New Medicines Committee Briefing May 2016 Brivaracetam (Briviact®) for Treatment of Partial Onset Seizures with Or Without Secondary Generalisation Epilepsy

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New Medicines Committee Briefing May 2016 Brivaracetam (Briviact®) for treatment of partial onset seizures with or without secondary generalisation epilepsy.

Brivaracetam (Briviact®) is to be reviewed for use within: Primary Care Secondary Care 

Summary:  Briviact® is indicated as an adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalised seizures in adult and adolescent patients from 16 years of age with epilepsy.  Briviact® would be an alternative treatment option to other adjunctive anti-epileptic drugs.  There are currently no direct head to head trials of brivaracetam with other anti-epileptic drugs.  Brivaracetam 50mg/day demonstrated a 12.8% reduction in partial-onset seizure frequency per week when compared to placebo.  A statistically significant reduction in partial-onset seizure frequency over a 28-day period was demonstrated for brivaracetam 50mg/day compared to placebo. (22% reduction, p=0.004)  The proportion of ≥50% responders was significantly higher for brivaracetam 50mg/day compared to placebo (32.7% vs. 16.7%, p=0.008)  Brivaracetam 100mg/day and 200mg/day demonstrated a statistically significant reduction in seizure frequency over 28 days (p<0.001) and higher ≥50 responder rates (p<0.001) compared with placebo.  Significantly higher seizure freedom rates over the 12 week treatment period were achieved with brivaracetam 100mg/day (5.2%) and 200mg/day (4.0%) against placebo (0.8%, p=0.003 and p=0.019)  A statistically significant reduction in seizure frequency compared to placebo was seen in levetiracetam-naïve and patients previously treated with levetiracetam (p<0.05)  Most frequently reported adverse reactions (>10%) with brivaracetam treatment are somnolence and dizziness whilst the most frequent adverse reactions which led to discontinuation of treatment were dizziness (0.8%) and convulsions (0.8%).  Briviact® is significantly more expensive for Initiation/maintenance (Primary Care £129.64 and Secondary care £146.86 to £155.57) than generic levetiracetam (Primary Care £16.88 excluding VAT and Secondary Care £7.62 including VAT).  Briviact® is a black triangle drug ( ) and is monitored intensively by the CHM and MHRA

Formulary application Consultant submitting application: Dr Carl-Christian Moor (Consultant Neurologist, Clinical Lead in Epilepsy)

Clinical Director supporting application:

The application is a request for Brivaracetam (Briviact®) to be considered for inclusion in the North Staffordshire Joint Formulary (NSJF) as adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalised seizures in patients over the age of 16 with epilepsy. In support of the application, Dr. Moor estimates that 20 patients will be prescribed the new drug long term and that the estimated annual cost will be £1685.32 per patient. The benefits of the drug will be reduction in mortality, improvement in quality of life, improved safety and tolerability as well as being convenient to administer.

Background

Epilepsy is a group of neurological diseases characterized by epileptic seizures. Epileptic seizures are episodes that can vary from brief and nearly undetectable to long periods of vigorous shaking. These episodes can result in physical injuries including occasionally broken bones. In epilepsy, seizures tend to recur, and have no immediate underlying cause. Seizures that occur due to a specific cause are not deemed to represent epilepsy. The cause of most cases of epilepsy is unknown, although some people develop epilepsy as the result of brain injury, stroke, brain tumors, infections of the brain, and birth defects. Known genetic mutations are directly linked to a small proportion of cases. Epileptic seizures are the result of excessive and abnormal nerve cell activity in the cortex of the brain. The diagnosis involves ruling out other conditions that might cause similar symptoms such as fainting and determining if another cause of seizures is present such as alcohol withdrawal or electrolyte problems. This may be partly done by imaging the brain and performing blood tests. Epilepsy can often be confirmed with an electroencephalogram (EEG), but a normal test does not rule out the condition. Accurate estimates of incidence and prevalence are difficult to achieve because identifying people who may have epilepsy is difficult. Epilepsy has been estimated to affect between 362,000 and 415,000 people in England. In addition, there will be further individuals, estimated to be 5–30%, so amounting to up to another 124,500 people, who have been diagnosed with epilepsy, but in whom the diagnosis is incorrect. Incidence is estimated to be 50 per 100,000 per year and the prevalence of active epilepsy in the UK is estimated to be 5–10 cases per 1000.1 As of 2013 about 22 million people worldwide have epilepsy whilst nearly 80% of cases occur in the developing world. In 2013 it resulted in 116,000 deaths, up from 112,000 deaths in 1990. Epilepsy becomes more common as people age. In the developed world, onset of new cases occurs most frequently in babies and the elderly. In the developing world onset is more common in older children and young adults, due to differences in the frequency of the underlying causes. About 5–10% of people will have an unprovoked seizure by the age of 80 and the chance of experiencing a second seizure is between 40 and 50%. In many areas of the world those with epilepsy either have restrictions placed on their ability to drive or are not permitted to drive until they are free of seizures for a specific length of time.

Epilepsy that occurs as a result of other issues can be prevented. Seizures are controllable with medication in about 70% of cases. In those whose seizures who do not respond to medication, then surgery, neurostimulation, or dietary changes may be considered. Not all cases of epilepsy are lifelong, and many people improve to the point that treatment is no longer needed.

Epilepsy is characterized by a long-term risk of recurrent seizures. These seizures may present in several ways depending on the part of the brain involved and the person's age. The most common type of seizures are convulsive (60%). Of these, one-third begin as generalised seizures from the start, affecting both hemispheres of the brain. Two-thirds begin as partial seizures (which affect one hemisphere of the brain) which may then progress to generalized seizures. The remaining 40% of

seizures are non-convulsive. An example of this type is the absence seizure, which presents as a decreased level of consciousness and usually lasts about 10 seconds. Partial seizures are often preceded by certain experiences, known as auras. They include sensory (visual, hearing, or smell), psychic, autonomic, and motor phenomena. Jerking activity may start in a specific muscle group and spread to surrounding muscle groups in which case it is known as a Jacksonian march. Automatisms may occur, which are non-consciously-generated activities and mostly simple repetitive movements like smacking of the lips or more complex activities such as attempts to pick up something.

There are six main types of generalized seizures: tonic-clonic, tonic, clonic, myoclonic, absence, and atonic seizures. They all involve loss of consciousness and typically happen without warning.

Tonic-clonic seizures occur with a contraction of the limbs followed by their extension along with arching of the back which lasts 10–30 seconds (the tonic phase). A cry may be heard due to contraction of the chest muscles, followed by a shaking of the limbs in unison (clonic phase). Tonic seizures produce constant contractions of the muscles. A person often turns blue as breathing is stopped. In clonic seizures there is shaking of the limbs in unison. After the shaking has stopped it may take 10–30 minutes for the person to return to normal; this period is called the "postictal state" or "postictal phase." Loss of bowel or bladder control may occur during a seizure. The tongue may be bitten at either the tip or on the sides during a seizure. In tonic-clonic seizure, bites to the sides are more common. Tongue bites are also relatively common in psychogenic non-epileptic seizures.

Myoclonic seizures involve spasms of muscles in either a few areas or all over. Absence seizures can be subtle with only a slight turn of the head or eye blinking. The person does not fall over and returns to normal right after it ends. Atonic seizures involve the loss of muscle activity for greater than one second. This typically occurs on both sides of the body.

About 6% of those with epilepsy have seizures that are often triggered by specific events and are known as reflex seizures. Those with reflex epilepsy have seizures that are only triggered by specific stimuli. Common triggers include flashing lights and sudden noises. In certain types of epilepsy, seizures happen more often during sleep, and in other types they occur almost only when sleeping.

