4.8.1 Control of the epilepsies

MHRA Drug Safety Update (November 2017): Antiepileptic drugs: updated advice on switching between different manufacturers' products

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:

  • Category 1: Phenytoin, carbamazepine, phenobarbital, primidone. For these drugs, doctors are advised to ensure that their patient is maintained on a specific manufacturer's product
  • Category 2: Valproate, lamotrigine, perampanel, rufinamide, clobazam, clonazepam, oxcarbazepine, eslicarbazepine, zonisamide, topiramate. 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 and treatment history
  • Category 3: Levetiracetam, lacosamide, tiagabine, gabapentin, pregabalin, ethosuximide, vigabatrin, brivaracetam. For these drugs, it is 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

MHRA Drug Safety Update (November 2017): In addition to the 3 risk-based categories of antiepileptic drugs, patient-related factors should be considered when deciding whether it is necessary to maintain continuity of supply for a specific product. For example; consider patient perception of differences in supply, co-morbid autism, mental health issues, or learning disability.

MHRA Drug Safety Update (January 2021): Antiepileptic drugs in pregnancy: updated advice following comprehensive safety review

Brivaracetam
  • Tablets 10mg, 25mg, 50mg, 75mg, 100mg (25mg-100mg twice daily = £129.64)
  • Oral solution 10mg/ml (25mg-100mg twice daily = £54.05-£216.22)
  • Solution for injection/infusion 10mg/ml (£22.28 per 5ml vial)

Indication

Notes

  1. In clinical studies, there was no observed benefit of brivaracetam versus placebo in patients taking levetiracetam concurrently.
  2. MHRA Category 3: It is usually unnecessary to ensure that patients are maintained on a specific manufacturer's product unless there are specific reasons such as patient anxiety and risk of confusion or dosing errors
  3. The routine commissioning of brivaracetam as an adjunctive treatment for partial-onset (focal) seizures is accepted in Devon (see Commissioning Policy for more details).
Carbamazepine
  • Tegretol tablets 100mg, 200mg, 400mg (£3.83 = 200mg x 84)
  • Tegretol modified release tablets 200mg, 400mg (£5.20 = 56 x 200mg)
  • Tegretol liquid sugar free 20mg/ml (£6.12 = 300ml)
  • Carbamazepine Essential Pharma suppository 125mg, 250mg (£8.03 = 125mg x 5)

Indications

Notes

  1. Prescribe by brand. MHRA Category 1: Doctors are advised to ensure that their patient is maintained on a specific manufacturer's product.
  2. Prescribing by brand name is not needed when prescribing for non-epilepsy conditions
Cenobamate
  • Ontozry tablets 50mg, 100mg, 150mg and 200mg (£182.00 = 200mg x 28)
  • Ontozry treatment initiation pack contains 14 x 12.5mg tablets and 14 x 25mg tablets

Indications

Notes

  1. Treatment to be started in tertiary care (NICE TA753).
    1. If an ECG is clinically indicated before commencing treatment, the specialist is responsible for arranging this. Practices should not be asked to undertake ECGs on behalf of the specialist.
    2. The specialist is responsible for prescribing cenobamate during dose titration and until the patient is established on a stabilised dose. Once stabilised on treatment, a GP may be asked to continue prescribing
  2. Drug reaction with eosinophilia and systemic symptoms (DRESS)
    1. No cases of DRESS were reported when the SmPC starting dose (12.5mg once daily) and titration schedule (dose increment every two weeks) were used in an open-label safety study of 1,340 patients with epilepsy. DRESS can be life-threatening or fatal. Three cases of DRESS were reported within 2 to 4 weeks of starting cenobamate during the development programme but these cases occurred in studies with high starting doses (50 mg or 100 mg once daily) and weekly or faster titration. The recommended titration schedule should not be exceeded.
    2. At the time of prescription, the specialist team should advise the patient of the signs and symptoms of DRESS and to seek immediate medical attention if symptoms develop by contacting the epilepsy specialist nurse and/or their GP. If a GP requires specialist advice and the epilepsy team is not available, a 24-hour on-call neurology consultant can be contacted via the University Hospitals Plymouth switchboard (01752 202082).
    3. Symptoms of DRESS include typically, although not exclusively, fever, rash associated with other organ system involvement, lymphadenopathy, liver function tests abnormalities and eosinophilia. Early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident.
  3. Prescribe by brand. The MHRA has not assigned a category to cenobamate. It is recommended to prescribe by brand in the meantime.
  4. Cenobamate is not recommended in women of childbearing potential not using contraception (Summary of Product Characteristics). The efficacy of hormonal contraceptives may be reduced by concomitant use with cenobamate. Women of reproductive potential concomitantly using oral contraceptives should practice additional or alternative non-hormonal measures of birth control during treatment with cenobamate and until 4 weeks after treatment discontinuation. Cenobamate was licensed in 2021 and is not listed in the current FSRH guidance Drug Interactions with Hormonal Contraceptives (issued 2019). Additional resources can be found here.
  5. For further information, see the Summary of Product Characteristics.
  6. Note for community pharmacies: cenobamate tablets are available to order only though Phoenix.
  7. NICE TA753: Cenobamate (Ontozry) is recommended as an option for treating focal onset seizures with or without secondary generalised seizures in adults with drug-resistant epilepsy that has not been adequately controlled with at least 2 antiseizure medicines (December 2021). It is recommended only if:
    1. it is used as an add-on treatment, after at least 1 other add-on treatment has not controlled seizures, and
    2. treatment is started in a tertiary epilepsy service.
Eslicarbazepine acetate
  • Zebinix tablets 800mg (£136.00 x 30 tablets)

