Topiramate: new indication in migraine prophylaxis Savvas Hadjikoutis MD, MRCP

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1 Topiramate: new indication in migraine prophylaxis Savvas Hadjikoutis MD, MRCP PRODUCT PROFILE Proprietary name: Topamax Constituent: topiramate Indication: prophylaxis of migraine headache; initiation of treatment should be restricted to specialist care and treatment should be managed under specialist supervision or shared-care arrangements Dosage and method of administration: in adults and children over 16, titration should begin at 25mg nightly for one week, then increased in increments of 25mg per day administered at one-week intervals; the recommended total daily dosage is 100mg in two divided doses; tablets should not be broken; can be taken without regard to meals; Topamax Sprinkle Capsules may be swallowed whole or may be administered by carefully opening the capsule and sprinkling the entire contents on a small amount (teaspoon) of soft food, eg apple sauce, mashed banana, ice cream or yoghurt; this drug/food mixture should be swallowed immediately and not chewed Contraindication: hypersensitivity to any component Precautions: subjects with known renal impairment may require a longer time to reach steady state at each dose; some patients, especially those with a predisposition to nephrolithiasis, may be at increased risk of renal stone formation and associated signs and symptoms such as renal colic, renal pain or flank pain; patients should be monitored for signs of depression and referred for appropriate treatment if necessary; patients and their carers should be advised to seek medical advice immediately should suicidal thoughts emerge; acute myopia with secondary angle-closure glaucoma has been reported rarely in both children and adults; hyperchloraemic, nonanion gap, metabolic acidosis is associated with treatment; before discontinuation of treatment, dosage should be gradually reduced over at least two weeks to minimise the possibility of rebound migraine headaches; significant weight loss may occur during longterm treatment; it is recommended that patients on long-term treatment should be regularly weighed and monitored for continuing weight loss Pregnancy and lactation: should not be used during pregnancy or breastfeeding Interactions: phenytoin and carbamazepine, digoxin, combined oral contraceptives, hydrochlorothiazide, metformin, pioglitazone Side-effects: 5 per cent or more: fatigue, paraesthesiae, dizziness, hypoaesthesia, language problems, nausea, diarrhoea, dyspepsia, dry mouth, weight decrease, anorexia, somnolence, difficulty with memory, difficulty with concentration/attention, insomnia, anxiety, mood problems, depression, taste perversion, abnormal vision Presentation/cost: 25mg, 50mg, 100mg, 200mg tablets: 25mg 60, 19.08; 50mg 60, 32.12; 100mg 60, 55.31; 200mg 60, ; 15mg, 25mg and 50mg Sprinkle: 15mg 60, 15.70; 25mg 60, 23.55; 50mg 60, The indications for topiramate (Topamax) have recently been extended to include migraine prophylaxis. This New products review presents the trial data for its efficacy and safety and suggests its role in treatment. Migraine is a recurrent, disabling neurological disorder, with an estimated people being absent from work or school every working day in the UK because of a migraine attack. The cost of missed workdays and impaired performance associated with migraines in the UK totals around 25 million each year. In addition to the wide range of drug treatments, topiramate (Topamax) has obtained a licence for use (under specialist supervision) in the prevention of migraine in patients over 16 years. Mechanism of action Migraine is considered a disorder characterised by neuronal hyperexcitability. As such, it is not surprising that certain antiepileptic drugs that act by modulating neuronal function and decreasing sensitisation through effects on voltage- and receptor-activated ion channels and preventing neurotransmitters and neuropeptide release are effective in the prophylactic management of migraine. 16 Prescriber 19 October