Postictal

After the active portion of a seizure, there is typically a period of confusion referred to as the postictal period before a normal level of consciousness returns. It usually lasts 3 to 15 minutes but may last for hours. Other common symptoms include feeling tired, headache, difficulty speaking, and abnormal behavior. Psychosis after a seizure is relatively common, occurring in 6–10% of people. Often people do not remember what happened during this time. Localized weakness, known as Todd's paralysis, may also occur after a partial seizure. When it occurs it typically lasts for seconds to minutes but may rarely last for a day or two.

Psychosocial

Epilepsy can have adverse effects on social and psychological well-being. These effects may include social isolation, stigmatization, or disability. They may result in lower educational achievement and worse employment outcomes. Learning disabilities are common in those with the condition, and especially among children with epilepsy. The stigma of epilepsy can also affect the families of those with the disorder.

Certain disorders occur more often in people with epilepsy, depending partly on the epilepsy syndrome present. These include depression, anxiety, obsessive–compulsive disorder (OCD), and migraine. Attention deficit hyperactivity disorder affects three to five times more children with epilepsy than children without the condition. ADHD and epilepsy have significant consequences on a

child's behavioral, learning, and social development. Epilepsy is also more common in children with autism.

Approximately, two thirds of people with active epilepsy have their epilepsy satisfactorily controlled with anti-epileptic drugs (AED’s). However, a number of people continue to have seizures despite monotherapy with AEDs. Once two AED’s have failed as monotherapy, the chances of remaining seizure free are low. Seizure control can be improved by combining AEDs. Combination therapy is recommended when treatment with two first line AEDs has failed. Choice of adjunctive AED depends on patient factors such as sex, reproductive potential, age, concomitant medications, pre-existing or comorbid conditions, other medical or psychiatric conditions. NICE recommends carbamazepine, clobazam, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, sodium valproate or topiramate as adjunctive treatment if first line treatments are ineffective or not tolerated. SIGN recommend lamotrigine as the drug of choice for partial onset seizures with carbamazepine or levetiracetam as alternatives if lamotrigine is poorly tolerated.2

One new alternative AED licensed for the treatment of partial onset seizures in patients over 16 years is brivaracetam, a ligand which acts on the synaptic vesicle protein 2A (SV2A), a transmembrane glycoprotein found at presynaptic level in neurons and in endocrine cells. Although the exact role of this protein remains to be elucidated it has been shown to modulate exocytosis of neurotransmitters. Binding to SV2A is believed to be the primary mechanism for brivaracetam anticonvulsant activity and offers an alternative to current preparations for those who require adjunctive anti-epileptic therapy. Brivaracetam will complement current anti-epileptic therapies and is to be considered for use in place of other branded adjunctive therapies in certain patients.

Current formulary status Brivaracetam (Briviact®) is not listed in the current North Staffordshire Joint Formulary. The drugs listed for management of epilepsy are listed in the table, below (colour codes added in text)

APC Approved Review: July 4.8.1 Control of the epilepsies 2014 Maintain patient on specific manufacturer’s products Restriction: Initiation and stabilisation by specialist Carbamazepine m/r 2 Anti-epileptics See Additional Information Box Prescribing Guide Restriction: Initiation and stabilisation by specialist Oxcarbazepine 2 Anti-epileptics Prescribing Guide Restriction: Initiation and stabilisation by specialist Phenobarbital 2 Anti-epileptics Prescribing Guide Restriction: Initiation and stabilisation by specialist Phenytoin 2 Anti-epileptics See Additional Information Box Prescribing Guide Restriction: Initiation and stabilisation by specialist Primidone 2 Anti-epileptics Prescribing Guide Restriction: Initiation and stabilisation by specialist Sodium valproate 2 Anti-epileptics Prescribing Guide Unnecessary to maintain patient on specific manufacturer’s products Clobazam 2 Restriction: Initiation and stabilisation by specialist Anti-epileptics Prescribing Guide Restriction: Initiation and stabilisation by specialist Clonazepam 2 Anti-epileptics Prescribing Guide Eslicarbazepine 2 Restriction: Initiation and stabilisation by specialist Anti-epileptics Prescribing Guide Restriction: Initiation and stabilisation by specialist Ethosuximide 2 Anti-epileptics Prescribing Guide Restriction: Initiation and stabilisation by specialist Gabapentin 2 Anti-epileptics Prescribing Guide Restriction: Initiation and stabilisation by specialist Anti-epileptics Lacosamide 2 Prescribing Guide  MTRAC Restriction: Initiation and stabilisation by specialist Lamotrigine 2 Anti-epileptics Prescribing Guide Restriction: Initiation and stabilisation by specialist Anti-epileptics Levetiracetam 2 Prescribing Guide  MTRAC Perampanel 2 Restriction: Initiation and stabilisation by specialist Anti-epileptics Prescribing Guide

 MTRAC Restriction: In line with NICE Guidance only Anti-epileptics Retigabine 2 Prescribing Guide  NICE TA232 Restriction: Initiation and stabilisation by specialist Anti-epileptics Topiramate 2 Prescribing Guide  MTRAC Restriction: Initiation and stabilisation by specialist Anti-epileptics Zonisamide 2 Prescribing Guide  MTRAC Restriction: By specialist only Vigabatrin Anti-epileptics Prescribing Guide

Additional Information July 2006: Carbamazepine: Carbamazepine suppositories are licensed for short-term treatment (maximum 7 days) only when oral therapy is temporarily not possible. Carbamazepine 125mg suppositories should be considered equivalent to 100mg tablets but plasma monitoring is recommended Phenytoin: Phenytoin 90mg in 15mL suspension may be considered approximately equivalent to capsules containing phenytoin sodium 100mg Phenytoin interacts significantly with NG feeds- please contact pharmacy for more information where necessary

Therapeutic class and mode of action

Brivaracetam is a highly selective, reversible ligand for synaptic vesicle protein 2A (SV2A), a transmembrane glycoprotein found at presynaptic level in neurons and in endocrine cells. Brivaracetam displays similar selectivity but higher affinity than levetiracetam, the other SV2A ligand which is available. Although the exact role of SV2A protein remains to be elucidated it has been shown to modulate exocytosis of neurotransmitters. Binding to SV2A is believed to be the primary mechanism for brivaracetam anticonvulsant activity.3

Licensed indication

Briviact® is indicated as adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalisation in adult and adolescent patients from 16 years of age with epilepsy.

Dosage and administration4,5,6

Briviact® 25mg, 50mg, 75mg & 100mg film coated tablets, 10mg/mL oral solution, 10mg/mL solution for injection/infusion. 10mg tablets are available but used only for dose down titration.

Brivaracetam may be initiated with either intravenous or oral administration. When converting from oral to intravenous administration or vice versa, the total daily dose and frequency of administration should be maintained. Brivaracetam solution for injection/infusion is an alternative for patients when oral administration is temporarily not feasible.

The recommended starting dose is either 50 mg/day or 100 mg/day based on physician assessment of required seizure reduction versus potential side effects. The dose should be administered in two equally divided doses, once in the morning and once in the evening. Based on individual patient response and tolerability, the dose may be adjusted in the dose range of 50 mg/day to 200 mg/day. The dose should be administered in two equally divided doses, once in the morning and once in the evening.

 Brivaracetam film-coated tablets must be taken orally swallowed whole with liquid and may be taken with or without food. Brivaracetam oral solution can be diluted in water or juice shortly before swallowing and may be taken with or without food. Brivaracetam oral solution can be administered via a nasogastric tube or a gastrostomy tube.  Brivaracetam may be administered as an intravenous bolus without dilution.

