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Venlafaxine

Pronunciation

Pronunciation

(ven la FAX een)

Index Terms

  • Venlafaxine HCl

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule Extended Release 24 Hour, Oral:

Effexor XR: 37.5 mg, 75 mg, 150 mg

Generic: 37.5 mg, 75 mg, 150 mg

Tablet, Oral:

Generic: 25 mg, 37.5 mg, 50 mg, 75 mg, 100 mg

Tablet Extended Release 24 Hour, Oral:

Generic: 37.5 mg, 75 mg, 150 mg, 225 mg

Brand Names: U.S.

  • Effexor XR

Pharmacologic Category

  • Antidepressant, Serotonin/Norepinephrine Reuptake Inhibitor

Pharmacology

Venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Venlafaxine and ODV have no significant activity for muscarinic cholinergic, H1-histaminergic, or alpha2-adrenergic receptors. Venlafaxine and ODV do not possess MAO-inhibitory activity. Venlafaxine functions like an SSRI in low doses (37.5 mg/day) and as a dual mechanism agent affecting serotonin and norepinephrine at doses above 225 mg/day (Harvey 2000; Kelsey 1996).

Absorption

Oral: ≥92%; extended-release has a slightly slower rate of absorption compared to immediate-release

Distribution

Vdss: Venlafaxine 7.5 ± 3.7 L/kg, ODV 5.7 ± 1.8 L/kg

Metabolism

Hepatic via CYP2D6 to active metabolite, O-desmethylvenlafaxine (ODV); other metabolites include N-desmethylvenlafaxine and N,O-didesmethylvenlafaxine

Excretion

Urine (~87%; 5% of total dose as unchanged drug; 29% of total dose as unconjugated ODV; 26% of total dose as conjugated ODV; 27% of total dose as minor inactive metabolites)

Clearance:

Adults with cirrhosis: Venlafaxine: Clearance is decreased by ~50%; ODV: Clearance is decreased by ~30%

Adults with more severe cirrhosis: Venlafaxine: Clearance is decreased by ~90%

Adults with renal impairment (GFR: 10-70 mL/minute): Venlafaxine: Clearance is decreased by ~24%; ODV: Clearance unchanged versus normal subjects

Adults on dialysis: Venlafaxine: Clearance decreased by ~57%; ODV: Clearance decreased by ~56%

Time to Peak

Immediate release: Venlafaxine: 2 hours, ODV: 3 hours

Extended release: Venlafaxine: 6.3 ± 2.3 hours, ODV: 11.6 ± 2.9 hours

Half-Life Elimination

Venlafaxine: 5 ± 2 hours (immediate-release), 10.7 ± 3.2 hours (extended-release); ODV: 11 ± 2 hours (immediate-release), 12.5 ± 3 hours (extended-release); prolonged with cirrhosis (venlafaxine: ~30%, ODV: ~60%), renal impairment (venlafaxine: ~50%, ODV: ~40%), and during dialysis (venlafaxine: ~180%, ODV: ~142%)

Protein Binding

Venlafaxine 27% ± 2%, ODV 30% ± 12%

Special Populations: Renal Function Impairment

Elimination half-life is prolonged and clearance is reduced.

Special Populations: Hepatic Function Impairment

Elimination half-life is prolonged and clearance decreased. In patients with Child-Pugh class A and Child-Pugh class B hepatic impairment, venlafaxine oral bioavailability was increased 2- to 3-fold.

Use: Labeled Indications

Generalized anxiety disorder (extended-release capsules only): Treatment of generalized anxiety disorder (GAD)

Major depressive disorder: Treatment of major depressive disorder (MDD)

Panic disorder (extended-release capsules only): Treatment of panic disorder, with or without agoraphobia

Social anxiety disorder (extended-release capsules and tablets only): Treatment of social anxiety disorder, also known as social phobia

Use: Unlabeled

Obsessive-compulsive disorder (OCD); hot flashes; neuropathic pain (including diabetic neuropathy); attention-deficit/hyperactivity disorder (ADHD); post-traumatic stress disorder (PTSD); migraine prophylaxis

Contraindications

Hypersensitivity to venlafaxine or any component of the formulation; use of MAOIs intended to treat psychiatric disorders (concurrently or within 14 days of discontinuing the MAOI); initiation of MAOI intended to treat psychiatric disorders within 7 days of discontinuing venlafaxine; initiation in patients receiving linezolid or IV methylene blue.

