CATEGORIES: Seizures, generalized tonic-clonic; Lennox-Gastaut syndrome; Seizures, partial; Pregnancy Category C; FDA Approved December 1996
Drug Classes: Anticonvulsants
BRAND NAMES: Topamax; Topamax Sprinkle
FOREIGN BRAND AVAILABILITY:
Epitomax (Finland);
Topamax Sprinkle (Hong Kong, Israel, Korea, New Zealand)
COST OF THERAPY:
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Topiramate is a sulfamate-substituted monosaccharide that is intended for use as an antiepileptic drug. Topamax tablets are available as 25, 100, and 200 mg round tablets for oral administration. Topamax sprinkle capsules are available as 15 and 25 mg sprinkle capsules for oral administration as whole capsules or opened and sprinkled onto soft food.
Topiramate is a white crystalline powder with a bitter taste. Topiramate is most soluble in alkaline solutions containing sodium hydroxide or sodium phosphate and having a pH of 9-10. It is freely soluble in acetone, chloroform, dimethylsulfoxide, and ethanol. The solubility in water is 9.8 mg/ml. Its saturated solution has a pH of 6.3. Topiramate has the molecular formula C12H21NO8S and a molecular weight of 339.37. Topiramate is designated chemically as 2,3:4,5-Di-O-isopropylidene-β-D-fructopyranose sulfamate.
Topamax tablets contain the following inactive ingredients: lactose monohydrate, pregelatinized starch, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, purified water, carnauba wax, hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, synthetic iron oxide (100 and 200 mg tablets), and polysorbate 80.
Topamax sprinkle capsules contain topirimate coated beads in a hard gelatin capsule. The inactive ingredients are: sugar spheres (sucrose and starch), povidone, cellulose acetate, gelatin, silicone dioxide, sodium lauryl sulfate, titanium dioxide, and black pharmaceutical ink.
Mechanism of Action
The precise mechanism by which topiramate exerts its antiseizure effect is unknown; however, electrophysiological and biochemical studies of the effects of topiramate on cultured neurons have revealed three properties that may contribute to topiramate's antiepileptic efficacy. First, action potentials elicited repetitively by a sustained depolarization of the neurons are blocked by topiramate in a time-dependent manner, suggestive of a state-dependent sodium channel blocking action. Second, topiramate increases the frequency at which γ-aminobutyrate (GABA) activates GABAA receptors, and enhances the ability of GABA to induce a flux of chloride ions into neurons, suggesting that topiramate potentiates the activity of this inhibitory neurotransmitter. This effect was not blocked by flumazenil, a benzodiazepine antagonist, nor did topiramate increase the duration of the channel open time, differentiating topiramate from barbiturates that modulate GABAA receptors. Third, topiramate antagonizes the ability of kainate to activate the kainate/AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid; non-NMDA) subtype of excitatory amino acid (glutamate) receptor, but has no apparent effect on the activity of N-methyl-D-aspartate (NMDA) at the NMDA receptor subtype. These effects of topiramate are concentration-dependent within the range of 1-200 μM.
Topiramate also inhibits some isoenzymes of carbonic anhydrase (CA-II and CA-IV). This pharmacologic effect is generally weaker than that of acetazolamide, a known carbonic anhydrase inhibitor, and is not thought to be a major contributing factor to topiramate's antiepileptic activity.
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 GABAA 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 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.
The pharmacokinetics of topiramate are linear with dose proportional increases in plasma concentration over the dose range studied (200-800 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 13-17% bound to human plasma proteins over the concentration range of 1-250 μg/ml.
Metabolism and Excretion
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 20-30 ml/min in humans following oral administration.
Pharmacokinetic Interactions
See also DRUG INTERACTIONS.
Antiepileptic Drugs
Potential interactions between topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. The effect of these interactions on mean plasma AUCs are summarized in DRUG INTERACTIONS and TABLE 3.
Special Populations
Renal Impairment
The clearance of topiramate was reduced by 42% in moderately renally impaired (creatinine clearance 30-69 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 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 20-30 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 (see DOSAGE AND ADMINISTRATION).
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
Clearance of topiramate was not affected by age (18-67 years), gender, or race.
