Novopharm Limited Date of preparation: Sept. 9, 2005. 30 Novopharm Court Toronto, Ontario. M1B 2K9 Control Number: 083079
SUMMARY PRODUCT INFORMATION. 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 11 DRUG INTERACTIONS 27 DOSAGE AND ADMINISTRATION 31 OVERDOSAGE 34 ACTION AND CLINICAL PHARMACOLOGY 34 STORAGE AND STABILITY 36 DOSAGE FORMS, COMPOSITION AND PACKAGING 37
PHARMACEUTICAL INFORMATION 38 CLINICAL TRIALS 39 COMPARATIVE BIOAVAILABILITY DATA 44 TOXICOLOGY 48 REFERENCES 52
Pr
NOVO-TOPIRAMATE
(topiramate) 25, 100 and 200 mg Tablets Antiepileptic/Migraine Prophylaxis
| Route of Administration | Dosage Form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| Oral | tablets 25 mg, 100 mg, 200 mg | Lactose For a complete listing see Dosage Forms, Composition and Packaging section . |
Epilepsy
NOVO-TOPIRAMATE (topiramate) is indicated as monotherapy for the management of patients (adults and children six years and older) with newly diagnosed epilepsy. NOVO-TOPIRAMATE (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
NOVO-TOPIRAMATE (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, or contraindication to, or troublesome side effects from acute abortive medications. Continuing therapy should be reviewed every six months. NOVO- 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
).
Patients who are hypersensitive to this drug or to any 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.
General
Antiepileptic drugs, including NOVO-TOPIRAMATE (topiramate), should be withdrawn gradually to minimize the potential of increased seizure frequency. In adult clinical trials, dosages were decreased by 100 mg/day at weekly intervals.
Carcinogenesis and Mutagenesis
See Product Monograph Part II: TOXICOLOGY- Carcinogenicity and Mutagenicity for discussion on animal data.
Endocrine and Metabolism
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 NOVO-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 NOVO-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).
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. Chronic metabolic acidosis in pediatric patients can reduce growth rates. The effect of topiramate on growth and bone-related sequelae has not been systematically investigated in pediatric or adult populations. Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing topiramate (using dose tapering). If the decision is made to continue patients on topiramate in the face of persistent acidosis, alkali treatment should be considered.
In a drug interaction study, a greater decrease from baseline in serum potassium values was seen with concomitant treatment than for either drug alone. At the end of each treatment period, 27% (3/12) 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 (nonspecific 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 topiramate and hydrochlorothiazide concomitantly. (See DRUG INTERACTIONS.)
A dietary supplement or increased food intake may be considered if the patient is losing weight while on this medication.
Hepatic/Biliary/Pancreatic
In hepatically impaired patients, NOVO-TOPIRAMATE should be administered with caution as the clearance of topiramate was decreased compared with normal subjects.
Neurologic
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:
psychomotor slowing, difficulty with concentration and speech or language problems, in particular, word-finding difficulties,
somnolence or fatigue and
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
).
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.)
ADVERSE REACTIONS, Less Common Clinical Trial Adverse Drug Reactions (<2%) and Post-Market Adverse Drug Reactions
In the double-blind phases of clinical trials with topiramate in approved and investigational indications, suicide attempts occurred at an incidence of 0.2% (13 reports/7,999 patients) on topiramate versus 0% (0 reports/3,150 patients) on placebo. One completed suicide was reported in a bipolar disorder trial in a patient on topiramate (see
).
Additional nonspecific 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 NOVO-TOPIRAMATE as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction
ADVERSE REACTIONS, Post-Market Adverse Drug Reactions)
with discontinuation of NOVO-TOPIRAMATE, may be helpful (see
.
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 sequalae including permanent vision loss.
Renal
Kidney Stones
A total of 32/1,715 (1.5%) 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 NOVO-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. 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 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 (CLCR < 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
Patients should be reminded to inform their doctor if they are pregnant or intend to become pregnant while on NOVO-TOPIRAMATE therapy.
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 NOVO-TOPIRAMATE to gauge whether it adversely affects their mental and/or motor performance.
Acute Myopia and Secondary Angle Closure Glaucoma
Patients taking NOVO-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
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, NOVO-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. The effect of NOVO-TOPIRAMATE on labour and delivery in humans is unknown.
