Drug Action
Memantine is a glutamate receptor antagonist. Nervous system
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Drug reference
Memantine is a glutamate receptor antagonist. Nervous system
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Moderate to severe dementia in Alzheimer’s disease ▶BY MOUTH ▶Adult: Initially 5 mg once daily, then increased in steps of 5 mg every week; usual maintenance 20 mg daily; maximum 20 mg per day Oscillopsia in multiple sclerosis ▶BY MOUTH ▶Adult: Initially 10 mg daily, then increased to 40 mg daily, over 1 week; increased if necessary to 60 mg daily, over 1 week, on specialist advice only l UNLICENSED USE g Memantine hydrochloride is used for oscillopsia in multiple sclerosis, l but is not licensed for this indication.
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Epilepsy. history of convulsions. risk factors for epilepsy
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NICE decisions ▶Donepezil, galantamine, rivastigmine, and memantine for the treatment of Alzheimer’s disease (updated June 2018) NICE TA217 Memantine monotherapy is recommended as an option for managing Alzheimer’s disease for people with: . moderate Alzheimer’s disease who are intolerant of or have a contra-indication to AChE inhibitors, or . severe Alzheimer’s disease. Treatment should be under the conditions specified in recommendation 1.5.5 in the NICE guideline on dementia. Healthcare professionals should not rely solely on assessment scales to determine the severity of Alzheimer’s disease when the patient has learning or other disabilities, or other communication difficulties. www.nice.org.uk/guidance/ta217
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→Appendix 1: memantine
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▶Common or very common Balance impaired. constipation. dizziness. drowsiness. dyspnoea. headache. hypersensitivity. hypertension ▶Uncommon Confusion. embolism and thrombosis. fatigue . fungal infection. hallucination. heart failure. vomiting ▶Rare or very rare Seizure ▶Frequency not known Hepatitis. pancreatitis. psychotic disorder
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Manufacturer advises avoid unless essential—no information available.
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Manufacturer advises avoid—no information available.
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Manufacturer advises avoid in severe impairment—no information available.
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Avoid if eGFR less than 5 mL/minute/1.73 m2. Dose adjustments Reduce dose to 10 mg daily if eGFR 30–49 mL/minute/1.73 m2, if well tolerated after at least 7 days dose can be increased in steps to 20 mg daily; reduce dose to 10 mg daily if eGFR 5–29 mL/minute/1.73 m2.
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For oral solution, manufacturer advises solution should be dosed onto a spoon or into a glass of water. For soluble tablets, manufacturer advises drink resulting solution immediately when dissolved in water.
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There can be variation in the licensing of different medicines containing the same drug. Soluble tablet CAUTIONARY AND ADVISORY LABELS 13 ▶Alzhok (Glenmark Pharmaceuticals Europe Ltd) Memantine hydrochloride 5 mg Alzhok 5mg soluble tablets sugar- free | 7 tablet P s Memantine hydrochloride 10 mg Alzhok 10mg soluble tablets sugar-free | 28 tablet P £29.09 DT = £29.09 Memantine hydrochloride 15 mg Alzhok 15mg soluble tablets sugar-free | 7 tablet P s Memantine hydrochloride 20 mg Alzhok 20mg soluble tablets sugar-free | 28 tablet P £58.18 DT = £58.18 Tablet ▶Memantine hydrochloride (Non-proprietary) Memantine hydrochloride 5 mg Memantine 5mg tablets | 7 tablet P s Memantine hydrochloride 10 mg Memantine 10mg tablets | 28 tablet P £34.50 DT = £3.08 | 56 tablet P £3.15–£13.98 Memantine hydrochloride 15 mg Memantine 15mg tablets | 7 tablet P s Memantine hydrochloride 20 mg Memantine 20mg tablets | 28 tablet P £69.01 DT = £9.98 ▶Ebixa (Lundbeck Ltd) Memantine hydrochloride 5 mg Ebixa 5mg tablets | 7 tablet P s Memantine hydrochloride 10 mg Ebixa 10mg tablets | 28 tablet P £34.50 DT = £3.08 Memantine hydrochloride 15 mg Ebixa 15mg tablets | 7 tablet P s Memantine hydrochloride 20 mg Ebixa 20mg tablets | 28 tablet P £69.01 DT = £9.98 ▶Maruxa (Consilient Health Ltd) Memantine hydrochloride 10 mg Marixino 10mg tablets | 28 tablet P £29.32 DT = £3.08 Memantine hydrochloride 20 mg Marixino 20mg tablets | 28 tablet P £58.65 DT = £9.98 ▶Nemdatine (Actavis UK Ltd) Memantine hydrochloride 5 mg Nemdatine 5mg tablets | 7 tablet P s Memantine hydrochloride 10 mg Nemdatine 10mg tablets | 56 tablet P £69.01 Memantine hydrochloride 15 mg Nemdatine 15mg tablets | 7 tablet P s Oral solution ▶Memantine hydrochloride (Non-proprietary) Memantine hydrochloride 10 mg per 1 ml Memantine 10mg/ml oral solution sugar free sugar-free | 50 ml P £61.61 DT = £55.14 sugar-free | 100 ml P £97.98–£123.23 ▶Ebixa (Lundbeck Ltd) Memantine hydrochloride 10 mg per 1 ml Ebixa 5mg/0.5ml pump actuation oral solution sugar-free | 50 ml P £61.61 DT = £55.14 sugar-free | 100 ml P £123.23 Form unstated ▶Memantine hydrochloride (Non-proprietary) Memantine 5mg/10mg/15mg/20mg tablets treatment initiation pack | 28 tablet P £43.13 DT = £43.13 ▶Alzhok (Glenmark Pharmaceuticals Europe Ltd) Alzhok soluble tablets treatment initiation pack sugar-free | 28 tablet P £40.97 ▶Ebixa (Lundbeck Ltd) Ebixa tablets treatment initiation pack | 28 tablet P £43.13 DT = £43.13 ▶Valios (Dr Reddy’s Laboratories (UK) Ltd) Valios 5mg/10mg/15mg/20mg orodispersible tablets initiation pack sugar-free | 28 tablet P £31.24 DT = £31.24 Orodispersible tablet EXCIPIENTS: May contain Aspartame ▶Valios (Dr Reddy’s Laboratories (UK) Ltd) Memantine hydrochloride 5 mg Valios 5mg orodispersible tablets sugar free sugar-free | 7 tablet P s Memantine hydrochloride 10 mg Valios 10mg orodispersible tablets sugar free sugar-free | 28 tablet P £24.99 DT = £24.99 Memantine hydrochloride 15 mg Valios 15mg orodispersible tablets sugar free sugar-free | 7 tablet P s Memantine hydrochloride 20 mg Valios 20mg orodispersible tablets sugar free sugar-free | 28 tablet P £49.98 DT = £49.98 Epilepsy and other seizure disorders Epilepsy Epilepsy control The object of treatment is to prevent the occurrence of seizures by maintaining an effective dose of one or more antiepileptic drugs. Careful adjustment of doses is necessary, starting with low doses and increasing gradually until seizures are controlled or there are significant adverse effects. When choosing an antiepileptic drug, the presenting epilepsy syndrome should first be considered. If the syndrome is not clear, the seizure type should determine the choice of treatment. Concomitant medication, co-morbidity, age, and sex should also be taken into account. The dosage frequency is often determined by the plasma- drug half-life, and should be kept as low as possible to encourage adherence with the prescribed regimen. Most antiepileptics, when used in the usual dosage, can be given twice daily. Lamotrigine p. 334, perampanel p. 338, phenobarbital p. 351, and phenytoin p. 339, which have long half-lives, can be given once daily at bedtime. However, with large doses, some antiepileptics may need to be given more frequently to avoid adverse effects associated with high peak plasma-drug concentration. Management When monotherapy with a first-line antiepileptic drug has failed, monotherapy with a second drug should be tried; the diagnosis should be checked before starting an alternative drug if the first drug showed lack of efficacy. The change from one antiepileptic drug to another should be cautious, slowly withdrawing the first drug only when the new regimen has been established. Combination therapy with two or more antiepileptic drugs may be necessary, but the concurrent use of antiepileptic drugs increases the risk of adverse effects and drug interactions. If combination therapy does not bring about worthwhile benefits, revert to the regimen (monotherapy or combination therapy) that provided the best balance between tolerability and efficacy. A single antiepileptic drug should be prescribed wherever possible. MHRA/CHM advice: Antiepileptic drugs: updated advice on switching between different manufacturers’ products (November 2017) The CHM has reviewed spontaneous adverse reactions received by the MHRA and publications that reported potential harm arising from switching of antiepileptic drugs in patients previously stabilised on a branded product to a generic. The CHM concluded that reports of loss of seizure control and/or worsening of side-effects around the time of switching between products could be explained as chance associations, but that a causal role of switching could not be ruled out in all cases. The following guidance has been issued to help minimise risk: . Different antiepileptic drugs vary considerably in their characteristics, which influences the risk of whether switching between different manufacturers’ products of a particular drug may cause adverse effects or loss of seizure control; . Antiepileptic drugs have been divided into three risk- based categories to help healthcare professionals decide whether it is necessary to maintain continuity of supply of a specific manufacturer’s product. These categories are listed below; . If it is felt desirable for a patient to be maintained on a specific manufacturer’s product this should be prescribed either by specifying a brand name, or by using the generic drug name and name of the manufacturer (otherwise known as the Marketing Authorisation Holder); . This advice relates only to antiepileptic drug use for treatment