Dosing: Adult

Depression: Oral:

Immediate-release tablets: Initial: 37.5 to 75 mg/day, administered in 2 or 3 divided doses; may increase in ≤75 mg/day increments at intervals of ≥4 days as tolerated; usual dosage: 75 to 225 mg/day (maximum dose: 375 mg/day) (APA 2010)

Extended-release capsules or tablets: Initial: 37.5 to 75 mg once daily; in patients who are initiated at 37.5 mg once daily, may increase to 75 mg once daily after 4 to 7 days; dose may then be increased by ≤75 mg/day increments at intervals of ≥4 days as tolerated; usual dosage: 75 to 225 mg once daily (maximum dose: 225 mg/day)

Note: Patients treated with a therapeutic dose with venlafaxine immediate release may be switched to venlafaxine extended release (ER) at the nearest equivalent dose (mg/day). Following the formulation switch individual dosage adjustments may be necessary.

Generalized anxiety disorder: Oral: Extended-release capsules: Initial: 37.5 to 75 mg once daily; in patients who are initiated at 37.5 mg once daily, may increase to 75 mg once daily after 4 to 7 days; may then be increased by ≤75 mg/day increments at intervals of ≥4 days as tolerated; usual dosage: 75 to 225 mg once daily (maximum dose: 225 mg/day)

Panic disorder: Oral: Extended-release capsules: Initial: 37.5 mg once daily for 1 week; may increase to 75 mg once daily after 7 days, may then be increased by ≤75 mg/day increments at intervals of ≥7 days; usual dosage: 75 to 225 mg once daily (maximum dose: 225 mg/day).

Social anxiety disorder: Oral: Extended-release capsules or tablets: 75 mg once daily; no evidence that doses >75 mg/day offer any additional benefit.

Attention-deficit disorder (off-label use): Oral: Initial: Doses vary between 18.75 to 75 mg/day; may increase after 4 weeks to 150 mg/day; if tolerated, doses up to 225 mg/day have been used (Maidment 2003).

Diabetic neuropathy (off-label use): Extended release: Oral: Initial: 37.5 mg or 75 mg once daily; increase by 75 mg each week to a maximum dosage of 225 mg daily based on tolerance and effect. An adequate duration to determine effect and to accomplish titration has been documented to be 4 to 6 weeks (Bril 2011; Kadiroglu 2008; Rowbotham 2004).

Hot flashes (off-label use): Oral: Immediate-release and extended release: Dosage range studied: 37.5 to 150 mg daily; therapy usually initiated with 37.5 mg daily to minimize adverse effects; dose may remain at 37.5 mg daily or titrated by 37.5 mg per week to a dose of 75 mg or 150 mg daily administered in a single daily dose or in divided doses (AACE [Goodman 2011]; Evans 2005; Loibl 2007; Loprinzi 2000; Loprinzi 2006).

Obsessive-compulsive disorder (off-label use): Oral: Titrate to usual dosage range of 150 to 300 mg/day; however, doses up to 375 mg/day have been used; response may be seen in 4 weeks (Phelps 2005).

Post-traumatic stress disorder (PTSD) (off-label use): Oral: Extended release formulation: 37.5 to 300 mg/day (Bandelow 2008; Benedek 2009).

Note: When discontinuing this medication after more than 1 week of treatment, it is generally recommended that the dose be tapered. If venlafaxine is used for 6 weeks or longer, the dose should be tapered over 2 weeks when discontinuing its use.

Discontinuation of therapy: When discontinuing venlafaxine after more than 1 week of treatment, it is generally recommended that the dose be tapered to minimize the incidence of withdrawal symptoms and allow for the detection of re-emerging symptoms. If it is used for 6 weeks or longer, the dose should be tapered over 2 weeks when discontinuing its use. In clinical studies with extended-release venlafaxine, tapering was achieved by reducing the daily dose by 75 mg at 1-week intervals.