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 NOVO-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 - to 3.2); at 24 months (n=l4), the mean change was +2.2 (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 (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 NOVO-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
and
.)
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). 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 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 : 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 / | 50-100 | 200-400 | 500 |
| Adverse Event | (n=444) | (n=329) | (n=113) |
| Body as a Whole-General Disorders | 18 | 18 | 19 |
| Fatigue | |||
| 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 & Peripheral Nervous System Disorders | 23 | 39 | 38 |
| Paresthesia | |||
| 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 |
| Migraine | 2 | 1 | 1 |
| Abnormal Coordination | 1 | 1 | 3 |
| Convulsions Aggravated | 1 | 0 | 2 |
| Convulsions Grand Mal | <1 | 1 | 2 |
| Gait Abnormal | <1 | <1 | 3 |
| Dyskinesia | 0 | 0 | 2 |
| Gastro-Intestinal System Disorders | 11 | 12 | 12 |
| Nausea | |||
| 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 |
| Table 1 (cont'd) : 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/ | 50-100 | 200-400 | 500 |
| Adverse Event | (n=444) | (n=329) | (n=113) |
| Heart Rate and Rhythm Disorders | 1 | 1 | 4 |
| Palpitation | |||
| Tachycardia | 1 | 0 | 2 |
| Metabolic and Nutritional Disorders Weight Decrease | 9 | 14 | 18 |
| Muscle-Skeletal System Disorders | 3 | 4 | 4 |
| Arthralgia | |||
| Myalgia | 2 | 1 | 2 |
| Muscle Weakness | 1 | 1 | 2 |
| Platelet, Bleeding, & Clotting Disorders | 1 | 2 | 1 |
| Epistaxis | |||
| Hematoma | 0 | 0 | 2 |
| Psychiatric Disorders | 11 | 15 | 19 |
| Somnolence | |||
| 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 | 3 | 1 | 8 |
| Menstrual Disorder | |||
| 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 | 5 | 9 | 6 |
| Infection Viral | |||
| Otitis Media | 2 | 1 | 2 |
| Table 1(cont'd) : Incidence of Treatment-Emergent Adverse Events in Monotherapy Trials in Adults a Where Rate Was >=2% in Any Topiramate Group | |||
| Topiramate Dose (mg/day) | |||
| Body System/ | 50-100 | 200-400 | 500 |
| Adverse Event | (n=444) | (n=329) | (n=113) |
| Respiratory System Disorders | 15 | 13 | 10 |
| Upper Respiratory Tract Infection | |||
| Pharyngitis | 5 | 5 | 2 |
| Sinusitis | 3 | 4 | 6 |
| Rhinitis | 3 | 3 | 5 |
| Bronchitis | 2 | 2 | 1 |
| Coughing | 2 | 2 | 2 |
| Dyspnea | 1 | 2 | 1 |
| Pneumonia | 1 | <1 | 3 |
| Skin and Appendages Disorders | 3 | 4 | 3 |
| Rash | |||
| 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 | 2 | 2 | 5 |
| Urinary Tract Infection | |||
| Micturition Frequency | 1 | 2 | 4 |
| Dysuria | <1 | 2 | 1 |
| Cystitis | <1 | 2 | 1 |
| Renal Calculus | <1 | 2 | 2 |
| Vision Disorders | 3 | 4 | 4 |
| Vision Abnormal | |||
| 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 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 / | 50-100 | 200-400 | 500 b |
| Adverse Event | (n=125) | (n=106) | (n=14) |
| Body as a Whole-General Disorders | 7 | 10 | 14 |
| Fatigue | |||
| 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 & Peripheral Nervous System Disorders | 27 | 17 | 29 |
| Headache | |||
| 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 |
| Gastro-Intestinal System Disorders | 9 | 7 | 7 |
| Diarrhea | |||
| 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 |
| Dyspepsia | 2 | 1 | 0 |
| Tooth Ache | 1 | 1 | 7 |
| Hearing and Vestibular Disorders Earache | 2 | 0 | 0 |
| Metabolic and Nutritional Disorders | 5 | 14 | 0 |
| Weight Decrease | |||
| Acidosis | 0 | 0 | 7 |
| Muscle-Skeletal System Disorders Arthralgia | 1 | 2 | 7 |
| Platelet, Bleeding, & Clotting Disorders Epistaxis | 2 | 4 | 14 |
| Table 2 (cont'd) : 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/ | 50-100 | 200-400 | 500 b |
| Adverse Event | (n=125) | (n-106) | (n=14) |
| Psychiatric Disorders | 13 | 13 | 14 |
| Anorexia | |||
| 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 | 0 | 0 | 13 |
| Vaginitis | |||
| Dysmenorrhea | 2 | 2 | 0 |
| Intermenstrual Bleeding | 0 | 2 | 0 |
| Reproductive Disorders, Male Testis Disorder | 2 | 0 | 0 |
