Topiramate

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Topiramate quick reference

Topiramate
Topiramate general drug information
 Pronunciation toe PYRE a mate (.wav file)
 Trade Name(s) Topamax
 How Supplied Tablets: 25 mg, 50 mg, 100 mg, and 200 mg
Sprinkle capsules: 15 mg, 25 mg
 Generic Availability No generics available
 Patent Expiry Date Treatment of seizures: September 26, 2008
Prophylactic treatment of migraine: October 13, 2015
 Classification Anticonvulsant
 Schedule Rx
 Pregnancy Category C
 Breast-feeding Breastfeeding should be done with caution since it may be excreted into the breastmilk. The potential benefit to the mother should be weighed against the potential risk to the infant when considering breast feeding.[1]
Topiramate chemical information
 IUPAC Name 2,3:4,5-Di-O-isopropylidene-Beta-D-fructopyranose sulfamate
 Empirical Formula (C12H21NO8S)
 Molecular Weight 339.36 g/mol
pharmacokinetic information  |  pharmacogenomic information
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Description

Topamax (topiramate) has a chemical structure that is unique in comparison with the other antiepileptic drugs (AEDs) in that it is a chemical derivative of the naturally occurring monosaccharide D-fructose. Topamax has a sulfamate moiety within its chemical structure; hence the "amate" ending in its name, topiramate. Topiramate possesses multiple mechanisms of action; therefore, it is often found to be helpful in a wide variety of forms of epilepsy and is often effective in epilepsies refractory to other medications. Topiramate has a long half life (about one day) and therefore has a long duration of action.

Topiramate has been designated by the FDA with "orphan drug" status for adjunctive treatment of Lennox-Gastaut syndrome, a severe juvenile form of epilepsy characterized by absence seizures and primary generalized tonic-clonic seizures. Topiramate is indicated for children greater than or equal to 2 years old with Lennox-Gastaut syndrome, and as monotherapy or adjunctive therapy for partial onset seizures or primary generalized tonic-clonic seizures. In addition, topiramate has been FDA approved for the prophylaxis of migraine headaches in adults. Topiramate is currently being studied as monotherapy or adjunctive therapy in bipolar disorder, including acute mania phases of bipolar disorder, as adjunctive treatment for atonic seizures, atypical absence seizures, myoclonic seizures, and infantile spasms, for cluster headaches, for neuropathic pain (diabetic neuropathy), and for alcohol dependence.

In general, topiramate is very well tolerated, with fatigue, somnolence, paresthesia, and cognitive impairment, including difficulty with memory, language, concentration, and attention as common complaints. In addition, topiramate may precipitate weight loss. Topiramate may worsen glaucoma or precipitate the formation of renal calculi, most likely due to it carbonic anhydrase inhibiting properties. [1][2][3]

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Mechanism of Action

Topiramate has many different mechanisms of action that account for its antiepileptic properties. Topiramate reduces voltage gated sodium channel current, thus reducing the number of action potentials that evoke a seizure. In addition, by blocking sodium channels, topiramate may prolong the amount of time the sodium channel is in the inactivated state, the refractory period, and hence, reduce the duration of seizures. For both of these reasons, topiramate is often touted as unique in its class because it can reduce the spread of seizures, rather than simply raising the seizure threshold, which is often how the more traditional anti-epileptic drugs work. Topiramate has also been postulated to activate a hyperpolarizing voltage gated potassium channel current. Third, topiramate enhances the inhibitory effects of GABA at the GABA-A receptor. Last, topiramate inhibits the excitatory glutamate receptors, specifically the AMPA/kainate subtype. Topiramate does not affect the NMDA receptor. In addition, topiramate inhibits carbonic anhydrase, notably isozymes II and IV, which is indicated in the side effects profile of the drug, but not the anticonvulsant effects of the drug. Carbonic anhydrase inhibition increases the risk of metabolic acidosis for topiramate, as well as an increased risk for paresthesias or renal calculi (kidney stones). Also, metabolic acidosis may account for some of the anorexic properties of topiramate, as weight loss may occur with this drug.[1][4]

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Time Required for Therapeutic Response

  • Steady state is reached in patients with normal renal function in about 4 days.[1]
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Pharmacokinetics

Absorption
Topiramate absorption is rapid; following a 400 mg oral dose, peak plasma concentrations occur roughly 2 hours post-dose.
The immediate release tablet formulation and sprinkle formulation are bioequivalent and may therefore be substituted for each other as therapeutic equivalents.
The tablet formulation has a relative bioavailability of about 80% in comparison to a solution of topiramate.
Topiramate bioavailability is not affected by food.[1]
Distribution
Topiramate pharmacokinetics are linear, meaning that the plasma concentration of topiramate increases proportionally with an increase in dose from 200-800 mg/day. This dose range was the only range evaluated by the manufacturer.
The mean plasma elimination half-life of topiramate is 21 hours after single or multiple doses; therefore, steady state is reached in patients with normal renal function in about 4 days.
Topiramate plasma protein binding is about 15-41%, over a topiramate blood concentration range of 0.5-250 micrograms per milliliter. The fraction of topiramate that is bound to human plasma proteins decreases as the blood concentration of topiramate increases.
The volume of distribution of topiramate is 0.6-0.8 L/kg, which suggests that it distributes into total body water.
Carbamazepine and phenytoin do not alter the plasma protein binding of topiramate. The therapeutic range for sodium valproate is roughly 85-125 micrograms per milliliter; sodium valproate at a concentration of 500 micrograms per milliliter decreased topiramate protein binding from 23% to 13%. Therefore, sodium valproate at therapeutic doses should not appreciably decrease topiramate protein binding. Topiramate does not alter sodium valproate protein binding.[1][5]

Metabolism
Topiramate is not primarily metabolized by the cytochrome P450 (CYP) family of hepatic isoenzymes. Topiramate is metabolized by hydrolysis, hydroxylation, and glucuronidation enzymatic processes to six different metabolites. Only 5% of an original topiramate administered dose is metabolized to these six metabolites. Topiramate is primarily renally eliminated unchanged into the urine. After oral administration of topiramate, oral plasma clearance, defined as clearance divided by bioavailability (Cl/F) is about 20-30 milliliters per minute in humans. Topiramate studies involving rats given probenecid, which inhibits tubular reabsorption, have demonstrated a significant increase in the renal clearance of topiramate. Therefore, renal tubular reabsorption of topiramate may theoretically occur in humans, although this process has not been evaluated in human studies.[1]

Excretion
Topiramate is primarily renally eliminated unchanged into the urine.[1]


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Special Population Pharmacokinetics

  • Renal insufficiency: Moderately renally impaired individuals with a creatinine clearance of 30-69 milliliters per minute per 1.73 meters squared demonstrated a reduction in topiramate clearance by 42% in comparison with individuals with normal renal function, defined as creatinine clearance greater than 70 milliliters per minute per 1.73 meters squared. Severely renally impaired individuals with a creatinine clearance of less than 30 milliliters per minute per 1.73 meters squared demonstrated a reduction in topiramate clearance by 54% in comparison with individuals with normal renal function. Topiramate undergoes glomerular filtration and tubular reabsorption. Some forms of renal insufficiency may differentially affect glomerular filtration rates (GFR) and tubular reabsorption rates such that topiramate clearance is not easily predicted by creatinine clearance and GFR.[1]
  • Hepatic insufficiency: Hepatically impaired individuals with hepatic insufficiency may exhibit a decreased topiramate clearance and a higher topiramate plasma concentration; however, the mechanism underlying the decreased topiramate clearance in hepatic insufficiency is not currently known.[1]
  • Hemodialysis: Hemodialysis does indeed clear topiramate. After oral administration of topiramate, oral plasma clearance, defined as clearance divided by bioavailability (Cl/F) is about 20-30 milliliters per minute in humans. Dialysis clearance of topiramate was found to be 120 milliliters per minute when blood flow through the dialyzer was set at a rate of 400 milliliters per minute. The clearance from hemodialyis (120 milliliters per minute) is about 4 times the oral plasma clearance in healthy adults (30 milliliters per minute). The higher clearance during hemodialysis will remove a clinically significant amount of topiramate during hemodialysis treatment; therefore, a supplemental topiramate dose may be necessary after hemodialysis in this particular patient population.[1]
  • Geriatric: Renal function should be carefully monitored in the geriatric patient population. Elderly subjects aged 65-85 years old were enrolled in a controlled clinical trial by the manufacturer. Compared to healthy young adults, the geriatric population in this study had a reduced creatinine clearance by about 20%. Both healthy young adults and the elderly obtain maximal plasma concentration at about 1-2 hours after dosing. After a single 100 mg dose, topiramate plasma and renal clearance were both reduced by about 20% in comparison with young healthy adults, indicating that topiramate is primarily renally eliminated. The half-life of topiramate was also longer in the elderly, by about 10%, in comparison with young healthy adults. Since the elderly had a reduced topiramate clearance, the AUC and maximum plasma concentration (Cmax) were also higher in the elderly, both by about 25%, in comparison with young healthy adults. Topiramate clearance is decreased in the elderly in proportion to the decrease in renal clearance within the elderly patient; hence, renal function should be carefully monitored in the geriatric patient population.[1]
  • Pediatric: Pediatric subjects aged 4-17 years old and taking topiramate and one or two other anticonvulsant drugs were enrolled in a controlled clinical trial by the manufacturer. Topiramate clearance was found to be independent of the dose in the pediatric population. Topiramate clearance is increased by about 50% in comparison with adults; hence, a shorter elimination half-life would be expected in the pediatric population in comparison with adults. Therefore, topiramate plasma concentration is expected to be lower in the pediatric population in comparison with adults.[1]
  • Gender: Topiramate clearance within healthy adults was not affected by race or gender.[1]
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Indications and Dosages

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FDA Approved Indications

Partial onset seizure and primary generalized tonic-clonic seizure, monotherapy

  • Starting dose:
    • Children greater than or equal to 10 years old and adults: 25 mg twice daily.
  • Maintenance dose:
    • 200 mg twice daily.
  • Titration schedule:

Week 1: 25 mg AM, 25 mg PM;
Week 2: 50 mg AM, 50 mg PM;
Week 3: 75 mg AM, 75 mg PM;
Week 4: 100 mg AM, 100 mg PM;
Week 5: 150 mg AM, 150 mg PM;
Week 6: 200 mg AM, 200 mg PM.

Adjunctive treatment of partial onset seizure, primary generalized tonic-clonic seizure, or Lennox-Gastaut syndrome

  • Starting dose:
    • Children and adolescents 2-16 years old:

1-3 mg/kg/day, up to 25 mg nightly for the first week.

  • Maintenance dose:
    • 5-9 mg/kg/day given in two divided doses

however, greater doses may be necessary to control seizures; titrate dose to response.

  • Titration schedule: Increase at 1-2 week intervals by 1-3 mg/kg/day given in two divided doses;

titrate dose to response.

Primary generalized tonic clonic seizure:
Use initial dose of 1-3 mg/kg/day, up to 25 mg nightly for the first week,
but use slower initial titration rate to a dose of 6 mg/kg/day given in two divided doses, by the end of eight weeks.
However, greater doses may be necessary to control seizures; titrate dose to response.

Adjunctive treatment of partial onset seizure

  • Starting dose:
    • Adolescents greater than or equal to 17 years old and adults:

25 mg per day to 25 mg twice daily for the first week.

  • Maintenance dose:
    • 100-200 mg twice daily

however, greater doses may be necessary to control seizures; titrate dose to response
maximum dose = 1600 mg per day;
doses above 1600 mg per day have not been extensively studied.

  • Titration schedule: Increase by 25 mg per day to 25 mg twice daily at weekly intervals;

titrate dose to response;
maximum dose = 1600 mg per day;
doses above 1600 mg per day have not been extensively studied.


Adjunctive treatment of primary generalized tonic-clonic seizure

  • Starting dose:
    • Adolescents greater than or equal to 17 years old and adults:

25 mg per day to 25 mg twice daily for the first week.

  • Maintenance dose:
    • 200 mg twice daily

however, greater doses may be necessary to control seizures; titrate dose to response;
maximum dose = 1600 mg per day;
doses above 1600 mg per day have not been extensively studied.

  • Titration schedule: Use a slower titration rate than listed above for partial onset seizure;

titrate up to the recommended dose of 200 mg twice daily by the end of eight weeks;
titrate dose to response;
maximum dose = 1600 mg per day;
doses above 1600 mg per day have not been extensively studied.

Migraine prophylaxis for adults

  • Starting dose:
    • 25 mg per day in the evening.
  • Maintenance dose:
    • 50 mg twice daily.

Brandes et al. conducted a randomized and controlled clinical trial for the prevention of migraines in adolescent patients and titrated the Topamax dose to clinical response, up to 100 mg twice daily.

  • Titration schedule:

Week 1: None in the AM, 25 mg PM;
Week 2: 25 mg AM, 25 mg PM;
Week 3: 25 mg AM, 50 mg PM;
Week 4: 50 mg AM, 50 mg PM.

Do not abruptly discontinue topiramate; taper the dose gradually in order to prevent rebound seizures.
[1][2][3][6]

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Non-FDA Approved Indications

  • Cluster headache
  • Neuropathic pain (diabetic neuropathy)
  • Alcohol dependence
  • Adjunct treatment for atonic seizure
  • Adjunct treatment for atypical absence seizure
  • Adjunct treatment for myoclonic seizure
  • Adjunct treatment for infantile spasm
  • Adjunct treatment or monotherapy for bipolar disorder, including acute mania
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Dosage Adjustment

Renal insufficiency: Individuals with moderate renal insufficiency, defined as a creatinine clearance of 30-69 milliliters per minute per 1.73 meters squared, and individuals with severe renal insufficiency, defined as a creatinine clearance of less than 30 milliliters per minute per 1.73 meters squared, should begin topiramate therapy utilizing one-half of the usual starting dose and should have their response titrated to a recommended dose of one-half of the usual maintenance dose. Individuals with moderate or severe renal insufficiency may also have a longer time to reach steady state after each dose adjustment in comparison with individuals with normal renal function.[1]
Hepatic insufficiency: Dose adjustment for hepatically insufficient individuals is not currently available.[1]
Hemodialysis: The higher clearance during hemodialysis will remove a clinically significant amount of topiramate during hemodialysis treatment; therefore, a supplemental topiramate dose may be necessary after hemodialysis in this particular patient population.[1]
Geriatric: Similar to healthy adults, the geriatric patient with a creatinine clearance of less than 70 milliliters per minute per 1.73 meters squared should begin topiramate therapy utilizing one-half of the usual starting dose and should have their response titrated to a recommended dose of one-half of the usual maintenance dose. Geriatric patients with moderate or severe renal insufficiency may also have a longer time to reach steady state after each dose adjustment in comparison with individuals with normal renal function.[1]
Pediatric: See doses for FDA approved indications within the pediatric population.[1]
Gender: Topiramate clearance within healthy adults was not affected by race or gender. Therefore, no dose adjustment is necessary with regards to race or gender.[1]

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Dosage Limits

  • Adults:

Adjunct treatment of primary generalized tonic-clonic seizure or partial onset seizure: 1600 mg/day.
Monotherapy for partial onset seizure or primary generalized tonic-clonic seizure: 200 mg twice daily.
Migraine prophylaxis: 50 mg twice daily.

  • Elderly:

Adjunct treatment of primary generalized tonic-clonic seizure or partial onset seizure: 1600 mg/day.
Monotherapy for partial onset seizure or primary generalized tonic-clonic seizure: 200 mg twice daily.
Migraine prophylaxis: 50 mg twice daily.

  • Adolescents:

Greater than or equal to 17 years old:
Adjunct treatment of primary generalized tonic-clonic seizure or partial onset seizure: 1600 mg/day.
Monotherapy for partial onset seizure or primary generalized tonic-clonic seizure: 200 mg twice daily.
Migraine prophylaxis: 50 mg twice daily.

  • Adolescents:

Greater than or equal to 10 years old and less than 17 years old:
Adjunct treatment of partial onset seizure or Lennox-Gastaut syndrome: 9 mg/kg/day in two divided doses.
Adjunct treatment of primary generalized tonic-clonic seizure: 6 mg/kg/day in two divided doses.
Monotherapy for partial onset seizure or primary generalized tonic-clonic seizure: 200 mg twice daily.
Higher doses may be necessary to control seizures; titrate dose to response.