2 50% reduction Change in Patients lost to in monthly body weight study due to frequency side-effects 200mg 52% -3.8% 33% 100mg 54% -3.8% 20% 50mg 36% -2.4% 17% placebo 23% +0.3% 10% Table 1. Reduction in migraine frequency, change in body weight and patients dropping out of study with 200mg, 100mg and 50mg topiramate and placebo 2 Topiramate is a chemically novel and clinically broad-spectrum neuroactive drug. 1 It has a negative effect on voltage-activated Na and Ca channels and glutamate receptor modulation, and a positive effect on GABA receptors. It also inhibits carbonic anhydrase activity. Collectively, modulation of each of these processes leads to a reduction of excitatory neurotransmission and enhancement of inhibitory neurotransmission. Clinical trials Several large, randomised, doubleblind, placebo-controlled pivotal trials have now established topiramate as an effective migraine preventive treatment. In the first pivotal phase III clinical trial of 487 patients, 2 the efficacy and safety of topiramate (50, 100 and 200mg per day) was assessed in the prevention of migraine headaches in a 26-week, multicentre, randomised, doubleblind, placebo-controlled study (MIGR-001). The responder rate (patients with 50 per cent reduction in monthly migraine frequency) was 52 per cent for patients receiving topiramate 200mg per day (p<0.001 vs placebo), 54 per cent for patients receiving 100mg per day (p<0.001), and 36 per cent for those taking 50mg per day (p=0.039, see Table 1). Patients receiving placebo had a reduction rate of 23 per cent. Topiramate treatment was also associated with reduced consumption of acute treatment medications, and the onset of efficacy was observed within the first month of treatment. The 200mg per day dose was not significantly more effective than the 100mg dose. The most common adverse events were paraesthesiae, fatigue, nausea, anorexia and abnormal taste. Body weight was reduced an average of 3.8 per cent in patients in both the 100mg and 200mg per day groups. The efficacy and safety of topiramate (50, 100 and 200mg per day) in the prevention of migraine headaches was assessed in a second 26-week, multicentre, randomised, double-blind, placebo-controlled study (MIGR 002). 3 A total of 483 patients were randomised to the four treatment groups (placebo and topiramate 50mg, 100mg and 200mg per day). A significantly greater proportion of patients exhibited at least a 50 per cent reduction in mean monthly migraines in the groups treated with topiramate 50mg per day (39 per cent, p=0.009), 100mg per day (49 per cent, p<0.001) and 200mg per day (47 per cent, p<0.001). The onset of efficacy was observed as early as the first month of treatment. The effects of topiramate on health-related quality of life measures (HRQoL) were assessed in a 18 Prescriber 19 October

3 pooled analysis of three 26-week topiramate migraine trials. 4 Topiramate 100mg per day was associated with significant improvements in HRQoL in patients with migraine up to six months following initiation of treatment. How topiramate compares to other products The relative efficacy of many commonly prescribed prophylactic drugs has not been well established. In 2000, the US Headache Consortium published an exhaustive, evidence-based review of the medical literature to identify which of the available migraine prophylactic medications demonstrated efficacy based on the quality of published scientific evidence. 5 The conclusion of the review was that only four medications propranolol, amitriptyline (unlicensed indication), timolol and sodium valproate (unlicensed indication) had good-quality evidence of efficacy in migraine prophylaxis ( 50 per cent responder rate compared to placebo). No formal head-to-head comparison trials of topiramate with other drugs for migraine prevention have been carried out. However, a large, randomised, double-blind, controlled trial (MIGR- 003, n=575) provides additional support for the efficacy and safety of topiramate in migraine prevention. 6 In this trial, topiramate 100mg per day was associated with significant improvement in migraine frequency, rate of rescue medication use and 50 per cent responder rate compared with placebo. In addition, this trial included propranolol as an active control. Although the study was not designed to compare the two agents, topiramate 100mg per day was at least as effective as 160mg per day propranolol, and similar from a tolerability perspective. Side-effects and interactions Side-effects The most common treatment-limiting adverse events observed in the clinical trials (occurring in 3 per cent or more of all topiramate- Prescriber 19 October