of epilepsy; it does not apply to their use in other indications (e.g. mood stabilisation, neuropathic pain); . Please report on a Yellow Card any suspected adverse Nervous system reactions to antiepileptic drugs; . Dispensing pharmacists should ensure the continuity of supply of a particular product when the prescription specifies it. If the prescribed product is unavailable, it may be necessary to dispense a product from a different manufacturer to maintain continuity of treatment of that antiepileptic drug. Such cases should be discussed and agreed with both the prescriber and patient (or carer); . Usual dispensing practice can be followed when a specific product is not stated. Category 1 Carbamazepine p. 327, phenobarbital, phenytoin, primidone p. 352. For these drugs, doctors are advised to ensure that their patient is maintained on a specific manufacturer’s product. Category 2 Clobazam p. 353, clonazepam p. 354, eslicarbazepine acetate p. 329, lamotrigine, oxcarbazepine p. 337, perampanel, rufinamide p. 342, topiramate p. 348, valproate, zonisamide p. 350. For these drugs, the need for continued supply of a particular manufacturer’s product should be based on clinical judgement and consultation with the patient and/or carer taking into account factors such as seizure frequency, treatment history, and potential implications to the patient of having a breakthrough seizure. Non-clinical factors as for Category 3 drugs should also be considered. Category 3 Brivaracetam p. 325, ethosuximide p. 330, gabapentin p. 331, lacosamide p. 333, levetiracetam p. 336, pregabalin p. 341, tiagabine p. 347, vigabatrin p. 349. For these drugs, it is usually unnecessary to ensure that patients are maintained on a specific manufacturer’s product as therapeutic equivalence can be assumed, however, other factors are important when considering whether switching is appropriate. Differences between alternative products (e.g. product name, packaging, appearance, and taste) may be perceived negatively by patients and/or carers, and may lead to dissatisfaction, anxiety, confusion, dosing errors, and reduced adherence. In addition, difficulties for patients with co-morbid autism, mental health problems, or learning disability should also be considered. Antiepileptic hypersensitivity syndrome Antiepileptic hypersensitivity syndrome is a rare but potentially fatal syndrome associated with some antiepileptic drugs (carbamazepine, lacosamide, lamotrigine, oxcarbazepine, phenobarbital, phenytoin, primidone, and rufinamide); rarely cross-sensitivity occurs between some of these antiepileptic drugs. Some other antiepileptics (eslicarbazepine, stiripentol, and zonisamide) have a theoretical risk. The symptoms usually start between 1 and 8 weeks of exposure; fever, rash, and lymphadenopathy are most commonly seen. Other systemic signs include liver dysfunction, haematological, renal, and pulmonary abnormalities, vasculitis, and multi-organ failure. If signs or symptoms of hypersensitivity syndrome occur, the drug should be withdrawn immediately, the patient must not be re-exposed, and expert advice should be sought. Risk of suicidal thoughts and behaviour The MHRA has advised (August 2008) that all antiepileptic drugs are associated with a small increased risk of suicidal thoughts and behaviour. Symptoms may occur as early as one week after starting treatment. Patients should be advised to seek medical advice if they develop any mood changes, distressing thoughts, or feelings about suicide or harming themselves, and should be referred for appropriate treatment if necessary. Interactions Interactions between antiepileptics are complex and may increase toxicity without a corresponding increase in Nervous system antiepileptic effect. Interactions are usually caused by hepatic enzyme induction or inhibition; displacement from protein binding sites is not usually a problem. These interactions are highly variable and unpredictable. Withdrawal Antiepileptic drugs should be withdrawn under specialist supervision. Avoid abrupt withdrawal, particularly of barbiturates and benzodiazepines, because this can precipitate severe rebound seizures. Reduction in dosage should be gradual and, in the case of barbiturates, withdrawal of the drug may take months. The decision to withdraw antiepileptic drugs from a seizure-free patient, and its timing, is often difficult and depends on individual circumstances. Even in patients who have been seizure-free for several years, there is a significant risk of seizure recurrence on drug withdrawal. In patients receiving several antiepileptic drugs, only one drug should be withdrawn at a time. Driving If a driver has a seizure (of any type) they must stop driving immediately and inform the Driver and Vehicle Licensing Agency (DVLA) Patients who have had a first unprovoked epileptic seizure or a single