Venlafaxine

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

Pharmacology

Mechanism of Action

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).

Pharmacokinetics/Pharmacodynamics

Absorption

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

Distribution

V_dss: 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 to 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%

Use in Specific Populations

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 (unipolar): Treatment of unipolar 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: Off Label

Episodic migraine preventioncyes

Data from a limited number of small clinical trials suggest that venlafaxine may be beneficial for the prevention of migraine Bulut 2004, Ozyalcin 2005, Tarlaci 2009.

The

Narcolepsy with cataplexyyes

Based on the American Academy of Sleep Medicine practice parameters for the treatment of narcolepsy and other hypersomnias of central origin, venlafaxine given for cataplexy may be effective based on clinical experience, committee consensus, and a case study of 4 patients.

Neuropathic pain associated with diabetes mellitusbyes

Venlafaxine has been evaluated in the management of diabetic neuropathy in controlled trials and meta-analyses demonstrating favorable effects in pain intensity and relief Kadiroglu 2008, Rowbotham 2004, Rudroju 2013.

European Federation of Neurological Societies (EFNS) guidelines consider venlafaxine first-line therapy in the management of diabetic neuropathy, supported by strong evidence

Obsessive-compulsive disordercyes

Data from a limited number of active comparator clinical trials suggest that venlafaxine may be beneficial for the treatment of obsessive-compulsive disorder (OCD) Albert 2002, Denys 2003, Denys 2004.

Based on the American Psychiatric Association practice guidelines for the treatment of patients with OCD and the Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders, venlafaxine may be considered in patients with OCD and little or no response to SSRI monotherapy or an SSRI in combination with cognitive behavior therapy APA [Koran 2007], Katzman 2014.

Posttraumatic stress disorderbyes

Data from two randomized, double-blind trials support the use of venlafaxine in the treatment of posttraumatic stress disorder (PTSD) for the symptoms of reexperiencing, avoidance and numbing, and hyperarousal Davidson 2006a, Davidson 2006b.

Based on the World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders and the American Psychiatric Association guideline watch (March 2009) on the practice guideline for the treatment of patients with acute stress disorder and posttraumatic stress disorder, venlafaxine given for PTSD is an effective and recommended treatment option in the management of this condition. Based on the VA/DoD guidelines for the management of PTSD and acute stress disorder, venlafaxine is effective and recommended as monotherapy in patients who cannot or choose not to engage in trauma-focused psychotherapy.

Premenstrual dysphoric disorderc

Data from a limited number of patients studied suggest that venlafaxine may be beneficial for the treatment of premenstrual dysphoric disorder

Vasomotor symptoms associated with menopauseayes

Data from several randomized controlled studies support the efficacy of venlafaxine for the reduction of hot flash frequency and/or severity in women with natural or medically induced menopause Evans 2005, Loibl 2007, Loprinzi 2000, Loprinzi 2006.

Based on the

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.

Dosage and Administration

Dosing: Adult

Episodic migraine prevention (off-label use): Oral: Extended release: Initial: 37.5 mg once daily for 3 days; increase based on response and tolerability by 75 mg increments to a target dose of 75 to 150 mg once daily (Bulut 2004; CHS [Pringsheim 2012]; EFNS [Evers 2009]).

Generalized anxiety disorder: Oral: Extended release: Initial: 37.5 to 75 mg once daily; in patients who are initiated at 37.5 mg once daily, 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).

Major depressive disorder (unipolar): Oral:

Extended release: 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; thereafter, may increase dose in increments of ≤75 mg/day at intervals of ≥4 days based on response and tolerability (slower intervals of every 2 to 4 weeks are appropriate in less clinically urgent situations); usual dosage: 75 to 225 mg once daily (manufacturer's maximum dose: 225 mg/day; guidelines support doses of up to 375 mg/day based on limited experience) (APA 2010). Some experts use more rapid titrations (every 2 to 3 days) in combination with an antipsychotic (eg, quetiapine) for patients with psychotic features (Wijkstra 2010).

Immediate release: Initial: 37.5 to 75 mg/day; daily doses >37.5 mg are administered in 2 or 3 divided doses; may increase dose in increments of ≤75 mg/day at intervals of ≥4 days based on response and tolerability (slower intervals of every 2 to 4 weeks are appropriate in less clinically urgent situations); usual dosage: 75 to 375 mg/day (APA 2010) (maximum dose: 375 mg/day).

