topiramate 25 MG Oral Tablet
Generic Name: TOPIRAMATE
Brand Name: TOPIRAMATE
- Substance Name(s):
- TOPIRAMATE
WARNINGS
Acute Myopia and Secondary Angle Closure GlaucomaA syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving topiramate.
Symptoms include acute onset of decreased visual acuity and/or ocular pain.
Ophthalmologic 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 discontinuation of topiramate as rapidly as possible, according to the judgment 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 HyperthermiaOligohidrosis (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.
Suicidal Behavior and IdeationAntiepileptic drugs (AEDs), including topiramate, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication.
Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo.
In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated.
There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed.
Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.
The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication.
The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.
Table 3 shows absolute and relative risk by indication for all evaluated AEDs.
Table 3 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing topiramate or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness.
Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.
Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior or the emergence of suicidal thoughts, behavior or thoughts about self-harm.
Behaviors of concern should be reported immediately to healthcare providers.
Metabolic AcidosisHyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis) is associated with topiramate treatment.
This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of topiramate on carbonic anhydrase.
Such electrolyte imbalance has been observed with the use of topiramate in placebo-controlled clinical trials and in the post-marketing period.
Generally, topiramate-induced metabolic acidosis occurs early in treatment although cases can occur at any time during treatment.
Bicarbonate decrements are usually mild-moderate (average decrease of 4 mEq/L at daily doses of 400 mg in adults and at approximately 6 mg/kg/day in pediatric patients); rarely, patients can experience severe decrements to values below 10 mEq/L.
Conditions or therapies that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, surgery, ketogenic diet, or drugs) may be additive to the bicarbonate lowering effects of topiramate.
In adults, the incidence of persistent treatment-emergent decreases in serum bicarbonate (levels of less than 20 mEq/L at two consecutive visits or at the final visit) in controlled clinical trials for adjunctive treatment of epilepsy was 32% for 400 mg/day, and 1% for placebo.
Metabolic acidosis has been observed at doses as low as 50 mg/day.
The incidence of persistent treatment-emergent decreases in serum bicarbonate in adults in the epilepsy controlled clinical trial for monotherapy was 15% for 50 mg/day and 25% for 400 mg/day.
The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value less than 17 mEq/L and greater than 5 mEq/L decrease from pretreatment) in the adjunctive therapy trials was 3% for 400 mg/day, and 0% for placebo and in the monotherapy trial was 1% for 50 mg/day and 7% for 400 mg/day.
Serum bicarbonate levels have not been systematically evaluated at daily doses greater than 400 mg/day.
In pediatric patients (less than 16 years of age), the incidence of persistent treatment-emergent decreases in serum bicarbonate in placebo-controlled trials for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial onset seizures was 67% for topiramate (at approximately 6 mg/kg/day), and 10% for placebo.
The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value less than 17 mEq/L and greater than 5 mEq/L decrease from pretreatment) in these trials was 11% for topiramate and 0% for placebo.
Cases of moderately severe metabolic acidosis have been reported in patients as young as 5 months old, especially at daily doses above 5 mg/kg/day.
In pediatric patients (10 years up to 16 years of age), the incidence of persistent treatment-emergent decreases in serum bicarbonate in the epilepsy controlled clinical trial for monotherapy was 7% for 50 mg/day and 20% for 400 mg/day.
The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value less than 17 mEq/L and greater than 5 mEq/L decrease from pretreatment) in this trial was 4% for 50 mg/day and 4% for 400 mg/day.
Some manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor.
Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis, and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fractures.
Chronic metabolic acidosis in pediatric patients may also reduce growth rates.
A reduction in growth rate may eventually decrease the maximal height achieved.
The effect of topiramate on growth and bone-related sequelae has not been systematically investigated.
Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended.
If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing topiramate (using dose tapering).
If the decision is made to continue patients on topiramate in the face of persistent acidosis, alkali treatment should be considered.
Cognitive/Neuropsychiatric Adverse Events Adults Adverse events most often associated with the use of topiramate were related to the central nervous system and were observed in the epilepsy population.
