Topiramate 25 mg Tablet, Film Coated, 30-count — NDC 63187-077-30 (Billing 63187-0077-30)

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. 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 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, 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 trial… [Excerpted — this section continues on DailyMed.]

ADVERSE REACTIONS The data described in the following section were obtained using topiramate tablets. Monotherapy Epilepsy The adverse events in the controlled trial that occurred most commonly in adults in the 400 mg/day group and at a rate higher than the 50 mg/day group were: paresthesia, weight decrease, somnolence, anorexia, dizziness, and difficulty with memory NOS [see Table 5 ]. The adverse events in the controlled trial that occurred most commonly in children (10 years up to 16 years of age) in the 400 mg/day group and at a rate higher than the 50 mg/day group were: weight decrease, upper respiratory tract infection, paresthesia, anorexia, diarrhea, and mood problems [see Table 6 ].

Approximately 21% of the 159 adult patients in the 400 mg/day group who received topiramate as monotherapy in the controlled clinical trial discontinued therapy due to adverse events. Adverse events associated with discontinuing therapy (≥2%) included depression, insomnia, difficulty with memory (NOS), somnolence, paresthesia, psychomotor slowing, dizziness, and nausea. Approximately 12% of the 57 pediatric patients in the 400 mg/day group who received topiramate as monotherapy in the controlled clinical trial discontinued therapy due to adverse events.

Adverse events associated with discontinuing therapy (≥5%) included difficulty with concentration/attention. The prescriber should be aware that these data 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 the clinical study. 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. Table 5: Incidence of Treatment-Emergent Adverse Events in the Monotherapy Epilepsy Trial in Adults a Where Rate Was at Least 2% in the 400 mg/day Topiramate Group and Greater Than the Rate in the 50 mg/day Topiramate Group Topiramate Dosage (mg/day) Body System/ Adverse Event 50 (N= 160) 400 (N=159) a 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. Body as a Whole-General Disorders Asthenia 4 6 Leg Pain 2 3 Chest Pain 1 2 Central & Peripheral Nervous System Disorders Paresthesia 21 40 Dizziness 13 14 Hypoaesthesia 4 5 Ataxia 3 4 Hypertonia 0 3 Gastro-Intestinal System Disorders Diarrhea 5 6 Constipation 1 4 Gastritis 0 3 Dry Mouth 1 3 Gastroesophageal Reflux 1 2 Liver and Biliary System Disorders Gamma-GT Increased 1 3 Metabolic and Nutritional Disorders Weight Decrease 6 16 Psychiatric Disorders Somnolence 9 15 Anorexia 4 14 Difficulty with Memory NOS 5 10 Insomnia 8 9 Depression 7 9 Difficulty with Concentration/Attention 7 8 Anxiety 4 6 Psychomotor Slowing 3 5 Mood Problems 2 5 Confusion 3 4 Cognitive Problem NOS 1 4 Libido Decreased 0 3 Reproductive Disorders, Female Vaginal Hemorrhage 0 3 Red Blood Cell Disorders Anemia 1 2 Resistance Mechanism Disorders Infection Viral 6 8 Infection 2 3 Respiratory System Disorders Bronchitis 3 4 Rhinitis 2 4 Dyspnea 1 2 Skin and Appendages Disorders Rash 1 4 Pruritus 1 4 Acne 2 3 Special Senses Other, Disorders Taste Perversion 3 5 Urinary System Disorders Cystitis 1 3 Renal Calculus 0 3 Urinary Tract Infection 1 2 Dysuria 0 2 Micturition Frequency 0 2 Table 6: Incidence of Treatment-Emergent Adverse Events in the Monotherapy Epilepsy Trial in Children Ages 10 up to 16 Years a Where Rate Was at Least 5% in the 400 mg/day Topiramate Group and Greater Than the Rate in the 50 mg/day Topiramate Group Topiramate Dosage (mg/day) Body System/ Adverse Event 50… [Excerpted — this section continues on DailyMed.]

Drug Interactions: In vitro studies indicate that topiramate does not inhibit enzyme activity for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5 isozymes.

PRECAUTIONS Hyperammonemia and Encephalopathy Associated with Concomitant Valproic Acid Use Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. In most cases, symptoms and signs abated with discontinuation of either drug.

This adverse event is not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy.

Although not studied, an interaction of topiramate and valproic acid may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. Kidney Stones A total of 32/2,086 (1.5%) of adults exposed to topiramate during its adjunctive epilepsy therapy development reported the occurrence of kidney stones, an incidence about 2 to 4 times greater than expected in a similar, untreated population.

In the double-blind monotherapy epilepsy study, a total of 4/319 (1.3%) of adults exposed to topiramate reported the occurrence of kidney stones. 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 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 (usually tingling of the extremities), an effect associated with the use of other carbonic anhydrase inhibitors, appears to be a common effect of topiramate.

Paresthesia was more frequently reported in the monotherapy epilepsy trials versus the adjunctive therapy epilepsy trials. In the majority of instances, paresthesia did not lead to treatment discontinuation. 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 in patients with reduced renal function (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 Patients Patients and their caregivers should be informed of the availability of a Medication Guide, and they should be instructed to read the Medication Guide prior to taking topiramate tablets.

Patients should be instructed to take topiramate tablets only as prescribed. 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, their caregivers, and families should be counseled that AEDs, including topiramate, may increase the risk of suicidal thoughts and behavior and should… [Excerpted — this section continues on DailyMed.]

DRUG ABUSE AND DEPENDENCE The abuse and dependence potential of topiramate has not been evaluated in human studies.