Topiramate

Cognitive dysfunction (confusion, psychomotor slowing, difficulty with concentration/attention, difficulty with memory, speech or language problems), psychiatric disturbances (depression or mood disorders), and sedation (somnolence or fatigue) may occur with use; incidence may be related to rapid titration and higher doses; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). May also cause paresthesia, dizziness, and ataxia.

Hyperammonemia with or without encephalopathy may occur with monotherapy or in combination with valproic acid and has been documented in patients who have tolerated each drug alone; incidence may be dose-related. Risk may be increased in patients with inborn errors of metabolism or decreased hepatic mitochondrial activity. May be asymptomatic; monitor for lethargy, vomiting, or unexplained changes in mental status.

May be associated with hyperchloremic nonanion gap metabolic acidosis due to inhibition of carbonic anhydrase and increased renal bicarbonate loss. Decreases in serum bicarbonate are relatively common (up to 67% of epilepsy patients and 77% of migraine patients) but usually mild-to-moderate (average decrease of 4 mEq/L at dose of 400 mg/day in adults and 6 mg/kg/day in children). However, risk may be increased in patients with a predisposing condition (renal, respiratory and/or hepatic impairment), diarrhea, ketogenic diet, status epilepticus, or concurrent treatment with other drugs which may cause acidosis. Metabolic acidosis may occur at dosages as low as 50 mg/day. Serum bicarbonate should be monitored, as well as potential complications of chronic acidosis (nephrolithiasis, nephrocalcinosis, osteomalacia/osteoporosis, and reduced growth rates and/or reduced weight in children). Dose reduction or discontinuation (by tapering dose) should be considered in patients with persistent or severe metabolic acidosis. If treatment is continued, alkali supplementation should be considered.

May be associated with oligohidrosis and hyperthermia, most frequently in children; use caution and monitor closely during strenuous exercise, during exposure to high environmental temperature, or in patients receiving other carbonic anhydrase inhibitors and drugs with anticholinergic activity.

Has been associated with acute myopia and secondary angle-closure glaucoma in adults and children, typically within 1 month of initiation; discontinue in patients with acute onset of decreased visual acuity and/or ocular pain.

Topiramate exhibits weak carbonic anhydrase inhibitory properties and may increase the risk of kidney stones about 2 to 4 times that of the untreated population. Kidney stones have been reported in children and adults (incidence higher in males). Consider avoiding use in patients on a ketogenic diet. The risk of kidney stones may be reduced by increasing fluid intake.

Pooled analysis of trials involving various antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify healthcare provider immediately if symptoms occur.

Has been reported independent of increased intraocular pressure; generally reversible upon discontinuation. Consider discontinuation if visual problems occur at any time during treatment. Disease-related concerns:

Use with caution in patients with depression or suicidal tendencies.

The exacerbation and development of eating disorders, including anorexia nervosa and bulimia, has been reported in case reports of adolescents receiving topiramate for migraines or chronic headaches and an adult receiving topiramate for epilepsy. Prior to initiation of topiramate screen for a history of eating disorder symptoms, eating disorder risk factors (eg, history of dieting behavior), cognitive symptoms of eating disorders (eg, weight or shape concerns, fear of gaining weight, drive for thinness), and any recent changes in social functioning including increased withdrawal or isolation. Inquire whether the patient has unrealistic or unhealthy weight goals. Evaluate exercise habits (eg, look for over-exercising or compulsive exercising above that of similarly athletic peers) and dietary intake; assess rigid patterns or avoidance of specific categories of foods and preoccupation with maintaining a “healthy diet” or experimentation with fad diets. In adolescents assess developmental weight history with growth curves. Monitor eating behaviors and weight closely in patients receiving topiramate who have eating disorder symptoms or risk factors (Lebow 2015; Rosenow 2002).

Use caution with hepatic impairment; clearance may be reduced. Dosage adjustment may be required.

Use caution with renal impairment; clearance may be reduced. Dosage adjustment may be required. Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

Use with caution; dosage adjustment may be necessary. Weight loss, cognitive impairment, sedation, and gait/balance disturbances may be more pronounced in the older adult cohort (Sommer 2010). Other warnings/precautions:

Do not discontinue abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal. Doses were also gradually withdrawn in migraine prophylaxis studies (decreased in weekly intervals by 25-50 mg/day).