Continuing Education Activity

This activity provides a detailed overview of topiramate, a second-generation antiepileptic drug approved by the FDA in 1996. Topiramate is indicated for the management of epilepsy and migraines and is also approved for chronic weight management in individuals with a body mass index greater than 30 kg/m². This discussion focuses on the pharmacology of topiramate, including its mechanism of action, dosing guidelines, pharmacokinetics, significant drug interactions, clinical toxicology, and monitoring requirements. Additionally, this session covers adverse events associated with topiramate, highlighting key considerations for interprofessional teams involved in the care of patients with epilepsy, migraine, and related conditions.

This activity aims to enhance healthcare professionals' capabilities in prescribing and managing topiramate therapy effectively by examining off-label uses and the latest clinical evidence. The goal is to equip participants with the knowledge necessary to implement optimal treatment plans and adjust dosages to minimize adverse effects while maximizing therapeutic benefits. This will support healthcare professionals in making well-informed decisions in their clinical practice, thereby improving patient outcomes while managing epilepsy, migraine, and weight management.

Objectives:

• Evaluate the mechanism of action of topiramate.
• Identify the indications of topiramate.
• Determine the recommended clinical monitoring for patients receiving topiramate.
• Implement effective collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients who might benefit from topiramate treatment.

Indications

Topiramate is an antiepileptic drug (AED), a group of medications primarily indicated for treating seizure disorders, reflecting their designation as "antiepileptic." These drugs are also traditionally used as mood stabilizers in psychiatry, with expanding applications over time.[1] Topiramate, specifically, is an anticonvulsant that received FDA approval in 1996 for use as monotherapy and adjunctive therapy in epilepsy, as well as for treating migraine disorders.[2]

FDA-Approved Indications

Topiramate is approved as monotherapy for epilepsy for individuals aged 2 years and older with primary generalized onset tonic-clonic or partial-onset seizures.[3] Additionally, it is sanctioned for adjunctive therapy in adults and pediatric populations from ages 2 to 16 years with primary generalized onset tonic-clonic seizures, partial-onset seizures, and for those aged 2 years or older with seizures associated with Lennox-Gastaut syndrome.[4][5] Topiramate is approved for migraine prevention in adults. Furthermore, it is approved for chronic weight management in individuals with a body mass index over 30 kg/m² and as part of a fixed-dose combination with phentermine for obesity management.[6][7][8]

Off-Label Uses

Topiramate has numerous off-label applications, including the treatment of neuropathic pain, psychotropic drug-induced weight gain, alcohol and tobacco dependence, prevention of cluster headaches, binge eating disorder, bulimia nervosa, and obesity with hypertension. Topiramate is also used in preventing neuralgiform attacks, adjunctive therapy in bipolar disorder, and managing unipolar depression, borderline personality disorder, obsessive-compulsive disorder, posttraumatic stress disorder, Tourette syndrome, Prader-Willi syndrome, and essential tremor.[9][10] Topiramate has shown efficacy in treating alcohol use disorder in individuals unresponsive to naltrexone/acamprosate and is considered as effective and safe as naltrexone for reducing heavy alcohol consumption, irrespective of genetic polymorphisms.[11] Additionally, topiramate is utilized for binge eating disorders.[12][13] An emerging drug-device combination using the SipNose intranasal delivery platform, which facilitates direct nose-to-brain transport, is being developed for binge eating disorder treatment. However, it has not yet received FDA approval.[14]

Mechanism of Action

Although topiramate's precise mechanism of action remains unclear, sufficient evidence explains its anticonvulsant activity.[15][16] Topiramate blocks voltage-gated sodium channels, likely leading to sustained depolarization control during seizures.[17] Topiramate reduces membrane depolarization via AMPA/Kainate receptors and enhances GABA-A receptor activity, strengthening inhibitory effects.[6] Additionally, topiramate acts as a weak carbonic anhydrase inhibitor; acidosis in the brain partially protects against seizures by downregulating NMDA receptor activity. Overall, the influence of topiramate on these channels is the primary explanation for its antiepileptic effects.[18][19] The efficacy of topiramate in migraine is likely due to inhibitory effects on AMPA and kainate subtypes of glutamate receptors and, to a lesser extent, voltage-gated calcium channels. Calcitonin gene-related peptide (CGRP) has emerged as a therapeutic target for migraine. Topiramate inhibits the release of CGRP and glutamate from trigeminal neurovascular nerve endings, effectively disrupting cortical spreading depression and demonstrating efficacy in managing both epilepsy and migraine.[20] In individuals with frequent episodic migraines, topiramate may prevent the transition to chronic migraine.[21]

Pharmacokinetics

Absorption: Topiramate is well absorbed from the gastrointestinal tract, with peak plasma levels typically achieved in 2 to 3 hours. The bioavailability exceeds 80%. Concomitant ingestion of food delays the time to reach peak plasma concentration but does not significantly alter the extent of absorption. Thus, topiramate can be administered without regard to meals. Topiramate follows linear and predictable pharmacokinetics over the recommended dose range (15 to 400 mg/d).

