Pronunciation:

(toe PYRE a mate)

U.S. Brand Names:

Generic Available:

Canadian Brand Names:

Use:

Use - Unlabeled/Investigational:

Pregnancy Risk Factor:

Pregnancy Implications:

Lactation:

Contraindications:

Warnings/Precautions:

Concurrent Disease:

Organ dysfunction: Use cautiously in patients with hepatic or renal impairment

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

Concurrent Drug Therapy:

Valproate: Hyperammonemia with or without encephalopathy may occur. Use with caution in patients with inborn errors of metabolism or decreased hepatic mitochondrial activity; risk may be increased.

Key Adverse Reactions:

Acidosis: Topiramate may decrease serum bicarbonate concentrations, due to inhibition of carbonic anhydrase and increased renal bicarbonate loss. Decreased serum bicarbonate may occur commonly (up to 67% of patients), while treatment-emergent metabolic acidosis is less common. Risk may be increased in patients with a predisposing condition (renal, respiratory and/or hepatic impairment), ketogenic diet, or concurrent treatment with other drugs which may cause acidosis. Serum bicarbonate should be monitored, as well as potential complications of chronic acidosis (nephrolithiasis, osteomalacia, and reduced growth rates 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.

Kidney stones: The risk of kidney stones is about 2-4 times that of the untreated population, the risk of this event may be reduced by increasing fluid intake.

Hyperthermia: May be associated (rarely) with severe oligohydrosis and hyperthermia, most frequently in children; use caution and monitor closely during strenuous exercise, during exposure to high environmental temperature, or in patients receiving drugs with anticholinergic activity.

CNS Effects: May cause paresthesias. Sedation, psychomotor slowing, confusion, and mood disturbances may occur with topiramate use.

Withdrawal: Avoid abrupt withdrawal of topiramate therapy, it should be withdrawn/tapered slowly to minimize the potential of increased seizure frequency.

Special populations:

Safety and efficacy have not been established in children <2 years of age.

Pregnancy: Use caution in pregnant women

Adverse Reactions:

>10%:

Central nervous system: Dizziness, ataxia, somnolence, psychomotor slowing, nervousness, memory difficulties, speech problems, fatigue

Endocrine & metabolic: Serum bicarbonate decreased (up to 67%; marked reductions to <17 mEq/L have been reported in up to 11% of patients)

Gastrointestinal: Nausea

Neuromuscular & skeletal: Paresthesia, tremor

Ocular: Nystagmus, diplopia, abnormal vision

Respiratory: Upper respiratory infection

1% to 10%:

Cardiovascular: Chest pain, edema

Central nervous system: Language problems, abnormal coordination, confusion, depression, difficulty concentrating, hypoesthesia, hallucination, psychosis, suicide attempt

Endocrine & metabolic: Hot flashes; metabolic acidosis (hyperchloremia, nonanion gap); dehydration

Gastrointestinal: Dyspepsia, abdominal pain, anorexia, constipation, xerostomia, gingivitis, weight loss, diarrhea, vomiting

Genitourinary: Impotence, dysuria

Neuromuscular & skeletal: Myalgia, weakness, back pain, leg pain, rigors, hypertonia, arthralgia

Ocular: Conjunctivitis

Otic: Hearing decreased

Renal: Nephrolithiasis, renal calculus

Respiratory: Pharyngitis, sinusitis, epistaxis

Miscellaneous: Flu-like symptoms

<1%: Apraxia, AV block, bone marrow depression, delirium, dyskinesia, encephalopathy (with valproate therapy), eosinophilia, granulocytopenia, manic reaction, neuropathy, pancytopenia, paranoid reaction, photosensitivity, psychosis, suicidal behavior, tinnitus

Postmarketing and/or case reports: Accommodation abnormality, allergic reactions, alopecia, erythema multiforme, eye pain, hepatic failure, hepatitis, hyperammonemia (with valproate therapy), hyperthermia (severe), migraine aggravated, oligohydrosis, pancreatitis, pemphigus, rash. renal tubular acidosis, Stevens-Johnson syndrome, syndrome of acute myopia/secondary angle-closure glaucoma, toxic epidermal necrolysis, tremor, vertigo

Overdosage/Toxicology:

Drug Interactions:

