See 4.8.1 Control of the epilepsies

NICE CG137 recommends drug treatment be individualised according to seizure type, epilepsy syndrome, co-medication and co-morbidity, patient's lifestyle, and the preferences of the person, their family and/or carers as appropriate, see full guidance for further details. In clinical practice the type of seizure can be used to guide treatment choice.

Side effect and interaction profiles should direct the choice of drug for the individual patient.

Different antiepileptic drugs (AEDs) 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. See MHRA Drug Safety Update - Antiepileptic drugs: new advice on switching between different manufacturers' products for a particular drug (November 2013).

Valproate Medicines

Specific information to support adherence to the Valproate Pregnancy Prevention Programme during the Covid-19 pandemic can be found here.

In April 2018 the MHRA issued a strengthened Drug Safety Update for valproate medicines which are now contraindicated in women and girls of childbearing potential unless conditions of Pregnancy Prevention Programme are met and only if other treatments are ineffective or not tolerated, as judged by an experienced specialist. All women and girls (and their parent, caregiver, or responsible person, if necessary) must be fully informed of the risks and the need to avoid exposure to valproate medicines in pregnancy.

• GPs must identify and recall all women and girls who may be of childbearing potential, provide the Patient Guide and check they have been reviewed by a specialist in the last year and are on highly effective contraception.
• Specialists must book in review appointments at least annually with women and girls under the Pregnancy Prevention Programme and re-evaluate treatment as necessary; explain clearly the conditions as outlined in the supporting materials; and complete and sign the Risk Acknowledgement Form — copies of the form must be given to the patient or patient/caregiver/responsible person and sent to their GP.
• See MHRA Drug Safety Update (April 2018) for further details.

See also resources for: contraception for drugs with teratogenic potential, and prescribing in pregnancy and lactation

Starting treatment

• The decision to start anti-epileptic drug (AED) treatment should be made after full discussion of the risks and benefits and should be made between the person with epilepsy (and family/carers as appropriate) and an epilepsy specialist.
• AED therapy should only be started once the diagnosis is confirmed, except in exceptional circumstances.
• AED therapy is generally recommended after a second epileptic seizure. AED therapy can be considered after a first unprovoked seizure in certain circumstances (neurological deficit, EEG shows unequivocal epileptic activity, the risk of a further seizure is considered unacceptable by the individual/carer, brain imaging shows structural abnormality).
• The risk of sudden death in epilepsy (SUDEP) can be minimised by optimising seizure control and being aware of the potential consequences of nocturnal seizures.
• AEDs have been associated with a small increased risk of suicidal thoughts and behaviour; this can occur as early as 1 week after starting treatment. Patients should be advised to seek medical advice if they develop mood changes or suicidal thoughts. Citalopram is an appropriate option for patients with epilepsy requiring an antidepressant. See 4.3.3 Selective serotonin re-uptake inhibitors.

An epilepsy specialist should:

• recommend initiation of appropriate treatment
• plan continuation of treatment
• manage or provide guidance for withdrawal of treatment

Monotherapy

• Monotherapy with a single AED is preferred.
• If treatment with the initial AED is unsuccessful give a different AED (either an alternative first-line or a second-line drug). Increase the second AED to an adequate or maximum tolerated dose
  • if the second AED is helpful, slowly taper off the first AED,
  • if the second AED is unhelpful, taper either the first or second drug, depending on reasons for lack of success (relative efficacy, side effects, tolerability) before starting another drug
• Caution is required when switching AEDs.

Combination therapy

• Review diagnosis of epilepsy and adherence to medication.
• Consider combination therapy when:
  • treatment with two first line AEDs has failed
  • the first well-tolerated drug substantially improves seizure control, but fails to produce seizure freedom at maximal dosage
• The choice of drugs in combination should be matched to the patient's epileptic syndrome or seizure type(s) and should be limited to two or at most three AEDs.
• If the second drug is unhelpful, taper either the first or second drug (depending on relative efficacy, side effects and tolerability) before starting another drug.
• If trials of combination therapy do not bring about worthwhile benefits, revert to the regimen (monotherapy or combination therapy) that has provided the best balance between tolerability and reducing seizure frequency.

Treatment options

NICE CG137 (May 2021 update): treatment recommendations have been amended to take into account MHRA advice on antiepileptic drugs in pregnancy.

See section 4.8 Antiepileptic drugs

Prolonged or repeated seizures in the community

Patients experiencing convulsive seizures which last longer than 5 minutes or three or more seizures in an hour require prompt care and treatment.