Distribution: Topiramate displays plasma protein binding ranging from 15% to 41%. The fraction of bound topiramate decreases as blood concentration increases.

Metabolism: Topiramate undergoes metabolism through hydroxylation, hydrolysis, and glucuronidation.

Excretion: Topiramate is eliminated primarily through renal excretion, both unchanged and as metabolites. Clearance in adults is 20 to 30 mL/min. The mean plasma elimination half-life is approximately 21 hours, varying with age and the concomitant use of enzyme-inducing or inhibiting drugs. Clearance increases in patients taking concomitant enzyme-inducing drugs such as phenytoin, barbiturates, and carbamazepine.[22]

Administration

Available Dosage Forms and Strengths

Topiramate is available for both adult and pediatric populations in 2 oral preparations: immediate-release (taken twice daily) and extended-release (taken once daily). Patients should not crush the tablets due to their bitter taste. There is also a sprinkle capsule formulation that may be added to a small amount of soft food; administration of topiramate may occur without regard to meals. The oral solution is available at a concentration of 25 mg/mL. Alcohol should be avoided for 6 hours before and after administering topiramate.[22] Importantly, some extended-release formulations of topiramate are not bioequivalent.

Adult Dosage

Monotherapy for partial-onset seizures and primary generalized tonic-clonic seizures: The suggested dose for topiramate in adults and pediatric patients 10 years and older is 400 mg/d in 2 divided doses. A slow titration schedule of 25 to 50 mg/d in weekly increments is preferred to decrease the frequency of adverse effects.[23]

Adjunctive therapy for primary generalized tonic-clonic seizures, partial-onset seizures, or Lennox-Gastaut Syndrome: The suggested total daily dose of topiramate as an adjunctive treatment in adults with partial onset seizures is 200 to 400 mg/d in 2 divided doses for primary generalized tonic-clonic seizures. Treatment should be initiated at a lower dose (25 to 50 mg/d) followed by an up-titration of 25 to 50 mg/d weekly.[24][25]

Migraine prevention: According to guidelines from the American Academy of Neurology, topiramate is an effective therapy for migraine prevention (level A), significantly decreasing the frequency and severity of migraine attacks. The recommended dose range is 25 to 50 mg. Patients with a favorable response to topiramate pharmacotherapy within 4 to 8 weeks should continue treatment for at least 6 months to achieve maximum benefit. Dose escalation up to 200 mg may be required in selected patients.[26] According to consensus from the American Academy of Neurology and American Headache Society, children and adolescents receiving topiramate experience a decrease in headache days and migraine attacks.[27]

Specific Patient Populations

Hepatic impairment: Topiramate plasma concentrations may be increased in patients with hepatic impairment. However, the increase is not significant, and no dose adjustment is generally suggested.

Renal impairment: Half the standard dose is recommended for moderate to severe renal impairment and ESRD. As topiramate is removed by dialysis, a supplemental dose may be required during hemodialysis.[28]

Pregnancy considerations: A topiramate dose of less than 200 mg daily does not affect the pharmacokinetic levels of oral contraceptive pills containing 35 μg of ethinyl estradiol. The dose of topiramate used for migraine prevention (25 to 50 mg) is not supposed to reduce contraceptive efficacy.[29] According to clinical data from the NAAED pregnancy registry, there may be an increased risk of oral cleft (1.4%) when infants are exposed to topiramate. First-trimester exposure to topiramate monotherapy is associated with an increased frequency of cleft lip with or without cleft palate and small for gestational age. A study indicates an increased risk of autism spectrum disorders and intellectual disability due to prenatal exposure to topiramate.[30] Topiramate should be considered in pregnancy only after a comprehensive risk-benefit evaluation.[26]

Breastfeeding considerations: Maternal doses of topiramate up to 200 mg daily produce a low concentration in infant serum. Sedation and diarrhea have been reported in breastfed infants, but most infants tolerate the drug in milk well. The infant should be monitored for diarrhea, drowsiness, irritability, weight gain, and developmental milestones. Caution is required in exclusively breastfed infants and simultaneous use of antiepileptics or psychotropic drugs.[31]

Pediatric patients: The meta-analysis aimed to evaluate the efficacy and safety of topiramate in pediatric migraine. Topiramate was associated with higher rates of adverse drug reactions such as weight loss and paresthesia. Topiramate is effective in reducing the number of monthly headache days in patients under the age of 18 who experience migraines, thus alleviating the burden of migraine-related symptoms.[32] Oligohidrosis, hyperthermia, and reduction in bone mineral density have been reported in pediatric patients.

