Nu-Topiramate Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

EPILEPSY

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

NU-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.

MIGRAINE

NU-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. NU-TOPIRAMATE 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.

Geriatrics (> 65 years of age):

There is limited information in patients over 65 years of age. (see WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics)

CONTRAINDICATIONS

Patients who are hypersensitive to this drug or to any nonmedicinal ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph.

Topiramate for the indication prophylaxis of migraine is contraindicated in pregnancy and in women of childbearing potential who are not using an effective method of contraception (see WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women, Migraine, ADVERSE REACTIONS, Pregnancy Registries to Date (August 2009) and DOSAGE AND ADMINISTRATION, Dosing Considerations).

WARNINGS AND PRECAUTIONS

General

Antiepileptic drugs, including NU-TOPIRAMATE (topiramate), should be withdrawn gradually to minimize the potential for seizures or increased seizure frequency.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, topiramate 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, NU-TOPIRAMATE should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency. In clinical trials in adult patients receiving topiramate 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 NU-TOPIRAMATE is medically required, appropriate monitoring is recommended (see DOSAGE AND ADMINISTRATION, General).

Hyperammonemia and Encephalopathy

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.

Carcinogenesis and Mutagenesis

See Product Monograph Part II: TOXICOLOGY, Carcinogenicity and Mutagenicity for discussion on animal data.

Endocrine and Metabolism

Oligohidrosis and Hyperthermia

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 NU-TOPIRAMATE, 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 NU-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. (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions)

Metabolic Acidosis

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 pretreatment) 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 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 mmol/L and >5 mmol/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.

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 pretreatment) 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.

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.

Decreases in Serum Potassium with Concomitant Treatment with Hydrochlorothiazide (HCTZ)

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 NU-TOPIRAMATE and hydrochlorothiazide concomitantly (see DRUG INTERACTIONS).

Nutritional Supplementation

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

Hepatic/Biliarv/Pancreatic

Decreased Hepatic Function

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

Neurologic

Central Nervous System Effects

Adverse events most often associated with the use of topiramate 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:

i). psychomotor slowing, difficulty with concentration and speech or language problems, in particular, word-finding difficulties,

ii). somnolence or fatigue and

iii). 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.)

Additional non-specific CNS effects occasionally observed with topiramate 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

Paresthesia, 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 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.

Ophthalmologic

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 a few days to 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 NU-TOPIRAMATE as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of NU-TOPIRAMATE, 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.

Maculopathy, including visual field defect, has been observed very rarely in post marketing reports (See ADVERSE REACTIONS, Post-Market Adverse Drug Reactions).

Psychiatric

Suicidal ideation and behaviour

Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications.

All patients treated with antiepileptic drugs, irrespective of indication, should be monitored for signs of suicidal ideation and behaviour and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

An FDA meta-analysis of randomized placebo controlled trials, in which antiepileptic drugs were used for various indications, has shown a small increased risk of suicidal ideation and behaviour in patients treated with these drugs. The mechanism of this risk is not known.

There were 43,892 patients treated in the placebo controlled clinical trials that were included in the meta-analysis. Approximately 75% of patients in these clinical trials were treated for indications other than epilepsy and, for the majority of non-epilepsy indications the treatment (antiepileptic drug or placebo) was administered as monotherapy. Patients with epilepsy represented approximately 25% of the total number of patients treated in the placebo controlled clinical trials and, for the majority of epilepsy patients, treatment (antiepileptic drug or placebo) was administered as adjunct to other antiepileptic agents (i.e., patients in both treatment arms were being treated with one or more antiepileptic drug). Therefore, the small increased risk of suicidal ideation and behaviour reported from the meta-analysis (0.43% for patients on antiepileptic drugs compared to 0.24% for patients on placebo) is based largely on patients that received monotherapy treatment (antiepileptic drug or placebo) for non-epilepsy indications. The study design does not allow an estimation of the risk of suicidal ideation and behaviour for patients with epilepsy that are taking antiepileptic drugs, due both to this population being the minority in the study, and the drug-placebo comparison in this population being confounded by the presence of adjunct antiepileptic drug treatment in both arms.

Renal

Kidney Stones

A total of 32/1,715 (1.9%) of patients exposed to topiramate 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: 27/1,092 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 topiramate dosage, duration of topiramate 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 NU-TOPIRAMATE, 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 NU-TOPIRAMATE treatment.

Adjustment of Dose in Renal Failure

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/l.73m²) 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).

Information for Patients

Pregnant Women

EPILEPSY

Patients should be reminded to inform their doctor if they are pregnant or intend to become pregnant while on NU-TOPIRAMATE therapy. NU-TOPIRAMATE should be used during pregnancy only if potential benefit justifies the potential risk to the fetus.

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. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

MIGRAINE

Prophylactic treatment of migraine: Taking NU-TOPIRAMATE to prevent migraine attacks does not outweigh the risk of malformations to the fetus. Consequently, NU-TOPIRAMATE is contraindicated in pregnancy and in women of childbearing potential who are not using an effective method of contraception (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women, Migraine and DOSAGE AND ADMINISTRATION, Dosing Considerations).

Adequate Hydration

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.

Effects on Ability to Drive and Use Machines

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 NU-TOPIRAMATE to gauge whether it adversely affects their mental and/or motor performance.

Acute Myopia and Secondary Angle Closure Glaucoma

Patients taking NU-TOPIRAMATE 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).

Special Populations

Pregnant Women

EPILEPSY

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

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

Pregnancy registry data suggest that there may be an association between the use of topiramate during pregnancy and congenital malformations (e.g., craniofacial defects, such as cleft lip/palate, hypospadias, and anomalies involving various body systems). This has been reported with topiramate monotherapy and topiramate as part of a polytherapy regimen (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions, Pregnancy Registries).

In addition, data from these registries and other studies suggest that, compared with monotherapy, there may be an increased risk of teratogenic effects associated with the use of anti-epileptic drugs in combination therapy.

NU-TOPIRAMATE should be used during pregnancy only if potential benefit justifies the potential risk to the fetus. In treating and counselling women of childbearing potential, the prescribing physician should weigh the benefits of therapy against the risks. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

To provide information regarding the effects of in utero exposure to topiramate, physicians are advised to recommend that pregnant patients taking NU-TOPIRAMATE enroll in the North American Antiepileptic Drug (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/.

The effect oftopiramate on labour and delivery in humans is unknown.

MIGRAINE

Prophylactic treatment of migraine: In pregnancy, the occurrence of seizures presents a significant risk for the mother and child. Prescribing NU-TOPIRAMATE to prevent seizures therefore outweighs the risk of malformations to the fetus. However, taking NU-TOPIRAMATE to prevent migraine attacks does not outweigh this risk. Consequently, NU-TOPIRAMATE is contraindicated in pregnancy and in women of child bearing potential who are not using an effective method of contraception (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION, Dosing Considerations).

Nursing Women: 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 NU-TOPIRAMATE 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.

Pediatrics (<2 years of age): Safety and effectiveness in children under 2 years of age have not been established.

Weight Loss in Pediatrics (> 2 years of age): Topiramate 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 topiramate. The long-term effects of reduced weight gain in pediatric patients are not known.

Geriatrics (>65 years of age): There is limited information in patients over 65 years of age. The possibility of age-associated renal function abnormalities should be considered when using NU-TOPIRAMATE. (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions.)

Monitoring and Laboratory Tests

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). Hypokalemia Observed During Concomitant Treatment with Hydrochlorothiazide:

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).

ADVERSE REACTIONS

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.

EPILEPSY

Adverse Drug Reaction Overview for Monotherapy

Adults

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 1.1).

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%).

Pediatrics

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 1.2).

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.

Clinical Trial Adverse Drug Reactions

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 1.1: Incidence of Treatment-Emergent Adverse Events in Monotherapy Trials in

Adults^a Where Rate Was ≥2% in Any Topiramate Group

Topiramate Dosage (mg/day)

Body System/Adverse Event

50-100 (n=444)

200-400 (n=329)

500

(n=113)

Body As a Whole - General Disorders

Fatigue 18 18 19 Injury 9 8 4 Asthenia 4 5 4 Back Pain 3 2 5 Pain 3 2 5 Chest Pain 2 2 3 Fever 1 2 3 Syncope 2 1 1 Leg Pain 2 2 1 Peripheral Edema 1 <1 2

Central and Peripheral Nervous System Disorders

Paresthesia 23 39 38 Headache 23 16 19 Dizziness 16 13 13 Hypoesthesia 5 5 12 Language Problems 4 5 6 Ataxia 3 5 4 Speech Disorders/Related Speech Problems 2 3 3 Vertigo 2 3 4 Tremor 3 2 3 Hypertonia 1 2 2 Involuntary Muscle Contractions 1 2 4 Sensory Disturbances 1 1 4

Topiramate Dosage (mg/day)

Body System/Adverse Event

50-100 (n=444)

200-400 (n=329)

500

(n=113)

Migraine 2 1 1 Abnormal Co-ordination 1 1 3 Convulsions Aggravated 1 0 2 Convulsions Grand Mal <1 1 2 Gait Abnormal <1 <1 3 Dyskinesia 0 0 2

Gastrointestinal System Disorders

Nausea 11 12 12 Diarrhea 6 8 12 Abdominal Pain 6 8 7 Dyspepsia 5 5 4 Vomiting 4 3 2 Constipation 2 3 1 Dry Mouth 1 2 6 Gastroenteritis 2 1 2 Gastritis 1 2 2 Tooth Ache 1 1 2 Gastrointestinal Disorder NOS <1 <1 2 Hemorrhoids <1 <1 2 Stomatitis Ulcerative <1 0 2

Hearing and Vestibular Disorders

Tinnitus 1 2 2

Heart Rate and Rhythm Disorders

Palpitation 1 1 4 Tachycardia 1 0 2

Metabolic and Nutritional Disorders

Weight Decrease 9 14 18

Musculoskeletal System Disorders

Arthralgia 3 4 4 Myalgia 2 1 2 Muscle Weakness 1 1 2

Platelet, Bleeding and Clotting Disorders

Epistaxis 1 2 1 Hematoma 0 0 2

Topiramate Dosage (mg/day)

Body System/Adverse Event

50-100 (n=444)

200-400 (n=329)

500

(n=113)

Psychiatric Disorders

Somnolence 11 15 19 Anorexia 8 14 11 Insomnia 9 8 9 Difficulty with Memory NOS 6 10 9 Depression 7 10 4 Difficulty with Concentration/Attention 6 9 8 Nervousness 6 7 8 Mood Problems 5 6 4 Anxiety 4 6 5 Confusion 4 5 7 Psychomotor Slowing 2 5 8 Cognitive Problems NOS 2 3 3 Agitation 2 2 3 Emotional Lability 1 3 2 Aggressive Reaction 2 1 2 Libido Decreased 1 2 1 Depression Aggravated <1 2 3 Impotence 1 1 2

Reproductive Disorders, Female

Menstrual Disorder 3 1 8 Dysmenorrhea 2 2 0 Intermenstrual Bleeding 2 1 0 Menorrhagia 1 1 2 Pregnancy Unintended 1 1 2 Mastitis 0 0 2

Reproductive Disorders, Male

Premature Ejaculation 0 0 2

Resistance Mechanism Disorders

Infection Viral 5 9 6 Otitis Media 2 1 2

Respiratory System Disorders

Upper Respiratory Tract Infection 15 13 10 Pharyngitis 5 5 2 Sinusitis 3 4 6

Topiramate Dosage (mg/day)

Body System/Adverse Event

50-100 (n=444)

200-400 (n=329)

500

(n=113)

Rhinitis 3 3 5 Bronchitis 2 2 1 Coughing 2 2 2 Dyspnea 1 2 1 Pneumonia 1 <1 3

Skin and Appendages Disorders

Rash 3 4 3 Alopecia 3 3 1 Acne 1 3 2 Pruritus 1 3 1 Increased Sweating 1 <1 2 Maculopapular Rash 1 0 2

Special Senses Other, Disorders

Taste Perversion 3 5 6

Urinary System Disorders

Urinary Tract Infection 2 2 5 Micturition Frequency 1 2 4 Dysuria <1 2 1 Cystitis <1 2 1 Renal Calculus <1 2 2

Vision Disorders

Vision Abnormal 3 4 4 Diplopia 1 1 2 ^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 1.2: 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

Topiramate Dosage (mg/day)

Body System/Adverse Event

50-100 (n=125)

200-400 (n=106)

500^b (n=14)

Body As a Whole - General Disorders

Fatigue 7 10 14 Fever 2 11 7 Injury 4 2 14 Asthenia 0 3 7 Back Pain 2 2 0 Allergic Reaction 1 1 7 Allergy 0 1 7 Influenza-Like Symptoms 0 0 7