| Resistance Mechanism Disorders | 4 | 7 | 7 |
| Infection Viral | |||
| Infection | 2 | 6 | 0 |
| Otitis Media | 2 | 1 | 7 |
| Respiratory System Disorders | 26 | 25 | 21 |
| Upper Respiratory Tract Infection | |||
| 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 | 3 | 4 | 21 |
| Rash | |||
| 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 |
| Table 2 (cont'd) : 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 Dose (mg/day) | |||
| Body System/ | 50-100 | 200-400 | 500 b |
| Adverse Events | (n=125) | (n=106) | (n=14) |
| Urinary System Disorders | 2 | 2 | 7 |
| Urinary Incontinence | |||
| 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 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 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 5).
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very special conditions the adverse reaction rates observed in the clinical trials may not reject 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 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/ | Placebo | 200-400 | 600-1,000 |
| Adverse Event | (n=216) | (n=113) | (n=414) |
| Body as a Whole | 1.4 | 8.0 | 3.1 |
| Asthenia | |||
| 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 |
| Nervous System | 15.3 | 28.3 | 32.1 |
| Dizziness | |||
| 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 |
| Coordination Abnormal | 1.9 | 5.3 | 3.6 |
| Hypoesthesia | 0.9 | 2.7 | 1.2 |
| Abnormal Gait | 1.4 | 1.8 | 2.2 |
| Gastrointestinal System | 7.4 | 11.5 | 12.1 |
| Nausea | |||
| 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 | 9.7 | 30.1 | 27.8 |
| Somnolence | |||
| 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 |
| 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 |
| Table 3 (cont'd) : 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 Dose (mg/day) | |||
| Body System/ | Placebo | 200-400 | 600-1,000 |
| Adverse Event | (n=216) | (n=113) | (n=414) |
| Respiratory System | 2.3 | 7.1 | 3.1 |
| Pharyngitis | |||
| 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 | 5.6 | 14.2 | 10.4 |
| Diplopia | |||
| Vision Abnormal | 2.8 | 14.2 | 10.1 |
| White Cell and RES Leukopenia | 0.5 | 2.7 | 1.2 |
Patients in these add-on trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo.
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 4: Incidence (%) of Dose-Related Adverse Events From Placebo-Controlled, Add-on Epilepsy Trials in ADULTS
| Topiramate Dosage (mg/day) | ||||
| Adverse Event | Placebo | 200 | 400 | 600-1,000 |
| (n=216) | (n=45) | (n=68) | (n=414) | |
| Fatigue | 13.4 | 11.1 | 11.8 | 29.7 |
| Nervousness | 7.4 | 13.3 | 17.6 | 19.3 |
| Difficulty with | 1.4 | 6.7 | 8.8 | 14.5 |
| Concentration/Attention | ||||
| Confusion | 4.2 | 8.9 | 10.3 | 13.8 |
| Depression | 5.6 | 8.9 | 7.4 | 13 |
| 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 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 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 | 5 | 16.3 |
| Fatigue | ||
| Injury | 12.9 | 14.3 |
| Allergic Reaction | 1 | 2 |
| Central and Peripheral Nervous System Disorders | 5 | 8.2 |
| Gait Abnormal | ||
| 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 |
| Gastrointestinal System Disorders | 5 | 6.1 |
| Nausea | ||
| Saliva Increased | 4 | 6.1 |
| Constipation | 4 | 5.1 |
| Gastroenteritis | 2 | 3.1 |
| Metabolic and Nutritional Disorders | 1 | 9.2 |
| Weight Decrease | ||
| Thirst | 1 | 2 |
| Platelet, Bleeding and Clotting Disorders | 4 | 8.2 |
| Purpura | ||
| Epistaxis | 1 | 4.1 |
| Nervous Disorders | 15.8 | 25.5 |
| Somnolence | ||
| 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 | 3 | 7.1 |
| Infection Viral | ||
| Infection | 3 | 3.1 |
| Respiratory System Disorders | 36.6 | 36.7 |
| Upper Respiratory Tract Infection | ||
| Pneumonia | 1 | 5.1 |
| Table 5 (cont'd) : 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) |
| Skin and Appendages Disorders | 2 | 3.1 |
| Skin Disorder | ||
| Alopecia | 1 | 2 |
| Dermatitis | 0 | 2 |
| Hypertrichosis | 1 | 2 |
| Rash Erythematous | 0 | 2 |
| Urinary System Disorders Urinary Incontinence | 2 | 4.1 |
| Vision Disorders | 1 | 2 |
| Eye Abnormality | ||
| 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 and migraine prophylaxis, 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).