isolated seizure must not drive for 6 months; driving may then be resumed, provided the patient has been assessed by a specialist as fit to drive and investigations do not suggest a risk of further seizures. Patients with established epilepsy may drive a motor vehicle provided they are not a danger to the public and are compliant with treatment and follow up. To continue driving, these patients must be seizure-free for at least one year (or have a pattern of seizures established for one year where there is no influence on their level of consciousness or the ability to act); also, they must not have a history of unprovoked seizures. Note: additional criteria apply for drivers of large goods or passenger carrying vehicles—consult DVLA guidance. Patients who have had a seizure while asleep are not permitted to drive for one year from the date of each seizure, unless: . a history or pattern of sleep seizures occurring only ever while asleep has been established over the course of at least one year from the date of the first sleep seizure; or . an established pattern of purely asleep seizures can be demonstrated over the course of three years if the patient has previously had seizures whilst awake (or awake and asleep). The DVLA recommends that patients should not drive during medication changes or withdrawal of antiepileptic drugs, and for 6 months after their last dose. If a seizure occurs due to a prescribed change or withdrawal of epilepsy treatment, the patient will have their driving license revoked for 1 year; relicensing may be considered earlier if treatment has been reinstated for 6 months and no further seizures have occurred. Pregnancy Women of child-bearing potential should discuss with a specialist the impact of both epilepsy, and its treatment, on the outcome of pregnancy. There is an increased risk of teratogenicity associated with the use of antiepileptic drugs (especially if used during the first trimester and particularly if the patient takes two or more antiepileptic drugs). Valproate is associated with the highest risk of serious developmental disorders (up to 30–40% risk) and congenital malformations (approx. 10% risk). Valproate must not be used in females of childbearing potential unless the conditions of the Pregnancy Prevention Programme are met and alternative treatments are ineffective or not tolerated; during pregnancy, it must not be used for epilepsy, unless it is the only possible treatment. There is also an increased risk of teratogenicity with phenytoin, primidone, phenobarbital, lamotrigine, and carbamazepine. Topiramate carries an increased risk of congenital malformations (including cleft palate, hypospadias, and anomalies involving various body systems) if taken in the first trimester of pregnancy. There is not enough evidence to establish the risk of teratogenicity with other antiepileptic drugs. Prescribers should also consider carefully the choice of antiepileptic therapy in pre-pubescent girls who may later become pregnant. Women of child-bearing potential who take antiepileptic drugs should be given advice about the need for an effective contraception method to avoid unplanned pregnancy—for further information, see Conception and contraception in the individual drug monographs. Some antiepileptic drugs can reduce the efficacy of hormonal contraceptives, and the efficacy of some antiepileptics may be affected by hormonal contraceptives. Women who want to become pregnant should be referred to a specialist for advice in advance of conception. For some women, the severity of seizure or the seizure type may not pose a serious threat, and drug withdrawal may be considered; therapy may be resumed after the first trimester. If treatment with antiepileptic drugs must continue throughout pregnancy, then monotherapy is preferable at the lowest effective dose. Once an unplanned pregnancy is discovered it is usually too late for changes to be made to the treatment regimen; the risk of harm to the mother and fetus from convulsive seizures outweighs the risk of continued therapy. The likelihood of a woman who is taking antiepileptic drugs having a baby with no malformations is at least 90%, and it is important that women do not stop taking essential treatment because of concern over harm to the fetus. To reduce the risk of neural tube defects, folate supplementation is advised before conception and throughout the first trimester. In the case of sodium valproate p. 344 and valproic acid p. 372 an urgent consultation is required to reconsider the benefits and risks of valproate therapy. The concentration of antiepileptic drugs in the plasma can change during pregnancy. Doses of phenytoin, carbamazepine, and lamotrigine should be adjusted on the basis of plasma-drug concentration monitoring; the dose of other antiepileptic drugs should be monitored carefully during pregnancy