TOPIRAMATE (Page 5 of 12)

6.2 Clinical Trials Experience With Topiramate Extended-Release Capsules

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 clinical practice. In the topiramate extended-release capsules study, a dose of 200 mg per day was administered to a limited number of patients; therefore, these results cannot be directly compared to immediate-release topiramate experience.

The safety data presented below are from 249 patients with partial epilepsy on concomitant AEDs who participated in the topiramate extended-release capsules study [see Clinical Studies (14.4)].

Table 10 displays the incidence of adverse reactions that occurred in ≥2% of patients and numerically greater than placebo.

Table 10: Incidence (≥2%) of Adverse Reactions in Placebo-Controlled Adjunctive Therapy Clinical Trial in Patients With Partial-Onset Seizures

Body System / Adverse Reaction

Placebo (N=125)

Topiramate Extended-Release Capsules (200 mg) (N=124)

General Disorders Fatigue Asthenia Irritability

511

622

Nervous System Disorders Somnolence Dizziness Paresthesia Aphasia Dysarthria Memory impairment

262011

1277222

Psychiatric Disorder Psychomotor retardation

0

2

Cardiovascular Disorders, General Hypertension

1

3

Metabolic and Nutritional Disorders Weight decrease Decreased appetite Anorexia

021

742

In the controlled clinical study using topiramate extended-release capsules, 8.9% of patients who received topiramate extended-release capsules and 4% who received placebo discontinued as a result of adverse reactions.

6.3 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of immediate-release topiramate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole-General Disorders: oligohydrosis and hyperthermia [see Warnings and Precautions (5.3)], hyperammonemia, hyperammonemic encephalopathy [see Warnings and Precautions (5.10)] , hypothermia with concomitant valproic acid [see Warnings and Precautions (5.12)]

Gastrointestinal System Disorders: hepatic failure (including fatalities), hepatitis, pancreatitis

Skin and Appendage Disorders: bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), pemphigus [see Warnings and Precautions (5.9)]

Urinary System Disorders: kidney stones, nephrocalcinosis [see Warnings and Precautions (5.4), (5.11)]

Vision Disorders: acute myopia, secondary angle closure glaucoma [see Warnings and Precautions (5.1)] , maculopathy

Hematological Disorders: decrease of the International Normalized Ratio (INR) or prothrombin time when given concomitantly with Vitamin K antagonist anticoagulant medications such as warfarin.

7 DRUG INTERACTIONS

7.1 Antiepileptic Drugs

Concomitant administration of phenytoin or carbamazepine with topiramate resulted in a clinically significant decrease in plasma concentrations of topiramate when compared to topiramate given alone. A dosage adjustment may be needed [see Clinical Pharmacology (12.3)].

Concomitant administration of valproic acid and topiramate has been associated with hypothermia and hyperammonemia with and without encephalopathy. Examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions (5.10, 5.12), Clinical Pharmacology (12.3)].

7.2 Other Carbonic Anhydrase Inhibitors

Concomitant use of topiramate, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide or acetazolamide) may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Patients should be monitored for the appearance or worsening of metabolic acidosis when topiramate extended-release capsules are given concomitantly with another carbonic anhydrase inhibitor [see Clinical Pharmacology (12.3)].

7.3 CNS Depressants

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

7.4 Oral Contraceptives

The possibility of decreased contraceptive efficacy and increased breakthrough bleeding may occur in patients taking combination oral contraceptive products with topiramate extended-release capsules. 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 (12.3)].

7.5 Hydrochlorothiazide (HCTZ)

Topiramate Cmax and AUC increased when HCTZ was added to immediate-release topiramate. The clinical significance of this change is unknown. The addition of HCTZ to topiramate extended-release capsules may require a decrease in the topiramate extended-release capsules dose [see Clinical Pharmacology (12.3)].

7.6 Pioglitazone

A decrease in the exposure of pioglitazone and its active metabolites were noted with the concurrent use of pioglitazone and immediate-release topiramate in a clinical trial. The clinical relevance of these observations is unknown; however, when topiramate extended-release capsules are added to pioglitazone therapy or pioglitazone is added to topiramate extended-release capsules therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state [see Clinical Pharmacology (12.3)].

7.7 Lithium

An increase in systemic exposure of lithium following topiramate doses of up to 600 mg/day can occur. Lithium levels should be monitored when co-administered with high-dose topiramate extended-release capsules [see Clinical Pharmacology (12.3)].

7.8 Amitriptyline

Some patients may experience a large increase in amitriptyline concentration in the presence of topiramate extended-release capsules and any adjustments in amitriptyline dose should be made according to the patient’s clinical response and not on the basis of plasma levels [see Clinical Pharmacology (12.3)].

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