Central and Peripheral Nervous System Disorders

Headache 27 17 29 Dizziness 9 8 0 Paresthesia 4 11 7 Language Problems 0 3 7 Convulsions Grand Mal 2 0 7 Hypertonia 0 0 7 Hyperkinesia 2 0 21 Migraine 2 1 0 Muscle Contractions Involuntary 1 2 0 Tremor 2 0 0 Vertigo 0 3 0 Cramps Legs 2 0 0 Gait Abnormal 2 0 0

Collagen Disorders

Auto-antibody Response 0 0 7

Gastrointestinal System Disorders

Diarrhea 9 7 7 Vomiting 8 6 14 Abdominal Pain 6 4 14 Nausea 4 5 14 Gastroenteritis 6 0 7 Constipation 1 0 7 Gastrointestinal Disorder NOS 0 0 7

Topiramate Dosage (mg/day)

Body System/Adverse Event

50-100 (n=125)

200-400 (n=106)

500^b (n=14)

Dyspepsia 2 1 0 Tooth Ache 1 1 7

Hearing and Vestibular Disorders

Earache 2 0 0

Metabolic and Nutritional Disorders

Weight Decrease 5 14 0 Acidosis 0 0 7

Musculoskeletal System Disorders

Arthralgia 1 2 7

Platelet, Bleeding and Clotting Disorders

Epistaxis 2 4 14

Psychiatric Disorders

Anorexia 13 13 14 Somnolence 14 9 0 Difficulty with Concentration/Attention 6 13 7 Insomnia 5 4 14 Nervousness 5 6 0 Mood Problems 2 8 0 Difficulty with Memory NOS 4 2 14 Cognitive Problems NOS 1 6 0 Psychomotor Slowing 3 3 0 Aggressive Reaction 2 3 7 Depression 0 5 0 Sleep Disorder 2 2 0 Personality Disorder (Behaviour Problems) 2 2 0 Anxiety 2 1 0 Confusion 0 3 0 Emotional Lability 2 1 0

Red Blood Cell Disorders

Anemia 1 2 0

Reproductive Disorders, Female

Vaginitis 0 0 13 Dysmenorrhea 2 2 0 Intermenstrual Bleeding 0 2 0

Topiramate Dosage (mg/day)

Body System/Adverse Event

50-100 (n=125)

200-400 (n=106)

500^b (n=14)

Reproductive Disorders, Male

Testis Disorder 2 0 0

Resistance Mechanism Disorders

Infection Viral 4 7 7 Infection 2 6 0 Otitis Media 2 1 7

Respiratory System Disorders

Upper Respiratory Tract Infection 26 25 21 Pharyngitis 9 5 21 Rhinitis 5 6 21 Sinusitis 3 6 14 Bronchitis 2 4 0 Asthma 2 1 0 Coughing 2 1 0

Skin and Appendages Disorders

Rash 3 4 21 Dermatitis 1 0 7 Alopecia 1 3 0 Acne 2 0 0 Nail Disorder 2 0 0 Pruritus 0 2 0 Rash Erythematous 2 0 0

Urinary System Disorders

Urinary Incontinence 2 2 7 Renal Calculus 0 0 7 Micturition Frequency 0 2 0 Urinary Tract Infection 2 0 0

Vascular Disorders

Flushing 1 4 7

Vision Disorders

Conjunctivitis 2 2 0 ^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. ^b. Due to n=14 in the 500 mg topiramate group, an incidence of 7% represents one patient. Adverse Drug Reaction Overview for Adjunctive Therapy

Adults

The most commonly observed adverse events associated with the adjunctive use of topiramate at dosages of 200 to 400 mg/day in controlled trials in adults that were seen at greater frequency in patients treated with topiramate and did not appear to be dose related within this dosage range were: somnolence, dizziness, ataxia, speech disorders and related speech problems, psychomotor slowing, nystagmus, and paresthesia (see Table 1.3).

The most common dose-related adverse events at dosages of 200 to 1,000 mg/day were: nervousness, difficulty with concentration or attention, confusion, depression, anorexia, language problems, and mood problems (see Table 1.4).

Pediatrics

Adverse events associated with the use of topiramate at dosages of 5 to 9 mg/kg/day in worldwide pediatric clinical trials that were seen at greater frequency in patients treated with topiramate were: fatigue, somnolence, anorexia, nervousness, difficulty with concentration/attention, difficulty with memory, aggressive reaction, and weight decrease (see Table 1.5).

Clinical Trial Adverse Drug Reactions

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 1.3: Incidence of Treatment-Emergent Adverse Events in Placebo-Controlled,

Add-On Epilepsy Trials in ADULTS^a,b (Events that occurred in ≥2% of patients treated with Topiramate and occurred more frequently in patients treated with Topiramate than placebo-treated patients)

Topiramate Dosage (mg/day)

Body System/Adverse Event

Placebo (n=216)

200-400 (n=113)

600-1,000 (n=414)

Body As a Whole

Asthenia 1.4 8.0 3.1 Back Pain 4.2 6.2 2.9 Chest Pain 2.8 4.4 2.4 Influenza-Like Symptoms 3.2 3.5 3.6 Leg Pain 2.3 3.5 3.6 Hot Flushes 1.9 2.7 0.7

Topiramate Dosage (mg/day)

Body System/Adverse Event

Placebo (n=216)

200-400 (n=113)

600-1,000 (n=414)

Nervous System

Dizziness 15.3 28.3 32.1 Ataxia 6.9 21.2 14.5 Speech Disorders/Related Speech Problems 2.3 16.8 11.4 Nystagmus 9.3 15.0 11.1 Paresthesia 4.6 15.0 19.1 Tremor 6.0 10.6 8.9 Language Problems 0.5 6.2 10.4 Co-ordination Abnormal 1.9 5.3 3.6 Hypoesthesia 0.9 2.7 1.2 Abnormal Gait 1.4 1.8 2.2

Gastrointestinal System

Nausea 7.4 11.5 12.1 Dyspepsia 6.5 8.0 6.3 Abdominal Pain 3.7 5.3 7.0 Constipation 2.3 5.3 3.4 Dry Mouth 0.9 2.7 3.9

Metabolic and Nutritional

Weight Decrease 2.8 7.1 12.8

Neuropsychiatric

Somnolence 9.7 30.1 27.8 Psychomotor Slowing 2.3 16.8 20.8 Nervousness 7.4 15.9 19.3 Difficulty with Memory 3.2 12.4 14.5 Confusion 4.2 9.7 13.8 Depression 5.6 8.0 13.0 Difficulty with Concentration/Attention 1.4 8.0 14.5 Anorexia 3.7 5.3 12.3 Agitation 1.4 4.4 3.4 Mood Problems 1.9 3.5 9.2 Aggressive Reaction 0.5 2.7 2.9 Apathy 0 1.8 3.1 Depersonalization 0.9 1.8 2.2 Emotional Lability 0.9 1.8 2.7

Topiramate Dosage (mg/day)

Body System/Adverse Event

Placebo (n=216)

200-400

(n=113)

600-1,000 (n=414)

Reproductive, Female (n=59) (n=24) (n=128) Breast Pain, Female 1.7 8.3 0 Dysmenorrhea 6.8 8.3 3.1 Menstrual Disorder 0 4.2 0.8

Reproductive, Male (n=157) (n=89) (n=286) Prostatic Disorder 0.6 2.2 0

Respiratory System

Pharyngitis 2.3 7.1 3.1 Rhinitis 6.9 7.1 6.3 Sinusitis 4.2 4.4 5.6 Dyspnea 0.9 1.8 2.4

Skin and Appendages

Pruritus 1.4 1.8 3.1

Vision

Diplopia 5.6 14.2 10.4 Vision Abnormal 2.8 14.2 10.1

White Cell and RES

Leukopenia 0.5 2.7 1.2 ^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.

Table 1.4: Incidence (%) of Dose-Related Adverse Events From Placebo-Controlled,

Add-On Epilepsy Trials in Adults

Topiramate Dosage (mg/day)

Adverse Event

Placebo (n=216)

200

(n=45)

400 (n=68)

600-1,000 (n=414)

Fatigue 13.4 11.1 11.8 29.7

Nervousness 7.4 13.3 17.6 19.3

Difficulty with Concentration/Attention 1.4 6.7 8.8 14.5

Confusion 4.2 8.9 10.3 13.8

Depression 5.6 8.9 7.4 13

Topiramate Dosage (mg/day)

Adverse Event

Placebo

(n=216)

200 (n=45)

400

(n=68)

600-1,000 (n=414)

Anorexia 3.7 4.4 5.9 12.3

Language Problems 0.5 2.2 8.8 10.1

Anxiety 6 2.2 2.9 10.4

Mood Problems 1.9 0 5.9 9.2

In six double-blind clinical trials, 10.6% of subjects (n=113) assigned to a topiramate dosage of 200 to 400 mg/day in addition to their standard AED therapy discontinued due to adverse events, compared to 5.8% of subjects (n=69) receiving placebo. The percentage of subjects discontinuing due to adverse events appeared to increase at dosages above 400 mg/day. Overall, approximately 17% of all subjects (n=527) who received topiramate in the double-blind trials discontinued due to adverse events, compared to 4% of the subjects (n=216) receiving placebo.

Table 1.5 lists treatment-emergent adverse events that occurred in at least 2% of children treated with 5 to 9 mg/kg/day topiramate in controlled trials that were numerically more common than in patients treated with placebo.

Table 1.5: Incidence (%) of Treatment-Emergent Adverse Events in Worldwide

Pediatric Add-on Epilepsy Clinical Trials Experience (2-16 years of Age)^a,b

(Events that Occurred in ≥2% of Patients Treated with Topiramate and Occurred More Frequently in Patients Treated with Topiramate Than Placebo-Treated Patients)

Body System/Adverse Event

Placebo

(n=101)

Topiramate

(n=98)

Body As a Whole – General Disorders

Fatigue 5 16.3 Injury 12.9 14.3 Allergic Reaction 1 2

Central and Peripheral Nervous System Disorders

Gait Abnormal 5 8.2 Ataxia 2 6.1 Hyperkinesia 4 5.1 Dizziness 2 4.1 Speech Disorders/Related Speech Problems 2 4.1 Convulsions Aggravated 3 3.1 Hyporeflexia 0 2

Body System/Adverse Event

Placebo (n=101)

Topiramate

(n=98)

Gastrointestinal System Disorders

Nausea 5 6.1 Saliva Increased 4 6.1 Constipation 4 5.1 Gastroenteritis 2 3.1

Metabolic and Nutritional Disorders

Weight Decrease 1 9.2 Thirst 1 2

Platelet, Bleeding and Clotting Disorders

Purpura 4 8.2 Epistaxis 1 4.1

Nervous Disorders

Somnolence 15.8 25.5 Anorexia 14.9 24.5 Nervousness 6.9 14.3 Personality Disorder (Behaviour Problems) 8.9 11.2 Difficulty with Concentration/Attention 2 10.2 Aggressive Reaction 4 9.2 Insomnia 6.9 8.2 Mood Problems 6.9 7.1 Difficulty with Memory NOS^C 0 5.1 Emotional Lability 5 5.1 Confusion 3 4.1 Psychomotor Slowing 2 3.1

Reproductive Disorders, Female

Leukorrhea 0 2.3

Resistance Mechanism Disorders

Infection Viral 3 7.1 Infection 3 3.1

Respiratory Systems Disorders

Upper Respiratory Tract Infection 36.6 36.7 Pneumonia 1 5.1

Skin and Appendages Disorders

Skin Disorder 2 3.1 Alopecia 1 2

Body System/Adverse Event

Placebo (n=101)

Topiramate

(n=98)

Dermatitis 0 2 Hypertrichosis 1 2 Rash Erythematous 0 2

Urinary System Disorders

Urinary Incontinence 2 4.1

Vision Disorders

Eye Abnormality 1 2 Vision Abnormal 1 2

White Cell and RES Disorders

Leukopenia 0 2 ^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. Not otherwise specified.

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. In open extensions of the controlled clinical trials, approximately 9% of the 303 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%), language problems (1.3%), and difficulty with concentration/attention (1.3%).

When the safety experience of patients receiving topiramate as adjunctive therapy in both double-blind and open-label trials (1,446 adults and 303 children) was analyzed, a similar pattern of adverse events emerged.

Less Common Clinical Trial Adverse Drug Reactions (<2%)

Adverse events that occurred less frequently but were considered potentially medically relevant included: taste perversion, cognitive problems (not otherwise specified) and psychosis/psychotic symptoms.

In adult and pediatric patients, nephrolithiasis was reported rarely. Isolated cases of thromboembolic events have also been reported; a causal association with the drug has not been established.

In clinical trials with topiramate, the occurrence rate for all potential cases of oligohidrosis (decreased sweating) was 0.25%.

In clinical trials for topiramate in epilepsy, migraine prophylaxis and other investigational indications (obesity, bipolar disorder and diabetic peripheral neuropathy), suicide-related adverse events^‡ occurred at a rate of 0.8% (84 reports/10,846 patients) in topiramate versus 0.2% (5 reports/3,150 patients) in placebo groups. Although the average exposure time for patients on topiramate (approximately 10 months) was longer than for those on placebo (approximately 5 months), these adverse events were reported randomly over the exposure period. Suicide attempts occurred in 0.3% (33 reports/10,846 patients) of the topiramate-treated patients compared to 0% in placebo groups. Of these 33 attempts, one completed suicide was reported in a double-blind bipolar disorder trial and 3 in the open-label phase of the bipolar disorder trials (see WARNINGS AND PRECAUTIONS, Neurologic, Central Nervous System Effects).

MIGRAINE

Adverse Drug Reaction Overview

Table 1.6 includes those adverse events reported for patients in four multicentre, randomized, double-blind, placebo-controlled, parallel-group migraine prophylaxis clinical trials where the incidence rate in any topiramate treatment group was at least 2% and was greater than that for placebo patients. Most of the adverse events were mild or moderate in severity and most occurred more frequently during the titration period than during the maintenance period.

Clinical Trial Adverse Drug Reactions

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 1.6: Incidence % of Treatment-Emergent Adverse Events in Placebo-Controlled

Migraine Trials Where Rate Was at Least 2% in Any Topiramate Group and Greater Than the Rate in Placebo-Treated Patients^a

Topiramate Dosage (mg/day)

Body System/Adverse Event

Placebo (n=445)

50

(n=235)

100

(n=386)

200

(n=514)

Body As a Whole – General Disorders

Fatigue 11 14 15 19 Injury 7 9 6 6 Asthenia 1 <1 2 2 Fever 1 1 1 2 Influenza-Like Symptoms <1 <1 <1 2 Allergy <1 2 <1 <1

Central and Peripheral Nervous System Disorders

Paresthesia 6 35 51 49

^‡ Suicide-related adverse events include suicidal ideation, suicide attempt, suicide and any evidence of self-harm

Topiramate Dosage (mg/day)

Body System/Adverse Event

Placebo (n=445)

50

(n=235)

100

(n=386)

200

(n=514)

Dizziness 10 8 9 12 Hypoesthesia 2 6 7 8 Language Problems 2 7 6 7 Involuntary Muscle Contractions 1 2 2 4 Ataxia <1 1 2 1 Speech Disorders/Related Speech Problems <1 1 <1 2

Gastrointestinal System Disorders

Nausea 8 9 13 14 Diarrhea 4 9 11 11 Abdominal Pain 5 6 6 7 Dyspepsia 3 4 5 3 Dry Mouth 2 2 3 5 Vomiting 2 1 2 3 Gastroenteritis 1 3 3 2

Hearing and Vestibular Disorders

Tinnitus 1 <1 1 2

Metabolic and Nutritional Disorders

Weight Decrease 1 6 9 11 Thirst <1 2 2 1

Musculoskeletal System Disorders

Arthralgia 2 7 3 1

Neoplasms

Neoplasm NOS <1 2 <1 <1

Psychiatric Disorders

Anorexia 6 9 15 14 Somnolence 5 8 7 10 Difficulty with Memory NOS 2 7 7 11 Difficulty with Concentration/Attention 2 3 6 10 Insomnia 5 6 7 6 Anxiety 3 4 5 6 Mood Problems 2 3 6 5 Depression 4 3 4 6 Nervousness 2 4 4 4 Confusion 2 2 3 4

Topiramate Dosage (mg/day)

Body System/Adverse Event

Placebo (n=445)

50

(n=235)

100

(n=386)

200

(n=514)

Psychomotor Slowing 1 3 2 4 Libido Decreased 1 1 1 2 Aggravated Depression 1 1 2 2 Agitation 1 2 2 1 Cognitive Problems NOS 1 <1 2 2

Reproductive Disorders, Female

Menstrual Disorder 2 3 2 2

Reproductive Disorders, Male

Ejaculation Premature 0 3 0 0

Resistance Mechanism Disorders

Viral Infection 3 4 4 3 Otitis Media <1 2 1 1

Respiratory System Disorders

Upper Respiratory Tract Infection 12 13 14 12 Sinusitis 6 10 6 8 Pharyngitis 4 5 6 2 Coughing 2 2 4 3 Bronchitis 2 3 3 3 Dyspnea 2 1 3 2 Rhinitis 1 1 2 2

Skin and Appendages Disorders

Pruritus 2 4 2 2

Special Sense Other, Disorders

Taste Perversion 1 15 8 12 Taste Loss <1 1 1 2

Urinary System Disorders

Urinary Tract Infection 2 4 2 4 Renal Calculus 0 0 1 2

Vision Disorders

Vision Abnormal <1 1 2 3 Blurred Vision^b 2 4 2 4 Conjunctivitis 1 1 2 1

Topiramate Dosage (mg/day)

Body System/Adverse Event

Placebo (n=445)

50

(n=235)

100

(n=386)

200

(n=514)

^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. ^b. Blurred vision was the most common term considered as vision abnormal. Blurred vision was an included term that accounted for >50% of events coded as vision abnormal, a preferred term

Of the 1,135 patients exposed to topiramate in the placebo-controlled studies, 25% discontinued due to adverse events, compared to 10% of the 445 placebo patients. The most common adverse events associated with discontinuing therapy in the topiramate-treated patients included paresthesia (6.7%), fatigue (4.3%), nausea (4.0%), difficulty with concentration/attention (2.9%), insomnia (2.7%), anorexia (2.1%), and dizziness (2.0%).

In the 6-month migraine prophylaxis controlled trials, the proportion of patients who experienced one or more cognitive-related events was 19% for topiramate 50 mg/day, 22% for 100 mg/day, 28% for 200 mg/day and 10% for placebo. These dose-related adverse reactions typically began in the titration phase and often persisted into the maintenance phase, but infrequently began in the maintenance phase.

Table 1.7 shows adverse events that were dose-dependent.

Table 1.7: Incidence (%) of Dose-Related Adverse Events from Placebo-Controlled

Migraine Trials^a

Topiramate Dosage (mg/day)

Adverse Event

Placebo (n=445)

50

(n=235)

100

(n=386)

200

(n=514)

Paresthesia 6 35 51 49

Fatigue 11 14 15 19

Nausea 8 9 13 14

Anorexia 6 9 15 14

Dizziness 10 8 9 12

Weight Decrease 1 6 9 11

Difficulty with Memory NOS 2 7 7 11

Diarrhea 4 9 11 11

Difficulty with Concentration/Attention 2 3 6 10

Somnolence 5 8 7 10

Hypoesthesia 2 6 7 8

Anxiety 3 4 5 6

Depression 4 3 4 6

Topiramate Dosage (mg/day)

Adverse Event

Placebo (n=445)

50

(n=235)

100

(n=386)

200

(n=514)

Mood Problems 2 3 6 5

Dry Mouth 2 2 3 5

Confusion 2 2 3 4

Involuntary Muscle Contractions 1 2 2 4

Abnormal Vision <1 1 2 3

Renal Calculus 0 0 1 2 ^a. The incidence rate of the adverse event in the 200 mg/day group was ≥2% than the rate in both the placebo group and the 50 mg/day group.

Other Adverse Events Observed During Migraine Clinical Trials

For the prophylactic treatment of migraine headache, topiramate has been administered to 1,367 patients in all clinical studies (includes double-blind and open-label extension). 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 following additional adverse events that were not described earlier were reported by greater than 1% of the 1,367 topiramate-treated patients in the controlled clinical trials:

Body as a Whole: pain, chest pain, allergic reaction

Central and Peripheral Nervous System Disorders: headache, vertigo, tremor, sensory disturbance, migraine aggravated

Gastrointestinal System Disorders: constipation, gastroesophageal reflux, tooth disorder Musculoskeletal System Disorders: myalgia

Platelet, Bleeding and Clotting Disorders: epistaxis

Reproductive Disorders, Female: intermenstrual bleeding

Resistance Mechanism Disorders: infection, genital moniliasis

Respiratory System Disorders: pneumonia, asthma

Skin and Appendages Disorders: rash, alopecia

Vision Disorders: abnormal accommodation, eye pain

Post-Market Adverse Drug Reactions

In addition to the adverse events reported during clinical trial testing of topiramate, the following adverse drug reactions have been reported in patients receiving marketed topiramate from worldwide use since approval. Adverse drug reactions from spontaneous reports during the worldwide post-marketing experience with topiramate are included in Table below. The adverse drug reactions are ranked by frequency, using the following convention (all calculated per patient-years of estimated exposure):

Very common ≥ 1/10

Common ≥ 1/100 and < 1/10 Uncommon ≥ 1/1,000 and < 1/100 Rare ≥ 1/10,000 and < 1/1,000 Very rare < 1/10,000

The frequencies provided below reflect reporting rates for adverse drug reactions from spontaneous reports, and do not represent more precise estimates that might be obtained in clinical or experimental studies.

Table 1.8 Post marketing reports of adverse drug reactions

1 see WARNINGS AND PRECAUTIONS, Endocrine and Metabolism

2 see WARNINGS AND PRECAUTIONS, Hyperammonemia and Encephalopathy and DRUG INTERACTIONS, Drug-Drug Interactions

3 see WARNINGS AND PRECAUTIONS, Neurologic

4 see WARNINGS AND PRECAUTIONS, Ophthalmologic

5 see WARNINGS AND PRECAUTIONS, Renal and DRUG INTERACTIONS, Drug-Drug Interactions 6 The majority of these reports have been in children

Oligohidrosis (decreased sweating) has been rarely reported with the use of topiramate. The majority of spontaneous post-marketing reports have been in children. Adverse events that may be related to potential cases of oligohidrosis include dehydration, hyperthermia, and heat intolerance. Adequate hydration prior to activities such as exercise or exposure to warm temperatures is recommended (see WARNINGS AND PRECAUTIONS, Endocrine and Metabolism).

To date, there have been rare spontaneous, post-marketing reports of metabolic acidosis. In some cases, acidosis resolved after dosage reduction or upon discontinuation of topiramate (see WARNINGS AND PRECAUTIONS, Endocrine and Metabolism).

Rare reports of encephalopathy with or without hyperammonemia have been received for patients treated with topiramate while also taking valproate or other antiepileptic medications (see WARNINGS AND PRECAUTIONS, General and DRUG INTERACTIONS, Drug-Drug Interactions).

There have been rare spontaneous postmarketing reports of suicide attempts and suicide-related adverse events, including fatalities, in patients treated with topiramate alone or in combination with other medications (see WARNINGS AND PRECAUTIONS, Neurologic, Central Nervous System Effects).

The following adverse experiences have not been listed above and data are insufficient to support an estimate of their incidence or to establish causation.

Reports of increases in liver function tests in patients taking topiramate with and without other medications have been received. Isolated reports have been received of hepatitis and hepatic failure occurring in patients taking multiple medications while being treated with topiramate.

Isolated reports have also been received for bullous skin and mucosal reactions (including Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme and pemphigus). The majority of these reports have occurred in patients taking other medications that can be associated with bullous skin and mucosal reactions.

Pregnancy Registries to Date (August 2009)

Post-marketing data from two prospective pregnancy registries have documented outcomes in approximately 648 women (445 from NA pregnancy registry and 203 from UK pregnancy registry) exposed to topiramate during the first trimester of pregnancy. Both registries reported an increase in the risk of malformations (see examples below) with exposure to topiramate monotherapy or in combination with other anti-epileptic drugs (AED’s) over and above the reference population and background rates from the literature. Further information will be added as it becomes available (see WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women).

North American Registry

Of the 265 women exposed to topiramate monotherapy, 12 pregnancies resulted in major malformations (e.g., craniofacial defects, such as cleft lip/palate, hypospadias, and anomalies involving various body systems). The rate of all malformations for topiramate was 4.5% (45.3/1000, n=265) vs. 2.2% (21.6/1000, n=3427) for the reference population and 1.8% (17.6/1000, n=340) for the background rates.

UK Registry

Of the 203 pregnancies that involved topiramate use (mono- and polytherapy), 16 pregnancies resulted in major malformations (e.g., cleft lip and palate, pyloric stenosis, anal atresia, hypospadias). The overall rate of major malformations among topiramate monotherapy exposures was 4.3% (43/1000; n= 70)

When used for the treatment of epilepsy, NU-TOPIRAMATE should be used during pregnancy only if potential benefit justifies the potential risk to the fetus.

