Topiramate

(BAN, USAN, rINN)
Topiramate Chemical formula
Synonyms: KW-6485; McN-4853; RWJ-17021; Topiramaatti; Topiramat; Topir amato; Topir amatum. 2,3:4,5-DiO-isopropylidenetopyranose sulphamate.
Cyrillic synonym: Топирамат.

💊 Chemical information

Chemical formula: C12H21NO8S = 339.4.
CAS — 97240-79-4.
ATC — N03AX11.
ATC Vet — QN03AX11.

Pharmacopoeias.

In US.

USP 31

(Topiramate). A white to off-white powder. Freely soluble in dichloromethane. Store in airtight containers at a temperature of 20° to 25°, excursions permitted between 15° and 30°. Protect from light.

💊 Adverse Effects

Adverse effects associated with topiramate therapy include ataxia, impaired concentration, confusion, dizziness, fatigue, paraesthesia or hypoaesthesia, drowsiness, and difficulties with memory or cognition. Agitation, anxiety, nervousness, emotional lability, and mood disorders may also occur. Other reported adverse effects include abdominal pain, anorexia, asthenia, diplopia, leucopenia, nausea, nystagmus, insomnia, psychomotor retardation, impaired speech, altered taste, visual disturbances, and weight loss.

Effects on mental function.

For a review of the effects of antiepileptic therapy including topiramate on cognition and mood (including the risk of suicidal ideation).

Effects on the nervous system.

Hyperthermia was reported in 10.5% of patients taking topiramate compared with 0.15% of patients taking other antiepileptic drugs in one centre.1 Children under the age of 6 years, patients on daily doses of 6 mg/kg or more, and those exposed to high ambient temperatures were most at risk. Licensed product information recommends that children should be monitored closely for decreased sweating and hyperthermia, especially during warm or hot weather. Caution is also advised when giving topiramate with other drugs known to cause similar effects, for example, carbonic anhydrase inhibitors and antimuscarinics. Hemiparesis that resolved on withdrawal of topiramate has been reported2 in 2 patients, although both already had compromised neurological function.
1. Ziad EK, et al. Age, dose, and environmental temperature are risk factors for topiramate-related hyperthermia. Neurology 2005; 65: 1139–40
2. Stephen LJ, et al. Transient hemiparesis with topiramate. BMJ 1999; 318: 845.

Effects on sexual function.

Topiramate has been associated with sexual dysfunction1,2 in male and female patients; in all cases symptoms resolved with dosage reduction or withdrawal of the drug.
1. Holtkamp M, et al. Erectile dysfunction with topiramate. Epilepsia 2005; 46: 166–7
2. Sun C, et al. Reversible anorgasmia with topiramate therapy for headache: a report of 7 patients. Headache 2006; 46: 1450–3.

💊 Precautions

Topiramate should be used with caution in patients with renal or hepatic impairment. Adequate hydration is recommended to reduce the risk of developing renal calculi, especially in predisposed patients. Care is required when withdrawing topiramate therapy—see also Uses and Administration, below.

Breast feeding.

For comment on antiepileptic therapy and breast feeding.

Driving.

For a comment on antiepileptic drugs and driving.

Pregnancy.

For comments on the management of epilepsy during pregnancy.

💊 Interactions

For reports of an increased risk of hepatic impairment in patients taking topiramate with valproate.
1. Bourgeois BFD. Drug interaction profile of topiramate. Epilepsia 1996; 37: (suppl 2): S14–S17
2. Contin M, et al. Topiramate therapeutic monitoring in patients with epilepsy: effect of concomitant antiepileptic drugs. Ther Drug Monit 2002; 24: 332–7
3. Mimrod D, et al. A comparative study of the effect of carbamazepine and valproic acid on the pharmacokinetics and metabolic profile of topiramate at steady state in patients with epilepsy. Epilepsia 2005; 46: 1046–54.

Cardiac glycosides.

For the effect of topiramate on digoxin.

Sex hormones.

For the effects of antiepileptics including topiramate on oral contraceptives.

