Prescribing issues associated with anticonvulsant medications for epilepsy

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Key concepts

Key concepts:

Sodium valproate is used first line for generalised epilepsy syndromes except in women of child bearing potential For people with partial seizures and for women of child bearing potential lamotrigine or carbamazepine are the preferred initial treatment choices All anticonvulsant medications are associated with adverse effects which in rare circumstances can be potentially life-threatening An increased risk of anxiety, depression and suicidality has been associated with the use of anticonvulsants Some anticonvulsants, particularly phenytoin and carbamazepine, induce and increase the production of hepatic enzymes which can result in clinically significant drug interactions Routine therapeutic drug monitoring of anticonvulsants has limited clinical use

Updated information on prescribing anticonvulsants to women of childbearing age available from Balancing the benefits and risks of prescribing antiepileptic medicines in women bpac^nz, October 2018

Anticonvulsant medications are primarily used for the treatment of epilepsy, but may also have a place in the treatment of neuropathic pain, bipolar affective disorder and migraine prophylaxis.

Treatment with anticonvulsant medication is usually initiated after a history of two seizures, when further seizures are likely and when the benefit of treatment is anticipated to outweigh the adverse effects of medication. There is some evidence that initiating anticonvulsants after a single seizure may not result in improvement in the long term prognosis and may not reduce the risk of injury or mortality.^1,2

Selection of an anticonvulsant is generally guided by the type of epileptic seizure, the risk of adverse effects and the presence of co-morbidities. Sodium valproate is used first line for generalised epilepsy syndromes. However, in women of child bearing potential, low dose lamotrigine (<200 mg/day) or carbamazepine are preferred because of the teratogenicity associated with sodium valproate (see below for more information).³ For patients with partial seizures, lamotrigine or carbamazepine are the preferred initial treatment choices.⁴

The goal of successful pharmacological treatment in epilepsy is the complete control of seizures. However for some people this may not be achievable without intolerable adverse effects.⁵ Table 1 summarises the prescribing issues associated with common anticonvulsant medications.

Table 1: Prescribing issues associated with common anticonvulsant medications^1,6,7,8

Multiple drug interactions and adverse effects may occur with all anticonvulsants. This table highlights the key areas of concern only. Seek further information if required.

Type of epilepsy	Adverse effects	Interactions	Monitoring	Notes
Sodium valproate
All types of epilepsy First-line for generalised epilepsies	Common – weight gain, tremor, GI disturbance and hair loss (usually mild) Thrombocytopenia Hepatic failure Pancreatitis Other blood dyscrasias	Interacts with: Most other anticonvulsants, in general raising blood levels (particularly lamotrigine) TCAs Benzodiazepines Warfarin Aspirin (combination may result in easier bruising)	CBC, LFT, electrolytes at baseline, at three months and then annually Repeat tests if clinical suspicion of haematological or hepatic damage If warfarin commenced, check INR after 5–7 days (warfarin dose decrease may be required)	Avoid in women of childbearing potential Regarded as less sedating than other anticonvulsants
Carbamazepine
Partial epilepsies (first-line), also in generalised or mixed epilepsies May worsen absence or myoclonic seizures	Common - nausea and vomiting, sedation, dizziness and ataxia Allergic rash (may be severe) Leucopenia Hyponatraemia (action not required if sodium stable above 125 mmol/L) Hepatotoxicity Other blood dyscrasias	Increased plasma concentration (increasing the risk of toxicity) if used with: Azole antifungals Macrolide antibiotics SSRIs e.g. fluoxetine Induces hepatic enzymes and reduces the effect of some medications including: Oestrogens and progestogens TCAs Warfarin Calcium channel blockers Statins	CBC, LFT, electrolytes at baseline Repeat tests if clinical suspicion of haematological or hepatic damage If warfarin commenced, check INR after 5–7 days (warfarin dose increase may be required)	Use slow release preparations Carbamazepine or lamotrigine are the anticonvulsant drugs of choice in pregnancy
Lamotrigine
Most forms of epilepsy Alternate first-line for partial epilepsies	Common – allergic rash, headache, dizziness, blurred vision Serious allergic rash particularly: In children If dose increased rapidly If dose increased rapidly in combination with sodium valproate	Plasma concentration is increased by sodium valproate Plasma concentration is decreased by enzyme inducing anticonvulsants, oestrogens and progestogens	Not routinely indicated	Start low, go slow to avoid allergic rash Lamotrigine or carbamazepine are the anticonvulsant drugs of choice in pregnancy Avoid doses over 200 mg in women of childbearing potential
Phenytoin
Most forms of epilepsy May worsen absence or myoclonic seizures	Common - headache, tiredness, nausea, dizziness, drowsiness and insomnia Allergic rash (may be severe) Hirsutism, coarsening of facial features, acne and gingival hyperplasia Hepatotoxicity Blood dyscrasias	Induces hepatic enzymes and reduces the effect of some medications including: Oestrogens and progestogens TCAs Warfarin Calcium channel blockers Statins	CBC, LFT, electrolytes at baseline, at three months and then annually Repeat tests if clinical suspicion of haematological or hepatic damage If warfarin commenced, check INR after 5–7 days (warfarin dose increase may be required)	Therapeutic drug monitoring is useful due to non-linear pharmacokinetics e.g. when adjusting dose or adding additional medications with potential for interaction No longer widely used (narrow therapeutic index, long term toxicity)
Gabapentin
Partial and secondarily generalised tonic-clonic seizures May worsen absence or myoclonic seizures	Common – dizziness, tiredness and nausea Weight gain, peripheral oedema Allergic rash (may be severe)	No clinically important drug interactions	Not routinely indicated	More widely used for neuropathic pain than epilepsy
Topiramate
Generalised seizures Partial epilepsy	Common – ataxia, confusion, dizziness, tiredness Weight loss Acute angle closure glaucoma Kidney stones Cognitive impairment (up to 15%) particularly if used with sodium valproate	Can decrease serum concentration of digoxin and oral contraceptives by about 30%	Not routinely indicated	Often used as adjunctive therapy Patients should be advised to have adequate fluid intake

