Epilepsy

Prescribing Notes:

• All drugs for control of epilepsy should be initiated by hospital specialists only; initiation can be in secondary care or in primary care on the advice of a specialist.
• Anti-seizure medication should be commenced after two or more clinically definite seizures or after one seizure in a patient with a clearly epileptiform EEG or causative lesion on brain imaging. Treatment may also be considered after a single attack if the risk of a second seizure is considered to be high, discussion with the patient and their preference should be considered.
• If a second seizure occurs before the patient is seen by a specialist then start an appropriate first choice agent. Phone the specialist for advice if required.
• The choice of agent is determined by the epilepsy syndrome, type of seizure, other medication, co-morbidities and the age and sex of the patient.
• Treatment with a single agent is preferred. A combination of drugs may be used in refractory patients.
• In order to minimise side-effects It is essential to initiate anti-epileptic drugs at a low dose and titrate the dose gradually as per BNF.
• When switching patients from one drug to another the dose should be reduced /increased gradually. Seek specialist advice.
• Therapeutic drug monitoring should only be considered in patients where non-compliance or patient toxicity is suspected or when managing drug interactions.
• The effectiveness of hormonal contraceptives may be considerably reduced by some anti-seizure medication. This should be considered when discussing choice of contraception.
• The MHRA have divided anti-epileptic drugs into 3 categories in order to determine whether it is necessary to maintain continuity of supply of a specific manufacturer’s products. See ‘Antiepileptic drugs: new advice on switching between different manufacturers’ products’.
• The following categories relate only to the treatment of epilepsy, it does not apply to the use of these drugs for other indications e.g. mood stabilisation, neuropathic pain.
• If a patient has to be maintained on a particular product this should be prescribed by brand name or the name of the manufacturer should be stated on the prescription.
• In order to maintain continuity of supply, when a specified product is unavailable, pharmacists may dispense a product from a different manufacturer if discussed and agreed with both the prescriber and patient/carer.

Prescribing Notes:

• The choice of agent is determined by the type of seizure, age and sex of patient, potential side-effects, co-morbidities and patient preference.
• Consider all other suitable therapeutic options before newly prescribing valproate in all patients (male and female) younger than 55 years.
• Sodium valproate should not be used in any individual of childbearing potential unless other treatments are ineffective or not tolerated, including in young females below the age of puberty.
• Sodium valproate must not be used in any female able to have children unless patient has a pregnancy prevention programme in place. This includes the completion of a signed risk acknowledgement form for female patients starting valproate and at annual review.
• Sodium valproate is contraindicated for epilepsy during pregnancy unless there is no other effective treatment available.
• Refer to MHRA guidance on valproate.
• Where valproate is used in male patients, refer to recommendations for valproate use in men: as a precaution, men and their partners should use effective contraception - MHRA Drug Safety Update 5 Sept 24. This includes the completion of a signed risk acknowledgement form for male patients starting valproate. 
• To obtain risk materials for a specific brand of valproate, including pregnancy prevention materials, see external links to the eMC (SPC & patient leaflets) found next to the medicines choices above or access the eMC website valproate search and click on “Risk Materials” next to that medicine.
• Different AED preparations may vary in bioavailability. The MHRA (November 2013) provides clear information on which products should be maintained and which are suitable for changing to generic.
• However, SIGN 143 recommends that wherever possible, patients should not routinely be switched between different manufacturers of anti-seizure medication.
• The requirement for anti-seizure medication treatment should be made by an expert in epilepsy in conjunction with the patient. Information on first seizure clinic in NHS Lothian can be found on local intranet pages or RefHelp, information from NHS Fife is available here (logon required) and for NHS Borders please see local information. 
• Anti-seizure medications which induce hepatic enzymes may impair the efficacy of hormonal contraceptives.
• To minimise the risk of contraceptive failure a female using a combined hormonal contraceptive or a progesterone only pill, should be prescribed an anti-seizure medication that does not induce hepatic enzymes; see table on page 31 of SIGN 143 and the Contraception section in the Obstetrics, gynaecology, and urinary-tract disorders of this formulary.
• The dose of lamotrigine may need to be adjusted in females who start or stop hormonal contraceptives; see Summary of Product Characteristics.
• All anti-seizure medication carry a risk of teratogenicity. Increasing the number of drugs increases the risk; ideally, females planning to conceive should use adequate contraception until on monotherapy. See Treatment of epilepsy in pregnancy pathway.
• If first choice agent fails at maximum tolerated dose, gradually change over to another first/second choice medicine. If monotherapy fails, a combination of medicines may be tried i.e. monotherapy with 2 different anti-seizure medications has failed.
• The use of drugs in combination should where possible be limited to 2 or 3 anti-seizure medications.
• Therapy should be reviewed early to assess seizure control, compliance, adverse effects.
• Gradual withdrawal of anti-seizure medications may be considered after 2 years free of seizures but note implications for driving. Specialist advice should be sought. Withdraw drugs slowly over a few months.

Prescribing Notes:

• The choice of agent is determined by the type of seizure, age and sex of patient, potential side-effects, co-morbidities and patient preference.
• Different AED preparations may vary in bioavailability. The MHRA (November 2013) provides clear information on which products should be maintained and which are suitable for changing to generic.
• The requirement for anti-seizure medication treatment should be made by an expert in epilepsy in conjunction with the patient. Information on first seizure clinic in NHS Lothian can be found on RefHelp, information from NHS Fife is available here (logon required) and for NHS Borders please see local information.
• Anti-seizure medications which induce hepatic enzymes may impair the efficacy of hormonal contraceptives.
• To minimise the risk of contraceptive failure a female using a combined hormonal contraceptive or a progesterone only pill, should be prescribed an anti-seizure medication that does not induce hepatic enzymes; see table on page 31 of SIGN 143 and the Contraception section in the Obstetrics, gynaecology, and urinary-tract disorders of this formulary.
• The dose of lamotrigine may need to be adjusted in females who start or stop hormonal contraceptives; see Summary of Product Characteristics.
• All anti-seizure medications carry a risk of teratogenicity. Increasing the number of drugs increases the risk; ideally, females planning to conceive should use adequate contraception until on monotherapy. See Treatment of epilepsy in pregnancy pathway.
• Dose-related adverse effects of carbamazepine may be reduced by using the modified-release formulation.
• Carbamazepine liquid (like the plain tablets) is usually given in two or three divided doses. If giving doses higher than 400mg/day it is recommended to divide the daily dose into 4 equal doses. Doses>800mg/day of liquid may cause bloating due to the sorbitol content.
• Carbamazepine liquid will produce higher peak levels than the same dose in tablet form. This can sometimes cause side effects if the frequency of dosing is not adjusted when switching from tablets to the liquid. However, no problems are anticipated if the patient is switched from the liquid (given twice daily) to tablets. In theory tablets should be better tolerated and provide the same control.
• If first choice agent fails at maximum tolerated dose, gradually change over to another first/second choice medicine. If monotherapy fails, a combination of medicines may be tried i.e. monotherapy with 2 different anti-seizure medications has failed.
• The use of drugs in combination should where possible be limited to 2 or 3 anti-seizure medications.
• Routine plasma drug level monitoring is unnecessary.
• Therapy should be reviewed early to assess seizure control, compliance, adverse effects.
• Gradual withdrawal of anti-seizure medication may be considered after 2 years free of seizures but note implications for driving. Specialist advice should be sought. Withdraw drugs slowly over a few months.

Prescribing Notes:

Generalised, convulsive status epilepticus refers to five or more minutes of continuous seizures, or two or more discrete seizures between which there is incomplete recovery of consciousness. Achieving seizure control quickly is a major determinant of good outcome.

The priority in status epilepticus management is to achieve rapid termination of seizures, regardless of the agent used.

Where possible, treatment should be initiated in the community prior to hospital. A possible underlying cause (e.g. hypoglycaemia, hypoxia etc) must be considered.

Note that where the term ‘seizure’ is used in this therapeutic pathway it refers to a ‘a focal to bilateral tonic-clonic seizure’ – a seizure that starts in one area of the brain, then spreads to both sides of the brain as a tonic-clonic seizure. This term replaces ‘secondarily generalized seizure’.

• Treatment should be given if convulsion lasts longer than 5 minutes.
• Buccal midazolam, rectal diazepam, intravenous lorazepam or intravenous diazepam can be given by a trained healthcare professional. Choice of drug and route of administration will be dependent on whether or not there is intravenous access.
• Carers may administer buccal midazolam or rectal diazepam where an individual agreed protocol has been drawn up for the patient by the specialist.
• Information regarding training for the administration of buccal midazolam for can be obtained by contacting the epilepsy specialist nurses.
• Note that Epistatus is a different strength to another buccal preparation (Buccolam) and midazolam injection.
• Buccal midazolam should be prescribed by brand name. Care must be taken when prescribing and dispensing this product. Ensure that patients and carers receive the product they are expecting and are familiar with.
• In some cases, rectal paraldehyde may be administered in the community for prolonged seizures, according to individual patient protocol.
• If still fitting at 10 minutes and, if not already in hospital, call an ambulance. A second dose may be given sooner than 10 minutes if resuscitation facilities are available (SIGN 143 advise that a second dose is ideally given in a clinical setting).
• Although SIGN 143 recommends lorazepam injection, this requires refrigeration and may therefore not be suitable for GP use.
• Refer to local guidelines and protocols, for Status Epilepticus NHS Lothian Neurology Protocols (intranet), NHS Fife Protocol (logon required) and NHS Borders Protocol (intranet).
• If convulsion continues beyond 30 minutes (established status epilepticus), patient will need hospitalisation and preferably admission to ITU.
• Clobazam may be prescribed to prevent status epilepticus in patients with a previous history of status or who are known to be at risk if their seizures accelerate or begin to cluster. It may also be prescribed for those whose seizures occur or accelerate at certain times e.g. during menstruation or intercurrent infections. Prescriptions should be endorsed ‘SLS’.

Prescribing Notes:

Generalised, convulsive status epilepticus refers to five or more minutes of continuous seizures, or two or more discrete seizures between which there is incomplete recovery of consciousness. Achieving seizure control quickly is a major determinant of good outcome.

The priority in status epilepticus management is to achieve rapid termination of seizures, regardless of the agent used.

Where possible, treatment should be initiated in the community prior to hospital. A possible underlying cause (e.g. hypoglycaemia, hypoxia etc) must be considered.