Indications

Notes

  1. MHRA Category 2: 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 and treatment history. If the patient is stable on a particular generic preparation there is no requirement to switch to branded prescribing
Ethosuximide
  • Capsules 250mg (£173.00 = 56 capsules)
  • Syrup 250mg/5ml (£173.00 = 200ml)

Indications

Notes

  1. MHRA Category 3: It is usually unnecessary to ensure that patients are maintained on a specific manufacturer's product unless there are specific reasons such as patient anxiety and risk of confusion or dosing errors
Gabapentin
  • Capsules 100mg, 300mg, 400mg (£3.24 = 100 x 400mg)
  • Tablets 600mg, 800mg (£29.06 = 100 x 800mg)
  • Liquid 50mg/ml

Indications

Notes

  1. MHRA Category 3: It is usually unnecessary to ensure that patients are maintained on a specific manufacturer's product unless there are specific reasons such as patient anxiety and risk of confusion or dosing errors
  2. MHRA Drug Safety Update (October 2017): Be aware of risk of CNS depression, including severe respiratory depression, with gabapentin, and consider whether dose adjustments might be necessary in patients at higher risk of respiratory depression, including:
    1. Elderly people
    2. Patients with compromised respiratory function
    3. Patients with respiratory or neurological disease
    4. Patients with renal impairment
    5. Patients taking other CNS depressants
  3. MHRA Drug Safety Update (April 2019): Pregabalin (Lyrica), gabapentin (Neurontin) and risk of abuse and dependence
    1. evaluate patients carefully for a history of drug abuse and dependence before prescribing pregabalin and gabapentin
    2. observe patients on pregabalin and gabapentin for possible signs of abuse and dependence, for example, drug-seeking behaviour, dose escalation, and development of tolerance
    3. ensure patients are aware of the risk of potentially fatal interactions with other medicines that cause CNS depression, particularly opioid medicines, and with alcohol
Lacosamide
  • Tablets 50mg, 100mg, 150mg, 200mg (£8.77 = 200mg x 56 tablets)
  • Syrup 10mg/1ml (£25.74 = 200ml)
  • Intravenous infusion 10mg/ml 200mg vial

Indications

Notes

  1. MHRA Category 3: It is usually unnecessary to ensure that patients are maintained on a specific manufacturer's product unless there are specific reasons such as patient anxiety and risk of confusion or dosing errors
Lamotrigine
  • Generic lamotrigine tablets 25mg, 50mg, 100mg, 200mg (£1.25 = 200mg daily)
  • Generic lamotrigine dispersible tablets 2mg, 5mg, 25mg, 100mg (£3.57 = 200mg daily)
  • Lamictal tablets 25mg, 50mg, 100mg, 200mg (£58.68 = 200mg daily)
  • Lamictal dispersible tablets 2mg, 5mg, 25mg, 100mg (£69.04 = 200mg daily)

Indications

  • Epilepsy
  • Prevention of depressive episodes associated with bipolar disorder