Older patients: Dosage adjustment of topiramate may be required for patients with creatinine clearance <70 mL/min/1.73 m².

Adverse Effects

Adverse effects are dose-dependent and vary between patients with epilepsy and migraine, as the trials use different doses based on the condition.[22]

The most common adverse effects in epilepsy trials included central nervous system involvement (paresthesia, fatigue, cognitive problems, dizziness, somnolence, psychomotor slowing, memory/concentration difficulties, nervousness, confusion), endocrine/metabolism issues (weight loss, anorexia), respiratory problems (infection), and miscellaneous effects (fever, flushing).[33][34] In trials involving patients with migraine, the most common adverse effects are paresthesia and dysgeusia.[35]

Severe adverse drug reactions include:

• Acute myopia and secondary angle-closure glaucoma [36]
• Oligohidrosis and hyperthermia (uncommon, reversible with cessation of the drug) [37]
• 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.[38]
• Suicidal behavior and ideation [39]
• Cognitive/neuropsychiatric adverse reactions: The influence of topiramate on the hippocampus-related memory processes influences spatial memory but does not significantly affect the learning process.[40]
• Fetal toxicity: Exposure during pregnancy is associated with congenital malformations and developmental delay. Increased risk of recurrent malformations in future pregnancies.[41]
• 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 patients 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 citrate is recommended in patients with kidney stones.[42]
• Paresthesia is the most common cause of discontinuation.[43]
• Adjustment of dose in renal failure: Dose adjustment is necessary for patients with moderate-to-severe renal impairment.[44]
• Hepatotoxicity: A literature review indicates that <1% of subjects have increased serum aminotransferase levels during long-term topiramate therapy. The hepatotoxicity is believed to be due to a toxic intermediate formation. Cases with lactic acidosis and hyperammonemia may be caused by mitochondrial dysfunction.[45]

Drug-Drug Interactions

• Concurrent use of topiramate and metformin increases the risk of metabolic acidosis. Simultaneous use is contraindicated.[46]
• Topiramate increases the oral clearance of high-dose estrogen contraceptives and can lead to contraception failure (>200 mg/d).[47]
• Clearance of topiramate may be reduced when used with amitriptyline. Use with caution.[47]
• Concurrent administration of topiramate with carbamazepine requires dose adjustments due to reduced topiramate concentrations.[48]
• Concurrent use of carbonic anhydrase inhibitors like acetazolamide, dorzolamide, and brinzolamide with topiramate may increase the risk of metabolic acidosis and nephrolithiasis. Avoid co-administration.[16]
• Concurrent use of topiramate with benzodiazepines, alcohol, thalidomide, and bromperidol can cause sedation and excessive CNS depression.
• An increase in systemic exposure to lithium may occur with high doses of topiramate (600 mg/d). Therefore, it is advisable to monitor lithium levels when co-administering high-dose topiramate.

Contraindications

Topiramate is a relatively safe drug, and the list of absolute contraindications is minimal. As a carbonic anhydrase inhibitor, topiramate can precipitate the development of metabolic acidosis and is, therefore, contraindicated in individuals currently with (or prone to) metabolic acidosis. Other contraindications include those with a history of a proven allergy to topiramate or individuals who have consumed (or will consume) alcohol within 6 hours.[26]

Warnings and Precautions

Acute myopia and secondary angle-closure glaucoma: Ophthalmologic findings associated with topiramate may include myopia, increased intraocular pressure, ocular hyperemia, macular striae, choroidal detachment, anterior chamber shallowing, mydriasis, and retinal pigment epithelial detachment. Supraciliary effusion can precipitate anterior displacement of the lens and iris, leading to secondary angle-closure glaucoma. Symptoms typically emerge within one month of initiating topiramate. Unlike primary narrow-angle glaucoma, secondary-angle closure glaucoma induced by topiramate can occur in pediatric and adult populations. Discontinuation of topiramate may be required.[36] Drug-induced choroidal effusion syndrome should be considered as a possible cause of bilateral acute angle-closure glaucoma in patients with myopia and a shallow anterior chamber.[49]

Negative effects on growth: According to product labeling, topiramate can reduce body weight in pediatric populations. Additionally, a reduction in height velocity and height change has been noted with topiramate use. Adverse effects on weight and height are evident across all age subgroups of topiramate users. Therefore, careful growth monitoring is essential in children receiving prolonged topiramate treatment.