++
Suicide-related adverse events include suicidal ideation, suicide attempt, suicide and any evidence of self-harm.
MIGRAINE
Adverse Drug Reaction Overview
Deleted: ,
Deleted: and other investigational indications (obesity, bipolar disorder and diabetic peripheral neuropathy) Table 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
| Table 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 / | Placebo | 50 | 100 | 200 |
| Adverse Event | (n=445) | (n=235) | (n=386) | (n=514) |
| Body as a Whole - General Disorders | 11 | 14 | 15 | 19 |
| Fatigue | ||||
| 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 | 6 | 35 | 51 | 49 |
| Paresthesia | ||||
| 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 | 8 | 9 | 13 | 14 |
| Nausea | ||||
| Diarrhea | 4 | 9 | 11 | 11 |
| Abdominal Pain | 5 | 6 | 6 | 7 |
| Dyspesia | 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 | 1 | 6 | 9 | 11 |
| Weight Decrease | ||||
| Thirst | <1 | 2 | 2 | 1 |
| Musculoskeletal System Disorders Arthralgia | 2 | 7 | 3 | 1 |
| Neoplasms Neoplasm NOS | <1 | 2 | <1 | <1 |
| Psychiatric Disorders | 6 | 9 | 15 | 14 |
| Anorexia | ||||
| 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 |
| 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 |
| Table 6 (cont'd) : 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 / | Placebo | 50 | 100 | 200 |
| Adverse Event | (n=445) | (n=235) | (n=386) | (n=514) |
| Reproductive Disorders, Female Menstrual Disorder | 2 | 3 | 2 | 2 |
| Reproductive Disorders, Male Ejaculation Premature | 0 | 3 | 0 | 0 |
| Resistance Mechanism Disorders | 3 | 4 | 4 | 3 |
| Viral Infection | ||||
| Otitis Media | <1 | 2 | 1 | 1 |
| Respiratory System Disorders | 12 | 13 | 14 | 12 |
| Upper Respiratory Tract Infection | ||||
| 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 | 1 | 15 | 8 | 12 |
| Taste Perversion | ||||
| Taste Loss | <1 | 1 | 1 | 2 |
| Urinary System Disorders | 2 | 4 | 2 | 4 |
| Urinary Tract Infection | ||||
| Renal Calculus | 0 | 0 | 1 | 2 |
| Vision Disorders | <1 | 1 | 2 | 3 |
| Vision Abnormal | ||||
| Blurred Vision b | 2 | 4 | 2 | 4 |
| Conjunctivitis | 1 | 1 | 2 | 1 |
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.
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 7 shows adverse events that were dose-dependent.