Note that where the term ‘seizure’ is used in this therapeutic pathway it refers to a ‘a focal to bilateral tonic-clonic seizure’ – a seizure that starts in one area of the brain, then spreads to both sides of the brain as a tonic-clonic seizure. This term replaces ‘secondarily generalized seizure’.

• Sodium valproate should not be used in any individual of childbearing potential unless other treatments are ineffective or not tolerated, including in young females below the age of puberty.
• Consider other suitable therapeutic options before prescribing valproate in all patients (male and female) younger than 55 years.
• Where intravenous valproate is used in male patients, refer to recommendations for valproate use in men: as a precaution, men and their partners should use effective contraception MHRA Drug Safety Update 5 Sept 24.
• Maintenance doses should not be started in these populations without neurology input, refer to MHRA guidance on valproate. 
• Sodium valproate is contra-indicated for epilepsy during pregnancy unless there is no other effective treatment available.
• To obtain risk materials for a specific brand of valproate, including pregnancy prevention materials see external links to the eMC (SPC & patient leaflets) found next to the medicines choices above or access the eMC website valproate search and click on “Risk Materials” next to that medicine.
• Refer to local guidelines and protocols, for Status Epilepticus NHS Lothian Neurology Protocols (intranet), NHS Fife Protocol (logon required) and NHS Borders Protocol (intranet). 
• Sodium valproate is first choice in severe renal failure. Use alternative where possible in acute liver failure or if there are concerns about mitochondrial disease.
• Refer to hospital guideline for preparation and administration instructions for the off-label sodium valproate and levetiracetam doses for established status epilepticus approved for use.

Prescribing Notes:

• All medicines in this pathway are for specialist initiation refer to local and national guidance including MHRA drug safety updates and SMC approvals for further guidance. External links to the Scottish Medicines Consortium, BNF and eMC (SPC & patient leaflets) and drug interaction checker can be found next to the medicines choices above.
• The choice of agent is determined by the type of seizure, age and sex of patient, potential side-effects, co-morbidities and patient preference.
• Topiramate is contraindicated in pregnancy and in any individual of childbearing potential unless the conditions of a Pregnancy Prevention Programme are fulfilled. This follows a review by the MHRA which concluded that the use of topiramate during pregnancy is associated with significant harm to the unborn child. Harms included a higher risk of congenital malformation, low birth weight and a potential increased risk of intellectual disability, autistic spectrum disorder and attention deficit hyperactivity disorder in children of mothers taking topiramate during pregnancy. 
• See MHRA guidance topiramate safety measures.

Prescribing Notes:

• Refer to SIGN Guideline 143 'Diagnosis and management of epilepsy in adults' and RCOG Epilepsy in Pregnancy (Green-top Guideline No. 68) for specialist advice.
• The MHRA issued strengthened safety advice regarding sodium valproate and use in any individual of childbearing potential. The MHRA guidance should be referred to for full information. Sodium valproate should not be prescribed to any individual of childbearing potential or pregnant females unless other treatments are ineffective or not tolerated.     
• Prescribers must consider all other suitable therapeutic options before newly prescribing valproate in patients younger than 55 years. 
• When choosing to prescribe Valproate, 2 specialists should independently consider and document that there is no other effective or tolerated treatment for all patients aged under 55 years. 
• Females should be advised to obtain medical advice before a planned pregnancy. Females with epilepsy (on anti-seizure medication or with a family history of neural tube defects or BMI>30) should take folic acid 5mg daily in the pre-conception period and for at least the first 12 weeks of pregnancy.
• Females with epilepsy who are planning to become pregnant should be offered referral to the epilepsy service for advice regarding their current anticonvulsant therapy.
• All anti-seizure medication carries a risk of teratogenicity. Increasing the number of drugs increases the risk; ideally, females planning to conceive should use adequate contraception until on monotherapy.
• Topiramate is contraindicated in pregnancy and in any individual of childbearing potential unless the conditions of a Pregnancy Prevention Programme are fulfilled. This follows a review by the MHRA which concluded that the use of topiramate during pregnancy is associated with significant harm to the unborn child. Harms included a higher risk of congenital malformation, low birth weight and a potential increased risk of intellectual disability, autistic spectrum disorder and attention deficit hyperactivity disorder in children of mothers taking topiramate during pregnancy. 
• See MHRA guidance topiramate safety measures. 
• To obtain risk materials including pregnancy prevention materials for a specific brand of topiramate, see external links to the eMC (SPC & patient leaflets) found next to the medicines choices above or access the eMC website topiramate search and click on “Risk Materials” next to that medicine.
• All infants born to mothers taking hepatic enzyme-inducing anti-epileptic drugs (e.g. carbamazepine, phenobarbital, phenytoin, topiramate) should receive vitamin K1 1mg intramuscularly at birth. If there are additional risk factors for haemorrhagic disease of the newborn (e.g. females receiving hepatic enzyme-inducing anti-epileptic drugs plus maternal liver disease, anticipated premature delivery and bleeding), oral vitamin K1 should also be given in the last month of pregnancy. It is recommended that these females should take water soluble oral vitamin K, 10mg daily.