In adults, the most frequent of these can be classified into three general categories: 1) Cognitive-related dysfunction (e.g.
confusion, psychomotor slowing, difficulty with concentration/attention, difficulty with memory, speech or language problems, particularly word-finding difficulties); 2) Psychiatric/behavioral disturbances (e.g.
depression or mood problems); and 3) Somnolence or fatigue.
Cognitive-Related Dysfunction The majority of cognitive-related adverse events were mild to moderate in severity, and they frequently occurred in isolation.
Rapid titration rate and higher initial dose were associated with higher incidences of these events.
Many of these events contributed to withdrawal from treatment [see ADVERSE REACTIONS , Table 5 and Table 7].
In the original add-on epilepsy controlled trials (using rapid titration such as 100 to 200 mg/day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse events was 42% for 200 mg/day, 41% for 400 mg/day, 52% for 600 mg/day, 56% for 800 and 1000 mg/day, and 14% for placebo.
These dose-related adverse reactions began with a similar frequency in the titration or in the maintenance phase, although in some patients the events began during titration and persisted into the maintenance phase.
Some patients who experienced one or more cognitive-related adverse events in the titration phase had a dose-related recurrence of these events in the maintenance phase.
In the monotherapy epilepsy controlled trial, the proportion of patients who experienced one or more cognitive-related adverse events was 19% for topiramate 50 mg/day and 26% for 400 mg/day.
Psychiatric/Behavioral Disturbances Psychiatric/behavioral disturbances (depression or mood problems) were dose-related for the epilepsy population.
Somnolence/Fatigue Somnolence and fatigue were the adverse events most frequently reported during clinical trials of topiramate for adjunctive epilepsy.
For the adjunctive epilepsy population, the incidence of somnolence did not differ substantially between 200 mg/day and 1000 mg/day, but the incidence of fatigue was dose-related and increased at dosages above 400 mg/day.
For the monotherapy epilepsy population in the 50 mg/day and 400 mg/day groups, the incidence of somnolence was dose-related (9% for the 50 mg/day group and 15% for the 400 mg/day group) and the incidence of fatigue was comparable in both treatment groups (14% each).
Additional nonspecific CNS events commonly observed with topiramate in the add-on epilepsy population include dizziness or ataxia.
Pediatric Patients In double-blind adjunctive therapy and monotherapy epilepsy clinical studies, the incidences of cognitive/neuropsychiatric adverse events in pediatric patients were generally lower than observed in adults.
These events included psychomotor slowing, difficulty with concentration/attention, speech disorders/related speech problems and language problems.
The most frequently reported neuropsychiatric events in pediatric patients during adjunctive therapy double-blind studies were somnolence and fatigue.
The most frequently reported neuropsychiatric events in pediatric patients in the 50 mg/day and 400 mg/day groups during the monotherapy double-blind study were headache, dizziness, anorexia, and somnolence.
No patients discontinued treatment due to any adverse events in the adjunctive epilepsy double-blind trials.
In the monotherapy epilepsy double-blind trial, 1 pediatric patient (2%) in the 50 mg/day group and 7 pediatric patients (12%) in the 400 mg/day group discontinued treatment due to any adverse events.
The most common adverse event associated with discontinuation of therapy was difficulty with concentration/attention; all occurred in the 400 mg/day group.
Withdrawal of AEDsAntiepileptic drugs, including topiramate, should be withdrawn gradually to minimize the potential of increased seizure frequency.
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 (2,796 subject years of exposure).
This represents an incidence of 0.0035 deaths per 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).
OVERDOSAGE
Overdoses of topiramate have been reported.
Signs and symptoms included convulsions, drowsiness, speech disturbance, blurred vision, diplopia, mentation impaired, lethargy, 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.
Topiramate overdose has resulted in severe metabolic acidosis (see WARNINGS ).
A patient who ingested a dose between 96 and 110 g topiramate was admitted to hospital with coma lasting 20 to 24 hours followed by full recovery after 3 to 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.
DESCRIPTION
Topiramate is a sulfamate-substituted monosaccharide.
Topiramate tablets are available as 25 mg, 50 mg, 100 mg, and 200 mg circular tablets for oral administration.
