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. In addition, Topiramate has approval for chronic weight management for individuals with a body mass index over 30. Topiramate received FDA approval in 1996 for treating epilepsy as monotherapy or adjunctive therapy. This activity will highlight the indications, mechanism of action, and adverse event profile pertinent to interprofessional team members in managing patients with epilepsy, migraine, and related conditions. It also lists other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions, toxicity, and monitoring related to topiramate therapy.

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 in epilepsy, adjunctive therapy in epilepsy, and migraine disorder.[2]

Topiramate has received approval for monotherapy in epilepsy in those two years or older with primary generalized onset tonic-clonic or partial-onset seizures.[3] Adjunctive therapy is approved for adults and pediatric populations ages 2 to 16 years 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 disorders, topiramate has been approved for prophylaxis in adults (FDA, 2012). Topiramate has received approval for chronic weight management for individuals with a body mass index over 30 kg/m.[6] A fixed-dose combination of topiramate and phentermine is approved by FDA for the management of obesity.[7]

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.[8][9]

Mechanism of Action

Although the precise mechanism of action of topiramate is unknown, there is sufficient evidence to explain the drug's anticonvulsant activity.[10][11] Topiramate blocks voltage-gated sodium channels, most likely leading to sustained depolarization control during seizures.[12] 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 partially protects 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.[13][14] The efficacy of topiramate in migraine is likely due to inhibitory effects on the AMPA and kainate subtypes of glutamate receptors and, to a lesser extent, voltage-gated calcium channels.[15]

Pharmacokinetics

Absorption: Topiramate is well absorbed from the GIT, with peak plasma levels usually achieved in 2 to 3 hours. The bioavailability is greater than 80%. Concomitant ingestion of food slows the time required to reach peak plasma concentration, but the extent of absorption is not significantly altered. Consequently, topiramate can be administered regardless of meal time. Topiramate follows linear and predictable pharmacokinetics over the recommended dose range (15 to 400 mg/day).[16]

Distribution: Topiramate has plasma proteins-plasma protein binding of (15% to 41%). The fraction of bound topiramate decreases as blood concentration increases.

Metabolism: Topiramate is metabolized by hydroxylation, hydrolysis, and glucuronidation.

Excretion: Topiramate is eliminated by renal excretion in unchanged form and as metabolites. The clearance of topiramate in adults is 20 to 30 mL/min. The mean plasma elimination half-life is approximately 21 hours. The elimination half-life varies according to age and concomitant use of enzyme-inducing or inhibitor drugs. The clearance increases in patients taking concomitant enzyme-inducing drugs such as phenytoin, barbiturates, and carbamazepine.[16]

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.[16] It is important to recognize that some extended-release formulations of topiramate are not bioequivalent.

Monotherapy for partial onset seizures, primary generalized tonic-clonic seizures: The suggested dose for topiramate in adults and pediatric patients ten years and older is 400 mg/day in two divided doses. A slow titration schedule of 25 to 50 mg/day weekly increments is preferred to decrease the frequency of adverse effects.[17] 

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/day & 400 mg/day in two divided doses with primary generalized tonic-clonic seizures. It is suggested that treatment be initiated at a lower dose(25 to 50 mg/day) followed by an up-titration of 25 to 50 mg/day every week.[18][19]              

Migraine Prevention: According to American Academy of Neurology guidelines, topiramate is an effective therapy for migraine prevention (level A), significantly decreasing migraine attack frequency and severity. The recommended dose range is 25-50 mg. Patients with a favorable response to topiramate pharmacotherapy within 4 to 8 weeks should continue treatment for at least six months to acquire maximum benefit. Dose escalation up to 200 mg may be required in selected patients.[20] According to a consensus from the American Academy of Neurology and American Headache Society guidelines, children and adolescents receiving topiramate have a decrease in headache days and migraine attacks.[21]

Use in Specific Patient Population

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

Patients with Renal Impairment:  Half of the usual dose is suggested for moderate to severe renal impairment and ESRD. As topiramate is removed by dialysis, a supplemental dose may be required during hemodialysis.[22]

Pregnancy Considerations: A topiramate dose of less than 200 mg daily does not affect the pharmacokinetic levels of oral contraceptive pills that contain 35 micrograms of ethinyl estradiol. The dose of topiramate used for migraine prevention (25–50 mg) is not supposed to reduce contraceptive efficacy. (ACOG 2020)[23] According to the clinical data from the NAAED (North American Antiepileptic Drug) pregnancy registry, there may be a increased risk of oral cleft (1.4%) when infants are exposed to topiramate.[24] First-trimester exposure to topiramate monotherapy is associated with increased occurrence of cleft lip with or without cleft palate (FDA former Pregnancy Category D). A recent study indicates an increased risk of autism spectrum disorders and intellectual disability due to prenatal exposure to topiramate.[25] Topiramate should be considered in pregnancy after a comprehensive risk-benefit evaluation.[20]

