Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

• The following adverse reactions are discussed in more detail in other sections of the labeling:
• Acute Myopia and Secondary Angle Closure [see WARNINGS AND PRECAUTIONS]
• Oligohidrosis and Hyperthermia [see WARNINGS AND PRECAUTIONS]
• Metabolic Acidosis [see WARNINGS AND PRECAUTIONS]
• Suicidal Behavior and Ideation [see WARNINGS AND PRECAUTIONS]
• Cognitive/Neuropsychiatric Adverse Reactions [see WARNINGS AND PRECAUTIONS]
• Fetal Toxicity [see WARNINGS AND PRECAUTIONS and Use in Specific Populations]
• Withdrawal of Antiepileptic Drugs (AEDs) [see WARNINGS AND PRECAUTIONS]
• Sudden Unexplained Death in Epilepsy (SUDEP) [see WARNINGS AND PRECAUTIONS]
• Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid [VPA] Use [see WARNINGS AND PRECAUTIONS]
• Kidney Stones [see WARNINGS AND PRECAUTIONS]
• Hypothermia with Concomitant Valproic Acid (VPA) Use [see WARNINGS AND PRECAUTIONS]
• Paresthesia [see WARNINGS AND PRECAUTIONS]

The data described in the following sections were obtained using TOPAMAX® (topiramate) Tablets.

Monotherapy Epilepsy

Adults ≥ 16 Years

The adverse reactions in the controlled trial that occurred most commonly in adults in the 400 mg/day TOPAMAX® group and at a rate higher ( ≥ 5 %) than in the 50 mg/day group were: paresthesia, weight decrease, anorexia, somnolence, and difficulty with memory (see Table 5).

Approximately 21% of the 159 adult patients in the 400 mg/day group who received topiramate as monotherapy in the controlled clinical trial discontinued therapy due to adverse reactions. The

most common ( ≥ 2% more frequent than low-dose 50 mg/day TOPAMAX® ) adverse reactions causing discontinuation in this trial were difficulty with memory, fatigue, asthenia, insomnia, somnolence, and paresthesia.

Pediatric Patients 6 to < 16 Years of Age

The adverse reactions in the controlled trial that occurred most commonly in pediatric patients in the 400 mg/day TOPAMAX® group and at a rate higher ( ≥ 5%) than in the 50 mg/day group were fever, weight decrease, mood problems, cognitive problems, infection, flushing, and paresthesia (see Table 5).

Approximately 14% of the 77 pediatric patients in the 400 mg/day group who received TOPAMAX® as monotherapy in the controlled clinical trial discontinued therapy due to adverse reactions. The most common ( ≥ 2% more frequent than low-dose 50 mg/day TOPAMAX® ) adverse reactions resulting in discontinuation in this trial were difficulty with concentration/attention, fever, flushing, and confusion.

Table 5: Incidence of Treatment-Emergent Adverse Reactions in Monotherapy Epilepsy Where the Rate Was at Least 2% in Any TOPAMAX® Group and the Rate in the 400 mg/day TOPAMAX® Group Was Greater Than the Rate in the 50 mg/day TOPAMAX® Group for Adults ( ≥ 16 Years) and Pediatric (6 to < 16 Years) Patients in Study TOPMAX-EPMN-106

Adjunctive Therapy Epilepsy

The most commonly observed adverse reactions associated with the use of TOPAMAX® at dosages of 200 to 400 mg/day in controlled trials in adults with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, that were seen at greater frequency in TOPAMAX®-treated patients and did not appear to be dose-related were somnolence, dizziness, ataxia, speech disorders and related speech problems, psychomotor slowing, abnormal vision, difficulty with memory, paresthesia and diplopia (see Table 6). The most common dose-related adverse reactions at dosages of 200 to 1,000 mg/day were fatigue, nervousness, difficulty with concentration or attention, confusion, depression, anorexia, language problems, anxiety, mood problems, and weight decrease (see Table 8).

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

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

Approximately 28% of the 1757 adults with epilepsy who received TOPAMAX® at dosages of 200 to 1,600 mg/day in clinical studies discontinued treatment because of adverse reactions; an individual patient could have reported more than one adverse reaction. These adverse reactions were psychomotor slowing (4.0%), difficulty with memory (3.2%), fatigue (3.2%), confusion (3.1%), somnolence (3.2%), difficulty with concentration/attention (2.9%), anorexia (2.7%), depression (2.6%), dizziness (2.5%), weight decrease (2.5%), nervousness (2.3%), ataxia (2.1%), and paresthesia (2.0%). Approximately 11% of the 310 pediatric patients who received TOPAMAX® at dosages up to 30 mg/kg/day discontinued due to adverse reactions. Adverse reactions associated with discontinuing therapy included aggravated convulsions (2.3%), difficulty with concentration/attention (1.6%), language problems (1.3%), personality disorder (1.3%), and somnolence (1.3%).