Topiramate is a white crystalline powder with a bitter taste.
Topiramate USP is most soluble in alkaline solutions containing sodium hydroxide or sodium phosphate and having a pH of 9 to 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 and has the following structural formula: Topiramate tablets contain the following inactive ingredients: anhydrous lactose, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, magnesium stearate, purified water, polyvinyl alcohol, titanium dioxide, polyethylene glycol and talc.
In addition, individual tablets contain: 50 mg tablets: iron oxide yellow 100 mg tablets: iron oxide yellow, and D&C Yellow # 10 Aluminum Lake 200 mg tablets: iron oxide red, lecithin (soya), and iron oxide black image of chemical structure
CLINICAL STUDIES
The studies described in the following sections were conducted using topiramate tablets.
Epilepsy Monotherapy Controlled TrialThe effectiveness of topiramate as initial monotherapy in adults and children 10 years of age and older with partial onset or primary generalized seizures was established in a multicenter, randomized, double-blind, parallel-group trial.
The trial was conducted in 487 patients diagnosed with epilepsy (6 to 83 years of age) who had 1 or 2 well-documented seizures during the 3-month retrospective baseline phase who then entered the study and received topiramate 25 mg/day for 7 days in an open-label fashion.
Forty-nine percent of subjects had no prior AED treatment and 17% had a diagnosis of epilepsy for greater than 24 months.
Any AED therapy used for temporary or emergency purposes was discontinued prior to randomization.
In the double-blind phase, 470 patients were randomized to titrate up to 50 mg/day or 400 mg/day.
If the target dose could not be achieved, patients were maintained on the maximum tolerated dose.
Fifty eight percent of patients achieved the maximal dose of 400 mg/day for ≥ 2 weeks, and patients who did not tolerate 150 mg/day were discontinued.
The primary efficacy assessment was a between group comparison of time to first seizure during the double-blind phase.
Comparison of the Kaplan-Meier survival curves of time to first seizure favored the topiramate 400 mg/day group over the topiramate 50 mg/day group (p=0.0002, log rank test; Figure 1 ).
The treatment effects with respect to time to first seizure were consistent across various patient subgroups defined by age, sex, geographic region, baseline body weight, baseline seizure type, time since diagnosis, and baseline AED use.
Figure 1: Kaplan-Meier Estimates of Cumulative Rates for Time to First Seizure Adjunctive Therapy Controlled Trials in Patients With Partial Onset SeizuresThe effectiveness of topiramate as an adjunctive treatment for adults with partial onset seizures was established in six multicenter, randomized, double-blind, placebo-controlled trials, two comparing several dosages of topiramate and placebo and four 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 two antiepileptic drugs (AEDs) in addition to topiramate tablets or placebo.
In each study, patients were stabilized on optimum dosages of their concomitant AEDs during baseline phase lasting between 4 and 12 weeks.
Patients who experienced a prespecified minimum number of partial onset seizures, with or without secondary generalization, during the baseline phase (12 seizures for 12-week baseline, 8 for 8-week baseline, or 3 for 4-week baseline) 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.
In five of the six studies, patients received active drug beginning at 100 mg per day; the dose was then increased by 100 mg or 200 mg/day increments weekly or every other week until the assigned dose was reached, unless intolerance prevented increases.
In the sixth study (119), the 25 or 50 mg/day initial doses of topiramate were followed by respective weekly increments of 25 or 50 mg/day until the target dose of 200 mg/day was reached.
After titration, patients entered a 4, 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 .
Adjunctive Therapy Controlled Trial in Pediatric Patients Ages 2 to 16 Years With Partial Onset SeizuresThe effectiveness of topiramate as an adjunctive treatment for pediatric patients ages 2 to 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 two 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 six 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 per day; the dose was then increased by 25 mg to 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 per day was reached, unless intolerance prevented increases.
After titration, patients entered an 8-week stabilization period.
Adjunctive Therapy Controlled Trial in Patients With Primary Generalized Tonic-Clonic SeizuresThe effectiveness of topiramate as an adjunctive 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 two 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 three 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 per day for four weeks; the dose was then increased by 50 mg to 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 per day was reached, unless intolerance prevented increases.