4 Placebo Topiramate Topiramate Topiramate (n=445) 50mg per day 100mg per day 200mg per day (n=235) (n=386) (n=514) paraesthesiae fatigue loss of appetite nausea diarrhoea weight loss taste alteration somnolence insomnia memory difficulty language difficulties concentration difficulty mood changes anxiety Table 2. Incidence of most common adverse events in multicentre clinical trials 7 treated patients) were paraesthesiae, fatigue, nausea, difficulty with concentration and attention, and insomnia (see Table 2). 7 There were no clinically important changes in clinical laboratory tests of liver function, renal function or haematological parameters, or abnormalities in vital sign measurement or neurological examination. Paraesthesiae are usually transient and self-limiting. They may occur for the first days to weeks of a dosage increase and require no treatment. The commonest cognitive side-effects are memory difficulties, language problems (word searching or word delay) and impaired concentration. Topiramate is also associated with weight loss (average body weight decrease 2-7 per cent). These side-effects are usually dose related. Topiramate is a carbonic anhydrase inhibitor and may promote renal stone formation by reducing urinary citrate excretion and by increasing urinary ph. The incidence of renal stones in the topiramate migraine trials was, however, low (0.8 per cent). All patients should be instructed in adequate hydration. Transient acute myopia and angle-closure glaucoma are rare, but they have been reported during topiramate therapy. Symptoms are self-limited and typically resolve within one to two weeks of discontinuation. 8 Drug interactions Formal drug interaction studies have shown that no interactions occur with sumatriptan or propranolol. At topiramate dosages of mg per day no interactions occur with the combined oral contraceptive pill (COC). 9 At dosages above 200mg per day, however, decreases have been observed in ethinylestradiol. In those circumstances, a COC containing at least 50µg oestrogen should be used. Alternatives include injectable progestogenonly contraceptives or nonhormonal preparations, eg IUDs, condoms, etc. Pregnancy The effects of topiramate on human fetal development are uncertain. Malformations have been reported in experimental studies with rats, mice and rabbits. When and how to use topiramate in migraine prevention Topiramate is licensed for migraine prophylaxis in adults and children aged over 16 years. Treatment needs to be initiated by a specialist and continued under specialist supervision or sharedcare agreements. Topiramate has been studied in the largest controlled trials ever completed in migraine preventive therapy, and offers migraine patients an important choice for prophylaxis. According to clinical evidence and recommendations, 10,11 topiramate should be considered as a potential alternative to beta-blockers, sodium valproate and amitriptyline. It should be the treatment of choice in migraine patients who also suffer from epilepsy. The recommended total daily dose for prophylaxis is 100mg administered in two divided doses. The starting dose is 25mg once per day, increased by 25mg every two weeks to achieve the maintenance dose of 50mg twice daily. In the patient who tends to experience side effects more than most, a starting dose of 15mg may be prudent (a 15mg sprinkle capsule is available). Therapeutic benefit may be experienced as early as one month. However, patients should be instructed that an adequate trial requires at least two to three months, and that not all patients 20 Prescriber 19 October

5 Key points topiramate is licensed as a new option in migraine prophylaxis it has been studied in the largest controlled trials ever completed in migraine preventive therapy multiple mechanisms that reduce brain excitability lead to a beneficial effect in migraine 100mg per day dose reduces migraine frequency by >50 per cent in about 50 per cent of patients therapeutic benefit may be experienced as early as one month the 100mg per day dose appears to be well tolerated will become headache free on the drug. For well-controlled migraine patients, topiramate can be continued for as long as desired. However, if migraine frequency is reduced by per cent after approximately three to six months, a drug holiday may be considered. Topiramate is more expensive than longer-established drugs for migraine prophylaxis. The annual cost of topiramate 100mg daily is 391 compared to propranolol 160mg daily 25, amitriptyline 75mg daily 50 and sodium valproate 1200mg daily References 1. Whit HS. Molecular pharmacology of topiramate: Managing seizures and preventing migraine. Headache 2005;45 (suppl 1):S48-S Silberstein SD, Neto W, Schmitt J, et al. Topiramate in migraine prevention: results of a large, controlled trial. Arch Neurol 2004;61: Brandes JL, Saper JR, Diamond M, et al. Topiramate for migraine prevention: a randomised controlled trial. JAMA 2004;291: Dahlof C, Papadopoulos G, Jacobs O, et al. Topiramate improves healthrelated quality of life when used to prevent migraine. Poster presented at the 15 th Annual Migraine Trust International Symposium. London; September Silberstein SD. Practice parameter: evidence based guidelines for migraine headache. Report of the quality Standards Subcommittee of the American Academy. Neurology 2005;55: Diener HC, Tfelt-Hansen P, Dahlof C, et al. Topiramate in migraine prophylaxis: results from a placebo-controlled trial with propranolol as an active control. J Neurol 2004;251: Adelman S, Cabez MSA, Jacobs D, et al. Analysis of safety data obtained from over 1500 patients receiving topiramate for migraine prevention. Poster presented at the American Headache Society 46 th Annual Scientific Meeting. Vancouver, British Columbia, Canada; June Fraunfelder FW, Fraunfelder FT, Keates EU. Topiramate-associated acute, bilateral, secondary angle-closure glaucoma. Ophthalmology 2004; 111: Doose DR, Wang SS, Padmanabhan M, et al. Effect of topiramate or carbamazepine on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in healthy obese and nonobese female subjects. Epilepsia 2003;44: Modi S, Loweder D. Medications for migraine prophylaxis. American Family Physician 2006;73: Silberstein S. Topiramate in migraine prevention. Headache 2005; 45(suppl 1):S57-S Topiramate for migraine prophylaxis. Drug and Therapeutics Bulletin 2006;44:62-4. Dr Hadjikoutis is consultant neurologist at Morriston Hospital, Swansea 22 Prescriber 19 October