Table 4.

Clinically Important Drug Combinations Involving AEDs (Level 1-2)

AED	Added Drug	Clinical Consequence	Level of Importance (1-2)	Precautions
Carbamazepine	Oral contraceptives	Induction of estrogen metabolism, reduction in serum concentrations, and loss of contraceptive effect	Level 1: Should be avoided	Avoid the combination (or use of oral contraceptives with >50 µg ethinylestradiol), utilize barrier contraception. Addition of 4 mg folic acid daily for women of child bearing potential if used
Carbamazepine	Antibiotics: Clarithromycin, erythromycin, troleandomycin	Inhibition of carbamazepine metabolism, elevated serum concentrations, giving rise to potential serious toxicity if the antibiotics are added	Level 1: Should be avoided	Avoid macrolide antibiotics that inhibit CYP3A4, prefer azithromycin or spiramycin
Carbamazepine	Dextropropoxyphene	Inhibition of carbamazepine metabolism, elevated serum concentrations, giving rise to potential serious toxicity if the analgesic drug is added	Level 1: Should be avoided	The combination should be avoided.
Lamotrigine	Oral contraceptives	Induction of lamotrigine metabolism, reduction in serum concentrations by 50 %, and reduced seizure control, if OCs are added	Level 1: Should be avoided	The combination should be avoided. Alternatively, increase in lamotrigine dose and monitor closely
Valproic acid	Lamotrigine	Inhibition of lamotrigine metabolism and elevated serum concentrations giving rise to skin rashes, or neurotoxic effects if lamotrigine is added to valproic acid A synergistic pharmacological effect and improved seizure control	Level 2: Dosage adjustments and monitoring are needed	Low initial dose and slow titration of lamotrigine dose when initiating therapy, about 50 % of the dose used in monotherapy is required A dose reduction of both drugs may reduce risk of adverse effects without affecting the efficacy
Valproic acid	Phenobarbital	Inhibition of phenobarbital metabolism resulting in elevated serum concentrations, and risk of intoxication if valproic acid is added as a second drug	Level 2: Dosage adjustments and monitoring are needed	A reduction in phenobarbital dose by up to 80 %
Carbamazepine (or phenobarbital, phenytoin, primidone)	Oral anticoagulant: Warfarin	Induction of warfarin metabolism, reduced serum concentrations, increasing the risk of coagulation that may be fatal if enzyme-inducing AEDs are added	Level 2: Dosage adjustments and monitoring are needed	An increase in the warfarin dose required to maintain the INR, close monitoring of INR.
Carbamazepine (or phenobarbital, phenytoin, primidone)	Immunsuppressants: Ciclosporin, tacrolimus	Induction of immunosuppressant metabolism, reduction in serum concentrations, and potential therapeutic failure if enzymeinducing AEDs are added	Level 2: Dosage adjustments and monitoring are needed	Increase in the dose of immunosuppressant to avoid therapeutic failure, important for drugs with a narrow therapeutic range

AEDs=Antiepileptic drugs. Several references are used, see text for details.