 Brivaracetam may be diluted in a compatible diluent and administered as a 15-minute intravenous infusion. The medicinal product must not be mixed with other medicinal products. There is no experience with twice daily intravenous administration of brivaracetam for a period longer than 4 days.

Safety and adverse effects Contraindications Hypersensitivity to the active substance or other pyrrolidone derivatives or any of the excipients (Croscarmellose Sodium, Lactose monohydrate, Betadex, Lactose anhydrous, Magnesium stearate, Polyvinyl alcohol, Titanium dioxide (E171), Macrogol 3350, Talc, Iron oxide yellow (E172), Iron oxide black (E172), Iron oxide red (E172)).

Adverse Events In all controlled and uncontrolled trials in patients with epilepsy, 2,388 subjects have received brivaracetam, of whom 1,740 have been treated for ≥ 6 months, 1,363 for ≥ 12 months, 923 for ≥24 months and 569 for ≥ 60 months (5 years).4,5,6 The most frequently reported adverse reactions (>10 %) with brivaracetam treatment were: somnolence (14.3 %) and dizziness (11.0 %). They were usually mild to moderate in intensity. Somnolence and fatigue (8.2 %) were reported at a higher incidence with increasing dose. The types of adverse reactions reported during the first 7 days of treatment were similar to those reported for the overall treatment period. The discontinuation rate due to adverse reactions was 3.5 %, 3.4 % and 4.0 % for patients randomized to brivaracetam at respectively the dose of 50 mg/day, 100 mg/day and 200 mg/day and 1.7 % for patients randomized to placebo. The adverse reaction most frequently resulting in discontinuation of brivaracetam therapy were dizziness (0.8 %) and convulsion (0.8 %).

Tabulated list of adverse reactions In the table below, adverse reactions, which were identified based on review of the full brivaracetam clinical studies safety database, are listed by System Organ Class and frequency. The frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. System organ class Frequency Adverse reactions from clinical trials Infections and infestations Common Influenza Blood and lymphatic system disorders Uncommon Neutropenia Metabolism and nutrition disorders Common Decreased appetite Psychiatric disorders Common Depression, anxiety, insomnia, irritability Uncommon Suicidal ideation, psychotic disorder, aggression, agitation Nervous system disorders Very common Dizziness, somnolence Common Convulsion, vertigo Respiratory, thoracic and mediastinal Common Upper respiratory tract infections, cough disorders Gastrointestinal disorders Common Nausea, vomiting, constipation General disorders and administration site Common Fatigue conditions

Description of selected adverse reactions Neutropenia has been reported in 0.5% (6/1099) brivaracetam patients and 0% (0/459) placebo patients. Four of these subjects had decreased neutrophil counts at baseline, and experienced

additional decrease in neutrophil counts after initiation of brivaracetam treatment. None of the 6 cases of neutropenia were severe, required any specific treatment or led to discontinuation of brivaracetam and none had associated infections.

Suicidal ideation has been reported in 0.3% (3/1099) brivaracetam patients and 0.7% (3/459) placebo patients. In the short-term clinical studies of brivaracetam in epilepsy patients, there were no cases of completed suicide or suicide attempt; however both have been reported in open-label extension studies.

Open-label extension studies In patients who were followed up in the open-label extension studies for up to 8 years, the safety profile was similar to that observed in the short-term, placebo-controlled studies.

Elderly Of the 130 elderly subjects enrolled in the brivaracetam phase 2/3 development program (44 with epilepsy), 100 were 65-74 years of age and 30 were 75-84 years of age. The safety profile in elderly patients appears to be similar to that observed in younger adult patients.

Incidence of behavioural problems with brivaracetam compared to levetiracetam A meta-analysis compared the incidence of behavioural problems in levetiracetam and brivaracetam trials, used as adjunctive therapy in adults with uncontrolled partial-onset epilepsy.7 The incidence of non-psychotic behavioural TEAEs was found to be a third lower with brivaracetam treatment (83/1214, 6.8%) compared with levetiracetam (73/672, 10.9%), whereas the incidences in placebo arms were similar (18/425, 4.2% and 17/351, 4.8%, respectively). The placebo-adjusted incidences were 2.6% for brivaracetam and 6.1% for levetiracetam. The odds ratio (brivaracetam/levetiracetam) was 0.68 [95% CI 0.32-1.45]. Subjects without concomitant levetiracetam treated with brivaracetam experienced a similar rate of non-psychotic behavioural TEAEs (67/983, 6.8%) compared with subjects taking concomitant levetiracetam (16/231, 6.9%) (Corresponding placebo groups: 7/79, 8.9% versus 11/346, 3.2%). Despite lacking statistical significance, the absolute and placebo-adjusted incidence of nonpsychotic behavioural TEAEs were found to be numerically lower for brivaracetam compared with levetiracetam.

Drug Interactions

Interaction with other medicinal products and other forms of interaction Formal interaction studies have only been performed in adults. Pharmacodynamic interactions Concomitant treatment with levetiracetam In the clinical studies, although the numbers were limited, there was no observed benefit of brivaracetam versus placebo in patients taking levetiracetam concurrently. No additional safety or tolerability concern was observed. Interaction with alcohol In a pharmacokinetic and pharmacodynamic interaction study between brivaracetam 200 mg single dose and ethanol 0.6 g/L continuous infusion in healthy subjects, there was no pharmacokinetic interaction but brivaracetam approximately doubled the effect of alcohol on psychomotor function, attention and memory. Intake of brivaracetam with alcohol is not recommended. Pharmacokinetic interactions Effects of other agents on the pharmacokinetics of brivaracetam In vitro data suggest that brivaracetam has a low interaction potential. The main disposition pathway of brivaracetam is by CYP-independent hydrolysis. A second disposition pathway involves hydroxylation mediated by CYP2C19. Brivaracetam plasma concentrations may increase when co-administered with CYP2C19 strong inhibitors (e.g. fluconazole, fluvoxamine), but the risk of a clinically relevant CYP2C19-mediated interaction is considered to be low.

Rifampicin In healthy subjects, co-administration with the strong enzyme inducer rifampicin (600 mg/day for 5 days), decreased brivaracetam area under the plasma concentration curve (AUC) by 45 %. Prescribers should consider adjusting the brivaracetam dose in patients starting or ending treatment with rifampicin. Strong enzyme inducing AEDs Brivaracetam plasma concentrations are decreased when co-administered with strong enzyme inducing AEDs (carbamazepine, phenobarbital, and phenytoin) but no dose adjustment is required. Other enzyme inducers Other strong enzyme inducers (such as St John´s wort (Hypericum perforatum)) may also decrease the systemic exposure of brivaracetam. Therefore, starting or ending treatment with St John's wort should be done with caution. Effects of brivaracetam on other medicinal products Brivaracetam given 50 or 150 mg/day did not affect the AUC of midazolam (metabolised by CYP3A4). The risk of clinically relevant CYP3A4 interactions is considered to be low. In vitro studies have shown that brivaracetam exhibits little or no inhibition of CYP450 isoforms except for CYP2C19. Brivaracetam may increase plasma concentrations of medicinal products metabolised by CYP2C19 (e.g. lanzoprazole, omeprazole, diazepam). When tested in vitro brivaracetam did not induce CYP1A1/2 but induced CYP3A4 and CYP2B6. No CYP3A4 induction was found in vivo (see midazolam above). CYP2B6 induction has not been investigated in vivo and brivaracetam may decrease plasma concentrations of medicinal products metabolised by CYP2B6 (e.g. efavirenz). In vitro interaction studies to determine the potential inhibitory effects on transporters concluded that there were no clinically relevant effects, except for OAT3. In vitro, Brivaracetam inhibits OAT3 with a half maximal inhibitory concentration 42-fold higher than the Cmax at the highest clinical dose. Brivaracetam 200mg/day may increase plasma concentrations of medicinal products transported by OAT3. Antiepileptic drugs Potential interactions between brivaracetam (50 mg/day to 200 mg/day) and other AEDs were investigated in a pooled analysis of plasma drug concentrations from all phase 2-3 studies, in a population pharmacokinetic analysis of placebo-controlled phase 2-3 studies, and in dedicated drug- drug interaction studies (for the following AEDs: carbamazepine, lamotrigine, phenytoin and topiramate). The effect of the interactions on the plasma concentration is summarised in table 1 (increase is indicated as “↑” and decrease as “↓”, area under the plasma concentration versus time curve as “AUC”, maximum observed concentration as Cmax).