Notes

  1. The CSM has advised prescribers to be alert for symptoms and signs suggestive of bone-marrow failure such as anaemia, bruising or infection. Aplastic anaemia, bone-marrow depression and pancytopenia have been associated rarely with lamotrigine
  2. MHRA Category 2: In the treatment of epilepsy 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 and treatment history. If the patient is stable on a particular generic preparation there is no requirement to switch to branded prescribing. Prescribing by brand name is not needed when prescribing for non-epilepsy conditions
Levetiracetam
  • Tablets 250mg, 500mg, 750mg, 1g (£5.50 = 1g x 60 tablets)
  • Oral solution sugar free 100mg/ml (£5.33 = 300ml)
  • Granules sugar free sachet 250mg, 500mg, 1g (£76.27 = 1g x 60 sachets)
  • Concentrate for I/V infusion 100mg/ml 5ml vial

Indications

Notes

  1. MHRA Category 3: It is usually unnecessary to ensure that patients are maintained on a specific manufacturer's product unless there are specific reasons such as patient anxiety and risk of confusion or dosing errors
  2. Levetiracetam granules are included for use in paediatric patients who cannot swallow the tablets, and cannot tolerate the oral solution.
Oxcarbazepine
  • Trileptal tablets 150mg, 300mg, 600mg (£48.96 = 600mg x 50 tablets)
  • Trileptal oral suspension sugar free 300mg/5ml (£48.96 = 250ml)

Indications

Notes

  1. MHRA Category 2: 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 and treatment history. If the patient is stable on a particular generic preparation there is no requirement to switch to branded prescribing.
Perampanel
  • Fycompa tablets 2mg, 4mg, 6mg, 8mg, 10mg, 12mg (£140.00 = 28 tablets)

Indications

Notes

  1. Perampanel prescribing must only be passed onto primary care once the patient is titrated and established on a stabilised dose.
  2. MHRA Category 2: 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 and treatment history. If the patient is stable on a particular generic preparation there is no requirement to switch to branded prescribing.
Phenytoin
  • Phenytoin Sodium Flynn hard capsules 25mg, 50mg, 100mg, 300mg (£54.00 = 100mg x 84 capsules)
  • Phenytoin sodium tablets 100mg (£23.00 = 28 tablets)
  • Epanutin infatabs chewable tablets 50mg (scored) (£13.18 = 200)
  • Epanutin suspension 30mg in 5ml (£4.27 = 500ml)
  • Intravenous injection 250mg/5ml
  • Suspension 90mg in 5ml (unlicensed preparation)

Indications

  • Epilepsy
  • Trigeminal neuralgia if carbamazepine inappropriate
  • Status epilepticus

Notes

  1. Phenytoin has a narrow therapeutic index and the relationship between dose and plasma concentration is non-linear; a small dose increase in some patients may produce large rises in plasma concentration with acute toxic side effects.
  2. 90mg of phenytoin (chewable tablets or suspension) is considered to be equivalent to 100mg of phenytoin sodium (capsules or tablets), so care is needed if patients are transferred from one preparation to another.
  3. Prescribe by brand. MHRA Category 1: Doctors are advised to ensure that their patient is maintained on a specific manufacturer's product.
  4. Prescribing by brand name is not needed when prescribing for non-epilepsy conditions
Pregabalin
  • Capsules 25mg, 50mg, 75mg, 100mg, 150mg, 200mg, 225mg, 300mg (£2.29 = 150mg twice daily)
  • Oral solution 20mg/ml (£99.48 = 473ml)

