TOPIRAMATE (topiramate 100 mg) Dailymed

Precautions

Hyperammonemia and EncephalopathyAssociated 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 be advised of the need to be alert for the emergence or worsening of 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.

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 they have gained sufficient experience on topiramate to gauge whether it adversely affects their mental performance and/or motor performance.

Additional food intake may be considered if the patient is losing weight while on this medication.

Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number, 1-888-233-2334 (see PRECAUTIONS: Pregnancy: Pregnancy Category C ).

Laboratory Tests:

Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended (see WARNINGS ).

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.

Antiepileptic Drugs

Potential interactions between topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. The effects of these interactions on mean plasma AUCs are summarized in Table 4.

In Table 4, the second column (AED concentration) describes what happens to the concentration of the AED uled in the first column when topiramate is added.

The third column (topiramate concentration) describes how the coadministration of a drug uled in the first column modifies the concentration of topiramate in experimental settings when topiramate was given alone.

Table 4: Summary of AED Interactions with Topiramate

AEDCo-administered	AEDConcentration	TopiramateConcentration
a = Plasma concentration increased 25% in some patients, generally those on a b.i.d. dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
AED = Antiepileptic drug.
NE = Not Evaluated.
TPM = Topiramate
Phenytoin	NC or 25% increasea	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxideb	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	15% increase

In addition to the pharmacokinetic interaction described in the above table, concomitant administration of valproic acid and topiramate has been associated with hyperammonemia with and without encephalopathy (see PRECAUTIONS, Hyperammonemia and Encephalopathy Associated with Concomitant Valproic Acid Use ).

Other Drug Interactions

In a single-dose study, serum digoxin AUC was decreased by 12% with concomitant topiramate administration. The clinical relevance of this observation has not been established.

Concomitant administration of topiramate and alcohol or other CNS depressant drugs has not been evaluated in clinical studies. Because of the potential of topiramate to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse events, topiramate should be used with extreme caution if used in combination with alcohol and other CNS depressants.

In a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), topiramate given in the absence of other medications at doses of 50 to 200 mg/day was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive. In another study, exposure to EE was statistically significantly decreased at doses of 200, 400, and 800 mg/day (18%, 21%, and 30%, respectively) when given as adjunctive therapy in patients taking valproic acid. In both studies, topiramate (50 mg/day to 800 mg/day) did not significantly affect exposure to NET. Although there was a dose dependent decrease in EE exposure for doses between 200 to 800 mg/day, there was no significant dose dependent change in EE exposure for doses of 50 to 200 mg/day. The clinical significance of the changes observed is not known. The possibility of decreased contraceptive efficacy and increased breakthrough bleeding should be considered in patients taking combination oral contraceptive products with topiramate. Patients taking estrogen containing contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding.

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of HCTZ (25 mg q24h) and topiramate (96 mg q12h) when administered alone and concomitantly. The results of this study indicate that topiramate C_max increased by 27% and AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The addition of HCTZ to topiramate therapy may require an adjustment of the topiramate dose. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of topiramate. Clinical laboratory results indicated decreases in serum potassium after topiramate or HCTZ administration, which were greater when HCTZ and topiramate were administered in combination.

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly. A 15% decrease in the AUC_τ,ss of pioglitazone with no alteration in C_max,ss was observed. This finding was not statistically significant. In addition, a 13% and 16% decrease in C_max,ss and AUC_τ,ss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in C_max,ss and AUC_τ,ss of the active keto-metabolite. The clinical significance of these findings is not known. When topiramate is added to pioglitazone therapy or pioglitazone is added to topiramate therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.

Multiple dosing of topiramate 100 mg every 12 hrs decreased the AUC and c_max of Lithium (300 mg every 8 hrs) by 20% (N=12, 6 M; 6 F).

The pharmacokinetics of a single dose of haloperidol (5 mg) were not affected following multiple dosing of topiramate (100 mg every 12 hr) in 13 healthy adults (6 M, 7 F).

There was a 12% increase in AUC and C_max for amitriptyline (25 mg per day) in 18 normal subjects (9 male; 9 female) receiving 200 mg/day of topiramate. Some subjects may experience a large increase in amitriptyline concentration in the presence of topiramate and any adjustments in amitriptyline dose should be made according to the patient's clinical response and not on the basis of plasma levels.

