TOPAMAX (topiramate) is indicated as monotherapy for the management of patients (adults and children six years and older) with newly diagnosed epilepsy.

TOPAMAX (topiramate) is also indicated as adjunctive therapy for the management of patients (adults and children two years and older) with epilepsy who are not satisfactorily controlled with conventional therapy.

TOPAMAX (topiramate) is indicated in adults for the prophylaxis of migraine headache. Prophylactic treatment of migraine may be considered in situations such as: adults experiencing four or more migraine attacks per month who fail to respond adequately to acute abortive therapy; recurring attacks that significantly interfere with the patient's daily routine; a pattern of increasing migraine attacks over time, with the risk of developing rebound headache from acute abortive therapies; or failure of, or contraindication to, or troublesome side effects from acute abortive medications. Continuing therapy should be reviewed every six months. TOPAMAX should not be used in the acute treatment of migraine attacks. Safety and efficacy of topiramate in the management or prevention of cluster headache, hemiplegic, basilar, ophthalmoplegic, or transformed migraine headaches have not been established.

There is limited information in patients over 65 years of age (see Warnings and Precautions, Special Populations, Geriatrics (>65 years of age)).

• Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see Dosage Forms, Composition and Packaging.

  
  

Antiepileptic drugs, including TOPAMAX (topiramate), should be withdrawn gradually to minimize the potential for seizures or increased seizure frequency. In clinical trials in adult patients with epilepsy, dosages were decreased by 50-100 mg/day at weekly intervals. In clinical trials of children, TOPAMAX was gradually withdrawn over a 2-8 week period. (See Dosage and Administration, General and Epilepsy.)

In patients without a history of seizures or epilepsy, TOPAMAX (topiramate) should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency. In clinical trials in adult patients receiving TOPAMAX for migraine prophylaxis dosages were decreased by 25-50 mg/day at weekly intervals. (See Dosage and Administration, General and Migraine.)

In situations where rapid withdrawal of TOPAMAX is medically required, appropriate monitoring is recommended. (See Dosage and Administration, General.)

There have been rare reports of patients, with or without previous history, experiencing hyperammonemia with or without encephalopathy while receiving topiramate alone or in combination with other antiepileptic medications. The majority of these cases indicate that concomitant administration of topiramate and valproic acid is associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse event is not due to a pharmacokinetic interaction. 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 (see Adverse Reactions, Post-Market Adverse Drug Reactions and Drug Interactions, Drug-Drug Interactions).

In patients who develop unexplained vomiting, lethargy, confusion or other changes in mental status, hyperammonemic encephalopathy should be considered and serum ammonia levels should be measured.

Oligohidrosis (decreased sweating) and hyperthermia, infrequently resulting in hospitalization, including fatalities, have been reported in patients treated with topiramate. Oligohidrosis and hyperthermia may have potentially serious sequelae and may be preventable by prompt recognition of symptoms and appropriate treatment. Decreased sweating and elevation of body temperature above normal characterized the cases reported in patients treated with topiramate. Some of the cases were reported after exposure to elevated environmental temperatures.

These reports have primarily involved children. Patients treated with TOPAMAX, especially pediatric patients, should be monitored closely for evidence of decreased sweating and increased body temperature, particularly in hot weather. Proper hydration before and during activities such as exercise or exposure to warm temperatures is recommended.

Caution should be used when TOPAMAX 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 (see Adverse Reactions, Post-Market Adverse Drug Reactions).

Hyperchloremic, non-anion gap, metabolic acidosis (i.e. decreased serum bicarbonate below the normal reference range in the absence of respiratory alkalosis) is associated with topiramate treatment. This decrease in serum bicarbonate is due to the inhibitory effect of topiramate on renal carbonic anhydrase. Generally, the decrease in bicarbonate occurs early in treatment although it can occur at any time during treatment. These decreases are usually mild to moderate (average decrease of 4 mmol/L at doses of 100 mg/day or above in adults and at approximately 6 mg/kg/day in pediatric patients). Rarely, patients have experienced decreases to values below 10 mmol/L. Conditions or therapies that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, surgery, ketogenic diet, or certain 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 mmol/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 a markedly abnormally low serum bicarbonate (i.e. absolute value <17 mmol/L and >5 mmol/L decrease from pre-treatment) in these trials was 3% for 400 mg/day, and 0% for placebo. 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 TOPAMAX (at approximately 6 mg/kg/day), and 10% for placebo. The incidence of a markedly abnormally low serum bicarbonate (i.e. absolute value <17 mmol/L and >5 mmol/L decrease from pre-treatment) in these trials was 11% for TOPAMAX 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.

The incidence of persistent treatment-emergent decreases in serum bicarbonate in placebo-controlled trials for adults for prophylaxis of migraine was 44% for 200 mg/day, 39% for 100 mg/day, 23% for 50 mg/day, and 7% for placebo. The incidence of a markedly abnormally low serum bicarbonate (i.e. absolute value <17 mmol/L and >5 mmol/L decrease from pre-treatment) in these trials was 11% for 200 mg/day, 9% for 100 mg/day, 2% for 50 mg/day, and <1% for placebo.

Safety and effectiveness in patients below the age of 2 years have not been established. Topiramate is associated with metabolic acidosis. Chronic untreated metabolic acidosis in pediatric patients may cause osteomalacia (rickets) and may 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.

Chronic metabolic acidosis in pediatric patients can reduce growth rates. The effect of topiramate on growth and bone-related sequelae has not been systematically investigated in pediatric or adult populations.

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.

In a drug interaction study, a greater decrease from baseline in serum potassium values was seen with concomitant treatment than for either drug alone. At the end of each treatment period, 27% (3/11) of subjects on topiramate treatment alone and 25% (3/12) of subjects on HCTZ treatment alone showed a serum potassium value of <3.6 mEq/L, compared to 61% (14/23) of subjects on concomitant drug treatment. One of the subjects who had hypokalemia with concomitant treatment also had an abnormal ECG (non-specific ST-T wave changes), which may have been related to the decrease in plasma potassium levels. Caution should be used when treating patients who are receiving TOPAMAX and hydrochlorothiazide concomitantly (see Drug Interactions).

A dietary supplement or increased food intake may be considered if the patient is losing weight while on this medication.

In hepatically impaired patients, TOPAMAX should be administered with caution as the clearance of topiramate was decreased compared with normal subjects.

Adverse events most often associated with the use of TOPAMAX were central nervous system related and were observed in both the epilepsy and migraine populations. In adults, the most significant of these can be classified into three general categories: 1) psychomotor slowing, difficulty with concentration and speech or language problems, in particular, word-finding difficulties, 2) somnolence or fatigue and 3) mood disturbances including irritability and depression.

In the controlled epilepsy adjunctive therapy trials, these events were generally mild to moderate and generally occurred early in therapy. While the incidence of psychomotor slowing does not appear to be dose related, both language problems and difficulty with concentration or attention increased in frequency with increasing dosage in the six double-blind trials, suggesting that these events are dose related (see Adverse Reactions, Post-Market Adverse Drug Reactions).

Central nervous system and psychiatric-related events were also more frequently reported in topiramate-treated subjects in the migraine prophylaxis trials. These included: anorexia, dizziness, difficulty with memory, somnolence, language problems, and difficulty with concentration and attention. Most of the events were mild or moderate in severity, some of which led to withdrawal from treatment (see Adverse Reactions, Migraine).

In the double-blind phases of clinical trials with topiramate in approved and investigational indications, suicide attempts occurred at an incidence of 0.2% (13 reports/7,999 patients) on topiramate versus 0% (0 reports/3150 patients) on placebo. One completed suicide was reported in a bipolar disorder trial in a patient on topiramate (see Adverse Reactions, Less Common Clinical Trial Adverse Drug Reactions (<2%) and Post-Market Adverse Drug Reactions).

Additional non-specific CNS effects occasionally observed with TOPAMAX as add-on epilepsy therapy include dizziness or imbalance, confusion and memory problems. Although the duration of the epilepsy monotherapy studies was considerably longer than the epilepsy adjunctive therapy studies, these adverse events were reported at lower incidences in the monotherapy trials.

