Your activity: 272 p.v.
your limit has been reached. plz Donate us to allow your ip full access, Email: sshnevis@outlook.com

Venlafaxine: Drug information

Venlafaxine: Drug information
(For additional information see "Venlafaxine: Patient drug information" and see "Venlafaxine: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US 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.

Brand Names: US
  • Effexor XR
Brand Names: Canada
  • ACT Venlafaxine XR;
  • APO-Venlafaxine XR;
  • Auro-Venlafaxine XR;
  • DOM-Venlafaxine XR;
  • Effexor XR;
  • GD-Venlafaxine XR [DSC];
  • M-Venlafaxine XR;
  • MYLAN-Venlafaxine XR [DSC];
  • PMS-Venlafaxine XR;
  • RIVA-Venlafaxine XR [DSC];
  • SANDOZ Venlafaxine XR;
  • TARO-Venlafaxine XR;
  • TEVA-Venlafaxine XR;
  • Venlafaxine XR
Pharmacologic Category
  • Antidepressant, Serotonin/Norepinephrine Reuptake Inhibitor
Dosing: Adult
Episodic migraine prevention

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

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

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).

Im mediate 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

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 2021).

Neuropathic pain associated with diabetes mellitus

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

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

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

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

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 2020).

Social anxiety disorder

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

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: Due to its short half-life, withdrawal symptoms are possible after abrupt discontinuation; consider tapering to avoid withdrawal and assess for symptom recurrence. 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 taper (eg, over 4 weeks) include history of antidepressant withdrawal symptoms or high doses of antidepressants (APA 2010; Hirsch 2021a). 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 2021b; 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).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Oral: Immediate release and extended release:

Altered kidney impairment (Nagler 2012; Troy 1994):

CrCl ≥30 mL/minute: No dosage adjustment necessary.

CrCl <30 mL/minute: Initial: 37.5 mg once daily; titrate cautiously, not to exceed 50% of the maximum recommended dose.

Note: The manufacturer recommends a 25% dose reduction in patients with CrCl 10 to 70 mL/minute (immediate release) and a 25% to 50% reduction with CrCl 30 to 89 mL/minute (extended release). However, due to high individual variability, the decrease in clearance of venlafaxine and its metabolite is only evident in subjects with CrCl <30 mL/minute (Troy 1994); doses in patients with higher CrCls should be individualized based on efficacy and tolerability.

Hemodialysis, intermittent (thrice weekly): Not dialyzable (venlafaxine and active metabolite, O-desmethylvenlafaxine); clearance of venlafaxine and O-desmethylvenlafaxine is reduced ~56% with high interpatient variability (Troy 1994).

Initial: 37.5 mg once daily; titrate cautiously, not to exceed 50% of the maximum recommended dose (Nagler 2012; Troy 1994).

Peritoneal dialysis: Venlafaxine and its active metabolite, O-desmethylvenlafaxine, are unlikely to be dialyzed (expert opinion).

Initial: 37.5 mg once daily; titrate cautiously, not to exceed 50% of the recommended maximum dose (Nagler 2012).

CRRT: Venlafaxine and its active metabolite, O-desmethylvenlafaxine, are unlikely to be removed by CRRT (expert opinion).

Initial: 37.5 mg once daily; titrate cautiously, not to exceed 50% of the maximum recommended dose (expert opinion).

PIRRT (eg, sustained, low-efficiency diafiltration): Venlafaxine and its active metabolite, O-desmethylvenlafaxine, are unlikely to be removed by PIRRT (expert opinion).

Initial: 37.5 mg once daily; titrate cautiously, not to exceed 50% of the maximum recommended dose (expert opinion).

Dosing: Hepatic Impairment: Adult

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.

Dosing: Pediatric

(For additional information see "Venlafaxine: Pediatric drug information")

Attention-deficit/hyperactivity disorder (ADHD): Limited data available; efficacy results variable: Note: Not recommended as first or second-line therapy in the management of ADHD (AAP [Wolraich 2019]; NICE 2018a); venlafaxine has shown minor positive benefits for some outcomes in small trials (Findling 2007; Olvera 1996; Zarinara 2010); robust evidence is lacking (NICE 2018b).

Children ≥6 years and Adolescents <17 years: Oral: Immediate release: Initial: 12.5 to 25 mg once daily for 1 week, then increase by 12.5 to 25 mg/day increments at weekly intervals based on response and tolerability to a weight-based maximum daily dose: Weight <30 kg: 50 mg/day in 2 divided doses; weight ≥30 kg: 75 mg/day in 3 divided doses (Olvera 1996; Zarinara 2010).