Anticholinergic drugs: Concurrent administration may increase the risk of oligohydrosis and/or hyperthermia; includes drugs with high anticholinergic activity such as antihistamines, cyclic antidepressants, and antipsychotics; use caution

Carbamazepine: May reduce topiramate levels 40%

Carbonic anhydrase inhibitors: Coadministration with other carbonic anhydrase inhibitors may increase the chance of nephrolithiasis and/or hyperthermia; includes acetazolamide

CNS depressants: Sedative effects may be additive with topiramate; monitor for increased effect; includes barbiturates, benzodiazepines, narcotic analgesics, ethanol, and other sedative agents

Digoxin: Blood levels of digoxin are decreased when coadministered with topiramate.

Estrogens: Blood levels of estrogens are decreased when coadministered with topiramate, this may lead to a loss of efficacy.

Oral contraceptives: See interaction with Estrogens; use of alternative contraception is recommended.

Phenytoin: May decrease topiramate levels by as much as 48%; topiramate may increase phenytoin concentration by 25%

Valproic acid: Hyperammonemia with or without encephalopathy has been reported in patients who tolerated either drug alone. These drugs may modestly decrease the serum concentrations of the other drug.

Ethanol/Nutrition/Herb Interactions:

Ethanol: Avoid ethanol (may increase CNS depression).

Food: Ketogenic diet may increase the possibility of acidosis.

Herb/Nutraceutical: Avoid evening primrose (seizure threshold decreased).

Stability:

Mechanism of Action:

Pharmacodynamics/Kinetics:

Absorption: Good; unaffected by food

Protein binding: 15% to 41%

Metabolism: Hepatic via P450 enzymes

Bioavailability: 80%

Half-life elimination: Mean: Adults: Normal renal function: 21 hours; shorter in pediatric patients; clearance is 50% higher in pediatric patients

Time to peak, serum: ~2-4 hours

Excretion: Urine (~70% to 80% as unchanged drug)

Dialyzable: ~30%

Dosage:

Children 2-16 years: Partial seizures (adjunctive therapy), primary generalized tonic-clonic seizures (adjunctive therapy), or seizure associated with Lennox-Gastaut syndrome: Initial dose titration should begin at 25 mg (or less, based on a range of 1-3 mg/kg/day) nightly for the first week; dosage may be increased in increments of 1-3 mg/kg/day (administered in 2 divided doses) at 1- or 2-week intervals to a total daily dose of 5-9 mg/kg/day.

Adults:

Partial onset seizures (adjunctive therapy), primary generalized tonic-clonic seizures (adjunctive therapy): Initial: 25-50 mg/day; titrate in increments of 25-50 mg per week until an effective daily dose is reached; the daily dose may be increased by 25 mg at weekly intervals for the first 4 weeks; thereafter, the daily dose may be increased by 25-50 mg weekly to an effective daily dose (usually at least 400 mg); usual maximum dose: 1600 mg/day

Note: A more rapid titration schedule has been previously recommended (ie, 50 mg/week), and may be attempted in some clinical situations; however, this may reduce the patient's ability to tolerate topiramate.

Migraine prophylaxis: Initial: 25 mg/day, titrated at weekly intervals in 25 mg increments, up to the recommended total daily dose of 100 mg/day given in 2 divided doses

Cluster headache (unlabeled uses): Initial: 25 mg/day, titrated at weekly intervals in 25 mg increments, up to 200 mg/day

Dosing adjustment in renal impairment: Clcr<70 mL/minute: Administer 50% dose and titrate more slowly

Hemodialysis: Supplemental dose may be needed during hemodialysis

Dosing adjustment in hepatic impairment: Clearance may be reduced

Administration:

Capsule sprinkles: May be swallowed whole or opened to sprinkle the contents on soft food (drug/food mixture should not be chewed).

Tablet: Because of bitter taste, tablets should not be broken.

Monitoring Parameters:

Patient Education:

Additional Information:

Anesthesia and Critical Care Concerns/Other Considerations:

Additional information viewable at http://www.fda.gov/medwatch/SAFETY/2003/safety03.htm#topamax2, last accessed January 6, 2004.

Dental Health: Effects on Dental Treatment:

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

Dosage Forms:

Capsule, sprinkle: 15 mg, 25 mg

Tablet: 25 mg, 50 mg, 100 mg, 200 mg

International Brand Names: