Monoamine oxidase inhibitors (MAOIs): Due to the risk of serotonin syndrome, Cymbalta should not be used in combination with non-selective irreversible MAOIs, or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of Cymbalta, at least 5 days should be allowed after stopping Cymbalta before starting an MAOI (see Contraindications).
The concomitant use of Cymbalta with selective, reversible MAOIs, like moclobemide, is not recommended (see Precautions). The antibiotic linezolid is a reversible non-selective MAOI and should not be given to patients treated with Cymbalta (see Precautions).
Inhibitors of CYP1A2: Because CYP1A2 is involved in Cymbalta metabolism, concomitant use of Cymbalta with potent inhibitors of CYP1A2 is likely to result in higher concentrations of Cymbalta. Fluvoxamine (100 mg once daily), a potent inhibitor of CYP1A2, decreased the apparent plasma clearance of Cymbalta by about 77% and increased AUC0-t 6-fold. Therefore Cymbalta should not be administered in combination with potent inhibitors of CYP1A2 like fluvoxamine (see Contraindications).
CNS medicinal products: The risk of using Cymbalta 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 Cymbalta is taken in combination with other centrally acting medicinal products or substances, including alcohol and sedative medicinal products (e.g. benzodiazepines, morphinomimetics, antipsychotics, phenobarbital, sedative antihistamines).
Serotonergic agents: In rare cases, serotonin syndrome has been reported in patients using SSRIs/SNRIs concomitantly with serotonergic agents. Caution is advisable if Cymbalta is used concomitantly with serotonergic agents like SSRIs, SNRIs, TCAs like clomipramine or amitriptyline, MAOIs like moclobemide or linezolid, St John's wort (Hypericum perforatum) or triptans, tramadol, pethidine and tryptophan (see Precautions).
Effect of Cymbalta on other medicinal products: Medicinal products metabolised by CYP1A2: The pharmacokinetics of theophylline, a CYP1A2 substrate, were not significantly affected by co-administration with Cymbalta (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 Cymbalta may experience an interaction with a CYP1A2 substrate.
Medicinal products metabolised by CYP2D6: Cymbalta is a moderate inhibitor of CYP2D6. When Cymbalta was administered at a dose of 60 mg twice daily with a single dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold. The co-administration of Cymbalta (40 mg twice daily) increases steady state AUC of tolterodine (2 mg twice daily) by 71%, but does not affect the pharmacokinetics of its active 5-hydroxyl metabolite and no dosage adjustment is recommended. Caution is advised if Cymbalta is co-administered with medicinal products that are predominantly metabolised by CYP2D6 (risperidone, TCAs such as nortriptyline, amitriptyline, and imipramine) particularly if they have a narrow therapeutic index (such as flecainide, propafenone and metoprolol).
Drugs highly bound to plasma proteins: Addition of Cymbalta with another drug that is highly bound to plasma proteins may increase free concentrations of the other drug, potentially resulting in adverse events.
Oral contraceptives and other steroidal agents: Results of in vitro studies demonstrate that Cymbalta does not induce the catalytic activity of CYP3A. Specific in vivo drug interaction studies have not been performed.
Anticoagulants and antiplatelet agents: Caution should be exercised when Cymbalta is combined with oral anticoagulants or antiplatelet agents due to a potential increased risk of bleeding attributable to a pharmacodynamic interaction. Furthermore, increases in INR values have been reported when Cymbalta was co-administered to patients treated with warfarin. However, concomitant administration of Cymbalta with warfarin under steady state conditions, in healthy volunteers, as part of a clinical pharmacology study, did not result in a clinically significant change in INR from baseline or in the pharmacokinetics of R- or S-warfarin.
Effects of other medicinal products on Cymbalta: Antacids and H2 antagonists: Co-administration of Cymbalta with aluminium- and magnesium-containing antacids or Cymbalta with famotidine had no significant effect on the rate or extent of Cymbalta absorption after administration of a 40 mg oral dose.
Inducers of CYP1A2: Population pharmacokinetic analyses have shown that smokers have almost 50% lower plasma concentrations of Cymbalta compared with non-smokers.