Paresthesia, an effect associated with the use of other carbonic anhydrase inhibitors, appears to be a common effect of TOPAMAX. Paresthesia was more frequently reported in the migraine prophylaxis and epilepsy monotherapy trials versus the adjunctive therapy trials in epilepsy. The higher incidence in the epilepsy monotherapy studies may have been related to the higher topiramate plasma concentrations achieved in the monotherapy studies. In the majority of instances, paresthesia did not lead to treatment discontinuation.

A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving TOPAMAX. 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 a few days to 1 month of initiating TOPAMAX therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with TOPAMAX has been reported in pediatric patients as well as adults. The primary treatment to reverse symptoms is discontinuation of TOPAMAX as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of TOPAMAX, may be helpful (see Adverse Reactions, Post-Market Adverse Drug Reactions).

In all cases of acute visual blurring and/or painful/red eye(s), immediate consultation with an ophthalmologist/emergency room is recommended.

Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss.

A total of 32/1715 (1.9%) of patients exposed to TOPAMAX during its epilepsy adjunctive therapy development reported the occurrence of kidney stones, an incidence about 10 times that expected in a similar, untreated population (M/F ratio: 27/1092 male; 5/623 female). In double-blind epilepsy monotherapy studies, a total of 8/886 (0.9%) of adults reported the occurrence of kidney stones. In the general population, risk factors for kidney stone formation include gender (male), ages between 20-50 years, prior stone formation, family history of nephrolithiasis, and hypercalciuria. Based on logistic regression analysis of the clinical trial data, no correlation between mean TOPAMAX dosage, duration of TOPAMAX therapy, or age and the occurrence of kidney stones was established; of the risk factors evaluated, only gender (male) showed a correlation with the occurrence of kidney stones. In the pediatric patients studied, there were no kidney stones observed.

Carbonic anhydrase inhibitors, e.g. acetazolamide, promote stone formation by reducing urinary citrate excretion and by increasing urinary pH. Concomitant use of TOPAMAX, a weak carbonic anhydrase inhibitor, with other carbonic anhydrase inhibitors may create a physiological environment that increases the risk of kidney stone formation, and should therefore be avoided (see Drug Interactions, Drug-Drug Interactions).

Patients, especially those with a predisposition to nephrolithiasis, may have an increased risk of renal stone formation and associated signs and symptoms such as renal colic, renal pain or flank pain. Increased fluid intake increases the urinary output, lowering the concentration of substances involved in stone formation. Therefore, adequate hydration is recommended to reduce this risk. None of the risk factors for nephrolithiasis can reliably predict stone formation during TOPAMAX treatment.

The major route of elimination of unchanged topiramate and its metabolites is via the kidney. Renal elimination is dependent on renal function and is independent of age. Patients with impaired renal function (CL_CR <70 mL/min/1.73 m²) or with end-stage renal disease receiving hemodialysis treatments may take 10 to 15 days to reach steady-state plasma concentrations as compared to 4 to 8 days in patients with normal renal function. As with all patients, the titration schedule should be guided by clinical outcome (i.e. seizure control, avoidance of side effects) with the knowledge that patients with known renal impairment may require a longer time to reach steady state at each dose (see Dosage and Administration, Dosing Considerations).

Patients should be reminded to inform their doctor if they are pregnant or intend to become pregnant while on TOPAMAX therapy.

Patients, especially those with predisposing factors, should be instructed to maintain an adequate fluid intake in order to minimize the risk of renal stone formation. Patients also should be instructed to increase and maintain fluid intake prior to and during activities such as exercise and exposure to warm temperatures to help prevent complications from decreased sweating.

Patients should be warned about the potential for somnolence, dizziness, confusion, and difficulty concentrating, and advised not to drive or operate machinery until they have gained sufficient experience on TOPAMAX to gauge whether it adversely affects their mental and/or motor performance.

Patients taking TOPAMAX should be told to immediately contact their doctor and/or go to the Emergency Room if they/their child experience(s) sudden worsening of vision, blurred vision or painful/red eye(s).

Like many other drugs, topiramate was teratogenic in mice, rats, and rabbits. In rats, topiramate crosses the placental barrier.

There are no studies using TOPAMAX in pregnant women. However, TOPAMAX therapy should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

In post-marketing experience, cases of hypospadias have been reported in male infants exposed in utero to TOPAMAX, with or without other anticonvulsants; however, a causal relationship with TOPAMAX has not been established.