Notes:
Phenobarbitone and primidone are effective in most forms of epilepsy except absence seizures. However they are no longer widely used due to multiple adverse effects particularly on the CNS and respiratory system. Their use is associated with tolerance, dependence and in elderly people, with falls, osteoporosis and fractures. Primidone can be effective for essential tremor.
Ethosuximide is only effective for absence seizures. It may worsen generalised tonic clonic seizures. It is not widely used.
Vigabatrin is used in treatment of epilepsy (via special authority) that is not well controlled with other anticonvulsants. It may worsen absence or myoclonic seizures. Its use has been limited by the risk of concentric irreversible visual field defects, which are seen in 30–40% of patients.⁹ These defects are usually initially asymptomatic and begin with bilateral nasal field loss. Refer for baseline visual field testing by perimetry with follow up tests every six months.¹⁰
Levetiracetam is only available by specialist application to the Special Access Panel. It is effective as adjunctive treatment of partial onset seizures with or without secondary generalisation.
Pregabalin is effective in the treatment of partial seizures with or without secondary generalisation. It is indicated in New Zealand as adjunctive therapy for patients with this type of epilepsy and also for neuropathic pain, however it is not subsidised.
Oxcarbazepine is not subsidised in New Zealand and therefore not widely used.

Adverse effects of anticonvulsant medication

All anticonvulsant medications are associated with adverse effects which may significantly impact on quality of life, contribute to non-compliance and in rare circumstances be potentially life-threatening.

Common dose related adverse effects

Initiation of anticonvulsants is associated with a number of very common dose related adverse effects including:

• Sedation, tiredness, dizziness, ataxia, tremor, slurred speech, confusion, decreased coordination
• Dry mouth, nausea, diarrhoea, GI disturbance

Typically these effects are of mild to moderate severity, are dose related and resolve within the first few weeks of treatment.

Adverse effects may be minimised by:⁵

• Choosing a slow release formulation when practical to avoid rapid rises in serum concentration
• Starting with a low dose and slowly increasing at one or two week intervals
• Using monotherapy if possible

Allergic rash is common with phenytoin, carbamazepine and lamotrigine. Gradual introduction of carbamazepine and lamotrigine is thought to significantly reduce the incidence of this. In general if a rash develops the medication should be withdrawn as allergic rashes have the potential to progress to severe skin and systemic reactions.

Mild haematological reactions can occur, e.g., leucopenia with carbamazepine and thrombocytopenia with sodium valproate. These changes are usually transitory, dose related and require no intervention, however in rare cases they may be life threatening.^11,12

Potentially life-threatening adverse effects

Rare, life-threatening adverse effects with anticonvulsants include:^11,12

• Skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis
• Systemic reactions e.g. hypersensitivity resulting in multi-organ failure
• Haematological reactions including thrombocytopenia, aplastic anaemia, agranulocytosis and leucopenia
• Hepatic failure

Routine monitoring has not been shown to be of value in identifying these conditions. Instead patients should be advised of the risks and asked to report any warning signs such as rash, fever, bruising and other signs of infection such as sore throat.

Abrupt withdrawal of any anticonvulsant medication has the potential to precipitate seizures or status epilepticus. Before an anticonvulsant medication is stopped e.g. because of a serious adverse effect, an additional anticonvulsant should first be added that can quickly obtain therapeutic levels. Consultation with a specialist is recommended.