Pediatric Pharmacokinetics
Pharmacokinetics of topiramate were evaluated in patients ages 4-17 years receiving 1 or 2 other antiepileptic drugs. Pharmacokinetic profiles were obtained after 1 week at doses of 1, 3, and 9 mg/kg/day. Clearance was independent of dose.
Pediatric patients have a 50% higher clearance and consequently shorter elimination half-life than adults. Consequently, the plasma concentration for the same mg/kg dose may be lower in pediatric patients compared to adults. As in adults, hepatic enzyme-inducing antiepileptic drugs decrease the steady-state plasma concentrations of topiramate.
The results of controlled clinical trials established the efficacy of topiramate as adjunctive therapy in adults and pediatric patients ages 2-16 years with partial onset seizures or primary generalized tonic-clonic seizures, and in patients 2 years of age and older with seizures associated with Lennox-Gastaut syndrome.
The studies described in the following sections were conducted using topiramate tablets.
Controlled Trials in Patients With Partial Onset Seizures
Adults With Partial Onset Seizures
The effectiveness of topiramate as an adjunctive treatment for adults with partial onset seizures was established in five multicenter, randomized, double-blind, placebo-controlled trials, two comparing several dosages of topiramate and placebo and three comparing a single dosage with placebo, in patients with a history of partial onset seizures, with or without secondarily generalized seizures.
Patients in these studies were permitted a maximum of 2 antiepileptic drugs (AEDs) in addition to topiramate tablets or placebo. In each study, patients were stabilized on optimum dosages of their concomitant AEDs during an 8-12 week baseline phase. Patients who experienced at least 12 (or 8, for 8 week baseline studies) partial onset seizures, with or without secondary generalization, during the baseline phase were randomly assigned to placebo or a specified dose of topiramate tablets in addition to their other AEDs.
Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 100 mg/day; the dose was then increased by 100 or 200 mg/day increments weekly or every other week until the assigned dose was reached, unless intolerance prevented increases. After titration, patients entered an 8 or 12 week stabilization period. The numbers of patients randomized to each dose, and the actual mean and median doses in the stabilization period are shown in TABLE 1.
Pediatric Patients Ages 2-16 Years With Partial Onset Seizures
The effectiveness of topiramate as an adjuncitve treatment for pediatric patients ages 2-16 years with partial onset seizures was established in a multicenter, randomized, double-blind, placebo-controlled trial, comparing topiramate and placebo in patients with a history of partial onset seizures, with or without secondarily generalized seizures.
Patients in this study were permitted a maximum of 2 antiepileptic drugs (AEDs) in addition to topiramate tablets or placebo. In this study, patients were stabilized on optimum dosages of their concomitant AEDs during an 8 week baseline phase. Patients who experienced at least 6 partial onset seizures, with or without secondarily generalized seizures, during the baseline phase were randomly assigned to placebo or topiramate tablets in addition to their other AEDs.
Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 25 or 50 mg/day; the dose was then increased by 25-150 mg/day increments every other week until the assigned dosage of 125, 175, 225, or 400 mg/day based on patients' weight to approximate a dosage of 6 mg/kg/day was reached, unless intolerance prevented increases. After titration, patients entered an 8 week stabilization period.
Controlled Trials in Patients With Primary Generalized Tonic-Clonic Seizures
The effectiveness of topiramate as an adjuntive treatment for primary generalized tonic-clonic seizures in patients 2 years old and older was established in a multicenter, randomized, double-blind, placebo-controlled trial, comparing a single dosage of topiramate and placebo.
Patients in this study were permitted a maximum of 2 antiepileptic drugs (AEDs) in addition to topiramate or placebo. Patients were stabilized on optimum dosages of their concomitant AEDs during an 8 week baseline phase. Patients who experienced at least 3 primary generalized tonic-clonic seizures during the baseline phase were randomly assigned to placebo or topiramate in addition to their other AEDs.
Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 50 mg/day for 4 weeks; the dose was then increased by 50-150 mg/day increments every other week until the assigned dose of 175, 225, or 400 mg/day based on patients' body weight to approximate a dosage of 6 mg/kg/day was reached, unless intolerance prevented increases. After titration, patients entered a 12 week stabilization period.
