Topiramate toxicity

Six patients with severe epilepsy developed stuporous encephalopathy with marked cognitive impairment when taking topiramate with valproate (5 patients) or when taking topiramate alone (1 patient). Four of the patients had hyperammonaemia which resolved when topiramate or valproate were withdrawn. The toxicity was possibly due to a synergistic effect of valproate and topiramate on liver ornithine metabolism resulting in hyperammonaemia. It was also possible that the encephalopathy was due to topiramate toxicity in at-risk patients such as those with pre-existing chronic encephalopathy. ... 

Drug overdose Seven cases of acute topiramate toxicity observed in two clinical units of poison centers have been described [333" ]. The doses of topiramate were 11-218 mg/kg. Somnolence was characteristic and vertigo, agitation, and mydriasis were less common. There was a metabolic acidosis in four cases. One patient who had not previously taken topiramate and who had taken 31 mg/kg had three secondarily generalized tonic-clonic seizures. All recovered without sequelae and were discharged after 4-8 days. 

Marriott D, Levy R, Doyle T, Ray J. Posa-conazole-induced topiramate toxicity. Ann Intern Med 2009 151(2) 143. 

Langmsin, L.J. Kaliciak, HA. Boone, SA. Fatal acute topiramate toxicity, JAncd.ToxicoL, 2003, 27, 323-324. [topiramate LC-MS gabapentin vigabatrin droperidol is internal standard]... 

Lithium toxicity occurred in a patient who was taking lithium and had topiramate added (608). 

Abraham G, Owen J. Topiramate can cause lithium toxicity. J Clin Psychopharmacol 2004 24 565-7. 

TOPIRAMATE ANTICANCER AND IMMUNOMODULATING DRUGS-IMATINIB t topiramate levels Imatinib is a potent inhibitor of CYP2C9-mediated metabolism of topiramate Watch for the early features of toxicity. If necessary, consider using alternative drugs while the patient is being given imatinib... 

Phenobarbital Phenytoin Primidone Felbamate Lamotrigine Tiagabide Topiramate Valproate Zonisamide Clobazam Clonazepam Diazepam usually compensated by the effect of the added drug risk of toxicity when interfering drug is discontinued drug... 

Table IV-1 -3 summarizes the mechanisms, indications for use, and potential toxic effects of some i newer anticonvulsants. Those listed are felbamate, gabapentin, lamotrigine, tiagabine, topiramate, and j...

TOXICITY Topiramate is well tolerated. Common adverse effects are somnolence, fatigue, weight loss, and nervousness. The drug can precipitate renal calcuh (probably due to inhibition of carbonic anhydrase). Topiramate has been associated with cognitive impairment patients may also complain about a change in the taste of carbonated beverages. 

Topiramate plasma levels may be reduced by carbamazepine. Carbamazepine levels are not affected by topiramate. However, one report suggests that the toxicity seen when topiramate is added to maximum tolerated doses of carbamazepine may respond to a reduction in the carbamazepine dose. 

In a study in 12 epileptic patients topiramate titrated up to a maximum of 400 mg twice daily had no effect on the steady-state plasma levels of carbamazepine 300 to 800 mg every 8 hours or on its main metabolite, carbamazepine-10,11-epoxide. An earlier study in epileptic patients also reported that topiramate does not affect the pharmacokinetics of carbamazepine. In contrast, another report describes 2 patients taking a maximum tolerated dose of carbamazepine who started treatment with topiramate and subsequently developed symptoms suggestive of carbamazepine toxicity. In both these cases, the symptoms resolved when the carbamazepine dose was reduced, and this enabled continued titration of the topiramate dose in one. A review of the clinical use of these two drugs found another 23 cases that fitted this pattern. Carbamazepine levels were not reported. ... 

Two isolated reports describe elevated serum-lithium levels and evidence of toxicity in patients also taking topiramate. No important pharmacokinetic interaction has been seen in healthy subjects. 

The reasons for these reactions are not known, but topiramate is mainly eliminated by renal excretion and high doses of topiramate may competitively interfere with lithium excretion. Similarly, lithium may affect topiramate clearance. Some of the toxicity could have been due to the adverse effects of either drug, with the weight loss in the first case possibly disturbing the sodium excretion, which could have affected the loss of lithium in the urine. 

These cases highlight the possible risk of elevated serum-lithium levels especially if high doses of topiramate are used. Patients on lithium should be aware of the symptoms of lithium toxicity and told to report them immediately should they occur. This should be reinforced when they are given topiramate. Consider monitoring lithium levels in patients newly started on this combination and carefully adjusting the dose of topiramate and/or lithium to minimise adverse effects. ... 

Drug overdose Of 16 796 toxic exposures to antiepileptic drugs (phenytoin, valproic acid, and carbamazepine) in the USA in 2006, 12 resulted in death, as reported by the US Toxic Surveillance System [67 ]. Some specific problems determined by overdose of some old and new antiepileptic drugs have been briefly reviewed. For example, topiramate can cause a significant metabolic acidosis, lamotrigine Stevens-Johnson syndrome, oxcarbazepine hyponatremia, and levetiracetam psychosis. Possible adoption of guidelines for critical care management of overdose are discussed. 

One patient who developed impaired vision while taking topiramate for symptomatic epilepsy had signs of a maculopathy [309" ]. The topiramate was withdrawn, but vision failed to improve significantly over 6 months of follow-up. The authors speculated that topiramate, like vigabatrin, may cause persistent visual impairment through direct retinal toxicity. 

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