Anticonvulsants and suicidality

An increased risk of anxiety, depression and suicidality has been associated with the use of anticonvulsants. It is recommended that all patients taking anticonvulsants for any indication are routinely assessed for symptoms of these conditions. This recommendation is based on a recent FDA meta-analysis of clinical trials involving 11 anticonvulsant drugs, reporting that patients taking these drugs had twice the risk of suicidal thoughts and behaviours than those patients taking a placebo (0.43% compared to 0.22%).¹³

See BPJ 14, June 2008 “Anticonvulsants associated with suicidality”.

Anticonvulsants and osteoporosis

Anticonvulsant medications (particularly phenytoin, sodium valproate, carbamazepine, primidone and phenobarbitone) are associated with a reduction in bone mineral density and an increased fracture risk.^14,15

Many guidelines recommend that all patients taking any anticonvulsant medication should be offered lifestyle and dietary advice to reduce the risk of osteoporosis.^14,16 Vitamin D supplementation should be considered for patients who have additional risk factors for osteoporosis.¹⁷

See BPJ 17, October 2008 “Prevention of osteoporosis”.

Dose adjustments

Dose adjustments may be required for patients with impaired hepatic function

Most anticonvulsant medications are metabolised by the liver. If hepatic function is impaired, lower doses may be required to avoid elevated serum drug levels. Gabapentin, pregabalin, levetiracetam and vigabatrin are excreted without metabolism by the liver and should not require dose adjustment in patients with impaired hepatic function.

Dose adjustments may be required for patients with impaired renal function

A reduction in renal excretion of some anticonvulsants and/or their active metabolites may result in an increase in adverse effects or toxicity and doses may need to be reduced.

Dose adjustment in elderly people

In many elderly people, changes in renal or hepatic function and altered pharmacodynamic response may increase the likelihood of adverse effects. Therefore lower doses of anticonvulsants may be required.

Enzyme induction

Some anticonvulsants, particularly phenytoin and carbamazepine induce and increase the production of hepatic enzymes. This can result in clinically significant drug interactions by increasing the metabolism of some co-administered drugs e.g. oral contraceptives, warfarin, calcium channel blockers and many antipsychotic and antidepressant drugs.

Enzyme induction can be associated with an increase in gamma-glutamyl transferase (GGT). An isolated increase in GGT (up to 1.5 – 2 times upper limit of normal) is not usually of concern unless it is associated with increases in transaminases which may signal hepatotoxicity, requiring further investigation. Alcohol use can increase the GGT level further.

Other enzyme inducing anticonvulsants include phenobarbitone and primidone. Topiramate and oxcarbazepine are inducers at high dose but at lower doses have some inhibiting properties.⁶ Sodium valproate is an inhibitor of specific isoenzymes and typically increases the concentrations of other anticonvulsants, particularly lamotrigine and the active metabolite of carbamazepine. Doses of lamotrigine should be halved while taking sodium valproate.

Routine therapeutic drug monitoring of anticonvulsants has limited clinical usefulness (except phenytoin)

Therapeutic drug monitoring (TDM) has traditionally been used to guide treatment decisions for patients with epilepsy.^7,18 However, there have been no randomised studies that demonstrate that TDM has a positive impact on clinical outcomes in patients with epilepsy.⁷ It is now recognised that the usefulness of routine TDM has been overemphasised and that optimal treatment should rely primarily on a careful assessment of the patient’s clinical state.^7,19

Despite this, TDM may be of benefit in some circumstances for some patients, because of the pharmacokinetic variability of anticonvulsant medications and the often unpredictable nature of epilepsy.⁷ However, a clinical decision should usually not be made based on the serum concentration alone.

TDM may be beneficial in the following specific clinical situations;⁷

• When pharmacokinetics (and consequently, dose requirement) alter, e.g. in children, in elderly people, in pregnancy, in people with co-morbidities or when a drug interaction is suspected
• When increasing the dose of an anticonvulsant with non-linear pharmacokinetics e.g. phenytoin (see sidebar)
• If seizures persist despite an apparently adequate dosage
• If toxicity is suspected or when it is difficult to assess this clinically, e.g. in children or people with mental disability

The importance of steady state

If TDM is to be clinically useful and comparable, samples should be taken after steady state has been reached and should be collected at the same time of day e.g. usually just prior to the next dose. The time to reach steady state varies widely for anticonvulsants and additionally there are diurnal fluctuations in the serum concentrations of drugs which have short elimination half lives (e.g. carbamazepine. sodium valproate).

For further information see Best Tests, July 2009, “Practical considerations for therapeutic drug monitoring”.