Duloxetine D/R

Carbapenem antibiotic causing clinically significant reduction in serum valproic acid concentration, potentially resulting in loss of seizure control.

Potent CYP1A2 inhibitor increases duloxetine AUC approximately 6-fold, Cmax about 2.5-fold, and t1/2 approximately 3-fold.

Carbapenem antibiotic causing clinically significant reduction in serum valproic acid concentration, potentially resulting in loss of seizure control.

Carbapenem antibiotic causing clinically significant reduction in serum valproic acid concentration, potentially resulting in loss of seizure control.

May potentiate upper gastrointestinal bleeding risk when used with duloxetine.

Can double the clearance of valproate, potentially decreasing valproate concentrations. Monitor valproate levels when introduced or withdrawn.

CYP1A2 inhibitor that may increase duloxetine concentrations.

Quinolone antimicrobial that inhibits CYP1A2 and may increase duloxetine concentrations.

Quinolone antimicrobial that inhibits CYP1A2 and may increase duloxetine concentrations.

May increase clearance of valproate, resulting in decreased valproate concentration and potentially increased seizure frequency. Monitor serum valproate concentrations.

Potent CYP2D6 inhibitor expected to increase duloxetine concentrations similarly to paroxetine.

Potent CYP2D6 inhibitor increases duloxetine AUC by about 60% at 20 mg daily; greater increases expected at higher doses.

Can double the clearance of valproate, potentially decreasing valproate concentrations. Monitor valproate levels when introduced or withdrawn.

Can double the clearance of valproate, potentially decreasing valproate concentrations. Monitor valproate levels when introduced or withdrawn.

Can double the clearance of valproate, potentially decreasing valproate concentrations. Monitor valproate levels when introduced or withdrawn.

Potent CYP2D6 inhibitor expected to increase duloxetine concentrations.

Elevates hepatic glucuronosyltransferase levels, increasing clearance of valproate. Monitoring of valproate concentrations recommended.

Duloxetine may potentiate bleeding risk; careful monitoring recommended when initiating or discontinuing duloxetine in patients on warfarin therapy.

No significant pharmacokinetic interaction with duloxetine at steady-state conditions.

No significant pharmacokinetic interaction with duloxetine at steady-state conditions.

Clonazepam The concomitant use of valproate and clonazepam may induce absence status in patients with a history of absence type seizures.

Diazepam Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Coadministration of valproate (1,500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate.

Ethosuximide Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg with valproate (800 to 1,600 mg/day) to healthy volunteers (n=6) was accompanied by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs.

Other drugs that inhibit CYP1A2 metabolism include cimetidine and quinolone antimicrobials such as ciprofloxacin and enoxacin [see Warnings and Precautions (5.12)].

Rufinamide Based on a population pharmacokinetic analysis, rufinamide clearance was decreased by valproate. Rufinamide concentrations were increased by <16% to 70%, dependent on concentration of valproate (with the larger increases being seen in pediatric patients at high doses or concentrations of valproate). Patients stabilized on rufinamide before being prescribed valproate should begin valproate therapy at a low dose, and titrate to a clinically effective dose [see Dosage and Administration (2.5)].

Tolbutamide From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients treated with valproate.