1% and < 10%) reported side effects were increased appetite, euphoric mood, confusion, decreased libido, irritability, ataxia, attention disturbance, abnormal coordination, memory impairment, tremor, dysarthria, paraesthesia, blurred vision, diplopia, vertigo, dry mouth, constipation, vomiting, flatulence, erectile dysfunction, fatigue, peripheral oedema, feeling drunk, oedema and abnormal gait.

Hypoglycaemic medication may need to be adjusted in diabetic patients who gain weight.

Considerations in Women

Pregnancy and lactation: pregabalin should not be used during pregnancy unless the benefit outweighs the risk. Effective contraception must be used in women of childbearing potential.

Breastfeeding is not recommended during treatment with pregabalin.

Others: Weight gain, which is often significant may be associated with polycystic ovary syndrome.

Main Mechanisms of Action

The precise mechanism of action of pregabalin is still unclear. Though an analogue of GABA, pregabalin is inactive at GABA_A and GABA_B receptors and it has no effect on GABA uptake or degradation. Pregabalin decreases central neuronal excitability by binding to an auxiliary subunit (a₂-delta protein) of a high voltage-gated calcium channel on neurons in the CNS. It reduces the release of certain neurotransmitters including glutamate, noradrenaline and substance P.

Pharmacokinetics

Oral bioavailability: > 90%.

Protein binding: does not bind to plasma proteins.

Metabolism: pregabalin is not metabolised in the liver and does not induce hepatic enzymes. It is excreted renally.

Elimination half-life: 6–7 hours.

Drug Interactions

Pregabalin does not affect the plasma concentration of other AEDs. In addition, it does not interact with a number of other drug types, including hormonal contraception.

However, pregabalin appears to be additive in the impairment of cognitive and gross motor function when co-administered with oxycodone (an opioid), and potentiates the effect of lorazepam and ethanol.

Patients with galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take pregabalin.

Main Disadvantages

As explained on page 438, it is probably too early to make any predictions for the role of pregabalin in the treatment of focal epilepsies. However, the high incidence of weight gain¹⁴² (consider the decline in the use of valproate because of this side effect and its causative relation with polycystic ovary syndrome in women), treatment emergent myoclonic jerks^142;143 and similarities with gabapentin¹⁴⁴ are not promising signs.

Clinical Applications

The antiepileptic efficacy of tiagabine is limited to focal seizures. Its role in clinical epileptology is probably limited to adjunctive medication in severe forms of focal epilepsies that failed to respond to other AED combinations.^146;147 It may also be effective in epileptic spasms of epileptic encephalopathies.

Dosage and Titration

Dosage and titration depend on co-medication.

Adults: start treatment with 4–5 mg/day for the first week. Titrate in increments of 4–5 mg/day every week in two divided doses up to 30–45 mg/day (in co-medication with enzyme-inducing drugs) or 15–30 mg/day (with non-enzyme-inducing drugs).

Children: start treatment with 0.1mg/kg/day and titrate in increments of 0.1 mg/kg/day every 1–2 weeks up to 0.5–2 mg/kg/day.

Children eliminate tiagabine more rapidly than adults.

Dosing: twice or preferably three times daily.

Therapeutic range: 50–250 nmol/L (80–450 μg/L).

Therapeutic drug monitoring: not useful.

Main Adverse Reactions

Common: fatigue, headache, dizziness, tremor, cognitive impairment, disturbed concentration, depression and word-finding difficulties.

Severe: none. Concerns that tiagabine like vigabatrin (another GABAergic AED) may cause visual field defects have not been substantiated.^148;149

Seizure exacerbation: treatment emergent absence status epilepticus has been reported in a significant number of patients. An opinion by a panel of experts that “treatment with tiagabine in recommended doses does not increase the risk of status epilepticus in patients with partial seizures”¹⁵⁰ probably refers to focal status epilepticus and not to the generalised absence status epilepticus where the main risk lies.

Considerations in Women

Pregnancy: category C.

Main Mechanisms of Action

Tiagabine is an AED specifically designed to increase GABA longevity in the synaptic cleft. It is a potent and selective inhibitor of GABA uptake into neurons and glial cells. This brain GABAergic mediated inhibition of tiagabine explains its antiepileptic effect on focal seizures and also explains its pro-absence effect.

Pharmacokinetics

Oral bioavailability: < 96%. High fat meals slow the rate of absorption.

Protein binding: 96%. Salicylic acid and naprofen displace tiagabine.

Metabolism: tiagabine is metabolised by hepatic cytochrome P450 before conjugation to inactive metabolites excreted in the urine and faeces. It is neither an hepatic enzyme inducer nor an inhibitor.

Elimination half-life: 7–9 hours decreasing to 2–3 hours in the presence of hepatic enzyme inducers. The metabolism of tiagabine is reduced in patients with hepatic dysfunction thus prolonging its half-life to 12–16 hours.

Drug Interactions

Enzyme-inducing AED (phenytoin, carbamazepine, phenobarbitone) significantly lower the plasma concentrations of tiagabine by a factor of 1.5–3 and shorten its half-life.

Valproate displaces tiagabine from its protein-binding sites.

Tiagabine does not affect other AEDs or hormonal contraception.

Main Disadvantages

1. Narrow spectrum antiepileptic efficacy to focal seizures only.
2. Tiagabine is a pro-absence drug. Its use is probably prohibited in IGE with absences. The pro-absence effect of tiagabine was expected because it is a GABAergic drug that also increases GABA-B, which is the main activator of absence seizures. This pro-absence effect of tiagabine has been confirmed in animals and humans.^151;152

Clinical Applications

Topiramate is a highly efficacious new, broad-spectrum AED, but significant adverse effects hinder its clinical use.^160–168 It is the most effective of all the new AEDs in focal seizures. In clinical use, topiramate has been recommended for all types of seizures, focal or generalised, and idiopathic or symptomatic, in adults and children including difficult-to-treat epileptic encephalopathies, such as West and Lennox-Gastaut syndromes.

Dosage and Titration

‘Start low and go slow’ is particularly important in topiramate treatment.

Adults and children over 16 years: start with 25 mg nocte for the first week and then titrate in increments of 25 or 50 mg/day in two equally divided doses at 1 or 2 week intervals. The recommended maintenance dose is 200–400 mg/day. Some authors use a maximum dose of 800 mg/day, but this is rarely tolerated.

Children 6–16 years: start with 25 mg or 1–3 mg/kg/day nocte for the first week. Titrate with increments of 1–3 mg/kg/day in two divided doses at 1 or 2 week intervals to a recommended maintenance dose of 5–9 mg/kg/day in two divided doses.

Children 2–6 years: start with 0.5–1 mg/kg/day nocte for the first week and then titrate as for older children.

Renally impaired patients: half of the usual dose is recommended. Patients with moderate or severe renal impairment may take 10–15 days to reach steady-state plasma concentrations compared with 4–8 days in patients with normal renal function.

Important note

Treatment with topiramate should start at a very low dosage and be titrated at a very slow pace. If the patient is unable to tolerate the titration regimen, smaller increments or longer intervals between increments can be used. Maintenance doses are usually reached in 2 months.
Tablets should not be broken.
Therapy should not be withdrawn suddenly because of the risk of aggravating seizures.

Dosing: twice daily.

Therapeutic range: 9–12 mg/L (15–60 μmol/L).

Therapeutic drug monitoring: not useful.

Main Adverse Reactions

Topiramate is an inferior new AED with respect to adverse reactions, which are common, multiple and sometimes severe or potentially fatal.^169;170 Withdrawal rates were low in controlled trials (4.8%), but appear to be much more frequent in non-comparative and post-marketing studies.^160;171 On the positive side, topiramate lacks significant idiosyncratic reactions.

Common: somnolence, anorexia, fatigue and nervousness are common as in other AEDs, but most of the other frequent adverse reactions are of concern.

Abnormal thinking, consisting of mental slowing and word-finding difficulties, has been reported in 31% of patients with titration rates of 100 mg/week.^172;173

Difficulty with concentration/attention, memory impairment, psychomotor slowing and speech disorders are often very severe even when treatment starts with small doses and titration is slow.

Behavioural and cognitive problems are a limiting factor in some children. Topiramate was reported to have a negative impact on cognition with impairment of performance on tests requiring verbal processing, which was consistent with subjective complaints of patients.^174;175

Weight loss (10% of patients) may be considered as beneficial by some women, but is sometimes relentless and extremely problematic.¹⁶⁰ A dietary supplement or increased food intake may be considered if the patient is losing weight or has inadequate weight gain while receiving topiramate.

