EBM Consult

Topiramate (Topamax): Drug Monograph

    Brand Names
    • Topamax  
    Drug Class
    • Antiepileptic (AED) agent  
    Indications
    • Initial monotherapy in patients ≥2 years of age with partial onset or primary generalized tonic-clonic seizures
    • Adjunct therapy in patients ≥2 years of age with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome
    • Migraine headache prophylaxis in adults and adolescents ≥12 years of age  
    Dosing (Adult)

    General Notes: Take without regard to meals. Sprinkle capsules: may be swallowed whole or administered by carefully opening the capsule and sprinkling entire contents on a small amount (tsp.) of soft food; swallow drug/food mixture immediately and do not chew or tore mixture for later use

    • Epilepsy mono-therapy:  
      • Week 1: 25 mg twice daily
      • Week 2: 50 mg twice daily
      • Week 3: 75 mg twice daily
      • Week 4: 100 mg twice daily
      • Week 5: 150 mg twice daily 
      • Week 6 and onward: 200 mg twice daily
    • Epilepsy (Adjunctive Therapy; ≥17 years):
      • Adjunctive for partial onset seizure, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome
        • Initial: 25-50 mg by mouth every day
        • Increase in increments of 25-50 mg/day every week to average dose of 200-400 mg/day in 2 divided doses
    • Migraine:  
      • Week 1: 25 mg/day each evening
      • Week 2: 25 mg twice daily
      • Week 3: 25 mg each morning and 50 mg each evening
      • Week 4 and onward: 50 mg twice daily
    Dosing (Pediatric)
    • Epilepsy mono-therapy, 2 -<10 years:  
      • 25 mg/day each evening for the 1st week 
      • May increase to 50 mg each evening in the 2nd week, then by 25-50 mg daily each subsequent week. Titration to the minimum maintenance dose should be attempted over 5-7 weeks; additional titration to a higher dose (up to the maximum maintenance dose) can be attempted in weekly increments by 25-50 mg daily, up to the maximum maintenance dose of each range of body weight.
      • Up to 11 kg: Minimum maintenance dose: 150 mg/day; maximum maintenance dose: 250 mg/day
      • 12-22 kg: Minimum maintenance dose: 200 mg/day; maximum maintenance dose: 300 mg/day
      • 23-31 kg: Minimum maintenance dose: 200 mg/day; maximum maintenance dose: 350 mg/day
      • 32-38 kg: Minimum maintenance dose: 250 mg/day; maximum maintenance dose: 350 mg/day
      • >38 kg: Minimum maintenance dose: 250 mg/day; maximum maintenance dose: 400 mg/day 
      • Administer in 2 equally divided doses; refer to PI for titration instructions 
    • Epilepsy mono-therapy, ≥10 years
      • Week 1: 25 mg twice daily (am and pm)
      • Week 2: 50 mg twice daily (am and pm)
      • Week 3: 75 mg twice daily (am and pm)
      • Week 4: 100 mg twice daily (am and pm)
      • Week 5: 150 mg twice daily (am and pm)
      • Week 6 and onward: 200 mg twice daily (am and pm)
    • Epilepsy adjunctive therapy, partial onset/primary generalized tonic-clonic seizures/LGS, 2-16 years:  
      • Week 1: 1-3 mg/kg/day (≤25 mg/day) each evening
      • Increase dose at 1- or 2-week intervals by increments of 1-3 mg/kg/day (administered in 2 divided doses)
      • Usual: 5-9 mg/kg/day in 2 divided doses
    • Migraine, ≥12 years:
      • Week 1: 25 mg each evening
      • Week 2: 25 mg twice daily
      • Week 3: 25 mg each morning and 50 mg each evening
      • Week 4 and onward: 50 mg twice daily
    Renal Dosing
    • CrCl < 70 mL/min:  
      • Administer 50% of usual adult dose 
    • Patients undergoing hemodialysis:
      • May require a supplemental dose  
