Topiramate

In acute Topiramate overdose, if the ingestion is recent, the stomach should be emptied immediately by lavage or by induction of emesis. Activated charcoal has been shown to adsorb topiramate in vitro. Treatment should be appropriately supportive. Hemodialysis is an effective means of removing topiramate from the body. (L1712)

Alcohol or central nervous system depression-producing medications administered concurrently with /topiramate/ may enhance CNS depression.

12 % increase in amitriptyline AUC and Cmax with concommitant use /of topiramate; some patients may experience large increases in amitriptyline concentration in the presents of topiramate; amitriptyline dosage adjustments should be made according to patient's clinical response and not on the basis of plasma levels.

Anticholinergic /agents/ or carbonic anhydrase inhibitors such as acetazolamide or dichlorphenamide predispose patients to heat-related disorders; caution should be used when administered concurrently with topiramate. Carbonic anhydrase inhibitors may create a physiological environment that increases the risk of renal stone formation; concommitant use should be avoided.

Mean carbamazepine area under the plasma concentration-time curve (AUC) was unchanged or changed by less than 10%, whereas the AUC of topiramate was decreased by 40% when these two medications were given concurrently during controlled clinical studies.

For more Interactions (Complete) data for TOPIRAMATE (12 total), please visit the HSDB record page.

Prospective studies suggest that less than 1% of subjects develop elevations in serum aminotransferase levels during long term topiramate therapy. Clinically apparent hepatotoxicity from topiramate is quite rare and usually arises in patients receiving multiple other anticonvulsants. Topiramate is metabolized by CYP 3A4 and may increase the risk of valproate or other anticonvulsant hepatotoxicity. A distinctive syndrome is the development of lethargy, weakness with marked serum aminotransferase elevations and hyperammonemia arising within 2 to 3 weeks of the addition (or dose increase) of topiramate to long term valproate therapy. While valproate alone can cause a similar syndrome, it appears much more common (~1%) with the combination than with valproate alone (~0.1%). This syndrome has several features suggestive of Reye syndrome (hyperammonemia, hypoglycemia, rapid reversal of injury) and in many instances is preceded by a acute viral illness. Topiramate by itself has only rarely been linked to clinically apparent liver injury and the clinical features and course of injury have not been well defined. Topiramate has not been linked to cases of the anticonvulsant hypersensitivity syndrome and is considered a safe alternative in patients with that syndrome.

Oral. Rapid with pleak plasma concentrations occurring after 2 hours and a bioavailability of 80%. The pharmacokinetic profile of the extended release formulation is non linear at 25 mg due to binding of topiramate to carbonic anhydrase in red blood cells. The peak plasma concentration was 24 hours after a single 200 mg oral dose of the extended release formulation. It is also bioequivalent to immediate-release tablet that has been administered twice-daily. Fluctuation of topiramate plasma concentrations at steady-state for Trokendi XR® administered once-daily was approximately 26% and 42% in healthy subjects and in epileptic patients, respectively, compared to approximately 40% and 51%, respectively, for immediate-release topiramate. When topiramate is given to elderly and young adults, the maximum plasma concentration was achieved in 1 to 2 hours.

It is not known if topiramate is distributed into breast milk; however, it is distributed into the milk of lactating rats. ...

/Topiramate/ (TPM) concentrations in plasma and breast milk were measured with fluorescence polarization immunoassay (FPIA) in five women with epilepsy treated with TPM during pregnancy and lactation. ... The mean milk/maternal plasma concentration ratio was 0.86 (range, 0.67-1.1) at 2-3 weeks after delivery. The milk/maternal plasma concentration ratios at sampling 1 and 3 months after delivery were similar (0.86 and 0.69, respectively). Two to 3 weeks after delivery, two of the breast-fed infants had detectable (>0.9 microM) concentrations of TPM, although below the limit of quantification (2.8 microM), and one had an undetectable concentration. Our limited data suggest free passage of TPM over the placenta and an extensive transfer into breast milk. Breast-fed infants had very low TPM concentrations, and no adverse effects were observed in the infants.

Distribution of topiramate into human milk has not been evaluated in controlled studies; however, limited data indicate that the drug may distribute extensively into milk in humans.

Signs and Symptoms of Overdose

The precise mechanism of action of topiramate is not known. However, studies have shown that topiramate blocks the action potentials elicited repetitively by a sustained depolarization of the neurons in a time-dependent manner, suggesting a state-dependent sodium channel blocking action. Topiramate also augments the activity of the neurotransmitter gamma-aminobutyrate (GABA) at some subtypes of the GABA_A receptor (controls an integral chloride channel), indicating a possible mechanism through potentiation of the activity of GABA. Topiramate also demonstrates antagonism of the AMPA/kainate subtype of the glutamate excitatory amino acid receptor. It also inhibits carbonic anhydrase (particularly isozymes II and IV), but this action is weak and unlikely to be related to its anticonvulsant actions.

Symptoms of overdose include abdominal pain, agitation, blurred vision, convulsions, depression, dizziness, double vision, drowsiness, impaired coordination, impaired mental activity, low blood pressure, reduced consciousness, severe diarrhea, sluggishness, and speech problems.

/HUMAN EXPOSURE STUDIES/ Reversible side effects of the sulfa-containing antiepileptic drug (AED), topiramate (TPM) are reported. These effects differ from those of other AEDs in that language impairment was the predominant cognitive complaint. Information was available for 42 patients exposed to TPM. Twenty-two (52%) complained of adverse effects; 12, specifically of deficits in language-related functions. Brief neuropsychological testing in four patients on TPM confirmed verbal deficits. These deficits could appear shortly after initiating TPM and disappear variably after drug withdrawal.

/SIGNS AND SYMPTOMS/ Overdoses of /topiramate/ have been reported. Signs and symptoms included convulsions, drowsiness, speech disturbance, blurred vision, diplopia, mentation impaired, lethargy, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness and depression. The clinical consequences were not severe in most cases, but deaths have been reported after poly-drug overdoses involving /topiramate/. Topiramate overdose has resulted in severe metabolic acidosis.

/CASE REPORTS/ During the premarketing development of topiramate, 10 sudden and unexplained deaths were reported among a cohort of patients receiving adjunctive therapy with the drug (2796 patient-years of exposure). Although the rate of these deaths exceeds that expected to occur in a healthy (nonepileptic) population matched for age and gender, this rate was similar to that occurring in a similar population of epileptic patients not receiving topiramate.

/CASE REPORTS/ Psychotic symptoms have been described in connection with the use of topiramate in individual cases. This is a report about a psychotic attack that happened for the first time and lasted for one night in a borderline patient who was treated with topiramate 250 mg/day shortly after the start of a febrile infection. After the infection had gone, topiramate was given again and titrated to 300 mg/day. No further psychotic symptoms were observed.

For more Human Toxicity Excerpts (Complete) data for TOPIRAMATE (26 total), please visit the HSDB record page.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Topiramate

vLess-DILI-concern

3

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015