Incidence in Epilepsy Controlled Clinical Trials – Adjunctive Therapy – Partial Onset Seizures, Primary Generalized Tonic-Clonic Seizures, and Lennox-Gastaut Syndrome

Table 6 lists treatment-emergent adverse reactions that occurred in at least 1% of adults treated with 200 to 400 mg/day TOPAMAX® in controlled trials that were numerically more common at this dose than in the patients treated with placebo. In general, most patients who experienced adverse reactions during the first eight weeks of these trials no longer experienced them by their last visit. Table 9 lists treatment-emergent adverse reactions that occurred in at least 1% of pediatric patients treated with 5 to 9 mg/kg TOPAMAX® in controlled trials that were numerically more common than in patients treated with placebo.

The prescriber should be aware that these data were obtained when TOPAMAX® was added to concurrent antiepileptic drug therapy and cannot be used to predict the frequency of adverse reactions in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with data obtained from other clinical investigations involving different treatments, uses, or investigators. Inspection of these frequencies, however, does provide the prescribing physician with a basis to estimate the relative contribution of drug and non-drug factors to the adverse reaction incidences in the population studied.

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

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

Table 6: Incidence of Treatment-Emergent Adverse Reactions in Placebo-Controlled,  Add-On Epilepsy Trials in Adults^a,b Where Incidence Was > 1% in Any TOPAMAX® Group and Greater Than the Rate in Placebo-Treated Patients

Incidence in Study 119 – Add-On Therapy– Adults with Partial Onset Seizures

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

The incidence of adverse reactions (Table 7) did not differ significantly between the 2 TOPAMAX® regimens. Because the frequencies of adverse reactions reported in this study were markedly lower than those reported in the previous epilepsy studies, they cannot be directly compared with data obtained in other studies.

Table 7: Incidence of Treatment-Emergent Adverse Reactions in Study 119^a,b Where Incidence Was ≥ 2% in the TOPAMAX® Group and Greater Than the Rate in Placebo-Treated Patients

Table 8: Incidence (%) of Dose-Related Adverse Reactions From Placebo-Controlled, Add-On Trials in Adults With Partial Onset Seizuresa

Table 9: Incidence (%) of Treatment-Emergent Adverse Reactions in Placebo-Controlled, Add-On Epilepsy Trials in Pediatric Patients (Ages 2 -16 Years)a,b (Reactions That Occurred in at Least 1% of TOPAMAX®-Treated Patients and Occurred More Frequently in TOPAMAX®-Treated Than Placebo-Treated Patients)

Other Adverse Reactions Observed During All Epilepsy Clinical Trials

TOPAMAX® has been administered to 2246 adults and 427 pediatric patients with epilepsy during all clinical studies, only some of which were placebo-controlled. During these studies, all adverse reactions were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse reactions, similar types of reactions were grouped into a smaller number of standardized categories using modified WHOART dictionary terminology. The frequencies presented represent the proportion of patients who experienced a reaction of the type cited on at least one occasion while receiving TOPAMAX®. Reported reactions are included except those already listed in the previous tables or text, those too general to be informative, and those not reasonably associated with the use of the drug.

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

Autonomic Nervous System Disorders: Infrequent: vasodilation.

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

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

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

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

Heart Rate and Rhythm Disorders: Infrequent: AV block.

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

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

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

Neoplasms: Infrequent: thrombocythemia. Rare: polycythemia.

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

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

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

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

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

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

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

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

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

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

Migraine

In the four multicenter, randomized, double-blind, placebo-controlled, parallel group migraine prophylaxis clinical trials, most of the adverse reactions with TOPAMAX® were mild or moderate in severity. Most adverse reactions occurred more frequently during the titration period than during the maintenance period.

Table 10 includes those adverse reactions reported for patients in the placebo-controlled trials where the incidence in any TOPAMAX® treatment group was at least 2% and was greater than that for placebo patients.

Table 10: Incidence of Treatment-Emergent Adverse Reactions in Placebo-Controlled, Migraine Trials Where Incidence Was ≥ 2 % in Any TOPAMAX® Group and Greater Than the Rate in Placebo-Treated Patients^a

Of the 1135 patients exposed to TOPAMAX® in the placebo-controlled studies, 25% discontinued due to adverse reactions, compared to 10% of the 445 placebo patients. The adverse reactions associated with discontinuing therapy in the TOPAMAX® -treated patients included paresthesia (7%), fatigue (4%), nausea (4%), difficulty with concentration/attention (3%), insomnia (3%), anorexia (2%), and dizziness (2%).