Prescribing Notes:

• The Commission on Human Medicines (CHM) has issued advice on prescribing of antiepileptic drugs (AEDs). These drugs have been classified into three categories to help prescribers and patients decide whether it is necessary to maintain continuity of supply of a specific manufacturer’s product. Further details can be found on the MHRA website See ‘Antiepileptic drugs: new advice on switching between different manufacturers’ products’:
  
  • Category 1 – Phenytoin, carbamazepine, phenobarbital, primidone – maintain patient on a specific manufacturer’s product.
  • Category 2 – Valproate, lamotrigine, perampanel, retigabine, rufinamide, clobazam, clonazepam, oxcarbazepine, eslicarbazepine, zonisamide, topiramate – the need for continued supply of a particular manufacturer’s product should be based on clinical judgement and consultation with patient and/or carer taking into account factors such as seizure frequency and treatment.
  • Category 3 – Levetiracetam, lacosamide, tiagabine, gabapentin, pregabalin, ethosuximide, vigabatrin – usually unnecessary to ensure that patients are maintained on a specific manufacturer’s product unless there are specific concerns such as patient anxiety, and risk of confusion or dosing errors.

Additional Prescribing Notes

• All drugs for control of epilepsy should be initiated by hospital specialists only; initiation can be in secondary care or in primary care on the advice of a specialist.
• Children should be referred to a specialist following the first seizure (some children will have been referred to A&E at the time of the seizure). A correct diagnosis is important since this will govern treatment. If a second seizure occurs before referral, then a specialist should be contacted for advice.
• Antiepileptic medication should be considered after two or more clinically definite seizures. Treatment may also be considered after a single attack if the risk of a second seizure is unacceptable. If first choice agent fails at maximum tolerated dose, gradually change over to another first choice agent. If monotherapy fails, a combination of first choice agents may be tried.
• The choice of agent is determined by the epilepsy syndrome, type of seizure, other medication, co-morbidities and the age and sex of the patient.
• Prophylaxis for febrile convulsions should be only on specialist advice.
• The requirement for anti-seizure medication treatment should be made by an expert in epilepsy in conjunction with the patient. Information on first seizure clinic in NHS Lothian can be found on local intranet pages or RefHelp, information from NHS Fife is available here (logon required) and for NHS Borders please refer to paediatrics via the normal route if non urgent or discuss with the on call paediatric consultant in more urgent cases.
• Treatment with a single agent is preferred. A combination of drugs may be used in refractory patients.
• The treatment plan for monitoring, including plasma drug levels, if clinically appropriate, will follow specialist advice.
• Therapy should be reviewed early to assess seizure control, compliance, adverse effects.
• In order to minimise side-effects, it is essential to initiate anti-epileptic drugs at a low dose and titrate the dose gradually as per BNFc.
• Therapy should be reviewed at 2 months to assess adherence, side-effects and seizure control (blood tests if required). If seizures are not controlled and there are no unacceptable side-effects, the maintenance drug dose should be increased.
• Switching patients from one drug to another should be gradual under specialist advice.
• If first choice agent fails at maximum tolerated dose, gradually change over to another first/second choice medicine. If monotherapy fails, i.e., monotherapy with 2 different anti-seizure medications has failed, a combination of medicines may be tried.
• The use of drugs in combination should, where possible, be limited to 2 or 3 anti-seizure medications.
• If a patient has to be maintained on a particular product this should be prescribed by brand name or the name of the manufacturer should be stated on the prescription.
• Different AED preparations may vary in bioavailability. The MHRA (November 2013) provides clear information on which products should be maintained and which are suitable for changing to generic.
• However, SIGN 143 recommends that wherever possible, patients should not routinely be switched between different manufacturers of anti-seizure medication.
• In order to maintain continuity of supply, when a specified product is unavailable, pharmacists may dispense a product from a different manufacturer if discussed and agreed with both the prescriber and patient/carer.
• Liquid formulations of antiepileptic drugs are sometimes available in several strengths. The dose should therefore be prescribed in ‘milligrams’ instead of ‘millilitres’. Sugar free formulations should be chosen where available.
• Liver dysfunction, particularly hepatic encephalopathy, has been associated with valproate especially in children under 3 years of age. See BNF-C.
• Anti-seizure medications which induce hepatic enzymes may impair the efficacy of hormonal contraceptives.
• To minimise the risk of contraceptive failure, females using a combined hormonal contraceptive or a progesterone only pill, should be prescribed an anti-seizure medication that does not induce hepatic enzymes; see table on page 31 of SIGN 143 and the Contraception section in the Obstetrics, gynaecology, and urinary-tract disorders of this formulary.
• All anti-seizure medications carry a risk of teratogenicity. Increasing the number of drugs increases the risk; ideally, females planning to conceive should use adequate contraception until on monotherapy. See Treatment of epilepsy in pregnancy pathway.
• Females of childbearing potential must use highly effective contraception if they are able to become pregnant.
• Any individual of childbearing potential should discuss with a specialist the impact of both epilepsy and treatment (in particular those taking sodium valproate or topiramate) on the outcome of pregnancy.
• Note some antiepileptic drugs may affect the efficacy of hormonal contraception. Advice on interactions is available in BNF or Faculty for Sexual and Reproductive Health.
• Topiramate is contraindicated in pregnancy and in any individual of childbearing potential unless the conditions of a Pregnancy Prevention Programme are fulfilled. This follows a review by the MHRA which concluded that the use of topiramate during pregnancy is associated with significant harm to the unborn child. Harms included a higher risk of congenital malformation, low birth weight and a potential increased risk of intellectual disability, autistic spectrum disorder and attention deficit hyperactivity disorder in children of mothers taking topiramate during pregnancy. 
• See MHRA guidance topiramate safety measures. 
• Levetiracetam may be a preferable choice for females of childbearing potential as it is not associated with teratogenicity or interaction with hormonal contraception.
• MHRA/CHM advice: Antiepileptic drugs in pregnancy: updated advice following comprehensive safety review (January 2021) noted valproate, in particular, is highly teratogenic and evidence supports that use in pregnancy leads to congenital malformations (approximately 10% risk) and neurodevelopmental disorders (approximately 30-40% risk).
• A retrospective observational study has indicated a possible association between valproate use in males around the time of conception and an increased risk of neurodevelopmental disorders in their children.
• See MHRA guidance valproate safety measures.
• Specialists should discuss the risks associated with antiepileptic drugs and untreated epilepsy during pregnancy with female patients when initiating treatment and during annual reviews; a safety information leaflet is available to aid discussion. Treatment should be reviewed according to the patient’s clinical condition and circumstance. Female patients should be advised not to stop their antiepileptic treatment without discussing this with their doctor, and to seek urgent medical advice if they are on antiepileptic drugs and think they could be pregnant. Those who are planning a pregnancy should be urgently referred to a specialist for advice on antiepileptic treatment and offered folic acid.
• With any antiepileptic drug used during pregnancy, monotherapy and use of the lowest effective dose are recommended where possible. Plasma concentrations of antiepileptic drugs (particularly lamotrigine and phenytoin) can be affected by physiological changes during pregnancy and post-partum.
• All pregnant females with epilepsy, whether taking medication or not, should be encouraged to notify the UK Epilepsy and Pregnancy Register.
• Young females taking antiepileptic monotherapy should generally be encouraged to breast-feed; if a female is on combination therapy or if there are other risk factors, such as premature birth, close monitoring is recommended. Patients and their family should be made aware of signs of toxicity in the infant and advised to seek medical advice if these occur.
• Lamotrigine has been associated with severe rashes in children.
• Lamotrigine and carbamazepine can make myoclonus worse.
• If phenobarbital is prescribed then an alcohol-free formulation, available as a ‘special’ oral solution 50mg/5mL should be administered. Proprietary brands contain large concentrations of alcohol and are not suitable for administration to children
• Carbamazepine should not be used in individuals of Han Chinese or Thai origin due to issues with the metabolizing capacity of these ethnicities.
• Carbamazepine liquid (like the standard release tablets) is usually given in two or three divided doses. If giving doses higher than 400mg/day it is recommended to divide the daily dose into 4 equal doses. Doses>800mg/day of liquid may cause bloating due to the sorbitol content.
• Carbamazepine liquid will produce higher peak levels than the same dose in tablet form. This can sometimes cause side effects if the frequency of dosing is not adjusted when switching from tablets to the liquid. However, no problems are anticipated if the patient is switched from the liquid (given twice daily) to tablets. In theory tablets should be better tolerated and provide the same control. Standard release carbamazepine tablets are used initially to optimise carbamazepine dose and change is then made to the modified release preparation. Gradual withdrawal of anti-seizure medication may be considered after 2 years free of seizures but note implications for driving. Specialist advice should be sought. Withdraw drugs slowly over a few months.
• The MHRA has recommended that children and their parents or carers should be advised to seek medical advice if any mood changes, distressing thoughts, or feelings about suicide or self-harming develop, and that the child should be referred for appropriate treatment if necessary. They should also be advised not to stop or switch antiepileptic treatment and to seek advice from a healthcare professional if concerned. MHRA/CHM advice: Antiepileptics: risk of suicidal thoughts and behaviour (August 2008).
• 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 acetate, 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 child should not be re-exposed, and expert advice should be sought.