Indications

Notes

  1. Pregabalin capsules have a flat pricing structure so it is most cost-effective to prescribe the least number of capsules to form the required dose and to prescribe twice daily instead of three times daily
  2. Oral solution is only included for people with swallowing difficulties
  3. Public Health England: Practitioners should prescribe pregabalin and gabapentin appropriately to minimise the risks of misuse and dependence, and should be able to identify and manage problems of misuse if they arise. Most patients who are given these drugs will use their medicines appropriately without misuse. Further information click here
  4. MHRA Category 3: It is usually unnecessary to ensure that patients are maintained on a specific manufacturer's product unless there are specific reasons such as patient anxiety and risk of confusion or dosing errors
  5. MHRA Drug Safety Update (April 2019): Pregabalin (Lyrica), gabapentin (Neurontin) and risk of abuse and dependence evaluate patients carefully for a history of drug abuse and dependence before prescribing pregabalin and gabapentin observe patients on pregabalin and gabapentin for possible signs of abuse and dependence, for example, drug-seeking behaviour, dose escalation, and development of tolerance ensure patients are aware of the risk of potentially fatal interactions with other medicines that cause CNS depression, particularly opioid medicines, and with alcohol
  6. MHRA Drug Safety Update (February 2021): Pregabalin (Lyrica): reports of severe respiratory depression.
    1. Pregabalin has been associated with reports of respiratory depression, in some cases without concomitant opioid treatment.
    2. Consider whether adjustments in dose or dosing regimen are necessary for patients at higher risk of respiratory depression, this includes people:
      1. with compromised respiratory function, respiratory or neurological disease, or renal impairment. See BNF or Summary of Product Characteristics for dosing in renal impairment
      2. taking other CNS depressants (including opioid-containing medicines)
      3. aged older than 65 years
    3. Advice to give to patients and carers is included in the safety update
  7. 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 MHRA Drug Safety Update (January 2021): Antiepileptic drugs in pregnancy: updated advice following comprehensive safety review
Rufinamide
  • Inovelon tablets 100mg, 200mg, 400mg (£102.96 = 400mg x 60 tablets)

Indications

Notes

    1. MHRA Category 2: 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 and treatment history. If the patient is stable on a particular generic preparation there is no requirement to switch to branded prescribing.
      Sodium valproate
      • Generic sodium valproate enteric coated tablets 200mg, 500mg (£4.93 = 500mg twice daily)
      • Generic sodium valproate liquid sugar free 200mg/5ml (£5.01 = 300ml)
      • Epilim liquid sugar free 200mg/5ml (£9.33 = 300mg)
      • Epilim Crushable tablets 100mg (£5.60 = 100)
      • Epilim enteric coated tablets 200mg, 500mg (£10.78 = 500mg twice daily)
      • Epilim Chrono modified release tablets 200mg, 300mg, 500mg (£16.30 = 500mg twice daily)
      • Episenta modified release capsules 150mg, 300mg (£13.00 = 300mg x 100)
      • Episenta modified release granules 500mg, 1g (£41.00 = 1g x 100 sachets)
      • Intravenous injection 400mg

        Indications

        Notes

        1. Sodium valproate is not licensed for the treatment of manic episodes associated with bipolar disorder
        2. Episenta has been included for patients with swallowing difficulties
        3. MHRA Category 2: In the treatment of epilepsy 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 and treatment history. If the patient is stable on a particular generic preparation there is no requirement to switch to branded prescribing. Prescribing by brand name is not needed when prescribing for non-epilepsy conditions
        4. Specific information to support adherence to the Valproate Pregnancy Prevention Programme during the Covid-19 pandemic can be found here.
        5. MHRA Drug Safety Update (April 2018): Valproate medicines (Epilim▼, Depakote▼): 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
          1. 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
          2. 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
          3. Use of valproate in pregnancy is contraindicated for bipolar disorder and must only be considered for epilepsy if there is no suitable alternative treatment
        6. 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.
        7. See resources for: contraception for drugs with teratogenic potential, and prescribing in pregnancy and lactation
        Tiagabine
        • Tablets 5mg, 10mg, 15mg (£156.13 = 15mg x 100 tablets)

        Indications

        Notes
        1. MHRA Category 3: It is usually unnecessary to ensure that patients are maintained on a specific manufacturer's product unless there are specific reasons such as patient anxiety and risk of confusion or dosing errors
        Topiramate
        • Generic topiramate tablets 25mg, 50mg, 100mg, 200mg (£13.07 = 400mg daily)
        • Topamax tablets 25mg, 50mg, 100mg, 200mg (£102.88 = 400mg daily)
        • Topamax Sprinkle capsules 15mg, 25mg, 50mg (£34.02 = 100mg daily)
        Indications


        Notes
        1. Topiramate has been associated with acute myopia with secondary angle-closure glaucoma, typically occurring within 1 month of starting treatment. Choroidal effusions resulting in anterior displacement of the lens and iris have also been reported. The CSM advises that if raised intra-ocular pressure occurs to seek specialist ophthalmological advice, to use appropriate measures to reduce intra-ocular pressure and to stop topiramate as rapidly as possible.
        2. MHRA Category 2: In the treatment of epilepsy 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 and treatment history. If the patient is stable on a particular generic preparation there is no requirement to switch to branded prescribing. Prescribing by brand name is not needed when prescribing for non-epilepsy conditions.
        3. See resources for: contraception for drugs with teratogenic potential, and prescribing in pregnancy and lactation
        Zonisamide
        • Zonegran capsules 25mg, 50mg, 100mg (£94.08 = 300mg daily)

          Indications

          Notes

          1. MHRA Category 2: 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 and treatment history. If the patient is stable on a particular generic preparation there is no requirement to switch to branded prescribing.
          Vigabatrin
          • Tablets 500mg
          • Granules for oral solution 500mg

            Notes

            1. Vigabatrin is associated with irreversible retinal toxicity in many patients. The onset of symptoms varies from 1 month to several years after starting. In most cases, visual field defects have persisted despite discontinuation, and further deterioration after discontinuation cannot be excluded. Product literature advises visual field testing before treatment and at 6-month intervals. Patients should be warned to report any new visual symptoms that develop and those with symptoms should be referred for an urgent ophthalmological opinion. Gradual withdrawal of vigabatrin should be considered.
            2. Subsequently, its indications are limited for use in combination therapy only when all other antiepileptic drug combination therapy has proved ineffective or poorly tolerated. It may only be used for monotherapy in infantile spasms (West's syndrome), where it remains first-line therapy. It should only be initiated by an epilepsy specialist.
            3. MHRA Category 3: It is usually unnecessary to ensure that patients are maintained on a specific manufacturer's product unless there are specific reasons such as patient anxiety and risk of confusion or dosing errors

            Barbiturates

            Phenobarbital
            • Tablets 15mg, 30mg, 60mg (£6.03 = 60mg x 28 tablets)
            • Elixir 15mg/5ml, contains alcohol (£83.00 = 500ml)
            • Oral solution 50mg/5ml, alcohol free (unlicensed preparation)
            • Injection 30mg/1ml, 200mg/ml

            Indications

            Notes

            1. Phenobarbital is included in the formulary for patients currently taking this drug. It is not expected that there will be any new initiations of treatment.
            2. Prescribe by brand. MHRA Category 1: Doctors are advised to ensure that their patient is maintained on a specific manufacturer's product.

            Benzodiazepines

            MHRA Drug Safety Update (March 2020): Benzodiazepines and opioids: reminder of risk of potentially fatal respiratory depression.

            • benzodiazepines (and benzodiazepine-like drugs) and opioid medicines (opioids) can both cause respiratory depression; when used together, additive effects on the central nervous system increase the risks of sedation, respiratory depression, coma, and death
              Clobazam
              • Tablets 10mg (£3.42 = 30)
              • Oral suspension 5mg/5ml (£90.00 = 150ml)

              Indications

              Notes

              1. MHRA Category 2: 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 and treatment history. If the patient is stable on a particular generic preparation there is no requirement to switch to branded prescribing.
              Clonazepam
              • Tablets 500 microgram, 2mg (£31.49 = 2mg x 100 tablets)
              • Intravenous injection 1mg/ml or infusion of 1mg
              • Liquid 250 micrograms/ml (unlicensed preparation)
              Indications

              Notes

                    1. MHRA Category 2: 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 and treatment history. If the patient is stable on a particular generic preparation there is no requirement to switch to branded prescribing.

                    Other antiepileptics

                    Acetazolamide, a carbonic anhydrase inhibitor, has a specific role in treating epilepsy associated with menstruation. It can also be used with other antiepileptics for refractory tonic-clonic, absence, and focal seizures. It is occasionally helpful in atypical absence, atonic, and tonic seizures.
                    Cannabidiol
                    • Oral solution 100mg/ml

                    Notes

                      1. NICE TA614: Cannabidiol (Epidyolex) with clobazam is recommended as an option for treating seizures associated with Dravet syndrome in people aged 2 years and older, only when the criteria of the NICE TA are met (December 2019)
                      2. NICE TA615: Cannabidiol (Epidyolex) with clobazam is recommended as an option for treating seizures associated with Lennox–Gastaut syndrome in people aged 2 years and older, only when the criteria of the NICE TA are met (December 2019)

                         

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