Patients treated with TOPAMAX® experienced mean percent reductions in body weight that were dose-dependent. This change was not seen in the placebo group. Mean changes of 0%, -2%, -3%, and -4% were seen for the placebo group, TOPAMAX® 50, 100, and 200 mg groups, respectively.

Table 11 shows adverse reactions that were dose-dependent. Several central nervous system adverse reactions, including some that represented cognitive dysfunction, were dose-related. The most common dose-related adverse reactions were paresthesia, fatigue, nausea, anorexia, dizziness, difficulty with memory, diarrhea, weight decrease, difficulty with concentration/attention, and somnolence.

Table 11: Incidence (%) of Dose-Related Adverse Reactions From Placebo-Controlled, Migraine Trials^a

Other Adverse Reactions Observed During Migraine Clinical Trials

TOPAMAX®, for the treatment of prophylaxis of migraine headache, has been administered to 1367 patients in all clinical studies (includes double-blind and open-label extension). During these studies, all adverse reactions were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse reactions, similar types of reactions were grouped into a smaller number of standardized categories using modified WHOART dictionary terminology.

The following additional adverse reactions that were not described earlier were reported by greater than 1% of the 1367 TOPAMAX®-treated patients in the controlled clinical trials:

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

Central & Peripheral Nervous System Disorders: Headache, vertigo, tremor, sensory disturbance, migraine aggravated.

Gastrointestinal System Disorders: Constipation, gastroesophageal reflux.

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.

Postmarketing and Other Experience

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

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

Read the Topamax (topiramate) Side Effects Center for a complete guide to possible side effects »

In vitro studies indicate that topiramate does not inhibit enzyme activity for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4/5 isozymes. In vitro studies indicate that topiramate is a mild inhibitor of CYP2C19 and a mild inducer of CYP3A4. Drug interactions with some antiepileptic drugs, CNS depressants and oral contraceptives are described here. For other drug interactions, please refer to Clinical Pharmacology (12.3).

Antiepileptic Drugs

Potential interactions between topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. Concomitant administration of phenytoin or carbamazepine with topiramate decreased plasma concentrations of topiramate by 48% and 40%, respectively when compared to TOPAMAX® given alone [see CLINICAL PHARMACOLOGY]

Concomitant administration of valproic acid and TOPAMAX® has been associated with hyperammonemia with and without encephalopathy. Concomitant administration of TOPAMAX® with valproic acid has also been associated with hypothermia (with and without hyperammonemia) in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see WARNINGS AND PRECAUTIONS or CLINICAL PHARMACOLOGY].

CNS Depressants

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

Oral Contraceptives

Exposure to ethinyl estradiol was statistically significantly decreased at doses of 200, 400, and 800 mg/day (18%, 21%, and 30%, respectively) when TOPAMAX® was given as adjunctive therapy in patients taking valproic acid. However, norethindrone exposure was not significantly affected. In another pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), TOPAMAX®, given in the absence of other medications at doses of 50 to 200 mg/day, was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive. The possibility of decreased contraceptive efficacy and increased breakthrough bleeding should be considered in patients taking combination oral contraceptive products with TOPAMAX®. Patients taking estrogen-containing contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding [see CLINICAL PHARMACOLOGY].

Metformin

Topiramate treatment can frequently cause metabolic acidosis, a condition for which the use of metformin is contraindicated [see CLINICAL PHARMACOLOGY].

Lithium

In patients, lithium levels were unaffected during treatment with topiramate at doses of 200 mg/day; however, there was an observed increase in systemic exposure of lithium (27% for Cmax and 26% for AUC) following topiramate doses of up to 600 mg/day. Lithium levels should be monitored when co-administered with high-dose TOPAMAX® [see CLINICAL PHARMACOLOGY].

Other Carbonic Anhydrase Inhibitors

Concomitant use of topiramate, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide, acetazolamide, or dichlorphenamide) may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Therefore, if TOPAMAX® is given concomitantly with another carbonic anhydrase inhibitor, the patient should be monitored for the appearance or worsening of metabolic acidosis [see CLINICAL PHARMACOLOGY].

Drug Abuse And Dependence

Controlled Substance

TOPAMAX® (topiramate) is not a controlled substance.

Abuse

The abuse and dependence potential of TOPAMAX® has not been evaluated in human studies.

Dependence

TOPAMAX® has not been systematically studied in animals or humans for its potential for tolerance or physical dependence.

Last reviewed on RxList: 11/9/2012
This monograph has been modified to include the generic and brand name in many instances.