and after birth, and adjustments made on a clinical basis. Plasma-drug concentration monitoring during pregnancy is also useful to check compliance. Additionally, in patients taking topiramate or levetiracetam, it is recommended that fetal growth should be monitored. Women who have seizures in the second half of pregnancy should be assessed for eclampsia before any change is made to antiepileptic treatment. Status epilepticus should be treated according to the standard protocol. Routine injection of vitamin K at birth minimises the risk of neonatal haemorrhage associated with antiepileptics. Withdrawal effects in the newborn may occur with some antiepileptic drugs, in particular benzodiazepines and phenobarbital. Epilepsy and Pregnancy Register All pregnant women with epilepsy, whether taking medication or not, should be encouraged to notify the UK Epilepsy and Pregnancy Register (Tel: 0800 389 1248). Breast-feeding Women taking antiepileptic monotherapy should generally be encouraged to breast-feed; if a woman is on combination therapy or if there are other risk factors, such as premature birth, specialist advice should be sought. All infants should be monitored for sedation, feeding difficulties, adequate weight gain, and developmental milestones. Infants should also be monitored for adverse effects associated with the antiepileptic drug particularly with newer antiepileptics, if the antiepileptic is readily transferred into breast-milk causing high infant serum-drug concentrations (e.g. ethosuximide, lamotrigine, primidone, and zonisamide), or if slower metabolism in the infant causes drugs to accumulate (e.g. phenobarbital and lamotrigine). Serum-drug concentration monitoring should be undertaken in breast-fed infants if suspected adverse reactions develop; if toxicity develops it may be necessary to introduce formula feeds to limit the infant’s drug exposure, or to wean the infant off breast-milk altogether. Primidone, phenobarbital, and the benzodiazepines are associated with an established risk of drowsiness in breast- fed babies and caution is required. Withdrawal effects may occur in infants if a mother suddenly stops breast-feeding, particularly if she is taking phenobarbital, primidone, or lamotrigine. Focal seizures with or without secondary generalisation Carbamazepine p. 327 and lamotrigine p. 334 are first-line options for treating newly diagnosed focal seizures; oxcarbazepine p. 337, sodium valproate p. 344 and levetiracetam p. 336 may be used if carbamazepine or lamotrigine are unsuitable or not tolerated. If monotherapy is unsuccessful with two of these first-line antiepileptic drugs, adjunctive treatment may be considered. Options for adjunctive treatment include carbamazepine, clobazam p. 353, gabapentin p. 331, lamotrigine, levetiracetam, oxcarbazepine, sodium valproate, or topiramate p. 348. If adjunctive treatment is ineffective or not tolerated, a tertiary epilepsy specialist should be consulted who may consider eslicarbazepine acetate p. 329, lacosamide p. 333, phenobarbital p. 351, phenytoin p. 339, pregabalin p. 341, tiagabine p. 347, vigabatrin p. 349 and zonisamide p. 350. Generalised seizures Tonic-clonic seizures Sodium valproate is the first-line treatment for newly diagnosed generalised tonic-clonic seizures (except in female patients who are premenopausal, see Valproate below). Lamotrigine is the alternative choice if sodium valproate is not suitable, but may exacerbate myoclonic seizures. In those with established epilepsy with generalised tonic-clonic seizures only, lamotrigine or sodium valproate may be prescribed as the first-line treatment. Carbamazepine and oxcarbazepine may also be considered in newly diagnosed and established tonic-clonic seizures, but may exacerbate myoclonic and absence seizures. Clobazam, lamotrigine, levetiracetam, sodium valproate or topiramate may be used as adjunctive treatment if monotherapy is ineffective or not tolerated. Absence seizures Ethosuximide p. 330, or sodium valproate (except in female patients who are premenopausal, see Valproate below), are the drugs of choice in absence seizures and syndromes; lamotrigine is a suitable alternative when ethosuximide and sodium valproate are unsuitable, ineffective or not tolerated. Sodium valproate should be used as the first choice if there is a high risk of generalised tonic-clonic seizures. A combination of any two of these drugs may be used if monotherapy is ineffective. Clobazam, clonazepam p. 354, levetiracetam, topiramate or zonisamide may be considered by a tertiary epilepsy specialist if adjunctive treatment fails. Carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine and vigabatrin are not recommended in absence seizures or syndromes. Myoclonic seizures Myoclonic seizures (myoclonic jerks) occur in a variety of syndromes, and response to treatment varies considerably. Sodium