Topiramate

Generic Name

Topiramate

Brand Names

Topamax

Topiragen

Trokendi XR

Qudexy XR

Topamax Sprinkle

Epitomax

Topamac

Qsymia (as combination with phentermine)

Drug Class

Antiepileptic drug

Carbonic anhydrase inhibitor derivative

Anticonvulsant

Migraine prophylactic agent

Mechanism of Action

Topiramate works through several mechanisms

It blocks voltage-dependent sodium channels to stabilize hyperexcitable neuronal membranes

It enhances the activity of the GABA-A receptor by increasing chloride influx

It antagonizes AMPA and kainate glutamate receptors to decrease excitatory neurotransmission

It inhibits carbonic anhydrase isoenzymes II and IV which contributes to metabolic acidosis and nephrolithiasis

It may also inhibit high-voltage-activated calcium channels which reduces presynaptic neurotransmitter release

Indications

Approved indications

Monotherapy and adjunctive treatment of partial-onset seizures in adults and children aged two years and older

Monotherapy and adjunctive treatment of primary generalized tonic-clonic seizures

Adjunctive treatment of seizures associated with Lennox-Gastaut syndrome

Migraine headache prophylaxis in adults and adolescents aged twelve years and older

Off-label indications

Bipolar disorder especially bipolar depression and mood stabilization

Alcohol dependence and craving reduction

Obesity and weight loss as in the combination Qsymia

Binge eating disorder

Post-traumatic stress disorder

Tardive dyskinesia

Essential tremor

Antipsychotic-induced weight gain

Neuropathic pain and trigeminal neuralgia

Dosage and Administration

For epilepsy

Adults usually start at 25 to 50 milligrams per day

Titrated weekly by 25 to 50 milligrams up to a target dose of 200 to 400 milligrams per day in two divided doses

Children are dosed based on weight starting at 1 to 3 milligrams per kilogram per day and titrated to 5 to 9 milligrams per kilogram per day

For migraine prophylaxis

Adults typically start with 25 milligrams per day at bedtime

Increased weekly by 25 milligrams to a target dose of 100 milligrams per day in divided doses

For bipolar disorder off-label

Typical dose is 100 to 200 milligrams per day adjusted based on response and tolerability

For weight loss in combination with phentermine

Start with 3.75 milligrams of topiramate combined with 23 milligrams of phentermine daily

Dose titrated over several weeks to a maintenance dose of 7.5 to 15 milligrams of topiramate with 46 to 92 milligrams of phentermine

Route of administration

Topiramate is administered orally

Available in immediate-release tablets in strengths of 25 milligrams 50 milligrams 100 milligrams and 200 milligrams

Available as sprinkle capsules in 15 milligrams and 25 milligrams that can be opened and sprinkled on soft food

Extended-release forms include Trokendi XR and Qudexy XR

Pharmacokinetics

Topiramate is well absorbed orally with a bioavailability of about 80 percent

Peak plasma concentration is reached in approximately two hours for immediate-release forms and 24 hours for extended-release forms

It has a low protein binding of around 15 percent

It is minimally metabolized and is excreted primarily unchanged in the urine

The elimination half-life is about 20 to 30 hours in individuals with normal renal function

Dose adjustments are necessary in renal impairment

Contraindications

Hypersensitivity to topiramate or formulation ingredients

Recent alcohol use with extended-release products

Metabolic acidosis in patients taking metformin

Pregnancy when used for weight loss or migraine prophylaxis due to teratogenicity

Angle-closure glaucoma or history of acute myopia induced by topiramate

Warnings and Precautions

Cognitive dysfunction is common especially with rapid titration or high doses and may include difficulty with concentration memory and word-finding

Metabolic acidosis may result from inhibition of carbonic anhydrase and may lead to complications like nephrolithiasis or bone demineralization

Monitor serum bicarbonate levels especially in patients with predisposing conditions

