Shared Care Guideline for Tiagabine (Gabitril®) for Use As Add on Therapy for Partial Seizures in Adults and Children Over 12

Dorset Medicines Advisory Group

SHARED CARE GUIDELINE FOR TIAGABINE (GABITRIL®) FOR USE AS ADD ON THERAPY FOR PARTIAL SEIZURES IN ADULTS AND CHILDREN OVER 12

INDICATION Licensed indications & therapeutic class Tiagabine is an anti-epileptic drug indicated as add-on therapy for partial seizures with or without secondary generalisation where control is not achieved by optimal doses of at least one other anti- epileptic drug. Tiagabine is licensed only for use in adults and children over the age of 12. It is not licensed for monotherapy. NICE CG137: Epilepsies: diagnosis and management (page 26) states: Offer carbamazepine, clobazam, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, sodium valproate or topiramate as adjunctive treatment to children, young people and adults with focal seizures if first-line treatments [carbamazepine or lamotrigine, levetiracetam, oxcarbazepine or sodium valoprate] are ineffective or not tolerated. If adjunctive treatment is ineffective or not tolerated, discuss with, or refer to, a tertiary epilepsy specialist. Other AEDs that may be considered by the tertiary epilepsy specialist are eslicarbazepine acetate, lacosamide, phenobarbital, phenytoin, pregabalin, tiagabine, vigabatrin and zonisamide. Carefully consider the risk–benefit ratio when using vigabatrin because of the risk of an irreversible effect on visual fields. NICE also has a “Do not do” recommendation in relation to tiagabine: “Do not offer carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine or vigabatrin as adjunctive treatment in children, young people and adults with childhood absence epilepsy, juvenile absence epilepsy or other absence epilepsy syndromes.” AREAS OF RESPONSIBILITY FOR SHARED CARE Patients should be at the centre of any shared care arrangements. Individual patient information and a record of their preferences should accompany shared care prescribing guidelines, where appropriate. Transfer of clinical responsibility to primary care should only be considered where the person’s clinical condition is stable or predictable. Referral to the GP should only take place once the GP has agreed to this in each individual case, and the hospital or specialist will continue to provide prescriptions until a successful transfer of responsibilities. The GP should confirm the agreement and acceptance of the shared care prescribing arrangement and that supply arrangements have been finalised. The secondary/tertiary provider must supply an adequate amount of the medication to cover the transition period. The patient should then be informed to obtain further prescriptions from the GP. When clinical responsibility for prescribing is transferred to general practice, it is important that the GP, or other primary care prescriber, is confident to prescribe the necessary medicines. Shared care agreements play a key role in enabling primary care prescribers to prescribe medicines with which they may not initially be familiar. Clinical responsibility for prescribing is held by the person signing the prescription, who must also ensure adequate monitoring.

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REFERRAL AND INITIATION Shared Care is only appropriate if it provides the optimum solution for the patient.

Specialist Responsibilities 1 To assess the suitability of the patient for treatment with tiagabine, ensuring it is in line with the local and national recommendations. 2 Determine a management strategy and ensure follow-up in conjunction with the GP. 3 Where appropriate:  to initiate and stabilise the patient on treatment, providing at least 28 days’ treatment;  assess response to first month’s treatment;  obtain consent from the patient’s GP to continue prescribing once treatment has been stabilised; the consultant will seek an agreement with the GP prior to agreeing a treatment plan with the patient;  monitor the patient and their therapy at appropriate intervals  ensure therapy is discontinued where applicable. 4 To explain the possible side effects of the medication to the patient and emphasise the importance of regular monitoring, where required 5 Ensure that patients know what to do and who to contact if they experience adverse events or an exacerbation of their condition. 6 To provide the GP with appropriate prescribing information and any additional information requested, and to offer telephone support. 7 In collaboration with the GP monitor the patient’s condition to ensure the safe use of tiagabine including signs of suicidal ideation, ophthalmological (visual filed) changes and skin reactions (rash or bruising) with ongoing treatment. 8 To be available for advice if the patient’s condition changes and to arrange follow up in clinic at intervals to monitor the progress of the disease and review the continued use of tiagabine. 9 To ensure that procedures are in place for the rapid re-referral of the patient by the GP. 10 To ensure the patient has given informed consent to their treatment. 11 To liaise with the GP on any suggested changes in prescribed therapy / notify GP of any changes in the patient’s condition as assessed on follow up. 12 To inform the GP when it is considered appropriate to discontinue treatment. 13 Report any adverse events, via https://yellowcard.mhra.gov.uk/.

General Practitioner Responsibilities 1 Initially, to refer the patient to the epilepsy specialist. To prescribe tiagabine at the agreed dose after the initial 28-day period and monitor the 2 patient’s ongoing response to tiagabine. 3 Carry out any agreed monitoring, reporting the results to the specialist if appropriate. 4 To deal with general health issues of the patient. 5 To liaise with the consultant regarding any complications or adverse effects of treatment. To consider any side-effects reported by the patient and to discuss with the consultant if 6 necessary.

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General Practitioner Responsibilities To avoid or appropriately manage the drug interactions as listed below and in the current 7 BNF. In particular addition, discontinuation or dose change of an enzyme-inducing antiepileptic agent 8 To ensure ongoing reviews of the patient’s condition. 9 Ensure that therapy is discontinued where applicable. 10 Report any adverse events, via https://yellowcard.mhra.gov.uk/.

