(1)venlafaxine and voriconazole both increase QTc interval. Use Caution/Monitor.Serious - Use Alternative (1)voriconazole will increase the level or effect of venlafaxine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.vorinostatMonitor Closely (1)vorinostat and venlafaxine both decrease QTc interval. Use Caution/Monitor.vortioxetineSerious - Use Alternative (1)venlafaxine, vortioxetine. Either increases effects of the other by serotonin levels. Avoid or Use Alternate Drug.voxelotorSerious - Use Alternative (1)voxelotor will increase the level or effect of venlafaxine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Voxelotor increases systemic exposure of sensitive CYP3A4 substrates. Avoid coadministration with sensitive CYP3A4 substrates with a narrow therapeutic index. Consider dose reduction of the sensitive CYP3A4 substrate(s) if unable to avoid.warfarinMonitor Closely (1)venlafaxine, warfarin. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Serotonin release by platelets plays an important role in hemostasis. SSRIs and SNRIs may increase anticoagulation effect of warfarin. .ziprasidoneMonitor Closely (2)venlafaxine, ziprasidone. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction). venlafaxine and ziprasidone both increase QTc interval. Modify Therapy/Monitor Closely.zolmitriptanMonitor Closely (1)zolmitriptan and venlafaxine both increase serotonin levels. Modify Therapy/Monitor Closely.Minor (1)venlafaxine, zolmitriptan. Mechanism: unknown. Minor/Significance Unknown. Risk of weakness, dyspnea, chest pain. >10% Headache (25-38%) Nausea (21-58%) Insomnia (15-24%) Asthenia (16-20%) Dizziness (11-24%) Ejaculation disorder (2-19%) Somnolence (12-26%) Dry mouth (12-22%) Diaphoresis (7-19%) Anorexia (15-17%) Nervousness (17-26%) Anorgasmia (5-13%) 1-10% Weight loss (1-6%) Abnormal vision (4-6%) Hypertension (2-5%) Impotence (4-6%) Paresthesia (2-3%) Tremor (1-10%) Vasodilation (2-6%) Vomiting (3-8%) Weight gain (2%) Flatulence (3-4%) Pruritus (1%) Yawning (3-8%) Dyspepsia (5-7%) Twitching (1-3%) Mydriasis (2%) <1% Angioedema Agranulocytosis Anemia Anuria Aneurism Bacteremia Myasthenia Syncope Suicide ideation/attempt Postmarketing Reports Chills Dyspnea Interstitial lung disease Takotsubo cardiomyopathy Anaphylaxis Catatonia Impaired coordination and balance Deep vein thrombophlebitis Delirium Black Box Warnings In short-term studies, antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults (<24 years) taking antidepressants for major depressive disorders and other psychiatric illnesses This increase was not seen in patients aged >24 years; slight decrease in suicidal thinking was seen in adults >65 years Not FDA approved for children; in children and young adults; benefits of taking antidepressants must be weighed against risks Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors; this should be done during initial 1-2 months of therapy and dosage adjustments Patient’s family should communicate any abrupt behavioral changes to healthcare provider Worsening behavior and suicidal tendencies that are not part of presenting symptoms may necessitate discontinuance of therapy Not FDA approved for treatment of bipolar depressionContraindications Hypersensitivity Coadministration with serotonergic drugs Coadministration with monoamine oxidase inhibitors (MAOIs) Concomitant MAOIs (including the MAOIs linezolid and intravenous methylene blue) administration within 14 days before initiating venlafaxine or within 7 days after discontinuing venlafaxine Initiation of venlafaxine in patient being treated with linezolid or IV methylene blue Cautions Risk of mydriasis; may trigger angle closure attack in patients with angle closure glaucoma with anatomically narrow angles without a patent iridectomy Use caution in bipolar mania, history of seizures, and cardiovascular disease May precipitate mania or hypomania episodes in patients with bipolar disorder; avoid monotherapy in bipolar disorder; screen patients presenting with depressive symptoms for bipolar disorder Use caution in hepatic or renal impairment Neonates exposed to serotonin-norepinephrine reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs) late in 3rd trimester of pregnancy have developed complications necessitating prolonged hospitalization, respiratory support, and tube feeding Clinical worsening and suicidal ideation may occur despite medication in adolescents and young adults (18-24 years) When discontinuing, taper dosage to avoid flulike symptoms May cause increase in nervousness, anxiety, or insomnia May impair ability to operate heavy machinery; depresses CNS Bone fractures reported with antidepressant therapy; consider possibility if patient experiences bone pain May cause significant increase in serum cholesterol Dose-dependent anorectic effects and weight loss reported in children and adult patients Dose-related increase in systolic and diastolic pressure reported Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine therapy rarely reported; possibility of these events should be considered in patients receiving therapy who present with progressive dyspnea, cough or chest discomfort; such patients should undergo a prompt medical evaluation, and discontinuation of therapy should be considered Potentially life-threatening serotonin syndrome with SSRIs and SNRIs when used in combination with other serotonergic agents including TCAs, buspirone tryptophan, fentanyl, tramadol, lithium, tryptophan, buspirone, amphetamines, St. John’s Wort, and triptans; symptoms include tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, rigidity, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma Venlafaxine in patient being treated with linezolid or IV methylene blue increases risk of serotonin syndrome; if linezolid or IV methylene blue must be administered, discontinue venlafaxine immediately and monitor for central nervous system (CNS) toxicity; therapy may be resumed 24 hours after last linezolid or methylene blue dose or after 2 weeks of monitoring, whichever comes first SSRIs and SNRIs may impair platelet aggregation and increase the risk of bleeding events, ranging from ecchymoses, hematomas, epistaxis, petechiae, and GI hemorrhage to life-threatening hemorrhage; concomitant use of aspirin, NSAIDs, warfarin, other anticoagulants, or other drugs known to affect platelet function may add to this risk Control