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. Monitor the infant for diarrhea, drowsiness, irritability, weight gain, and developmental milestones. Caution is required in exclusively breastfed infants and simultaneous use of antiepileptics or psychotropic drugs.[26]

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.[16]

The 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).[27][28]

The most common adverse effects in trials involving migraine patients were paresthesia and dysgeusia.[29]

Serious adverse drug reactions include:

• Acute myopia and secondary angle-closure glaucoma[30]
• Oligohidrosis and hyperthermia: uncommon and reversible with cessation of the drug.[31]
• 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.[32]
• Suicidal behavior and ideation[33]
• Cognitive/neuropsychiatric adverse reactions: influence of topiramate on the hippocampus-related memory processes influence spatial memory but does not significantly affect the learning process.[34]
• Fetal toxicity: Exposure during pregnancy is associated with congenital malformations and developmental delay. Increased risk of recurrent malformations in future pregnancies.[35]
• 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 citrates is recommended in patients with kidney stones.[36]
• Paresthesia: is the most common cause of discontinuation of the drug.[37]
• Adjustment of dose in renal failure: dose adjustment is necessary for patients with moderate-to-severe renal impairment.[38]
• Hepatotoxicity: A literature review indicates that <1% of subjects have increased serum aminotransferase levels during long-term topiramate treatment. The pathophysiology of hepatotoxicity is believed to be due to the formation of a toxic intermediate metabolic. Cases with lactic acidosis and hyperammonemia may be caused by mitochondrial dysfunction.[39]

Drug-Drug Interactions

• Topiramate increases the oral clearance of estrogen in an oral contraceptive at high dosages and can lead to contraception failure (>200 mg/day).[40]
• Clearance of topiramate may be reduced when used with amitriptyline. Use with caution.[40]
• Concurrent administration of topiramate with carbamazepine requires dose adjustments due to reduced topiramate concentrations.[41]
• Concurrent use of topiramate and metformin increases the risk of metabolic acidosis.[42]
• Concurrent use of carbonic anhydrase inhibitors like acetazolamide and dorzolamide brinzolamide with topiramate may increase the risk of metabolic acidosis and nephrolithiasis. Avoid combination.[11]
• Concurrent use of topiramate with benzodiazepines, alcohol, thalidomide, and bromperidol can cause sedation and excessive CNS depression.

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.[20]

Monitoring

Baseline and periodic serum bicarbonate levels are required monitoring protocols for individuals on topiramate due to concern for metabolic acidosis. Renal function tests should be monitored. According to the American Epilepsy Society, antiepileptic drug-level testing(including topiramate) should not be routinely obtained when the seizures are controlled with no adverse effects. However, monitoring topiramate levels is advised in special cases requiring weight-based dose adjustments in young children, patient adherence, polypharmacy, and suspected toxicity. Since there is variability in topiramate plasma concentration with concomitant AED use, monitoring plasma concentration may be beneficial for optimizing drug dosage.[14][43] As patient management is different, obtain serum prolactin levels to differentiate between psychogenic nonepileptic seizures (PNES) and generalized tonic-clonic or complex partial seizures.[44]

Monitor for a reduction in the frequency of the most debilitating seizures (drop attacks and tonic-clonic seizures) when topiramate is used for Lennox-Gastaut syndrome (LGS)[19]

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.[45]

Toxicity

Fortunately, there are no reports of fatalities with topiramate monotherapy. Symptoms of toxicity include sedation, speech disturbance, blurred vision, agitation, ataxia, convulsions, and abdominal pain. ABG analysis in topiramate overdose usually demonstrates hyperchloraemic normal anion gap metabolic acidosis.[46]

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.[47] If symptoms are refractory to ongoing treatment, hemodialysis can reduce topiramate concentrations.[22]

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 should prescribe topiramate for the specific indication. Neurologist and epileptologist consultation is required in refractory seizures and seizures associated with Lennox-Gastaut syndrome. For various off-label uses, consultation with other specialties may be essential. Nursing can monitor for any adverse events and patient compliance. Pharmacists play a crucial role in verifying the medication reconciliation and reporting to the prescriber if there is any significant interaction.

The brand name of topiramate may be confused with the brand name of a commonly used extended-release beta blocker. (ISMP look-alike-sound-alike names). Consequently, pharmacists must be careful while dispensing the drug.[48] Emergency medicine physicians and nurses should 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, psychiatric evaluation and support are necessary. Interprofessional coordination between clinicians (MDs, DOs, NPs, PAs), nurses, pharmacists, specialists, and other healthcare workers is necessary to decrease adverse events and improve patient outcomes related to topiramate treatment. [Level 5]