valproate is the drug of choice in newly diagnosed Nervous system myoclonic seizures (except in female patients who are premenopausal, see Valproate below); topiramate and levetiracetam are alternative options if sodium valproate is unsuitable but consideration should be given to the less favourable side-effect profile of topiramate. A combination of two of these drugs may be used if monotherapy is ineffective or not tolerated. If adjunctive treatment fails, a tertiary epilepsy specialist should be consulted and may consider clobazam, clonazepam, zonisamide or piracetam p. 424. Carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine and vigabatrin are not recommended for the treatment of myoclonic seizures. Sodium valproate and levetiracetam are effective in treating the generalised tonic-clonic seizures that coexist with myoclonic seizures in idiopathic generalised epilepsy. Atonic and tonic seizures Atonic and tonic seizures are usually seen in childhood, in specific epilepsy syndromes, or associated with cerebral damage or mental retardation. They may respond poorly to the traditional drugs. Sodium valproate is the drug of choice (except in female patients who are premenopausal, see Valproate below); lamotrigine can be added as adjunctive treatment. If adjunctive treatment is ineffective or not tolerated, a tertiary epilepsy specialist should be consulted, and may consider rufinamide p. 342 or topiramate. Carbamazepine, gabapentin, oxcarbazepine, pregabalin, tiagabine or vigabatrin are not recommended in atonic and tonic seizures. Epilepsy syndromes Some drugs are licensed for use in particular epilepsy syndromes. The epilepsy syndromes are specific types of epilepsy that are characterised according to a number of features including seizure type, age of onset, and EEG characteristics. For more information on epilepsy syndromes in children see BNF for children. Dravet syndrome A tertiary specialist should be involved in decisions regarding treatment of Dravet syndrome. Sodium valproate (except in pregnancy or females of childbearing potential, see Valproate below) or topiramate are first-line treatment options in children with Dravet syndrome. Clobazam or stiripentol p. 347 may be considered as adjunctive treatment in children and adults if first-line treatments are ineffective or not tolerated. Carbamazepine, gabapentin, lamotrigine, oxcarbazepine, phenytoin, pregabalin, tiagabine, and vigabatrin should not be used as they may exacerbate myoclonic seizures. Lennox-Gastaut syndrome A tertiary specialist should be involved in decisions regarding treatment of Lennox-Gastaut syndrome. Sodium valproate is the first-line drug for treating children with Lennox-Gastaut syndrome (except in pregnancy or females of childbearing potential, see Valproate below); lamotrigine can be used as adjunctive treatment in children and adults if sodium valproate is unsuitable, ineffective or not tolerated. If adjunctive treatment is ineffective or not tolerated, rufinamide and topiramate may be considered by tertiary specialists. Carbamazepine, gabapentin, oxcarbazepine, pregabalin, tiagabine, and vigabatrin should not be used. Felbamate [unlicensed] may be used in tertiary specialist centres when all other treatment options have failed. Antiepileptic drugs Carbamazepine and related antiepileptics Carbamazepine is a drug of choice for simple and complex focal seizures and is a first-line treatment option for generalised tonic-clonic seizures. It can be used as adjunctive treatment for focal seizures when monotherapy has been ineffective. It is essential to initiate carbamazepine Nervous system therapy at a low dose and build this up slowly. Carbamazepine may exacerbate tonic, atonic, myoclonic and absence seizures and is therefore not recommended if these seizures are present. Oxcarbazepine is licensed as monotherapy or adjunctive therapy for the treatment of focal seizures with or without secondary generalised tonic-clonic seizures. It can also be considered for the treatment of primary generalised tonic- clonic seizures [unlicensed]. Oxcarbazepine is not recommended in tonic, atonic, absence or myoclonic seizures due to the risk of seizure exacerbation. Eslicarbazepine acetate p. 329 is licensed for adjunctive treatment in adults with focal seizures with or without secondary generalisation. Ethosuximide Ethosuximide p. 330 is a first-line treatment option for absence seizures. It may also be prescribed as adjunctive treatment for absence seizures when monotherapy is ineffective. Ethosuximide is also licensed for myoclonic seizures. Gabapentin and pregabalin Gabapentin p. 331 and pregabalin p. 341 are used for the treatment of focal seizures with or without secondary generalisation. They are not recommended if tonic, atonic, absence or myoclonic seizures are present. Both are also licensed for the