Topiragen

Name: Topiragen

Topiragen Food Interactions

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of topiramate there are no specific foods that you must exclude from your diet when receiving topiramate.

Topiragen™ (topiramate) Tablets

Rx only

Clinical studies

The studies described in the following sections were conducted using topiramate tablets.

Epilepsy

Monotherapy Controlled Trial

The 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 Seizures

The 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 the 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 2-16 Years With Partial Onset Seizures

The effectiveness of topiramate as an adjunctive 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 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 Seizures

The 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 Syndrome

The 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 Seizures b

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 seizures.

Protocol Stabilization Dose Placeboa Target Topiramate Dosage (mg/day)
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
-
-
-
-
-
-
-
-
-
-
-
-

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

Comparisons with placebo: a p=0.080; b p< 0.010; c p< 0.001; d p< 0.050; e p=0.065; f p< 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 (<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.

Protocol Efficacy Results Placebo Target Topiramate Dosage (mg/day)
200 400 600 800 1,000 ≈ 6
mg/kg/day*
Partial Onset Seizures
Studies in Adults
YD N 45 45 45 46 - - -
Median % Reduction 11.6 27.2a 47.5b 44.7c - - -
% Responders 18 24 44d 46d - - -
YE N 47 - - 48 48 47 -
Median % Reduction 1.7 - - 40.8c 41.0c 36.0c -
% Responders 9 - - 40c 41c 36d -
Y1 N 24 - 23 - - - -
Median % Reduction 1.1 - 40.7e - - - -
% Responders 8 - 35d - - - -
Y2 N 30 - - 30 - - -
Median % Reduction -12.2 - - 46.4f - - -
% Responders 10 - - 47c - - -
Y3 N 28 - - - 28 - -
Median % Reduction -20.6 - - - 24.3c - -
% Responders 0 - - - 43c - -
119 N 91 168 - - - - -
Median % Reduction 20.0 44.2c - - - - -
% Responders 24 45c - - - - -
Studies in Pediatric Patients
YP N 45 - - - - - 41
Median % Reduction 10.5 - - - - - 33.1d
% Responders 20 - - - - - 39
Primary Generalized Tonic-Clonich
YTC N 40 - - - - - 39
Median % Reduction 9.0 - - - - - 56.7d
% Responders 20 - - - - - 56c
Lennox-Gastaut Syndromei
YL N 49 - - - - - 46
Median % Reduction -5.1 - - - - - 14.8d
% Responders 14 - - - - - 28g
Improvement in Seizure Severityj 28 - - - - - 52d

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.

Warnings

Acute Myopia and Secondary Angle Closure Glaucoma

A 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. 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 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 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.

SUICIDAL BEHAVIOR and IDEATION

Antiepileptic drugs (AEDs), including Topiramate Tablets, 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, 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 trails 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 Tablets 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 Acidosis

Hyperchloremic, 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 <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 <17 mEq/L and >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 (<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 <17 mEq/L and >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 <17 mEq/L and >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 100-200 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 AEDs

Antiepileptic drugs, including Topiragen™ Tablets, 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).

How supplied

Topiragen™ (topiramate) Tablets are available as:

25 mg: Round, white coated, unscored tablets debossed with “USL” on one side and “25” on the other side and supplied in bottles of 60 (NDC 0245-0711-60).

50 mg: Round, light yellow coated, unscored tablets debossed with “USL” on one side and “50” on the other side and supplied in bottles of 60 (NDC 0245-0712-60).

100 mg: Round, dark yellow coated, unscored tablets debossed with “USL” on one side and “100” on the other side and supplied in bottles of 60 (NDC 0245-0713-60).

200 mg: Round, dark red coated, unscored tablets debossed with “USL” on one side and “200” on the other side and supplied in bottles of 60 (NDC 0245-0714-60).

Store at 20 – 25° C (68 – 77° F). Excursions permitted to 15 – 30° C (59 – 86° F). [See USP Controlled Room Temperature.] Dispense in tight containers. Protect from moisture.

MEDICATION GUIDE

Topiragen™ (topiramate) Tablets
(toe-peer-uh-jen)

Read this Medication Guide before you start taking Topiragen™ Tablets and each time you get a refill. There may be new information., This information does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions about Topiragen™ Tablets, talk to your healthcare provider or pharmacist.