The effect of TOPAMAX on labor and delivery in humans is unknown.

Topiramate is excreted in the milk of lactating rats. The excretion of topiramate in human milk has not been evaluated in controlled studies. Limited observations in patients suggest an extensive excretion of topiramate into breast milk. Since the potential for serious adverse reactions in nursing infants exposed to TOPAMAX exists, the prescriber should decide whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother and the risks to the infant.

Safety and effectiveness in children under 2 years of age have not been established.

TOPAMAX administration is associated with weight loss in some children that generally occurs early in therapy. Of those pediatric subjects treated in clinical trials for at least a year who experienced weight loss, 96% showed a resumption of weight gain within the period tested. In 2-4-year-olds, the mean change in weight from baseline at 12 months (n=25) was +0.7 kg (range −1.1 to 3.2); at 24 months (n=14), the mean change was +2.2 kg (range −1.1 to 6.1). In 5-10-year-olds, the mean change in weight from baseline at 12 months (n=88) was +0.7 kg (range −6.7 to 11.8); at 24 months (n=67), the mean change was +3.3 kg (range −8.6 to 20.0). Weight decreases, usually associated with anorexia or appetite changes, were reported as adverse events for 9% of patients treated with TOPAMAX. The long-term effects of reduced weight gain in pediatric patients are not known.

There is limited information in patients over 65 years of age. The possibility of age-associated renal function abnormalities should be considered when using TOPAMAX (see Action and Clinical Pharmacology, Special Populations and Conditions).

It has been observed in clinical trials that topiramate-treated subjects experienced an average decrease in serum bicarbonate level of 4 mmol/L and an average increase in serum chloride level of 4 mmol/L (see Warnings and Precautions, Endocrine and Metabolism).

In a drug interaction study with the diuretic hydrochlorothiazide (HCTZ), the percentage of patients with a serum potassium measurement of <3.6 mEq/L was greater at the end of concomitant treatment than at the end of treatment for either drug alone: 27% (3/11) of subjects on topiramate treatment alone and 25% (3/12) of subjects on HCTZ alone versus 61% (14/22) of subjects on concomitant drug treatment (see Warnings and Precautions, Endocrine and Metabolism and Drug Interactions).

The majority of the most common adverse events in clinical trials were mild-moderate in severity and dose-related. These dose-related adverse events typically began in the titration phase and often persisted into the maintenance phase, but infrequently began in the maintenance phase. Rapid titration rate and higher initial dose were associated with higher incidences of adverse events leading to discontinuation.

The most commonly observed adverse events associated with the use of topiramate at dosages of 100 to 400 mg/day in controlled trials in adults with newly diagnosed epilepsy were: paresthesia, fatigue, headache, somnolence, dizziness, upper respiratory tract infection, anorexia, weight decrease, depression, and nausea (see Table 1).

Approximately 19% of the 886 adult patients who received topiramate as monotherapy in controlled clinical trials for patients with newly diagnosed epilepsy discontinued therapy due to adverse events. Adverse events associated with discontinuing therapy included paresthesia (2.6%), somnolence (2.5%), fatigue (2.3%), nausea (2.0%), and psychomotor slowing (1.6%).

The most commonly observed adverse events associated with the use of topiramate at dosages of 100 to 400 mg/day in controlled trials in children with newly diagnosed epilepsy were: upper respiratory tract infection, headache, anorexia, difficulty with concentration/attention, weight decrease, somnolence, paresthesia, fever, and fatigue (see Table 2).

Approximately 10% of the 245 pediatric patients who received topiramate as monotherapy in controlled clinical trials for patients with newly diagnosed epilepsy discontinued therapy due to adverse events. Adverse events associated with discontinuing therapy included difficulty with concentration/attention (2.0%). No pediatric patients withdrew due to psychomotor slowing.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Table 1: TOPAMAX

Incidence of Treatment-emergent Adverse Events in Monotherapy Trials in Adults^a Where Rate Was ≥2% in Any 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.



Table 2: TOPAMAX

Incidence of Treatment-emergent Adverse Events in Monotherapy Trials in Children Ages 6 up to 16 Years^a Where Rate Was ≥2% in Any Topiramate Group