Narcolepsy with cataplexy (off-label use): Limited data available: Oral: Immediate release and extended release: Some experts suggest doses of 37.5 to 75 mg twice daily (immediate release) or 37.5 to 150 mg once daily (extended release). Initiate at a low dose and gradually increase based on response and tolerability (Scammell 2019).

Neuropathic pain associated with diabetes mellitus (off-label use): Oral: Extended release: Initial: 37.5 mg or 75 mg once daily; increase by 75 mg each week to a maximum dosage of 225 mg once 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).

Obsessive-compulsive disorder (alternative agent) (off-label use): Note: Alternative for patients with limited or no response to SSRI therapy (APA [Koran 2007]). Oral: Immediate release and extended release: Initial: 75 mg once daily for extended release or 75 mg/day in 3 divided doses for immediate release; increase in increments of 75 mg every 2 weeks to 225 mg/day. Increase further based on response and tolerability up to 350 mg/day (Albert 2002; APA [Koran 2007]; Denys 2003).

Panic disorder: Oral: Extended release: 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).

Posttraumatic stress disorder (off-label use): Oral: Extended release: Initial: 37.5 mg once daily; increase based on response and tolerability by ≤75 mg/day increments at intervals of ≥4 days up to 300 mg once daily. Average doses in clinical trials were ~170 mg/day (Davidson 2006a; Davidson 2006b).

Premenstrual dysphoric disorder (alternative agent) (off-label use): Continuous daily dosing regimen: Oral: Extended release: Based on limited data, some experts suggest 37.5 mg once daily initially; over the first month, increase to a usual effective dose of 75 mg once daily; in subsequent menstrual cycles, further increases in dose (eg, in 37.5 mg increments per menstrual cycle) up to 150 mg/day may be necessary in some patients for optimal response (Casper 2019).

Social anxiety disorder: Oral: Extended release: Initial: 37.5 mg once daily; increase to 75 mg/day after 1 to 2 weeks (Stein 2018). May continue to increase in increments of 75 mg each week based on response and tolerability up to 225 mg once daily (Liebowitz 2005; Pollack 2014; Stein 2005); however, doses >75 mg/day have demonstrated greater adverse effects and without greater efficacy. Manufacturer’s labeling: Dosing in the prescribing information may not reflect current clinical practice: Initial and maximum dose: 75 mg/day.

Vasomotor symptoms associated with menopause (alternative agent) (off-label use): Note: Alternative for patients unable or unwilling to take estrogen (AACE [Goodman 2011]). Oral: Immediate release and extended release: Initial: 37.5 mg once daily; may increase dose after ≥1 week based on response and tolerability to 75 mg once daily for extended release or 75 mg/day in 2 to 3 divided doses for immediate release (AACE [Goodman 2011]; Evans 2005; Loibl 2007; Loprinzi 2000; Loprinzi 2006; NAMS 2015). Note: Doses up to 150 mg/day have been evaluated; however, compared to 75 mg/day, there was no greater efficacy and adverse effects were increased (Loprinzi 2000).

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

Discontinuation of therapy: When discontinuing antidepressant treatment that has lasted for >3 weeks, gradually taper the dose (eg, over 2 to 4 weeks) to minimize withdrawal symptoms and detect reemerging symptoms (APA 2010; WFSBP [Bauer 2015]). Reasons for a slower titration (eg, over 4 weeks) include use of a drug with a half-life <24 hours (eg, paroxetine, venlafaxine), prior history of antidepressant withdrawal symptoms, or high doses of antidepressants (APA 2010; Hirsch 2019). If intolerable withdrawal symptoms occur, resume the previously prescribed dose and/or decrease dose at a more gradual rate (Shelton 2001). Select patients (eg, those with a history of discontinuation syndrome) on long-term treatment (>6 months) may benefit from tapering over >3 months (WFSBP [Bauer 2015]). Evidence supporting ideal taper rates is limited (Shelton 2001; WFSBP [Bauer 2015]).