What is the most important information I should know about Topiragen™ Tablets?

  • Topiragen™ Tablets may cause eye problems. Serious eye problems include:
    • Any sudden decrease in vision with or without eye pain and redness
    • A blockage of fluid in the eye causing increased pressure in the eye (secondary angle closure glaucoma).
    • These eye problems can lead to permanent loss of vision if not treated. You should call your healthcare provider right away if you have any new eye symptoms.
  • Topiragen™ Tablets may cause decreased sweating and increased body temperature (fever). People, especially children, should be watched for signs of decreased sweating and fever, especially in hot temperatures. Some people may need to be hospitalized for this condition.
  • Like other antiepileptic drugs, Topiragen™ Tablets may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.

Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse or worry you:

  • thoughts about suicide or dying
  • attempts to commit suicide
  • new or worse depression
  • new or worse anxiety
  • feeling agitated or restless
  • panic attacks
  • trouble sleeping (insomnia)
  • new or worse irritability
  • acting aggressive, being angry or violent
  • acting on dangerous impulses
  • an extreme increase in activity and talking (mania)
  • other unusual changes in behavior or mood

Do not stop taking Topiragen™ Tablets without first talking to a healthcare provider.

  • Stopping Topiragen™ Tablets suddenly can cause serious problems.
  • Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.

How can I watch for early symptoms of suicidal thoughts and actions?

  • Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts or feelings.
  • Keep all follow-up visits with your healthcare provider as scheduled.
  • Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

What are Topiragen™ Tablets?

Topiragen™ Tablets are a prescription medicine used:

  • to treat certain types of seizures (partial onset seizures and primary generalized tonic-clonic seizures) in people 10 years and older
  • with other medicines to treat certain types of seizures (partial onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome) in adults and children 2 years and older

What Should I Tell My Healthcare Professional Before Taking Topiragen™ Tablets?

Before taking Topiragen™ Tablets, tell your healthcare provider about all of your medical conditions, including if you:

  • have or have had depression, mood problems or suicidal thoughts or behavior
  • have kidney problems, kidney stones, or are getting kidney dialysis
  • have a history of metabolic acidosis (too much acid in the blood)
  • have liver problems
  • have osteoporosis, soft bones or decreased bone density
  • have lung or breathing problems
  • have eye problems, especially glaucoma
  • have diarrhea
  • have a growth problem
  • are on a diet high in fat and low in carbohydrates, which is called a ketogenic diet
  • are having surgery
  • are pregnant or planning to become pregnant. It is not known if Topiragen™ Tablets will harm your unborn baby. If you become pregnant while taking Topiragen™ Tablets, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic medicine during pregnancy.
  • are breastfeeding. It is not known if Topiragen™ Tablets pass into breast milk and if it can harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take Topiragen™ Tablets.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements.

Topiragen™ Tablets and other medicines may affect each other causing side effects.

Especially, tell your healthcare provider if you take:

  • Valproic acid (Depakene®, Depakote®)
  • any medicines that impair or decrease your thinking, concentration or muscle coordination.
  • birth control pills. Topiragen™ Tablets may make your birth control pills less effective. Tell your healthcare provider if your menstrual bleeding changes while you are taking birth control pills with Topiragen™ Tablets.

Ask your healthcare provider if you are not sure if your medicine is listed above.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist each time you get a new medicine. Do not start a new medicine without talking with your healthcare provider.

How Should I Take Topiragen™ Tablets?

  • Take Topiragen™ Tablets exactly as prescribed.
  • Your healthcare provider may change your dose. Do not change your dose without talking to your healthcare provider.
  • Topiragen™ Tablets should be swallowed whole. Do not chew the tablets. They may leave a bitter taste.
  • Topiragen™ Tablets can be taken before, during, or after a meal. Drink plenty of fluids during the day. This may help prevent kidney stones while taking Topiragen™ Tablets.
  • If you take too many Topiragen™ Tablets, call your healthcare provider or poison control center right away or go to the nearest emergency room.
  • If you miss a single dose of Topiragen™ Tablets, take it as soon as you can. However, if you are within 6 hours of taking your next scheduled dose, wait until then to take your usual dose of Topiragen™ Tablets, and skip the missed dose. Do not double your dose. If you have missed more than one dose, you should call your healthcare professional for advice.
  • Do not stop taking Topiragen™ Tablets without talking to your healthcare provider. Stopping Topiragen™ Tablets suddenly may cause serious problems. If you have epilepsy and you stop taking Topiragen™ Tablets suddenly, you may have seizures that do not stop. Your healthcare provider will tell you how to stop taking Topiragen™ Tablets slowly.
  • Your healthcare provider may do blood tests while you take Topiragen™ Tablets.