Other warnings related to topiramate use are covered in adverse drug reactions.

Monitoring

Baseline and periodic serum bicarbonate levels are required for individuals on topiramate due to concerns about metabolic acidosis. Healthcare professionals should also monitor renal function tests. The American Epilepsy Society states that antiepileptic drug-level testing, including for topiramate, is not routinely necessary when seizures are controlled without adverse effects. However, monitoring topiramate levels is advisable in special cases, such as weight-based dose adjustments for young children, assessing patient adherence, managing polypharmacy, and detecting suspected toxicity. Due to variability in topiramate plasma concentration with concomitant antiepileptic drug use, monitoring plasma concentration may be beneficial for optimizing drug dosage.[19][50] Healthcare professionals should also obtain serum prolactin levels to differentiate between psychogenic nonepileptic seizures (PNES) and generalized tonic-clonic or complex partial seizures.[51]

Healthcare professionals should monitor for a reduction in the frequency of the most debilitating seizures, such as drop attacks and tonic-clonic seizures when using topiramate for Lennox-Gastaut syndrome (LGS).[25]

They should also monitor for a reduction in the frequency and severity of headaches. A decrease in the frequency of migraine days is a key measure of the efficacy of migraine prevention.[52] A network meta-analysis reported that topiramate increases the proportion of patients achieving a reduction of 50% or more in monthly migraine days compared to those receiving a placebo.[53]

Toxicity

Signs and Symptoms of Overdose

Symptoms of toxicity include sedation, speech disturbances, blurred vision, agitation, ataxia, convulsions, and abdominal pain. Arterial blood gas analysis in a topiramate overdose usually shows hyperchloremic normal anion gap metabolic acidosis.[54]

In 7 cases of topiramate toxicity observed by Poison Control Centers in Poland, somnolence was the most common symptom (66.7%), along with agitation, mydriasis, and vertigo (33.4%). One individual experienced 3 tonic-clonic seizures. There were no fatalities or long-term consequences.[55]

Management of Overdose

Currently, no specific antidote is available. If symptoms are refractory to ongoing treatment, hemodialysis can reduce topiramate concentrations.[28] A recent case report involved a 32-year-old woman who presented following the intentional ingestion of 36 g of topiramate. Following hemodialysis, significant neurological improvement occurred, including the resolution of encephalopathic features and cessation of myoclonic jerking. Gas chromatography/mass spectrometry showed a marked reduction in topiramate levels, underscoring the effectiveness of hemodialysis in managing severe topiramate toxicity by facilitating rapid clearance of the drug.[56]

Enhancing Healthcare Team Outcomes

Topiramate is FDA-approved for various types of epilepsy, migraine, and Lennox-Gastaut syndrome; however, it has numerous off-label uses and a significant adverse drug reaction profile. Therefore, healthcare professionals must continually educate themselves on the most up-to-date information regarding new medical information. Clinicians prescribe topiramate for specific indications. Neurologist and epileptologist consultations are required for refractory seizures and seizures associated with Lennox-Gastaut syndrome. For various off-label uses, consultation with other specialties may be essential. Nurses monitor for any adverse events and patient compliance. Pharmacists are crucial in verifying medication reconciliation and reporting significant interactions to the prescriber.

The brand name of topiramate may be confused with the brand name of a commonly used extended-release β-blocker. Consequently, pharmacists must be careful while dispensing the drug.[57] Emergency medicine physicians and nurses rapidly stabilize the patient in an overdose. Critical care physicians and medical toxicologists are crucial in managing patients with massive overdoses. Once the patient is stable, a psychiatric evaluation and support are necessary. Interprofessional coordination between clinicians (MDs, DOs, NPs, PAs), nurses, pharmacists, specialists, and other healthcare workers is essential to decrease adverse events and improve patient outcomes related to topiramate therapy.

Review Questions

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Disclosure: Kamron Fariba declares no relevant financial relationships with ineligible companies.

Disclosure: Abdolreza Saadabadi declares no relevant financial relationships with ineligible companies.