Controlled Trial in Patients With Lennox-Gastaut Syndrome
The effectiveness of topriamate as an adjuntive treatment for seizures associated with Lennox-Gastaut syndrome was established in a multicenter, randomized, double-blind, placebo-controlled trial comparing a single dosage of topiramate with placebo in patients 2 years of age and older.
Patients in this study were permitted a maximum of 2 antiepilepic drugs (AEDs) in addition to topiramate or placebo. Patients who were experiencing at least 60 seizures/month before study entry were stabilized on optimum dosages of their concomitant AEDs during a 4 week baseline phase. Following baseline, patients were randomly assigned to placebo or topiramate in addition to their other AEDs. Active drug was titrated beginning at 1 mg/kg/day for a week; the dose was then increased to 3 mg/kg/day for 1 week then to 6 mg/kg/day. After titration, patients entered an 8 week stabilization period. The primary measures of effectiveness were the percent reduction in drop attacks and a parental global rating of seizure severity.
In all add-on trials, the reduction in seizure rate from baseline during the entire double-blind phase was measured. The median percent reductions in seizure rates and the responder rates (fraction of patients with at least a 50% reduction) by treatment group for each study are shown in TABLE 2. As described above, a global improvement in seizure severity was also assessed in the Lennox-Gastaut trial.
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| * For Protocols YP and YTC, protocol-specified target dosages (<9.3 mg/kg/day) were assigned based on subject's weight to approximate a dosage of 6 mg/kg/day; these dosages corresponded to mg/day dosages of 125, 175, 225, and 400 mg/day. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Comparisons with placebo: | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| † p=0.080 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ‡ p ≤0.010 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| § p ≤0.001 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ¤ p ≤0.50 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ¶ p=0.065 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ** p ≤0.005 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| †† p=0.071 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ‡‡ Median % reduction and % responders are reported for PGTC seizures. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| §§ Median % reduction and % responders for drop attacks, i.e., toxic or atonic seizures. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ¤¤ Percent of subjects who were minimally, much, or very much improved from baseline. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subset analyses of the antiepileptic efficacy of topiramate tablets in these studies showed no differences as a function of gender, race, age, baseline seizure rate, or concomitant AED.
Topiramate tablets and sprinkle capsules are indicated as adjunctive therapy for adults and pediatric patients ages 2-16 years with partial onset seizures, or primary generalized tonic-clonic seizures, and in patients 2 years of age and older with seizures associated with Lennox-Gastaut syndrome.
Non-FDA Approved Indications
Topiramate has also shown efficacy as monotherapy in patients with refractory partial and generalized seizures. However, use of this drug as monotherapy has not been approved by the FDA. In one small study (n=11), an antimanic response has been reported to be reproducibly linked to the addition of topiramate. Use of topiramate as an antimanic agent has also not been approved by the FDA.
Topiramate is contraindicated in patients with a history of hypersensitivity to any component of this product.
Acute Myopia and Secondary Angle Closure Glaucoma
A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients recieving topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Opthalmologic findings can include myopia, anterior chamber shallowing, ocular hyperemia(redness) and increased intraocular pressure. Mydriasis may or may not be present. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating topiramate therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. The primary treatment to reverse symptoms is discontinution of topiramate as rapidly as possible, according to the judgement of the treating physician. Other measures, in conjunction with discontinuation of topiramate, may be helpful.
Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss.
Oligohidrosis and Hyperthermia
Oligohidrosis (decreased sweating), infrequently resulting in hospitalization, has been reported in association with topiramate use. Decreased sweating and an elevation in body temperature above normal characterized these cases. Some of the cases were reported after exposure to elevated environmental temperatures.
The majority of the reports have been in children. Patients, especially pediatric patients, treated with topiramate should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when topiramate is prescribed with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity.
Withdrawal of AEDs
Antiepileptic drugs, including topiramate, should be withdrawn gradually to minimize the potential of increased seizure frequency.