    Hepatic Dosing
    • None
    Dosage Forms
    • Tablets:   25 mg, 50 mg, 100 mg, 200 mg
    • Capsules, sprinkle:  15 mg, 25 mg  
    Black Box Warnings
    • None
    Contraindications
    • None
    Warnings
    • Acute myopia and secondary angle closure glaucoma.  Discontinue topiramate as rapidly as possible.
    • Oligohidrosis and hyperthermia.
    • Metabolic acidosis.  Consider dose reduction or discontinuation of topiramate if clinically appropriate. 
    • Suicidal behavior and ideation. 
    • Cognitive/neuropsychiatric. 
    • Fetal toxicity.  Use during pregnancy can cause cleft lip and/or palate. 
    • Withdrawal of AEDs - should be done gradually. 
    • Hyperammonemia and encephalopathy associated with or without concomitant valproic acid use.  
    • Kidney stones
    • Hypothermia  
    Adverse Reactions
    • Paresthesia
    • Anorexia
    • Weight decrease
    • Fatigue
    • Dizziness
    • Somnolence
    • Nervousness
    • Psychomotor slowing
    • Difficulty with memory
    • Difficulty with concentration/attention
    • Cognitive problems
    • Confusion
    • Mood problems
    • Fever
    • Infection
    • Flushing
    • Taste perversion  
    Overdose
    • Signs and symptoms include convulsions, drowsiness, speech disturbance, blurred vision, diplopia, mentation impaired, lethargy, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness, and depression.  
    • Overdose has resulted in severe metabolic acidosis.  
    • If the ingestion is recent, the stomach should be emptied immediately by lavage or by induction of emesis.  
    • Activated charcoal or hemodialysis may be used.  
    Antidote
    • None
    Drug Interactions
    • Antiepileptic drugs, such as phenytoin, carbamazepine, CBZ epoxide, valproic acid
    • CNS depressants 
    • Oral contraceptives: decreased contraceptive efficacy and increased breakthrough bleeding
    • Metformin - contraindicated with metabolic acidosis, an effect of topiramate    
    • Lithium levels should be monitored when co-administered with high-dose topiramate
    • Other carbonic anhydrase inhibitors * Antiepileptic drugs, such as phenytoin, carbamazepine, CBZ epoxide, valproic acid
    • CNS depressants 
    • Oral contraceptives: decreased contraceptive efficacy and increased breakthrough bleeding
    • Metformin - contraindicated with metabolic acidosis, an effect of topiramate    
    • Lithium levels should be monitored when co-administered with high-dose topiramate
    • Other carbonic anhydrase inhibitors  
    Special Populations
    • Pregnancy: Pregnancy Category D. Increased risk of cleft lip and/or palate.  
    • Labor and Delivery: Effect on labor and delivery in humans has not been established.  
    • Nursing Mothers: Caution should be exercised when administered to a nursing mother.  
    • Renal Impairment: CrCl < 70 mL/min/1.73 m2:  one-half of the adult dose.  Patients undergoing hemodialysis:  topiramate is cleared by hemodialysis. Dosage adjustment is necessary to avoid rapid drops in topiramate plasma concentration during hemodialysis.  
    • Hepatic Impairment: None
    • Pediatric Patients: Safety and effectiveness in patients below the age of 2 years have not been established for the adjunctive therapy treatment of partial onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome.  
    • Geriatric Patients: Dosage adjustment may be necessary for elderly with impaired renal function.  
    Pregnancy Rating
    • Category D  
    Breasfeeding
    • Caution should be exercised when administered to a nursing mother.  
    Chemical Structure