  • Children:

Greater than or equal to 2 years old and less than 10 years old:
Adjunct treatment of partial onset seizure or Lennox-Gastaut syndrome: 9 mg/kg/day in two divided doses.
Adjunct treatment of primary generalized tonic-clonic seizure: 6 mg/kg/day in two divided doses.
Higher doses may be necessary to control seizures; titrate dose to response.

  • Children:

Less than 2 years old:
Topamax is not recommended for this patient population.
Topamax has not been evaluated extensively in controlled clinical studies for this patient population.
[1][2][3]

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Administration

  • Route: oral Topamax tablets: 25, 50, 100, and 200 mg
  • Method:
    • Swallow tablets whole. Do not cut tablets, crush tablets, or chew tablets. Tablets may be taken with or without food.
  • Route: oral Topamax sprinkle capsules: 15, and 25 mg
  • Method:
    • Sprinkle capsules may be sprinkled onto food. Carefully twist off the clear portion of the Topamax capsule over a small portion of soft food, such as applesauce, custard, ice cream, oatmeal, pudding, or yogurt. Sprinkle all of the contents of the Topamax capsule onto such food products. Be sure to swallow the food/sprinkle mixture whole. Do not chew the small bead contents of the food/sprinkle mixture. You may drink fluids immediately after in order to make sure the entire food/sprinkle mixture is swallowed. Make the food/sprinkle mixture fresh each time, for each dose. Do not store any sprinkle/food mixture for use at a later time. Topamax sprinkle capsules may also be swallowed as whole capsules.[1]
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Monitoring Parameters

  • Seizure frequency
  • Migraine headache frequency
  • Serum bicarbonate: recommended at baseline and as periodic monitoring since topiramate is associated with metabolic acidosis
  • Serum creatinine (sCr)
  • Psychiatric and cognitive dysfunction
  • Hydration status[1]
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Contraindications/Precautions

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Contraindications

  • History of allergic hypersensitivity to any component of topiramate.
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Precautions

  • Metabolic acidosis: Hyperchloremic, non-anionic gap, metabolic acidosis may occur secondary to the inhibitory effect of topiramate on carbonic anhydrase.
  • Myopia and Secondary Angle Closure Glaucoma: Topiramate use has been associated with acute myopia resulting from secondary angle closure glaucoma.
  • Hyperthermia and oligohydrosis, particularly within the pediatric population.
  • Paresthesia, secondary to carbonic anhydrase inhibitory activity
  • Hyperammonemia and encephalopathy with concomitant valproic acid (Depakote) therapy
  • Nephrolitiasis: Carbonic anhydrase inhibitors decrease renal citrate excretion and increase urinary pH, thereby promoting the formation of kidney stones.ref name="Topamax PI"/>[4]
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Pregnancy indications

Category C

No Topamax studies in pregnant women currently exist. Experimental animal studies have shown that Topamax displays specific developmental toxicities, including teratogenicity. Topamax should be used in pregnant women only if the potential benefit to the mother exceeds the potential risk to the foetus. Post marketing reports of hypospadias have occurred in male infants exposed to Topamax in utero, with or without other anticonvulsants; hence, a causal relationship between Topamax and hypospadias can not be established.
Pregnant mice had an increased incidence of foetal malformations, particularly craniofacial defects, when given Topamax early in their pregnancy at oral doses of 20, 100, or 500 mg/kg. Utilizing a mg per meter squared basis, the 20 mg/kg dose is about 1/5 the recommended human dose of 200 mg twice daily. Foetal skeletal development and body weight were reduced at an oral Topamax dose of 500 mg/kg, about 5 times the recommended human dose.
Studies in rats have shown an increased incidence of foetal limb malformations when pregnant rats were given an oral Topamax dose of 400 mg/kg early in their pregnancy. This dose is about 10 times the recommended human dose. Rat foetal body weights were reduced with Topamax doses as low as 20 mg/kg, about 1/2 the recommended human dose. Rat offspring had delayed physical development when pregnant rats were given Topamax later on in their pregnancy and throughout their lactation period. Delayed physical development of rat offspring occurred at a dose of 200 mg/kg, about 5 times the recommended human dose. Post-weaning body weight gain was reduced when lactating rats were given an oral Topamax dose of 2 mg/kg, about 0.05 times the recommended human dose.
Rabbit studies with oral Topamax doses of 35 mg/kg, about twice the recommended human dose, revealed that foetal mortality was increased. Rabbit studies with oral Topamax doses of 120 mg/kg, about 6 times the recommended human dose, revealed that the risk for foetal teratogenic effects was increased, particularly rib and vertebral malformations.[1]

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Breast-feeding indications

Breastfeeding should be done with caution since topiramate may be excreted into the breastmilk. The potential benefit to the mother should be weighed against the potential risk to the infant when considering breast feeding.[1]

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Drug-Drug, -Food, -Herb Interactions

Click the link above to go to the drug interactions page.

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Adverse Reactions/Side Effects

Topiramate monotherapy epilepsy trial sponsored by the manufacturer. All subjects were adults on topiramate at a dose of 200 mg twice daily. Adverse Reactions Chart:
Incidence Body System Adverse Reactions
>10% All paresthesia (40%), weight decrease (16%), somnolence (15%), dizziness (14%), anorexia (14%), difficulty with memory (10%)
1-10% CNS insomnia (9%), depression (9%), difficulty with concentration/attention (8%), anxiety (6%), psychomotor slowing (5%), mood problems (5%), hypoaesthesia (5%), ataxia (4%), confusion (4%), cognitive problems (4%), hypertonia (3%)
Dermatologic rash (4%), pruritus (4%), acne (3%)
GI diarrhea (6%), constipation (4%), gastritis (3%), dry mouth (3%), gastroesophageal reflux (2%)
Genitourinary libido decreased (3%), vaginal hemorrhage (3%), cystitis (3%), renal calculi (3%), urinary tract infection (2%), dysuria (2%), micturition frequency (2%)
Neuromuscular/skeletal asthenia (6%), leg pain (3%), chest pain (2%)
Respiratory bronchitis (4%), rhinitis (4%), dyspnea (2%)
Miscellaneous infection, viral (8%), taste perversion (5%), increased gamma glutamyl transferase (obstructive jaundice) (3%), infection (3%), anemia (2%)

[1]

Adjunctive topiramate therapy epilepsy trial sponsored by the manufacturer. Subjects were utilizing 1-2 other antiepileptic medications for seizure control. This trial was placebo controlled. A pediatric population, aged 2-16 years old, was employed in this trial. Adverse Reactions Chart:
Incidence Body System Adverse Reactions
>10% All somnolence (26%), anorexia (24%), nervousness (14%), personality disorder/behavior problems (11%), difficulty with concentration/attention (10%)
1-10% CNS aggressive reaction (9%), insomnia (8%), difficulty with memory (5%), confusion (4%), psychomotor slowing (3%), neurosis (1%)
Dermatologic alopecia (2%), dermatitis (2%), hypertrichosis (2%), rash, erythematous (2%), eczema (1%), seborrhoea (1%), skin discoloration (1%)
GI appetite increased (1%)
Genitourinary urinary incontinence (4%), leukorrhoea (2%), nocturia (1%)
Respiratory pneumonia (5%)
Miscellaneous purpura (8%), infections, viral (7%), epistaxis (4%), leukopenia (2%), eye abnormalities (2%), abnormal vision (2%), double vision (1%), abnormal lacrimation (1%), myopia (1%), hematoma (1%), prothrombin increased (1%), thrombocytopenia (1%)

[1]

Topiramate migraine trial sponsored by the manufacturer. Adverse events are those reported by adult subjects on topiramate at a dose of 50 mg twice daily. Adverse Reactions Chart:
Incidence Body System Adverse Reactions
>10% All paresthesia (51%), fatigue (15%), anorexia (15%), upper respiratory tract infection (14%), nausea (13%), diarrhea (11%)
1-10% CNS dizziness (9%), hypoaesthesia (7%), somnolence (7%), difficulty with memory (7%), insomnia (7%), difficulty with concentration/attention (6%), language problems (6%), mood problems (6%), anxiety (5%), depression (4%), nervousness (4%), confusion (3%), psychomotor slowing (2%), aggravated depression (2%), agitation (2%), cognitive problems (2%), involuntary muscle contractions (2%), ataxia (2%), speech disorders/related speech problems (1%)
Dermatologic pruritus (2%)
GI abdominal pain (6%), dyspepsia (5%), dry mouth (3%), gastroenteritis (3%), vomiting (2%)
Genitourinary libido decrease (2%), menstrual disorder (2%), urinary tract infection (2%), renal calculi (1%)
Neuromuscular/skeletal injury (6%), arthralgia (3%), asthenia (2%)
Respiratory sinusitis (6%), pharyngitis (6%), coughing (4%), bronchitis (3%), dyspnea (3%), rhinitis (2%)
Miscellaneous weight decrease (9%), taste perversion (8%), viral infection (4%), thirst (2%), abnormal vision (2%), blurred vision (2%), conjunctivitis (2%), taste loss (1%), otitis media (1%), fever (1%), influenza-like symptoms (1%), allergy (1%), tinnitus (1%), neoplasm (<1%)

[1]

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Overdosage Measures

Topiramate overdose may result in severe metabolic acidosis. Topiramate overdose results in one or more of the following signs and symptoms: abdominal pain, low blood pressure, dizziness, drowsiness, lethargy, depression, agitation, impaired mental capacity, speech disturbances, blurred vision, double vision, abnormal coordination, stupor, convulsions, or coma. In the most severe state of topiramate overdose, stupor, convulsions, coma and death have been reported with topiramate overdose in combination with other anticonvulsant drugs. Generally, the clinical consequences of topiramate overdose without other anticonvulsant drug use are not severe.[1]
Treatment:

  • If topiramate was recently ingested in quantities that qualify as an overdose, then use gastric lavage or induce emesis in order to empty the patient's stomach.
  • Hemodialysis is an effective method for clearing topiramate in an acute overdose.
  • In vitro, activated charcoal can adsorb topiramate, so activated charcoal may be an effective method for clearing topiramate in an acute overdose.
  • Appropriate supportive measures may be necessary.[1]
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Product Information and Distribution