After titration, patients entered a 12-week stabilization period.
Adjunctive Therapy Controlled Trial in Patients With Lennox-Gastaut SyndromeThe effectiveness of topiramate as an adjunctive 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 two antiepileptic drugs (AEDs) in addition to topiramate or placebo.
Patients who were experiencing at least 60 seizures per 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 per day for a week; the dose was then increased to 3 mg/kg per day for one week then to 6 mg/kg per 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.
Table 1: Topiramate Dose Summary During the Stabilization Periods of Each of Six Double-Blind, Placebo-Controlled, Add-On Trials in Adults with Partial Onset Seizuresb Target Topiramate Dosage (mg/day) Protocol Stabilization Dose Placeboa 200 400 600 800 1,000 YD N Mean Dose Median Dose 42 5.9 6.0 42 200 200 40 390 400 41 556 600 – – – – – – YE N Mean Dose Median Dose 44 9.7 10.0 – – – – – – 40 544 600 45 739 800 40 796 1,000 Y1 N Mean Dose Median Dose 23 3.8 4.0 – – – 19 395 400 – – – – – – – – – Y2 N Mean Dose Median Dose 30 5.7 6.0 – – – – – – 28 522 600 – – – – – – Y3 N Mean Dose Median Dose 28 7.9 8.0 – – – – – – – – – 25 568 600 – – – 119 N Mean Dose Median Dose 90 8 8 157 200 200 – – – – – – – – – – – – a Placebo dosages are given as the number of tablets.
Placebo target dosages were as follows: Protocol Y1, 4 tablets/day; Protocols YD and Y2, 6 tablets/day; Protocol Y3 and 119, 8 tablets/day; Protocol YE, 10 tablets/day.
b Dose-response studies were not conducted for other indications or pediatric partial onset seizure.
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 below in Table 2 .
As described above, a global improvement in seizure severity was also assessed in the Lennox-Gastaut trial.
Table 2: Efficacy Results in Double-Blind, Placebo-Controlled, Add-On Epilepsy Trials Target Protocol Efficacy Results Placebo 200 400 600 800 1,000 ≈6 mg/kg/day* Partial Onset Seizures Studies in Adults YD Median % Reduction % Responders N 45 11.6 18 45 27.2a 24 45 47.5b 44d 46 44.7c 46d – – – – – – – – – YE Median % Reduction % Responders N 1.7 9 24 – – – – – – 48 40.8c 40c 48 41.0c 41c 47 36.0c 36d – – – Y1 Median % Reduction % Responders N 24 1.1 8 – – – 23 40.7e 35d – – – – – – – – – – – – Y2 Median % Reduction % Responders N 30 -12.2 10 – – – – – – 30 46.4f 47c – – – – – – – – – Y3 Median % Reduction % Responders N 28 -20.6 0 – – – – – – – – – 28 24.3c 43c – – – – – – 119N Median % Reduction % Responders 91 168 20.0 24 – 44.2c 45c – – – – – – – – – – – – – – Studies in Pediatric Patients YP Median T Reduction % Responders N 45 10.5 20 – – – – – – – – – – – – – – – 41 33.1d 39 Primary Generalized Tonic-Clonich YTC Median % Reduction % Responders N 40 9.0 20 – – – – – – – – – – – – – – – 39 56.7d 56c Lennox-Gastuat Syndromei YL Median % Reduction % Responders N 49 -5.1 14 – – – – – – – – – – – – – – – 46 14.8d 28g Improvement in Seizure Severityj 28 – – – – – – 52d Comparisons with placebo: a p=0.080; b p less than 0.010; c p less than 0.001; d p less than 0.050; e p=0.065; f p less than 0.005;g p=0.071; h Median % reduction and % responders are reported for PGTC Seizures; i Median % reduction and % responders for drop attacks, i.e., tonic or atonic seizures; j Percent of subjects who were minimally, much, or very much improved from baseline * For Protocols YP and YTC, protocol-specified target dosages (less than 9.3 mg/kg/day) were assigned based on subject’s weight to approximate a dosage of 6 mg/kg per day; these dosages corresponded to mg/day dosages of 125, 175, 225, and 400 mg/day.