treatment of neuropathic pain. Pregabalin is licensed for the treatment of generalised anxiety disorder. Lamotrigine Lamotrigine p. 334 is an antiepileptic drug recommended as a first-line treatment for focal seizures and primary and secondary generalised tonic-clonic seizures. It is also licensed for typical absence seizures in children (but efficacy may not be maintained in all children) and is an unlicensed treatment option in adults if first-line treatments have been unsuccessful. Lamotrigine can also be used as adjunctive treatment in atonic or tonic seizures if first-line treatment has failed [unlicensed]. Myoclonic seizures may be exacerbated by lamotrigine and it can cause serious rashes especially in children; dose recommendations should be adhered to closely. Lamotrigine is used either as sole treatment or as an adjunct to treatment with other antiepileptic drugs. Valproate increases plasma-lamotrigine concentration, whereas the enzyme-inducing antiepileptics reduce it; care is therefore required in choosing the appropriate initial dose and subsequent titration. When the potential for interaction is not known, treatment should be initiated with lower doses, such as those used with valproate. Levetiracetam and brivaracetam Levetiracetam p. 336 is used for monotherapy and adjunctive treatment of focal seizures with or without secondary generalisation, and for adjunctive treatment of myoclonic seizures in patients with juvenile myoclonic epilepsy and primary generalised tonic-clonic seizures. Levetiracetam may be prescribed alone and in combination for the treatment of myoclonic seizures, and under specialist supervision for absence seizures [both unlicensed]. Brivaracetam p. 325 is used as adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalisation. Phenobarbital and primidone Phenobarbital p. 351 is effective for tonic-clonic and focal seizures but may be sedative in adults. It may be tried for atypical absence, atonic, and tonic seizures. Rebound seizures may be a problem on withdrawal. Primidone p. 352 is largely converted to phenobarbital and this is probably responsible for its antiepileptic action. A low initial dose of primidone is essential. Phenytoin Phenytoin p. 339 is licensed for tonic-clonic and focal seizures but may exacerbate absence or myoclonic seizures and should be avoided if these seizures are present. It has a narrow therapeutic index and the relationship between dose and plasma-drug concentration is non-linear; small dosage increases in some patients may produce large increases in plasma concentration with acute toxic side-effects. Similarly, a few missed doses or a small change in drug absorption may result in a marked change in plasma-drug concentration. Monitoring of plasma-drug concentration improves dosage adjustment. When only parenteral administration is possible, fosphenytoin sodium p. 330, a pro-drug of phenytoin, may be convenient to give. Unlike phenytoin (which should only be given intravenously), fosphenytoin sodium may also be given by intramuscular injection. Rufinamide Rufinamide p. 342 is licensed for the adjunctive treatment of seizures in Lennox-Gastaut syndrome. It may be considered by a tertiary specialist for the treatment of refractory tonic or atonic seizures [unlicensed]. Topiramate Topiramate p. 348 can be given alone or as adjunctive treatment in generalised tonic-clonic seizures or focal seizures with or without secondary generalisation. It can be used as adjunctive treatment for seizures associated with Lennox-Gastaut syndrome and for absence, tonic and atonic seizures under specialist supervision [unlicensed]. It can also be considered as an option in myoclonic seizures [unlicensed]. Female patients should be fully informed of the risks related to the use of topiramate during pregnancy and the need to use effective contraception—for further information, see Conception and contraception and Pregnancy in the topiramate drug monograph. Valproate Sodium valproate p. 344 is effective in controlling tonic- clonic seizures, particularly in primary generalised epilepsy. It is a drug of choice in primary generalised tonic-clonic seizures, focal seizures, generalised absences and myoclonic seizures, and can be tried in atypical absence seizures. It is recommended as a first-line option in atonic and tonic seizures. Sodium valproate has widespread metabolic effects and monitoring of liver function tests and full blood count is essential. Because of its high teratogenic potential, valproate must not be used in females of childbearing potential unless the conditions of the Pregnancy Prevention Programme are met and alternative treatments are ineffective or not tolerated. During pregnancy, it must not be used for epilepsy unless it is the only possible treatment. For further information see Important safety information, Conception and