Generalized anxiety disorder, social anxiety, separation anxiety, or panic disorder: Limited data available:

Note: In pediatric patients, selective serotonin-norepinephrine reuptake inhibitor (SNRI) therapy may be considered a pharmacologic treatment option (not first-line) for moderate to severe anxiety disorders, ideally in combination with cognitive behavioral therapy (CBT); of the SNRIs with positive pediatric data evaluated in the AHRQ/Mayo review (ie, venlafaxine, duloxetine), a preferred SNRI has not been defined, although duloxetine does have FDA approval for this indication in pediatric patients ≥7 years of age. Therapeutic selection should be based on pharmacokinetic and pharmacodynamic data, patient tolerability, cost, and unique risks/precautions with specific agents (AACAP [Walter 2020]; AHRQ [Wang 2017]; Bushnell 2018; Dobson 2016; Strawn 2015).

Children ≥6 years and Adolescents: Oral: Extended release: Initial: 37.5 mg once daily for 1 week, then titrate slowly according to patient weight, available dosage form strengths, response, and tolerability (see the following table) (Rynn 2007).

Weight (kg)

Week 2

Week 3 to 4

Week 4 to 8

25 to <40 kg

37.5 mg or 75 mg

37.5 mg or 75 mg

37.5 mg, 75 mg, or 112.5 mg

40 to <50 kg

75 mg

75 mg or 112.5 mg

75 mg, 112.5 mg, or 150 mg

≥50 kg

75 mg

75 mg or 150 mg

75 mg, 150 mg, or 225 mg

Dosing based on 2 randomized, double-blind, placebo-controlled trials which showed, in the initial trial, statistically significant greater improvement in primary outcome and some secondary outcome measures compared to placebo; in the second trial, although not significant, improvement in primary outcome measures were reported and the secondary outcome showed statistically significant greater improvement than placebo (Rynn 2007).

Major depressive disorder (unipolar): Limited data available:

Note: In the management of depression in children and adolescents, if pharmacotherapy is deemed necessary with/without cognitive behavioral therapy (CBT), a selective serotonin reuptake inhibitor (SSRI) is recommended as first-line pharmacologic therapy; an SNRI, like venlafaxine, may be considered in SSRI-refractory cases with CBT; patients should be closely monitored for adverse effects (suicidal ideation) (AAP [Cheung 2018]; APA 2019; Ignaszewski 2018; NICE 2019). Therapy should be initiated at a low dose and titrated every 1 to 2 weeks based on response and tolerability (AAP [Cheung 2018]; Mullen 2018).

Children ≥12 years and Adolescents: Oral: Extended release: Initial: 37.5 mg once daily for week 1, then titrate with once-daily dosing by the following: Increase to 75 mg/day for week 2; increase to 112.5 mg/day for week 3; increase to 150 mg/day for weeks 4 to 6; if no response after week 6, may further increase to 225 mg/day. Dosing based on the Treatment of Resistant Depression in Adolescents (TORDIA) regimen which evaluated 166 patients 12 to 18 years of age with SSRI-resistant major depressive disorder who were switched to venlafaxine with or without CBT; results showed greater response when venlafaxine combined with CBT versus medication only (54.8% versus 40.5%) (Brent 2008; Emslie 2010).

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).

Switching antidepressants: Evidence for ideal antidepressant switching strategies in pediatric patients is sparse; strategies described in pediatric guidelines include a conservative approach (tapering and discontinuing the first SSRI or SNRI before adding the new antidepressant) and cross-titration (gradually discontinuing the first antidepressant while at the same time gradually increasing the new antidepressant). While consensus does not exist regarding which approach to utilize, it is important to note that the conservative approach runs the risk for exacerbation of symptoms or discontinuation syndrome; cross-titration may avoid these risks (AACAP [Walter 2020]). 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 a monoamine oxidase inhibitor. While not as common of a strategy, a direct switch may be considered when switching to another agent in the same or similar class (eg, when switching between 2 SNRIs), 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, pharmacodynamics), and the degree of symptom control desired (Ogle 2013; WFSBP [Bauer 2013]).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

There are no pediatric-specific recommendations; based on experience in adult patients, dosing adjustment suggested.

Dosing: Hepatic Impairment: Pediatric

There are no pediatric-specific recommendations; based on experience in adult patients, dosing adjustment suggested.

Dosing: Older Adult

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.

Dosage Forms: US

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

Generic Equivalent Available: US

Yes

Dosage Forms: Canada

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

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Effexor XR: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/020699s113lbl.pdf#page=49

Venlafaxine extended release tablet: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/022104s021lbl.pdf#page=35

Administration: Adult

Oral: Administer with food.

ER 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.

Bariatric surgery: Tablet, extended release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. IR tablet and ER capsule formulations that can be opened and sprinkled over soft food are available. If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery.

Administration: Pediatric

Oral:

Immediate-release tablet: Administer with food.

Extended-release capsule: Administer with food once daily at about the same time each day; swallow whole with fluid; do not crush, chew, divide, or place in water; capsule may be opened and entire contents sprinkled on spoonful of applesauce; swallow drug/food mixture immediately. Do not store for future use; do not chew contents (ie, pellets) of capsule; follow drug/food mixture with water to ensure complete swallowing of pellets.