Table 1: Pharmacokinetic interactions between brivaracetam and other AEDs AED co-administered Influence of AED on brivaracetam Influence of brivaracetam on AED plasma concentration plasma concentration Carbamazepine AUC 29 % ↓ Carbamazepine - None

Cmax 13 % ↓ Carbamazepine-epoxide ↑ No dose adjustment required (See below) No dose adjustment required. Clobazam No data available None Clonazepam No data available None Lacosamide No data available None Lamotrigine None None Levetiracetam None None Oxcarbazepine None None (monohydroxy derivative, MHD) Phenobarbital AUC 19 % ↓ None No dose adjustment required Phenytoin AUC 21 % ↓ None

No dose adjustment required a AUC 20% ↑ a Cmax 20% ↑ Pregabalin No data available None Topiramate None None Valproic acid None None Zonisamide No data available None a based on a study involving the administration of a supratherapeutic dose of 400 mg/day brivaracetam. Carbamazepine

Brivaracetam is a moderate reversible inhibitor of epoxide hydrolase resulting in an increased concentration of carbamazepine epoxide, an active metabolite of carbamazepine. In controlled studies, the carbamazepine epoxide plasma concentration increased by a mean of 37 %, 62 % and 98 % with little variability at brivaracetam doses of 50 mg/day, 100 mg/day and 200 mg/day respectively. No safety risks were observed. There was no additive effect of brivaracetam and valproate on the AUC of carbamazepine epoxide. Oral contraceptives Co-administration of brivaracetam (100 mg/day) with an oral contraceptive containing ethinylestradiol (0.03 mg) and levonorgestrel (0.15 mg) did not influence the pharmacokinetics of either substance. When brivaracetam was co-administered at a dose of 400 mg/day (twice the recommended maximum daily dose) with an oral contraceptive containing ethinylestradiol (0.03 mg) and levonorgestrel (0.15 mg), a reduction in estrogen and progestin AUCs of 27 % and 23 %, respectively, was observed without impact on suppression of ovulation. There was generally no change in the concentration-time profiles of the endogenous markers estradiol, progesterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), and sex hormone binding globulin (SHBG).

Presentation

Briviact 10 mg film-coated tablets • Packs of 14, 56 film-coated tablets and in multipacks containing 168 (3 packs of 56) film-coated tablets in PVC/PCTFE - Aluminium blisters • Packs of 100 x 1 film-coated tablet in PVC/PCTFE - Aluminium blisters Briviact 25 mg film-coated tablets • Packs of 14, 56 film-coated tablets and in multipacks containing 168 (3 packs of 56) film-coated tablets in PVC/PCTFE - Aluminium blisters • Packs of 100 x 1 film-coated tablet in PVC/PCTFE - Aluminium blisters Briviact 50 mg film-coated tablets • Packs of 14, 56 film-coated tablets and in multipacks containing 168 (3 packs of 56) film-coated tablets in PVC/PCTFE - Aluminium blisters • Packs of 100 x 1 film-coated tablet in PVC/PCTFE - Aluminium blisters Briviact 75 mg film-coated tablets • Packs of 14, 56 film-coated tablets and in multipacks containing 168 (3 packs of 56) film-coated tablets in PVC/PCTFE - Aluminium blisters • Packs of 100 x 1 film-coated tablet in PVC/PCTFE - Aluminium blisters Briviact 100 mg film-coated tablets • Packs of 14, 56 film-coated tablets and in multipacks containing 168 (3 packs of 56) film-coated tablets in PVC/PCTFE - Aluminium blisters • Packs of 100 x 1 film-coated tablet in PVC/PCTFE - Aluminium blisters Not all pack sizes may be marketed. Briviact 10mg/mL oral solution

300 ml amber glass bottle (type III) with a white child resistant closure (polypropylene) in a box also containing a 10 ml graduated oral dosing syringe (polypropylene, polyethylene) and an adaptor for the syringe (polyethylene). Briviact 10mg/mL solution for injection/infusion 10 mg/ml solution for injection/infusion is packed in 6mL nominal capacity glass vials (type I) with siliconised bromobutyl rubber stoppers and sealed with an aluminium/polypropylene tear off cap. Each single use vial contains an extractable volume of not less than 5.0mL of solution for injection/infusion. Each carton contains 10 vials. Guidance and Evidence Summary NICE advice is not NICE Guidance: it reviews the strengths and weaknesses of the relevant evidence to provide useful information for those working on the managed entry of new medicines for the NHS. NICE Guidance published NO NICE Advice published NO Efficacy There are currently no head to head trials that directly compare brivaracetam with other anti-epileptic drugs licensed for the treatment of partial onset seizures.

The efficacy of brivaracetam for the adjunctive therapy of partial-onset seizures (POS) was established in 3 randomized, double-blind, placebo-controlled, fixed-dose, multi-center studies in subjects 16 years of age and older. The daily dose of brivaracetam ranged from 5 to 200 mg/day across these studies. All studies had an 8-week baseline period followed by a 12-week treatment period with no up- titration. 1,558 patients received study drug of which 1,099 received brivaracetam. Study enrollment criteria required that patients have uncontrolled POS despite treatment with either 1 or 2 concomitant AEDs. Patients were required to have at least 8 POS during the baseline period. The primary endpoints in the phase 3 studies were the percent reduction in POS frequency over placebo and the 50 % responder rate based on 50 % reduction in POS frequency from baseline. The most commonly taken AEDs at the time of study entry were carbamazepine (40.6 %), lamotrigine (25.2 %), valproate (20.5 %), oxcarbazepine (16.0 %), topiramate (13.5 %), phenytoin (10.2 %) and levetiracetam (9.8 %). The median baseline seizure frequency across the 3 studies was 9 seizures per 28 days. Patients had a mean duration of epilepsy of approximately 23 years.

Ryvlin at al.8 evaluated the efficacy and safety/tolerability of brivaracetam versus placebo in patients with partial-onset seizures that were not fully controlled despite optimal treatment with one or two concomitant AEDs. Patients included were aged 16-70 years (mean age 37.2 years) with a history of partial-onset seizures with or without secondary generalisation, two or more partial-onset seizures/month for 3 months prior to screening and ≥8 during the 8-week prospective baseline period (median number of seizures per week at baseline = 1.95) and taking one or two concomitant AEDs at a stable and optimal dosage from ≥1 month prior to screening and throughout the study. Patients excluded were those with non-motor simple partial-onset seizures as the only seizure type, a history or presence of seizures occurring only in clusters before randomisation, and a history or presence of status epilepticus during the 12 months prior to screening or during baseline, a history or presence of pseudo-seizures, rapidly progressing brain disorder, tumours, serious infection, or terminal illness. Patients received either brivaracetam 20mg/day (n=99), 50mg/day (n=99), 100mg/day (n=1) or placebo (n=100) administered twice a day. Primary outcome was a reduction in partial-onset seizure frequency per week over the treatment period. The results of the study found that the reduction achieved with brivaracetam 50mg/day versus placebo was not statistically significant (6.5%. p=0.261). However, the reduction achieved with brivaracetam 100mg/day versus placebo was nominally significant. (11.7%, p=0.037). In terms of the median percentage reduction in partial-onset seizure frequency from baseline, the result was nominally greater with brivaracetam 100mg/day (32.5%) versus placebo (17%, p=0.004). Furthermore, the ≥50% response rate was nominally greater with brivaracetam 100mg/day (36%) than with placebo (20%, p+0.023, NNT=6).

Biton P et al.9 also evaluated the efficacy and safety/tolerability of brivaracetam as adjunctive treatment in adults with uncontrolled partial-onset seizures. Patients enrolled into the study were aged 16-70 years with well characterised partial epilepsy and two or more partial-onset seizures /month during the three months prior to screening and ≥8 during the 8-week prospective baseline period plus taking one or two concomitant AEDs at a stable optimal dosage from ≥1 month prior to and during the study. Patients excluded were non-motor simple partial seizures as the only seizure type, a history or presence of seizures occurring in clusters before randomisation and a history or presence of status epilepticus during one year prior to screening or during baseline or pseudo-seizures. Patients were randomised to either brivaracetam 5mg/day (n=97), 20mg/day (n=100), 50mg/day (n=101) or placebo (n=98) administered twice a day. Primary outcome was the reduction in partial- onset seizure frequency per week over the 12 week treatment period. In this study, the reduction achieved with brivaracetam 50mg over placebo was statistically significant (12.8%, p=0.025). Results were not significant for 5mg/day and 20mg/day compared to placebo. In addition, brivaracetam 50mg/day significantly reduced the median percent reduction in partial-onset seizure frequency against placebo (-30.5% vs. – 17.8%, p=0.003). Statistical significance was also shown as a reduction in the partial-onset frequency over a 28 day period for brivaracetam 50mg/day over placebo (22% reduction, p=0.004) There were also significantly more patients with a ≥50% reduction from baseline in seizure frequency/week in the 50mg/day group vs. placebo (32.7% vs. 16.7%, p=0.008, NNT=6). However, the study did not state the reduction in seizure frequency per week for the 5mg/day and 20mg/day groups. The study also found that four patients in the 50mg/day group were seizure free compared to none in the placebo group. In terms of the percentage reduction from baseline in partial- onset seizure frequency/week in levetiracetam naïve patients (n=230), there was a -14.7% reduction for placebo, -27% reduction for brivaracetam 5mg/day, -25.7% reduction for brivaracetam 20mg/day and -38.2% reduction for brivaracetam 50mg/day. For patients that had prior levetiracetam use (n=86), the percentage reduction from baseline in partial-onset seizure frequency/week was -25.1% (placebo), -24% (brivaracetam 5mg/day), 16.2% (brivaracetam 20mg/day) and -14.4% (brivaracetam 50mg/day). For those patients concomitantly using levetiracetam, the percentage reduction from baseline in partial-onset seizure frequency/week was -22.1% (placebo), -0.4% (brivaracetam 5mg/day), -16.2% (brivaracetam 20mg/day) and -14.4% (brivaracetam 50mg/day).

Klein et al.10 evaluated the efficacy, safety and tolerability of brivaracetam at fixed doses of 100mg/day and 200mg/day, compared to placebo, as adjunctive treatment in adults with uncontrolled partial- onset seizures despite treatment with one or two concomitant antiepileptic drugs. Patients included in the study were aged between 16 and 80 years with refractory partial-onset seizures with or epileptic syndrome that was uncontrolled with one or two concomitant AEDs at stable dosage for at least 1 month before visit 1 (3 months for phenobarbital, phenytoin and primidone). Patients were also required to have an EEG compatible with a diagnosis of partial-onset epilepsy within the previous 5 years along with a brain MRI/CT scan within the previous 2 years. Patients with ≥8 partial-onset seizures during the 8 week baseline period, with ≥ 2 seizures during each 4 week interval and ≥2 partial-onset seizures with or without secondary generalisation per month during the 3 months prior to preceding treatment were also included. Patients excluded included those taking levetiracetam either as a concomitant AED or within 90 days prior to first study visit and a history of status epilepticus in the year preceding enrolment or during baseline, psychogenic non-epileptic seizures, cluster seizures or non-motor simple partial seizures or rapidly progressing brain disorders or tumours. Patients were randomised to placebo (n=259), brivaracetam 100mg/day (n=252) or brivaracetam 20mg/day (n=249) taken in two equal daily doses. For the primary outcome of percent reduction in 28- day adjusted partial-onset seizure frequency was significantly greater with both 100mg/day (22.8%, 95% CI, 13.3 to 31.2, p<0.001) and 200mg/day (23.2%, 95% CI, 13.8 to 31.6, p<0.001) compared to placebo. In terms of the ≥50% responder rates, based on percent reduction in partial-onset seizure frequency from baseline to end of treatment, the results were significantly higher for 100mg/day and 200mg/day brivaracetam compared to placebo (21.6% for placebo, 38.9% for brivaracetam 100mg/day, OR 2.39, 95% CI, 1.6 to 3.60, p<0.001, NNT=6) and 37.8% for 200mg/day, OR 2.39, 95% CI, 1.5 to 3.3, p<0.001, NNT=6). Secondary outcomes were the median percent reduction in seizure frequency from baseline and seizure freedom during the treatment period. In terms of median

percent reduction in seizure frequency from baseline, the difference with brivaracetam 100mg/day (37.2%, p<0.001) and brivaracetam 200mg/day (35.6%, p<0.001) were significantly greater than placebo (17.6%). Furthermore, the seizure freedom during the treatment period was significantly higher with both brivaracetam 100mg/day (13/252, p=0.003) and 200mg/day (10/249) compared to placebo (2/259, p=0.019) For those patients who had previously used levetiracetam (n=413), the percent reduction over placebo in the 28-day adjusted partial-onset seizure frequency was 15.8% for brivaracetam 100mg/day (p=0.024) and 19.4% for 200mg/day (p=0.005). For the percent reduction in partial-onset seizure frequency from baseline to the end of the treatment period, the ≥50% responder rates were 16.8% for placebo, 28.7% for brivaracetam 100mg/day (p=0.016) and 31.3% for 200mg/day (p=0.007). In the levetiracetam naïve patients (n=347), the percent reduction over placebo in the 28- day adjusted partial onset seizure frequency was 29.5% for brivaracetam 100mg/day (p<0.001) and 27.1% for brivatracetam 200mg/day (p<0.001) whilst the ≥50% responder rates based on percent reduction in partial-onset seizure frequency from baseline to the end of the treatment period were 27.6% for placebo, 50.9% for brivaracetam 100mg/day (p<0.001) and 45.2% for brivaracetam 200mg/day (p=0.008).

The efficacy outcomes of the above three trials are summarized below.