Treatment emergent paraesthesia and abdominal pains may be confused with other systemic disorders.

Metabolic acidosis: hyperchloraemic, non-anion gap, metabolic acidosis (i.e. decreased serum bicarbonate below the normal reference range in the absence of respiratory alkalosis) is associated with use of topiramate. The incidence of persistent treatment-emergent decreases in serum bicarbonate is high and rises significantly with increasing topiramate dosages. Generally, the decrease in bicarbonate occurs early, though it can occur at any time during treatment.

Markedly abnormal low serum bicarbonate (i.e. an absolute value of < 17 mEq/L and > 5 mEq/L decrease from pretreatment levels) occurred in 11% of children receiving topiramate 6 mg/kg/day, and 3% of adults receiving 400 mg/day. In placebo-controlled trials of migraine prophylaxis in adults, markedly abnormally low serum bicarbonate levels occurred in 11% of those receiving 200 mg/day, 9% on 100 mg/day, 2% on 50 mg/day, and < 1% with placebo.

Diseases or therapies that predispose to acidosis, such as renal disease, severe respiratory disorders, status epilepticus, diarrhoea, surgery, ketogenic diet, or certain drugs (e.g. zonisamide) may be additive to the bicarbonate-lowering effects of topiramate.

Manifestations of acute or chronic metabolic acidosis may include hyperventilation, non-specific symptoms, such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor.

Depending on the underlying conditions, appropriate evaluation including serum bicarbonate levels is recommended with topiramate therapy.

Important note

Chronic, untreated metabolic acidosis may increase the risk of nephrolithiasis or nephrocalcinosis, and may also result in osteomalacia (rickets in paediatric patients) and/or osteoporosis with an increased risk of fractures. Chronic metabolic acidosis in paediatric patients may also reduce growth rates. A reduction in growth rate may eventually decrease the maximal height achieved. The effect of topiramate on growth and bone-related sequelae is unknown and has not been systematically investigated.

Nephrolithiasis: around 1.5% of adults and 0.6% children in clinical trials of topiramate developed renal stones. Risk factors for nephrolithiasis include prior stone formation, a family history of nephrolithiasis and hypercalciuria. None of these risk factors can reliably predict stone formation during topiramate treatment. In addition, patients taking other medication associated with nephrolithiasis, such as zonisamide, may be at increased risk.

Topiramate, like other carbonic anhydrase inhibitors, reduces urinary citrate excretion and increases urinary pH.

Important note

Patients receiving topiramate should increase their fluid intake as it may reduce the risk of: (1) developing renal stones; and (2) heat-related adverse events during exercise and exposure to particularly warm environments.

Acute myopia with secondary angle-closure glaucoma is a syndrome reported in adults and children treated with topiramate.¹⁷⁶ Symptoms typically occur within 1 month of the start of treatment and include acute onset of decreased visual acuity and/or ocular pain. Ophthalmological findings include bilateral myopia, anterior chamber shallowing, ocular hyperaemia and increased intra-ocular pressure with or without mydriasis. There may be supraciliary effusion resulting in anterior displacement of the lens and iris. Discontinuation of topiramate should be as rapid as is clinically feasible. Immediate specialist advice should be sought. If left untreated, elevated intra-ocular pressure can lead to serious sequelae including permanent visual loss.

Oligohidrosis and hyperthermia: hypohidrosis or more usually anhidrosis associated with hyperthermia, infrequently resulting in hospitalisation, has been reported in association with topiramate. Symptoms include decreased or absence of sweating, elevation of body temperature, red face and tiredness, which are worse on effort.

The majority of the reports have been in children and have occurred after exposure to hot environmental conditions. Patients, especially children, treated with topiramate should be monitored closely for evidence of such symptoms especially in hot weather.

Caution should be used when topiramate is prescribed with other drugs that predispose patients to heat-related disorders, such as zonisamide (such a combination should probably be avoided), other carbonic anhydrase inhibitors and anticholinergic drugs.

Considerations in Women

Pregnancy: category C. There is no reliable information on human teratogenicity, but in animals even subtoxic doses of topiramate are teratogenic.¹⁶

Breastfeeding: breastfeeding is not recommended because of extensive secretion of topiramate into human milk.

Interactions with hormonal contraception: there is a dose-dependent decrease in ethinyl estradiol exposure with topiramate doses between 200–800 mg/day, which may result in decreased efficacy of hormonal contraception and increased breakthrough bleeding.