Prescribing Notes:

• Prior to starting valproate, 2 specialists should independently consider and document that there is no other effective or tolerated treatment for all patients (male and female) aged under 55 years, or there are compelling reasons that the reproductive risks do not apply.
• Consider all other suitable therapeutic options before newly prescribing valproate in all patients (male and female) younger than 55 years.
• Sodium valproate should never be started in any females unless alternative treatments are not suitable, including in young females below the age of puberty. 
• Sodium valproate must not be used in any female able to have children unless patient has a pregnancy prevention programme in place. This includes the completion of a signed risk acknowledgement form for female patients starting valproate and at annual review.
• Sodium valproate is contraindicated for epilepsy during pregnancy unless there is no other effective treatment available.
• A retrospective observational study has indicated a possible associated between valproate use in males around the time of conception and an increased risk of neurodevelopmental disorders in their children. As a precaution, male patients taking valproate and their partners are recommended to use effective contraception during valproate treatment and for at least 3 months after stopping valproate. When the decision is taken to initiate valproate in male patients, a signed risk acknowledgement form for male patients must be completed. 
• See MHRA guidance valproate safety measures.
• To obtain risk materials including pregnancy prevention materials for a specific brand of valproate, see external links to the eMC (SPC & patient leaflets) found next to the medicines choices above or access the eMC website valproate search and click on "Risk Materials" next to that medicine.
• The MHRA has recommended that children and their parents or carers should be advised to seek medical advice if any mood changes, distressing thoughts, or feelings about suicide or self-harming develop, and that the child should be referred for appropriate treatment if necessary. They should also be advised not to stop or switch antiepileptic treatment and to seek advice from a healthcare professional if concerned.
• The Commission on Human Medicines (CHM) has issued advice on prescribing of antiepileptic drugs (AEDs). These drugs have been classified into three categories to help prescribers and patients decide whether it is necessary to maintain continuity of supply of a specific manufacturer’s product. Further details can be found on the MHRA website See ‘Antiepileptic drugs: new advice on switching between different manufacturers’ products’:
  