Key Efficacy Outcomes for Partial Onset Seizure Frequency per 28 Days Study Placebo Brivaracetam * Statistically significant (p-value) 50 mg/day 100 mg/day 200 mg/day Study Bivon et al. n= 96 n= 101 50 % Responder rate 16.7 32.7* ~ ~ (p=0.008) Percent reduction over placebo (%) NA 22.0* ~ ~ (p=0.0040) Study Ryvlin et al.(1) n = 100 n = 99 n = 100 50 % Responder rate 20.0 27.3 36.0(2) ~ (p=0.372) (p=0.023) Percent reduction over placebo (%) NA 9.2 20.5(2) ~ (p=0.0274) (p=0.0097) Study Klein et al. n = 259 n = 252 n = 249 50% Responder rate 21.6 ~ 38.9 37.8 (p<0.001) (p<0.001) Percent reduction over placebo (%) NA ~ 22.8* 23.2* (p<0.001) (p<0.001) n = randomised patients who received at least 1 dose of study medication ~ Dose not studied * Statistically significant (1) Approximately 20 % of the patients were on concomitant levetiracetam (2) The primary outcome for the study by Ryvlin et al. did not achieve statistical significance based on the sequential testing procedure, The 100 mg/day dose was nominally significant. In clinical studies, a reduction in seizure frequency over placebo was higher with the dose of 100 mg/day than with 50 mg/day. Apart from dose-dependent increases in incidences of somnolence and fatigue brivaracetam 50 mg/day and 100 mg/day had a similar safety profile including CNS-related AEs and with long-term use.

Overall, brivaracetam was efficacious for the adjunctive treatment of partial onset seizures in patients 16 years of age and older between 50 mg/day and 200 mg/day.

Figure 1 shows the percentage of patients (excluding patients with concomitant levetiracetam) by category of reduction from baseline in POS frequency per 28 days in all 3 studies. Patients with more than a 25 % increase in POS are shown at left as “worse”. Patients with an improvement in percent reduction in baseline POS frequency are shown in the 4 right-most categories. The percentages of patients with at least a 50 % reduction in seizure frequency were 20.3 %, 34.2 %, 39.5 %, and 37.8 % for placebo, 50 mg/day, 100 mg/day, and 200 mg/day, respectively.

Figure 1: Proportion of patients by category of seizure response for brivaracetam and placebo over 12 weeks across all three double-blind pivotal trials

In a pooled analysis of the three pivotal trials, no differences in efficacy (measured as 50 % responder rate) was observed within the dose range of 50 mg/day to 200 mg/day when brivaracetam is combined with inducing or non-inducing AEDs. In clinical studies 2.5 % (4/161), 5.1 % (17/332) and 4.0% (10/249) of the patients on brivaracetam 50 mg/day, 100 mg/day and 200 mg/day respectively became seizure free during the 12-week treatment period compared with 0.5 % (2/418) on placebo. Improvement in the median percent reduction in seizure frequency per 28 days has been observed in patients with type IC seizure (secondary generalized tonic-clonic seizures) at baseline treated with brivaracetam (66.6 % (n=62), 61.2 % (n=100) and 82.1 % (n=75) of the patients on brivaracetam 50 mg/day, 100 mg/day and 200 mg/day respectively as compared to placebo 33.3 % (n=115)). The efficacy of brivaracetam in monotherapy has not been established. Brivaracetam is not recommended for use as monotherapy.

Treatment with levetiracetam In two phase 3 randomised placebo-controlled studies, levetiracetam was administered as a concomitant AED in about 20 % of the patients. Although the number of subjects is limited, there was no observed benefit of brivaracetam versus placebo in patients taking levetiracetam concurrently which may reflect competition at the SV2A binding site. No additional safety or tolerability concerns were observed. In a third study, a pre-specified analysis demonstrated efficacy over placebo for 100 mg/day and 200 mg/day in patients with prior exposure to levetiracetam. The lower efficacy observed in these patients compared to the leveticacetam-naïve patients was likely due to the higher number of prior AEDs used and higher baseline seizure frequency. Elderly (65 years of age and above)

The three pivotal double-blind placebo-controlled studies included 38 elderly patients aged between 65 and 80 years. Although data are limited, the efficacy was comparable to younger subjects. Open label extension studies Across all studies, 81.7 % of the patients who completed randomized studies were enrolled in the long- term open-label extension studies. From entry into the randomized studies, 5.3 % of the subjects exposed to brivaracetam for 6 months (n=1,500) were seizure free compared to 4.6 % and 3.7 % for subjects exposed for 12 months (n=1,188) and 24 months (n=847), respectively. However, as a high proportion of subjects (26%) discontinued from the open-label studies due to a lack of efficacy, a selection bias may have occurred, as the subjects who stayed in the study responded better than those who have terminated prematurely.

Kwan et al.11 undertook a 4 week randomised study to gather further data on higher doses of brivaracetam (50mg/day – 150mg/day) used in phase 2b studies to confirm the safety and tolerability of adjunctive brivaracetam. Patients included in the study were aged 16-70 years with partial onset epilepsy or generalised epilepsy uncontrolled on 1-3 AEDs, ≥2 partial-onset seizures/month or ≥2 days with primary generalised seizures/month in a the 3 months prior to screening and ≥4 partial onset or generalised seizure days during the 4 week baseline period. Patients excluded were those with non- motor seizures or psychogenic non-epileptic seizures, status epilepticus in the year prior to screening, pseudo-seizures or cluster seizures as the only seizure type. Patients were randomised to receive brivaracetam (n=359) initiated at 20mg/day and up-titrated in a step-wise manner to 50, 100 or 150mg/day at 2 week intervals administered twice a day in equal doses. The study found that the ≥50% responder rate was significantly greater in the brivaracetam group (30.3%) compared with placebo (16.7%, p=0.006, NNT=7). The baseline-adjusted percentage reduction in partial-onset seizure frequency/week for the brivaracetam group over the placebo group was not statistically significant during the 16 week treatment period (7.3%, p=0.125). In addition, five patients who were treated with brivaracetam (1.5%) were seizure free of all seizure types during the 16 week treatment period versus none in the placebo group (p=0.337). Furthermore, the median time (95% CI) to the first seizure was 4 (4-5) days with brivaracetam vs. 3 (2-4) days with placebo. Median times (95% CI) to the fifth and tenth seizures were 18 (16-21) days and 38 (31-43) days with brivaracetam compared to 14 (11-19) Days and 36 (23-44) days with placebo. For patients concomitantly treated with levetiracetam (n=83), the baseline adjusted percentage reduction in partial onset seizure frequency/week for the brivaracetam group over the placebo group was 14.2% (p= not stated). The percent reduction from baseline in partial-onset seizures/week was -14.2% with placebo and -15.9% with brivaracetam (p=not stated). The ≥50% responder rate was lower in the brivaracetam group (13%) compared with the placebo group (18.2%, p=not stated). For patients without concomitant levetiracetam (n=348), the baseline- adjusted percentage reduction in partial-onset seizure frequency/week for the brivaracetam group over placebo group was 11.5% (p=not stated). The percent reduction from baseline in partial-onset seizures/week was -19.2% with placebo and -31.5% with brivaracetam (p=not stated). Again, the ≥50% responder rate was lower in the brivaracetam group (16.3%) compared with placebo (34.4%, p=not stated, NNT=6).

SMC recommended use within NHS Scotland NO Not reviewed. Due 11/07/2016 All Wales Medicines Strategy Group (AWSG) NO Not reviewed Regional Drug and Therapeutic Centre (RDTC): NO Not reviewed MTRAC NO

Not reviewed Cochrane Review: NO Review not yet available.

Cost analysis: Costs See table, below for comparative costs of drugs used in the treatment of ADHD.

