Continuing Education Activity

Topiramate is a medication used to manage and treat epilepsy and migraine, and it is in the second-generation anti-epileptic drugs class of drugs. This activity will highlight the indications, mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the interprofessional team in the management of patients with epilepsy, migraine, and related conditions.

Objectives:

• Describe the mechanism of action of topiramate.
• Identify the indications of topiramate.
• Review the appropriate monitoring of topiramate.
• Outline some interprofessional team strategies for improving care coordination and communication to advance topiramate and improve outcomes.

Indications

Topiramate is a compound that belongs to the family of medications called antiepileptic drugs (AEDs). AEDs are generally used for neurologic and psychiatric purposes.[1] The primary indication for this family of drugs is treating seizure disorders, hence the name "antiepileptic drugs." These are classically used as mood stabilizers in psychiatry, although their administrations have seen a broader application. Specifically, topiramate is an anticonvulsant drug that was initially FDA approved in 1996 for the treatment of monotherapy epilepsy, adjunctive therapy epilepsy, and migraine disorder.[2] It has received approval for monotherapy in epilepsy in those two years or older with primary generalized onset tonic-clonic seizures or partial-onset seizures.[3] Adjunctive therapy is approved for adults and pediatric populations ages 2 to 16 with primary generalized onset tonic-clonic seizures, partial-onset seizures, and those two years or older with Lennox-Gastaut syndrome-associated seizures.[4][5] For migraine disorder, topiramate has approval for prophylaxis in adults (FDA, 2012). For individuals with a body mass index over 30, topiramate has approval for chronic weight management.[6]

There are many off-label uses for topiramate, including neuropathic pain, psychotropic drug-induced weight gain, alcohol use disorders with tobacco dependence, cluster headache prevention, binge eating disorder, bulimia nervosa, obesity with hypertension, prevention of neuralgiform attacks, adjunctive therapy in bipolar disorder, unipolar depression, borderline personality disorder, obsessive-compulsive disorder, posttraumatic stress disorder, Tourette syndrome, Prader-Willie syndrome, essential tremor.[7][8]

Mechanism of Action

Although the precise mechanism of action of topiramate is unknown, there is sufficient evidence to explain the drug's anticonvulsant activity.[9][10] Topiramate blocks voltage-gated sodium channels, which most likely leads to control of sustained depolarizations during seizures.[11] Topiramate reduces membrane depolarization by AMPA/Kainate receptors. Topiramate enhances GABA (A) receptor activity, which enhances inhibitory effects.[6] Topiramate is a weak inhibitor of carbonic anhydrase; acidosis in the brain has partial protection against seizures by downregulating NMDA receptor activity. Overall, the effect of topiramate on these channels is the leading explanation of the antiepileptic action of the drug.[12][13]

Administration

Topiramate is available for the adult and pediatric populations in two oral preparations, immediate-release (taken twice daily) and extended-release (taken once daily). Patients should not crush the tablets since there is a bitter taste. There is a sprinkle capsule formulation that the patient may add to a small amount of soft food; topiramate administration may be without regard to meals. Alcohol should be avoided 6 hours before and after the administration of topiramate.[14]

A slow titration schedule of 25 to 50 mg/day weekly increments is preferred to decrease the frequency of adverse effects.[15]

Adverse Effects

Adverse effects are dose-dependent and differ between epilepsy and migraine patients in trials as the trials used different doses based on the condition.[14]

Most common adverse effects in epilepsy trials included the involvement of the central nervous system (paresthesia, fatigue, cognitive problems, dizziness, somnolence, psychomotor slowing, memory/concentration difficulties, nervousness, confusion), endocrine/metabolism (weight loss, anorexia), respiratory (infection), miscellaneous (fever, flushing).[16][17]

The most common adverse effects in trials involving migraine patients were paresthesia and dysgeusia.[18]

More dangerous side effects include:

• Acute myopia and secondary angle-closure glaucoma[19]
• Oligohidrosis and hyperthermia: uncommon and reversible with cessation of the drug.[20]
• Metabolic acidosis: due to inhibition of carbonic anhydrase isoenzymes, topiramate can lead to metabolic acidosis secondary to type II renal tubular acidosis, elevated urine pH, reduced urine citrate, hypercalciuria, calcium phosphate stone formation, bone mineralization defects.[21]
• Suicidal behavior and ideation[22]
• Cognitive/neuropsychiatric adverse reactions: influence of topiramate on the hippocampus-related memory processes influence spatial memory but does not significantly affect the learning process.[23]
• Fetal toxicity: Exposure during pregnancy is associated with congenital malformations and developmental delay. Increased risk of recurrent malformations in future pregnancies.[24]
• Hyperammonemia and encephalopathy: one case report describes a young patient developing metabolic encephalopathy with hypoxic respiratory failure, most likely due to concurrent use of valproic acid and topiramate. Clinicians should be cautious of possible hyperammonemia encephalopathy in any patient taking these medications presenting with impaired consciousness and cognitive decline.[4]
• Kidney stones: long term topiramate administration could induce urolithiasis; therefore, blood testing for acid-base balance, urinary pH, and citrates is recommended in patients suffering from kidney stones.[25]
• Paresthesia: is the most common cause for discontinuation of the drug.[26]
• Adjustment of dose in renal failure: dose adjustment is necessary for patients with moderate-to-severe renal impairment.[27]
• Decreased hepatic function: closer follow-up and more frequent serum concentration monitoring are necessary to optimize clinical outcomes.[28]

Contraindications

Topiramate is a relatively safe drug, as the list of absolute contraindications is minimal. As a carbonic anhydrase inhibitor, topiramate can precipitate metabolic acidosis development and is, therefore, contraindicated in individuals currently with (or prone to experiencing) metabolic acidosis. Other contraindications include those with a history of a proven allergy to topiramate or within six hours before and six hours after alcohol use.[29]

Monitoring

Baseline and periodic serum bicarbonate levels are required monitoring protocol for individuals on topiramate due to concern for hyperchloremic metabolic acidosis. 

Since there is variability in topiramate plasma concentration with concomitant AED use, monitoring of plasma concentration may be beneficial for optimizing drug dosage.[13][30]

Toxicity

Fortunately, there are no reports of fatalities with topiramate monotherapy. Symptoms of toxicity include sedation, speech disturbance, blurred vision, metabolic acidosis, agitation, ataxia, convulsions, and abdominal pain.

In seven cases of topiramate toxicity observed by Polish Poison Control Centers, the most common symptom for topiramate toxicity was somnolence (66.7%), along with agitation, mydriasis, and vertigo (33.4%). One individual experienced three tonic-clonic seizures. There were no fatalities or long-term consequences observed. 

 A specific antidote is not currently available.[31]

Enhancing Healthcare Team Outcomes

Topiramate, like many other pharmaceuticals, is only FDA-approved for a few conditions. However, there are many off-label uses for this drug. Off-label use means that a clinician prescribes the medication for an indication that was not researched and approved by the FDA. Physicians are not monitored regarding how they prescribe topiramate; therefore, it is up to the clinician to choose when to use a medication off-label based on clinical judgment and experience while calculating the risks and benefits.

Off-label use is more common with patient populations that are less likely to be included in clinical trials, such as psychiatric, pregnant, and pediatric patients. Therefore, it is the responsibility of healthcare professionals to continually educate themselves on the most up-to-date information regarding new medical information, especially regarding those medications used off-label, such as topiramate. Moreover, because of the relatively few contraindications associated with topiramate, healthcare teams should be less hesitant when considering the application of the off-label use of topiramate.[32]