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.
image of figure 1
HOW SUPPLIED
Topiramate tablets are available as debossed, film-coated, circular tablets in the following strengths and colors: 25 mg white (coded “S” on one side; “707” on the other) 50 mg yellow (coded “S” on one side; “710” on the other) 100 mg yellow (coded “S” on one side; “711” on the other) 200 mg brown (coded “S” on one side; “712” on the other) They are supplied as follows: 25 mg tablets Bottles of 30 NDC 54868-6016-1 Bottles of 60 NDC 54868-6016-0 Bottles of 90 NDC 54868-6016-2 Bottles of 120 NDC 54868-6016-3 50 mg tablets Bottles of 30 NDC 54868-6017-1 Bottles of 60 NDC 54868-6017-0 Bottles of 90 NDC 54868-6017-2 100 mg tablets Bottles of 30 NDC 54868-6014-1 Bottles of 60 NDC 54868-6014-0 Bottles of 90 NDC 54868-6014-2 200 mg tablets Bottles of 30 NDC 54868-6015-1 Bottles of 60 NDC 54868-6015-0 Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].
Protect from moisture.
Dispense in a tight container.
INDICATIONS AND USAGE
Monotherapy EpilepsyTopiramate tablets are indicated as initial monotherapy in patients 10 years of age and older with partial onset or primary generalized tonic-clonic seizures.
Effectiveness was demonstrated in a controlled trial in patients with epilepsy who had no more than 2 seizures in the 3 months prior to enrollment.
Safety and effectiveness in patients who were converted to monotherapy from a previous regimen of other anticonvulsant drugs have not been established in controlled trials.
Adjunctive Therapy EpilepsyTopiramate tablets are indicated as adjunctive therapy for adults and pediatric patients ages 2 to 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.
DOSAGE AND ADMINISTRATION
EpilepsyIn 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 tablets can be taken without regard to meals.
Monotherapy Use The recommended dose for topiramate monotherapy in adults and children 10 years of age and older is 400 mg/day in two divided doses.
Approximately 58% of patients randomized to 400 mg/day achieved this maximal dose in the monotherapy controlled trial; the mean dose achieved in the trial was 275 mg/day.
The dose should be achieved by titrating according to the following schedule: Morning Dose Evening Dose Week 1 25 mg 25 mg Week 2 50 mg 50 mg Week 3 75 mg 75 mg Week 4 100 mg 100 mg Week 5 150 mg 150 mg Week 6 200 mg 200 mg Adjunctive Therapy Use Adults (17 Years of Age and Over) – Partial Seizures, Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut SyndromeThe recommended total daily dose of topiramate as adjunctive therapy in adults with partial seizures is 200 to 400 mg/day in two divided doses, and 400 mg/day in two divided doses as adjunctive treatment in adults with primary generalized tonic-clonic seizures.
It is recommended that therapy be initiated at 25 to 50 mg/day followed by titration to an effective dose in increments of 25 to 50 mg/week.
Titrating in increments of 25 mg/week may delay the time to reach an effective dose.
Daily doses above 1,600 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, Adjunctive Therapy Controlled Trials in Patients With Primary Generalized Tonic-Clonic Seizures ).
Pediatric Patients (Ages 2 to 16 Years)– Partial Seizures, Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut SyndromeThe 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 to 9 mg/kg/day in two divided doses.
Titration should begin at 25 mg (or less, based on a range of 1 to 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 to 3 mg/kg/day (administered in two 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, Adjunctive Therapy Controlled Trials in Patients With Primary Generalized Tonic-Clonic Seizures ).
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.
Geriatric Patients (Ages 65 Years and Over):Dosage adjustment may be indicated in the elderly patient when impaired renal function (creatinine clearance rate ≤70 mL/min/1.73 m2) is evident (see : Patients with Renal Impairment and CLINICAL PHARMACOLOGY: Special Populations: Age, Gender, and Race ).
Patients Undergoing Hemodialysis:Topiramate is cleared by hemodialysis at a rate that is 4 to 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.