Note: appearance only available for brand-name product
Dose/form Drug color(s) Drug shape Markings or odor/flavor
25 mg tablet white round 25/TOP
50 mg tablet light yellow round 50/TOPAMAX
100 mg tablet yellow round 100/TOPAMAX
200 mg tablet salmon/pink round 200/TOPAMAX
15 mg sprinkle capsule clear/white cylindrical/capsule TOP/15 mg
25 mg sprinkle capsule clear/white cylindrical/capsule TOP/25mg
  • Inactive ingredients for tablets: lactose monohydrate, pregelatinized starch, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, purified water, carnauba wax, hypromellose, titanium dioxide, polyethylene glycol, synthetic iron oxide (50, 100, and 200 mg tablets), polysorbate 80.[1]
  • Topamax sprinkle capsules contain topiramate coated beads within the capsule. Inactive ingredients for sprinkle capsules: sugar spheres (sucrose and starch), povidone, cellulose acetate, gelatin, sorbitan monolaurate, sodium lauryl sulfate, titanium dioxide, black pharmaceutical ink.[1]
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Patient Information

  • Swallow Topamax tablets whole. Do not chew the tablets.
  • Topamax sprinkle capsules may be swallowed whole or sprinkled onto a small amount of soft food, such as applesauce, custard, ice cream, oatmeal, pudding, or yogurt. Be sure to drink some fluids right after to ensure that the entire amount of Topamax and food mixture is swallowed. Never store any of the Topamax and food mixture for use at a later time.
  • Topamax can be taken without regard to meals.
  • Drink plenty of fluids.
  • If you miss a single dose of Topamax, take the next dose as soon as you can. If you are within 6 hours of your next Topamax dose, wait until then to take the usual dose of Topamax, and skip the missed dose; do not double up on doses.
  • Storage of Topamax: Store tablets in a tightly closed vial at room temperature, 59 to 86 degrees Fahrenheit (15-30 degrees Celsius). Store sprinkle capsules in a tightly closed vial at or below 77 degrees Fahrenheit (25 degrees Celsius). Keep Topamax out of the reach of children and pets.[1]
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References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 1.23 1.24 1.25 1.26 1.27 1.28 1.29 1.30 1.31 1.32 1.33 Topamax® (topiramate) package insert. Titusville, NJ; Ortho-McNeil Neurologics, Inc.; 2007 March.
  2. ↑ 2.0 2.1 2.2 Lacy C, Armstrong L, Goldman M, Lance L. Lexi-Comp: Drug Information Handbook. Hudson, Ohio: American Pharmacists Association; 2007: 1707-1709.
  3. ↑ 3.0 3.1 3.2 Taketomo C, Hodding J, Kraus D. Lexi-Comp: Pediatric Dosage Handbook. Hudson, Ohio: American Pharmacists Association; 2006: 1384-1387.
  4. ↑ 4.0 4.1 McNamara, James. Pharmacotherapy of the Epilepsies. In: Brunton L, Lazo J, Parker K, eds. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 11th ed. New York, NY: McGraw-Hill; 2006: 501-508, 519-520.
  5. ↑ Bourgeois BF. Pharmacokinetics and metabolism of topiramate. Drugs Today (Barc). 1999;35(1):43-48.
  6. ↑ Brandes JL, Saper JR, Diamond M, Couch JR, Lewis DW, Schmitt J, Neto W, Schwabe S, Jacobs D. Topiramate for migraine prevention: a randomized controlled trial. JAMA. 2004;291(8):965-73.]
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PUBMED References