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: Adult

Episodic migraine prevention; Narcolepsy with cataplexy; Neuropathic pain associated with diabetes mellitus; Obsessive-compulsive disorder; Posttraumatic stress disorder; Premenstrual dysphoric disorder; Vasomotor symptoms associated with menopause

Medication Safety Issues
Sound-alike/look-alike issues:

Effexor may be confused with Effexor XR

Effexor XR may be confused with Enablex

Venlafaxine may be confused with Venclexta, venetoclax

Geriatric patients: High-risk medication:

Beers Criteria: Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) are identified in the Beers Criteria as potentially inappropriate medications to be used with caution in patients 65 years and older due to its potential to cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia; monitor sodium concentration closely when initiating or adjusting the dose in older adults (Beers Criteria [AGS 2019]).

Adverse Reactions (Significant): Considerations
Activation of mania or hypomania

Antidepressants (when used as monotherapy) may precipitate a mixed/manic episode in patients with bipolar disorder (Ref). Treatment-emergent mania or hypomania in patients with unipolar major depressive disorder (MDD) has been reported, as many cases of bipolar disorder present in episodes of MDD (Ref).

Mechanism: Non-dose-related; idiosyncratic. Unclear to what extent mood switches represent an uncovering of unrecognized bipolar disorder or a more direct pharmacologic effect independent of diagnosis (Ref).

Onset: Varied; a systematic review observed that the risk of switching increased significantly within the initial 2 years of antidepressant treatment in patients with unipolar MDD receiving an antidepressant as monotherapy but not thereafter (up to 4.6 years) (Ref).

Risk factors:

• Family history of bipolar disorder (Ref)

• Depressive episode with psychotic symptoms (Ref)

• Younger age at onset of depression (Ref)

• Antidepressant resistance (Ref)

Bleeding risk

Serotonergic antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs), may increase the risk of bleeding, particularly if used concomitantly with antiplatelets and/or anticoagulants. Multiple observational studies have found an association with SSRI use and a variety of bleeding complications (Ref), although prospective studies have not determined if the cause of the increased risk of bleeding is due to SSRI use alone. For SNRIs, less data exist compared to SSRIs and data supporting an association with bleeding are conflicting (Ref). However, there are case reports of bruises, ecchymoses, gingival hemorrhage, and vaginal hemorrhage associated with venlafaxine and some observational studies have observed an increased risk for postpartum hemorrhage (exposure during late gestation), stroke, and gastrointestinal hemorrhage in patients receiving SNRIs, predominately with studies using venlafaxine (Ref).

Mechanism: Possibly via inhibition of serotonin-mediated platelet activation (inhibition of the serotonin reuptake transporter) and subsequent platelet dysfunction. Venlafaxine is considered to display moderate affinity for the serotonin reuptake receptor. SNRIs may also increase gastric acidity, which can increase the risk of GI bleeding (Ref).

Onset: Varied; based on data evaluating SSRIs, it has been suggested that the onset of risk is likely delayed for several weeks until SNRI-induced platelet serotonin depletion becomes clinically significant (Ref), although the onset of bleeding may be more unpredictable if patients are taking concomitant antiplatelets, anticoagulants, or nonsteroidal anti-inflammatory drugs.

Risk factors:

Concomitant use of antiplatelets and/or anticoagulants (Ref)

Preexisting platelet dysfunction or coagulation disorders (eg, von Willebrand factor) (Ref)

Blood pressure elevations

Dose-dependent blood pressure increases have been reported; most occurrences are modest elevations and not clinically significant. Clinically significant increased blood pressure or hypertension have been observed, predominately in patients receiving high daily doses. Sinus tachycardia has also been reported (rarely) (Ref).

Mechanism: Dose-related; believed to increase blood pressure via its noradrenergic mechanism (Ref).

Risk factors:

• Preexisting hypertension (potential risk factor) (Ref)

• Males (potential risk factor) (Ref)

• Older adults (potential risk factor) (Ref)

Fragility fractures

Limited data from observational studies involving mostly older adults (≥50 years of age) suggest venlafaxine may be associated with an increased risk of bone fractures (Ref).

Mechanism: Time-related; mechanism not fully elucidated; postulated to be through a direct effect by serotonergic agents (selective serotonin reuptake inhibitors [SSRIs] or serotonin norepinephrine reuptake inhibitors [SNRIs]) on bone metabolism via interaction with 5-HT and osteoblast, osteocyte, and/or osteoclast activity. Of note, data evaluating the effects of serotonergic agents on bone mineral density primarily involve SSRIs rather than SNRIs (Ref).

Risk factors:

Long-term use (potential risk factor) (Ref)

Hepatotoxicity

Liver test abnormalities may occur with use, but ALT elevations are usually modest and self-limiting. However, postmarketing cases of hepatotoxicity, including hepatitis and cholestatic hepatitis, have been reported rarely, including cases occurring in patients without risk factors. The pattern of hepatic injury associated with venlafaxine has varied from cholestatic to hepatocellular hepatitis (Ref).

Mechanism: Unknown by which venlafaxine may cause liver injury; however, since metabolism occurs in the liver, primarily by CYP2D6, hepatotoxicity may be mediated by toxic intermediates of that metabolism. In addition, venlafaxine is susceptible to drug-drug interactions with agents that alter these microsomal enzymes. Idiosyncratic drug-induced liver injury (DILI) is due to either direct cellular injury (metabolic idiosyncratic DILI) or are immune-mediated (immune-allergic idiosyncratic DILI). Both metabolic and immunoallergic mechanisms have been suggested for venlafaxine; however, it has been reported that autoimmune (autoantibodies) and immunoallergic features (rash, fever, eosinophilia), more indicative of an immune-allergic mechanism, have been uncommon features or mild in cases of venlafaxine-associated DILI (Ref).

Onset: Varied; DILI associated with antidepressant use usually occurs within several days to 6 months after initiation; venlafaxine has been associated with an usual onset of injury within 1 to 3 months. In a case series of DILI associated with venlafaxine, the induction period ranged from 4 weeks to 10 months (Ref).

Risk factors:

• Polypharmacy, particularly with concomitant administration of multiple agents metabolized by the same CYP450 isoenzymes (Ref)

Hyponatremia

Venlafaxine is associated with syndrome of inappropriate antidiuretic hormone secretion (SIADH)and/or hyponatremia (including severe cases), predominantly in the elderly (Ref).

Mechanism: May cause SIADH via release of antidiuretic hormone (ADH) via serotonin effects on 5-HT receptors and norepinephrine effects on alpha-1 adrenergic receptors (Ref) or may cause nephrogenic SIADH by increasing the sensitivity of the kidney to ADH (Ref).

Onset: Intermediate; based on data involving selective serotonin reuptake inhibitors (SSRIs), hyponatremia usually develops within the first few weeks of treatment (Ref),

Risk factors:

Based on data involving SSRIs, risk factors include:

• Older age (Ref)

• Females (Ref)

• Concomitant use of diuretics (Ref)

• Low body weight (Ref)

• Lower baseline serum sodium concentration (Ref)

• Volume depletion (Ref)

• History of hyponatremia (potential risk factors) (Ref)

• Symptoms of psychosis (potential risk factors) (Ref)

Ocular effects

Serotonin norepinephrine reuptake inhibitors (SNRIs) are associated with acute angle-closure glaucoma (AACG) in case reports. AACG may cause symptoms including eye pain, changes in vision, swelling, and redness, which can rapidly lead to permanent blindness if not treated (Ref). In addition, SNRIs may be associated with an increased risk of cataract development (Ref).

Mechanism: AACG: Unclear; hypothesized SNRIs may increase the intraocular pressure via serotonergic and adrenergic effects on ciliary body muscle activation and pupil dilation (Ref). In addition, a pseudo-anticholinergic (although debatable for SNRIs) and a dopaminergic effect on ocular tissue cannot be excluded as potential mechanisms (Ref).

Risk factors:

For AACG:

• Females (Ref)

• ≥50 years of age (slight increase) (Ref)

• Hyperopia (slight increase) (Ref)

• Personal or family history of AACG (Ref)

• Patients of Inuit or Asian descent (Ref)

Serotonin syndrome

Serotonin syndrome has been reported and typically occurs with coadministration of multiple serotonergic drugs, but can occur following a single serotonergic agent at high therapeutic doses or supratherapeutic doses (Ref). The diagnosis of serotonin syndrome is made based on the Hunter Serotonin Toxicity Criteria (Ref) and may result in a spectrum of symptoms, such as anxiety, agitation, confusion, delirium, hyperreflexia, muscle rigidity, myoclonus, tachycardia, tachypnea, and tremor. Severe cases may cause hyperthermia, significant autonomic instability (ie, rapid and severe changes in blood pressure and pulse), coma, and seizures (Ref).

Mechanism: Dose-related; overstimulation of serotonin receptors (5-HT2A) by serotonergic agents (Ref).

Onset: Rapid; onset is typically within hours of an exposure (but delays of 24 hours or longer have been reported) (Ref).

Risk factors:

• Concomitant use of drugs that increase serotonin synthesis, block serotonin reuptake, and/or impair serotonin metabolism (eg, monoamine oxidase inhibitors [MAOIs]). Of note, concomitant use of some serotonergic agents, such as MAOIs, are contraindicated.

Sexual dysfunction

Venlafaxine is commonly associated with sexual disorder in both men and women. The following adverse reactions have been associated with use: Orgasm abnormal, anorgasmia, erectile dysfunction, decreased libido (Ref). Priapism has also been reported with duloxetine (Ref).

Mechanism: Based on data involving selective serotonin reuptake inhibitors, it has been postulated that increases in serotonin may affect other hormones and neurotransmitters involved in sexual function; in particular, testosterone’s effect on sexual arousal and dopamine’s role in achieving orgasm (Ref).