💊 Pharmacokinetics

Topiramate is readily absorbed after oral doses, with peak plasma concentrations achieved after about 2 hours. Bioavailability is not affected by the presence of food. Protein binding is about 9 to 17%. The volume of distribution in women is about half that in men. Topiramate crosses the placental barrier and is distributed into breast milk. In healthy subjects topiramate is not extensively metabolised; however, up to 50% of a dose may undergo metabolism in the liver in patients also receiving enzyme-inducing drugs. It is eliminated chiefly in urine, as unchanged drug and metabolites; mean plasma elimination half-life is about 21 hours. Steady-state concentrations are achieved after about 4 to 8 days in patients with normal renal function. Clearance is decreased in patients with impaired renal or hepatic function, and steady-state plasma concentrations may not be achieved for 10 to 15 days in the former. Children exhibit a higher clearance and shorter elimination halflife than adults. The pharmacokinetics of topiramate may be affected by use with other antiepileptics (see under Interactions, above).
1. Perucca E, Bialer M. The clinical pharmacokinetics of the newer antiepileptic drugs: focus on topiramate, zonisamide, and tiagabine. Clin Pharmacokinet 1996; 31: 29–46
2. Glauser TA, et al. Topiramate pharmacokinetics in infants. Epilepsia 1999; 40: 788–91
3. Öhman I, et al. Topiramate kinetics during delivery, lactation, and in the neonate: preliminary observations. Epilepsia 2002; 43: 1157–60
4. Ferrari AR, et al. Influence of dosage, age, and co-medication on plasma topiramate concentrations in children and adults with severe epilepsy and preliminary observations on correlations with clinical response. Ther Drug Monit 2003; 25: 700–8
5. Battino D, et al. Topiramate pharmacokinetics in children and adults with epilepsy: a case-matched comparison based on therapeutic drug monitoring data. Clin Pharmacokinet 2005; 44: 407–16.

💊 Uses and Administration

Topiramate, a sulfamate-substituted monosaccharide, is an antiepileptic used as adjunctive therapy in refractory partial seizures with or without secondary generalisation, seizures associated with the Lennox-Gastaut syndrome, and primary generalised tonic-clonic seizures. It may also be used as monotherapy in patients with newly diagnosed epilepsy who have generalised tonic-clonic seizures or partial seizures. Topiramate is also used for the prophylaxis of migraine. In the UK, for both adjunctive and monotherapy of epilepsy, the initial oral dose of topiramate is 25 mg at night for 1 week increased thereafter by increments of 25 or 50 mg at intervals of 1 to 2 weeks until the effective dose is reached. Daily doses of more than 25 mg should be taken in 2 divided doses. The usual daily dose for adjunctive therapy is 200 to 400 mg although some patients may require up to 800 mg daily. When used as monotherapy, usual doses range from 100 mg daily to a maximum of 400 mg daily. Similar target doses are also used in the USA for both adjunctive and monotherapy although higher initial doses of 50 mg daily with weekly increases thereafter are recommended in the licensed product information. For doses in children, see below. As with other antiepileptics, withdrawal of topiramate therapy or transition to or from another type of antiepileptic therapy should be made gradually to avoid precipitating an increase in the frequency of seizures. For a discussion on whether or not to withdraw antiepileptic therapy in seizure-free patients. The UK product information suggests decreasing the daily dose by 50 to 100 mg at weekly intervals. In the prophylaxis of migraine, topiramate is given orally in initial doses of 25 mg at night for 1 week, increased by 25-mg increments every week, to a usual dose of 50 mg twice daily. UK product information suggests decreasing the daily dose by 25 to 50 mg at weekly intervals when withdrawing topiramate therapy. Smaller increments or longer intervals between increments may be necessary if patients cannot tolerate the above regimens; US product information suggests that doses should be halved in patients with moderate to severe renal impairment regardless of indication (see also below).

Administration in children.

Topiramate is used as adjunctive therapy in children for refractory partial seizures with or without secondary generalisation, seizures associated with the LennoxGastaut syndrome, and primary generalised tonic-clonic seizures. It may also be used as monotherapy in those with newly diagnosed epilepsy who have generalised tonic-clonic seizures or partial seizures. In the UK, the initial oral dose for adjunctive therapy in children from 2 years of age is 25 mg. This is given as a single dose at night for 1 week, then increased by 1 to 3 mg/kg every 1 to 2 weeks until the effective dose is reached; these higher daily doses are divided and given twice daily. About 5 to 9 mg/kg daily is usually required, although up to 30 mg/kg has been given. For monotherapy, in children from 6 years of age, the initial daily oral dose is 0.5 to 1 mg/kg at night for the first week, increased thereafter by 0.5 to 1 mg/kg every 1 or 2 weeks, to a usual dose of 3 to 6 mg/kg daily in 2 divided doses; up to 16 mg/kg daily has been used. The adult dose (above) is recommended in those over 16 years of age. In the USA, licensed doses for adjunctive therapy are similar to those in the UK; however, monotherapy, which is limited to those 10 years of age and over, is given at usual adult doses.