  • Category 1 – Phenytoin, carbamazepine, phenobarbital, primidone – maintain patient on a specific manufacturer’s product.
  • Category 2 – Valproate, lamotrigine, perampanel, retigabine, rufinamide, clobazam, clonazepam, oxcarbazepine, eslicarbazepine, zonisamide, topiramate – the need for continued supply of a particular manufacturer’s product should be based on clinical judgement and consultation with patient and/or carer taking into account factors such as seizure frequency and treatment.
  • Category 3 – Levetiracetam, lacosamide, tiagabine, gabapentin, pregabalin, ethosuximide, vigabatrin – usually unnecessary to ensure that patients are maintained on a specific manufacturer’s product unless there are specific concerns such as patient anxiety, and risk of confusion or dosing errors.

Prescribing Notes:

• Prior to starting valproate, 2 specialists should independently consider and document that there is no other effective or tolerated treatment for all patients (male and female) aged under 55 years, or there are compelling reasons that the reproductive risks do not apply.
• Consider all other suitable therapeutic options before newly prescribing valproate in all patients (male and female) younger than 55 years. 
• Young females of childbearing potential should discuss with a specialist the impact of both epilepsy and treatment (in particular those taking sodium valproate) on the outcome of pregnancy. Note some antiepileptics may affect the efficacy of hormonal contraception. Advice on interactions is available in BNF or Faculty for Sexual and Reproductive Health.
• Valproate should never be started in any female unless alternative treatments are not suitable, including in young females below the age of puberty.
• Valproate must not be used in any female able to have children unless patient has a pregnancy prevention programme in place. This includes the completion of a signed risk acknowledgement form for female patients starting valproate and at annual review.
• Females with childbearing potential must use highly effective contraception if they are able to become pregnant.
• Valproate is contra-indicated for epilepsy during pregnancy unless there is no other effective treatment available.
• A retrospective observational study has indicated a possible associated between valproate use in males around the time of conception and an increased risk of neurodevelopmental disorders in their children. As a precaution, male patients taking valproate and their partners are recommended to use effective contraception during valproate treatment and for at least 3 months after stopping valproate. Where the decision is taken to initiate valproate in male patients, a signed risk acknowledgement form for male patients must be completed.
• See MHRA guidance valproate safety measures.
• To obtain risk materials including pregnancy prevention materials for a specific brand of valproate, see external links to the eMC (SPC & patient leaflets) found next to the medicines choices above or access the eMC website valproate search and click on the "Risk Materials" next to that medicine. 
• Lamotrigine has been associated with severe rashes in children.
• The MHRA has recommended that children and their parents or carers should be advised to seek medical advice if any mood changes, distressing thoughts, or feelings about suicide or self-harming develop, and that the child should be referred for appropriate treatment if necessary. They should also be advised not to stop or switch antiepileptic treatment and to seek advice from a healthcare professional if concerned.
• The Commission on Human Medicines (CHM) has issued advice on prescribing of antiepileptic drugs (AEDs). These drugs have been classified into three categories to help prescribers and patients decide whether it is necessary to maintain continuity of supply of a specific manufacturer’s product. Further details can be found on the MHRA website See ‘Antiepileptic drugs: new advice on switching between different manufacturers’ products’:
  
  • Category 1 – Phenytoin, carbamazepine, phenobarbital, primidone – maintain patient on a specific manufacturer’s product.
  • Category 2 – Valproate, lamotrigine, perampanel, retigabine, rufinamide, clobazam, clonazepam, oxcarbazepine, eslicarbazepine, zonisamide, topiramate – the need for continued supply of a particular manufacturer’s product should be based on clinical judgement and consultation with patient and/or carer taking into account factors such as seizure frequency and treatment.
  • Category 3 – Levetiracetam, lacosamide, tiagabine, gabapentin, pregabalin, ethosuximide, vigabatrin – usually unnecessary to ensure that patients are maintained on a specific manufacturer’s product unless there are specific concerns such as patient anxiety, and risk of confusion or dosing errors.