Suicidal thinking and behavior

Antidepressants are associated with an increased risk of suicidal ideation and suicidal tendencies in pediatric and young adult patients (18 to 24 years) in short-term studies. In adults >24 years of age, short-term studies did not show an increased risk of suicidal thinking and behavior, and in older adults ≥65 years of age, a decreased risk was observed, per the manufacturer’s labeling. Although data have yielded inconsistent results regarding the association of antidepressants and risk of suicide, particularly among adults, collective evidence shows a trend of an elevated risk of suicidality in younger age groups (Ref). Of note, the risk of a suicide attempt is inherent in major depression and may persist until remission occurs.

Mechanism: Not established; one of several postulated mechanisms is that antidepressants may energize suicidal patients to act on impulses; another suggests that antidepressants may produce a worsening of depressive symptoms, leading to the emergence of suicidal thoughts and actions (Ref).

Onset: Varied; increased risk observed in short-term studies (ie, <4 months) in pediatric and young adults; it is unknown whether this risk extends to longer-term use (ie, >4 months). In a large cohort study of adults 20 to 64 years of age, the rates of attempted suicide or self-harm in venlafaxine users were highest in the first 28 days of initiating treatment and in the first 28 days after stopping treatment (Ref).

Risk factors:

• Children and adolescents (Ref)

• Depression (risk of suicide is associated with major depression and may persist until remission occurs)

Withdrawal syndrome

Withdrawal syndrome, consisting of both somatic symptoms (eg, dizziness, chills, light-headedness, vertigo, shock-like sensations, paresthesia, fatigue, headache, nausea, tremor, diarrhea, visual disturbances) and psychological/behavioral symptoms (eg, aggressive behavior, anxiety, agitation, confusion, insomnia, irritability, mania, violent behavior), have been reported with serotonin norepinephrine reuptake inhibitors, primarily following abrupt discontinuation. Symptoms may be severe. Withdrawal symptoms may also occur following gradual tapering (Ref).

Mechanism: Withdrawal; due to reduced availability of serotonin in the CNS with decreasing levels of the serotonergic agent. Other neurotransmission systems, including increased glutamine and dopamine, may also be affected, as well as the hypothalamic-pituitary-adrenal axis (Ref).

Onset: Rapid; in case reports of withdrawal symptoms following venlafaxine discontinuation, symptoms usually appeared within a period of 24 to 48 hours after discontinuation (Ref).

Risk factors:

• Abrupt discontinuation (rather than gradual dosage reduction) of an antidepressant treatment that has lasted for >3 weeks, particularly a drug with a half-life <24 hours (eg, paroxetine, venlafaxine) (Ref)

• Prior history of antidepressant withdrawal symptoms (Ref)

• High dose (Ref)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Actual frequency may be dependent upon formulation and/or indication. Adverse reactions are reported for the ER tablet and ER capsule formulations. Reported adverse reactions are for adults unless otherwise specified.

>10%:

Dermatologic: Diaphoresis (11%)

Endocrine & metabolic: Weight loss (not necessarily associated with anorexia: children and adolescents: 18% to 47%; adults: <7%)

Gastrointestinal: Anorexia (8% to 22%), nausea (30%), xerostomia (15%)

Nervous system: Dizziness (16%), drowsiness (15%), insomnia (17% to 24%)

Neuromuscular & skeletal: Asthenia (13%)

1% to 10%:

Cardiovascular: Vasodilation (4%)

Endocrine & metabolic: Decreased libido (5%) (table 1), hypercholesterolemia (5%), orgasm abnormal (males: ≤10%) (table 2)

Venlafaxine: Adverse Reaction: Decreased Libido

Drug (Venlafaxine)

Placebo

Dosage Form

Number of Patients (Venlafaxine)

Number of Patients (Placebo)

5%

2%

Extended-release capsules

3,558

2,197

Venlafaxine: Adverse Reaction: Orgasm Abnormal

Drug (Venlafaxine)

Placebo

Population

Dosage Form

Number of Patients (Venlafaxine)

Number of Patients (Placebo)

Comments

10%

0.5%

Males

Extended-release capsules

1,440

923

Described as "abnormal ejaculation/orgasm"

Gastrointestinal: Constipation (9%), diarrhea (8%), vomiting (4%)

Genitourinary: Ejaculatory disorder (≤10%), impotence (5%)

Nervous system: Abnormal dreams (3%), anorgasmia (2% to 4%) (table 3), nervousness (7% to 10%), paresthesia (2%), yawning (4%)

Venlafaxine: Adverse Reaction: Anorgasmia

Drug (Venlafaxine)

Placebo

Population

Dosage Form

Number of Patients (Venlafaxine)

Number of Patients (Placebo)

4%

0.1%

Males

Extended-release capsules

1,440

923

2%

0.2%

Females

Extended-release capsules

2,118

1,274

Neuromuscular & skeletal: Tremor (5%)

Ophthalmic: Visual disturbance (4%)

<1%: Nervous system: Hypomania (Chand 2004)

Frequency not defined:

Cardiovascular: Hypotension, orthostatic hypotension, syncope, tachycardia

Dermatologic: Alopecia, ecchymoses, pruritus, skin photosensitivity, skin rash, urticaria

Endocrine & metabolic: Heavy menstrual bleeding, increased serum triglycerides, weight gain

Gastrointestinal: Abdominal pain (children and adolescents), bruxism, dysgeusia, dyspepsia (children and adolescents), gastrointestinal hemorrhage

Genitourinary: Abnormal uterine bleeding, urinary frequency, urinary incontinence, urinary retention

Nervous system: Agitation, akathisia, chills, confusion, depersonalization, hallucination, headache, hypertonia, manic reaction, myoclonus, seizure, suicidal ideation, suicidal tendencies

Neuromuscular & skeletal: Linear skeletal growth rate below expectation (children and adolescents, most notable for age <12 years), myalgia (children and adolescents)

Ophthalmic: Accommodation disturbance, mydriasis

Otic: Tinnitus

Respiratory: Epistaxis (children and adolescents)

Postmarketing:

Cardiovascular: Cardiomyopathy (takotsubo), hypertension (Pardal 2001), hypertensive crisis (Khurana 2003), increased blood pressure (Thase 1998), prolonged QT interval on ECG, sinus tachycardia (Osuagwu 2019), torsades de pointes, ventricular fibrillation, ventricular tachycardia, worsening of heart failure (Colucci 2008)

Dermatologic: Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis

Endocrine & metabolic: Hyponatremia (literature suggests an incidence ranging from <1% to 39% and even as high as 70%) (De Picker 2014; Jung 2011, Kirby 2002), increased serum prolactin, SIADH (Romero 2007)

Gastrointestinal: Gingival hemorrhage (Yavasoglu 2008), pancreatitis (Sevastru 2012)

Genitourinary: Erectile dysfunction (Montejo 2001), postpartum hemorrhage (Perotta 2019), priapism (Samuel 2000), sexual disorder (Kennedy 2000), vaginal hemorrhage (Linnebur 2002)

Hematologic & oncologic: Agranulocytosis, aplastic anemia, bruise (Carpenter 2016), mucous membrane bleeding, neutropenia, pancytopenia, prolonged bleeding time, thrombocytopenia

Hepatic: Abnormal hepatic function tests, cholestatic hepatitis (Stadlmann 2012), hepatitis (Horsmans 1999), hepatocellular hepatitis (Liver Tox NIH 2020), hepatotoxicity (Yildirim 2009), increased serum alanine aminotransferase (Liver Tox NIH 2020)

Hypersensitivity: Anaphylaxis, angioedema (Griffin 2021)

Nervous system: Apathy (Sato 2020), ataxia, balance impairment, delirium, dystonia, extrapyramidal reaction, hyperactive behavior (children and adolescents treated for ADHD) (Olvera 1996), kleptomania (Sakurada 2021), neuroleptic malignant syndrome, serotonin syndrome (Pan 2003), tardive dyskinesia, withdrawal syndrome (literature suggests an incidence ranging from 23% to 78%; can be severe, may include aggressive behavior, violent behavior, or blurred vision) (Fava 2018; Sablijic 2011)

Neuromuscular & skeletal: Dyskinesia, rhabdomyolysis

Ophthalmic: Acute angle-closure glaucoma (Ng 2002; Zhou 2018), increased intraocular pressure (open-angle glaucoma) (Botha 2016)

Respiratory: Dyspnea, eosinophilic pneumonitis (Fleisch 2000), interstitial pulmonary disease (Oh 2014), respiratory failure (Fleisch 2000)

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.

Warnings/Precautions

Concerns related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).

Disease-related concerns:

• Cardiovascular disease: Use caution in patients with recent history of MI, unstable heart disease, cerebrovascular conditions, or hyperthyroidism.

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

• 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.

Metabolism/Transport Effects

Substrate of CYP2C19 (minor), CYP2C9 (minor), CYP2D6 (minor), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP2D6 (weak)

Drug Interactions

Abrocitinib: Agents with Antiplatelet Properties may enhance the antiplatelet effect of Abrocitinib. Management: Do not use antiplatelet drugs with abrocitinib during the first 3 months of abrocitinib therapy. The abrocitinib prescribing information lists this combination as contraindicated. This does not apply to low dose aspirin (81 mg/day or less). Risk X: Avoid combination

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

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the antiplatelet effect of other Agents with Antiplatelet Properties. Risk C: 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. Risk D: 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. Risk C: 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. Risk C: 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. Management: If possible, avoid coadministration of direct-acting alpha-/beta-agonists and serotonin/norepinephrine reuptake inhibitors. If coadministered, monitor for increased sympathomimetic effects (eg, increased blood pressure, chest pain, headache). Risk D: Consider therapy modification

Alpha2-Agonists: Serotonin/Norepinephrine Reuptake Inhibitors may diminish the therapeutic effect of Alpha2-Agonists. Risk C: 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). Initiate amphetamines at lower doses, monitor frequently, and adjust doses as needed. Risk C: Monitor therapy

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

Aspirin: Serotonin/Norepinephrine Reuptake Inhibitors may enhance the antiplatelet effect of Aspirin. Risk C: 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. Risk D: Consider therapy modification