Administration in renal impairment.

Patients with moderate to severe renal impairment take longer to reach steady-state plasma concentrations of topiramate than patients with normal renal function (see Pharmacokinetics, above) and the dosage regimen may need adjusting; US licensed product information recommends that usual adult doses (see above) be halved in such patients. In patients undergoing haemodialysis a supplemental dose equal to about one-half of the daily dose should be given in divided doses (at the start and finish of the procedure).

Alcohol withdrawal and abstinence.

Topiramate may be of use as an adjunct in achieving and maintaining abstinence in patients with alcohol dependence1,2.
1. Johnson BA, et al. Oral topiramate for treatment of alcohol dependence: a randomised controlled trial. Lancet 2003; 361: 1677–85
2. Johnson BA, et al. Topiramate for treating alcohol dependence: a randomized controlled trial. JAMA 2007; 298: 1641–51.

Bipolar disorder.

Mood-stabilising antiepileptics such as carbamazepine and valproate are alternatives to lithium in the management of bipolar disorder. Topiramate has also been investigated after favourable case reports,1,2 but randomised controlled studies3,4 have produced disappointing results and a systematic review5 found insufficient evidence for its use as monotherapy or adjunctive therapy.
1. Teter CJ, et al. Treatment of affective disorder and obesity with topiramate. Ann Pharmacother 2000; 34: 1262–5
2. Erfurth A, Kuhn G. Topiramate monotherapy in the maintenance treatment of bipolar I disorder: effects on mood, weight and serum lipids. Neuropsychobiology 2000; 42 (suppl 1): 50–1
3. Kushner SF, et al. Topiramate monotherapy in the management of acute mania: results of four double-blind placebo-controlled trials. Bipolar Disord 2006; 8: 15–27
4. Chengappa KNR, et al. Adjunctive topiramate therapy in patients receiving a mood stabilizer for bipolar I disorder: a randomized, placebo-controlled trial. J Clin Psychiatry 2006; 67: 1698–1706
5. Vasudev K, et al. Topiramate for acute affective episodes in bipolar disorder. Available in The Cochrane Database of Systematic Reviews; Issu
1. Chichester: John Wiley; 2006 (accessed 09/06/08).

Epilepsy.

Topiramate is used1-5 in epilepsy for refractory partial seizures, for primary generalised tonic-clonic seizures,6and in patients with the Lennox-Gastaut syndrome;7 in the UK, it may be a first-line option in some circumstances. Starting topiramate therapy gradually improves tolerability without delaying therapeutic response.8 Topiramate has also been investigated in children with infantile spasms (as for example in West’s syndrome),9 severe myoclonic epilepsy,10 and juvenile myoclonic epilepsy;11 it has been tried as a second-line drug in absence seizures and for tonic or atonic seizures. A retrospective review12 and later studies13,14 of the use of topiramate in such drug-resistant childhood epilepsies have concluded that it is efficacious and well tolerated. Topiramate has also been investigated as an alternative antiepileptic in the management of refractory status epilepticus.15,16
1. Lyseng-Williamson KA, Yang LPH. Topiramate: a review of its use in the treatment of epilepsy. Drugs 2007; 67: 2231–56
2. Sachdeo RC, et al. Topiramate: clinical profile in epilepsy. Clin Pharmacokinet 1998; 34: 335–46
3. Garnett WR. Clinical pharmacology of topiramate: a review. Epilepsia 2000; 41 (suppl 1); S61–S65
4. Glauser TA, et al. Topiramate monotherapy in newly diagnosed epilepsy in children and adolescents. J Child Neurol 2007; 22: 693–9
5. Jette NJ, et al. Topiramate add-on for drug-resistant partial epilepsy. Available in The Cochrane Database of Systematic Reviews; Issu
3. Chichester: John Wiley; 2008 (accessed 27/08/08)
6. Biton V. A randomized, placebo-controlled study of topiramate in primary generalized tonic-clonic seizures. Neurology 1999; 52: 1330–7
7. Sachdeo RC, et al. A double-blind, randomized trial of topiramate in Lennox-Gastaut syndrome. Neurology 1999; 52: 1882–7
8. Biton V, et al. Topiramate titration and tolerability. Ann Pharmacother 2001; 35: 173–9
9. Glauser TA, et al. Long-term response to topiramate in patients with West syndrome. Epilepsia 2000; 41 (suppl 1): S91–S94
10. Nieto-Barrera M, et al. Topiramate in the treatment of severe myoclonic epilepsy in infancy. Seizure 2000; 9: 590–4
11. Biton V, Bourgeois BFD. Topiramate in patients with juvenile myoclonic epilepsy. Arch Neurol 2005; 62: 1705–8
12. Yeung S, et al. Topiramate for drug-resistant epilepsies. Eur J Paediatr Neurol 2000; 4: 31–3
13. Al Ajlouni S, et al. The efficacy and side effects of topiramate on refractory epilepsy in infants and young children: a multicenter clinical trial. Seizure 2005; 14: 459–63
14. Grosso S, et al. Efficacy and safety of topiramate in refractory epilepsy of childhood: long-term follow-up study. J Child Neurol 2005; 20: 893–7
15. Towne AR, et al. The use of topiramate in refractory status epilepticus. Neurology 2003; 60: 332–4
16. Bensalem MK, Fakhoury TA. Topiramate and status epilepticus: report of three cases. Epilepsy Behav 2003; 4: 757–60.