Main Mechanisms of Action

The antiepileptic effect of topiramate is probably due to multimodal mechanisms of action. These include blockage of voltage-dependent sodium channels, augmentation of the inhibitory activity of GABA at some subtypes of the GABA_A receptor, antagonism with the AMPA/kainate subtype of the glutamate receptor, and inhibition of the carbonic anhydrase enzyme, particularly isozymes II and IV.

Pharmacokinetics

Oral bioavailability: > 80%.

Protein binding: 15–41% over the blood concentration range of 0.5–250 μg/mL. The fraction bound decreases as blood concentration increases.

Metabolism: topiramate is not extensively metabolised and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). Six metabolites have been identified in humans, none of which constitutes more than 5% of an administered dose. The metabolites are formed via hydroxylation, hydrolysis and glucuronidation. There is evidence of renal tubular reabsorption of topiramate.

Elimination half-life: 21 hours.

Drug Interactions

The following antiepileptic drug–drug interactions are of clinical significance with topiramate co-medication.

In co-medication, phenytoin plasma levels may increase by 25% and topiramate decrease by 48%. Carbamazepine may decrease topiramate plasma by nearly half.

There is probably no interaction with lamotrigine and levetiracetam, and interactions with valproate are minimal.

Concomitant use with other carbonic anhydrase inhibitors, such as zonisamide, should probably be avoided.

See also interactions with hormonal contraception.

Main Disadvantages

Despite high efficacy, the current and future role of topiramate as a major AED is questionable, because of its very poor profile in terms of multiple and severe adverse reactions. The most important of these reactions are those that occur in children, some of which (metabolic acidosis) may have predictable detrimental growth and bone-related sequelae in long-term use.

Its use may be limited to severe epilepsies intractable to other, better tolerated, AEDs.

Clinical Applications

Valproate is one of the most effective broad-spectrum AEDs for all types of seizures and epilepsies. It has superior efficacy in all types of generalised seizures (idiopathic and symptomatic), all syndromes of IGE and photosensitive epilepsy than any other drug so far, with the probable exception of levetiracetam. The efficacy of valproate has been well documented in long-term and worldwide clinical practice and a few controlled studies.

However, valproate is far inferior to carbamazepine and other newer AEDs in the treatment of focal epilepsies.

Unlike many other AEDs, valproate appears to have a very low potential to aggravate seizures.¹⁸⁰ When seizure aggravation occurs with valproate, it is in a specific clinical context, such as overdose, encephalopathy, or hepatic or metabolic disorders.¹⁸⁰

Dosage and Titration

Adults: start with 200 mg/day in two equally divided doses for 3 days. Titrate in increments of 200 mg/day every 3 days to a maintenance dose of usually 1000–1500 mg/day (maximum 3000 mg/day) given in two equally divided doses. Higher initial dosage and faster titration rates are usually well tolerated.

Children: start with 10/mg/kg/day. Titrate in increments of 10 mg/kg/day every 3 days. The typical maintenance dose in childhood is 20–30 mg/kg/day in two equally divided doses.

Combined therapy: it may be necessary to increase the dose by 30–50% when used in combination with enzyme-inducing AEDs, such as phenytoin, phenobarbitone and carbamazepine. On withdrawal of these AEDs, it may be possible to reduce the dose of valproate.

Dosing: twice or three times daily, and once daily for slow release formulations.

Therapeutic range: 50–100 mg/L (300–700 μmol/L).

Therapeutic drug monitoring: often not useful, because of poor correlation between valproate dose and plasma levels. However, because of significant drug interactions, monitoring of valproate and AEDs given concomitantly may be helpful when enzyme-inducing drugs are added or withdrawn.

Main Adverse Reactions

Clinical note

Valproate is associated with serious adverse reactions particularly in children and women. Acute liver necrosis and acute pancreatitis, which may be fatal, are rare and more likely to occur in children receiving polypharmacy. An estimated 1–2% risk of neural tube defects, predominantly spina bifida aperta, in babies of women on valproate is well established,^181;182 and the overall risk of major teratogenic effects with valproate is 2–3 times higher than the background prevalence of major non-syndromic congenital anomalies. This together with polycystic ovary syndrome¹⁸³ and other endocrine side effects, makes the use of valproate in some women undesirable.¹⁸⁴

CNS-related adverse reactions: in contrast with other old AEDs, valproate is not usually associated with drowsiness and fatigability or significant dose-related effects on cognition or behaviour. Valproate encephalopathy is exceptional.