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

Bromopride: May enhance the adverse/toxic effect of Serotonin/Norepinephrine Reuptake Inhibitors. Risk X: 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. Risk C: Monitor therapy

Cephalothin: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Cephalothin. Specifically, the risk for bleeding may be increased. Risk C: 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. Risk C: 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. Risk C: 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. Risk C: 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. Risk X: Avoid combination

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

Desmopressin: Hyponatremia-Associated Agents may enhance the hyponatremic effect of Desmopressin. Risk C: 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. Risk C: 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. Risk C: Monitor therapy

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

Fenfluramine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: 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. Risk C: 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. Risk D: Consider therapy modification

Herbal Products with Anticoagulant/Antiplatelet Effects (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Risk C: Monitor therapy

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. Risk C: Monitor therapy

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

Icosapent Ethyl: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

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

Inotersen: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: 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. Risk X: Avoid combination

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. Risk C: Monitor therapy

Levomethadone: 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. Risk C: Monitor therapy

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

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

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

Lorcaserin (Withdrawn From US Market): 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. Risk C: 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. Risk C: 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. Risk C: Monitor therapy

Methadone: 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. Risk C: Monitor therapy

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

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. Risk C: Monitor therapy

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

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

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

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

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

Nonsteroidal Anti-Inflammatory Agents (Topical): Serotonin/Norepinephrine Reuptake Inhibitors may enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (Topical). Risk C: 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. Risk C: Monitor therapy

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

Opioid Agonists (metabolized by CYP3A4 and CYP2D6): 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. Risk C: Monitor therapy

Opioid Agonists (metabolized by CYP3A4): 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. Risk C: 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. Risk C: Monitor therapy

Ozanimod: May enhance the adverse/toxic effect of Serotonergic Agents (High Risk). Risk C: 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. Risk C: Monitor therapy

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

Propafenone: Venlafaxine may increase the serum concentration of Propafenone. Propafenone may increase the serum concentration of Venlafaxine. Risk C: Monitor therapy

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

Rasagiline: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Risk X: 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. Risk C: Monitor therapy

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

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

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

Selumetinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

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. Risk C: 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. Risk C: 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. Risk C: 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. Risk C: 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. Risk C: Monitor therapy

Thioridazine: CYP2D6 Inhibitors (Weak) may increase the serum concentration of Thioridazine. Management: Consider avoiding concomitant use of thioridazine and weak CYP2D6 inhibitors. If combined, monitor closely for QTc interval prolongation and arrhythmias. Some weak CYP2D6 inhibitors list use with thioridazine as a contraindication. Risk D: Consider therapy modification

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

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

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

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

Vitamin K Antagonists (eg, warfarin): Serotonin/Norepinephrine Reuptake Inhibitors may enhance the adverse/toxic effect of Vitamin K Antagonists. Specifically, the risk for bleeding may be increased. Risk C: Monitor therapy

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

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

Reproductive Considerations

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).

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).

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.

Breastfeeding Considerations

Venlafaxine and the active metabolite ODV are present in breast milk.

In one study, the mean relative infant dose (RID) of venlafaxine + ODV was 8.1% (range: 5% to 13%) when compared to a mean weight-adjusted maternal dose of 194 mg/day (range: 37.5 to 300 mg/day).

In general, breastfeeding is considered acceptable when the RID is <10% (Anderson 2016; Ito 2000). However some sources note breastfeeding should only be considered if the RID is <5% for psychotropic agents (Larsen 2015).

The mean RID of venlafaxine + ODV was calculated by the authors of a study using mean milk concentrations of 803.9 ng/mL (venlafaxine) and 1,424.2 ng/mL (ODV), providing an estimated daily infant dose via breast milk of 0.21 mg/kg/day (range: 0.071 to 0.375 mg/kg/day). This information is from a study of 13 mother-infant pairs. All but two women were using the extended release dosage form. The amount of ODV in breast milk increased over time and was greater 12 hours after the dose than earlier in the sampling interval. Venlafaxine and ODV could also be detected in infant serum (Newport 2009).

In comparison to other agents, information related to the use of venlafaxine in breastfeeding women is limited (Berle 2011). Infants of mothers using psychotropic medications should be monitored daily for changes in sleep, feeding patterns, and behavior (Bauer 2013) as well as infant growth and neurodevelopment (Sachs 2013; Sriraman 2015).

Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer recommends a decision be made to discontinue breastfeeding or to discontinue the drug, considering the importance of treatment to the mother. When first initiating an antidepressant in a breastfeeding woman, agents other than venlafaxine are preferred. Women successfully treated with venlafaxine during pregnancy may continue use while breastfeeding if there are no other contraindications (Berle 2011).