Evidence supporting ideal taper rates is limited. APA and NICE guidelines suggest tapering therapy over at least several weeks with consideration to the half-life of the antidepressant; antidepressants with a shorter half-life may need to be tapered more conservatively. In addition for long-term treated patients, WFSBP guidelines recommend tapering over 4 to 6 months. If intolerable withdrawal symptoms occur following a dose reduction, consider resuming the previously prescribed dose and/or decrease dose at a more gradual rate (APA 2010; Bauer 2002; Haddad 2001; NCCMH 2010; Schatzberg 2006; Shelton 2001; Warner 2006).

MAO inhibitor recommendations:

Switching to or from an MAO inhibitor intended to treat psychiatric disorders:

Allow 14 days to elapse between discontinuing an MAO inhibitor intended to treat psychiatric disorders and initiation of venlafaxine.

Allow 7 days to elapse between discontinuing venlafaxine and initiation of an MAO inhibitor intended to treat psychiatric disorders.

Dosing: Geriatric

Refer to adult dosing. No specific recommendations for elderly; use with caution

Discontinuation of therapy: Refer to adult dosing.

MAO inhibitor recommendations: Refer to adult dosing.

Dosing: Pediatric

Attention-deficit/hyperactivity disorder (off-label use) (Olvera 1996): Children and Adolescents: Oral: Initial: 12.5 mg/day

Children <40 kg: Increase by 12.5 mg/week to maximum of 50 mg/day in 2 divided doses

Children ≥40 kg: Increase by 25 mg/week to maximum of 75 mg/day in 3 divided doses

Mean dose: 60 mg or 1.4 mg/kg administered in 2 to 3 divided doses

Discontinuation of therapy: Refer to adult dosing.

MAO inhibitor recommendations: Refer to adult dosing.

Dosing: Renal Impairment

GFR 10 to 70 mL/minute:

Extended release: Reduce total daily dose by 25% to 50%

Immediate release: Reduce total daily dose by 25%

Hemodialysis: Reduce total daily dose by 50% or more

Dosing: Hepatic Impairment

Mild to moderate impairment (Child-Pugh class A and B): Reduce total daily dose by 50%. There is variability in clearance for patients with cirrhosis; therefore, a reduction in total daily dose of more than 50% may be necessary.

Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer’s labeling; however, a reduction in total daily dose of at least 50% or more is prudent in patients with cirrhosis.

Administration

Administer with food.

Extended-release formulations: Administer either in the morning or in the evening at approximately the same time each day. Swallow capsule or tablet whole with fluid; do not divide, crush, chew, or place in water. Contents of capsule may be sprinkled on a spoonful of applesauce and swallowed immediately without chewing; followed with a glass of water to ensure complete swallowing of the pellets.

Storage

Immediate-release tablets and extended-release capsules: Store at 20°C to 25°C (68°F to 77°F).

Extended-release tablets: Store at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). Protect from moisture and humidity.

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Consider therapy modification

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the antiplatelet effect of other Agents with Antiplatelet Properties. Monitor therapy

Alcohol (Ethyl): May enhance the adverse/toxic effect of Serotonin/Norepinephrine Reuptake Inhibitors. Specifically, risks of psychomotor impairment may be enhanced. Alcohol (Ethyl) may enhance the hepatotoxic effect of Serotonin/Norepinephrine Reuptake Inhibitors. Particularly duloxetine and milnacipran. Management: Patients receiving serotonin/norepinephrine reuptake inhibitors (SNRIs) should be advised to avoid alcohol. Monitor for increased psychomotor impairment and hepatotoxicity in patients who consume alcohol during treatment with SNRIs. Consider therapy modification

Alpha-/Beta-Agonists: Serotonin/Norepinephrine Reuptake Inhibitors may enhance the tachycardic effect of Alpha-/Beta-Agonists. Serotonin/Norepinephrine Reuptake Inhibitors may enhance the vasopressor effect of Alpha-/Beta-Agonists. Consider therapy modification

Alpha2-Agonists: Serotonin/Norepinephrine Reuptake Inhibitors may diminish the antihypertensive effect of Alpha2-Agonists. Exceptions: Apraclonidine. Monitor therapy

Analgesics (Opioid): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Anticoagulants: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Antipsychotic Agents: Serotonin Modulators may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Apixaban: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Apixaban. Specifically, the risk for bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely. Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

ARIPiprazole: CYP2D6 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Aspirin: Serotonin/Norepinephrine Reuptake Inhibitors may enhance the antiplatelet effect of Aspirin. Monitor therapy

Asunaprevir: May increase the serum concentration of CYP2D6 Substrates. Consider therapy modification

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Cephalothin: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Cephalothin. Specifically, the risk for bleeding may be increased. Monitor therapy

Collagenase (Systemic): Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Monitor therapy

CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Consider therapy modification

Dabigatran Etexilate: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Dabigatran Etexilate. Agents with Antiplatelet Properties may increase the serum concentration of Dabigatran Etexilate. This mechanism applies specifically to clopidogrel. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dapoxetine: May enhance the adverse/toxic effect of Serotonin Modulators. Avoid combination

Dasatinib: May enhance the anticoagulant effect of Agents with Antiplatelet Properties. Monitor therapy

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Deoxycholic Acid: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Monitor therapy

Edoxaban: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Glucosamine: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Consider therapy modification

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Ibritumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Imatinib: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Indinavir: Venlafaxine may decrease the serum concentration of Indinavir. Monitor therapy

Iobenguane I 123: Serotonin/Norepinephrine Reuptake Inhibitors may diminish the therapeutic effect of Iobenguane I 123. Avoid combination

Ioflupane I 123: Serotonin/Norepinephrine Reuptake Inhibitors may diminish the diagnostic effect of Ioflupane I 123. Monitor therapy

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Limaprost: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Linezolid: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Avoid combination

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

MAO Inhibitors: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This may cause serotonin syndrome. While methylene blue and linezolid are expected to interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to monographs specific to those agents for details. Exceptions: Linezolid; Methylene Blue; Tedizolid. Avoid combination

Metaxalone: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Methylene Blue: Serotonin/Norepinephrine Reuptake Inhibitors may enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Avoid combination

Methylene Blue: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Avoid combination

Metoclopramide: May enhance the adverse/toxic effect of Serotonin/Norepinephrine Reuptake Inhibitors. Management: Seek alternatives to this combination when possible. Monitor patients receiving metoclopramide with serotonin/norepinephrine reuptake inhibitors for signs of extrapyramidal symptoms, neuroleptic malignant syndrome, and serotonin syndrome. Consider therapy modification

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Multivitamins/Fluoride (with ADE): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with AE, No Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

NSAID (Nonselective): Serotonin/Norepinephrine Reuptake Inhibitors may enhance the antiplatelet effect of NSAID (Nonselective). Monitor therapy

Obinutuzumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Monitor therapy

Omega-3 Fatty Acids: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Panobinostat: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of sensitive CYP2D6 substrates when possible, particularly those substrates with a narrow therapeutic index. Consider therapy modification

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Monitor therapy

Pentoxifylline: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Perhexiline: CYP2D6 Inhibitors (Weak) may increase the serum concentration of Perhexiline. Monitor therapy

Perhexiline: CYP2D6 Substrates may increase the serum concentration of Perhexiline. Perhexiline may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Propafenone: May increase the serum concentration of Venlafaxine. Management: Monitor for increased venlafaxine levels/adverse effects (e.g., hallucinations, agitation, confusion) with propafenone initiation/dose increase. Conversely, monitor for decreased venlafaxine levels with profapenone discontinuation/dose decrease. Monitor therapy

Prostacyclin Analogues: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Rivaroxaban: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Rivaroxaban. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Monitor therapy

Salicylates: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result. Monitor therapy

Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Exceptions: Nicergoline; Tedizolid. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tedizolid: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Thrombolytic Agents: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tositumomab and Iodine I 131 Tositumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse events may be increased. Monitor therapy

TraMADol: Serotonin Modulators may enhance the adverse/toxic effect of TraMADol. The risk of seizures may be increased. TraMADol may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

TraZODone: Venlafaxine may enhance the serotonergic effect of TraZODone. This could result in serotonin syndrome. Consider therapy modification

Urokinase: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Urokinase. Avoid combination

Vitamin E (Systemic): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Venlafaxine may enhance the adverse/toxic effect of Vitamin K Antagonists. Specifically, the risk for bleeding may be increased. Monitor therapy

Voriconazole: May enhance the adverse/toxic effect of Venlafaxine. Voriconazole may increase the serum concentration of Venlafaxine. Monitor therapy

Test Interactions

May interfere with urine detection of phencyclidine and amphetamine (false-positives).