hypertension before initiating treatment; monitor blood pressure regularly during treatment Risks of sustained hypertension and impeded height and weight in children Drug-laboratory test interactions: False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been observed during venlafaxine therapy because of lack of specificity of the screening tests Hyponatremia Hyponatremia can occur as result of treatment with SNRIs; in many cases, hyponatremia appears to be the result of syndrome of Inappropriate antidiuretic hormone (SIADH)secretion; cases with serum sodium lower than 110 mmol/L reported; elderly patients may beat greater risk of developing hyponatremia with SNRIs Also, patients taking diuretics, or those who are otherwise volume-depleted, may be at greater risk; consider discontinuation of therapy in patients with symptomatic hyponatremia, and institute appropriate medical intervention Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls; signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest,and death Discontinuation syndrome There have been postmarketing reports of serious discontinuation symptoms which can be protracted and severe; completed suicide, suicidal thoughts, aggression and violent behavior reported in patients during reduction in dosage, including during discontinuation Other postmarketing reports describe visual changes (such as blurred vision or trouble focusing) and increased blood pressure after stopping or reducing dose If intolerable symptoms occur following a decrease in dose or upon discontinuation of treatment, then resuming previously prescribed dose may be considered Subsequently, the healthcare provider may continue decreasing the dose, but at a more gradual rate; in some patients, discontinuation may need to occur over a period of several months Sexual dysfunction Use may cause symptoms of sexual dysfunction in both male and female patients; inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider Use of SSRIs, may cause symptoms of sexual dysfunction; in male patients, SSRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction In female patients, SSRI/SNRI use may result in decreased libido and delayed or absent orgasm Important for prescribers to inquire about sexual function prior to initiation of therapy and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including underlying psychiatric disorder Discuss potential management strategies to support patients in making informed decisions about treatment Pregnancy There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including this drug, during pregnancy; healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/ Available data from published epidemiologic studies on this medication use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage or adverse fetal outcomes; available data from observational studies have identified a potential increased risk for preeclampsia when used during mid-to late pregnancy; exposure to SNRIs near delivery may increase risk for postpartum hemorrhage; there are risks associated with untreated depression in pregnancy and poor neonatal adaptation in newborns with exposure to SNRIs, including this drug, during pregnancy Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants; this finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depression who were euthymic and taking antidepressants at beginning of pregnancy Consider risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum Exposure to venlafaxine in mid to late pregnancy may increase risk for preeclampsia, and exposure to SNRIs near delivery may increase risk for postpartum hemorrhage Fetal/neonatal adverse reactions Neonates exposed to SNRIs late in third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding; such complications can arise immediately upon delivery; reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremors, jitteriness, irritability, and constant crying; these findings are consistent with either a direct toxic effect of SNRIs or possibly a drug discontinuation syndrome; it should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome Monitor neonates exposed to this medication in the third trimester of pregnancy for drug discontinuation syndrome Animal studies In animal studies, there was no evidence of malformations or fetotoxicity following administration during organogenesis at doses up to 2.5 times (rat) or 4 times (rabbit) maximum recommended human daily dose on a mg/m2 basis; postnatal mortality and decreased pup weights were observed following venlafaxine administration to pregnant rats during gestation and lactation at 2.5 times (mg/m2) maximum human daily dose Lactation Data from published literature report the presence of venlafaxine and its active metabolite in human milk and have not shown adverse reactions in breastfed infants; there are no data on effects of this drug on milk production; consider developmental and health benefits of breastfeeding along with mothers clinical need for this medication and any potential adverse effects on breastfed child from this medication or from underlying maternal conditionPregnancy Categories A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk. B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available. Mechanism of Action "Bicyclic" antidepressant; drug is structurally unrelated to SSRIs, MAOIs, and tricyclic antidepressants (TCAs), but it and its metabolite are potent inhibitors of serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake; it does not have MAOI activity or activity for H1 histaminergic, muscarinic cholinergic, or alpha2-adrenergic receptors Absorption Absorption: 92% Bioavailability: 45% Peak plasma time: 2-3 hr (immediate release); 5.5-9 hr (extended release) Concentration: Immediate release, 225-290 ng/mL; extended release, 150-260 ng/mL Distribution Protein bound: 27-30% Vd: Immediate release, 7.5 L/kg Metabolism Metabolized in liver by CYP2D6 Metabolites: O-desmethylvenlafaxine Enzymes inhibited: CYP2D6 (weak) Elimination Half-life: 5-11 hr (prolonged in renal or hepatic dysfunction) Dialyzable: No Excretion: Urine (87%) Oral Administration Take with food Extended-release tablets or capsules Administer as a single dose in either the morning or evening at approximately the same time each day Swallow tablet/capsule whole; do not divide, crush, chew, or dissolve in water Discontinuing Do not