Tremor is the more troublesome CNS adverse effect of valproate. There is great individual susceptibility to the development of tremor, which is usually mild, but may become very intense, socially embarrassing and disabling. It is reversible and declines when the dose is lowered.

Systemic: the most serious are fatal hepatotoxicity and acute haemorrhagic pancreatitis.

Hepatic failure resulting in fatalities is primarily age-dependent and occurs mainly in children receiving polypharmacy and with organic brain disease. The risk is 1/600 before the age of 3 years. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups (range 1/8000–1/10,000 between 3 and 20 years of age) and in monotherapy with valproate. Hepatic failure has usually occurred during the first 6 months of treatment. The diagnosis depends on clinical criteria with non-specific symptoms, such as malaise, weakness, lethargy, facial oedema, anorexia, vomiting and loss of seizure control. Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first 6 months. However, this may not be helpful because:

1. benign elevation of liver enzymes is common during valproate treatment
2. severe hepatotoxicity is not preceded by progressive elevation of liver enzymes.

Important note

Raised liver enzymes are common during treatment with valproate, particularly if used in conjunction with other AEDs. These are usually transient or respond to dose reduction. Patients with such biochemical abnormalities should be reassessed clinically and liver function tests should be performed more frequently. An abnormally low prothrombin level, particularly in association with other relevant abnormalities, requires withdrawal of valproate. Any concomitant use of salicylates should be stopped, since they employ the same metabolic pathway.

Acute haemorrhagic pancreatitis with markedly increased amylase and lipase levels is another rare, but serious, adverse effect of valproate treatment. It develops within the first 3 months of treatment, is more prevalent in children and with polytherapy.

Hyperammonaemic encephalopathy, which is sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders. When urea cycle enzymatic deficiency is suspected, metabolic investigations should be performed prior to treatment with valproate.

Thrombocytopenia and other haematological abnormalities:¹⁸⁵ it is recommended that platelet counts and coagulation tests are performed before initiating therapy and at periodic intervals, because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation and abnormal coagulation parameters. Evidence of haemorrhage, bruising or a disorder of haemostasis/coagulation is an indication for reduction or withdrawal of valproate.

Weight gain occurs in 20% of patients and is sometimes marked; women are more vulnerable. This is usually reversible if valproate is withdrawn early.

Hair loss and changes in hair texture or colour are relatively rare, usually occur in the early months of valproate treatment and may resolve spontaneously despite continuation of the drug.

Other adverse effects concern the gastrointestinal system (e.g. anorexia, constipation, dry mouth, stomatitis) and urogenital system (e.g. urinary incontinence, vaginitis, dysmenorrhoea, amenorrhoea, urinary frequency).

Considerations in Women

Valproate treatment in women raises many issues, see Table 4.3, page 64.

Pregnancy: category D. Valproate crosses the placenta and causes a spectrum of congenital anomalies, such as neural tube defects, craniofacial malformations and skeletal defects. The incidence of these anomalies is much higher when valproate is given as co-medication with other AEDs.

Interaction with hormonal contraception: none.

Other issues: see endocrine abnormalities.

Main Mechanisms of Action¹⁷⁸

The main mechanism of action is unknown and a combination of several mechanisms may be responsible:

1. Reduction of sustained, repetitive, high frequency firing by inhibiting voltage-sensitive sodium channels, activating calcium-dependent potassium conductance and possibly by direct action on other ion channels.
2. Valproate has a GABAergic effect through elevation of brain GABA by various mechanisms, such as inhibiting GABA-transaminase, enhancing GABA synthesising enzymes, increasing GABA release and inhibiting GABA uptake. However, this GABAergic action is observed only at high valproate levels and may explain its efficacy in other, but not absence, seizures. GABAergic drugs have a pro-absence action because they potentiate absences. Therefore, the most likely explanation for the effect of valproate on absence seizures is that this drug, like ethosuximide, reduces a low threshold (T-type) calcium-channel current,¹⁸⁶ but this effect has not been supported by other studies.¹⁸⁷

Pharmacokinetics

Oral bioavailability: almost complete. Absorption of valproate varies according to the formulation used. Absorption is rapid and peak levels are reached within 2 hours after oral administration of syrup or uncoated tablets. This is longer (3–8 hours) with enteric-coated tablets.