Headache.

Topiramate is used for the prophylaxis of migraine. Results from placebo-controlled studies1-5 have shown a significant reduction in frequency of migraines in those patients receiving prophylactic topiramate. Topiramate has been tried for prophylaxis of cluster headache attacks6 and chronic tension-type headache7. It has also been used to control headache due to raised intracranial pressure.
1. Storey JR, et al. Topiramate in migraine prevention: a doubleblind, placebo-controlled study. Headache 2001; 41: 968–75
2. Brandes JL, et al. Topiramate for migraine prevention: a randomized controlled trial. JAMA 2004; 291: 965–73
3. Silberstein SD, et al. Topiramate in migraine prevention: results of a large controlled trial. Arch Neurol 2004; 61: 490–5
4. Silberstein SD, et al. Efficacy and safety of topiramate for the treatment of chronic migraine: a randomized, double-blind, placebo-controlled trial. Headache 2007; 47: 170–80
5. Diener H-C, et al. Topiramate reduces headache days in chronic migraine: a randomized, double-blind, placebo-controlled study. Cephalalgia 2007; 27: 814–23
6. Láinez MJA, et al. Topiramate in the prophylactic treatment of cluster headache. Headache 2003; 43: 784–9
7. Lampl C, et al. A prospective, open-label, long-term study of the efficacy and tolerability of topiramate in the prophylaxis of chronic tension-type headache. Cephalalgia 2006; 26: 1203–8.

Hyperhidrosis.

Reduced sweating has been associated with topiramate therapy (see Effects on the Nervous System under Adverse Effects, above). There have been 2 case reports1,2 of the use of topiramate in the treatment of hyperhidrosis.
1. Owen DB, Meffert JJ. The suppression of primary palmarplantar hyperhidrosis by topiramate. Br J Dermatol 2003; 148: 826–7
2. Hoehn-Saric R. Facial hyperhidrosis-induced social fear alleviated with topiramate. J Clin Psychiatry 2006; 67: 1157.

Motor neurone disease.

Topiramate has been tried as a potential therapy for amyotrophic lateral sclerosis but with disappointing results.1
1. Cudkowicz ME, et al. A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis. Neurology 2003; 61: 456–64.

Neuropathic pain.

Although carbamazepine is the drug of choice in the treatment of trigeminal neuralgia, topiramate has also been tried successfully.1 It has also been tried2,3 in the treatment of diabetic neuropathy and of phantom limb pain4.
1. Zvartau-Hind M, et al. Topiramate relieves refractory trigeminal neuralgia in MS patients. Neurology 2000; 55: 1587–8
2. Raskin P, et al. Topiramate vs placebo in painful diabetic neuropathy: analgesic and metabolic effects. Neurology 2004; 63: 865–73
3. Donofrio PD, et al. Safety and effectiveness of topiramate for the management of painful diabetic peripheral neuropathy in an open-label extension study. Clin Ther 2005; 27: 1420–31
4. Harden RN, et al. Topiramate for phantom limb pain: a timeseries analysis. Pain Med 2005; 6: 375–8.

Obesity.

Weight loss has been associated with topiramate therapy (see Adverse Effects, above) and it has been tried as an adjunct in the treatment of obesity and in overweight patients; topiramate appears to be reasonably well tolerated. It has also been tried in binge eating (see below).
1. Astrup A, Toubro S. Topiramate: a new potential pharmacological treatment for obesity. Obes Res 2004; 12 (suppl): 167S–173S.
2. Kirov G, Tredget J. Add-on topiramate reduces weight in overweight patients with affective disorders: a clinical case series. BMC Psychiatry 2005; 5: 19. Available at: http://www.biomedcentral.com/ content/pdf/1471-244X-5-19.pdf (accessed 09/06/08
3. Khazaal Y, et al. Long-term topiramate treatment of psychotropic drug-induced weight gain: a retrospective chart review. Gen Hosp Psychiatry 2007; 29: 446–9
4. Eliasson B, et al. Weight loss and metabolic effects of topiramate in overweight and obese type 2 diabetic patients: randomized double-blind placebo-controlled trial. Int J Obes 2007; 31: 1140–7.

Psychiatric disorders.

Topiramate has been tried in several psychiatric disorders, including schizophrenia1, disturbed behaviour2, post-traumatic stress disorder3, and social anxiety disorder4. It has also been tried in binge eating.5-7 For its use in bipolar disorder see above.
1. Tiihonen J, et al. Topiramate add-on in treatment-resistant schizophrenia: a randomized, double-blind, placebo-controlled, crossover trial. J Clin Psychiatry 2005; 66: 1012–15
2. Nickel MK, et al. Topiramate treatment of aggression in female borderline personality disorder patients: a double-blind, placebo-controlled study. J Clin Psychiatry 2004; 65: 1515–19
3. Berlant JL. Prospective open-label study of add-on and monotherapy topiramate in civilians with chronic nonhallucinatory posttraumatic stress disorder. BMC Psychiatry 2004; 4: 24. Available at: http://www.biomedcentral.com/content/pdf/ 1471-244X-4-24.pdf (accessed 09/06/08
4. Van Ameringen M, et al. An open trial of topiramate in the treatment of generalized social phobia. J Clin Psychiatry 2004; 65: 1674–8
5. Nickel C, et al. Topiramate treatment in bulimia nervosa patients: a randomized, double-blind, placebo-controlled trial. Int J Eat Disord 2005; 38: 295–300
6. Tata AL, Kockler DR. Topiramate for binge-eating disorder associated with obesity. Ann Pharmacother 2006; 40: 1993–7
7. Claudino AM, et al. Double-blind, randomized, placebo-controlled trial of topiramate plus cognitive-behavior therapy in bingeeating disorder. J Clin Psychiatry 2007; 68: 1324–32.

Tre m o r.

A beta blocker is often the first drug used in patients with essential tremor who require regular treatment; however, topiramate1,2 has also been tried.
1. Galvez-Jimenez N, Hargreave M. Topiramate and essential tremor. Ann Neurol 2000; 47: 837–8
2. Ondo WG, et al. Topiramate in essential tremor: a double-blind, placebo-controlled trial. Neurology 2006; 66: 672–7.

💊 Preparations

Proprietary Preparations

Arg.: Neutop; Topamac; Topictal; Topirex; Austral.: To p a m a x ; Austria: To p a m a x ; Belg.: To p a m a x ; Braz.: To p a m a x ; Canad.: To p a m a x ; Chile: Topamax; Toprel; Cz.: To p am a x ; Top ir a g i s ; Denm.: Epitomax; Topimax; Fin.: To p i m a x ; Fr.: Epitomax; Ger.: To p a m a x ; Gr.: To p a m a c ; Hong Kong: To p a m a x ; Hung.: To p a m a x ; India: Top a m a c ; To p ama te; Indon.: To p a m a x ; Irl.: Topamax; Israel: Topamax; Ital.: Topamax; Malaysia: To p a m a x ; Mex.: To p a m a x ; Neth.: Epitomax; Topamax; Norw.: To p i m a x ; NZ: To p a m a x ; Philipp.: Topamax; Pol.: To p a m a x ; Port.: To p a m ax ; To p t r i x ; Rus.: To p a m a x ( Топамакс); S.Afr.: To pa m ax ; Singapore: To p a m a x ; Spain: Bipomax; Topamax; Swed.: Topimax; Switz.: Topamax; Thai.: To p am a x ; Turk.: To pa m ax ; UK: To p ama x; USA: To p a m a x; Venez.: To p a m a x .
Published November 27, 2018.