Switching antidepressants: Evidence for ideal antidepressant switching strategies is limited; strategies include cross-titration (gradually discontinuing the first antidepressant while at the same time gradually increasing the new antidepressant) and direct switch (abruptly discontinuing the first antidepressant and then starting the new antidepressant at an equivalent dose or lower dose and increasing it gradually). Cross-titration (eg, over 1 to 4 weeks depending upon sensitivity to discontinuation symptoms and adverse effects) is standard for most switches, but is contraindicated when switching to or from an MAOI. A direct switch may be an appropriate approach when switching to another agent in the same or similar class (eg, when switching between two SSRIs), when the antidepressant to be discontinued has been used for <1 week, or when the discontinuation is for adverse effects. When choosing the switch strategy, consider the risk of discontinuation symptoms, potential for drug interactions, other antidepressant properties (eg, half-life, adverse effects, and pharmacodynamics), and the degree of symptom control desired (WFSBP [Bauer 2013]; Hirsch 2018; Ogle 2013).

Switching to or from an MAOI:

Allow 14 days to elapse between discontinuing an MAOI and initiation of venlafaxine.

Allow 7 days to elapse between discontinuing venlafaxine and initiation of an MAOI according to manufacturer labeling; however, experts recommend a 14-day washout period before initiating an MAOI (APA 2010).

Dosing: Geriatric

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

Discontinuation of therapy: Refer to adult dosing.

Switching antidepressants: Refer to adult dosing.

Dosing: Pediatric

Attention-deficit/hyperactivity disorder (ADHD): Limited data available: Children and Adolescents 8 to <17 years: Oral: Immediate release: Initial: 12.5 mg then titrate: Children <40 kg: Increase by 12.5 mg/week to maximum daily dose: 50 mg/day in 2 divided doses or Children ≥40 kg: Increase by 25 mg/week to maximum daily dose: 75 mg/day in 3 divided doses. Dosing based on an open-label clinical 5-week trial of 16 children and adolescents (mean age: 11.6 ± 2.3 years); mean dose: 60 mg/day (1.4 mg/kg/day) in 2 to 3 divided doses; ten patients completed the study [2 were lost to follow-up; 5 discontinued therapy due to adverse effects (4 had an increase in hyperactivity; 1 had severe nausea)]; venlafaxine decreased behavioral symptoms (but not cognitive symptoms) in 7 of 16 subjects (44%) (Olvera 1996). An initial dose of 37.5 mg given 3 times/day was used in an 11-year-old female with ADHD; the dose was slowly titrated to 100 mg given 3 times/day; after 6 weeks the patient showed moderate to marked improvement in symptoms, but developed hypertension; the dose was then decreased to 75 mg given 3 times/day with normalization of blood pressure (Pleak 1995).

Autism spectrum disorders: Limited data available: Children ≥ 3 years and Adolescents: Oral: Immediate release: One retrospective report is available; 10 patients (3 to 21 years of age; mean 10.5 ± 5.6 years) with autism spectrum disorders (autism, Asperger's syndrome, and pervasive developmental disorders not otherwise specified) received initial doses of 12.5 mg/day administered once daily at breakfast; doses were gradually titrated based on clinical response and side effects; mean final dose: 24.4 mg/day; range: 6.25 to 50 mg/day; 6 of the 10 patients were sustained-treatment responders (Hollander 2000).

Depression: Limited data available: Children ≥7 years and Adolescents ≤17 years: Note: Due to the lack of demonstrated efficacy and concerns about an increased risk for suicidal behavior, venlafaxine should be reserved for pediatric patients with major depression who do not respond to fluoxetine or sertraline (Dopheide 2006). Oral:

Immediate release: One double-blind, placebo-controlled, 6-week study is available; 33 children and adolescents (8 to 17 years of age) with major depression completed the trial (16 received venlafaxine; for children 8 to 12 years, doses were initiated at 12.5 mg once daily for 3 days, then increased to 12.5 mg twice daily for 3 days, then increased to 12.5 mg given 3 times/day for the rest of the study; for adolescents 13 to 17 years, doses were initiated at 25 mg once daily for 3 days, then increased to 25 mg twice daily for 3 days, then increased to 25 mg given 3 times/day for the rest of the study; both venlafaxine and placebo patients improved over time; however, no significant difference in symptoms was noted between groups (ie, venlafaxine did not have a significant effect on symptoms or specific behaviors); the authors suggest this lack of efficacy may be due to the low doses used and short duration of treatment (Mandoki 1997).

