ition of CYP2B6 by ezogabine has not been eva luated. In addition, in vitro studies in human primary hepatocytes showed that ezogabine and NAMR did not induce CYP1A2 or CYP3A4/5 activity. Therefore, ezogabine is unlikely to affect the pharmacokinetics of substrates of the major cytochrome P450 isoenzymes through inhibition or induction mechanisms.
Ezogabine is neither a substrate nor an inhibitor of P-glycoprotein, an efflux transporter. NAMR is a P-glycoprotein inhibitor. Data from an in vitro study showed that NAMR inhibited P-glycoprotein–mediated transport of digoxin in a concentration-dependent manner, indicating that NAMR may inhibit renal clearance of digoxin. Administration of POTIGA at therapeutic doses may increase digoxin serum concentrations [see Drug Interactions (7.2)].
Interactions with Antiepileptic Drugs: The interactions between POTIGA and concomitant AEDs are summarized in Table 6.
Table 6. Interactions Between POTIGA and Concomitant Antiepileptic Drugs AED
Dose of AED
(mg/day)
Dose of POTIGA
(mg/day)
Influence of POTIGA on AED
Influence of AED on POTIGA
Dosage Adjustment
Carbamazepinea,b
600-2,400
300-1,200
None
31% decrease in AUC,
23% decrease in Cmax,
28% increase in clearance
consider an increase in dosage of POTIGA when adding carbamazepinec
Phenytoina,b
120-600
300-1,200
None
34% decrease in AUC,
18% decrease in Cmax,
33% increase in clearance
consider an increase in dosage of POTIGA when adding phenytoinc
Topiramatea
250-1,200
300-1,200
None
None
None
Valproatea
750-2,250
300-1,200
None
None
None
Phenobarbital
90
600
None
None
None
Lamotrigine
200
600
18% decrease in AUC,
22% increase in clearance
None
None
Othersd
None
None
None
aBased on results of a Phase 2 study.
bInducer for uridine 5'-diphosphate (UDP)-glucuronyltransferases (UGTs).
cA decrease in dose of POTIGA should be considered when carbamazepine or phenytoin is discontinued.
dZonisamide, valproic acid, clonazepam, gabapentin, levetiracetam, oxcarbazepine, phenobarbital, pregabalin, topiramate, clobazam, and lamotrigine, based on a population pharmacokinetic analysis using pooled data from Phase 3 clinical trials.
Oral Contraceptives: In one study examining the potential interaction between ezogabine (150 mg 3 times daily for 3 days) and the combination oral contraceptive norgestrel/ethinyl estradiol (0.3 mg/0.03 mg) tablets in 20 healthy females, no significant alteration in the pharmacokinetics of either drug was observed.
In a second study examining the potential interaction of repeated ezogabine dosing (250 mg 3 times daily for 14 days) and the combination oral contraceptive norethindrone/ethinyl estradiol (1 mg/0.035 mg) tablets in 25 healthy females, no significant alteration in the pharmacokinetics of either drug was observed.
Alcohol: In a healthy volunteer study, the coadministration of ethanol 1g/kg (5 standard alcohol drinks) over 20 minutes and ezogabine (200 mg) resulted in an increase in the ezogabine Cmax and AUC by 23% and 37%, respectively [see Drug Interactions (7.3)].
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogene |
