Monoamine oxidase inhibitors (MAOI): Adverse reactions, some of which were serious, have been reported in patients who have recently been discontinued from a monoamine oxidase inhibitor (including reversible MAOIs such as linezolid and intravenous methylene blue) and started on antidepressants with pharmacological properties similar to desvenlafaxine (SNRIs or SSRIs), or who have recently had SNRI or SSRI therapy discontinued prior to initiation of an MAOI (see DOSAGE & ADMINISTRATION and PRECAUTIONS). Concomitant use of desvenlafaxine in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see CONTRAINDICATIONS).
Central nervous system (CNS)-active agents: The risk of using desvenlafaxine in combination with other CNS-active drugs has not been systematically evaluated. Consequently, caution is advised when desvenlafaxine is taken in combination with other CNS-active drugs.
Serotonin syndrome: As with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, may occur with desvenlafaxine treatment, particularly with concomitant use of other agents that may affect the serotonergic neurotransmitter system (including triptans, SSRIs, other SNRIs, amphetamines, lithium, sibutramine opioids (e.g., fentanyl and its analogues, tramadol, dextromethorphan, tapentadol, meperidine, methadone, pentazocine) or St. John's Wort (Hypericum perforatum), with drugs that impair metabolism of serotonin (such as MAOIs, including linezolid [an antibiotic which is a reversible non-selective MAOI] and methylene blue), or with serotonin precursors (such as tryptophan supplements) (see DOSAGE & ADMINISTRATION, CONTRAINDICATIONS and PRECAUTIONS).
If concomitant treatment with desvenlafaxine and an SSRI, an SNRI or a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of desvenlafaxine with serotonin precursors (such as tryptophan supplements) is not recommended (see PRECAUTIONS).
Ethanol: A clinical trial has shown that desvenlafaxine does not increase the impairment of mental and motor skills caused by ethanol. However, as with all CNS-active drugs, patients should be advised to avoid alcohol consumption while taking desvenlafaxine.
Potential for other drugs to affect desvenlafaxine: Inhibitors of CYP3A4: CYP3A4 is minimally involved in desvenlafaxine elimination. In a clinical trial, ketoconazole (200 mg BID) increased the area under the concentration vs. time curve (AUC) of desvenlafaxine (400 mg single dose) by approximately 43%, a weak interaction, and Cmax by about 8%. Concomitant use of desvenlafaxine with potent inhibitors of CYP3A4 may result in higher exposure to desvenlafaxine.
Inhibitors of other CYP enzymes: Based on in vitro data, drugs that inhibit CYP isozymes 1A1, 1A2, 2A6, 2D6, 2C8, 2C9, 2C19, and 2E1 are not expected to have significant impact on the pharmacokinetic profile of desvenlafaxine.
Potential for desvenlafaxine to affect other drugs: Drugs metabolized by CYP2D6: Clinical trials have shown that desvenlafaxine does not have a clinically relevant effect on CYP2D6 metabolism at a dose of 100 mg daily. When desvenlafaxine succinate was administered at a dose of 100 mg daily in conjunction with a single 50 mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased approximately 17%. When 400 mg was administered, the AUC of desipramine increased approximately 90%. When desvenlafaxine succinate was administered at a dose of 100 mg daily in conjunction with a single 60 mg dose of codeine, a CYP2D6 substrate metabolized to morphine, the AUC of codeine was unchanged, the AUC of morphine decreased approximately 8%. Concomitant use of desvenlafaxine with a drug metabolized by CYP2D6 may result in increased concentrations of that drug and decreased concentrations of its CYP2D6 metabolites.
Drugs metabolized by CYP3A4: In vitro, desvenlafaxine does not inhibit, or induce the CYP3A4 isozymes. In a clinical trial, desvenlafaxine (400 mg daily) decreased the AUC of midazolam (single 4 mg dose), a CYP3A4 substrate, by approximately 31%. In a second study, PRISTIQ 50 mg daily was co-administered with a single 4 mg dose of midazolam. The AUC and Cmax of midazolam decreased by approximately 29% and 14%, respectively. Concomitant use of desvenlafaxine with a drug metabolized by CYP3A4 may result in lower exposures to that drug.
Drugs metabolized by a combination of both CYP2D6 and CYP3A4 (tamoxifen and aripiprazole): Clinical studies have shown that desvenlafaxine (100 mg daily) does not have a clinically relevant effect on drugs metabolized by a combination of both CYP2D6 and CYP3A4 enzymes.
A single 40 mg dose of tamoxifen, which is metabolized to active metabolites 4-hydroxy-tamoxifen and endoxifen primarily by CYP2D6 with minor contributions to metabolism by CYP3A4, was administered in conjunction with desvenlafaxine succinate (100 mg daily). The AUC increased by 3% with concomitant administration of desvenlafaxine succinate. The AUC of 4-hydroxy-tamoxifen increased by 9%. Endoxifen AUC was decreased by 12%.
Desvenlafaxine succinate was administered at a dose of 100 mg daily in conjunction with a single 5 mg dose of aripiprazole, a CYP2D6 and CYP3A4 substrate metabolized to the active metabolite dehydro-aripiprazole. The AUC of aripiprazole increased by 6%, with concomitant administration of desvenlafaxine succinate. The AUC of dehydro-aripiprazole increased by 3%, with concomitant administration.
Drugs metabolized by CYP1A2, 2A6, 2C8, 2C9 and 2C19: In vitro, desvenlafaxine does not inhibit CYP1A2, 2A6, 2C8, 2C9, and 2C19 isozymes and would not be expected to affect the pharmacokinetics of drugs that are metabolized by these CYP isozymes.
P-glycoprotein transporter: In vitro, desvenlafaxine is not a substrate or an inhibitor for the P-glycoprotein transporter.
Drug-laboratory test interactions: False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking desvenlafaxine. This is due to lack of specificity of the screening tests. False-positive test results may be expected for several days following discontinuation of desvenlafaxine therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish desvenlafaxine from PCP and amphetamine.
Electroconvulsive therapy: There are no clinical data establishing the risks and/or benefits of electroconvulsive therapy combined with desvenlafaxine treatment for MDD.