Extended release: A large multicenter double-blind, placebo-controlled study of venlafaxine-ER in children and adolescents 7 to 17 years of age with major depression is ongoing; this study is using higher doses; initial: 37.5 mg/day for 1 week; with increases to 75 mg/day for weeks 2 to 8; results are not yet available (Weller 2000). One report of two 16-year-old patients used higher doses of venlafaxine (final doses: 112.5 mg/day and 150 mg/day) in combination with lithium to successfully treat major depression (Walter 1998).

Discontinuation of therapy: Consider planning antidepressant discontinuation for lower-stress times, recognizing non-illness-related factors could cause stress or anxiety and be misattributed to antidepressant discontinuation (Hathaway 2018). Upon discontinuation of antidepressant therapy, gradually taper the dose to minimize the incidence of discontinuation syndromes (withdrawal) and allow for the detection of reemerging disease state symptoms (eg, relapse). Evidence supporting ideal taper rates after illness remission 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. After long-term (years) antidepressant treatment, WFSBP guidelines recommend tapering over 4 to 6 months, with close monitoring during and for 6 months after discontinuation. If intolerable discontinuation 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; Fenske 2009; 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.

Administration

Oral: 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

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

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

Almotriptan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Alosetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

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

Amphetamines: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Anticoagulants: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants. Exceptions: Bemiparin; Enoxaparin; Heparin. Monitor therapy

Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Exceptions: Alosetron; Ondansetron; Ramosetron. Monitor therapy

Antipsychotic Agents: Serotonergic Agents (High Risk) may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonergic agents may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonergic Agents (High Risk). 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

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

Bemiparin: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Bemiparin. Management: Avoid concomitant use of bemiparin with antiplatelet agents. If concomitant use is unavoidable, monitor closely for signs and symptoms of bleeding. Consider therapy modification

Brexanolone: Serotonin/Norepinephrine Reuptake Inhibitors may enhance the CNS depressant effect of Brexanolone. Monitor therapy

Bromopride: May enhance the adverse/toxic effect of Serotonin/Norepinephrine Reuptake Inhibitors. Avoid combination

BusPIRone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. 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

Cyclobenzaprine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

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

Dapoxetine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Do not use serotonergic agents (high risk) with dapoxetine or within 7 days of serotonergic agent discontinuation. Do not use dapoxetine within 14 days of monoamine oxidase inhibitor use. Dapoxetine labeling lists this combination as contraindicated. Avoid combination

Dasatinib: May enhance the anticoagulant effect of Agents with Antiplatelet Properties. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. 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

Dexmethylphenidate-Methylphenidate: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Dextromethorphan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. 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

Eletriptan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Enoxaparin: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Enoxaparin. Management: Discontinue antiplatelet agents prior to initiating enoxaparin whenever possible. If concomitant administration is unavoidable, monitor closely for signs and symptoms of bleeding. Consider therapy modification

Ergot Derivatives: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Exceptions: Nicergoline. Monitor therapy

Fat Emulsion (Fish Oil Based): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Monitor therapy

FentaNYL: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) if these agents are combined. Monitor therapy

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

Heparin: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Heparin. Management: Decrease the dose of heparin or agents with antiplatelet properties if coadministration is required. Consider therapy modification

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Management: Avoid combination when possible. If used, monitor more closely for evidence of bleeding. Discontinue herbal products with anticoagulant or antiplatelet actions 2 weeks prior to surgical, dental, or invasive procedures. Consider therapy modification

Ibritumomab Tiuxetan: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. 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

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

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

Iobenguane Radiopharmaceutical Products: Serotonin/Norepinephrine Reuptake Inhibitors may diminish the therapeutic effect of Iobenguane Radiopharmaceutical Products. Management: Discontinue all drugs that may inhibit or interfere with catecholamine transport or uptake for at least 5 biological half-lives before iobenguane administration. Do not administer these drugs until at least 7 days after each iobenguane dose. Avoid combination

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

Lasmiditan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. 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

Lorcaserin: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Meperidine: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) if these agents are combined. Monitor therapy