Action:

• Remain with the person.
• Protect head during the seizure.
• When seizure stops, check airways, breathing etc.
• If prescribed, treat with either buccal midazolam or rectal diazepam.
• Call emergency services if:
  • the seizure is continuing 5 minutes after the emergency medication has been administered
  • the person has a history of frequent episodes of serial seizures or has convulsive status epilepticus or this is the first episode requiring emergency treatment
  • there are concerns of difficulties monitoring the person's airway, breathing, circulation or other vital signs.

Treatment options see section 4.8 Antiepileptic drugs

• Midazolam buccal liquid
• Diazepam rectal tubes

Whilst Buccolam is not licensed for patients aged 18 years and older, NICE CG137 recommends buccal midazolam as first-line treatment for prolonged or repeated seizures in adults in the community. Rectal diazepam (licensed) may be used if preferred, or if midazolam is not available.

NICE guidance on continuing treatment

Continuing AED therapy should be planned by a specialist. If the management is straightforward, then continuation may be in primary care.

Regular blood level monitoring should only be carried out if clinically indicated, e.g. detection of non-adherence, suspected toxicity, adjustment of phenytoin dose, specific clinical conditions such as organ failure.

Some specific routine blood tests should be conducted; clotting studies before surgery in patients taking valproate, FBC, U&E, LFT, vitamin D and bone metabolism in patients taking enzyme inducing drugs and valproate should be conducted every 2-5 years. Asymptomatic minor abnormalities are not necessarily an indication to change medication.

Available data suggest that long-term use of carbamazepine, phenytoin, primidone and sodium valproate is associated with decreased bone mineral density that may lead to osteopenia, osteoporosis, and increased fractures in at-risk patients. Vitamin D supplementation should be considered for at-risk patients who are taking the above medicines and phenobarbital long-term. Patients taking AEDs should receive dietary and other lifestyle advice to minimise the risk of osteoporosis.

Withdrawing anti-epileptic medication

Appendix H of the full NICE CG137 provides tables for the prognosis of remission of seizures

The decision to withdraw medication should be taken by the individual/carer and the specialist after full discussion of the risks and benefits of withdrawal. Withdrawal should be managed by, or be under the guidance of, the specialist.

NICE guidance on withdrawing AEDs:

• Withdraw one AED at a time, over at least 2 to 3 months
• Withdraw benzodiazepines and barbiturates over ≥ 6 months to prevent withdrawal symptoms and/or seizure recurrence
• Advise patients that if seizures recur during withdrawal to reverse the last dose reduction and seek medical advice

In order to enable informed decisions and choice, and to reduce misunderstandings, women and girls with epilepsy and their partners, as appropriate, must be given accurate information and counselling about contraception, conception, pregnancy, caring for children and breastfeeding, and menopause.

Discuss with women and girls of childbearing potential, and their parents and/or carers if appropriate, the risk of AEDs causing malformations and possible neurodevelopmental impairments in an unborn child. Assess the risks and benefits of treatment with individual drugs. Specific information on valproate medicines and the conclusions from the MHRA review of other key antiepileptic drugs in pregnancy (January 2021) are provided below.

Valproate Medicines

Specific information to support adherence to the Valproate Pregnancy Prevention Programme during the Covid-19 pandemic can be found here.

In April 2018 the MHRA issued a strengthened Drug Safety Update for valproate medicines which are now contraindicated in women and girls of childbearing potential unless conditions of Pregnancy Prevention Programme are met and only if other treatments are ineffective or not tolerated, as judged by an experienced specialist. All women and girls (and their parent, caregiver, or responsible person, if necessary) must be fully informed of the risks and the need to avoid exposure to valproate medicines in pregnancy.

• GPs must identify and recall all women and girls who may be of childbearing potential, provide the Patient Guide and check they have been reviewed by a specialist in the last year and are on highly effective contraception.
• Specialists must book in review appointments at least annually with women and girls under the Pregnancy Prevention Programme and re-evaluate treatment as necessary; explain clearly the conditions as outlined in the supporting materials; and complete and sign the Risk Acknowledgement Form — copies of the form must be given to the patient or patient/caregiver/responsible person and sent to their GP.
• See MHRA Drug Safety Update (April 2018) for further details.

The Medicines and Healthcare Products Regulatory Agency's (MHRA) Toolkit (Pregnancy Prevention Programme) on the risks of valproate medicines in female patients, provides resources to ensure female patients are better informed about the risks of taking valproate medicines during pregnancy.