    • Scientific Name: 2,3:4,5-Di-O-isopropylidene-β-D-fructopyranose sulfamate
    • Empirical Formula: C12H21NO8S
    • Molecular Weight: 339.36  
    Mechanism of Action
    • The precise mechanisms by which topiramate exerts its anticonvulsant and migraine prophylaxis effects are unknown; however, preclinical studies have revealed four properties that may contribute to topiramate's efficacy for epilepsy and migraine prophylaxis. Electrophysiological and biochemical evidence suggests that topiramate, at pharmacologically relevant concentrations, blocks voltage-dependent sodium channels, augments the activity of the neurotransmitter gamma-aminobutyrate at some subtypes of the GABA-A receptor, antagonizes the AMPA/kainate subtype of the glutamate receptor, and inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV.  
    Pharmacodynamics
    • Topiramate has anticonvulsant activity in rat and mouse maximal electroshock seizure (MES) tests. Topiramate is only weakly effective in blocking clonic seizures induced by the GABA A receptor antagonist, pentylenetetrazole.  Topiramate is also effective in rodent models of epilepsy, which include tonic and absence-like seizures in the spontaneous epileptic rat (SER) and tonic and clonic seizures induced in rats by kindling of the amygdala or by global ischemia.  
    Pharmacokinetics
    • The sprinkle formulation is bioequivalent to the immediate-release tablet formulation and, therefore, may be substituted as a therapeutic equivalent.
    • Absorption: Absorption of topiramate is rapid, with peak plasma concentrations occurring at approximately 2 hours following a 400 mg oral dose. The relative bioavailability of topiramate from the tablet formulation is about 80% compared to a solution. The bioavailability of topiramate is not affected by food. 
    • Distribution: The pharmacokinetics of topiramate are linear with dose proportional increases in plasma concentration over the dose range studied (200 to 800 mg/day). The mean plasma elimination half-life is 21 hours after single or multiple doses. Steady-state is thus reached in about 4 days in patients with normal renal function. Topiramate is 15% to 41% bound to human plasma proteins over the blood concentration range of 0.5 to 250 μg/mL. The fraction bound decreased as blood concentration increased. Carbamazepine and phenytoin do not alter the binding of topiramate. Sodium valproate, at 500 μg/mL (a concentration 5 to 10 times higher than considered therapeutic for valproate) decreased the protein binding of topiramate from 23% to 13%. Topiramate does not influence the binding of sodium valproate. 
    • Metabolism and Elimination: Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). Six metabolites have been identified in humans, none of which constitutes more than 5% of an administered dose. The metabolites are formed via hydroxylation, hydrolysis, and glucuronidation. There is evidence of renal tubular reabsorption of topiramate. In rats, given probenecid to inhibit tubular reabsorption, along with topiramate, a significant increase in renal clearance of topiramate was observed. This interaction has not been evaluated in humans. Overall, oral plasma clearance (CL/F) is approximately 20 to 30 mL/min in adults following oral administration. 
    • Special Populations
      • Renal Impairment: The clearance of topiramate was reduced by 42% in moderately renally impaired (creatinine clearance 30 to 69 mL/min/1.73 m2) and by 54% in severely renally impaired subjects (creatinine clearance <30 mL/min/1.73 m2) compared to normal renal function subjects (creatinine clearance >70 mL/min/1.73 m2).  Since topiramate is presumed to undergo significant tubular reabsorption, it is uncertain whether this experience can be generalized to all situations of renal impairment. It is conceivable that some forms of renal disease could differentially affect glomerular filtration rate and tubular reabsorption resulting in a clearance of topiramate not predicted by creatinine clearance. In general, however, use of one-half the usual starting and maintenance dose is recommended in patients with moderate or severe renal impairment.  
      • Hemodialysis: Topiramate is cleared by hemodialysis. Using a high-efficiency, counterflow, single pass- dialysate hemodialysis procedure, topiramate dialysis clearance was 120 mL/min with blood flow through the dialyzer at 400 mL/min. This high clearance (compared to 20 to 30 mL/min total oral clearance in healthy adults) will remove a clinically significant amount of topiramate from the patient over the hemodialysis treatment period. Therefore, a supplemental dose may be required.
      • Hepatic Impairment: In hepatically impaired subjects, the clearance of topiramate may be decreased; the mechanism underlying the decrease is not well understood.
