Table 3.

Mechanisms, clinical consequences, severity, and frequencies of pharmacokinetic drug-drug interactions involving antiepileptic drugs and other CNS-active drugs identified in patients ≥65 years (n = 882) in home care services and nursing homes.

Antiepileptic drug	Substrates for these enzymes and possible interactions	Clinical effects and potential consequences#	Severity$	Frequencies
Enzyme inducers
Carbamazepine, n = 189
Enzyme-inducing properties, CYP 3A4, 2C9, 1A2, or UGTs	Benzodiazepines	Decrease in serum concentrations of substrates of these enzymes and possibly a decrease in clinical efficacy.	B	32
	Haloperidol	Dose adjustment needed. Decreased serum concentration of haloperidol by 50% but varies with dose of carbamazepine.$	B	7
	Lamotrigine	Dose adjustment needed. Decreased serum concentration of lamotrigine by 50%.	B	6
	Amitriptyline	Dose adjustment needed. Decreased serum concentration of amitriptyline by 50–60%.$	B	5
	Risperidone	Dose adjustment needed. Serum concentration of risperidone and active metabolite reduced by 65% and 50%, respectively.	B	4
	Quetiapine	Dose adjustment needed. Maximum serum concentrations of quetiapine reduced by nearly 80%.	A	3
	Valproic acid	Dose adjustments needed for both drugs. Carbamazepine concentration increased by 25–50%, while valproate concentration reduced by 30%.	B	2
Phenobarbital, n = 63
Enzyme-inducing properties, CYP 3A4 or UGT	Haloperidol	Dose adjustment needed because of decreased serum concentration of haloperidol by 50%.	B	2
Enzyme inhibitory properties on CYP 2C19∗	Risperidone	Dose adjustment needed. Increased serum concentration of risperidone and thus a potential increase of adverse effects or toxicity.	B	1
Phenytoin, n = 39
Enzyme-inducing properties, CYP 3A4 or UGT	Haloperidol	Dose adjustment needed. Decrease in serum concentrations of substrates of these enzymes and possibly a decrease in clinical efficacy because of decreased serum concentration of haloperidol by 50%.	B	1
Enzyme inhibitors
Valproic acid, n = 93
Enzyme inhibitory properties on CYP 2C9/19, 3A4?, UGTs	Lamotrigine	Dose adjustment needed because of an increase in the serum concentrations of substrates of these enzymes. Clearance of lamotrigine reduced by 50%, potentially causing skin rashes and neurotoxic effects.	B	11
	Amitriptyline, carbamazepine	Dose adjustment needed because of decrease of first-pass metabolism of amitriptyline. For carbamazepine, see above.	B	2∗∗
	Clomipramine, phenobarbital, phenytoin	Dose adjustment needed because clearance of phenobarbital reduces by 40% and thus there is a risk of intoxication.	B	3∗∗
In total				79 ∗∗

Clinical effects and potential consequences based on Norwegian and Danish interaction databases in addition to a review by Johannessen and Landmark, 2010 [1]. ^∗Weak inhibition based on Johannessen and Landmark 2010 [1]. ^#According to the Danish drug interaction database. ^$The Norwegian interaction database (DRUID) denotes severity of drug-drug interactions according to a three-point severity scale: A, should not be combined, B, take precautions, and C, of academic interest. Herein, only drug-drug interactions in categories A and B are shown. Drug-drug interactions involving the antiepileptic drugs felbamate (with carbamazepine, diazepam, phenobarbital, phenytoin, and valproic acid), oxcarbazepine (with lamotrigine, phenobarbital, and phenytoin), rufinamide (with carbamazepine and felbamate), stiripentol (with carbamazepine, felbamate, phenobarbital, phenytoin, and valproic acid), topiramate (>200 mg/day with phenytoin), and valproic acid (with clozapine, imipramine, nortriptyline, and rufinamide) were not identified and therefore not included. ^∗∗Duplicates not shown and not counted.