Protein binding: valproate is highly protein bound (about 90%). However, if the plasma level of valproic acid rises above 120 mg/L or if the serum albumin concentration is lowered, the binding sites may become saturated, causing the amount of free drug to rise rapidly, out of proportion to any increase in dosage. Valproate may displace phenobarbitone or phenytoin from plasma protein binding sites.

Metabolism: hepatic. Valproate has a complex metabolism. It is rapidly and nearly totally eliminated by hepatic metabolism as numerous metabolites that contribute to its efficacy and toxicity. The major elimination pathway is via glucuronidation (40–60%). The remainder is largely metabolised via oxidation pathways, beta-oxidation accounting for 30–40% and ω-oxidation, which is cytochrome P450 dependent. Only 1–3% of the ingested dose is excreted unchanged in the urine. Two metabolites of valproate, 2-ene-valproic acid and 4-ene-valproic acid, are among the most pharmacologically active and have a similar potency to the parent drug. They are both produced by the action of cytochrome P450 enzymes induced by other AEDs. They are eliminated primarily in the urine.

Elimination half-life: this is variable, but generally appears to be 8–12 hours (range 4–16 hours). It is shorter in patients receiving enzyme-modifying AEDs or in long-term valproate treatment of children and adults. Many antipsychotic and antidepressants drugs result in competitive metabolism or enzyme inhibition when given as co-medication with valproate.

Drug Interactions

There are numerous drug interactions with valproate because:

1. its metabolism is sensitive to enzymatic induction
2. it inhibits the metabolism of other drugs
3. it has a high affinity for serum proteins; it may be displaced or displace other drugs.

Effect of other AEDs on valproate: enzyme inducers particularly those that elevate levels of UGTs, such as phenobarbitone, phenytoin and carbamazepine, may increase the clearance of valproate thus reducing plasma valproate levels by 30–50%.

The addition of ethosuximide may reduce the serum concentration of valproate.

Effects of valproate on other AEDs: valproate does not interact with most of the new AEDs. A notable exception is lamotrigine. Valproate is a potent inhibitor of UGT-dependent metabolism of lamotrigine, and doubles¹⁸⁸ or triples⁷³ its plasma half-life.

The addition of valproate to ethosuximide or phenobarbitone may double the serum concentration of these AEDs with concomitant toxicity.

Important note

There is evidence of severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations should be measured, if possible, and the barbiturate dosage decreased, if appropriate.

Serum levels of carbamazepine decrease to around 17%, while those of carbamazepine-10,11-epoxide increase by 45% on co-administration with valproate.

Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Valproate significantly increases the free fraction of phenytoin and reduces total plasma concentrations.

Valproate does not interact with hormonal contraception.

Main Disadvantages

The superior efficacy of valproate in generalised seizures is hindered by serious acute and chronic adverse reactions. It is particularly unsuitable for:

1. women, because of hormonal changes, weight gain and teratogenicity; it is virtually impossible to prescribe valproate to young women today (see Table 4.3, page 64).
2. young children, particularly those under the age of 2 years, who are at a considerably increased risk of developing fatal hepatotoxicity especially those on multiple anticonvulsants or with congenital metabolic disorders, mental retardation or organic brain disease.

Valproate is the superior AED for generalised epilepsies, but its use in focal epilepsies is of very limited value. In my opinion, valproate is needed in only exceptional cases and only as adjunctive treatment in patients with focal and secondarily GTCS because:

1. the doses of valproate required to be effective are much higher in focal than generalised epilepsies
2. side effects, particularly in some women, make its use undesirable
3. there are now other more effective and safer drugs for focal seizures.

Clinical Applications

The use of vigabatrin as an AED is, in practice, limited to infantile (epileptic) spasms for which it is the initial treatment of choice.

Exceptionally vigabatrin may be used cautiously in the treatment of patients with intractable focal seizures that have failed to respond to all other appropriate AED combinations and surgical evaluation.

Dosage and Titration

Adults: start with 500 mg/day and titrate in increments of 500 mg/day every week. Typical adult maintenance dose is 1000–3000 mg/day given in two equally divided doses.

Because the excretion is mainly renal, the dose should be reduced in patients with renal insufficiency and creatinine clearance below 60 mL/L.

Children with infantile spasms: start with 50 mg/kg/day and adjust according to the response over 7days up to 150–200 mg/kg/day.

