Pharmacology

Pharmacology. The exact mechanism of action as an antiepileptic is not established, but various explanations are as follows:

Pharmacokinetics. Topiramate has favorable pharmacokinetic characteristics and fewer drug interactions than some traditional antiepileptic drugs. The important points are as follows:

Formulations. An extended-release preparation of topiramate, compared with the immediate-release formulation, provides equivalent plasma exposure with an extended absorption profile (34). The extended-release formulation offers a once-daily alternative to twice-daily topiramate, with reduced fluctuations in blood levels of the drug. A study using computer simulations of population pharmacokinetics has shown that dosing irregularities with the once-daily extended-release formulation should pose no greater risk than with twice-daily immediate-release topiramate (03). In the event of a delayed or omitted extended-release dose, topiramate concentrations can be restored by administering the delayed/omitted dose at any time during the next dosing interval.

Pharmacogenetics. Heavy drinkers with alcohol dependence carrying the single nucleotide polymorphism rs2832407 in GRIK1 gene, which encodes the kainate GluK1 receptor subunit, are more likely to respond to treatment with topiramate, resulting in reduction of heavy drinking days (20). This finding will contribute to the personalized management of alcoholism.

Therapeutic drug monitoring. In addition to clinical observations, analysis of plasma concentration of topiramate is of importance for the individual adjustment of the administered dose to the patient. A liquid chromatography mass spectrometry–based validated method can simultaneously determine topiramate and its main metabolites in plasma over the selected analytical range (25). A bioanalytical method for the analysis of topiramate in plasma samples by capillary electrophoresis with capacitively coupled contactless conductivity detection of plasma samples has enabled the identification of 80% of undermedicated patients (18).

Clinical trials

In double-blind, placebo-controlled trials, add-on therapy with topiramate given 400 mg daily to 1000 mg daily reduced the seizure rate by 50% or more in 35% to 52% of adult patients with resistant partial epilepsy (with or without secondarily generalized seizures) compared with 0% to 19% of placebo recipients. A 200 mg daily dosage was less effective. Randomized, double-blind clinical trials are listed in Table 1.

Table 1. Clinical Trials of Topiramate

Indications

Off-label uses

Contraindications

Topiramate is contraindicated in patients with hypersensitivity to any component of the product.

Goals and duration of treatment

Topiramate is used as an add-on therapy to other antiepileptic drugs with the aim of controlling seizures as completely as possible. The possibility exists of intolerance of topiramate at relatively low doses. Those who tolerate topiramate have a good chance of seizure control. The drug requires about 2 months to elicit its full effect. Therapy is for an indefinite duration, although the experience of follow-up is currently about 7 years. Therapy should not be withdrawn suddenly, as a risk of aggravation of seizures exists.

Topiramate, administered orally with a treatment latency of more than 8 days, resulted in cessation of seizures in 27.4% of treatment-resistant status epilepticus and superrefractory status epilepticus and can be considered an alternative to other options for treating these conditions (11).

Dosing

The total daily adult dose of topiramate is 400 mg daily in 2 divided doses. Therapy is started at 50 mg daily and titrated to the effective dose. In children, a dose of 0.5 to 1 mg/kg daily followed by weekly increments of 0.5 to 1 mg/kg or up to 6 mg/kg daily is the norm. When clinicians individualize topiramate dosage according to clinical response, the stabilized topiramate dosage as add-on therapy is influenced by baseline seizure frequency.

Special considerations

Pediatric. Topiramate has been used in clinical trials on pediatric patients. Although topiramate has been approved for prevention of migraine in children as young as 12 years, a metaanalysis of randomized controlled trials shows that topiramate may not achieve a more effective clinical trial endpoint than placebo in the prevention of migraines in patients less than 18 years of age, and may lead to more adverse effects (21).

Geriatric. No age-related differences in effectiveness or adverse effects have been seen; however, topiramate should be used with caution in age-associated renal insufficiency.

Pregnancy. Topiramate has demonstrated selective developmental toxicity in experimental animals, including teratogenicity. There is an association between topiramate use early in pregnancy and the risk of oral clefts (17). It should be used in pregnancy only if potential benefits outweigh potential risks. Serum concentrations of topiramate decline gradually throughout pregnancy, and therapeutic drug monitoring may be useful (32).

Renal insufficiency. Clearance of topiramate is impaired and the dose needs to be reduced.

Interactions

Oral contraceptives. Topiramate can reduce the estrogen component of oral contraceptive medications.

Other antiepileptic drugs. Concentration of concomitantly given phenytoin may increase 25%, and topiramate decreases by 48%. With carbamazepine, topiramate concentration may decrease by 40%. Concentration of concomitantly administered valproic acid may decrease by 11%, and topiramate may decrease by 14%. Interactions with other antiepileptic drugs are either not evaluated or insignificant.

Digoxin. Serum digoxin area under the curve decreases by 12% with concomitant topiramate.

Phentermine. A fixed-dose combination of topiramate and phentermine, an appetite-suppressant amphetamine, has been refused marketing authorization in the European Union after being licensed in the United States for weight control in obesity. The combination is also in clinical development for sleep apnea syndrome. Adverse effects of the 2 drugs in this combination are due to synergistic interaction and include psychiatric disorders, cardiac arrhythmias, and metabolic acidosis.

Adverse effects

A systematic review of antiepileptic drugs using the indication of epilepsy alone is not enough for the evaluation of adverse events of any antiepileptic drug; however, the addition of trials for nonepilepsy indications can improve the assessment (09).

Renal stones. One and a half percent of the patients in clinical trials with topiramate were reported to develop renal stones, but nonambulatory and neurologically impaired individuals in a long-term care facility appeared to be at higher risk of developing kidney stones with topiramate (13). The mechanism is that topiramate, like other carbonic anhydrase inhibitors, reduces urinary citrate excretion and increases urinary pH. Increased fluid intake, by increasing urinary output, reduces the concentration of substances involved in stone formation. A nationwide population-based cohort study in Taiwan, conducted between 1997 and 2008, concluded that the incidence of renal stones in patients treated with topiramate was no higher than in age- and gender-matched controls (28).

Oligohidrosis and hyperthermia. These have been reported as adverse effects associated with use of topiramate. Sweat production is decreased, as detected by a pilocarpine iontophoresis sweat test. The effect seems to be more significant in children than in adults.

Paresthesias. These are associated with the use of carbonic anhydrase inhibitors and can be controlled by supplemental potassium.

Drowsiness, psychomotor slowing, and cognitive impairment. These effects are dose-related and occur more frequently at higher doses. It is difficult to differentiate them from similar effects known to occur with concomitant antiepileptic drugs. Mental slowing and word-finding difficulties can be significantly reduced by using 25 mg dose increments fortnightly as opposed to 100 mg weekly. Topiramate at a dose of 100 mg is effective in the treatment of migraine, but electrophysiological studies have shown that cognitive functions are adversely affected (26).

Topiramate is known to cause language impairment. Neuropsychological studies and fMRI findings suggest a mechanism by which topiramate impairs cognitive processing in language network areas (34).

Visual adverse effects. The following adverse effects have been documented with topiramate therapy: abnormal vision, acute secondary angle-closure glaucoma, acute myopia, and suprachoroidal effusions. All findings are reversible if recognized early and if the drug is discontinued.