When used for the prophylactic treatment of migraines, NU-TOPIRAMATE is not to be used in pregnancy and in women of child bearing potential who are not using an effective method of contraception (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women, Migraine and DOSAGE AND ADMINISTRATION, Dosing Considerations).

DRUG INTERACTIONS

Drug-Drug Interactions

In all of the studies below, except where noted, the maximum topiramate dose administered was 200 mg/day.

Antiepileptic Drugs

Potential interactions between topiramate and standard AEDs were measured in controlled clinical pharmacokinetic studies in patients with epilepsy. The effects of these interactions on plasma concentrations are summarized in Table 1.9.

Table 1.9: Drug Interactions with Topiramate Therapy

AED

Co-administered

AED

Concentration

Topiramate Concentration

Phenytoin

Carbamazepine (CBZ)

CBZ epoxide*

Valproic acid

Phenobarbital

Primidone

Lamotrigine

↔**

↔

↔

↓11%

↔

↔

↔

↓59%

↓40%

NS

↓14%

NS

NS

13% decrease at topiramate doses up to 400 mg/day * Is not administered but is an active metabolite of carbamazepine

↔ No effect on plasma concentration (≤ 15% change)

** Plasma concentrations increased 25% in some patients, generally those on a b.i.d. dosing regimen of phenytoin ↓ Plasma concentrations decrease in individual patients

NS Not studied

AED Antiepileptic drug

Effects of topiramate on Other Antiepileptic Drugs

The addition of topiramate to other antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital, primidone) has no effect on their steady-state plasma concentrations, except in the occasional patient, where the addition of topiramate to phenytoin may result in an increase of plasma concentrations of phenytoin.

The effect of topiramate on the steady-state pharmacokinetics of phenytoin may be related to the frequency of phenytoin dosing. A slight increase in steady-state phenytoin plasma concentrations was observed, primarily in patients receiving phenytoin in two divided doses. The slight increase may be due to the saturable nature of phenytoin pharmacokinetics and inhibition of phenytoin metabolism CYP2C19.

The addition of topiramate therapy to phenytoin should be guided by clinical outcome. In general, as evidenced in clinical trials, patients do not require dose adjustments. However, any patient on phenytoin showing clinical signs or symptoms of toxicity should have phenytoin levels monitored. The effects of these interactions on plasma concentrations are summarized in Table 1.9.

Effects of Other Antiepileptic Drugs on Topiramate

Phenytoin and Carbamazepine

Phenytoin and carbamazepine decrease the plasma concentration of topiramate. The addition or withdrawal of phenytoin and/or carbamazepine during adjunctive therapy with NU-TOPIRAMATE may require adjustment of the dose of NU-TOPIRAMATE. This should be done by titrating to clinical effect.

Valproic Acid

The addition or withdrawal of valproic acid does not produce clinically significant changes in plasma concentrations of topiramate, and therefore, does not warrant dosage adjustment of NU-TOPIRAMATE. The effects of these interactions on plasma concentrations are summarized in Table 1.9.

Rare post-marketing reports of encephalopathy with or without hyperammonemia have been received for patients treated with topiramate alone or in combination with valproic acid or other antiepileptic medications. The majority of the cases reported concomitant administration of topiramate and valproic acid. Thus, caution is advised when polytherapy is necessary (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions and WARNINGS AND PRECAUTIONS, General).

Other Drug Interactions

Digoxin: In a single-dose study, serum digoxin AUC decreased 12% due to concomitant topiramate administration (200 mg/day). Multiple-dose studies have not been performed. When NU-TOPIRAMATE is added or withdrawn in patients on digoxin therapy, careful attention should be given to the routine monitoring of serum digoxin.

CNS Depressants: Concomitant administration of topiramate and alcohol or other CNS depressant drugs has not been evaluated in clinical studies. It is recommended that NU-TOPIRAMATE not be used concomitantly with alcohol or other CNS depressant drugs.

Oral Contraceptives:

Topiramate (50-200 mg/day) in Healthy Volunteers

In a pharmacokinetic interaction study in healthy volunteers, subjects were stratified into obese versus non-obese (n=12 versus n=12) with both groups concomitantly administered a combination oral contraceptive product containing 1 mg norethindrone plus 35 µg ethinyl estradiol and topiramate (50 to 200 mg/day) given in the absence of other medications. For the ethinyl estradiol component, both obese and non-obese volunteers showed a decrease in mean AUC and C_max at 200 mg/day (-10.7% and -9.4% versus -15.2% and -11.3%, respectively) that were not statistically significant. Changes in individual subjects ranged from decreases of approximately 35% to 90% in 5 individuals to increases of approximately 35% to 60% in 3 individuals. At the 50 and 100 mg/day topiramate doses, similar changes in mean C_max and AUC were observed for non-obese volunteers. The clinical significance of these changes is unknown. For the norethindrone component, only the non-obese group showed a decrease (-11.8%). In view of the dose-dependent decreases seen in the ethinyl estradiol component in epileptic patients receiving topiramate as adjunctive therapy (below), and the fact that the recommended dose is up to 400 mg/day, there may be greater decreases seen at doses above 200 mg/day as monotherapy.

Topiramate as Adjunctive Therapy with Valproic Acid in Epileptic Patients In a pharmacokinetic interaction study, epileptic patients received topiramate as adjunctive therapy with valproic acid and a combination oral contraceptive product containing norethindrone (1 mg) plus ethinyl estradiol (35 µg). In this study, topiramate did not significantly affect the oral clearance of norethindrone. The serum levels of the estrogenic component decreased by 18%, 21% and 30% at daily doses of 200, 400 and 800 mg of topiramate, respectively. There are minimal clinical data regarding interaction of valproic acid and oral contraceptives.

In view of both of the above study findings, the efficacy of low-dose (e.g. 20 µg) oral contraceptives may be reduced in both the monotherapy and adjunctive therapy situation with topiramate. For topiramate doses up to 200 mg/day, which includes the recommended dose for migraine prophylaxis of 100 mg/day, the mean reduction in norethindrone and ethinyl estradiol exposure from topiramate treatment is not significant, although marked changes in individual patients are possible. In the treatment of epilepsy at doses greater than 200 mg/day, significant dose-dependent decreases in ethinyl estradiol exposure are expected. Patients on topiramate doses greater than 200 mg/day who are taking oral contraceptives should receive a preparation containing not less than 30 µg of estrogen. Patients taking oral contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding.

Hydrochlorothiazide (HCTZ): A parallel-arm drug-drug interaction study conducted in healthy volunteers (12 males, 11 females) evaluated the steady-state pharmacokinetics of the diuretic HCTZ (25 mg q24h) and topiramate (96 mg q12h) when administered alone and concomitantly. The results of this study indicate that mean topiramate C_max increased by 27% and mean AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of this statistically significant change is unknown. Thus, the concomitant use of topiramate and HCTZ may require a downward adjustment of the topiramate dose. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of topiramate. In addition, greater decreases in serum potassium were seen with concomitant treatment than with either drug alone, both in terms of percentage of patients with a serum potassium measurement of <3.6 mEq/L at the end of each treatment period [61% (14/23) with concomitant treatment versus 27% (3/11) with topiramate alone versus 25% (3/12) with HCTZ alone] and in mean change from baseline (approximately -0.60 mEq/L for concomitant treatment versus -0.25 mEq/L for topiramate alone versus -0.12 mEq/L for HCTZ alone). 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. See also WARNINGS AND PRECAUTIONS, Endocrine and Metabolism.

Metformin: A drug-drug interaction study conducted in 18 healthy volunteers, ages 18-37, evaluated the steady-state pharmacokinetics of metformin and topiramate in plasma when metformin (500 mg b.i.d.) was given alone and when metformin and topiramate (50, 75 and 100 mg) were given simultaneously for 6 consecutive days. The results of this study indicated that metformin mean C_max and mean AUC_0-12h increased by 18% and 25%, respectively, while mean CL/F decreased 20% when metformin was co-administered with topiramate (up-titrated to 100 mg b.i.d.). Topiramate did not affect metformin t_max. The effects of higher doses of topiramate (>100 mg b.i.d.) on metformin are unknown. The clinical significance of the effect of topiramate on metformin pharmacokinetics is unclear. Oral plasma clearance of topiramate appears to be reduced when administered with metformin. The extent of change in the clearance is unknown. The clinical significance of the effect of metformin on topiramate pharmacokinetics is unclear. When NU-TOPIRAMATE is added or withdrawn in patients on metformin therapy, careful attention should be given to the routine monitoring for adequate control of their diabetic disease state.

Glyburide: A drug-drug interaction study conducted in 28 patients with type 2 diabetes, ages 38- 68 years and BMIs 25-40 kg/m², evaluated the steady-state pharmacokinetics of glyburide and topiramate in plasma when glyburide (5 mg/day) was given alone and when glyburide and topiramate (150 mg/day) were given concomitantly for 48 consecutive days. Glyburide systemic exposure was statistically significantly reduced when combined with topiramate such that mean C_max and mean AUC₂₄ decreased by 22% and 25%, respectively, while mean CL/F increased by 21%. Systemic exposure of the active metabolites, 4-trans-hydroxyglyburide and 3-cis-hydroxyglyburide, was also statistically significantly reduced by 13% and 15%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide. The clinical significance of the effect of glyburide on topiramate pharmacokinetics is unclear. Mild to moderate declines in serum bicarbonate without metabolic acidosis were associated with the addition of topiramate (see WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Metabolic Acidosis). The effects of higher doses of topiramate (>150 mg/day) on glyburide are unknown. When topiramate is added to glyburide therapy or glyburide is added to topiramate therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.

Pioglitazone: A drug-drug interaction study conducted in healthy volunteers (26 males, 26 females) evaluated the steady-state pharmacokinetics of topiramate and the antidiabetic agent, pioglitazone, when administered alone and concomitantly. The pharmacokinetic parameters of topiramate were not affected; mean pioglitazone AUC decreased by 15%, and mean C_max increased non-significantly by 10%, but with individual subjects showing large increases and 3 of the 4 highest values recorded by males. In addition, each of the active hydroxy-metabolite and the active keto-metabolite showed mean decreases in C_max and AUC (approximately 15% for the hydroxy-metabolite and 60% for the keto-metabolite). The clinical significance of these findings is not known. When NU-TOPIRAMATE is added to pioglitazone therapy or pioglitazone is added to NU-TOPIRAMATE therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.

Lithium:

Healthy Volunteers

A drug-drug interaction study conducted in twelve healthy volunteers, ages 20-40 years, evaluated the steady-state pharmacokinetics of lithium in plasma when lithium (300 mg q8h) was administered for 14 days and topiramate (up-titrated to 100 mg q12h) was given concomitantly for the last 6 days. Based on the data analysis of twelve subjects, systemic exposure of lithium was statistically significantly reduced in the presence of topiramate such that C_max and AUC_0-8h decreased by 20% and 18%, respectively, while mean CL/F and CL_R increased by 36% and 12%, respectively. One subject did not have measurable trough lithium concentrations on Day 14, potentially indicating missed dose administration. By excluding this subject from the analyses, systemic exposure of lithium was slightly reduced in the presence of topiramate (12% for C_max, 10% for AUC_0-8) while mean CL/F and CL_R increased by 11% and 16%, respectively. The clinical significance of the effect of topiramate on lithium pharmacokinetics is unclear. The effects of higher doses of topiramate (>200 mg/day) on the pharmacokinetics of lithium are unknown.

Patients with Bipolar Disorder

A drug-drug interaction study conducted in 31 patients with various types of bipolar disorder, ages 20-60 years, evaluated the steady-state pharmacokinetics of lithium and topiramate when administered concomitantly. Subjects were randomized to receive either low doses of topiramate of up to 200 mg/day or high doses of topiramate of up to 600 mg/day. Pharmacokinetic profiles for lithium were obtained following 1 week and 3 weeks of continuous lithium dosing. The pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of up to 200 mg/day, and were unaffected by short-term treatment with topiramate (1 week) at doses up to 600 mg/day. Following treatment with topiramate at doses of up to 600 mg/day for 3 weeks, there was an observed statistically significant increase in systemic exposure of lithium (about 27% for both C_max and AUC). Topiramate exposure for both the low and high dose groups was similar following 1 week and 3 weeks of continuous treatment in the presence of lithium. The effects of higher doses of topiramate (>600 mg/day) on lithium have not been studied and are unknown. Lithium levels should be monitored when co-administered with topiramate and dose adjustments for lithium should be based on both lithium levels and clinical outcome for the patient.