contraception, and Pregnancy in the sodium valproate and valproic acid p. 372 drug monographs. Valproic acid (as semisodium valproate) is licensed for acute mania associated with bipolar disorder. Zonisamide Zonisamide p. 350 can be used alone for the treatment of focal seizures with or without secondary generalisation in adults with newly diagnosed epilepsy, and as adjunctive treatment for refractory focal seizures with or without secondary generalisation in adults and children aged 6 years and above. It can also be used under the supervision of a specialist for refractory absence and myoclonic seizures [unlicensed indications]. Benzodiazepines Clobazam p. 353 may be used as adjunctive therapy in the treatment of generalised tonic-clonic and refractory focal seizures. It may be prescribed under the care of a specialist for refractory absence and myoclonic seizures. Clonazepam p. 354 may be prescribed by a specialist for refractory absence and myoclonic seizures, but its sedative side-effects may be prominent. Other drugs Acetazolamide p. 1244, a carbonic anhydrase inhibitor, has a specific role in treating epilepsy associated with menstruation. Piracetam p. 424 is used as adjunctive treatment for cortical myoclonus. Status epilepticus Convulsive status epilepticus Immediate measures to manage status epilepticus include positioning the patient to avoid injury, supporting respiration including the provision of oxygen, maintaining blood pressure, and the correction of any hypoglycaemia. Parenteral thiamine p. 1141 should be considered if alcohol abuse is suspected; pyridoxine hydrochloride p. 1141 should be given if the status epilepticus is caused by pyridoxine hydrochloride deficiency. Seizures lasting longer than 5 minutes should be treated urgently with intravenous lorazepam p. 355 (repeated once after 10 minutes if seizures recur or fail to respond). Intravenous diazepam p. 360 is effective but it carries a high risk of thrombophlebitis (reduced by using an emulsion formulation). Absorption of diazepam from intramuscular injection or from suppositories is too slow for treatment of status epilepticus. Patients should be monitored for respiratory depression and hypotension. Where facilities for resuscitation are not immediately available, diazepam p. 360 can be administered as a rectal solution or midazolam oromucosal solution p. 356 can be given into the buccal cavity. Important If, after initial treatment with benzodiazepines, seizures recur or fail to respond 25 minutes after onset, phenytoin sodium, fosphenytoin sodium p. 330, or phenobarbital sodium should be used; contact intensive care unit if seizures continue. If these measures fail to control seizures 45 minutes after onset, anaesthesia with thiopental sodium p. 354, midazolam, or a non-barbiturate anaesthetic such as propofol p. 1400 [unlicensed indication], should be instituted with full intensive care support. Phenytoin sodium can be given by slow intravenous injection, followed by the maintenance dosage if appropriate. Alternatively, fosphenytoin sodium (a pro-drug of phenytoin), can be given more rapidly and when given intravenously causes fewer injection-site reactions than phenytoin sodium. Although it can also be given intramuscularly, absorption is too slow by this route for treatment of status epilepticus. Doses of fosphenytoin sodium should be expressed in terms of phenytoin sodium. Non-convulsive status epilepticus The urgency to treat non-convulsive status epilepticus depends on the severity of the patient’s condition. If there is incomplete loss of awareness, usual oral antiepileptic therapy should be continued or restarted. Patients who fail to respond to oral antiepileptic therapy or have complete lack of awareness can be treated in the same way as for convulsive status epilepticus, although anaesthesia is rarely needed. Febrile convulsions Brief febrile convulsions need no specific treatment; antipyretic medication (e.g. paracetamol p. 465), is commonly used to reduce fever and prevent further convulsions but evidence to support this practice is lacking. Prolonged febrile convulsions (those lasting 5 minutes or longer), or recurrent febrile convulsions without recovery must be treated actively (as for convulsive status epilepticus). Long-term anticonvulsant prophylaxis for febrile convulsions is rarely indicated. Nervous system Other drugs used for Epilepsy and other seizure disorders Magnesium sulfate, p. 1112 ANTIEPILEPTICS
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Initially 5 mg once daily, then increased in steps
First-line fragment. Read the complete Indications and Dose section above.
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Initially 10 mg daily, then increased to 40 mg
First-line fragment. Read the complete Indications and Dose section above.
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