28 day course cost Primary care excl VAT Brivaracetam tablets Initiation/Maintenance dose: 50-100mg daily in 2 divided doses £129.64 Induction dose: Days 1-14:500mg twice daily. Days 15- Levetiracetam tablets 28:1000mg twice daily £5.57 Maintenance dose: 500mg twice daily to 1500mg twice daily £4.10 to £11.31

NORTH STOKE ON Drug Tariff STAFFORDSHIRE TRENT CCG Medicine Description Packsize Current Price UHNM ROYAL STOKE (VAT included) CCG Based on Total Based on Total Act (excl.VAT) Act Cost (VAT not Cost (VAT not included) included) BRIVARACETAM 10mg TABLETS 14 £34.64 £0.00 £0.00 £0.00 BRIVARACETAM 25mg TABLETS 56 £129.64 £0.00 £0.00 £0.00 BRIVARACETAM 50mg TABLETS 56 £129.64 £0.00 £0.00 £0.00 BRIVARACETAM 75mg TABLETS 56 £129.64 £0.00 £0.00 £0.00 BRIVARACETAM 100mg TABLETS 56 £129.64 £0.00 £0.00 £0.00 BRIVARACETAM 100mg/mL ORAL SOLUTION 300ml £115.83 £0.00 £0.00 £0.00 BRIVARACETAM 100mg/mL SOLUTION FOR INJECTION/INFUSION 10 vials £222.75 £0.00 £0.00 £0.00 CARBAMAZEPINE 100mg CHEWABLE TABLETS 56 Discontinued £4.74 £110.62 £288.24 CARBAMAZEPINE 200mg CHEWABLE TABLETS 56 Discontinued £0.00 £39.04 £127.24 CARBAMAZEPINE 100mg TABLETS 84 £2.07 £595.01 £20,933.76 £27,791.80 CARBAMAZEPINE 200mg TABLETS 84 £3.83 £477.20 £18,774.48 £35,217.64 CARBAMAZEPINE 400mg TABLETS 56 £5.02 £339.10 £3,352.43 £5,867.22 CARBAMAZEPINE 200mg M/R TABLETS 56 £5.20 £814.08 £19,923.69 £32,379.57

NORTH STOKE ON Drug Tariff STAFFORDSHIRE TRENT CCG Medicine Description Packsize Current Price UHNM ROYAL STOKE (VAT included) CCG Based on Total Based on Total Act (excl.VAT) Act Cost (VAT not Cost (VAT not included) included) CARBAMAZEPINE 400mg M/R TABLETS 56 £10.24 £1,109.64 £24,533.68 £38,209.30 CARBAMAZEPINE 100mg/5mL SF LIQUID 300ml £6.12 £1,598.50 £8,327.47 £11,242.52 CLOBAZAM 10mg TABLETS 30 £2.99 £460.52 £2,806.86 £4,725.22 CLOBAZAM 2.5mg/5mL ORAL SUSPENSION - Special order £0.00 £0.00 £145.47 CLOBAZAM 5mg/5mL ORAL SUSPENSION 150ml £90.00 £970.09 £83.14 £2,149.13 CLOBAZAM 10mg/5mL ORAL SUSPENSION 150ml £95.00 £0.00 £124.16 £7,614.93 ESLICARBAZEPINE TABLET 800mg 30 £136.00 £2,163.62 £12,805.15 £44,638.67 GABAPENTIN 100mg CAPSULES 100 £2.81 £1,745.29 £17,658.66 £32,468.69 GABAPENTIN 300mg CAPSULES 100 £3.44 £3,224.37 £64,186.35 £90,017.33 GABAPENTIN 400mg CAPSULES 100 £4.17 £384.87 £5,393.67 £8,264.87 GABAPENTIN 100mg TABLETS - Price not available £0.00 £0.00 £135.39 GABAPENTIN 300mg TABLETS - Price not available £0.00 £1,759.21 £0.00 GABAPENTIN 400mg TABLETS - Price not available £0.00 £181.67 £1,417.81 GABAPENTIN 600mg TABLETS 100 £8.66 £2,102.53 £21,395.25 £32,728.45 GABAPENTIN 800mg TABLETS 100 £30.14 £0.00 £2,958.51 £5,001.07 GABAPENTIN 250mg/5mL SOLUTION 150ml £68.96 £4,313.85 £6,869.76 £20,897.10 GABAPENTIN 300mg/5mL SOLUTION - Special order £0.00 £0.00 £2,854.27 GABAPENTIN 500mg/5mL SOLUTION - Special order £0.00 £0.00 £2,290.50 LACOSAMIDE 50mg TABLETS 14 £10.81 £847.50 £4,054.20 £12,277.76 LACOSAMIDE 100mg TABLETS 14/56 £21.62/£86.50 £2,936.65 £10,701.04 £20,485.00 LACOSAMIDE 150mg TABLETS 14/56 £32.44/£129.74 £129.74 £7,021.24 £13,053.23 LACOSAMIDE 200mg TABLETS 56 £144.16 £172.99 £13,190.59 £28,111.67 LACOSAMIDE 10mg/mL SYRUP 200ml £25.74 £2,471.57 £1,714.20 £7,284.84 LACOSAMIDE 200mg/20mL Injection (Vial) 1 £29.70 £1,370.24 £0.00 £0.00 LAMOTRIGINE 2mg CHEWABLE/DISPERSIBLE TABLETS 30 £12.54 £139.76 £384.42 £657.32 LAMOTRIGINE 5mg DISPERSIBLE TABLETS 28 £2.69 £76.75 £4,395.00 £2,976.76 LAMOTRIGINE 25mg DISPERSIBLE TABLETS 56 £2.71 £79.22 £3,352.69 £4,343.69 LAMOTRIGINE 100mg DISPERSIBLE TABLETS 56 £4.57 £140.88 £1,304.25 £1,893.93 LAMOTRIGINE 25mg TABLETS 56 £1.57 £312.03 £13,532.90 £15,070.33 LAMOTRIGINE 50mg TABLETS 56 £1.66 £408.33 £25,872.96 £24,433.03