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Efficacy Trial Articles

  1. Brandes JL, Saper JR, Diamond M, Couch JR, Lewis DW, Schmitt J, Neto W, Schwabe S, Jacobs D. Topiramate for migraine prevention: a randomized controlled trial. JAMA. 2004;291(8):965-73.
  2. Gilliam FG, Veloso F, Bomhof MA, Gazda SK, Biton V, Ter Bruggen JP, Neto W, Bailey C, Pledger G, Wu SC. A dose comparison trial of topiramate as monotherapy in recently diagnosed partial epilepsy. Neurology. 2003;60(2):196-202.
  3. Privitera MD, Brodie MJ, Mattson RH, Chadwick DW, Neto W, Wang S. Topiramate, carbamazepine and valproate monotherapy: double blind comparison in newly diagnosed epilepsy. Acta Neurol Scand. 2003;107(3):165-175.
  4. Ben-Menachem E, Henriksen O, Dam M, Mikkelsen M, Schmidt D, Reid S, Reife R, Kramer L, Pledger G, Karim R. Double blind, placebo controlled trial of topiramate as add on therapy in patients with refractory partial seizures. Epilepsia. 1996;37(6):539-543.
  5. Faught E, Wilder BJ, Ramsay RE, Reife RA, Kramer LD, Pledger GW, Karim RM. Topiramate placebo controlled dose ranging trial in refractory partial epilepsy using 200, 400, and 600 mg daily dosages. Neurology. 1996;46(6):1684-1690.
  6. Privitera M, Fincham R, Penry J, Reife R, Kramer L, Pledger G, Karim R. Topiramate placebo controlled dose ranging trial in refractory partial epilepsy using 600, 800, and 1,000 mg daily dosages. Neurology. 1996;46(6):1678-1683.
  7. Sharief M, Viteri C, Ben-Menachem E, Weber M, Reife R, Pledger G, Karim R. Double blind, placebo controlled study of topiramate in patients with refractory partial epilepsy. Epilepsy research. 1996;25(3):217-224.
  8. Tassinari CA, Michelucci R, Chauvel P, Chodkiewicz J, Shorvon S, Henriksen O, Dam M, Reife R, Pledger G, Karim R. Double blind, placebo controlled trial of topiramate (600 mg daily) for the treatment of refractory partial epilepsy. Epilepsia. 1996;37(8):763-768.
  9. Yen DJ, Yu HY, Guo YC, Chen C, Yiu CH, Su MS. A double blind, placebo controlled study of topiramate in adult patients with refractory partial epilepsy. Epilepsia. 2000;41(9):1162-1166.
  10. Wang Y, Zhou D, Pauli E, Stefan H. Topiramate on ictal seizure semiology: a quantitative, randomized, low and medium dose controlled study. Epilepsy research. 2001;46(3):271-277.
  11. Elterman RD, Glauser TA, Wyllie E, Reife R, Wu SC, Pledger G. A double blind, randomized trial of topiramate as adjunctive therapy for partial onset seizures in children. Neurology. 1999;52(7):1338-1344.
  12. Glauser TA, Levisohn PM, Ritter F, Sachdeo RC. Topiramate in Lennox Gastaut syndrome: open label treatment of patients completing a randomized controlled trial. Epilepsia. 2000;41(supplement 1):S86-S90.
  13. Sachdeo RC, Glauser TA, Ritter F, Reife R, Lim P, Pledger G. A double blind, randomized trial of topiramate in Lennox Gastaut syndrome. Neurology. 1999;52(9):1882-1887.
  14. Biton V, Montouris GD, Ritter F, Riviello JJ, Reife R, Lim P, Pledger G. A randomized, placebo controlled study of topiramate in primary generalized tonic clonic seizures. Neurology. 1999;52(7):1330-1337.
  15. Crawford P. An audit of topiramate use in a general neurology clinic. Seizure. 1998;7(3):207-211.
  16. Dooley JM, Camfield PR, Smith E, Langevin P, Ronen G. Topiramate in intractable childhood onset epilepsy - a cautionary note. Can J Neurol Sci. 1999;26(4):271-273.
  17. Tatum WO, French JA, Faught E, Morris GL, Liporace J, Kanner A, Goff SL, Winters L, Fix A. Post marketing experience with topiramate and cognition. Epilepsia. 2001;42(9):1134-1140.
  18. Abou-Khalil B. Topiramate in the long term management of refractory epilepsy. Epilepsia. 2000;41(supplement 1):S72-S76.
  19. Lhatoo SD, Wong IC, Sander JW. Prognostic factors affecting long term retention of topiramate in patients with chronic epilepsy. Epilepsia. 2000;41(3):338-341.
  20. Tartara A, Sartori I, Manni R, Galimberti CA, Di Fazio M, Perucca E. Efficacy and safety of topiramate in refractory epilepsy: a long term prospective trial. Ital J Neurol Sci. 1996;17(6):429-432.
  21. Baker GA, Currie NG, Light MJ, Schneiderman JH. The effects of adjunctive topiramate therapy on seizure severity and health related quality of life in patients with refractory epilepsy: a Canadian study. Seizure. 2002;11(1):6-15.
  22. Singh BK, White-Scott S. Role of topiramate in adults with intractable epilepsy, mental retardation, and developmental disabilities. Seizure. 2002;11(1):47-50.
  23. Kelly K, Stephen LJ, Sills GJ, Brodie MJ. Topiramate in patients with learning disability and refractory epilepsy. Epilepsia. 2002;43(4):399-402.
  24. Kellett MW, Smith DF, Stockton PA, Chadwick DW. Topiramate in clinical practice: first year's postlicensing experience in a specialist epilepsy clinic. J Neurol Neurosurg Psychiatry. 1999;66(6):759-763.
  25. Waugh J, Goa KL. Topiramate: as monotherapy in newly diagnosed epilepsy. CNS Drugs. 2003;17(13):985-992.
  26. Suppes T. Review of the use of topiramate for treatment of bipolar disorder. J. Clin. Psychopharmacol. 2002;22(6):599-609.
  27. Ormrod D, McClellan K. Topiramate: a review of its use in childhood epilepsy. Paediatric Drugs. 2001;3(4):293-319.
  28. Uldall P, Buchholt JM. Clinical experiences with topiramate in children with intractable epilepsy. Eur J Paediatr Neurol. 1999;3(3): 105-111.
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Therapeutic Class Comparison Articles

  1. Lacerda G, Krummel T, Sabourdy C, Ryvlin P, Hirsch E. Optimizing therapy of seizures in patients with renal or hepatic dysfunction. Neurology. 2006;67(12 Supplement 4):S28-33.
  2. Asconape JJ. Some common issues in the use of antiepileptic drugs. Seminars in Neurology. 2002;22(1):27-39.
  3. Bourdet SV, Gidal BE, Alldredge BK. Pharmacological management of epilepsy in the elderly. J Am Pharm Assoc (Wash). 2001;41(3):421-436.
  4. Willmore LJ. Choice and use of newer anticonvulsant drugs in older patients. Drugs & aging. 2000;17(6):441-452.
  5. Wong IC, Lhatoo SD. Adverse reactions to new anticonvulsant drugs. Drug Saf. 2000;23(1):35-56..