Adverse Reactions

Note: Actual frequency may be dependent upon formulation and/or indication.

>10%:

Central nervous system: Headache (38%), insomnia (15% to 24%), drowsiness (12% to 20%), dizziness (11% to 20%)

Dermatologic: Diaphoresis (10% to 14%)

Endocrine & metabolic: Weight loss (children & adolescents 18% to 47%; adults 2% to 7%)

Gastrointestinal: Nausea (21% to 35%), xerostomia (12% to 17%), anorexia (8% to 17%)

Genitourinary: Abnormal ejaculation (8% to 19%)

Neuromuscular & skeletal: Weakness (8% to 19%)

1% to 10%:

Cardiovascular: Vasodilation (3% to 4%), hypertension (dose related; 3% in patients receiving <100 mg/day, up to 13% in patients receiving >300 mg/day), palpitations (3%), chest pain (≥1%), edema (≥1%), tachycardia (≥1%)

Central nervous system: Nervousness (6% to 10%), abnormal dreams (3% to 7%), anxiety (5%), yawning (3% to 5%), agitation (3%), depression (3%), twitching (3%), anorgasmia (females: 2% to 4%; more common in males), paresthesia (2% to 3%), abnormality in thinking (≥1%), amnesia (≥1%), chills (≥1%), confusion (≥1%), depersonalization (≥1%), hypoesthesia (≥1%), migraine (≥1%), trismus (≥1%), vertigo (≥1%)

Dermatologic: Pruritus (1%), ecchymoses (≥1%)

Endocrine & metabolic: Decreased libido (3% to 8%), hypercholesterolemia (5%), orgasm abnormal (2% to 5%), albuminuria (≥1%), weight gain (≥1%), increased serum triglycerides

Gastrointestinal: Constipation (8% to 10%), diarrhea (8%), dyspepsia (7%), abdominal pain (6%), vomiting (3% to 5%), flatulence (4%), dysgeusia (≥1%), increased appetite (≥1%)

Genitourinary: Impotence (4% to 6%), urinary disorder (≥1%)

Neuromuscular & skeletal: Tremor (4% to 5%), neck pain (≥1%)

Ophthalmic: Visual disturbance (4% to 5%), accommodation disturbance (≥1%), mydriasis (≥1%)

Respiratory: Pharyngitis (7%), dyspnea (≥1%), increased cough (≥1%)

Miscellaneous: Accidental injury (4%), fever (≥1%)