Multiple dosing of topiramate (100 mg every 12 hrs) in 24 healthy volunteers (14 M, 10 F) did not affect the pharmacokinetics of single dose sumatriptan either orally (100 mg) or subcutaneously (6 mg).

There was a 25% decrease in exposure to risperidone (2 mg single dose) in 12 healthy volunteers (6 M, 6 F) receiving 200 mg/day of topiramate. Therefore, patients receiving risperidone in combination with topiramate should be closely monitored for clinical response.

Multiple dosing of topiramate (200 mg/day) in 34 healthy volunteers (17 M, 17 F) did not affect the pharmacokinetics of propranolol following daily 160 mg doses. Propranolol doses of 160 mg/day in 39 volunteers (27M, 12F) had no effect on the exposure to topiramate at a dose of 200 mg/day of topiramate.

Multiple dosing of topiramate (200 mg/day) in 24 healthy volunteers (12 M, 12 F) did not affect the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine. Similarly, a 1 mg subcutaneous dose of dihydroergotamine did not affect the pharmacokinetics of a 200 mg/day dose of topiramate in the same study.

Concomitant use of topiramate, a carbonic anhydrase inhibitor, with other carbonic anhydrase inhibitors, e.g., acetazolamide or dichlorphenamide, may create a physiological environment that increases the risk of renal stone formation, and should therefore be avoided.

Drug/Laboratory Tests Interactions

There are no known interactions of topiramate with commonly used laboratory tests.

Carcinogenesis, Mutagenesis, Impairmentof Fertility:

An increase in urinary bladder tumors was observed in mice given topiramate (20, 75, and 300 mg/kg) in the diet for 21 months. The elevated bladder tumor incidence, which was statistically significant in males and females receiving 300 mg/kg, was primarily due to the increased occurrence of a smooth muscle tumor considered histomorphologically unique to mice. Plasma exposures in mice receiving 300 mg/kg were approximately 0.5 to 1 times steady-state exposures measured in patients receiving topiramate monotherapy at the recommended human dose (RHD) of 400 mg, and 1.5 to 2 times steady-state topiramate exposures in patients receiving 400 mg of topiramate plus phenytoin. The relevance of this finding to human carcinogenic risk is uncertain. No evidence of carcinogenicity was seen in rats following oral administration of topiramate for 2 years at doses up to 120 mg/kg (approximately 3 times the RHD on a mg/m² basis).

Topiramate did not demonstrate genotoxic potential when tested in a battery of in vitro and in vivo assays. Topiramate was not mutagenic in the Ames test or the in vitro mouse lymphoma assay; it did not increase unscheduled DNA synthesis in rat hepatocytes in vitro; and it did not increase chromosomal aberrations in human lymphocytes in vitro or in rat bone marrow in vivo.

No adverse effects on male or female fertility were observed in rats at doses up to 100 mg/kg (2.5 times the RHD on a mg/m² basis).

Pregnancy: .

Topiramate has demonstrated selective developmental toxicity, including teratogenicity, in experimental animal studies. When oral doses of 20, 100, or 500 mg/kg were administered to pregnant mice during the period of organogenesis, the incidence of fetal malformations (primarily craniofacial defects) was increased at all doses. The low dose is approximately 0.2 times the recommended human dose (RHD=400 mg/day) on a mg/m² basis. Fetal body weights and skeletal ossification were reduced at 500 mg/kg in conjunction with decreased maternal body weight gain.

In rat studies (oral doses of 20, 100, and 500 mg/kg or 0.2, 2.5, 30, and 400 mg/kg), the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased among the offspring of dams treated with 400 mg/kg (10 times the RHD on a mg/m² basis) or greater during the organogenesis period of pregnancy. Embryotoxicity (reduced fetal body weights, increased incidence of structural variations) was observed at doses as low as 20 mg/kg (0.5 times the RHD on a mg/m² basis). Clinical signs of maternal toxicity were seen at 400 mg/kg and above, and maternal body weight gain was reduced during treatment with 100 mg/kg or greater.