Cognitive/Neuropsychiatric Adverse Events
Adults
Adverse events most often associated with the use of topiramate were central nervous system (CNS) related. In adults, the most significant of these can be classified into two general categories: (1) psychomotor slowing, difficulty with concentration, and speech or language problems, in particular, word-finding difficulties and (2) somnolence or fatigue. Additional nonspecific CNS effects occasionally observed with topiramate as add-on therapy include dizziness or imbalance, confusion, memory problems, and exacerbation of mood disturbances (e.g., irritability and depression).
Reports of psychomotor slowing, speech and language problems, and difficulty with concentration and attention were common in adults. Although in some cases these events were mild to moderate, they at times led to withdrawal from treatment. The incidence of psychomotor slowing is only marginally dose-related, but both language problems and difficulty with concentration or attention clearly increased in frequency with increasing dosage in the five double-blind trials (see TABLE 5).
Somnolence and fatigue were the most frequently reported adverse events during clinical trials with topiramate. These events were generally mild to moderate and occurred early in therapy. While the incidence of somnolence does not appear to be dose-related, that of fatigue increases at dosages above 400 mg/day.
Pediatric Patients
In double-blind clinical studies, the incidences of cognitive/neuropsychiatric adverse events in pediatric patients were generally lower than previously observed in adults. These events included psychomotor slowing, difficutly with concentration/attention, speech disorders/related speech problems and language problems. The most frequently reported neuropsychiatric events in this population were somnolence and fatigue. No patients discontinued treatment due to adverse events in double-blind trials.
Sudden Unexplained Death in Epilepsy (SUDEP)
During the course of premarketing development of topiramate tablets, 10 sudden and unexplained deaths were recorded among a cohort of treated patients (2796 subject years of exposure). This represents an incidence of 0.0035 deaths/ patient year. Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving topiramate (ranging from 0.0005 for the general population of patients with epilepsy, to 0.003 for a clinical trial population similar to that in the topiramate program, to 0.005 for patients with refractory epilepsy).
General
Kidney Stones
A total of 32/2086 (1.5%) of adults exposed to topiramate during its development reported the occurrence of kidney stones, an incidence about 2-4 times than expected in a similar, untreated population. As in the general population, the incidence of stone formation among topiramate treated patients was higher in men. Kidney stones have also been reported in pediatric patients.
An explanation for the association of topiramate and kidney stones may lie in the fact that topiramate is a weak carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors, e.g., acetazolamide or dichlorphenamide, promote stone formation by reducing urinary citrate excretion and by increasing urinary pH. The concomitant use of topiramate with other carbonic anhydrase inhibitors or potentially in patients on a ketogenic diet may create a physiological environment that increases the risk of kidney stone formation, and should therefore be avoided.
Increased fluid intake increases the urinary output, lowering the concentration of substances involved in stone formation. Hydration is recommended to reduce new stone formation.
Paresthesia
Paresthesia, an effect associated with the use of other carbonic anhydrase inhibitors, appears to be a common effect of topiramate.
Adjustment of Dose in Renal Failure
The major route of elimination of unchanged topiramate and its metabolites is via the kidney. Dosage adjustment may be required (see DOSAGE AND ADMINISTRATION).
Decreased Hepatic Function
In hepatically impaired patients, topiramate should be administered with caution as the clearance of topiramate may be decreased.
Information for the Patient
Patients taking topiramate should be told to seek immediate medical attention if they experience blurred vision or periorbital pain.
Patients, especially pediatric patients, treated with topiramate should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather.
Patients, particularly those with predisposing factors, should be instructed to maintain an adequate fluid intake in order to minimize the risk of renal stone formation (see General, for support regarding hydration as a preventative measure).
Patients should be warned about the potential for somnolence, dizziness, confusion, and difficulty concentrating and advised not to drive or operate machinery until they have gained sufficient experience on topiramate to gauge whether it adversely affects their mental and/or motor performance.
Additional food intake may be considered if the patient is losing weight while on this medication.
Please refer to the important information included with the prescription on how to take topiramate sprinkle capsules.