Dosing: despite its short half-life (5–7 hours), vigabatrin may be given once or twice daily, because inhibition of GABA-transaminase (GABA-T) results in a relatively long duration of action, and GABA levels in the CSF can remain elevated for up to 120 hours after a single oral dose.

Therapeutic range: 6–278 μmol/L, which is irrelevant in clinical practice.

Therapeutic drug monitoring: totally unnecessary.

Main Adverse Reactions

Visual field defects are the main concern.¹⁹⁸ Other adverse reactions include sedation, dizziness, headache, ataxia, paraesthesia, memory, cognitive and behavioural disturbances, weight gain and tremor. There is no evidence of idiosyncratic adverse reactions.

Visual field defects: there is a high prevalence of visual field defects occurring in around one-third of patients (adults and children)¹⁹⁹ treated with vigabatrin. Vigabatrin also produces retinal electrophysiological changes in nearly all patients.^148;198;200

Visual field loss resulting from vigabatrin is not usually reversible. However, visual acuity, colour vision and the loss of amplitude on the electroretinogram may be reversible in patients with minimal or no field loss. There is some evidence that visual field defects remain stable with continuous treatment. It is, therefore, feasible to continue treatment with vigabatrin in these cases, provided visual field monitoring is performed regularly.

In one study involving 24 children treated with vigabatrin, visual field constriction or abnormal ocular electrophysiological studies were seen in over 50% of cases.¹⁹⁹

The mechanism of vigabatrin-induced visual field defects are probably due to reversible oedema of the myelin in the optic nerves, retinal cone system dysfunction or both.

Main Mechanisms of Action

The mechanism of vigabatrin’s antiepileptic action is by selective and irreversible inhibition of GABA-T, thus preventing the breakdown of GABA. Vigabatrin produces dose-dependent increases in GABA concentrations in the CSF, and decreases in GABA-T activity. Raised brain GABA levels inhibit the propagation of abnormal hypersynchronous seizure discharges.

Vigabatrin may also cause a decrease in excitation-related amino acids.

Pharmacokinetics

Oral bioavailability: 80–100%.

Protein binding: none.

Metabolism: it is not metabolised and 70% is excreted unchanged in the urine. It is eliminated by the kidneys by glomerular filtration.

Elimination half-life: 5–8 hours (not clinically important).

Drug Interactions

There are no drug interactions of any clinical significance except lowering the concentration of phenytoin.

Considerations in Women

Pregnancy: category C.

Breastfeeding: only small amounts of the drug are excreted in breast milk.

Interactions with hormonal contraception: none.

Main Disadvantages

Visual field defects have virtually eliminated vigabatrin from common clinical practice except for infantile spasms.

Aggravation of seizures: vigabatrin is a pro-absence agent which aggravates absence seizures and provokes absence status epilepticus.²⁰¹ This alone would prohibit use of vigabatrin in IGEs with absences. The pro-absence effect of vigabatrin should be expected because it is a GABAergic drug that also increases GABA-B, which is the main activator of absence seizures.

Vigabatrin, in addition to its aggravation effect on typical absence seizures, may also exaggerate atypical absences (such as those occurring in Lennox-Gastaut syndrome) and myoclonic seizures (such as those occurring in progressive or non-progressive myoclonic epilepsies).

Useful Clinical Note

Visual field defects may not be clinically detectable. Therefore, patients should be monitored with perimetry prior to and every 6 months during vigabatrin treatment. Electrophysiological testing is considered to be more accurate than perimetry for the direct vigabatrin effect on the outer retina.²⁰² The manufacturers of vigabatrin provide a procedure for testing children under 9 years of age for visual field defects.

Clinical Applications

Zonisamide appears to be an effective broad-spectrum AED^86;203;205 with extensive clinical use, mainly in Japan.²⁰⁴ It is efficacious in focal seizures with or without GTCS, primarily and secondarily generalised seizures^86;203;206 including epileptic spasms of West syndrome,²⁰⁷ other epileptic encephalopathies such as Ohtahara syndrome,²⁰⁸ and progressive and probably other myoclonic epilepsies such as Unverricht-Lundborg syndrome.

Dosage and Titration

‘Start low and go slow’ is a important part of zonisamide treatment.²⁰⁴ Significant adjustments are needed in co-medication with hepatic-enzyme inducers.

Adults: start with no more than 100 mg/day for the first week and titrate in increments of 100 mg/day every 1–3 weeks. Usual adult maintenance dose is 400–600 mg/day given in two equally divided doses. Some patients respond well to a smaller maintenance dose of 200 mg/day and some authors recommend one single dose before sleep.

Marked renal impairment (creatinine clearance < 20 mL/min) requires slower dose escalation and lower maintenance doses.

Children: start with 1–2/mg/kg/day for the first week and titrate in increments of 1–2 mg/kg/day every 2 weeks. Usual childhood maintenance dose is 4–8 mg/kg/day (maximum 12 mg/kg/day) in two equally divided doses.

Therapeutic range: 15–40 mg/L (45–180 μmol/L).

Therapeutic drug monitoring: useful, though there is insufficient evidence to support a clear relation between the plasma concentration of zonisamide and the clinical response.²⁰⁵ Zonisamide monitoring may be needed in order to adjust the dosage in co-medication with phenytoin, phenobarbitone or carbamazepine.

Main Adverse Reactions

Zonisamide causes many adverse reactions.

Common: sedation, somnolence, fatigue, dizziness, agitation, irritability, anorexia, weight loss, nausea, diarrhoea, dyspepsia, dry mouth, slowing of mental activity, depression, ataxia, visual hallucinations, photosensitivity, resting and postural hand tremors.

Serious: some of the adverse reactions are similar to those of topiramate. These are:

1. cognitive impairment including word-finding difficulty; this is worse in children with plasma concentrations > 140 μmol/L
2. weight loss and anorexia that may become very severe
3. nephrolithiasis in 4% of patients on prolonged zonisamide therapy
4. oligohidrosis and anhidrosis often accompanied by hyperthermia, especially in children and hot environments.

Additional severe adverse reactions are those seen with the sulfonamides, such as rash, Stevens-Johnson syndrome and toxic epidermal necrolysis. The incidence of rash requiring discontinuation of therapy has been approximately 2% in clinical trials.

Zonisamide is contraindicated in patients who have demonstrated hypersensitivity to sulfonamides or zonisamide.^209;210

Depression and psychosis may be common, particularly in children. In one study, 14 of 74 patients experienced psychotic episodes within a few years of commencement of zonisamide.²¹¹

Seizure exacerbation: treatment emergent status epilepticus has been reported in 1.1% of treated patients, compared to 0 in placebo-treated individuals.^8;9

Considerations in Women

Pregnancy: category C.

Breastfeeding: the transfer rate of zonisamide through the breast milk is high at about 50%.

Interaction with oral hormonal contraception: none.

Main Mechanisms of Action

The antiepileptic mechanism of zonisamide is probably multimodal. Zonisamide blocks the sustained repetitive firing of voltage-sensitive sodium channels and reduces voltage-dependent T-type calcium current without affecting L-type calcium current. It has mild carbonic anhydrase activity and inhibits excitatory glutamatergic transmission. It exhibits free radical scavenging properties.

Pharmacokinetics

Bioavailability: 100%.

Protein binding: 40–60%.

Metabolism and route of elimination: zonisamide is metabolised in the liver and eliminated by the kidneys. It undergoes extensive hepatic metabolism to a number of metabolites by cytochrome P450 (CYP 3A4). Its metabolism is markedly increased by enzyme-inducing drugs. It does not induce hepatic enzymes. Nearly half of zonisamide is excreted unchanged in the urine.

Half-life elimination: 63 hours decreasing to 27–38 hours in the presence of hepatic enzyme inducers.

Interaction with Other Drugs

Serum concentrations of zonisamide are altered by drugs that either induce or inhibit CYP3A4. Phenytoin, phenobarbitone and carbamazepine increase zonisamide plasma clearance and reduce its half-life to 27–38 hours. Valproate also reduces its half life to 46 hours.

Zonisamide does not appear to affect phenytoin, but significantly increases the plasma concentration of carbamazepine-epoxide when added to carbamazepine.

Concomitant administration of carbonic anhydrase inhibitors, such as acetazolamide or topiramate, is probably ill advised because of the increased potential for renal stone and metabolic acidosis.

Main Disadvantages

Zonisamide has significant adverse reactions, some of which may be severe such as cognitive, psychotic episodes, anhidrosis and hyperthermia, nephrolithiasis and Stevens-Johnson syndrome. It also has many interactions with other AEDs in polytherapy.