What are the potential side effects of topiramate in patients with a history of seizures, migraines, or obesity, particularly in older adults or those with impaired renal function?

Side Effects of Topiramate

The most common side effects of topiramate include paresthesias (tingling of extremities), cognitive impairment, fatigue, decreased appetite, nausea, diarrhea, weight loss, and taste disturbances, with paresthesias occurring in 28-51% of patients depending on dose. 1, 2, 3

Most Frequent Adverse Effects

Neurological and Sensory Effects

• Paresthesias (tingling of arms and legs) represent the most common side effect, occurring in 35% at 50 mg/day, 51% at 100 mg/day, and 49% at 200 mg/day (versus 6% on placebo), and are typically mild to moderate in severity 3
• Cognitive impairment manifests as confusion, problems with concentration, attention, memory, and/or speech difficulties 2
• Dizziness and loss of muscle coordination can occur, particularly when combined with other seizure medications 2
• Mood disturbances including depression, mood problems, irritability, and nervousness are reported 1, 2

Gastrointestinal and Metabolic Effects

• Appetite suppression and weight loss occur commonly, which can be beneficial in obesity treatment but requires monitoring 1, 2
• Taste perversion (dysgeusia), nausea, diarrhea, and constipation are frequently reported 1, 4
• Dry mouth is a common complaint 1

General Systemic Effects

• Fatigue and sleepiness occur frequently, particularly during dose titration 1, 2, 3
• Insomnia can develop, especially if taken later in the day 1, 5
• Palpitations may occur due to the phentermine component when used in combination therapy 1

Serious Adverse Effects Requiring Immediate Attention

Metabolic Acidosis

• Topiramate causes metabolic acidosis through carbonic anhydrase inhibition, manifesting as tiredness, loss of appetite, irregular heartbeat, and impaired consciousness 2
• Serum bicarbonate monitoring is mandatory before and periodically during treatment 6, 2
• This risk is particularly elevated in patients with pulmonary pathology 7

Acute Eye Problems

• Sudden vision decrease (acute myopia) with or without eye pain can occur 2
• Secondary angle closure glaucoma from fluid blockage causing increased intraocular pressure represents a medical emergency 2
• These conditions can lead to blindness if untreated and require immediate discontinuation 2

Thermoregulatory Dysfunction

• Decreased sweating (oligohidrosis) and fever occur especially in children and hot temperatures 2
• Patients require close monitoring for decreased sweating and elevated body temperature, with some requiring hospitalization 2

Renal Complications

• Kidney stone formation occurs in 1.3-1.5% of patients, representing a 2-4 fold increased risk versus the general population 6, 2
• The mechanism involves reduced urinary citrate excretion and increased urinary pH from carbonic anhydrase inhibition 2
• Adequate hydration is essential to minimize stone formation risk 6, 2

Hyperammonemia

• High blood ammonia levels can occur, particularly when combined with valproic acid, causing decreased alertness, fatigue, and vomiting 2
• Hyperammonemic encephalopathy presents with acute alterations in consciousness and/or cognitive function with lethargy or vomiting 2
• An ammonia level should be measured in patients with unexplained lethargy, vomiting, or mental status changes 2

Special Population Considerations

Renal Impairment

• Topiramate clearance decreases by 42% in moderate renal impairment (creatinine clearance 30-69 mL/min/1.73m²) and 54% in severe impairment (creatinine clearance <30 mL/min/1.73m²) 2
• Dose reduction to one-half the usual starting and maintenance dose is required in moderate or severe renal impairment 2
• Hemodialysis removes significant amounts of topiramate (dialysis clearance 120 mL/min), necessitating supplemental dosing 2

Older Adults

• Elderly patients experience 21% reduced plasma clearance and 19% reduced renal clearance compared to young adults, resulting in 23% higher maximum plasma concentrations and 25% higher AUC 2
• Dosage adjustment is indicated when creatinine clearance is ≤70 mL/min/1.73m² 2

Pregnancy and Teratogenicity

• Topiramate carries teratogenic risks with various abnormalities described in animal offspring 2
• Female patients of childbearing potential require counseling on contraception and monthly pregnancy testing should be considered 6
• Topiramate may reduce oral contraceptive efficacy, with 18-30% decreased ethinyl estradiol exposure at doses of 200-800 mg/day 2

Critical Safety Warnings

Discontinuation Protocol

• Never discontinue topiramate abruptly as this can precipitate seizures even in patients taking it for migraine prevention 5
• Taper by taking one capsule every other day for at least 1 week before complete cessation 6, 5
• Continue topiramate throughout any perioperative period to prevent seizure risk 5

Drug Interactions

• Avoid combining with other carbonic anhydrase inhibitors (acetazolamide, dichlorphenamide) or ketogenic diets, which increase kidney stone risk 2
• Avoid alcohol and CNS depressants as topiramate potentiates sedation and dizziness 2
• Avoid use with or within 14 days of MAO inhibitors 6

Contraindications

• Absolute contraindications include: cardiovascular disease or uncontrolled hypertension, untreated hyperthyroidism, pregnancy without reliable contraception, and concurrent MAO inhibitor use 1

Timing and Severity Patterns

• Most adverse effects occur more frequently during titration rather than the maintenance period 3
• Adverse events are generally mild to moderate in severity 8, 3
• Discontinuation rates due to adverse events: 10.9% with topiramate versus 6.1% with placebo in chronic migraine trials 8
• Common reasons for discontinuation at 100 mg/day: paresthesia (8%), fatigue (5%), nausea (2%), and difficulty with concentration (2%) 3