What Should I Avoid While Taking Topiragen™ Tablets?

  • Do not drink alcohol while taking Topiragen™ Tablets. Topiragen™ Tablets and alcohol can affect each other causing side effects such as sleepiness and dizziness.
  • Do not drive a car or operate heavy machinery until you know how Topiragen™ Tablets affect you. Topiragen™ Tablets can slow your thinking and motor skills.

What are the Possible Side Effects of Topiragen™ Tablets?

Topiragen™ Tablets may cause serious side effects including :

See "what is the most important information I should know about Topiragen™ Tablets?"

  • Metabolic Acidosis. Metabolic acidosis can cause:
    • tiredness
    • loss of appetite
    • irregular heartbeat
    • impaired consciousness
  • High blood ammonia levels. High ammonia in the blood can affect your mental activities, slow your alertness, make you feel tired or cause vomiting. This has happened when Topiragen™ Tablets is taken with a medicine called valproic acid (Depakene® and Depakote®).
  • Kidney stones. Drink plenty of fluids when taking Topiragen™ Tablets to decrease your chances of getting kidney stones.
  • Effects on Thinking and Alertness. Topiragen™ Tablets may affect how you think, and cause confusion, problems with concentration, attention, memory or speech. Topiragen™ Tablets may cause depression or mood problems, tiredness and sleepiness.
  • Dizziness or Loss of Muscle Coordination.

Call your healthcare provider right away if you have any of the symptoms above.

The most common side effects of Topiragen™ Tablets include:

  • tingling of the arms and legs (paresthesia)
  • not feeling hungry
  • nausea
  • a change in the way food taste
  • diarrhea
  • weight loss
  • nervousness
  • upper respiratory tract infection

Tell your healthcare provider about any side effect that bothers you or that does not go away.

These are not all the possible side effects of Topiragen™ Tablets. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA 1-800-FDA-1088.

How Should I Store Topiragen™ Tablets?

  • Store Topiragen™ Tablets at room temperature, 59°F to 86°F (15°C to 30°C).
  • Store Topiragen™ Tablets in a tightly closed container
  • Keep Topiragen™ Tablets dry and away from moisture
  • Keep Topiragen™ Tablets and all medicines out of the reach of children.

General Information About Topiragen™ Tablets.

Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use Topiragen™ Tablets for a condition for which it was not prescribed. Do not give Topiragen™ Tablets to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about Topiragen™ Tablets. If you would like more information, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about Topiragen™ Tablets that is written for health professionals.

For more information, go to www.upsher-smith.com or call 1-800-654-2299.

What Are the Ingredients of Topiragen™ Tablets?

Active Ingredient: topiramate

Inactive Ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, partially hydrolyzed polyvinyl alcohol, polyethylene glycol, sodium starch glycolate, talc, titanium dioxide, iron oxide yellow (50 mg and 100 mg only), and iron oxide red (50 mg and 200 mg only).

DEPAKENE® and DEPAKOTE® are registered trademarks of Abbott Laboratories

Manufactured by
UPSHER-SMITH Laboratories, Inc.
Minneapolis, MN 55447

101998-01
Revised 0509

PRINCIPAL DISPLAY PANEL - 25 mg Tablet Bottle Label

NDC 0245-0711-60

Topiragen™
(topiramate) Tablets

25 mg

PHARMACIST:
PLEASE DISPENSE
WITH ATTACHED
MEDICATION GUIDE.

60 Tablets
Rx only

UPSHER-SMITH

PRINCIPAL DISPLAY PANEL - 50 mg Tablet Bottle Label

NDC 0245-0712-60

Topiragen™
(topiramate) Tablets

50 mg

PHARMACIST:
PLEASE DISPENSE
WITH ATTACHED
MEDICATION GUIDE.

60 Tablets
Rx only

UPSHER-SMITH

PRINCIPAL DISPLAY PANEL - 100 mg Tablet Bottle Label

NDC 0245-0713-60

Topiragen™
(topiramate) Tablets

100 mg

PHARMACIST:
PLEASE DISPENSE
WITH ATTACHED
MEDICATION GUIDE.

60 Tablets
Rx only

UPSHER-SMITH

PRINCIPAL DISPLAY PANEL - 200 mg Tablet Bottle Label

NDC 0245-0714-60

Topiragen™
(topiramate) Tablets

200 mg

PHARMACIST:
PLEASE DISPENSE
WITH ATTACHED
MEDICATION GUIDE.

60 Tablets
Rx only

UPSHER-SMITH

Topiragen 
topiramate tablet, coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0245-0711
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
topiramate (topiramate) topiramate 25 mg
Inactive Ingredients
Ingredient Name Strength
silicon dioxide  
lactose monohydrate  
magnesium stearate  
cellulose, microcrystalline  
polyvinyl alcohol  
POLYETHYLENE GLYCOL 3350  
sodium starch glycolate Type A potato  
talc  
titanium dioxide  
Product Characteristics
Color WHITE Score no score
Shape ROUND Size 6mm
Flavor Imprint Code USL;25
Contains     
Packaging
# Item Code Package Description
1 NDC:0245-0711-60 60 TABLET, COATED (TABLET) in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA078499 01/07/2010
Topiragen 
topiramate tablet, coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0245-0712
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
topiramate (topiramate) topiramate 50 mg
Inactive Ingredients
Ingredient Name Strength
silicon dioxide  
lactose monohydrate  
magnesium stearate  
cellulose, microcrystalline  
polyvinyl alcohol  
POLYETHYLENE GLYCOL 3350  
sodium starch glycolate Type A potato  
talc  
titanium dioxide  
Product Characteristics
Color YELLOW (light yellow) Score no score
Shape ROUND Size 7mm
Flavor Imprint Code USL;50
Contains     
Packaging
# Item Code Package Description
1 NDC:0245-0712-60 60 TABLET, COATED (TABLET) in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA078499 01/07/2010
Topiragen 
topiramate tablet, coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0245-0713
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
topiramate (topiramate) topiramate 100 mg
Inactive Ingredients
Ingredient Name Strength
silicon dioxide  
lactose monohydrate  
magnesium stearate  
cellulose, microcrystalline  
polyvinyl alcohol  
POLYETHYLENE GLYCOL 3350  
sodium starch glycolate Type A potato  
talc  
titanium dioxide  
Product Characteristics
Color YELLOW (dark yellow) Score no score
Shape ROUND Size 9mm
Flavor Imprint Code USL;100
Contains     
Packaging
# Item Code Package Description
1 NDC:0245-0713-60 60 TABLET, COATED (TABLET) in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA078499 01/07/2010
Topiragen 
topiramate tablet, coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0245-0714
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
topiramate (topiramate) topiramate 200 mg
Inactive Ingredients
Ingredient Name Strength
silicon dioxide  
lactose monohydrate  
magnesium stearate  
cellulose, microcrystalline  
polyvinyl alcohol  
POLYETHYLENE GLYCOL 3350  
sodium starch glycolate Type A potato  
talc  
titanium dioxide  
Product Characteristics
Color RED Score no score
Shape ROUND Size 11mm
Flavor Imprint Code USL;200
Contains     
Packaging
# Item Code Package Description
1 NDC:0245-0714-60 60 TABLET, COATED (TABLET) in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA078499 01/07/2010
Labeler - Upsher-Smith Laboratories, Inc. (047251004)
Establishment
Name Address ID/FEI Operations
Upsher-Smith Laboratories, Inc. 047251004 ANALYSIS
Establishment
Name Address ID/FEI Operations
Upsher-Smith Laboratories, Inc. 618927206 ANALYSIS, MANUFACTURE
Establishment
Name Address ID/FEI Operations
Upsher-Smith Laboratories, Inc. 809088862 ANALYSIS
Revised: 01/2010   Upsher-Smith Laboratories, Inc.
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