Laboratory Tests
There are no known interactions of topiramate with commonly used laboratory tests.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
An increase in urinary bladder tumors was observed in mice given topiramate (20, 75, and 300 mg/kg) in the diet for 21 months. The elevated bladder tumor incidence, which was statistically significant in males and females receiving 300 mg/kg, was primarily due to the increased occurrence of a smooth muscle tumor considered histomorphologically unique to mice. Plasma exposures in mice receiving 300 mg/kg were approximately 0.5 to 1 times steady-state exposures measured in patients receiving topiramate monotherapy at the recommended human dose (RHD) of 400 mg, and 1.5 to 2 times steady-state topiramate exposures in patients receiving 400 mg of topiramate plus phenytoin. The relevance of this finding to human carcinogenic risk is uncertain. No evidence of carcinogenicity was seen in rats following oral administration of topiramate for 2 years at doses up to 120 mg/kg (approximately 3 times the RHD on a mg/m2 basis).
Topiramate did not demonstrate genotoxic potential when tested in a battery of in vitro and in vivo assays. Topiramate was not mutagenic in the Ames test or the in vitro mouse lymphoma assay; it did not increase unscheduled DNA synthesis in rat hepatocytes in vitro; and it did not increase chromosomal aberrations in human lymphocytes in vitro or in rat bone marrow in vivo.
No adverse effects on male or female fertility were observed in rats at doses up to 100 mg/kg (2.5 times the RHD on a mg/m2 basis).
Pregnancy Category C
Topiramate has demonstrated selective developmental toxicity, including teratogenicity, in experimental animal studies. When oral doses of 20, 100, or 500 mg/kg were administered to pregnant mice during the period of organogenesis, the incidence of fetal malformations (primarily craniofacial defects) was increased at all doses. The low dose is approximately 0.2 times the recommended human dose (RHD = 400 mg/day) on a mg/m2 basis. Fetal body weights and skeletal ossification were reduced at 500 mg/kg in conjunction with decreased maternal body weight gain.
In rat studies (oral doses of 20, 100, and 500 mg/kg or 0.2, 2.5, 30, and 400 mg/kg), the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased among the offspring of dams treated with 400 mg/kg (10 times the RHD on a mg/m2 basis) or greater during the organogenesis period of pregnancy. Embryotoxicity (reduced fetal body weights, increased incidence of structural variations) was observed at doses as low as 20 mg/kg (0.5 times the RHD on a mg/m2 basis). Clinical signs of maternal toxicity were seen at 400 mg/kg and above, and maternal body weight gain was reduced during treatment with 100 mg/kg or greater.
In rabbit studies (20, 60, and 180 mg/kg or 10, 35, and 120 mg/kg orally during organogenesis), embryo/fetal mortality was increased at 35 mg/kg (2 times the RHD on a mg/m2 basis) or greater, and teratogenic effects (primarily rib and vertebral malformations) were observed at 120 mg/kg (6 times the RHD on a mg/m2 basis). Evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35 mg/kg and above.
When female rats were treated during the latter part of gestation and throughout lactation (0.2, 4, 20, and 100 mg/kg or 2, 20, and 200 mg/kg), offspring exhibited decreased viability and delayed physical development at 200 mg/kg (5 times the RHD on a mg/m2 basis) and reductions in pre- and/or postweaning body weight gain at 2 mg/kg (0.05 times the RHD on a mg/m2 basis) and above. Maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/kg or greater.
In a rat embryo/fetal development study with a postnatal component (0.2, 2.5, 30 or 400 mg/kg during organogenesis; noted above), pups exhibited delayed physical development at 400 mg/kg (10 times the RHD on a mg/m2 basis) and persistent reductions in body weight gain at 30 mg/kg (1 times the RHD on a mg/m2 basis) and higher.
There are no studies using topiramate in pregnant women. Topiramate should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.
In postmarketing experience, cases of hypospadias have been reported in male infants exposed in utero to topiramate, with or without other anticonvulsants; however, a causal relationship with topiramate has not been established.
Labor and Delivery
In studies of rats where dams were allowed to deliver pups naturally, no drug-related effects on gestation length or parturition were observed at dosage levels up to 200 mg/kg/day.
The effect of topiramate on labor and delivery in humans is unknown.
Nursing Mothers
Topiramate is excreted in the milk of lactating rats. The excretion of topiramate in human milk has not been evaluated in controlled studies. Limited observations in patients suggest an extensive secretion of topiramate into breast milk. Since many drugs are excreted in human milk, and because the potential for serious adverse reactions in nursing infants to topiramate is unknown, the potential benefit to the mother should be weighed against the potential risk to the infant when considering recommendations regarding nursing.
Pediatric Use
Safety and effectiveness in patients below the age of 2 years have not been established.
Geriatric Use
In clinical trials, 2% of patients were over 60. No age related difference in effectiveness or adverse effects were seen. There were no pharmacokinetic differences related to age alone, although the possibility of age-associated renal functional abnormalities should be considered.
Race and Gender Effects
Evaluation of effectiveness and safety in clinical trials has shown no race or gender related effects.
Antiepileptic Drugs
Potential interactions between topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. The effects of these interactions on mean plasma AUCs are summarized in TABLE 3.
In TABLE 3, the second column (AED Concentration) describes what happens to the concentration of the AED listed in the first column when topiramate is added.
The third column (Topiramate Concentration) describes how the coadministration of a drug listed in the first column modifies the concentration of topiramate in experimental settings when topiramate was given alone.
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| * Plasma concentration increased 25% in some patients, generally those on a bid dosing regimen of phenytoin. | ||||||||||||||||||||||||
| † Is not administered but is an active metabolite of carbamazepine. | ||||||||||||||||||||||||
| NC Less than 10% change in plasma concentration. | ||||||||||||||||||||||||
| AED Antiepileptic drug. | ||||||||||||||||||||||||
| NE Not Evaluated. | ||||||||||||||||||||||||
Other Drug Interactions
The data described in the following section were obtained using topiramate tablets.
The most commonly observed adverse events associated with the use of topiramate at dosages of 200-400 mg/day in controlled trials in adults with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, that were seen at greater frequency in topiramate-treated patients and did not appear to be dose-related were: somnolence, dizziness, ataxia, speech disorders and related speech problems, psychomotor slowing, abnormal vision, difficulty with memory, paresthesia and diplopia (see TABLE 4). The most common dose-related adverse events at dosages of 200-1000 mg/day were: fatigue, nervousness, difficulty with concentration or attention, confusion, depression, anorexia, language problems, anxiety, mood problems, and weight decreased (see TABLE 5).
Adverse events associated with the use of topiramate at dosages of 5-9 mg/kg/day in controlled trials in pediatric patients with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, that were seen at greater frequency in topiramate-treated patients were: fatigue, somnolence, anorexia, nervousness, difficulty with concentration/attention, difficulty with memory, aggressive reaction, and weight decrease (see TABLE 6).
In controlled clinical trials in adults, 11% of patients receiving topiramate 200-400 mg/day as adjunctive therapy discontinued due to adverse events. This rate appeared to increase at dosages above 400 mg/day. Adverse events associated with discontinuing therapy included somnolence, dizziness, anxiety, difficulty with concentration or attention, fatigue, and paresthesia and increased at dosages above 400 mg/day. None of the pediatric patients who received topiramate adjunctive therapy at 5-9 mg/kg/day in controlled clinical trials discontinued due to adverse events.
Approximately 28% of the 1757 adults with epilepsy who received topiramate at dosages of 200-1600 mg/day in clinical studies discontinued treatment because of adverse events; an individual patient could have reported more than one adverse event. These adverse events were: psychomotor slowing (4.0%), difficulty with memory (3.2%), fatigue (3.2%), confusion (3.1%), somnolence (3.2%), difficulty with concentration/attention (2.9%), anorexia (2.7%), depression (2.6%), dizziness (2.5%), weight decrease (2.5%), nervousness (2.3%), ataxia (2.1%), and paresthesia (2.0%). Approximately 11% of the 310 pediatric patients who received topiramate at dosages up to 30 mg/kg/day discontinued due to adverse events. Adverse events associated with discontinuing therapy included aggravated convulsions (2.3%), difficulty with concentration/attention (1.6%), language problems (1.3%), personality disorder (1.3%), and somnolence (1.3%).
Incidence in Controlled Clinical Trials — Add-On Therapy
TABLE 4 lists treatment-emergent adverse events that occurred in at least 1% of adults treated with 200-400 mg/day topiramate in controlled trials that were numerically more common at this dose than in the patients treated with placebo. In general, most patients who experienced adverse events during the first 8 weeks of these trials no longer experienced them by their last visit. TABLE 6 lists treatment-emergent adverse events that occurred in at least 1% of pediatric patients treated with 5-9 mg/kg topiramate in controlled trials that were numerically more common than in patients treated with placebo.
The prescriber should be aware that these data were obtained when topiramate was added to concurrent antiepileptic drug therapy and cannot be used to predict the frequency of adverse events in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with data obtained from other clinical investigations involving different treatments, uses, or investigators. Inspection of these frequencies, however, does provide the prescribing physician with a basis to estimate the relative contribution of drug and non-drug factors to the adverse event incidences in the population studied.
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| * Patients in these add-on trials were receiving 1-2 concomitant antiepileptic drugs in addition to topiramate or placebo. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| † Values represent the percentage of patients reporting a given adverse event. Patients may have reported more than one adverse event during the study and can be included in more than one adverse event category. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ‡ Adverse events reported by at least 1% of patients in the topiramate 200-400 mg/day group and more common than in the placebo group are listed in this table. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| * Dose-response studies were not conducted for other adult indications or for pediatric indications. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| * Events that occurred in at least 1% of topiramate-treated patients and occurred more frequently in topiramate-treated than placebo-treated patients. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| † Patients in these add-on trials were receiving 1-2 concomitant antiepileptic drugs in addition to topiramate or placebo. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ‡ Values represent the percentage of patients reporting a given adverse event. Patients may have reported more than one adverse event during the study and can be included in more than one adverse event category. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Other Adverse Events Observed
Other events that occurred in more than 1% of adults treated with 200-400 mg of topiramate in placebo-controlled trials but with equal or greater frequency in the placebo group were: headache, injury, anxiety, rash, pain, convulsions aggravated, coughing, fever, diarrhea, vomiting, muscle weakness, insomnia, personality disorder, dysmenorrhea, upper respiratory tract infection, and eye pain.
Other Adverse Events Observed During All Clinical Trials
Topiramate, initiated as adjunctive therapy, has been administered to 1757 adults and 310 pediatric patients with epilepsy during all clinical studies. During these studies, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using modified WHOART dictionary terminology. The frequencies presented represent the proportion of patients who experienced an event of the type cited on at least one occasion while receiving topiramate. Reported events are included except those already listed in the previous table or text, those too general to be informative, and those not reasonably associated with the use of the drug.
Events are classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent occurring in at least 1/100 patients; infrequent occurring in 1/100 to 1/1000 patients; rare occurring in fewer than 1/1000 patients.
Postmarketing and Other Experience
In addition to the adverse experiences reported during clinical testing of topiramate, the following adverse experiences have been reported worldwide in patients receiving topiramate post-approval. These adverse experiences have not been listed above and data are insufficient to support an estimate of their incidence or to establish causation. The listing is alphabetized: bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), hepatic failure (including fatalities), hepatitis, pancreatitis, pemphigus, and renal tubular acidosis.
The abuse and dependence potential of topiramate has not been evaluated in human studies.
Overdoses of topiramate have been reported. Signs and symptoms included convulsions, drowsiness, speech disturbance, blurred vision, diplopia, mentation impaired, lethargy, metabolic acidosis, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness and depression. The clinical consequences were not severe in most cases, but deaths have been reported after poly-drug overdoses involving topiramate.
A patient who ingested a dose between 96 and 110 g topiramate was admitted to hospital with coma lasting 20-24 hours followed by full recovery after 3-4 days.
In acute topiramate overdose, if the ingestion is recent, the stomach should be emptied immediately by lavage or by induction of emesis. Activated charcoal has been shown to adsorb topiramate in vitro. Treatment should be appropriately supportive. Hemodialysis is an effective means of removing topiramate from the body.
Topiramate has been shown to be effective in adults and pediatric patients ages 2-16 years with partial onset seizures or primary generalized tonic-clonic seizures, and in patients 2 years of age and older with seizures associated with Lennox-Gastaut syndrome. In the controlled add-on trials, no correlation has been demonstrated between trough plasma concentrations of topiramate and clinical efficacy. No evidence of tolerance has been demonstrated in humans. Doses above 400 mg/day (600, 800, or 1000 mg/day) have not been shown to improve responses in dose-response studies in adults with partial onset seizures.
It is not necessary to monitor topiramate plasma concentrations to optimize topiramate therapy. On occasion, the addition of topiramate to phenytoin may require an adjustment of the dose of phenytoin to achieve optimal clinical outcome. Addition or withdrawal of phenytoin and/or carbamazepine during adjunctive therapy with topiramate may require adjustment of the dose of topiramate. Because of the bitter taste, tablets should not be broken.
Topiramate can be taken without regard to meals.
Adults (17 years of age and over)
The recommended total daily dose of topiramate as adjunctive therapy is 400 mg/day in two divided doses. In studies of adults with partial onset seizures, a daily dose of 200 mg/day has inconsistent effects and is less effective than 400 mg/day. It is recommended that therapy be initiated at 25-50 mg/day followed by titration to an effective dose in increments of 25-50 mg/week. Titrating in increments of 25 mg/week may delay the time to reach an effective dose. Daily doses above 1600 mg have not been studied.
In the study of primary generalized tonic-clonic seizures the initial titration rate was slower than in previous studies; the assigned dose was reached at the end of 8 weeks (see CLINICAL STUDIES, Controlled Trials in Patients With Primary Generalized Tonic-Clonic Seizures).
Pediatric Patients (ages 2-16 years) — Partial Seizures, Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut Syndrome
The recommended total daily dose of topiramate as adjunctive therapy for patients with partial seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome is approximately 5-9 mg/kg/day in 2 divided doses. Titration should begin at 25 mg (or less, based on a range of 1-3 mg/kg/day) nightly for the first week. The dosage should then be increased at 1 or 2 week intervals by increments of 1-3 mg/kg/day (administered in 2 divided doses), to achieve optimal clinical response. Dose titration should be guided by clinical outcome.
In the study of primary generalized tonic-clonic seizures the initial titration rate was slower than in previous studies; the assigned dose of 6 mg/kg/day was reached at the end of 8 weeks (see CLINICAL STUDIES, Controlled Trials in Patients With Primary Generalized Tonic-Clonic Seizures).
Administration of Topiramate Sprinkle Capsules
Topiramate sprinkle capsules may be swallowed whole or may be administered by carefully opening the capsule and sprinkling the entire contents on a small amount (teaspoon) of soft food. This drug/food mixture should be swallowed immediately and not chewed. It should not be stored for future use.
Patients With Renal Impairment
In renally impaired subjects (creatinine clearance less than 70 ml/min/1.73 m2), one-half of the usual adult dose is recommended. Such patients will require a longer time to reach steady-state at each dose.
Patients Undergoing Hemodialysis
Topiramate is cleared by hemodialysis at a rate that is 4-6 times greater than a normal individual. Accordingly, a prolonged period of dialysis may cause topiramate concentration to fall below that required to maintain an anti-seizure effect. To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of topiramate may be required. The actual adjustment should take into account (1) the duration of dialysis period, (2) the clearance rate of the dialysis system being used, and (3) the effective renal clearance of topiramate in the patient being dialyzed.
Patients With Hepatic Disease
In hepatically impaired patients topiramate plasma concentrations may be increased. The mechanism is not well understood.
Topamax Tablets
Topamax is available as debossed, coated, round tablets in the following strengths and colors:
Storage: Topamax tablets should be stored in tightly-closed containers at controlled room temperature, 15-30°C (59-86°F). Protect from moisture.
Topamax Sprinkle Capsules
Topamax sprinkle capsules contain small, white to off-white spheres. The gelatin capsules are white and clear. They are marked as follows:
Storage: Topamax sprinkle capsules should be stored in tightly-closed containers at or below 25°C (77°F). Protect from moisture.
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