Table 7: Incidence (%) of Dose-Related Adverse Events From Placebo-Controlled Migraine Trialsa
| Topiramate Dosage (mg/kg) | ||||
| Adverse Event | Placebo | 50 | 100 | 200 |
| (n=445) | (n=235) | (n=386) | (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 |
| 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 1367 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 1367 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 DisordersReproductive Disorders, FemaleResistance Mechanism DisordersRespiratory System Disorders
: epistaxis
: intermenstrual bleeding
: infection, genital moniliasis
: pneumonia, asthma
Skin and Appendages Disorders
: rash, alopecia
Vision Disorders:
abnormal accommodation, eye pain
Post-Market Adverse Drug Reactions
In addition to the adverse experiences reported during clinical trial testing of topiramate the following adverse experiences have been reported in patients receiving marketed topiramate from worldwide use since approval. There are insufficient data to support an estimate of their incidence or to establish causation. The most frequently reported adverse events in spontaneous post-marketing reports on topiramate include:
Psychiatric
: somnolence or sedation, hallucination(s), depression, anorexia, aggressive reaction, psychosis, thinking abnormal, insomnia, emotional lability, delusion, amnesia, confusion,
nervousness, agitation, concentration impaired, personality disorder, anxiety
Central and Peripheral Nervous SystemMetabolic and NutritionalVision: Gastrointestinal:
: convulsions aggravated, paresthesia, speech disorder, ataxia, dizziness, convulsions, headache, hyperkinesia, convulsions grand mal, hypoaesthesia
: weight decrease, metabolic acidosis, hypokalemia, hyperchloremia
vision abnormal (includes vision decreased, vision blurred, visual disturbance, visual impairment, amblyopia); rarely reported: diplopia, glaucoma, myopia, eye pain
nausea, diarrhea, abdominal pain, constipation, vomiting
Body as a Whole General Disorders
-
: fatigue, fever, dehydration, flushing, hot flushes
Urinary System
: renal calculus
Skin and Appendages
: rash, alopecia, sweating decreased
White Cell and RES Disorders
: leucopenia, thrombocytopenia
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
).
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 DRUG INTERACTIONS). 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. Very rare 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.
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
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 8.
Table 8: Drug Interactions with Topiramate Therapy
| AED Co-administered | AED Concentration | Topiramate Concentration |
| Phenytoin | - * * | |59% |
| Carbamazepine (CBZ) | - | |40% |
| CBZ epoxide * | - | NS |
| Valproic acid | |11% | |14% |
| Phenobarbital | - | NS |
| Primidone | - | NS |
| Lamotrigine | - | 15% decrease |
* 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 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 (CYP2Cmeph). 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.
Effects of Other Antiepileptic Drugs on NOVO-TOPIRAMATE
Phenytoin and carbamazepine decrease the plasma concentration of topiramate. The addition or withdrawal of phenytoin and/or carbamazepine during adjunctive therapy with NOVO- TOPIRAMATE may require adjustment of the dose of NOVO-TOPIRAMATE. This should be done by titrating to clinical effect. 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 NOVO-TOPIRAMATE. Rare post-marketing reports of encephalopathy with or without hyperammonemia have been received for patients treated with topiramate, while also taking valproate or other antiepileptic medications. Thus, caution is advised when polytherapy with valproate is necessary (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions).
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 NOVO-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 NOVO- 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 ug 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 Cmax 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 Cmax 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 ug). 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 ug) 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 ug 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. Hvdrochlorothiazide (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 Cmax 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 measurements of <3.6 mEq/L at the end of each treatment period [6l% (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 metforinin and topiramate (50, 75 and 100 mg) were given simultaneously for 6 consecutive days. The results of this study indicated that metformin mean Cmax and mean AUC0-12h 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 tmax. 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 NOVO-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. 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%, mean Cmax increased non-significantly by 10%, but with individual subjects showing large increases, and 3 of the 4 highest values were recorded by males. In addition, each of the active hydroxy-metabolite and the active keto-metabolite showed mean decreases in Cmax and AUC (approximately 15% for the hydroxy-metabolite and 60% for the keto-metabolite). The clinical significance of these findings is not known. When NOVO-TOPIRAMATE is added to pioglitazone therapy or pioglitazone is added to NOVO-TOPIRAMATE therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.
Risperidone
: There was an approximate 25% decrease in each of Cmax and AUC of the atypical anti-psychotic risperidone (2 mg single dose) in 12 healthy volunteers (6 males, 6 females) receiving 200 mg/day of topiramate. Therefore, patients 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).