Metaxalone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Methylene Blue: Serotonin/Norepinephrine Reuptake Inhibitors may enhance the serotonergic effect of Methylene Blue. 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

Mirtazapine: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Monoamine Oxidase Inhibitors (Antidepressant): May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Avoid combination

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

Nefazodone: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents (Nonselective): Serotonin/Norepinephrine Reuptake Inhibitors may enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (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

Ondansetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Opioid Agonists: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Exceptions: FentaNYL; Meperidine; TraMADol. Monitor therapy

Oxitriptan: Serotonergic Agents (High Risk) may enhance the serotonergic effect of Oxitriptan. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. 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

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

Ramosetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

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

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

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

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

Selective Serotonin Reuptake Inhibitors: May enhance the antiplatelet effect of Serotonin/Norepinephrine Reuptake Inhibitors. Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, mental status changes) when these agents are combined. In addition, monitor for signs and symptoms of bleeding. Exceptions: Dapoxetine. Monitor therapy

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

Serotonergic Agents (High Risk, Miscellaneous): Serotonin/Norepinephrine Reuptake Inhibitors may enhance the serotonergic effect of Serotonergic Agents (High Risk, Miscellaneous). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Serotonin 5-HT1D Receptor Agonists (Triptans): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Exceptions: Almotriptan; Eletriptan. Monitor therapy

Serotonin/Norepinephrine Reuptake Inhibitors: May enhance the antiplatelet effect of other Serotonin/Norepinephrine Reuptake Inhibitors. Serotonin/Norepinephrine Reuptake Inhibitors may enhance the serotonergic effect of other Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, mental status changes) when these agents are combined. In addition, monitor for signs and symptoms of bleeding. Monitor therapy

Solriamfetol: Venlafaxine may enhance the hypertensive effect of Solriamfetol. Monitor therapy

St John's Wort: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. St John's Wort may decrease the serum concentration of Serotonergic Agents (High Risk). Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Syrian Rue: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

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

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

TraMADol: Serotonin/Norepinephrine Reuptake Inhibitors may enhance the adverse/toxic effect of TraMADol. Specifically, the risk for serotonin syndrome/serotonin toxicity and seizures may be increased. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and seizures when these agents are combined. Monitor therapy

TraZODone: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Tricyclic Antidepressants: Serotonin/Norepinephrine Reuptake Inhibitors may enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes when these agents are combined. Monitor therapy

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

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

Test Interactions

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

Adverse Reactions

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

>10%:

Central nervous system: Insomnia (18%), dizziness (16%), drowsiness (15%)

Dermatologic: Diaphoresis (11%)

Gastrointestinal: Nausea (30%), xerostomia (15%)

Neuromuscular & skeletal: Weakness (13%)

1% to 10%:

Cardiovascular: Vasodilation (4%), hypotension (<2%), orthostatic hypotension (<2%), syncope (<2%), tachycardia (<2%), increased blood pressure (1%)

Central nervous system: Nervousness (7%), yawning (4%), anorgasmia (2% to 4%), abnormal dreams (3%), paresthesia (2%), agitation (<2%), akathisia (<2%), apathy (<2%), chills (<2%), confusion (<2%), depersonalization (<2%), hallucination (<2%), hypertonia (<2%), manic reaction (<2%), myoclonus (<2%), seizure (<2%)

Dermatologic: Alopecia (<2%), ecchymoses (<2%), pruritus (<2%), skin photosensitivity (<2%), skin rash (<2%), urticaria (<2%)

Endocrine & metabolic: Orgasm abnormal (men: ≤10%), decreased libido (5%), hypercholesterolemia (5%), hypermenorrhea (<2%), weight gain (<2%), weight loss (<2%)

Gastrointestinal: Anorexia (10%), constipation (9%), diarrhea (8%), vomiting (4%), bruxism (<2%), dysgeusia (<2%), gastrointestinal hemorrhage (<2%)

Genitourinary: Ejaculatory disorder (≤10%), impotence (5%), abnormal uterine bleeding (<2%), urinary frequency (<2%), urinary incontinence (<2%), urinary retention (<2%), urination disorder (<2%)

Neuromuscular & skeletal: Tremor (5%)

Ophthalmic: Visual disturbance (4%), accommodation disturbance (<2%), mydriasis (<2%)