In rabbit studies (20, 60, and 180 mg/kg or 10, 35, and 120 mg/kg orally during organogenesis), embryo/fetal mortality was increased at 35 mg/kg (2 times the RHD on a mg/m² basis) or greater, and teratogenic effects (primarily rib and vertebral malformations) were observed at 120 mg/kg (6 times the RHD on a mg/m² basis). Evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35 mg/kg and above.

When female rats were treated during the latter part of gestation and throughout lactation (0.2, 4, 20, and 100 mg/kg or 2, 20, and 200 mg/kg), offspring exhibited decreased viability and delayed physical development at 200 mg/kg (5 times the RHD on a mg/m² basis) and reductions in pre- and/or postweaning body weight gain at 2 mg/kg (0.05 times the RHD on a mg/m² basis) and above. Maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/kg or greater.

In a rat embryo/fetal development study with a postnatal component (0.2, 2.5, 30, or 400 mg/kg during organogenesis; noted above), pups exhibited delayed physical development at 400 mg/kg (10 times the RHD on a mg/m² basis) and persistent reductions in body weight gain at 30 mg/kg (1 times the RHD on a mg/m² basis) and higher.

There are no studies using topiramate in pregnant women. Topiramate 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 topiramate, with or without other anticonvulsants; however, a causal relationship with topiramate has not been established.

To provide information regarding the effects of in utero exposure to topiramate tablets, physicians are advised to recommend that pregnant patients taking topiramate tablets enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number, 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

Labor and Delivery:

In studies of rats where dams were allowed to deliver pups naturally, no drug-related effects on gestation length or parturition were observed at dosage levels up to 200 mg/kg/day.

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

Nursing Mothers:

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 secretion of topiramate into breast milk. Since many drugs are excreted in human milk, and because the potential for serious adverse reactions in nursing infants to topiramate is unknown, the potential benefit to the mother should be weighed against the potential risk to the infant when considering recommendations regarding nursing.

Pediatric Use:

Safety and effectiveness in patients below the age of 2 years have not been established for the adjunctive therapy treatment of partial onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome. Safety and effectiveness in patients below the age of 10 years have not been established for the monotherapy treatment of epilepsy. 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 (see WARNINGS ).

Geriatric Use:

In clinical trials, 3% of patients were over 60. No age related difference in effectiveness or adverse effects were evident. However, clinical studies of topiramate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Dosage adjustment may be necessary for elderly with impaired renal function (creatinine clearance rate ≤70 mL/min/1.73 m²) due to reduced clearance of topiramate (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION ).

Race and Gender Effects:

Evaluation of effectiveness and safety in clinical trials has shown no race or gender related effects.

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(N=57)	400(N=57)
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
Fever	0	9
Central & Peripheral Nervous System Disorders
Paresthesia	2	16
Gastro-Intestinal System Disorders
Diarrhea	5	11
Metabolic and Nutritional Disorders
Weight Decrease	7	21
Psychiatric Disorders
Anorexia	11	14
Mood Problems	2	11
Difficulty with Concentration/Attention	4	9
Cognitive Problems NOS	0	7
Nervousness	4	5
Resistance Mechanism Disorders
Infection Viral	4	9
Infection	2	7
Respiratory System Disorders
Upper Respiratory Tract Infection	16	18
Rhinitis	2	7
Bronchitis	2	7
Sinusitis	2	5
Skin and Appendages Disorders
Alopecia	2	5

Adjunctive Therapy Epilepsy

The most commonly observed adverse events associated with the use of topiramate at dosages of 200 to 400 mg/day in controlled trials in adults with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, that were seen at greater frequency in topiramate-treated patients and did not appear to be dose-related were: somnolence, dizziness, ataxia, speech disorders and related speech problems, psychomotor slowing, abnormal vision, difficulty with memory, paresthesia and diplopia [see Table 7]. The most common dose-related adverse events at dosages of 200 to 1,000 mg/day were: fatigue, nervousness, difficulty with concentration or attention, confusion, depression, anorexia, language problems, anxiety, mood problems, and weight decrease [see Table 9].

Adverse events associated with the use of topiramate at dosages of 5 to 9 mg/kg/day in controlled trials in pediatric patients with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, that were seen at greater frequency in topiramate-treated patients were: fatigue, somnolence, anorexia, nervousness, difficulty with concentration/attention, difficulty with memory, aggressive reaction, and weight decrease [see Table 10].

In controlled clinical trials in adults, 11% of patients receiving topiramate 200 to 400 mg/day as adjunctive therapy discontinued due to adverse events. This rate appeared to increase at dosages above 400 mg/day. Adverse events associated with discontinuing therapy included somnolence, dizziness, anxiety, difficulty with concentration or attention, fatigue, and paresthesia and increased at dosages above 400 mg/day. None of the pediatric patients who received topiramate adjunctive therapy at 5 to 9 mg/kg/day in controlled clinical trials discontinued due to adverse events.

Approximately 28% of the 1,757 adults with epilepsy who received topiramate at dosages of 200 to 1,600 mg/day in clinical studies discontinued treatment because of adverse events; an individual patient could have reported more than one adverse event. These adverse events were: psychomotor slowing (4%), difficulty with memory (3.2%), fatigue (3.2%), confusion (3.1%), somnolence (3.2%), difficulty with concentration/attention (2.9%), anorexia (2.7%), depression (2.6%), dizziness (2.5%), weight decrease (2.5%), nervousness (2.3%), ataxia (2.1%), and paresthesia (2%). Approximately 11% of the 310 pediatric patients who received topiramate at dosages up to 30 mg/kg/day discontinued due to adverse events. Adverse events associated with discontinuing therapy included aggravated convulsions (2.3%), difficulty with concentration/attention (1.6%), language problems (1.3%), personality disorder (1.3%), and somnolence (1.3%).

Incidence in Epilepsy Controlled ClinicalTrials - Adjunctive Therapy Partial Onset Seizures, PrimaryGeneralized Tonic-Clonic Seizures, and Lennox-Gastaut Syndrome

Table 7 uls treatment-emergent adverse events that occurred in at least 1% of adults treated with 200 to 400 mg/day topiramate in controlled trials that were numerically more common at this dose than in the patients treated with placebo. In general, most patients who experienced adverse events during the first eight weeks of these trials no longer experienced them by their last visit. Table 10 uls treatment-emergent adverse events that occurred in at least 1% of pediatric patients treated with 5 to 9 mg/kg topiramate in controlled trials that were numerically more common than in patients treated with placebo.

The prescriber should be aware that these data were obtained when topiramate was added to concurrent antiepileptic drug therapy and 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 clinical studies. 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.

Other Adverse Events Observed During Double-Blind Epilepsy Adjunctive Therapy Trials

Other events that occurred in more than 1% of adults treated with 200 to 400 mg of topiramate in placebo-controlled epilepsy trials but with equal or greater frequency in the placebo group were: headache, injury, anxiety, rash, pain, convulsions aggravated, coughing, fever, diarrhea, vomiting, muscle weakness, insomnia, personality disorder, dysmenorrhea, upper respiratory tract infection, and eye pain.

Table 7: Incidence of Treatment-Emergent Adverse Events in Placebo-Controlled, Add-On Epilepsy Trials in Adults^a,b Where Rate Was > 1% in Any Topiramate Group and Greater Than the Rate in Placebo-Treated Patients