      • Age, Gender, and Race: The pharmacokinetics of topiramate in elderly subjects (65 to 85 years of age, N=16) were evaluated in a controlled clinical study. The elderly subject population had reduced renal function (creatinine clearance [-20%]) compared to young adults. Following a single oral 100 mg dose, maximum plasma concentration for elderly and young adults was achieved at approximately 1 to 2 hours. Reflecting the primary renal elimination of topiramate, topiramate plasma and renal clearance were reduced 21% and 19%, respectively, in elderly subjects, compared to young adults. Similarly, topiramate half-life was longer (13%) in the elderly. Reduced topiramate clearance resulted in slightly higher maximum plasma concentration (23%) and AUC (25%) in elderly subjects than observed in young adults. Topiramate clearance is decreased in the elderly only to the extent that renal function is reduced. As recommended for all patients, dosage adjustment may be indicated in the elderly patient when impaired renal function (creatinine clearance rate ≤70 mL/min/1.73 m 2) is evident.  It may be useful to monitor renal function in the elderly patient. Clearance of topiramate in adults was not affected by gender or race.  
      • Pediatric:
        • Pharmacokinetics of topiramate were evaluated in patients aged 2 to <16 years. Patients received either no or a combination of other antiepileptic drugs. A population pharmacokinetic model was developed on the basis of pharmacokinetic data from relevant topiramate clinical studies. This dataset contained data from 1217 subjects including 258 pediatric patients aged 2 to <16 years (95 pediatric patients <10 years of age).
        • Pediatric patients on adjunctive treatment exhibited a higher oral clearance (L/h) of topiramate compared to patients on mono-therapy, presumably because of increased clearance from concomitant enzyme-inducing antiepileptic drugs. In comparison, topiramate clearance per kg is greater in pediatric patients than in adults and in young pediatric patients (down to 2 years) than in older pediatric patients. Consequently, the plasma drug concentration for the same mg/kg/day dose would be lower in pediatric patients compared to adults and also in younger pediatric patients compared to older pediatric patients. Clearance was independent of dose.
        • As in adults, hepatic enzyme-inducing antiepileptic drugs decrease the steady state plasma concentrations of topiramate.  
    Counseling Points
    • Patients should be instructed to take topiramate only as prescribed.  
    • Patients should be instructed to not stop topiramate without first talking to a health care provider.  
    • Patients should be advised not to drink alcohol while taking topiramate.  
    • Patients should be told to seek immediate medical attention if they experience blurred vision, visual disturbances, or periorbital pain.  
    • Patients, especially pediatric patients, should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather.  Patients should contact their health care professionals immediately if they develop a high or persistent fever, or decreased sweating. 
    • Patients should be warned about the potential significant risk for metabolic acidosis that nay be asymptomatic and may be associated with adverse effects on kidneys (e.g., kidney stones, nephrocalcinosis), bones (e.g., osteoporosis, osteomalacia, and/or rickets in children), and growth (e.g., growth delay/retardation) in pediatric patients, and on the fetus.  
    • Patients should be counseled that topiramate may increase the risk of suicidal thoughts and behavior. Patients should be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior or the emergence of suicidal thoughts, or behavior or thoughts about self-harm. Behaviors of concern should be reported immediately to health care providers.  
    • Patients should be warned about the potential for somnolence, dizziness, confusion, difficulty concentrating, or visual effects and advised not to drive or operate machinery until they have gained sufficient experience on topiramate to gauge whether it adversely affects their mental performance, motor performance, and/or vision.  
    • Some patients with epilepsy will continue to have unpredictable seizures even when taking topiramate.  They should be told to exercise appropriate caution when engaging in any activities where loss of consciousness could result in serious danger to themselves or those around them. 
    • Inform pregnant women and women of childbearing potential that use of topiramate during pregnancy can cause fetal harm, including an increased risk for cleft lip and/or cleft palate. There may also be risks to the fetus from chronic metabolic acidosis. Advise women of childbearing potential who are not planning a pregnancy to use effective contraception while using topiramate.  There is a potential for decreased contraceptive efficacy when using estrogen-containing birth control with topiramate.  
    • Patients should be warned about the possible development of hyperammonemia with or without encephalopathy and instructed to contact their physician if they develop unexplained lethargy, vomiting, or changes in mental status.  
    • Patients, especially those with predisposing factors, should be instructed to maintain an adequate fluid intake in order to minimize the risk of kidney stone formation.  
    • Instruct patients that if a single dose is missed, to take that dose as soon as possible, skip it if it cannot be take at least 6 hours before the next scheduled dose, and not to double the dose. Advise the patient to contact physician if >1 dose is missed.
    References
    • Topiramate (Topamax).  Product Insert.  Janssen Pharmaceuticals, Inc.  Titusville, NJ.  2012.  

MESH Terms & Keywords

  • Topiramate, Topamax, Antiepileptic, AED