Amitriptyline
: There was a 12% increase in both AUC and Cmax for the tricylic 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 anti-histamine pizotifen following daily
1.5 mg doses. There was a mean 12% and 15% decrease respectively in topiramate Cmax 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 propranol following daily 160 mg doses. There was a 17% increase in Cmax 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 16% increases for each of Cmax and AUC at 160 mg/day propranolol.
Other Carbonic Anhydrase Inhibitors
: Concomitant use of NOVO-TOPIRAMATE, a weak carbonic anhydrase inhibitor, with other carbonic anhydrase inhibitors, e.g. acetazolamide, may create a physiological environment that increases the risk of renal stone formation, and should therefore be avoided if possible.
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 topiramate with commonly used laboratory tests.
Dosing Considerations
Patients with renal impairment Patients undergoing hemodialysis Patients with hepatic disease
Recommended Dose and Dosage Adjustment
NOVO-TOPIRAMATE (topiramate) Tablets can be taken without regard to meals.
Epilepsy
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:
| Week 1 | Weeks 2-3 | Weeks 3-4 | |
| Morning Dose | None | 25 mg | 50 mg |
| Evening Dose | 25 mg | 25 mg | 50 mg |
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
Adults (Age I7 years and older)
It is recommended that NOVO-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 NOVO-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.
Migraine
The usual total daily dose of NOVO-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 7). The recommended titration rate for topiramate for migraine prophylaxis to 100 mg/day is:
| Morning Dose | Evening Dose | |
| Week 1 | None | 25 mg |
| Week 2 | 25 mg | 25 mg |
| Week 3 | 25 mg | 50 mg |
| Week 4 | 50 mg | 50 mg |
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/l.73m2), 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 NOVO-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 NOVO- 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.
Overdoses of topiramate have been reported. Signs and symptoms included convulsions, drowsiness, speech disturbances, blurred vision, diplopia, mentation impaired, lethargy, abnormal coordination, 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
).
A patient who ingested a dose calculated to be between 96 and 110 g topiramate was admitted to hospital with coma lasting 20-24 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.
Pharmacodynamics
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, 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 Cmax following multiple twice-a-day oral doses of 100 mg to healthy subjects was 6.76 ug/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 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 (Cmax) of 1.5 ug/mL was achieved within 2 to 3 hours (Tmax). 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.
: 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 ug/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 q12h 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
: Pharmacokinetics of topiramate were evaluated in patients ages 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.
: Plasma clearance of topiramate is unchanged in elderly subjects in the absence of underlying renal disease.
: Although direct comparison studies of pharmacokinetics have not been conducted, analysis of plasma concentration data from clinical efficacy trials have 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.
: 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 (CLCR <70 mL/min/l.73m2), 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.
: Topiramate is effectively removed from plasma by hemodialysis (see
).
NOVO-TOPIRAMATE (topiramate) is stored in white high density polyethylene (HDPE) bottles between 15oC - 30oC. Protect from moisture.
Availability of Dosage Forms
NOVO-TOPIRAMATE (topiramate) is available in the following strengths as described below: 25 mg: white to off-white, round, film-coated tablets, engraved N on one side and 25 on the other side. 100 mg: yellow, round, film-coated tablets, engraved N on one side and 100 on the other side. 200 mg: salmon-coloured, round, film-coated tablets, engraved N on one side and 200 on the other side. NOVO-TOPIRAMATE Tablets are available in HDPE bottles with white polypropylene child resistant caps and desiccant in sizes of 60 and 100 tablets.
Composition
Active ingredient: topiramate. Non-medicinal ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized corn starch, sodium starch glycolate, and film-coating containing the following: 25 mg glycerol triacetate, hydroxypropyl methylcellulose, hypromellose, macrogol, polydextrose, polyethylene glycol, titanium dioxide, triacetin. 100 mg hydroxypropyl methylcellulose, hypromellose, iron oxide yellow, macrogol, polyethylene glycol, polysorbate, titanium dioxide. 200 mg hydroxypropyl methylcellulose, hypromellose, iron oxide red, lactose monohydrate, macrogol, polyethylene glycol, titanium dioxide. Product Monograph is available upon request. NOVO-TOPIRAMATE Tablets are manufactured by: Novopharm Limited 30 Novopharm Court Toronto, Ontario M1B 2K9