Monoamine Oxidase Inhibitors: Severe adverse reactions have been reported in patients who have recently been discontinued from a MAOI and started on venlafaxine, or have recently had venlafaxine therapy discontinued prior to initiation of a MAOI (see Contraindications). These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness and hyperthermia with features resembling NMS, seizures, and death.
CNS-Active Drugs: The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated. Consequently, caution is advised when venlafaxine 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 venlafaxine treatment, particularly with concomitant use of other agents that may affect the serotonergic neurotransmitter system including triptans, SSRIs, other SNRIs, amphetamines, lithium, sibutramine, fentanyl and its analogues, tramadol, dextromethorphan, tapentadol, meperidine, methadone, pentazocine, or St. John's Wort (Hypericum perforatum), with drugs that impair the 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 Contraindications and Precautions).
If concomitant treatment with venlafaxine 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 venlafaxine with serotonin precursors such as tryptophan supplements is not recommended (see Precautions).
Drugs that Prolong QT Interval: The risk of QTc prolongation and/or ventricular arrhythmias (e.g., TdP) is increased with concomitant use of other drugs which prolong the QTc interval (e.g., some antipsychotics and antibiotics) (see Precautions).
Indinavir: A pharmacokinetic study with indinavir has shown a 28% decrease in area under the concentration versus time curve (AUC) and a 36% decrease in Cmax for indinavir. Indinavir did not affect the pharmacokinetics of venlafaxine and O-desmethylvenlafaxine (ODV). The clinical significance of this interaction is unknown.
Ethanol: Venlafaxine has been shown not to 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 venlafaxine.
Haloperidol: A pharmacokinetic study with haloperidol has shown a 42% decrease in total oral clearance, a 70% increase in AUC, an 88% increase in Cmax, but no change in half-life. This should be taken into account in patients treated with haloperidol and venlafaxine concomitantly.
Cimetidine: At steady-state, cimetidine has been shown to inhibit first-pass metabolism of venlafaxine. However, cimetidine had no effect on the pharmacokinetics of ODV. The overall pharmacological activity of venlafaxine plus ODV is expected to increase only slightly in most patients. In the elderly and in patients with hepatic dysfunction this interaction may be more pronounced.
Imipramine: Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine. However, desipramine AUC, Cmax, and Cmin increased by about 35% in the presence of venlafaxine. There was an increase of 2-OH-desipramine AUC by 2.5- to 4.5-fold. Imipramine did not affect the pharmacokinetics of venlafaxine and ODV. This should be taken into account in patients treated with imipramine and venlafaxine concomitantly.
Ketoconazole: A pharmacokinetic study with ketoconazole in extensive metabolizers (EM) and poor metabolizers (PM) of CYP2D6 resulted in higher plasma concentrations of both venlafaxine and ODV in subjects following administration of ketoconazole. Venlafaxine Cmax increased by 26% in EM subjects and 48% in PM subjects. Cmax values for ODV increased by 14% and 29% in EM and PM subjects, respectively. Venlafaxine AUC increased by 21% in EM subjects and 70% in PM subjects. AUC values for ODV increased by 23% and 33% in EM and PM subjects, respectively (see Potential for Other Drugs to Affect Venlafaxine as follows).
Metoprolol: Concomitant administration of venlafaxine (50 mg every 8 hours for 5 days) and metoprolol (100 mg every 24 hours for 5 days) to healthy volunteers in a pharmacokinetic interaction study for both drugs resulted in increase in plasma concentrations of metoprolol by approximately 30% - 40% without altering the plasma concentrations of its active metabolite, α-hydroxymetoprolol. Venlafaxine appeared to reduce the blood pressure lowering effect of metoprolol in this study of healthy volunteers. The clinical relevance of this finding in hypertensive patients is unknown. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, ODV. Caution should be exercised with co-administration of venlafaxine and metoprolol.
Risperidone: Venlafaxine increased risperidone AUC by 32% but did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone). The clinical significance of this interaction is unknown.
Diazepam: Diazepam does not appear to affect the pharmacokinetics of either venlafaxine or ODV. Venlafaxine has no effects on the pharmacokinetics and pharmacodynamics of diazepam and its active metabolite, desmethyldiazepam.
Lithium: The steady-state pharmacokinetics of venlafaxine and ODV are not affected when lithium is co-administered. Venlafaxine has no effect on the pharmacokinetics of lithium (previously mentioned CNS - Active Drugs).
Drugs Highly Bound to Plasma Proteins: Venlafaxine is not highly bound to plasma proteins (27% bound); therefore, administration of venlafaxine to a patient taking another drug that is highly protein bound is not expected to cause increased free concentrations of the other drug.
Drugs Metabolized by Cytochrome P450 Isoenzymes: Studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. Venlafaxine did not inhibit CYP3A4, CYP1A2, and CYP2C9 in vitro. This was confirmed by in vivo studies with the following drugs: alprazolam (CYP3A4), caffeine (CYP1A2), carbamazepine (CYP3A4), diazepam (CYP3A4 and CYP2C19) and tolbutamide (CYP2C9).
Potential for Other Drugs to Affect Venlafaxine: The metabolic pathways for venlafaxine include CYP2D6 and CYP3A4. Venlafaxine is primarily metabolized to its active metabolite, ODV, by the cytochrome P450 enzyme CYP2D6. CYP3A4 is a minor pathway relative to CYP2D6 in the metabolism of venlafaxine.
CYP2D6 Inhibitors: Concomitant use of CYP2D6 inhibitors and venlafaxine may reduce the metabolism of venlafaxine to ODV, resulting in increased plasma concentrations of venlafaxine and decreased concentrations of ODV. As venlafaxine and ODV are both pharmacologically active, no dosage adjustment is required when venlafaxine is co-administered with a CYP2D6 inhibitor.
CYP3A4 Inhibitors: Concomitant use of CYP3A4 inhibitors and venlafaxine may increase the levels of venlafaxine and ODV (see previously mentioned Ketoconazole). Therefore, caution is advised when combining venlafaxine with a CYP3A4 inhibitor.
CYP2D6 and CYP3A4 Inhibitors: The concomitant use of venlafaxine with drug treatment(s) that potentially inhibits both CYP2D6 and CYP3A4, the primary metabolizing enzymes for venlafaxine, has not been studied. However, this concomitant use would be expected to increase venlafaxine plasma concentrations. Therefore, caution is advised when combining venlafaxine with any agent(s) that produces simultaneous inhibition of these two enzyme systems.
Electroconvulsive Therapy: There are no clinical data establishing the benefit of electroconvulsive therapy combined with venlafaxine treatment.
Drug-Laboratory Test Interactions: False-positive urine immunoassay screening tests for PCP and amphetamine have been reported in patients taking venlafaxine. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of venlafaxine therapy.
Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish venlafaxine from PCP and amphetamine.