See also resources for: contraception for drugs with teratogenic potential, and prescribing in pregnancy and lactation

Other antiepileptic medicines

MHRA Drug Safety Update (January 2021): Antiepileptic drugs in pregnancy: updated advice following comprehensive safety review
Risks associated with valproate medicines are addressed above. This review covered other key antiepileptic drugs selected for review on the basis of their place in UK clinical practice.
Summary of key conclusions of 2021 review:

1. Lamotrigine – Studies involving more than 12,000 pregnancies exposed to lamotrigine monotherapy consistently show that lamotrigine at maintenance doses is not associated with an increased risk of major congenital malformations
2. Levetiracetam – Studies involving more than 1,800 pregnancies exposed to levetiracetam do not suggest an increased risk of major congenital malformations
3. For both lamotrigine and levetiracetam, the data on neurodevelopmental outcomes are more limited than those for congenital malformations. The available studies do not suggest an increased risk of neurodevelopmental disorders or delay associated with in-utero exposure to either lamotrigine or levetiracetam; however, the data is inadequate to rule out definitively the possibility of an increased risk
4. For the other key antiepileptic drugs, data show:
   1. an increased risk of major congenital malformations associated with carbamazepine, phenobarbital, phenytoin, and topiramate use during pregnancy. See below for pregabalin (Drug Safety Update, April 2022) and topiramate (Drug Safety Update, July 2022).
   2. the possibility of adverse effects on neurodevelopment of children exposed in utero to phenobarbital and phenytoin
   3. an increased risk of fetal growth restriction associated with phenobarbital, topiramate, and zonisamide use during pregnancy

Actions for prescribers:

1. At initiation and as part of the recommended annual review for patients with epilepsy, specialists should discuss with women the risks associated with antiepileptic drugs and with untreated epilepsy during pregnancy and review their treatment according to their clinical condition and circumstances – we have produced a safety information leaflet to assist with this discussion. There is a separate safety information leaflet for pregabalin.
2. Urgently refer women who are planning to become pregnant for specialist advice on their antiepileptic treatment
3. All women using antiepileptic drugs who are planning to become pregnant should be offered 5mg per day of folic acid before any possibility of pregnancy
4. For lamotrigine, levetiracetam or any antiepileptic drugs that can be used during pregnancy, it is recommended to
   1. use monotherapy whenever possible
   2. use the lowest effective dose (see the safety update for key dose monitoring advice, including for lamotrigine and levetiracetam)
   3. report any suspected adverse effects experienced by the mother or baby to the Yellow Card scheme

Reminder of advice to give to women with epilepsy

1. Do not stop taking antiepileptic drugs without discussing it with your doctor
2. If you are taking an antiepileptic drug and think you may be pregnant, seek urgent medical advice, including urgent referral to your specialist
3. Read the patient information leaflets that accompany your medicines and other information provided by your healthcare professional.

MHRA Drug Safety Update (April 2022): Pregabalin (Lyrica): findings of safety study on risks during pregnancy

1. an observational study of more than 2,700 pregnancies exposed to pregabalin has shown use in the first trimester to be associated with a slightly increased risk of major congenital malformations compared with exposure to no antiepileptic drugs or to lamotrigine or to duloxetine
2. continue to provide counselling to patients using pregabalin on:
   1. the potential risks to an unborn baby (see separate patient safety leaflet)
   2. the need to use effective contraception during treatment
3. continue to avoid use of pregabalin during pregnancy unless clearly necessary and only if the benefit to the patient clearly outweighs the potential risk to the fetus – ensure the patient has a full understanding of the benefits, risks, and alternatives, and is part of the decision-making process
4. Follow the advice for prescribers of antiepileptic drugs under the 2021 MHRA safety review, click here and see above.

MHRA Drug Safety Update (July 2022): Topiramate (Topamax): start of safety review triggered by a study reporting an increased risk of neurodevelopmental disabilities in children with prenatal exposure

1. A new safety review has been triggered by a large observational study reporting that prenatal exposure to topiramate is associated with an increased risk of autism spectrum disorders, intellectual disability, and neurodevelopmental disorders
2. Ensure any patients of childbearing potential know to use highly effective contraception throughout treatment with topiramate
3. Counsel patients on the importance of avoiding pregnancy during topiramate use due to these emerging data and also the established increased risks of major congenital malformations and fetal growth restriction in babies exposed to topiramate in-utero
4. Topiramate may reduce the effectiveness of steroidal contraceptives, including oral contraceptives, therefore consider alternative or concomitant methods. See the Drug Safety Update for advice
5. For epilepsy, urgently refer anyone on topiramate who is planning a pregnancy or who is pregnant for specialist advice on their antiepileptic treatment.
6. For advice to give to patients, see the Drug Safety Update.