Risperidone:

Healthy Volunteers

A drug-drug interaction study was conducted in 12 healthy volunteers (6 males, 6 females), ages 28-40 years, with single-dose administration of risperidone (2 mg) and multiple doses of topiramate (titrated up to 200 mg/day). In the presence of topiramate, systemic exposure of the total active moiety (risperidone + 9-hydroxyrisperidone) was reduced such that mean AUC_0-∞ was 11% lower and mean C_rnax was statistically significantly (18%) lower. In the presence of topiramate, systemic exposure of risperidone was statistically significantly reduced such that mean C_max and AUC_0-∞ were 29% and 23% lower, respectively. The pharmacokinetics of 9-hydroxyrisperidone were unaffected. The effects of a single dose (2 mg/day) of risperidone on the pharmacokinetics of multiple doses of topiramate have not been studied. Therefore, patients receiving risperidone in combination with topiramate should be closely monitored for clinical response to risperidone.

Patients with Bipolar Disorder

A drug-drug interaction study conducted in 52 patients with various types of bipolar disorder (24 males, 28 females), ages 19-56 years, evaluated the steady-state pharmacokinetics of risperidone and topiramate when administered concomitantly. Eligible subjects were stabilized on a risperidone dose of 1-6 mg/day for 2 to 3 weeks. Topiramate was then titrated up to escalating doses of 100, 250 and 400 mg/day along with risperidone for up to 6 weeks. Risperidone was then tapered and discontinued over 4 weeks while maintaining topiramate (up to 400 mg/day). There was a statistically significant reduction in risperidone systemic exposure (16% and 33% for AUC₁₂ and 13% and 34% for C_max at the 250 and 400 mg/day doses, respectively). Minimal alterations were observed in the pharmacokinetics of the total active moiety (risperidone plus 9-hydroxyrisperidone) and 9-hydroxyrisperidone. Topiramate systemic exposure was slightly reduced (12.5% for mean C_max and 11% for mean AUC₁₂) in the presence of risperidone, which achieved statistical significance. There were no clinically significant changes in the systemic exposure of the risperidone total active moiety or of topiramate. The effects of higher doses of topiramate (>400 mg/day) are unknown. Patients with bipolar disorder receiving risperidone in combination with topiramate should be closely monitored for clinical response to risperidone.

Haloperidol: The pharmacokinetics of a single dose of the antipsychotic haloperidol (5 mg) were not affected following multiple dosing of topiramate (200 mg/day) in 13 healthy adults (6 males, 7 females).

Venlafaxine: A drug-drug interaction study was conducted in 26 healthy volunteers (16 males/10 females, ages 18-40 years, BMI ranging from 25 to 30 kg/m²) to evaluate the interaction between venlafaxine and topiramate. Subjects received single 150-mg doses of extended release venlafaxine and multiple doses of topiramate titrated up to 150 mg/day. The single-dose pharmacokinetics of venlafaxine were unaffected by treatment with topiramate. While the C_max, AUC_∞ and CL/F of the active metabolite, O-desmethylvenlafaxine were unaffected, the renal clearance of the active metabolite was increased by 53% during treatment with topiramate. These observed increases in urinary excretion of O-desmethylvenlafaxine during treatment with topiramate did not affect systemic exposure. The steady-state pharmacokinetics of topiramate were unaffected by repeated daily-dose administration of venlafaxine for 5 days. The effects of higher doses of topiramate (>150 mg/day) on the pharmacokinetics of venlafaxine and higher doses of venlafaxine up to the maximum dose of 375 mg/day on the pharmacokinetics of topiramate are unknown.

Amitriptyline: There was a 12% increase in both AUC and C_max for the tricyclic antidepressant amitriptyline (25 mg/day) in 18 normal subjects (9 males, 9 females) receiving 200 mg/day of topiramate. Individual subjects experienced large changes in amitriptyline concentration, either up or down, in the presence of topiramate; any adjustments in amitriptyline dose should be made according to patients’ clinical response and not on the basis of plasma levels.

Pizotifen: Multiple dosing of topiramate (200 mg/day) in 19 healthy volunteers (12 males, 7 females) had little effect on the pharmacokinetics of the antihistamine pizotifen following daily 1.5 mg doses. There was a mean 12% and 15% decrease respectively in topiramate C_max and AUC in the volunteers (12 males and 7 females) receiving 200 mg/day topiramate and 1.5 mg/day pizotifen. This is not considered to be clinically significant.

Dihydroergotamine: Multiple dosing of topiramate (200 mg/day) in 24 healthy volunteers (12 males, 12 females) had little effect on the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine and a 1 mg subcutaneous dose of dihydroergotamine similarly had little effect on the pharmacokinetics of a 200 mg/day dose of topiramate.

Sumatriptan: Multiple dosing of topiramate (200 mg/day) in 24 healthy volunteers (14 males, 10 females) had little effect on the pharmacokinetics of single doses of the anti-migraine medication sumatriptan, either orally (100 mg) or subcutaneously (6 mg).

Propranolol: Multiple dosing of topiramate (100, then 200, mg/day) in 34 healthy volunteers (17 males, 17 females) had little effect on the pharmacokinetics of propranolol following daily 160 mg doses. There was a 17% increase in C_max of the metabolite 4-OH propranolol at 100 mg/day topiramate. Propranolol doses of 80, then 160, mg/day in 39 volunteers (27 males, 12 females) had a dose-dependent effect on exposure to topiramate (200 mg/day), reaching approximately a 9% and 16% increase for each of C_max and a 9% and 17% increase for AUC at 80 and 160 mg/day propranolol respectively.

Diltiazem: A drug-drug interaction study was conducted in 28 healthy volunteers (13 males/15 females, ages 18-45 years and BMIs 25-35 kg/m²) to evaluate the interaction between topiramate and diltiazem. Eligible subjects received single 240-mg doses of extended-release diltiazem and multiple doses of topiramate titrated to 150 mg/day. Systemic exposure of diltiazem was statistically significantly reduced during topiramate treatment, where C_max and AUC_∞ were 10% and 25% lower, respectively, following single-dose administration. There was an increase in diltiazem CL/F by approximately 30%. Systemic exposure of the active metabolite, desacetyl diltiazem, was statistically significantly reduced during treatment with topiramate where C_max and AUC₃₆ were 27% and 18% lower, respectively. The single-dose pharmacokinetics of the active metabolite, N-demethyl-diltiazem, were unaffected by topiramate. Following repeated daily-dose administration of diltiazem for 5 days, steady-state systemic exposure of topiramate was greater during treatment with diltiazem, where C_max and AUC₁₂ were approximately 17% and 20% higher, respectively, and CL/F was 16% lower. The effects of higher doses of topiramate (>150 mg/day) on the pharmacokinetics of diltiazem or its metabolites have not been studied. Overall, the clinical significance of these observations is unclear.

Flunarizine:

Patients with Migraine - Effects of topiramate on the pharmacokinetics of flunarizine The dose of flunarizine used in this study is one-half of the recommended daily dose. A drug-drug interaction study was conducted in forty seven patients with a history migraine (13 males, 34 females), ages 20-53 years, evaluated the steady-state pharmacokinetics of flunarizine when topiramate was administered concomitantly. Subjects were taking flunarizine for at least 4 weeks before study start. One subgroup was administered only flunarizine (5 mg q24h) for 81 days, and, a second subgroup received flunarizine (5 mg q24h) for 81 days and topiramate (up-titrated to 50 mg/day and then to 100 mg/day) from Day 4 to a.m. dose on Day 82 concomitantly.

Mean C_max of flunarizine decreased by 22% with concomitant administration of topiramate at 50 mg/day. During concomitant treatment with topiramate at 100 mg/day, Cmax estimates returned to those observed during treatment with flunarizine alone. Mean AUC_0-24 for flunarizine was similar with concomitant administration of topiramate at 50 mg/day and 16% higher with topiramate at 100mg/day compared to treatment with flunarizine alone. Mean CL/F of flunarizine was unaffected by treatment with topiramate. Systemic exposure of topiramate (C_max and AUC_0-12) doubled with increasing topiramate dose from 50 mg/day to 100 mg/day. Mean CL/F was similar during both dose periods and was consistent with previously observed estimates in healthy volunteers. These alterations are unlikely to be of clinical significance. However, there are no data on the effects of higher doses of topiramate on flunarizine levels. There is also no information on the interaction of topiramate and flunarizine in patients with history of seizure or epilepsy.

Agents Predisposing to Nephrolithiasis: Topiramate, when used concomitantly with other agents predisposing to nephrolithiasis, such as carbonic anhydrase inhibitors, e.g. acetazolamide, may increase the risk of nephrolithiasis. While using NU-TOPIRAMATE, agents like these should be avoided since they may create a physiological environment that increases the risk of renal stone formation (see WARNINGS AND PRECAUTIONS, Renal).

Drug-Food Interactions

There was no clinically significant effect of food on the bioavailability of topiramate.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

There are no known interactions of NU-TOPIRAMATE with commonly used laboratory tests.

DOSAGE AND ADMINISTRATION

General

In patients with or without a history of seizures or epilepsy, topiramate should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency (see WARNINGS AND PRECAUTIONS, General).

In clinical trials in adult patients with epilepsy, dosages were decreased by 50-100 mg/day at weekly intervals. In clinical trials of children, topiramate was gradually withdrawn over a 2-8 week period.

In clinical trials in adult patients receiving topiramate for migraine prophylaxis dosages were decreased by 25-50 mg/day at weekly intervals (see WARNINGS AND PRECAUTIONS, General).

In situations where rapid withdrawal of topiramate is medically required, appropriate monitoring is recommended (see WARNINGS AND PRECAUTIONS, General).

Dosing Considerations

• Patients with renal impairment
• Patients undergoing hemodialysis
• Patients with hepatic disease
• Prophylactic treatment of migraine: In pregnancy, the occurrence of seizures presents a significant risk for the mother and child. Prescribing NU-TOPIRAMATE to prevent seizures therefore outweighs the risk of malformations to the fetus. However, taking NU-TOPIRAMATE to prevent migraine attacks does not outweigh this risk. Consequently, NU-TOPIRAMATE is contraindicated in pregnancy and in women of child bearing potential who are not using an effective method of contraception (see CONTRAINDICATIONS).

Recommended Dose and Dosage Adjustment

NU-TOPIRAMATE (topiramate) tablets can be taken without regard to meals.

EPILEPSY

Monotherapy

Adults and Children (Age 6 years and older)

The recommended initial target dose for topiramate monotherapy in adults and children 6 years of age and older is 100 mg/day and the maximum recommended dose is 400 mg/day, administered in two divided doses, as needed and tolerated.

The recommended titration rate for topiramate monotherapy to 100 mg/day is:

If doses above 100 mg/day are required, the dose may be increased at weekly intervals in increments of 50 mg/day to a maximum of 400 mg/day. Dose and titration rate should be guided by clinical outcome. Some patients may benefit from a slower titration schedule. Daily doses above 400 mg have not been adequately studied. Only 14 pediatric patients have received 500 mg/day topiramate in controlled clinical trials (see ADVERSE REACTIONS, EPILEPSY, Clinical Trial Adverse Drug Reactions, Table 1.2).

Adjunctive Therapy

Adults (Age 17 years and older)

It is recommended that NU-TOPIRAMATE as adjunctive therapy be initiated at 50 mg/day, followed by titration as needed and tolerated to an effective dose. At weekly intervals, the dose may be increased by 50 mg/day and taken in two divided doses. Some patients may benefit from lower initial doses, e.g. 25 mg and/or a slower titration schedule. Some patients may achieve efficacy with once-a-day dosing.

The recommended total daily maintenance dose is 200-400 mg/day in two divided doses. Doses above 400 mg/day have not been shown to improve responses and have been associated with a greater incidence of adverse events. The maximum recommended dose is 800 mg/day. Daily doses above 1,600 mg have not been studied.

Children (Ages 2-16 years)

It is recommended that NU-TOPIRAMATE as adjunctive therapy be initiated at 25 mg (or less, based on a range of 1 to 3 mg/kg/day) nightly for the first week followed by titration as needed and tolerated to an effective dose. The dosage should then be increased at 1- or 2-week intervals by increments of 1 to 3 mg/kg/day (administered in two divided doses). Some patients may benefit from lower initial doses and/or a slower titration schedule.

The recommended total daily maintenance dose is approximately 5 to 9 mg/kg/day in two divided doses.

Drug Discontinuation

In patients with a history of seizures or epilepsy, NU-TOPIRAMATE should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency. In clinical trials, daily dosages were decreased in weekly intervals by 50-100 mg in adults with epilepsy.

In clinical trials of children, topiramate was gradually withdrawn over a 2-8 week period.

In situations where rapid withdrawal of NU-TOPIRAMATE is medically required, appropriate monitoring is recommended.