Otic: Tinnitus (<2%)

Frequency not defined:

Cardiovascular: Hypertension, increased pulse

Central nervous system: Suicidal ideation

Endocrine & metabolic: Increased serum triglycerides

Hematologic & oncologic: Hematoma, petechia

Respiratory: Epistaxis

<1%, postmarketing, and/or case reports: Abnormal hepatic function tests, agranulocytosis, anaphylaxis, angioedema, angle-closure glaucoma, aplastic anemia, ataxia, cardiomyopathy (takotsubo), delirium, dyspnea, eosinophilic pneumonitis, erythema multiforme, extrapyramidal reaction (including dystonia, dyskinesia), hepatitis, hypomania, hyponatremia, increased intraocular pressure (open-angle glaucoma) (Botha 2016), increased serum prolactin, interstitial pulmonary disease, mucous membrane bleeding, neuroleptic malignant syndrome, neutropenia, pancreatitis, pancytopenia, prolonged bleeding time, prolonged Q-T Interval on ECG, rhabdomyolysis, serotonin syndrome, SIADH, Stevens-Johnson syndrome, tardive dyskinesia, thrombocytopenia, toxic epidermal necrolysis, ventricular fibrillation, ventricular tachycardia (including torsades de pointes), withdrawal syndrome

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

Pregnancy Risk Factor

C

Pregnancy Considerations

Venlafaxine and its active metabolite ODV cross the human placenta (Rampono 2009).

Nonteratogenic adverse events have been observed with venlafaxine or other SNRIs/SSRIs when used during pregnancy. Cyanosis, apnea, respiratory distress, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypo- or hypertonia, hyper-reflexia, jitteriness, irritability, constant crying, and tremor have been reported in the neonate immediately following delivery after exposure to venlafaxine, SSRIs, or other SNRIs late in the third trimester. Prolonged hospitalization, respiratory support, or tube feedings may be required. Some symptoms may be due to the toxicity of the SNRI/SSRIs or a discontinuation syndrome and may be consistent with serotonin syndrome associated with treatment.

Due to pregnancy-induced physiologic changes, some pharmacokinetic parameters of venlafaxine may be altered. Women should be monitored for decreased efficacy (Klier 2007; ter Horst 2014; Westin 2018). The risk of bleeding, including postpartum hemorrhage may be increased following maternal use of venlafaxine (Palmsten Hernández-Díaz 2013; Reis 2010).

Untreated or inadequately treated mental illness may lead to poor compliance with prenatal care. The ACOG recommends that therapy with SSRIs or SNRIs during pregnancy be individualized. Use of a single agent is preferred. According to their recommendations, treatment of depression during pregnancy should incorporate the clinical expertise of the mental health clinician, obstetrician, primary care provider, and pediatrician (ACOG 2008).

If treatment for major depressive disorder is initiated for the first time during pregnancy, agents other than venlafaxine are preferred (Larsen 2015; MacQueen 2016). Women effectively treated with venlafaxine prior to pregnancy may continue treatment (Larsen 2015).

If treatment for major depressive disorder is initiated for the first time in females planning a pregnancy, agents other than venlafaxine are preferred (Larsen 2015).

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

What is this drug used for?

• It is used to treat low mood (depression).
• It is used to treat anxiety.
• It is used to treat panic attacks.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Trouble sleeping
• Weight loss
• Anxiety
• Lack of appetite
• Loss of strength and energy
• Fatigue
• Tremors
• Constipation
• Sweating a lot
• Nausea
• Passing gas
• Dry mouth
• Nightmares
• Yawning

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Depression like thoughts of suicide, anxiety, emotional instability, or confusion.
• Low sodium like headache, difficulty focusing, trouble with memory, confusion, weakness, seizures, or change in balance.
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; 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
• Eye edema
• Agitation
• Irritability
• Panic attacks
• Mood changes
• Behavioral changes
• Severe headaches
• Severe dizziness
• Seizures
• Chest pain
• Shortness of breath
• Decreased sex drive
• Sexual dysfunction
• Cough
• Bone pain
• Serotonin syndrome like dizziness, severe headache, agitation, sensing things that seem real but are not, fast heartbeat, abnormal heartbeat, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea.
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.