Topiramate 50 mg Tablet, 30-count — NDC 63187-228-30 (Billing 63187-0228-30)

WARNINGS 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. 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 200 mg/day, 9% for 100 mg/day, 2% for 50 mg/day, and <1% for placebo. 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-re… [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 4 ]. 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 5 ].

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 4: 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 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 System/ Adverse Event Topiramate Dosage (mg/day) 50 (N=160) 400 (N=159) Body as a Whole- General Disorders Asthenia Leg Pain Chest Pain 4 2 1 6 3 2 Central & Peripheral Nervous system Disorders Paresthesia Dizziness Hypoaesthesia Ataxia Hypertonia 21 13 4 3 0 40 14 5 4 3 Gastro-Intestinal System Disorders Diarrhea Constipation Gastritis Dry Mouth Gastroesophageal Reflux 5 1 0 1 1 6 4 3 3 2 Liver and Biliary System Disorders Gamma-GT Increased 1 3 Metabolic and nutritional Disorders Weight Decrease 6 16 Psychiatric Disorders Somnolence Anorexia Difficulty with Memory NOS Insomnia Depression Difficulty with Concentration/Attention Anxiety Psychomotor Slowing Mood Problems Confusion Cognitive Problem NOS Libido Decreased 9 4 5 8 7 7 4 3 2 3 1 0 15 14 10 9 9 8 6 5 5 4 4 3 Reproductive Disorders, female Vaginal Hemorrhage 0 3 Red Blood Cell disorders Anemia 1 2 Table 5: Incidence of Treatment-Emergent Adverse Events in the Monotherapy Epilepsy Trail in Children Ages 10 up to 16 Yearsa 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 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 System/ Adverse Event Topiramate Dosage (mg/day) b 50 (N=57) 400 (N=57) Body as a Whole-General Disorders Fever 0 9 Central & Peripheral Nervous system Disorders Paresthesia 2 16 Gastro-Intestinal System Disorders… [Excerpted — this section continues on DailyMed.]

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 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 PRECAUTIONS: Kidney Stones , 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… [Excerpted — this section continues on DailyMed.]

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