Smoking Status — Duloxetine bioavailability (AUC) appears to be reduced by about one-third in smokers. Dosage modifications are not recommended for smokers.

Race — No specific pharmacokinetic study was conducted to investigate the effects of race.

Renal Insufficiency — Limited data are available on the effects of duloxetine in patients with end-stage renal disease (ESRD). After a single 60-mg dose of duloxetine, Cmax and AUC values were approximately 100% greater in patients with end-stage renal disease receiving chronic intermittent hemodialysis than in subjects with normal renal function. The elimination half-life, however, was similar in both groups. The AUCs of the major circulating metabolites, 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate, largely excreted in urine, were approximately 7- to 9-fold higher and would be expected to increase further with multiple dosing. For this reason, Cymbalta is not recommended for patients with end-stage renal disease (requiring dialysis) or severe renal impairment (estimated creatinine clearance [CrCl] < 30 mL/min) (see DOSAGE AND ADMINISTRATION). Population PK analyses suggest that mild to moderate degrees of renal dysfunction (estimated CrCl 30-80 mL/min) have no significant effect on duloxetine apparent clearance.

Hepatic Insufficiency — Patients with clinically evident hepatic insufficiency have decreased duloxetine metabolism and elimination. After a single 20-mg dose of Cymbalta, 6 cirrhotic patients with moderate liver impairment (Child-Pugh Class B) had a mean plasma duloxetine clearance about 15% that of age- and gender-matched healthy subjects, with a 5-fold increase in mean exposure (AUC). Although Cmax was similar to normals in the cirrhotic patients, the half-life was about 3 times longer (see PRECAUTIONS). It is recommended that duloxetine not be administered to patients with any hepatic insufficiency (see DOSAGE AND ADMINISTRATION).

Nursing Mothers — The disposition of duloxetine was studied in 6 lactating women who were at least 12-weeks postpartum. Duloxetine 40 mg BID was given for 3.5 days. Lactation did not influence duloxetine pharmacokinetics. Like many other drugs, duloxetine is detected in breast milk, and steady-state concentrations in breast milk are about one-fourth those in plasma. The amount of duloxetine in breast milk is approximately 7 µg/day while on 40 mg BID dosing. The excretion of duloxetine metabolites into breast milk was not examined. Because the safety of duloxetine in infants is not known, nursing while on Cymbalta is not recommended (see DOSAGE AND ADMINISTRATION).

Drug-Drug Interactions

(also see PRECAUTIONS, DRUG INTERACTIONS)

Potential for Other Drugs to Affect Duloxetine

Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism.

Inhibitors of CYP1A2 — When duloxetine 60 mg was co-administered with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to male subjects (n=14) duloxetine AUC was increased approximately 6-fold, the Cmax was increased about 2.5-fold, and duloxetine t_½ was increased approximately 3-fold. Other drugs that inhibit CYP1A2 metabolism include cimetidine and quinolone antimicrobials such as ciprofloxacin and enoxacin.

Inhibitors of CYP2D6 — Because CYP2D6 is involved in duloxetine metabolism, concomitant use of duloxetine with potent inhibitors of CYP2D6 would be expected to, and does, result in higher concentrations (on average 60%) of duloxetine (see PRECAUTIONS, DRUG INTERACTIONS).

Dual Inhibition of CYP1A2 and CYP2D6 — Concomitant administration of duloxetine 40 mg BID with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to CYP2D6 poor metabolizer subjects (n=14) resulted in a 6-fold increase in duloxetine AUC and Cmax.

Studies with Benzodiazepines

Lorazepam — Under steady-state conditions for duloxetine (60 mg Q 12 hours) and lorazepam (2 mg Q 12 hours), the pharmacokinetics of duloxetine were not affected by co-administration.

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