		Topiramate Dosage (mg/day)
Body System/Adverse Eventc	Placebo(N=291)				200 to 400(N=183)			600 to 1,000(N=414)
a Patients in these add-on trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo.
b 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.
c Adverse events reported by at least 1% of patients in the topiramate 200 to 400 mg/day group and more common than in the placebo group are uled in this table.
Body as a Whole-General Disorders
Fatigue	13				15			30
Asthenia	1				6			3
Back Pain	4				5			3
Chest Pain	3				4			2
Influenza-Like Symptoms	2				3			4
Leg Pain	2				2			4
Hot Flushes	1				2			1
Allergy	1				2			3
Edema	1				2			1
Body Odor	0				1			0
Rigors	0				1			<1
Central & Peripheral Nervous System Disorders
Dizziness	15				25			32
Ataxia	7				16			14
Speech Disorders/Related Speech Problems	2				13			11
Paresthesia	4				11			19
Nystagmus	7				10			11
Tremor	6				9			9
Language Problems	1				6			10
Coordination Abnormal	2				4			4
Hypoaesthesia	1				2			1
Gait Abnormal	1				3			2
Muscle Contractions Involuntary	1				2			2
Stupor	0				2			1
Vertigo	1				1			2
Gastro-Intestinal System Disorders
Nausea	8				10			12
Dyspepsia	6				7			6
Abdominal Pain	4				6			7
Constipation	2				4			3
Gastroenteritis	1				2			1
Dry Mouth	1				2			4
Gingivitis	<1				1			1
GI Disorder	<1				1			0
Hearing and Vestibular Disorders
Hearing Decreased	1				2			1
Metabolic and Nutritional Disorders
Weight Decrease	3				9			13
Muscle-Skeletal System Disorders
Myalgia	1				2			2
Skeletal Pain	0				1			0
Platelet, Bleeding, & Clotting Disorders
Epistaxis	1				2			1
Psychiatric Disorders
Somnolence	12				29			28
Nervousness	6				16			19
Psychomotor Slowing	2				13			21
Difficulty with Memory	3				12			14
Anorexia	4				10			12
Confusion	5				11			14
Depression	5				5			13
Difficulty with Concentration/Attention	2				6			14
Mood Problems	2				4			9
Agitation	2				3			3
Aggressive Reaction	2				3			3
Emotional Lability	1				3			3
Cognitive Problems	1				3			3
Libido Decreased	1				2			<1
Apathy	1				1			3
Depersonalization	1				1			2
Reproductive Disorders, Female
Breast Pain	2				4			0
Amenorrhea	1				2			2
Menorrhagia	0				2			1
Menstrual Disorder	1				2			1
Reproductive Disorders, Male
Prostatic Disorder	<1				2			0
Resistance Mechanism Disorders
Infection	1				2			1
Infection Viral	1				2			<1
Moniliasis	<1				1			0
Respiratory System Disorders
Pharyngitis	2				6			3
Rhinitis	6				7			6
Sinusitis	4				5			6
Dyspnea	1				1			2
Skin and Appendages Disorders
Skin Disorder	<1				2			1
Sweating Increased	<1				1			<1
Rash Erythematous	<1				1			<1
Special Sense Other, Disorders
Taste Perversion	0				2			4
Urinary System Disorders
Hematuria	1				2			<1
Urinary Tract Infection	1				2			3
Micturition Frequency	1				1			2
Urinary Incontinence	<1				2			1
Urine Abnormal	0				1			<1
Vision Disorders
Vision Abnormal	2				13			10
Diplopia	5				10			10
White Cell and RES Disorders
Leukopenia	1				2			1

Incidence in Study 119 Add-OnTherapy Adults with Partial Onset Seizures

Study 119 was a randomized, double-blind, placebo-controlled, parallel group study with 3 treatment arms: 1) placebo; 2) topiramate 200 mg/day with a 25 mg/day starting dose, increased by 25 mg/day each week for 8 weeks until the 200 mg/day maintenance dose was reached; and 3) topiramate 200 mg/day with a 50 mg/day starting dose, increased by 50 mg/day each week for 4 weeks until the 200 mg/day maintenance dose was reached. All patients were maintained on concomitant carbamazepine with or without another concomitant antiepileptic drug.

The incidence of adverse events (Table 8) did not differ significantly between the 2 topiramate regimens. Because the frequencies of adverse events reported in this study were markedly lower than those reported in the previous epilepsy studies, they cannot be directly compared with data obtained in other studies.

Table 8: Incidence of Treatment-Emergent Adverse Events in Study 119^a,b Where Rate Was ≥ 2% in the Topiramate Group and Greater Than the Rate in Placebo-Treated Patients