Kidney stones may occur due to urinary alkalinization and low citrate excretion

Ensure adequate fluid intake to minimize risk

Hyperammonemia and encephalopathy may occur particularly in patients taking concomitant valproate

Monitor ammonia levels if unexplained lethargy or vomiting occur

Acute myopia and angle-closure glaucoma can develop suddenly and require immediate discontinuation and ophthalmologic evaluation

Oligohidrosis and hyperthermia particularly in children may impair thermoregulation

Monitor during heat exposure

Monitor for suicidal thoughts or behavior as with other antiepileptic drugs

Withdrawal seizures can occur with abrupt discontinuation

Taper slowly over several weeks

Adverse Effects

Very common

Paresthesia

Anorexia

Fatigue

Somnolence

Dizziness

Cognitive slowing

Nausea

Weight loss

Taste perversion

Common

Mood changes including depression or anxiety

Visual disturbances

Diarrhea or constipation

Back pain

Insomnia or sleep disturbances

Difficulty with memory or concentration

Tremors

Abdominal pain

Uncommon to rare

Kidney stones

Glaucoma

Metabolic acidosis

Hyperammonemic encephalopathy

Pancytopenia

Rash or Stevens-Johnson syndrome

Hepatotoxicity

Suicidal ideation

Psychosis or hallucinations

Overdose

Symptoms may include somnolence agitation confusion dizziness hypotension metabolic acidosis seizures visual disturbances and coma

Supportive treatment includes airway protection hydration seizure control and correction of acidosis

Hemodialysis may be beneficial due to the renal route of elimination

Drug Interactions

Enzyme-inducing antiepileptics such as phenytoin and carbamazepine can increase topiramate clearance and reduce efficacy

Topiramate may reduce serum concentrations of oral contraceptives particularly at doses of 200 milligrams or more per day

Nonhormonal contraception is advised in women of reproductive age

Valproic acid used concurrently can increase the risk of hyperammonemia

Carbonic anhydrase inhibitors such as acetazolamide and zonisamide may increase risk of metabolic acidosis and kidney stones

CNS depressants such as alcohol and benzodiazepines may have additive effects on sedation or cognitive dysfunction

Use in Special Populations

Pregnancy

Topiramate is associated with increased risk of oral clefts and other birth defects

Avoid use especially for non-seizure indications

Use effective contraception in women of childbearing potential

Lactation

Topiramate is excreted in breast milk

Use caution and monitor infant for sedation or poor feeding

Pediatrics

Approved for use in children aged two years and older for seizures and adolescents for migraine prevention

Monitor for growth suppression cognitive effects and thermoregulatory issues

Geriatrics

Increased sensitivity to adverse effects especially cognitive impairment and renal function decline

Start at lower doses

Renal impairment

Topiramate clearance is reduced

Dose adjustment required in patients with creatinine clearance below 70 milliliters per minute

Hepatic impairment

Use with caution

Although metabolism is limited hepatic dysfunction may alter pharmacokinetics

Monitoring Parameters

Serum bicarbonate

Renal function

Ammonia levels if using with valproate or in symptomatic patients

Mood and behavior changes

Seizure frequency

Body weight

Cognitive performance

Intraocular pressure if visual symptoms develop

Comparative Pharmacology

Topiramate versus lamotrigine

Topiramate causes more cognitive and metabolic adverse effects

Lamotrigine is more suitable for mood stabilization

Topiramate versus valproate

Topiramate is less teratogenic but may be less effective for generalized seizures

Valproate is contraindicated in pregnancy

Topiramate versus zonisamide

Both inhibit carbonic anhydrase but topiramate has broader indications including migraine

Topiramate versus gabapentin

Topiramate is more effective for migraine prevention while gabapentin is preferred for neuropathic pain

Formulations Available

Immediate-release tablets

Sprinkle capsules

Extended-release capsules

Fixed-dose combinations such as Qsymia

Regulatory Status

Prescription-only

Not classified as a controlled substance

Approved by FDA EMA and other health authorities

Included in the WHO Model List of Essential Medicines