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Pharmacokinetics Articles

  1. Ohman I, Vitols S, Luef G, Soderfeldt B, Tomson T. Topiramate kinetics during delivery, lactation, and in the neonate: preliminary observations. Epilepsia. 2002;43(10):1157-1160.
  2. Bourgeois BF. Pharmacokinetics and metabolism of topiramate. Drugs Today (Barc). 1999;35(1):43-48.
  3. Johannessen SI, Battino D, Berry DJ, Bialer M, Kramer G, Tomson T, Patsalos PN. Therapeutic drug monitoring of the newer antiepileptic drugs. 2003;25(3):347-363.
  4. Adin J, Gomez MC, Blanco Y, Herranz JL, Armijo JA. Topiramate serum concentration-to-dose ratio: influence of age and concomitant antiepileptic drugs and monitoring implications. Ther. Drug Monitor. 2004;26(3):251-257.
  5. Battino D, Croci D, Rossini A, Messina S, Mamoli D, Perucca E. Topiramate pharmacokinetics in children and adults with epilepsy: a case-matched comparison based on therapeutic drug monitoring data. Clin. Pharmacokinet. 2005;44(4):407-416.
  6. Shank RP, Doose DR, Streeter AJ, Bialer M. Plasma and whole blood pharmacokinetics of topiramate: the role of carbonic anhydrase. Epilepsy Res. 2005;63(2-3):103-112.
  7. Tomson T. Gender aspects of pharmacokinetics of new and old AEDs: pregnancy and breast feeding. Ther. Drug Monit. 2005;27(6): 718-721.
  8. Mikaeloff Y, Rey E, Soufflet C, d'Athis P, Echenne B, Vallee L, Bouhours P, Grinspan A, Dulac O, Pons G, Chiron C. Topiramate pharmacokinetics in children with epilepsy aged from 6 months to 4 years. Epilepsia. 2004;45(11): 1448-52.
  9. Dahlin MG, Ohman IK. Age and antiepileptic drugs influence topiramate plasma levels in children. Pediatric Neurology. 2004;31(4):248-253.
  10. Rosenfeld WE, Doose DR, Walker SA, Baldassarre JS, Reife RA. A study of topiramate pharmacokinetics and tolerability in children with epilepsy. Pediatric Neurology. 1999;20(5):339-344.
  11. Glauser TA, Miles MV, Tang P, Clark P, McGee K, Doose DR. Topiramate pharmacokinetics in infants. Epilepsia. 1999;40(6):788-791.
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Drug Interaction Articles

  1. Harden CL, Leppik I. Optimizing therapy of seizures in women who use oral contraceptives. Neurology. 2006;67(12 Supplement 4): S56-58.
  2. Doose DR, Wang SS, Padmanabhan M, Schwabe S, Jacobs D, Bialer M. Effects of topiramate or carbamazepine on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in healthy obese and nonobese female subjects. Epilepsia. 2003;44(4):540-549.
  3. Crawford P. Interactions between antiepileptic drugs and hormonal contraception. CNS Drugs. 2002;16(4):263-272.
  4. Sachdeo RC, Sachdeo SK, Levy RH, Streeter AJ, Bishop FE, Kunze KL, Mather GG, Roskos LK, Shen DD, Thummel KE, Trager WF, Curtin CR, Doose DR, Gisclon LG, Bialer M. Topiramate and phenytoin pharmacokinetics during repetitive monotherapy and combination therapy to epileptic patients. Epilepsia. 2002;43(7):691-696.
  5. Britzi M, Perucca E, Soback S, Levy RH, Fattore C, Crema F, Gatti G, Doose DR, Maryanoff BE, Bialer M. Pharmacokinetic and metabolic investigation of topiramate disposition in healthy subjects in the absence and in the presence of enzyme induction by carbamazepine. Epilepsia. 2005;46(3): 378-384.
  6. Mimrod D, Specchio LM, Britzi M, Perucca E, Specchio N, LaNeve A, Soback S, Levy RH, Gatti G, Doose DR, Maryanoff BE, Bialer M. A comparative study of the effect of carbamazepine and valproic acid on the pharmacokinetics and metabolic profile of topiramate at steady state in patients with epilepsy. Epilepsia. 2005;46(7): 1046-1054.
  7. Bialer M, Doose DR, Murthy B, Curtin C, Wang SS, Twyman RE, Schwabe S. Pharmacokinetic interactions of topiramate. Clin. Pharmacokinet. 2004;43(12): 763-780.
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Adverse Effects Articles

  1. Arcas J, Ferrer T, Roche MC, Martinez Bermejo A, Lopez-Martin V. Hypohidrosis related to the administration of topiramate to children. Epilepsia. 2001;42(10):1363-1365.
  2. Evans RW. Reversible palinopsia and the Alice in Wonderland syndrome associated with topiramate use in migraineurs. Headache. 2006;46(5):815-818.
  3. Zesiewicz TA, Tullidge A, Tidwell J, Sullivan KL, Hauser RA. Topiramate induced psychosis in patients with essential tremor: report of 2 cases. Clinical neuropharmacology. 2006;29(3):168-169.
  4. Gorman MP, Soul JS. Neonatal hypocalcemic seizures in siblings exposed to topiramate in utero. Pediatric neurology. 2007;36(4):274-276.
  5. Lee ST, Chu K, Park JE, Park JH, Lee SH, Kim M. Paresthesia as a favorable predictor of migraine prophylaxis using topiramate. Eur J Neurol. 2007;14(6):654-658.
  6. Mula M, Sander JW. Negative effects of antiepileptic drugs on mood in patients with epilepsy. Drug Saf. 2007;30(7):555-567.
  7. Delpirou-Nouh C, Gelisse P, Chanez P, Carlander B. Migraine and Topiramate Induced Dyspnea. Headache. 2007 Sep 14; Epub ahead of print.
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Pharmacoeconomic Articles

  1. Brown JS, Papadopoulos G, Neumann PJ, Friedman M, Miller JD, Menzin J. Cost-effectiveness of topiramate in migraine prevention: results from a pharmacoeconomic model of topiramate treatment. Headache. 2005;45(8):1012-1022.
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External Links

Clinical treatment guidelines

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