Zonegran Drug Interactions

Effect of Zonegran on cytochrome P450 enzymes: In-vitro studies using human liver microsomes show no or little (<25%) inhibition of cytochrome P450 isozymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2El or 3A4 at zonisamide levels approximately two-fold or greater than clinically relevant unbound serum concentrations.
Therefore, Zonegran is not expected to affect the pharmacokinetics of other medicinal products via cytochrome P450-mediated mechanisms, as demonstrated for carbamazepine, phenytoin, ethinylestradiol and desipramine in vivo.
Potential for Zonegran to affect other medicinal products: Antiepileptic medicinal products: In epileptic patients, steady-state dosing with Zonegran resulted in no clinically relevant pharmacokinetic effects on carbamazepine, lamotrigine, phenytoin, or sodium valproate.
Oral contraceptives: In clinical studies in healthy subjects, steady-state dosing with Zonegran did not affect serum concentrations of ethinylestradiol or norethisterone in a combined oral contraceptive.
Carbonic anhydrase inhibitors: Zonegran should be used with caution in adult patients treated concomitantly with carbonic anhydrase inhibitors such as topiramate and acetazolamide, as there are insufficient data to rule out a possible pharmacodynamic interaction (see Precautions).
Zonegran should not be used as co-medication in paediatric patients with other carbonic anhydrase inhibitors such as topiramate and acetazolamide (see Precautions).
P-gp substrate: An in vitro study shows that zonisamide is a weak inhibitor of P-gp (MDR1) with an IC₅₀ of 267 µmol/l and there is the theoretical potential for zonisamide to affect the pharmacokinetics of substances which are P-gp substrates. Caution is advised when starting or stqpping zonisamide treatment or changing the zonisamide dose in patients who are also receiving medicinal products which are P-gp substrates (e.g. digoxin, quinidine).
Potential medicinal product interactions affecting Zonegran: In clinical studies co-administration of lamotrigine had no apparent effect on zonisamide pharmacokinetics. The combination of Zonegran with other medicinal products that may lead to urolithiasis may enhance the risk of developing kidney stones; therefore the concomitant administration of such medicinal products should be avoided.
Zonisamide is metabolised partly by CYP3A4 (reductive cleavage), and also by N-acetyl-transferases and conjugation with glucuronic acid; therefore, substances that can induce or inhibit these enzymes may affect the pharmacokinetics of zonisamide: Enzyme induction: Exposure to zonisamide is lower in epileptic patients receiving CYP3A4-inducing agents such as phenytoin, carbamazepine, and phenobarbitone. These effects are unlikely to be of clinical significance when Zonegran is added to existing therapy; however, changes in zonisamide concentrations may occur if concomitant CYP3A4-inducing antiepileptic or other medicinal products are withdrawn, dose adjusted or introduced, an adjustment of the Zonegran dose may be required. Rifampicin is a potent CYP3A4 inducer. If co-administration is necessary, the patient should be closely monitored and the dose of Zonegran and other CYP3A4 substrates adjusted as needed.
CYP3A4 inhibition: Based upon clinical data, known specific and non-specific CYP3A4 inhibitors appear to have no clinically relevant effect on zonisamide pharmacokinetic exposure parameters. Steady-state dosing of either ketoconazole (400 mg/day) or cimetidine (1200 mg/day) had no clinically relevant effects on the single-dose pharmacokinetics of zonisamide given to healthy subjects. Therefore, modification of Zonegran dosing should not be necessary when co-administered with known CYP3A4 inhibitors.
Paediatric population: Interaction studies have only been performed in adults.