MIGRAINE

Adults

The usual total daily dose of NU-TOPIRAMATE as treatment for prophylaxis of migraine headache is 100 mg/day administered in two divided doses. Dose and titration rate should be guided by clinical outcome. If required, longer intervals between dose adjustments can be used. No extra benefit has been demonstrated from the administration of doses higher than 100 mg/day and the incidence of some adverse events increases with increasing dose (see ADVERSE REACTIONS, MIGRAINE, Table 1.7).

The recommended titration rate for topiramate for migraine prophylaxis to 100 mg/day is:

Drug Discontinuation

In patients without a history of seizures or epilepsy, NU-TOPIRAMATE should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency. In clinical trials, daily dosages were decreased in weekly intervals by 25-50 mg in adults receiving topiramate at doses up to 100 mg/day for migraine prophylaxis.

In situations where rapid withdrawal of NU-TOPIRAMATE is medically required, appropriate monitoring is recommended.

Pediatrics

The safety and efficacy of topiramate in the management or prevention of migraine in pediatrics have not been established.

Patients with Renal Impairment

In renally impaired subjects (creatinine clearance less than 70 mL/min/1.73 m²), one-half of the usual adult dose is recommended. Such patients will require a longer time to reach steady-state at each dose.

Patients Undergoing Hemodialysis

Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than a normal individual. Accordingly, a prolonged period of dialysis may cause topiramate concentration to fall below that required to maintain an antiseizure effect. To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of NU-TOPIRAMATE may be required. The actual adjustment should take into account 1) the duration of dialysis, 2) the clearance rate of the dialysis system being used, and 3) the effective renal clearance of topiramate in the patient being dialyzed.

Patients with Hepatic Disease

In hepatically impaired patients, topiramate plasma concentrations are increased approximately 30%. This moderate increase is not considered to warrant adjustment of the NU-TOPIRAMATE dosing regimen. Initiate topiramate therapy with the same dose and regimen as for patients with normal hepatic function. The dose titration in these patients should be guided by clinical outcome, i.e. seizure control, and avoidance of adverse effects. Such patients will require a longer time to reach steady-state at each dose.

Geriatrics

See WARNINGS AND PRECAUTIONS section.

Missed Dose

The missed dose should be taken as soon as possible. If it is almost time for the next dose, the missed dose should not be taken. Instead, the next scheduled dose should be taken. Doses should not be doubled.

Administration

Tablets should not be broken.

OVERDOSAGE

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Overdoses of topiramate have been reported. Signs and symptoms included convulsions, drowsiness, speech disturbances, blurred vision, diplopia, mentation impaired, lethargy, abnormal co-ordination, stupor, hypotension, abdominal pain, agitation, dizziness and depression. The clinical consequences were not severe in most cases but deaths have been reported after polydrug overdoses involving topiramate.

Topiramate overdose can result in severe metabolic acidosis (see WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Metabolic Acidosis).

The highest topiramate overdose reported was calculated to be between 96 and 110 g and resulted in coma lasting 20 to 24 hours followed by full recovery after 3 to 4 days.

In acute topiramate overdose, if the ingestion is recent, the stomach should be emptied immediately by lavage or by induction of emesis. Activated charcoal has been shown to adsorb topiramate in vitro. Treatment should be appropriately supportive. Hemodialysis has been shown to be an effective means of removing topiramate from the body. The patient should be well hydrated.

ACTION AND CLINICAL PHARMACOLOGY

Pharmacodynamics

NU-TOPIRAMATE (topiramate) is a novel agent classified as a sulfamate substituted monosaccharide. Three pharmacological properties of topiramate are believed to contribute to its anticonvulsant activity. First, topiramate reduces the frequency at which action potentials are generated when neurons are subjected to a sustained depolarization indicative of a state-dependent blockade of voltage-sensitive sodium channels. Second, topiramate markedly enhances the activity of GABA at some types of GABA receptors. Because the antiepileptic profile of topiramate differs markedly from that of the benzodiazepines, it may modulate a benzodiazepine-insensitive subtype of GABA_A receptor. Third, topiramate antagonizes the ability of kainate to activate the kainate/AMPA subtype of excitatory amino acid (glutamate) receptors but has no apparent effect on the activity of N-methyl-D-aspartate (NMDA) at the NMDA receptor subtype.

In addition, topiramate inhibits some isoenzymes of carbonic anhydrase. This pharmacologic effect is much weaker than that of acetazolamide, a known carbonic anhydrase inhibitor, and is not thought to be a major component of topiramate’s antiepileptic activity.

Pharmacokinetics

Topiramate exhibits low intersubject variability in plasma concentrations and therefore has predictable pharmacokinetics. The pharmacokinetics of topiramate are linear with plasma clearance remaining constant and area under the plasma concentration curve increasing in a dose-proportional manner over a 100 to 400 mg single oral dose range in healthy subjects. Patients with normal renal function may take 4 to 8 days to reach steady-state plasma concentrations. The mean C_max following multiple twice-a-day oral doses of 100 mg to healthy subjects was 6.76 µg/mL. The mean plasma elimination half-lives from multiple 50 mg and 100 mg q12h doses of topiramate were approximately 21 hours. The elimination half-life did not significantly change when switching from single dose to multiple dose.

In well-controlled add-on trials, no correlation has been demonstrated between trough plasma concentrations and its clinical efficacy. It is not necessary to monitor topiramate plasma concentrations to optimize therapy with NU-TOPIRAMATE.

No evidence of tolerance requiring increased dosage has been demonstrated in patients during 5 years of use.

Concomitant multiple-dose administration of topiramate, 100 to 400 mg q12h, with phenytoin or carbamazepine shows dose-proportional increases in plasma concentrations of topiramate.

Absorption: Topiramate is rapidly and well absorbed. Following oral administration of 100 mg topiramate to healthy subjects, a mean peak plasma concentration (C_max) of 1.5 µg/mL was achieved within 2 to 3 hours (T_max). The mean extent of absorption from a 100 mg oral dose of ¹⁴C-topiramate was at least 81% based on the recovery of radioactivity from the urine.

There was no clinically significant effect of food on the bioavailability of topiramate.

Distribution: Approximately 13% to 17% of topiramate is bound to plasma proteins. A low capacity binding site for topiramate in/on erythrocytes that is saturable above plasma concentrations of 4 µg/mL has been observed.

The volume of distribution varied inversely with the dose. The mean apparent volume of distribution was 0.80 to 0.55 L/kg for a single-dose range of 100 to 1200 mg.

Metabolism: Topiramate is not extensively metabolized (≈20%) in healthy volunteers. It is metabolized up to 50% in patients receiving concomitant antiepileptic therapy with known inducers of drug-metabolizing enzymes. Six metabolites formed through hydroxylation, hydrolysis and glucuronidation, have been isolated, characterized and identified from plasma, urine and feces of humans. Each metabolite represents less than 3% of the total radioactivity excreted following administration of ¹⁴C-topiramate.

Two metabolites which retained most of the structure of topiramate were tested and found to have little or no pharmacological activity.

Excretion: In humans, the major route of elimination of unchanged topiramate and its metabolites is via the kidney (at least 81% of the dose). Approximately 66% of a dose of ¹⁴C-topiramate was excreted unchanged in the urine within 4 days. The mean renal clearance for 50 mg and 100 mg of topiramate, following ql2h dosing, was approximately 18 mL/min and 17 mL/min, respectively. Evidence exists for renal tubular reabsorption of topiramate. This is supported by studies in rats where topiramate was co-administered with probenecid, and a significant increase in renal clearance of topiramate was observed. This interaction has not been evaluated in humans. Overall, plasma clearance (CL/F) is approximately 20 to 30 mL/min in humans following oral administration.

Special Populations and Conditions

Pediatrics: Pharmacokinetics of topiramate were evaluated in patients aged 4 to 17 years receiving one or two other antiepileptic drugs. Pharmacokinetic profiles were obtained after one week at doses of 1, 3, and 9 mg/kg/day. As in adults, topiramate pharmacokinetics were linear with clearance independent of dose and steady-state plasma concentrations increasing in proportion to dose. Compared with adult epileptic patients, mean topiramate clearance is approximately 50% higher in pediatric patients. Steady-state plasma topiramate concentrations for the same mg/kg dose are expected to be approximately 33% lower in children compared to adults. As with adults, hepatic enzyme-inducing antiepileptic drugs (AEDs) decrease the plasma concentration of topiramate.

Geriatrics: Plasma clearance of topiramate is unchanged in elderly subjects in the absence of underlying renal disease.

Race, Gender and Age: Although direct comparison studies of pharmacokinetics have not been conducted, analysis of plasma concentration data from clinical efficacy trials has shown that race, gender and age appear to have no effect on the plasma clearance of topiramate. In addition, based on pooled analyses, race and gender appear to have no effect on the efficacy of topiramate.

Hepatic Insufficiency: The plasma clearance of topiramate is decreased in patients with moderate to severe hepatic impairment.

Renal Insufficiency: The plasma and renal clearance of topiramate are decreased in patients with impaired renal function (CL_CR <70 mL/min/l.73 m²), and the plasma clearance is decreased in patients with end-stage renal disease. As a result, higher steady-state topiramate plasma concentrations are expected for a given dose in renally impaired patients as compared to those with normal renal function.

Hemodialysis: Topiramate is effectively removed from plasma by hemodialysis (see DOSAGE AND ADMINISTRATION).

STORAGE AND STABILITY

NU-TOPIRAMATE tablets should be stored in tightly closed containers at controlled room temperature (15 to 30°C). Protect from moisture.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Availability of Dosage Forms

NU-TOPIRAMATE 25 mg Tablets: White to off-white, round, film-coated tablets. Engraved “TP” over “25” on one side. Available in bottles of 100.

NU-TOPIRAMATE 50 mg Tablets: Light yellow, round, film-coated tablets. Engraved “TP” over “50” on one side. Available in bottles of 100.

NU-TOPIRAMATE 100 mg Tablets: Mustard yellow, round, film-coated tablets. Engraved “TP” over “100” on one side. Available in bottles of 100.

NU-TOPIRAMATE 200 mg Tablets: Reddish-brown, round, film-coated tablets. Engraved “TP” over “200” on one side. Available in bottles of 100.

Composition

NU-TOPIRAMATE (topiramate) tablets contain the following inactive ingredients: methylcellulose, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, titanium dioxide, purified water, yellow iron oxide (50 mg and 100 mg strengths) and red iron oxide (200 mg strength).

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: topiramate

Chemical Name: 2,3:4,5-bis-O-(1 -methylethylidene)-β-D-fructopyranose sulfamate

Molecular formula and molecular weight: C₁₂H₂₁NO₈S, 339.36

Structural Formula:

O

O

O

H₃C

H₃C

O

O

CH₃

CH₃

O

S NH₂

O O

Physicochemical properties: Topiramate is a white crystalline powder having a bitter taste.

Topiramate is most soluble in alkaline solutions containing sodium hydroxide or sodium phosphate with a pH of 9 to 10. It is freely soluble in acetone, chloroform, dimethylsulfoxide and ethanol. The solubility in water is 9.8 mg/mL. Its saturated solution has a pH of 6.3.

CLINICAL TRIALS

Comparative Bioavailability Studies

A comparative bioavailability study was performed on 17 healthy male human volunteers under fasting conditions. The rate and extent of absorption of topiramate was measured and compared following a single oral dose of NU-TOPIRAMATE (topiramate) or TOPAMAX® tablets. The results from measured data are summarized in Table 2.

Table 2: Summary Table of the Comparative Bioavailability Data

EPILEPSY

Monotherapy Controlled Trials

The effectiveness of topiramate as monotherapy in adults and children 6 years of age and older with newly diagnosed epilepsy was established in a multicentre, randomized, double-blind, parallel-group trial that compared the safety and efficacy of 2 doses of topiramate as monotherapy for the treatment of newly diagnosed or recurrent epilepsy.

The trial was conducted in 487 patients (6 to 83 years of age) who had a new diagnosis of epilepsy (partial onset or generalized) or a diagnosis of recurrent epilepsy while not taking antiepileptic drugs (AEDs). Patients who had either 1 or 2 well-documented seizures during the 3-month retrospective baseline phase entered the study and received topiramate 25 mg/day for 7 days in an open-label fashion. Any AED therapy used for temporary or emergency purposes was discontinued prior to randomization. Following that phase, patients were randomized to receive topiramate 50 mg/day or topiramate 400 mg/day. Patients remained in the double-blind phase until they experienced a first partial onset or generalized tonic-clonic seizure, until termination of the double-blind phase 6 months after randomization of the last subject, or until withdrawal for protocol-specified reasons. The primary efficacy assessment was based on the comparison between topiramate dose groups with respect to time to first partial onset or generalized tonic-clonic seizure during the double-blind phase. Comparison of the Kaplan-Meier survival curves of time to first seizure favoured topiramate 400 mg/day over topiramate 50 mg/day (p=0.0002, log rank test). The separation between the groups in favour of the higher dose group occurred early in the titration phase and was statistically significant as early as 2 weeks post-randomization (p=0.046), when, by following the weekly titration schedule, the subjects in the higher dose group had achieved a maximum topiramate dose of 100 mg/day. The higher dose group was also superior to the lower dose group with respect to the proportion of subjects who remained seizure-free, based on the Kaplan-Meier estimates, for a minimum of 6 months of therapy (82.9% vs. 71.4%; p=0.005), and for a minimum of 1 year of therapy (75.7% vs. 58.8%; p=0.001). The ratio of hazard rates for time to first seizure was 0.516 (95% confidence interval, 0.364 to 0.733). The treatment effects with respect to time to first seizure were consistent across various subject subgroups defined by age, sex, geographic region, baseline body weight, baseline seizure type, time since diagnosis, and baseline AED use.

Adjunctive Therapy Controlled Trials in Adults with Partial Onset Seizures

The effectiveness of topiramate as adjunctive therapy in adults with refractory partial onset seizures, with or without secondarily generalized seizures, was established in six multicentre, outpatient, randomized, double-blind, placebo-controlled trials. Patients in all six studies were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate therapy (target doses of 200, 400, 600, 800, or 1,000 mg/day) or placebo.

In all six add-on trials, the primary efficacy measurement was reduction in seizure rate from baseline during the entire double-blind phase; responder rate (fraction of patients with at least a 50% reduction) was also measured. The median percent reductions in seizure rates and the responder rates by treatment group for each study are shown in Table 3.1.

Table 3.1: Median Percent Seizure Rate Reduction and Percent Responders in Six

Double-Blind, Placebo-Controlled, Add-On Trials in Adults with Partial Onset Seizures

Target Topiramate Dosage (mg/day)

Protocol Efficacy Results Placebo 200 400 600 800 1,000

YD n 45 45 45 46 -- -- Median % Reduction 13.1 29.6^a 47.8^c 44.7^d -- -- % Responders 18 27 47^b 46^b -- --

YE n 47 -- -- 48 48 47 Median % Reduction 1.2 -- -- 40.7^d 41.0^d 37.5^d % Responders 9 -- -- 44^d 40^c 38^c Y1 n 24 -- 23 -- -- -- Median % Reduction 1.1 -- 40.7^a -- -- -- % Responders 8 -- 35^b -- -- -- Y2 n 30 -- -- 30 -- -- Median % Reduction -12.2 -- -- 46.4^c -- -- % Responders 10 -- -- 47^c -- -- Y3 n 28 -- -- -- 28 -- Median % Reduction -17.8 -- -- -- 35.8^c -- % Responders 0 -- -- -- 43^c --

Target Topiramate Dosage (mg/day)

Protocol Efficacy Results Placebo 200 400 600 800 1,000

YF/YG n 42 -- -- -- -- 167 Median % Reduction 1.2 -- -- -- -- 50.8^d % Responders 19 -- -- -- -- 52^d

Comparisons with placebo: ^ap > 0.05; ^bp < 0.05; ^cp ≤ 0.01; ^dp ≤ 0.001

Across the six efficacy trials in adults, 232 of the 527 topiramate patients (44%) responded to treatment with at least a 50% seizure reduction during the double-blind phase; by comparison, only 25 of the 216 placebo-treated patients (12%) showed the same level of treatment response. When the treatment response was defined more rigorously as a 75% or greater decrease from baseline in seizure rate during double-blind treatment, 111 of the 527 topiramate patients (21%) in the 200 to 1,000 mg/day groups, but only 8 of the 216 placebo patients (4%), demonstrated this level of efficacy. In addition, 24 (5%) of the patients treated with topiramate became seizure-free, compared with 0% in the placebo group (p ≤ 0.01). At target dosages of 400 mg/day and higher, the percent of treatment responders was statistically greater for patients treated with topiramate than placebo-treated patients.

Pooled analyses of secondarily generalized seizure rates for all patients who had this seizure type during the studies show statistically significant percent reductions in the topiramate groups when compared with placebo. The median percent reduction in the rate of generalized seizures was 57% for patients treated with topiramate compared with -4% for placebo-treated patients. Among patients treated with topiramate, 109 (55%) of 198 had at least a 50% reduction in generalized seizure rate compared with 24 (27%) of 88 placebo-treated patients.

The dose titration in the original clinical trials was 100 mg/day the first week, 100 mg b.i.d. the second week, and 200 mg b.i.d. the third week. In a 12-week, double-blind trial, this titration rate was compared to a less rapid rate beginning at 50 mg/day. There were significantly fewer adverse experiences leading to discontinuation and/or dosage adjustment in the group titrated at the less rapid rate. Seizure rate reductions were comparable between the groups at all time points measured.

Adjunctive Therapy Controlled Trials in Children with Partial Onset Seizures

The effectiveness of topiramate as an adjunctive treatment for children with partial onset seizures was established in a multicentre, 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 or placebo. Patients were stabilized on optimal dosages of their concomitant AEDs during an 8-week baseline phase. Included were patients who experienced at least six partial onset seizures, with or without secondarily generalized seizures, during the baseline phase. Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 25 or 50 mg/day; the dose was then increased by 25 to 150 mg/day increments every other week until the assigned dosage of 125, 175, 225, or 400 mg/day, based on patient’s weight to approximate a dosage of 6 mg/kg per day, was reached. After titration, patients entered an 8-week stabilization period.

The reduction in seizure rate from baseline during the entire double-blind phase was measured. The median percent reduction in seizure rate and the responder rate (fraction of patients with at least a 50% reduction) were also measured and the key results are shown in Table 3.2.

Table 3.2: Median Percent Seizure Rate Reduction and Percent Responders in a

Double-Blind, Placebo-Controlled, Add-On Trial in Pediatric Patients with Partial Onset Seizures

Target Topiramate Dosage

Protocol Efficacy Results Placebo 6 mg/kg/day* p value

YP N 45 41 Median % Reduction 10.5 33.1 0.034 % Responders 20 39 0.08

* For Protocol YP, protocol-specified target dosages (<9.3 mg/kg/day) were assigned based on subject’s weight to approximate a dosage of 6 mg/kg/day; these dosages corresponded to mg/day dosages of 125, 175, 225, and 400 mg/day.

Forty patients received topiramate during the double-blind study and continued topiramate treatment in the open-label study. During the open-label study, dose escalation was permitted if required. The percent responders increased to 53% at a median average dose of 7.5 mg/kg/day.

Additional Adjunctive Therapy Clinical Data

Some data demonstrating efficacy of topiramate as adjunctive therapy in adults and a small number of pediatric patients for primary generalized tonic-clonic seizures and seizures associated with Lennox-Gastaut syndrome are available from randomized, double-blind, placebo-controlled trials.

In the epilepsy clinical trials in approximately 1300 patients, daily dosages were decreased when required in weekly intervals by 50 to 100 mg in adults and over a 2 to 8 week period in children; transition was permitted to a new antiepileptic regimen when clinically indicated.

MIGRAINE

Controlled Trials in the Prophylactic Treatment of Migraine

The results of 2 multicentre, randomized, double-blind, placebo-controlled, parallel-group clinical trials established the effectiveness of topiramate in the prophylactic treatment of migraine headache. The design of both trials was identical, enrolling patients with a history of migraine, with or without aura, for at least 6 months, according to the International Headache Society diagnostic criteria. Patients with a history of cluster headaches or basilar, ophthalmoplegic, hemiplegic, or transformed migraine headaches were excluded from the trials. Patients were required to have completed a washout of any prior migraine preventive medications before starting the baseline phase.

Patients who experienced 3 to 12 migraine periods (each migraine period was defined as any occurrence of migraine headache that started and ended, or recurred within a 24-hour interval) over the 4 weeks in the baseline phase were equally randomized to either topiramate 50 mg/day, 100 mg/day, 200 mg/day, or placebo and treated for a total of 26 weeks (8-week titration period and 18-week maintenance period). Treatment was initiated at 25 mg/day for one week, and then the daily dosage was increased by 25-mg increments each week until reaching the assigned target dose or maximum tolerated dose (administered twice daily). Up to 2 dose adjustments were allowed after the second week of treatment during the double-blind phase if unacceptable tolerability problems occurred. When needed, rescue medications were allowed for the acute treatment of headache or migraine-associated symptoms.

Effectiveness of treatment was assessed through the reduction in migraine headache frequency, as measured by the change in 4-week migraine period rate from the baseline phase to double-blind treatment in each topiramate treatment group compared to placebo.

In the first study, a total of 469 patients (416 females, 53 males), ranging in age from 13 to 70 years, were randomized and provided efficacy data. Two hundred and sixty-five patients completed the entire 26-week double-blind phase. The median average daily dosages were 47.8 mg/day, 88.3 mg/day, and 132.1 mg/day in the target dose groups of topiramate 50, 100, and 200 mg/day, respectively.

The mean migraine headache frequency rate at baseline was approximately 5.5 migraine headaches/28 days and was similar across treatment groups. The change in the mean 4-week migraine headache frequency from baseline to the double-blind phase was -1.3, -2.1, and -2.2 in the topiramate 50, 100, and 200 mg/day groups, respectively, versus -0.8 in the placebo group (see Figure 3.1). The differences between the topiramate 100 and 200 mg/day groups versus placebo were statistically significant (p<0.001 for both comparisons; confidence intervals vs. placebo: topiramate 100 mg/day [-1.93, -0.55], and topiramate 200 mg/day [-2.04, -0.62]). The changes in migraine frequency represent a median percent reduction of 31%, 53%, and 55% in the topiramate 50, 100, and 200 mg/day groups, respectively, versus 21% in the placebo group.

In the second study, a total of 468 patients (406 females, 62 males), ranging in age from 12 to 65 years, were randomized and provided efficacy data. Two hundred and fifty-five patients completed the entire 26-week double-blind phase. The median average daily dosages were 46.5 mg/day, 85.6 mg/day, and 150.2 mg/day in the target dose groups of topiramate 50, 100, and 200 mg/day, respectively.

The mean migraine headache frequency rate at baseline was approximately 5.5 migraine headaches/28 days and was similar across treatment groups. The change in the mean 4-week migraine headache period frequency from baseline to the double-blind phase was -1.4, -2.1, and -2.4 in the topiramate 50, 100, and 200 mg/day groups, respectively, versus -1.1 in the placebo group (see Figure 3.1). The differences between the topiramate 100 and 200 mg/day groups versus placebo were statistically significant (p=0.008 and p<0.001, respectively; confidence intervals vs. placebo: topiramate 100 mg/day [-1.76, -0.27], and topiramate 200 mg/day [-2.06, -0.57]). The changes in migraine frequency represent a median percent reduction of 35%, 49%, and 48% in the topiramate 50, 100, and 200 mg/day groups, respectively, versus 19% in the placebo group.

In both studies, there were no apparent differences in treatment effect within age, gender or racial subgroups.

In the migraine prophylaxis clinical trials in approximately 900 patients, daily dosages were decreased when required in weekly intervals by 25 to 50 mg in adults receiving topiramate at doses up to 100 mg/day.

Figure 3.1: Reduction in 4-Week Migraine Headache Frequency (Studies TOPMAT-

MIGR-001 and TOPMAT-MIGR-002)

Additional efficacy measures that were assessed, in both studies, included responder rate, cumulative response rate, change in average monthly migraine attack rate, change in the average monthly rate of rescue medication use, change in the average number of monthly migraine days and onset of action defined as the earliest month that there was a statistically significant difference between each topiramate treatment group and placebo with respect to the primary efficacy endpoint that was maintained for the remainder of the double-blind phase.

DETAILED PHARMACOLOGY

Preclinical

In Vitro Studies

Electrophysiological and biochemical studies on cultured neurons have revealed three properties that may contribute to the antiepileptic efficacy of topiramate. Action potentials elicited repetitively by a sustained depolarization of the neurons were blocked by topiramate in a time-dependent manner, suggestive of a state-dependent sodium channel blocking action. Topiramate increased the frequency at which γ-aminobutyrate (GABA) activated GABA_A receptors, and enhanced the ability of GABA to induce a flux of chloride ions into neurons, suggesting that topiramate potentiates the activity of this inhibitory neurotransmitter.

Because the antiepileptic profile of topiramate differs markedly from that of the benzodiazepines, it may modulate a benzodiazepine-insensitive subtype of GABA_A receptor. Topiramate antagonized the ability of kainate to activate the kainate/AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) subtype of excitatory amino acid (glutamate) receptor, but had no apparent effect on the activity of N-methyl-D-aspartate (NMDA) at the NMDA receptor subtype. These effects of topiramate were concentration-dependent over a range of 1 µM to 200 µM, with minimum activity observed at 1 µM to 10 µM.