NORTH STOKE ON Drug Tariff STAFFORDSHIRE TRENT CCG Medicine Description Packsize Current Price UHNM ROYAL STOKE (VAT included) CCG Based on Total Based on Total Act (excl.VAT) Act Cost (VAT not Cost (VAT not included) included) LAMOTRIGINE 100mg TABLETS 56 £2.31 £285.04 £63,532.34 £56,200.13 LAMOTRIGINE 200mg TABLETS 56 £2.95 £3.33 £28,083.29 £40,914.00 LAMOTRIGINE LIQUID 50mg/5ml - Special order £0.00 £239.26 £0.00 LEVETIRACETAM 250mg TABLETS 60 £3.18 £1,539.51 £26,545.84 £32,893.12 LEVETIRACETAM 500mg TABLETS 60 £4.39 £2,049.11 £81,290.46 £93,635.32 LEVETIRACETAM 750mg TABLETS 60 £6.06 £174.86 £18,460.58 £18,349.09 LEVETIRACETAM 1,000mg TABLETS 60 £7.54 £769.33 £46,024.96 £68,204.92 LEVETIRACETAM 250mg GRANULES 60 £22.41 £0.00 £52.19 £0.00 LEVETIRACETAM 500mg GRANULES 60 £39.46 £0.00 £0.72 £218.93 LEVETIRACETAM 1000mg GRANULES 60 £76.27 £0.00 £1.29 £0.00 LEVETIRACETAM 250mg/5mL ORAL SOLUTION - Special order £0.00 £3.01 £0.00 LEVETIRACETAM 500mg/5mL ORAL SOLUTION 300ml £8.20 £3,851.69 £16,912.69 £21,309.16 LEVETIRACETAM 500mg/5mL INFUSION 10 vials £127.31 £11,815.68 £0.00 £0.00 OXCARBAZEPINE 150mg TABLETS 50 £8.74 £50.09 £2,010.67 £1,227.03 OXCARBAZEPINE 300mg TABLETS 50 £6.89 £224.52 £6,043.65 £4,072.86 OXCARBAZEPINE 600mg TABLETS 50 £39.10 £0.00 £2,402.59 £5,849.33 OXCARBAZEPINE 300mg/5mL SUSPENSION 250ml £48.96 £223.25 £0.00 £2,308.89 PERAMPANEL 2mg TABLETS 7 £35.00 £3,252.17 £11,613.43 £23,478.70 PERAMPANEL 4mg TABLETS 28 £140.00 £619.50 £4,466.78 £5,763.85 PERAMPANEL 6mg TABLETS 28 £140.00 £140.00 £11,311.48 £8,356.14 PERAMPANEL 8mg TABLETS 28 £140.00 £310.80 £4,401.75 £4,663.24 PERAMPANEL 10mg TABLETS 28 £140.00 £177.60 £5,048.88 £1,812.52 PERAMPANEL 12mg TABLETS 28 £140.00 £0.00 £0.00 £1,490.80 PREGABALIN 25mg CAPSULES 56 £64.40 £8,017.35 £54,095.48 £77,303.38 PREGABALIN 50mg CAPSULES 84 £96.60 £16,411.37 £115,069.40 £190,961.61 PREGABALIN 75mg CAPSULES 56 £64.40 £26,484.15 £251,577.76 £342,508.38 PREGABALIN 100mg CAPSULES 84 £96.60 £8,684.10 £81,013.98 £138,603.97 PREGABALIN 150mg CAPSULES 56 £64.40 £13,447.88 £213,597.97 £295,360.56 PREGABALIN 200mg CAPSULES 84 £96.60 £6,731.85 £58,909.29 £66,694.96 PREGABALIN 225mg CAPSULES 56 £64.40 £0.00 £20,017.91 £24,138.81

NORTH STOKE ON Drug Tariff STAFFORDSHIRE TRENT CCG Medicine Description Packsize Current Price UHNM ROYAL STOKE (VAT included) CCG Based on Total Based on Total Act (excl.VAT) Act Cost (VAT not Cost (VAT not included) included) PREGABALIN 300mg CAPSULES 56 £64.40 £12,172.55 £159,413.54 £234,932.27 PREGABALIN 75mg/5mL ORAL SOLUTION - Special order £0.00 £1,857.82 £0.00 PREGABALIN 100mg/5mL ORAL SOLUTION 473ml £99.48 £220.85 £1,655.73 £5,088.03 RETIGABINE STARTER PACK 50mg/100mg TABLETS 21+42 £24.33 £0.00 £0.00 £30.11 RETIGABINE 50mg TABLETS 21/84 £4.87/£19.46 £0.00 £0.00 £0.00 RETIGABINE 100mg TABLETS 21/84 £9.73/£38.93 £0.00 £0.00 £0.00 RETIGABINE 200mg TABLETS 84 £77.86 £0.00 £0.00 £0.00 RETIGABINE 300mg TABLETS 84 £116.78 £0.00 £0.00 £0.00 RETIGABINE 400mg TABLETS 84 £127.68 £0.00 £0.00 £0.00 TIAGABINE 5mg TABLETS 100 £52.04 £0.00 £1,127.47 £0.00 TIAGABINE 10mg TABLETS 100 £104.09 £0.00 £0.00 £0.00 TIAGABINE 15mg TABLETS 100 £156.13 £0.00 £0.00 £0.00 TOPIRAMATE 25mg TABLETS 60 £1.77 £154.67 £5,841.95 £9,665.98 TOPIRAMATE 50mg TABLETS 60 £2.12 £186.59 £7,246.74 £9,576.61 TOPIRAMATE 100mg TABLETS 60 £3.16 £154.15 £7,264.54 £9,615.26 TOPIRAMATE 200mg TABLETS 60 £14.08 £0.00 £9,527.93 £5,323.88 TOPIRAMATE(TOPAMAX) 15mg SPRINKLE CAPSULES 60 £22.05 £39.14 £1,841.79 £1,479.62 TOPIRAMATE(TOPAMAX) 25mg SPRINKLE CAPSULES 60 £16.29 £54.21 £5,824.97 £9,887.33 TOPIRAMATE(TOPAMAX) 50mg SPRINKLE CAPSULES 60 £49.73 £467.76 £11,355.50 £15,236.44 TOPIRAMATE ORAL SOLUTION 25mg/5ml 100ml £114.77 £0.00 £2,022.57 £0.00 VIGABATRIN(SABRIL) 500mg SACHETS 50 £24.60 £441.17 £523.40 £1,917.39 VIGABATRIN 500mg TABLETS 100 £44.41 £0.00 £1,052.98 £0.00 ZONISAMIDE 25mg CAPSULES 14 £8.82 £562.92 £5,058.22 £7,469.09 ZONISAMIDE 50mg CAPSULES 56 £47.04 £1,030.85 £5,995.71 £10,905.39 ZONISAMIDE 100mg CAPSULES 56 £62.72 £1,862.33 £18,971.71 £29,030.09

ZONISAMIDE ORAL SUSPENSION 50mg/5ml - Special order £0.00 £0.00 £4,414.88 TOTAL COST £151,999.42 £1,687,051.27 £2,417,952.06

References

1 Epilepsies: diagnosis and management. Clinical Guideline 137. National institute for Clinical excellence. January 2012. https://www.nice.org.uk/guidance/cg137/resources/epilepsies-diagnosis- and-management-35109515407813 2 SIGN. SIGN 143: Diagnosis and management of epilepsy in adults. May 2015. 2015; Available from: http://www.sign.ac.uk/guidelines/fulltext/143.index.html. Date accessed March 2016 3 Briviact® (Brivaracetam) formulary application support pack. UCB Pharmaceuticals, January 2016 4 Summary of product characteristics (SPC). Briviact film-coated tablets. UCB Pharma Limited. Last Updated on eMC 21-Jan-2016. https://www.medicines.org.uk/emc/medicine/31452 5 Summary of product characteristics (SPC). Briviact 10mg/mL oral solution. UCB Pharma Limited. Last Updated on eMC 21-Jan-2016. https://www.medicines.org.uk/emc/medicine/31453 6 Summary of product characteristics (SPC). Briviact 10mg/mL solution for injection/infusion. UCB Pharma Limited. Last Updated on eMC 22-Jan-2016. https://www.medicines.org.uk/emc/medicine/31457 7 D’Souza J et al. Meta-analysis of nonpsychotic behavioral treatment emergent adverse events in brivaracetam and levetiracetam development programs. Epilepsia. 2012;53(Suppl 5):11 8 Ryvlin P et al. Adjunctive brivaracetam in adults with uncontrolled focal epilepsy: Results from a double-blind, randomized, placebo-controlled trial. Epilepsia. 2014;55(1):47-56 9 Biton V et al. Brivaracetam as adjunctive treatment for uncontrolled partial epilepsy in adults: A phase 3 randomised double-blind, placebo-controlled trial. Epilepsia. 2014;55(1):57-66 10 Klein P et al. A randomized, double blind, placebo-controlled, multicentre, parallel group study to evaluate the efficacy and safety of brivaracetam in adult patients with uncontrolled partial-onset seizures. Epilepsia. 2015;doi:10.1111/epi13212 11 Kwan P et al. Adjunctive brivaracetam for uncontrolled focal and generalized epilepsies: Results of a phase 3 double-blind randomised placebo controlled flexible dose trial. Epilepsia. 2014;55(1):38-46

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