MAOIs: Due to the risk of serotonergic syndrome, duloxetine should not be used in combination with non-selective irreversible monoamine oxidase inhibitors (MAOIs), or within at least 14 days of discontinuing treatment with MAOIs. Based on the half-life of duloxetine, at least 5 days should be allowed after stopping duloxetine before starting MAOIs (see Contraindications).
For selective, reversible MAOIs, like moclobemide, the risk of serotonin syndrome is lower. However, the concomitant use of duloxetine with selective, reversible MAOIs is not recommended (see Precautions).
Serotonin Syndrome: In rare cases, serotonin syndrome has been reported in patients using SSRIs (e.g. paroxetine, fluoxetine) concomitantly with serotonergic medicinal products. Caution is advisable if duloxetine is used concomitantly with serotonergic antidepressants like SSRIs, tricyclics like clomipramine or amitriptyline, St. John's wort (Hypericum perforatum), venlafaxine or triptans, tramadol, pethidine and tryptophan.
Drugs metabolized by CYP1A2: In a clinical study, the pharmacokinetics of theophylline, a CYP1A2 substrate, were not significantly affected by co-administration with duloxetine (60 mg twice daily). The study was performed in males and it cannot be excluded that females having a lower CYP1A2 activity and higher plasma concentrations of duloxetine may experience an interaction with CYP1A2 substrate.
Inhibitors of CYP1A2: Because CYP1A2 is involved in duloxetine metabolism, concomitant use of duloxetine with potent inhibitors of CYP1A2 will likely result in higher concentrations of duloxetine. Fluvoxamine (100 mg once daily), a potent inhibitor of CYP1A2, decreased the apparent plasma clearance of duloxetine by about 77% and increased AUC0-t 6-fold. Therefore, duloxetine should not be administered in combination with potent inhibitors of CYP1A2 like fluvoxamine (see Contraindications).
Inducers of CYP1A2: Population pharmacokinetics studies have shown that smokers have almost 50% lower plasma concentrations of duloxetine compared with non-smokers.
Drugs metabolized by CYP2D6: Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine was administered at a dose of 60 mg twice daily with a single dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased by 3-fold. The co-administration of duloxetine increases steady state AUC of tolterodine (2 mg twice daily) by 71%, but does not affect the pharmacokinetics of its 5-hydroxyl metabolite. Therefore, caution should be used if duloxetine is co-administered with medications that are predominantly metabolized by CYP2D6 and which have a narrow therapeutic index.
Inhibitors of CYP2D6: As CYP2D6 is involved in duloxetine metabolism, concomitant use of duloxetine with potent inhibitors of CYP2D6 may result in higher concentrations of duloxetine.
Paroxetine (20 mg once daily) decreased the apparent plasma clearance of duloxetine by about 37%. Caution is advised if administering duloxetine with inhibitors of CYP2D6 (e.g., SSRIs).
CNS medicinal products: The risk of using duloxetine in combination with other CNS-active medicinal products has not been systematically evaluated, except in the cases described in this section. Consequently, caution is advised when Duloxetine (Cymbalta) is taken in combinations with other centrally acting medicinal products and substances including alcohol and sedative medicinal products (e.g. benzodiazepines, morphinomimetics, antipsychotics, phenobarbital, sedative antihistamines). Concomitant use of other drugs with serotonergic activity (e.g., SNRIs, SSRIs, triptans or tramadol) may result in serotonin syndrome.
Drugs highly bound to plasma protein: Duloxetine is highly bound to plasma proteins (>90%). Therefore, administration of duloxetine to a patient taking another drug that is highly protein bound may cause an increase in free concentrations of either drug.
Antacids and H2 antagonists: Co-administration of duloxetine with aluminium- and magnesium-containing antacids or duloxetine with famotidine had no significant effect on the rate or extent of duloxetine absorption after administration of a 40 mg oral dose.
Oral contraceptives and other steroidal agents: Results of in vitro studies demonstrate that duloxetine does not inhibit or induce the catalytic activity of CYP3A. Specific in vivo drug interaction studies have not been performed.