Patient's role (or that of carer) 1 Report to the specialist or GP if he/she does not have a clear understanding of the treatment. 2 Attend appropriate consultant and GP appointments. 3 Share any concerns in relation to treatment with tiagabine with their GP or consultant, particularly:  Signs of suicidal ideation or behaviour  Signs of spontaneous bruising  Visual disturbance  Pregnancy or suspected pregnancy 4 To seek help urgently from a healthcare professional if suspected side effects appear, or the patient is otherwise unwell.

SUPPORTING INFORMATION Licensed indications & therapeutic class Tiagabine is an anti-epileptic drug indicated as add-on therapy for partial seizures with or without secondary generalisation, where control is not achieved by optimal doses of at least one other anti- epileptic drug. Tiagabine has not been studied in children aged under 12 years of age and should not be used in this age group. Tiagabine is not licensed for monotherapy. Dose, route of administration and duration of treatment The following table summarizes the dose recommendations: Initial daily dose Weekly increments Maintenance dose Patients not taking enzyme 5-10mg 5-10mg/day 15-30mg/day inducing drugs Patients that are taking enzyme 5-10mg 5-10mg/day 30-45mg/day inducing drugs Tiagabine should be taken orally with meals. The initial daily dose should be taken as a single dose or divided into two doses. The daily maintenance dose should be divided into two or three single doses. Adverse effects (incidence, identification, importance and management) Common or very common Abdominal pain; behaviour abnormal; concentration impaired; depression; diarrhea; dizziness; emotional lability; fatigue; gait abnormal; insomnia; nausea; nervousness; speech disorder; tremor; vision disorders; vomiting

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Uncommon Drowsiness; psychosis; skin reactions Rare or very rare Delusions; hallucination Cautions and contra-indications Contraindications  Hypersensitivity to the active substance(s) or to any of the excipients listed in the summary of product characteristics.  Severely impaired liver function.  Tiagabine in combination with St John's Wort (Hypericum perforatum). Cautions  Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. Therefore, patients should be monitored for signs of suicidal ideation and behaviours. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.  Tiagabine is eliminated by hepatic metabolism and therefore caution should be exercised when administering the product to patients with impaired hepatic function. Reduced doses and/or dose intervals should be used and patients should be monitored closely for adverse events such as dizziness and tiredness.  Anti-epileptic agents that induce hepatic enzymes (such as phenytoin, carbamazepine, phenobarbital and primidone) enhance the metabolism of tiagabine. Consequently, patients taking enzyme-inducing drugs may require doses of tiagabine above the usual dose range.  Although there is no evidence of withdrawal seizures following tiagabine, it is recommended to taper off treatment over a period of 2-3 weeks.  Serious rash, including vesiculobullous rash, has occurred in patients receiving tiagabine  Spontaneous bruising has been reported. Therefore, if bruising is observed full blood count, including platelet count is to be performed.  Rare cases of visual field defects have been reported with tiagabine. If visual symptoms develop, the patient should be referred to an ophthalmologist for further evaluation including perimetry.  Tiagabine tablets contain lactose and therefore should not be used in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption.  Rapid titration and/or large dose increments of tiagabine may not be well-tolerated and should be avoided.  It is preferable not to use tiagabine during pregnancy or breast-feeding unless in the opinion of the physician, the potential benefits of treatment outweigh the potential risks Clinically important drug interactions and their management Concomitant use with drugs involving CYP 3A4/5 metabolism: Anti-epileptic agents that induce hepatic enzymes (such as phenytoin, carbamazepine, phenobarbital and primidone) enhance the metabolism of tiagabine. The plasma concentration of tiagabine may be reduced by a factor 1.5-3 by concomitant use of these drugs. Following a given dose of tiagabine, the estimated plasma concentration in non-induced patients is more than twice that in patients receiving enzyme-inducing agents. To achieve similar systemic exposures of tiagabine, non-induced patients require lower and less frequent doses of tiagabine 4 Dorset Medicines Advisory Group than induced patients. These patients may also require a slower titration of tiagabine compared to that of induced patients. Dosage adjustment of tiagabine should be considered whenever a change in patient's metabolic enzyme-inducing status occurs as a result of the addition, discontinuation, or dose change of the enzyme-inducing agent. The combination of tiagabine with St John Wort (Hypericum perforatum) may lead to lower exposure and loss of efficacy of tiagabine, due to the potent induction of CYP3A4 by St John Wort (increasing tiagabine metabolism). Therefore, the combination of tiagabine with St John's Wort is contra-indicated.

This list is not exhaustive. The manufacturer’s summary of product characteristics (SPC) and the most current edition of the British National Formulary should be consulted for full information on contra-indications, warnings, side-effects and drug interactions.

Peer-reviewed references for product usage

1. NICE CG137: Epilepsies and their management (April 2018) https://www.nice.org.uk/Guidance/cg137 2. BNF online https://www.medicinescomplete.com 3. Summary of product characteristics for Gabitril® (accessed 07/02/2019) https://www.medicines.org.uk/emc/product/5420/smpc

Refer to page 10 of NHS England’s guidance on Responsibility for prescribing between Primary & Secondary/Tertiary Care for more information/guidance about taking on prescribing of specialist medicines.

Contacts for more detailed information – Specialist Epilepsy Team at Poole Hospital NHSFT

Contact Details Telephone Number Email

Consultant Neurologist: [email protected] Dr R Page

Epilepsy Specialist Nurses: [email protected] Michelle Knight 01202 442231 [email protected] Cindy Sharland

Drug costs

Strength Packsize Cost Gabitril® 5mg tablets 100 tablet £52.04 Gabitril® 10mg tablets 100 tablet £104.09 Gabitril® 15mg tablets 100 tablet £156.13

Written By Neurology working group Date Feb 19 Approved By Dorset Medicines Advisory Group Date March 19 Date of next review April 2021 or before, in light of new evidence or information.