Contraception

AEDs can interact with hormonal contraceptives; see Contraception Guidance for more information

Epilepsy itself is a condition for which there are no restrictions on the use of contraceptive methods, but restrictions may apply if certain antiepileptic drugs (AEDs) are used.

If a patient is using oral contraception, an AED that does not induce hepatic enzymes is preferable.

Combined hormonal contraceptive (CHC)

When a CHC is given with an enzyme inducing AED the efficiency of the contraceptive is reduced. Other non-hormonal methods of contraception should be used.

AEDs which induce hepatic enzymes

• Carbamazepine
• Eslicarbazepine
• Oxcarbazepine
• Phenobarbitone
• Phenytoin
• Primidone
• Topiramate

Progestogen only contraception (POP)

POP is not recommended for women taking enzyme inducing AEDs.

Progestogen implants are not suitable for women taking enzyme inducing AEDs.

Women started on an enzyme-inducing AED should be advised to use a reliable contraceptive method unaffected by enzyme inducers (e.g. progestogen-only injectable, Cu-IUD, levonorgestrel-releasing intrauterine system or non-hormonal methods).

For advice concerning CHCs and depot progestogens, it is advisable to contact:

• Devon Sexual Health (Barnstaple, Exeter, and Torbay) (electronic referral system available)
  • A patient can self-refer by phoning 0300 303 3989 for a consultation within 24 hours. Please give relevant treatment information to the patient to bring to clinics, i.e. results of previous cultures and any treatments.
• SHiP (Sexual Health in Plymouth)
• See also Drug interactions with hormonal contraception.

See also resources for: contraception for drugs with teratogenic potential, and prescribing in pregnancy and lactation

Pregnancy

All AEDs have potential harmful effects on the unborn child, as does epilepsy. Women and girls with epilepsy need accurate information during pregnancy, and the possibility of status epilepticus and SUDEP should be discussed with all women and girls who plan to stop AED therapy

Pre-conception counselling by a specialist is recommended. To reduce the risk of neural tube defects adequate folate supplements are advised for women before and during pregnancy; to prevent recurrence of neural tube defects, women should receive folic acid 5mg daily. This dose may also be appropriate for women receiving antiepileptic drugs. See section 9.1 Anaemias and some other blood disorders. Those who wish to become pregnant should be referred to an appropriate specialist for advice. Women who become pregnant should be counselled and offered antenatal screening (alpha-fetoprotein measurement and a second trimester ultrasound scan).

Routine injection of vitamin K at birth minimises the risk of neonatal haemorrhage associated with antiepileptics.

The concentration of antiepileptic drugs in the blood can change during pregnancy, particularly in the later stages. The dose of antiepileptics should be monitored carefully during pregnancy and after birth, and adjustments made on a clinical basis.

The care of pregnant women should be shared between the obstetrician and epilepsy specialist. The reporting of the pregnancy to the UK Epilepsy and Pregnancy Register is encouraged (Tel: 0800 389 1248)

Full NICE guidance contains more details of these issues.

The Medicines and Healthcare Products Regulatory Agency's (MHRA) Toolkit (Pregnancy Prevention Programme) on the risks of valproate medicines in female patients, provides resources to ensure female patients are better informed about the risks of taking valproate medicines during pregnancy.

Breastfeeding

Prescribers should consult individual drug advice in the SPC and the BNF (available at https://bnf.nice.org.uk/) when prescribing AEDs for women and girls who are breastfeeding. The decision regarding AED therapy and breastfeeding should be made between the woman or girl and the prescriber, and be based on the risks and benefits of breastfeeding against the potential risks of the drug affecting the child.

See also resources for: contraception for drugs with teratogenic potential, and prescribing in pregnancy and lactation

Patients with epilepsy may drive a motor vehicle (but not a large goods or passenger carrying vehicle) provided that they have been seizure-free for one year or, if subject to attacks only while asleep, have established a 3-year period of asleep attacks without awake attacks. Those affected by drowsiness should not drive or operate machinery.

Anti-epileptics can make patients drowsy or sleepy and cause blurred vision or double vision when starting treatment. Care must be taken if driving or when operating any type of machinery. It is essential that epilepsy as well as sudden disabling attacks of loss, or partial loss, of consciousness is reported to the Driver and Vehicle Authority (DVLA). The DVLA will then make a medical assessment of the illness, asking the patient's doctor(s) where necessary.

For more information, see https://www.gov.uk/epilepsy-and-driving

It is also recommended that the patient informs their insurance company if they are taking these drugs. If they do not, and have an accident, it could affect any insurance cover.