In addition, topiramate inhibits some isoenzymes of carbonic anhydrase. This pharmacologic effect is much weaker than that of acetazolamide, a known carbonic anhydrase inhibitor, and is not thought to be a major component of topiramate’s antiepileptic activity.

In Vivo Studies

Pharmacodynamics

Topiramate was initially found to possess anticonvulsant activity in the maximal electroshock seizure (MES) test in mice. Subsequent studies revealed that topiramate was also highly effective in the MES test in rats. In both species, anticonvulsant activity was evident within 30 minutes after oral administration, reached a peak 1 to 6 hours after dosing, and gradually declined thereafter.

Topiramate’s anticonvulsant activity in rodents was further evaluated using chemical convulsants (pentylenetetrazole, bicuculline, picrotoxin, strychnine) to induce clonic or tonic seizures. Topiramate was either weak or inactive in blocking chemically induced seizures.

Topiramate was found to effectively block seizures in mouse and rat models of hereditary epilepsy, in some animal models of kindled epilepsy, and in a rat model of stroke-induced epilepsy. In the spontaneous epileptic rat (SER) model of hereditary epilepsy, topiramate blocked the clonic motor seizures and the absence-like seizures monitored by EEG recordings.

The potency of topiramate in blocking MES seizures is similar to that of phenytoin and carbamazepine, and much greater than that of valproate. The oral ED₅₀ of topiramate at the time of peak activity was 20 to 50 mg/kg in mice and 5 to 15 mg/kg in rats.

Studies in mice receiving concomitant administration of topiramate and carbamazepine or phenobarbital showed synergistic anticonvulsant activity, while combination with phenytoin showed additive anticonvulsant activity.

An investigation of the possible development of tolerance to the anticonvulsant activity revealed no tolerance in rats dosed orally with topiramate for 14 days at twice the ED₅₀ value. When mice were dosed orally for 5 days at four times the ED₅₀ value, a small but significant degree of tolerance did occur.

Topiramate was examined for effects on central nervous system (CNS) function, particularly reflex activity and motor co-ordination. A quantitative measure of CNS impairment was obtained by calculating the dose required to cause a loss of righting reflex (LRR) in either 3% (TD3) or 50% (TD₅₀) of mice tested, or the dose that caused 50% (TD₅₀) of mice or rats to be unable to remain ambulatory on a rotating rod or reel. A protective index (PI) was obtained by calculating the ratio of the TD₅₀ dose to the ED₅₀ dose in the MES test (or the TD3 dose to the ED97 dose). The calculated PI values for topiramate compared favourably to those of the reference anticonvulsants phenytoin, carbamazepine, valproate (divalproex), and phenobarbital, particularly in rats. An evaluation of acute effects in dogs indicated that impairment of CNS function occurred only at doses several times the ED50 dose in the MES test in rats and mice. Topiramate was evaluated for effects on general behaviour in mice, rats, and dogs at doses ranging from 10 to 1,000 mg/kg. Dose-related effects in mice and rats included a decrease in spontaneous motor activity, and a decrease in body tone and respiratory activity. In dogs, emesis occurred in one of three dogs at 100 mg/kg (p.o.), and at 500 mg/kg (p.o.) one of three dogs exhibited preconvulsant activity and one of three convulsed. Recovery was complete at six hours after dosing. When administered i.v. to rats at doses ranging from 1 mg/kg to 10 mg/kg, topiramate had no effect on EEG activity, cerebral pH, spinal reflexes, or neuromuscular conduction. In mice, topiramate at doses of 30 mg/kg (p.o.) or greater prolonged pentobarbital-induced sleep time threefold to eightfold in a dose-dependent manner. In rats pretreated with topiramate at 60 mg/kg or 200 mg/kg (p.o.) one hour prior to inducing sleep with ethanol, sleep time was prolonged 38% and 54%, respectively. When rats were pretreated with these doses of topiramate four hours prior to inducing sleep with ethanol, there was no prolongation of sleep time.

In cardiovascular studies, topiramate, when given i.v. to anesthetized dogs at doses up to 10 mg/kg, caused a small, dose-related increase in blood pressure, which was associated with a slight decrease in heart rate. There was no effect on electrocardiographic measures at these doses. Topiramate, when administered to spontaneously hypertensive rats at doses of 30 mg/kg i.p. and 100 mg/kg p.o. caused a biphasic response in mean arterial pressure; an initial transient increase was followed by a modest decrease in blood pressure that persisted for about 12 hours. Topiramate, at concentrations up to 10 µM, elicited no biologically significant effects on coronary flow, contractile force, or flow rate in the isolated guinea pig heart.

In GI studies, topiramate at concentrations up to 100 µM had no effect on basal or pentagastrin-stimulated gastric acid secretion in the isolated mouse stomach assay. Topiramate weakly inhibited gastric acid secretion in rats and dogs.

Topiramate and acetazolamide were examined for effects on renal function using rats anesthetized with pentobarbital. Both compounds were infused i.v. at 9 or 90 µM/kg/h. At each dose, both compounds produced changes in renal function, including an increase in urinary flow rate, solute clearance and urinary pH. Also, a decrease in urinary osmolality and decreases in arterial blood pH and plasma bicarbonate concentration were observed. The effects of both dosage levels of topiramate were similar to, but less than, those of acetazolamide. Renal vascular resistance, heart rate, and glomerular filtration rate did not differ from pre-treatment control values.

Pharmacokinetics

Studies performed in rats and dogs employing ¹⁴C-topiramate show that topiramate is rapidly and well absorbed after oral administration and that unchanged topiramate is the major component in plasma for several hours after dosing. The absolute bioavailability of topiramate is approximately 100% in male and female rats.

Topiramate is poorly bound to plasma proteins (9% to 17%) in the mouse, rat, rabbit, dog and monkey, but there appears to be a low capacity erythrocyte binding site for the drug in all species studied. Studies in rats show that following oral administration of ¹⁴C-topiramate, total radioactivity does not accumulate in any tissue. Topiramate did distribute across the blood-brain barrier, with brain tissue concentrations of total radioactivity being about 40% of plasma concentrations 6 hours after a single oral dose.

The metabolism of topiramate has been investigated in mice, rats, rabbits and dogs. The metabolic pathways, primarily hydroxylation or hydrolysis of the isopropylidene groups and subsequent conjugation, were qualitatively similar in all species studied.

The major route of elimination of unchanged topiramate and its metabolites in all species studied is via the kidney. All species excreted a significant proportion of the dose in urine as intact topiramate; however, the proportion of metabolites excreted tended to be higher in species with shorter plasma half-lives.

TOXICOLOGY

In acute and long-term studies conducted in mice, rats, dogs and rabbits, exposure to topiramate was well tolerated.

Acute Toxicity

Table 3.3: Acute Toxicity Studies Performed with Topiramate

Species/

Strain

Route of

Administration

No. Animals/ Group

M/F [Age]

Dose

Range (mg/kg)

Estimated LD50

(mg/kg)

Mouse Oral 2/2 or 5/5 1000-3375 M 2338 Crl:COBS gavage [6-8 weeks] F 2915 CD^®-1 (ICR)BR Mouse i.p. 5/5 or 2/2 500-1700 M 605 Crl:COBS [6-8 weeks] F 710 CD^®-1 (ICR)BR Species/

Strain

Route of

Administration

No. Animals/

Group

M/F [Age]

Dose

Range (mg/kg)

Estimated

LD50

(mg/kg)

Rat Oral 5/5 or 2/2 1500-4220 M 3745 Crl:COBS^® gavage [7-8 weeks] F 2436 (WI)BR Rat i.p. 5/5 or 2/2 750-2550 M 1633 Crl:COBS^® [7-8 weeks] F 1227 (WI)BR Dog p.o. 1/1 or 2/2 270-400 No deaths Beagle [approx. 1 yr.]

Chronic Toxicity

Table 3.4: Multiple-Dose Toxicity Studies

Species/Strain

Sex

Route of

Administration

No. Animals/ Group

M/F

Dose

(mg/kg/day) Duration Results

Rat

Crl:CD^®(SD)

Male & Female

Oral

gavage

15/15 10, 90, 750 3 months Lower body weight and weight gain; CNS signs; diuresis with some hemoconcentration; higher kidney and liver weights with hepatocytic hypertrophy; and urothelial hyperplasia with some

microcalculi (few females). Findings principally at 90 and 750 mg/kg per day.

Rat

Crl:CD^®(SD)

Male & Female

Oral

gavage

and

during

recovery

10, 90, 750 3 months

plus 4-week recovery

period

Some slight effects (lower body weight gain and lower urine sodium) occurred at 10 mg/kg, the lowest dosage tested in this study; however, they are considered to be of no toxicological concern.

Effects at ≥ 90 mg/kg were similar to those occurring in other 3-month and/or 12-month rat studies. Recovery occurred for all changes except for the increased water consumption and hyperplasia of the

transitional epithelium of the bladder.

Species/Strain

Sex

Route of

Administration

No. Animals/ Group

M/F

Dose

(mg/kg/day) Duration Results

Rat

Crl:COBS^®(WI)

Male & Female

Oral (diet) 25/25 10, 55, 300 12 months Lower body weight and weight gain with lower food efficiency (300 mg/kg per day only); lower erythrocyte parameters and triglycerides; higher serum chloride and cholesterol; higher kidney and liver weights with hepatocytic hypertrophy; urothelial hyperplasia with urinary calculi; and gastric epithelial hyperplasia. Only body weight, chloride and gastric changes seen at 10 mg/kg per day. Rat

Crl:COBS^®(WI)

Male & Female

Oral (diet) 26/23

treated

untreated

Male: > 300

Female: ≥

450

11 months plus 4-, 9-, and 20-week recovery

periods

Lower weight gain; higher gastrin levels and gastric epithelial hyperplasia. No effect on gastric

enterochromaffin-like cells (often associated with tumour formation in the presence of high gastrin levels). During recovery phase, all changes were reversible.

Dog/Beagle

Male & Female

p.o. 4/4 10, 40, 150 3 months Lower weight gain, food

consumption, and food efficiency; hemodilution; lower transaminases and urine specific gravity; higher urine pH, serum alkaline

phosphatase and chloride; and higher liver weights. No significant morphological changes. Observations

essentially at 40 and 150 mg/kg per day only.

Dog/Beagle

Male & Female

p.o. 4/4 10, 30, 100 12 months Sporadic emesis at all dosage levels. Lower body weight gain; hemodilution; higher urine pH, serum alkaline phosphatase and chloride; and higher liver weights. No significant morphologic changes. Only findings seen below 100 mg/kg per day were emesis, and higher alkaline phosphatase and chloride. Reproductive Toxicity

Despite maternal and paternal toxicity as low as 8 mg/kg/day, no effects on fertility were observed in male or female rats dosed up to 100 mg/kg/day.

As with other antiepileptic drugs, topiramate was teratogenic in mice, rats and rabbits. In mice, fetal weights and skeletal ossification were reduced at 500 mg/kg/day in conjunction with maternal toxicity. Overall numbers of fetal malformations in mice were increased for all drug-treated groups (20, 100, and 500 mg/kg/day), but no significant differences or dosage-response relationships were observed for overall or specific malformations, suggesting that other factors such as maternal toxicity may be involved. In rats, dosage-related maternal and embryo/fetal toxicity (reduced fetal weights and/or skeletal ossification) were observed down to 20 mg/kg/day with teratogenic effects (limb and digit defects) at 400 mg/kg/day and above. In rabbits, dosage-related maternal toxicity was noted down to 10 mg/kg/day with embryo/fetal toxicity (increased lethality) down to 35 mg/kg/day, and teratogenic effects (rib and vertebral malformations) at 120 mg/kg/day.

The teratogenic effects seen in rats and rabbits were similar to those seen with carbonic anhydrase inhibitors, which have not been associated with malformations in humans. Effects on growth were also indicated by lower weights at birth and during lactation for pups from female rats treated with 20 or 100 mg/kg/day during gestation and lactation. In rats, topiramate crosses the placental barrier.

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 100 mg/kg/day.

Carcinogenicity

Tumours of smooth muscle origin in the urinary bladder were seen only in mice (oral dosages up to 300 mg/kg for 21 months) and appear to be unique to the species. Since no human counterpart exists, they were not considered clinically relevant. No such findings occurred in the rat carcinogenicity study (oral dosages up to 120 mg/kg/day for 24 months).

Mutagenicity

In a battery of in vitro and in vivo mutagenicity assays, topiramate did not show genotoxic potential. REFERENCES

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