<1% (Limited to important or life-threatening): Abnormal behavior, abnormal gait, abnormal healing, abortion, acne vulgaris, adjustment disorder, ageusia, agranulocytosis, alcohol abuse, alcohol intolerance, alcohol intoxication, alopecia, altered sense of smell, amenorrhea, anaphylaxis, anemia, aneurysm, angina pectoris, angle-closure glaucoma, apathy, aphasia, appendicitis, arthritis, arthropathy, asthma, atelectasis, atrophic striae, attempted suicide, bacteremia, balanitis, basophilia, bigeminy, biliary colic, bladder pain, blepharitis, bone spur, bradycardia, bruxism, buccoglossal syndrome, bundle branch block, bursitis, candidiasis, carcinoma, cardiac arrhythmia (including atrial fibrillation, supraventricular tachycardia, ventricular extrasystoles, ventricular fibrillation, ventricular tachycardia, and torsades de pointes), cardiovascular disease (mitral valve and circulatory disturbance), cataract, cellulitis, central nervous system stimulation, cerebrovascular accident, cervicitis, changes in LDH, cheilitis, chest congestion, chills, cholecystitis, cholelithiasis, chromatopsia, colitis, congenital anomalies, congestive heart failure, conjunctival edema, conjunctivitis, corneal lesion, coronary artery disease, crystalluria, cystitis, deafness, decreased pupillary reflex, deep vein thrombosis, dehydration, delirium, delusions, dementia, diabetes mellitus, diplopia, duodenitis, dysphagia, dyspnea, dysuria, eczema, electric shock-like sensation, emotional lability, endometriosis, eosinophilia, erythema multiforme, esophagitis, extrapyramidal reaction, eye pain, facial paralysis, first degree atrioventricular block, furunculosis, gastroenteritis, gastroesophageal reflux disease, gastrointestinal ulcer, gingivitis, glossitis, glycosuria, goiter, gout, granuloma, Guillain-Barré syndrome, hair discoloration, hematoma, hemochromatosis, hemorrhage (eye, GI, gum, mucocutaneous, rectal, retinal, subconjunctival, uterine, vaginal), hemorrhoids, hepatic effects (including GGT elevation; abnormalities of unspecified liver function tests; liver damage, necrosis, or failure; and fatty liver), hepatitis, homicidal ideation, hostility, hyperacidity, hyperacusis, hypercalciuria, hyperesthesia, hyperreflexia, hyperthyroidism, hypertonia, hyperuricemia, hyperventilation, hypoglycemia, hypohidrosis, hypokalemia, hypokinesia, hypomenorrhea, hyponatremia, hypophosphatemia, hyporeflexia, hypotension, hypothyroidism, hypotonia, hypoventilation, hysteria, ileitis, impulse control disorder, increased energy, increased intraocular pressure (open-angle glaucoma) (Botha 2016), increased libido, increased serum prolactin, interstitial pulmonary disease (including eosinophilic pneumonia), intestinal obstruction, keratitis, labyrinthitis, laryngismus, laryngitis, leukocytosis, leukoderma, leukopenia, leukorrhea, lichenoid dermatitis, loss of consciousness, lymphadenopathy, lymphocytosis, melena, menopause, miliaria, miosis, multiple myeloma, muscle spasm, myasthenia, nephrolithiasis, neuralgia, neuritis, neuropathy, neutropenia, night sweats, nystagmus, oliguria, onychia sicca, oral candidiasis, oral mucosa ulcer, oral paresthesia, orchitis, ostealgia, osteoporosis, osteosclerosis, otitis externa, otitis media, ovarian cyst, pancreatitis, pancytopenia, panic, papilledema, paranoia, paresis, parotitis, pathological fracture, pelvic pain, periodontitis, peripheral vascular disease, petechial rash, plantar fasciitis, pleurisy, pneumonia, polyuria, proctitis, prolonged bleeding time, prolonged erection, prostatic disease, pruritic rash, psoriasis, psychosis, psychotic depression, pulmonary embolism, purpura, pustular rash, pyelonephritis, pyuria, rectal disease, renal failure, renal function abnormality, renal pain, rhabdomyolysis, rheumatoid arthritis, rupture of tendon, salpingitis, scleritis, seborrhea, seizure, serotonin syndrome, SIADH, sialorrhea, sinus arrhythmia, skin atrophy, skin discoloration, skin hypertrophy, skin photosensitivity, sleep apnea, speech disturbance, Stevens-Johnson syndrome, stomatitis, stupor, suicidal ideation (reported at a frequency up to 2% in children/adolescents with major depressive disorder), tenosynovitis, thrombocythemia, thrombocytopenia, thyroiditis, thyroid nodule, tongue discoloration, uremia, urinary incontinence, urinary urgency, urolithiasis, urticaria, uterine spasm, uveitis, vaginal dryness, vaginitis, vesicobullous dermatitis, visual field defect, voice disorder, withdrawal syndrome, xeroderma, xerophthalmia

ALERT: U.S. Boxed Warning

Suicidality and antidepressant drugs:

Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of venlafaxine or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Venlafaxine is not approved for use in pediatric patients.

Warnings/Precautions

Major psychiatric warnings:

• Suicidal thinking/behavior: [US Boxed Warning]: Antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults (18 to 24 years of age) in short-term studies of major depressive disorder (MDD) and other psychiatric disorders; consider risk prior to prescribing. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥65 years. Closely monitor patients of all ages for clinical worsening, suicidality, or unusual changes in behavior, particularly during the first few months of therapy or during periods of dosage adjustments (increases or decreases); the patient’s family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. A medication guide concerning the use of antidepressants in children and teenagers should be dispensed with each prescription. Venlafaxine is not approved for use in pediatric patients.

• The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy.

• Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their health care provider if any of these symptoms or worsening depression or psychosis occur.

Concerns related to adverse effects:

• Anxiety/insomnia: May cause increase in anxiety, nervousness, and insomnia.

• Bleeding risk: May impair platelet aggregation resulting in increased risk of bleeding events, particularly if used concomitantly with aspirin, NSAIDs, warfarin, or other anticoagulants. Bleeding related to SSRI or SNRI use has been reported to range from relatively minor bruising and epistaxis to life-threatening hemorrhage.

• CNS depression: Has a low potential to impair cognitive or motor performance; caution operating hazardous machinery or driving.

• Dyslipidemia: May cause significant increases in serum total cholesterol and triglycerides; monitor during long-term treatment.

• Fractures: Bone fractures have been associated with antidepressant treatment. Consider the possibility of a fragility fracture if an antidepressant-treated patient presents with unexplained bone pain, point tenderness, swelling, or bruising (Rabenda, 2013; Rizzoli, 2012).

• Hypertension: Dose-related increases in systolic and diastolic blood pressure have been documented. Monitor blood pressure regularly, and if sustained increases noted, consider dose reduction or discontinuation.

• Ocular effects: May cause mild pupillary dilation which in susceptible individuals can lead to an episode of narrow-angle glaucoma. Consider evaluating patients who have not had an iridectomy for narrow-angle glaucoma risk factors.

• Pulmonary events: Interstitial lung disease and eosinophilic pneumonia have been rarely reported. May present as progressive dyspnea, cough, and/or chest pain. Prompt evaluation and possible discontinuation of therapy may be necessary.

• Serotonin syndrome: Potentially life-threatening serotonin syndrome (SS) has occurred with serotonergic agents (eg, SSRIs, SNRIs), particularly when used in combination with other serotonergic agents (eg, triptans, TCAs, fentanyl, lithium, tramadol, buspirone, St John’s wort, tryptophan) or agents that impair metabolism of serotonin (eg, MAO inhibitors intended to treat psychiatric disorders, other MAO inhibitors [ie, linezolid and intravenous methylene blue]). Monitor patients closely for signs of SS such as mental status changes (eg, agitation, hallucinations, delirium, coma); autonomic instability (eg, tachycardia, labile blood pressure, diaphoresis); neuromuscular changes (eg, tremor, rigidity, myoclonus); GI symptoms (eg, nausea, vomiting, diarrhea); and/or seizures. Discontinue treatment (and any concomitant serotonergic agent) immediately if signs/symptoms arise.

• Sexual dysfunction: May cause or exacerbate sexual dysfunction.

• SIADH and hyponatremia: SSRIs and SNRIs have been associated with the development of SIADH; hyponatremia has been reported rarely (including severe cases with serum sodium <110 mmol/L). Age (the elderly), volume depletion, and/or concurrent use of diuretics likely increases risk. Discontinue treatment in patients with symptomatic hyponatremia.

• Weight loss and anorectic effects: Dose-dependent weight loss has been observed in both pediatric and adult patients; weight loss was not limited to those experiencing reduced appetite.

Disease-related concerns:

• Cardiovascular disease: May cause sustained increase in blood pressure or tachycardia. Control pre-existing hypertension prior to initiation of venlafaxine. Use caution in patients with recent history of MI, unstable heart disease, cerebrovascular conditions, or hyperthyroidism. Hypertensive effect is dose related and increases are generally modest (12 to 15 mm Hg diastolic).

• Hepatic impairment: Use caution; clearance is decreased and plasma concentrations are increased; dosage reduction recommended.

• Mania/hypomania: May precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Patients presenting with depressive symptoms should be screened for bipolar disorder, including details regarding family history of suicide, bipolar disorder, and depression. Venlafaxine is not FDA approved for the treatment of bipolar depression.

• Renal impairment: Use caution; clearance is decreased and plasma concentrations are increased; dosage reduction recommended.

• Seizure disorders: Use caution in patients with a previous seizure disorder; discontinue in any patient who develops seizures.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Use with caution in the elderly; may have a higher risk of SIADH or hyponatremia.

• Pediatric: Small differences in height and weight have been observed in pediatric patients receiving venlafaxine, particularly those <12 years of age, compared to placebo.