Prescribing Notes:

• Prior to starting valproate, 2 specialists should independently consider and document that there is no other effective or tolerated treatment for all patients (male and female) aged under 55 years, or there are compelling reasons that the reproductive risks do not apply.
• Consider all other suitable therapeutic options before newly prescribing valproate in all patients (male and female) younger than 55 years.
• Young females of childbearing potential should discuss with a specialist the impact of both epilepsy and treatment (in particular those taking sodium valproate) on the outcome of pregnancy. Note some antiepileptics may affect the efficacy of hormonal contraception. Advice on interactions is available in BNF or Faculty for Sexual and Reproductive Health.
• Valproate should never be started in any female unless alternative treatments are not suitable, including in young females below the age of puberty.
• Valproate must not be used in any female able to have children unless patient has a pregnancy prevention programme in place. This includes the completion of a signed risk acknowledgement form for female patients starting valproate and at annual review.
• Females of childbearing potential must use highly effective contraception if they are able to become pregnant.
• Valproate is contra-indicated for epilepsy during pregnancy unless there is no other effective treatment available.
• A retrospective observational study has indicated a possible association between valproate use in males around the time of conception and an increased risk of neurodevelopmental disorders in their children. As a precaution, male patients taking valproate and their partners are recommended to use effective contraception during valproate treatment and for at least 3 months after stopping valproate. Where the decision is taken to initiate valproate in male patients, a signed risk acknowledgement form for male patients must be completed.
• See MHRA guidance valproate safety measures.
• To obtain risk materials including pregnancy prevention materials for a specific brand of valproate, see external links to the eMC (SPC & patient leaflets) found next to the medicines choices above or access the eMC website valproate search and click on "Risk Materials" next to that medicine. 
• The MHRA has recommended that children and their parents or carers should be advised to seek medical advice if any mood changes, distressing thoughts, or feelings about suicide or self-harming develop, and that the child should be referred for appropriate treatment if necessary. They should also be advised not to stop or switch antiepileptic treatment and to seek advice from a healthcare professional if concerned.
• Carbamazepine should not be used in individuals of Han Chinese or Thai origin due to issues with the metabolizing capacity of these ethnicities.
• Carbamazepine liquid (like the plain tablets) is usually given in two or three divided doses. If giving doses higher than 400mg/day it is recommended to divide the daily dose into 4 equal doses. Doses>800mg/day of liquid may cause bloating due to the sorbitol content.
• Carbamazepine liquid will produce higher peak levels than the same dose in tablet form. This can sometimes cause side effects if the frequency of dosing is not adjusted when switching from tablets to the liquid. However, no problems are anticipated if the patient is switched from the liquid (given twice daily) to tablets. In theory tablets should be better tolerated and provide the same control.
• Standard release carbamazepine tablets are used initially to optimise carbamazepine dose and change is then made to the modified release preparation.
• The Commission on Human Medicines (CHM) has issued advice on prescribing of antiepileptic drugs (AEDs). These drugs have been classified into three categories to help prescribers and patients decide whether it is necessary to maintain continuity of supply of a specific manufacturer’s product. Further details can be found on the MHRA website See ‘Antiepileptic drugs: new advice on switching between different manufacturers’ products’:
  
  • Category 1 – Phenytoin, carbamazepine, phenobarbital, primidone – maintain patient on a specific manufacturer’s product.
  • Category 2 – Valproate, lamotrigine, perampanel, retigabine, rufinamide, clobazam, clonazepam, oxcarbazepine, eslicarbazepine, zonisamide, topiramate – the need for continued supply of a particular manufacturer’s product should be based on clinical judgement and consultation with patient and/or carer taking into account factors such as seizure frequency and treatment.
  • Category 3 – Levetiracetam, lacosamide, tiagabine, gabapentin, pregabalin, ethosuximide, vigabatrin – usually unnecessary to ensure that patients are maintained on a specific manufacturer’s product unless there are specific concerns such as patient anxiety, and risk of confusion or dosing errors.

Prescribing Notes:

General Prescribing Notes

• Generalised, convulsive status epilepticus refers to five or more minutes of continuous seizures, or two or more discrete seizures between which there is incomplete recovery of consciousness. Achieving seizure control quickly is a major determinant of good outcome.
• The priority in status epilepticus management is to achieve rapid termination of seizures, regardless of the agent used.
• Where possible, treatment should be initiated in the community prior to hospital. A possible underlying cause (e.g. hypoglycaemia, hypoxia etc) must be considered.
• Follow the Advanced Paediatric Life Support (APLS) guideline and refer to local guidelines and protocols.
• Note that where the term ‘seizure’ is used in this therapeutic pathway it refers to a ‘a focal to bilateral tonic-clonic seizure’ – a seizure that starts in one area of the brain, then spreads to both sides of the brain as a tonic-clonic seizure. This term replaces ‘secondarily generalized seizure’.
• Treatment should be given if convulsion lasts longer than 5 minutes. Buccal midazolam is an alternative to rectal diazepam. This drug should be given by a trained healthcare professional or carer, according to the individually agreed protocol drawn up for the patient by the specialist.
• In some cases, rectal paraldehyde may be administered in the community for prolonged seizures, according to individual patient protocol.
• If still fitting at 10 minutes and, if not already in hospital, call an ambulance. A second dose may be given sooner than 10 minutes if resuscitation facilities are available (SIGN 143 advise that a second dose is ideally given in a clinical setting).
• IV lorazepam can be used if there is vascular access.
• Although SIGN 143 recommends lorazepam injection, this requires refrigeration and may therefore not be suitable for GP use.
• If convulsion continues beyond 30 minutes (established status epilepticus), patient will need hospitalisation and preferably admission to ITU.
• Clobazam may be prescribed to prevent status epilepticus in patients with a previous history of status or who are known to be at risk if their seizures accelerate or begin to cluster. It may also be prescribed for those whose seizures occur or accelerate at certain times e.g. during menstruation or intercurrent infections. Prescriptions should be endorsed ‘SLS’.