		Topiramate Dosage (mg/day)
Body System/ Adverse Eventc	Placebo(N=92)	200(N=171)
a Patients in these add-on trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo.
b 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.
c Adverse events reported by at least 2% of patients in the topiramate 200 mg/day group and more common than in the placebo group are uled in this table.
Body as a Whole-General Disorders
Fatigue	4	9
Chest Pain	1	2
Cardiovascular Disorders, General
Hypertension	0	2
Central & Peripheral Nervous System Disorders
Paresthesia	2	9
Dizziness	4	7
Tremor	2	3
Hypoasthesia	0	2
Leg Cramps	0	2
Language Problems	0	2
Gastro-Intestinal System Disorders
Abdominal Pain	3	5
Constipation	0	4
Diarrhea	1	2
Dyspepsia	0	2
Dry Mouth	0	2
Hearing and Vestibular Disorders
Tinnitus	0	2
Metabolic and Nutritional Disorders
Weight Decrease	4	8
Psychiatric Disorders
Somnolence	9	15
Anorexia	7	9
Nervousness	2	9
Difficulty with Concentration/Attention	0	5
Insomnia	3	4
Difficulty with Memory	1	2
Aggressive Reaction	0	2
Respiratory System Disorders
Rhinitis	0	4
Urinary System Disorders
Cystitis	0	2
Vision Disorders
Diplopia	0	2
Vision Abnormal	0	2

Table 9: Incidence (%) of Dose-Related Adverse Events From Placebo-Controlled, Add-On Trials in Adults with Partial Onset Seizures^a

		Topiramate Dosage (mg/day)
Adverse Event	Placebo(N = 216)	200(N = 45)	400(N = 68)	600 to 1,000(N = 414)
a Dose-response studies were not conducted for other adult indications or for pediatric indications.
Fatigue	13	11	12	30
Nervousness	7	13	18	19
Difficulty with Concentration/Attention	1	7	9	14
Confusion	4	9	10	14
Depression	6	9	7	13
Anorexia	4	4	6	12
Language problems	<1	2	9	10
Anxiety	6	2	3	10
Mood problems	2	0	6	9
Weight decrease	3	4	9	13

Table 10: Incidence (%) of Treatment-Emergent Adverse Events in Placebo-Controlled, Add-On Epilepsy Trials in Pediatric Patients Ages 2 to 16 Years^a,b (Events that Occurred in at Least 1% of Topiramate-Treated Patients and Occurred More Frequently in Topiramate-Treated Than Placebo-Treated Patients)

Body System/ Adverse Event	Placebo(N=101)	Topiramate(N=98)
a Patients in these add-on trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo.
b 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
Fatigue	5	16
Injury	13	14
Allergic Reaction	1	2
Back Pain	0	1
Pallor	0	1
Cardiovascular Disorders, General
Hypertension	0	1
Central & Peripheral Nervous System Disorders
Gait Abnormal	5	8
Ataxia	2	6
Hyperkinesia	4	5
Dizziness	2	4
Speech Disorders/Related Speech Problems	2	4
Hyporeflexia	0	2
Convulsions Grand Mal	0	1
Fecal Incontinence	0	1
Paresthesia	0	1
Gastro-Intestinal System Disorders
Nausea	5	6
Saliva Increased	4	6
Constipation	4	5
Gastroenteritis	2	3
Dysphagia	0	1
Flatulence	0	1
Gastroesophageal Reflux	0	1
Glossitis	0	1
Gum Hyperplasia	0	1
Heart Rate and Rhythm Disorders
Bradycardia	0	1
Metabolic and Nutritional Disorders
Weight Decrease	1	9
Thirst	1	2
Hypoglycemia	0	1
Weight Increase	0	1
Platelet, Bleeding, & Clotting Disorders
Purpura	4	8
Epistaxis	1	4
Hematoma	0	1
Prothrombin Increased	0	1
Thrombocytopenia	0	1
Psychiatric Disorders
Somnolence	16	26
Anorexia	15	24
Nervousness	7	14
Personality Disorder (Behavior Problems)	9	11
Difficulty with Concentration/Attention	2	10
Aggressive Reaction	4	9
Insomnia	7	8
Difficulty with Memory NOS	0	5
Confusion	3	4
Psychomotor Slowing	2	3
Appetite Increased	0	1
Neurosis	0	1
Reproductive Disorders, Female
Leukorrhoea	0	2
Resistance Mechanism Disorders
Infection Viral	3	7
Respiratory System Disorders
Pneumonia	1	5
Respiratory Disorder	0	1
Skin and Appendages Disorders
Skin Disorder	2	3
Alopecia	1	2
Dermatitis	0	2
Hypertrichosis	1	2
Rash Erythematous	0	2
Eczema	0	1
Seborrhoea	0	1
Skin Discoloration	0	1
Urinary System Disorders
Urinary Incontinence	2	4
Nocturia	0	1
Vision Disorders
Eye Abnormality	1	2
Vision Abnormal	1	2
Diplopia	0	1
Lacrimation Abnormal	0	1
Myopia	0	1
White Cell and RES Disorders
Leukopenia	0	2

Other Adverse Events Observed DuringAll Epilepsy Clinical Trials

Topiramate has been administered to 2,246 adults and 427 pediatric patients with epilepsy during all clinical studies, only some of which were placebo controlled. During these studies, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using modified WHOART dictionary terminology. The frequencies presented represent the proportion of patients who experienced an event of the type cited on at least one occasion while receiving topiramate. Reported events are included except those already uled in the previous tables or text, those too general to be informative, and those not reasonably associated with the use of the drug.

Events are classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent occurring in at least 1/100 patients; infrequent occurring in 1/100 to 1/1000 patients; rare occurring in fewer than 1/1000 patients.

Autonomic Nervous System Disorders: Infrequent: vasodilation.

Body as a Whole: Frequent: syncope. Infrequent: abdomen enlarged. Rare: alcohol intolerance.

Cardiovascular Disorders, General: Infrequent: hypotension, postural hypotension, angina pectoris.

Central & Peripheral Nervous System Disorders: Infrequent : neuropathy, apraxia, hyperaesthesia, dyskinesia, dysphonia, scotoma, ptosis, dystonia, visual field defect, encephalopathy, EEG abnormal. Rare: upper motor neuron lesion, cerebellar syndrome, tongue paralysis.

Gastrointestinal System Disorders: Infrequent: hemorrhoids, stomatitis, melena, gastritis, esophagitis. Rare: tongue edema.

Heart Rate and Rhythm Disorders: Infrequent: AV block.

Liver and Biliary System Disorders: Infrequent: SGPT increased, SGOT increased.

Metabolic and Nutritional Disorders: Infrequent: dehydration, hypokalemia, alkaline phosphatase increased, hypocalcemia, hyperlipemia, hyperglycemia, xerophthalmia, diabetes mellitus. Rare: hyperchloremia, hypernatremia, hyponatremia, hypocholesterolemia, hypophosphatemia, creatinine increased.

Musculoskeletal System Disorders: Frequent: arthralgia. Infrequent: arthrosis.

Neoplasms: Infrequent: thrombocythemia. Rare: polycythemia.

Platelet, Bleeding, and Clotting Disorders: Infrequent: gingival bleeding, pulmonary embolism.

Psychiatric Disorders: Frequent: impotence, hallucination, psychosis, suicide attempt. Infrequent: euphoria, paranoid reaction, delusion, paranoia, delirium, abnormal dreaming. Rare: libido increased, manic reaction.

Red Blood Cell Disorders: Frequent: anemia. Rare: marrow depression, pancytopenia.

Reproductive Disorders, Male: Infrequent: ejaculation disorder, breast discharge.

Skin and Appendages Disorders: Infrequent: urticaria, photosensitivity reaction, abnormal hair texture. Rare: chloasma.

Special Senses Other, Disorders: Infrequent: taste loss, parosmia.

Urinary System Disorders: Infrequent: urinary retention, face edema, renal pain, albuminuria, polyuria, oliguria.

Vascular (Extracardiac) Disorders: Infrequent: flushing, deep vein thrombosis, phlebitis. Rare: vasospasm.

Vision Disorders: Frequent: conjunctivitis. Infrequent: abnormal accommodation, photophobia, strabismus. Rare: mydriasis, iritis.

White Cell and Reticuloendothelial System Disorders: Infrequent: lymphadenopathy, eosinophilia, lymphopenia, granulocytopenia. Rare: lymphocytosis.

Postmarketing and Other Experience

In addition to the adverse experiences reported during clinical testing of topiramate, the following adverse experiences have been reported worldwide in patients receiving topiramate post-approval.

These adverse experiences have not been uled above and data are insufficient to support an estimate of their incidence or to establish causation. The uling is alphabetized: bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), hepatic failure (including fatalities), hepatitis, maculopathy, pancreatitis, pemphigus, and renal tubular acidosis.