Other warnings/precautions:

• Discontinuation syndrome: Abrupt discontinuation or interruption of antidepressant therapy has been associated with a discontinuation syndrome. Symptoms arising may vary with antidepressant however commonly include nausea, vomiting, diarrhea, headaches, lightheadedness, dizziness, diminished appetite, sweating, chills, tremors, paresthesias, fatigue, somnolence, and sleep disturbances (eg, vivid dreams, insomnia). Less common symptoms include electric shock-like sensations, cardiac arrhythmias (more common with tricyclic antidepressants), myalgias, parkinsonism, arthralgias, and balance difficulties. Psychological symptoms may also emerge such as agitation, anxiety, akathisia, panic attacks, irritability, aggressiveness, worsening of mood, dysphoria, mood lability, hyperactivity, mania/hypomania, depersonalization, decreased concentration, slowed thinking, confusion, and memory or concentration difficulties. Greater risks for developing a discontinuation syndrome have been associated with antidepressants with shorter half-lives, longer durations of treatment, and abrupt discontinuation. For antidepressants of short or intermediate half-lives, symptoms may emerge within 2 to 5 days after treatment discontinuation and last 7 to 14 days (APA 2010; Fava 2006; Haddad 2001; Shelton 2001; Warner 2006).

Monitoring Parameters

Blood pressure should be regularly monitored, especially in patients with a high baseline blood pressure; may cause mean increase in heart rate of 4-9 beats/minute; cholesterol; mental status for depression, suicide ideation (especially at the beginning of therapy or when doses are increased or decreased), anxiety, social functioning, mania, panic attacks; signs/symptoms of serotonin syndrome, hyponatremia, discontinuation symptoms; height and weight should be monitored in children; intraocular pressure and mydriasis (in patients with raised ocular pressure or at risk of acute narrow angle glaucoma) (APA, 2010)

Pregnancy Risk Factor

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Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies. Venlafaxine and its active metabolite ODV cross the human placenta. An increased risk of teratogenic effects following venlafaxine exposure during pregnancy has not been observed, based on available data. The risk of spontaneous abortion may be increased. Neonatal seizures and neonatal abstinence syndrome have been noted in case reports following maternal use of venlafaxine during pregnancy. Nonteratogenic effects in the newborn following SSRI/SNRI exposure late in the third trimester include respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hyper- or hypotonia, hyper-reflexia, jitteriness, irritability, constant crying, and tremor. Symptoms may be due to the toxicity of the SNRI or a discontinuation syndrome and may be consistent with serotonin syndrome associated with treatment. The long-term effects of in utero SNRI/SSRI exposure on infant development and behavior are not known.

Due to pregnancy-induced physiologic changes, some pharmacokinetic parameters of venlafaxine may be altered. Women should be monitored for decreased efficacy. The ACOG recommends that therapy with SSRIs or SNRIs during pregnancy be individualized; treatment of depression during pregnancy should incorporate the clinical expertise of the mental health clinician, obstetrician, primary health care provider, and pediatrician. According to the American Psychiatric Association (APA), the risks of medication treatment should be weighed against other treatment options and untreated depression. For women who discontinue antidepressant medications during pregnancy and who may be at high risk for postpartum depression, the medications can be restarted following delivery. Treatment algorithms have been developed by the ACOG and the APA for the management of depression in women prior to conception and during pregnancy.

Pregnant women exposed to antidepressants during pregnancy are encouraged to enroll in the National Pregnancy Registry for Antidepressants (NPRAD). Women 18 to 45 years of age or their health care providers may contact the registry by calling 844-405-6185. Enrollment should be done as early in pregnancy as possible.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience insomnia, weight loss, lack of appetite, loss of strength and energy, fatigue, tremors, constipation, sweating a lot, nausea, vomiting, dry mouth, nightmares, or yawning. Have patient report immediately to prescriber signs of depression (suicidal ideation, anxiety, emotional instability, or confusion), signs of low sodium (headache, difficulty focusing, memory impairment, confusion, weakness, seizures, or change in balance), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), passing out, vision changes, eye pain, eye irritation, agitation, irritability, panic attacks, mood changes, behavioral changes, severe headache, severe dizziness, severe anxiety, seizures, angina, shortness of breath, sexual dysfunction, cough, bone pain, or signs of serotonin syndrome (dizziness, severe headache, agitation, hallucinations, tachycardia, abnormal heartbeat, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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