Midazolam

• Buccal midazolam should be prescribed by brand name. Care must be taken when prescribing and dispensing this product. Ensure that patients and carers receive the product they are expecting and are familiar with. Please check the information provided with patient correspondence to confirm the product requested, as this will reflect the product the patient/carer has been counselled to use.
• Midazolam 10mg/ml oromucosal solution (5ml) Veriton Pharma Ltd or as the brand, Epistatus 50mg/5ml oromucosal solution bottle (Veriton Pharma Ltd) is the preparation supplied by Royal Hospital for Children and Young People (RHCYP) on discharge. Information regarding training for the administration of buccal midazolam can be obtained by contacting the epilepsy specialist nurses. See NHS Lothian Teaching Guideline On Administering Buccal Midazolam (NHS Lothian intranet).
• Information for General Practitioners & Community Pharmacists in NHS Lothian: Epistatus 50mg/5ml oromucosal solution bottle (Veriton Pharma Ltd) or Midazolam Oromucosal Liquid 10mg in 1 ml (5ml bottle) can be found by ticking the specials box on GP prescribing systems (include additional notes to the dispenser to supply the product manufactured by Veriton Pharma Ltd).
• NHS Borders and NHS Fife may supply the Epistatus prefilled syringes on discharge according to the individual seizure plan which has been agreed. Information regarding training for the administration of buccal midazolam can be obtained by contacting the epilepsy specialist nurses.
• Epistatus prefilled syringes are not graduated/marked and can only be used to deliver the total dose contained in the prefilled syringe.
• Note that Epistatus is a different strength to another buccal preparation (Buccolam) and midazolam injection.

Prescribing Notes:

• Generalised, convulsive status epilepticus refers to five or more minutes of continuous seizures, or two or more discrete seizures between which there is incomplete recovery of consciousness. Achieving seizure control quickly is a major determinant of good outcome.
• The priority in status epilepticus management is to achieve rapid termination of seizures, regardless of the agent used.
• Where possible, treatment should be initiated in the community prior to hospital. A possible underlying cause (e.g. hypoglycaemia, hypoxia etc) must be considered.
• Note: that where the term ‘seizure’ is used in this therapeutic pathway it refers to a ‘a focal to bilateral tonic-clonic seizure’ – a seizure that starts in one area of the brain, then spreads to both sides of the brain as a tonic-clonic seizure. This term replaces ‘secondarily generalized seizure’.

Prescribing Notes:

• The choice of agent is determined by the type of seizure, age and sex of patient, potential side-effects, co-morbidities and patient preference.
• Everolimus dispersible tablets (Votubia) are SMC approved (June 2018) for the adjunctive treatment of patients aged 2 years and older whose refractory partial-onset seizures, with or without secondary generalisation, are associated with tuberous sclerosis complex.
• Topiramate is contraindicated in pregnancy and in any individual of childbearing potential unless the conditions of a Pregnancy Prevention Programme are fulfilled. This follows a review by the MHRA which concluded that the use of topiramate during pregnancy is associated with significant harm to the unborn child. Harms included a higher risk of congenital malformation, low birth weight and a potential increased risk of intellectual disability, autistic spectrum disorder and attention deficit hyperactivity disorder in children of mothers taking topiramate during pregnancy. 
• See MHRA guidance topiramate safety measures. 
• To obtain risk materials including pregnancy prevention materials for a specific brand of topiramate, see external links to the eMC (SPC & patient leaflets) found next to the medicines choices above or access the eMC website topiramate search and click on “Risk Materials” next to that medicine. 
• The MHRA has recommended that children and their parents or carers should be advised to seek medical advice if any mood changes, distressing thoughts, or feelings about suicide or self-harming develop, and that the child should be referred for appropriate treatment if necessary. They should also be advised not to stop or switch antiepileptic treatment and to seek advice from a healthcare professional if concerned.
• The Commission on Human Medicines (CHM) has issued advice on prescribing of antiepileptic drugs (AEDs). These drugs have been classified into three categories to help prescribers and patients decide whether it is necessary to maintain continuity of supply of a specific manufacturer’s product. Further details can be found on the MHRA website See ‘Antiepileptic drugs: new advice on switching between different manufacturers’ products’:
  
  • Category 1 – Phenytoin, carbamazepine, phenobarbital, primidone – maintain patient on a specific manufacturer’s product.
  • Category 2 – Valproate, lamotrigine, perampanel, retigabine, rufinamide, clobazam, clonazepam, oxcarbazepine, eslicarbazepine, zonisamide, topiramate – the need for continued supply of a particular manufacturer’s product should be based on clinical judgement and consultation with patient and/or carer taking into account factors such as seizure frequency and treatment.
  • Category 3 – Levetiracetam, lacosamide, tiagabine, gabapentin, pregabalin, ethosuximide, vigabatrin – usually unnecessary to ensure that patients are maintained on a specific manufacturer’s product unless there are specific concerns such as patient anxiety, and risk of confusion or dosing errors.