Monitoring Parameters

BP should be regularly monitored, especially in patients with a high baseline BP pressure; may cause mean increase in heart rate of 4 to 9 beats/minute; lipid panel; closely monitor patients for depression, clinical worsening, suicidality, psychosis, or unusual changes in behavior (eg, anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, mania, social functioning), particularly during the initial 1 to 2 months of therapy or during periods of dosage adjustments (increases or decreases); signs/symptoms of serotonin syndrome such as mental status changes (eg, agitation, hallucinations, delirium, coma), autonomic instability (eg, tachycardia, labile BP, diaphoresis), neuromuscular changes (eg, tremor, rigidity, myoclonus), GI symptoms (eg, nausea, vomiting, diarrhea), and/or seizures; 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).

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

Onset of action:

Anxiety disorders (generalized anxiety, panic, obsessive-compulsive disorder [OCD], posttraumatic stress disorder [PTSD]): Initial effects may be observed within 2 weeks of treatment, with continued improvements through 4 to 6 weeks (WFSBP [Bandelow 2012]); some experts suggest up to 12 weeks of treatment may be necessary for response, particularly in patients with OCD and PTSD (BAP [Baldwin 2014]; Katzman 2014; WFSBP [Bandelow 2012]).

Depression: Initial effects may be observed within 1 to 2 weeks of treatment, with continued improvements through 4 to 6 weeks (Papakostas 2006; Posternak 2005; Szegedi 2009).

Premenstrual dysphoric disorder: Initial effects may be observed within the first few days of treatment, with response at the first menstrual cycle of treatment (ISPMD [Nevatte 2013]).

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

Protein binding: Venlafaxine 27% ± 2%, ODV 30% ± 12%

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

Bioavailability: Oral: ~45%

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%)

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

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%

Pharmacokinetics: Additional Considerations

Renal function impairment: Elimination half-life is prolonged and clearance is reduced.

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, and clearance was reduced by 40% (Mullish 2014; manufacturer’s labeling). In patients with Child-Pugh class C hepatic impairment, clearance was reduced by 90% (Mullish 2014).

Pricing: US

Capsule ER 24 Hour Therapy Pack (Effexor XR Oral)

37.5 mg (per each): $17.42

75 mg (per each): $19.51

150 mg (per each): $21.25

Capsule ER 24 Hour Therapy Pack (Venlafaxine HCl ER Oral)

37.5 mg (per each): $0.06 - $4.16

75 mg (per each): $0.06 - $4.67

150 mg (per each): $0.14 - $5.08

Tablet, 24-hour (Venlafaxine HCl ER Oral)

37.5 mg (per each): $2.26 - $8.90

75 mg (per each): $1.49 - $9.97

150 mg (per each): $0.62 - $10.86

225 mg (per each): $1.54 - $20.83

Tablets (Venlafaxine HCl Oral)

25 mg (per each): $0.14 - $1.94

37.5 mg (per each): $0.15 - $2.00

50 mg (per each): $0.15 - $2.06

75 mg (per each): $0.16 - $2.18

100 mg (per each): $0.17 - $2.32

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Altven (AU);
  • Alventa (HR, RO);
  • Ansifix SR (EC);
  • Avenfax XR (SG);
  • Blossom (CN);
  • Calmdown (TW);
  • Cofexor XL ER (KR);
  • Delvena (EG);
  • Deprevix (HK);
  • Dobupal (ES);
  • Easyfor SR (TW);
  • Efectin (AT, CZ, HU);
  • Efectin EP (RO);
  • Efectin ER (BG);
  • Efexiva (SI);
  • Efexor (AE, AR, AU, BE, BH, BR, CH, CO, DK, EE, FI, GB, GR, ID, IE, IL, IT, JO, LU, NL, NZ, PE, PK, SA, SE, TR, ZA);
  • Efexor Depot (IS, NO);
  • Efexor XL (MT);
  • Efexor XR (AE, BH, BR, CL, CN, CO, CY, EC, EE, HK, KR, KW, LB, LT, MX, MY, PE, PH, PT, QA, SA, SG, TH, VE);
  • Effexor (FR);
  • Effexor SR (JP);
  • Effexor XR (BB);
  • Elafax (AR, PY, UY);
  • Elafax XR (PY, UY);
  • Evaxiner (CR, DO);
  • Evaxiner XR (GT, HN, NI, PA, SV);
  • Falven (HU);
  • Faxine (TW);
  • Faxnerva (EG);
  • Ganafax (AR);
  • Idixor (EG);
  • Lafax (BD);
  • Lanvexin (LV);
  • Levensa SR (KR);
  • Maxine (PH);
  • Neurofax SR (LK);
  • Nevola (BD);
  • Odifen (ZA);
  • Rafax XR (TW);
  • Rudomel XL (GB);
  • Sesaren XR (EC);
  • Trevilor (DE);
  • Valosine (TH, TW);
  • Vandral Retard (ES);
  • Vaxor (JO);
  • Velapax (RU);
  • Velaxim (PL);
  • Velaxin (HK, HU, UA);
  • Venax (BD);
  • Venexor (HK, JO);
  • Venexor XR (TZ);
  • Venexor XR SR (KR);
  • Venia (AT);
  • Veniz XR (LK);
  • Veniz-XR (IN);
  • Venla (IL);
  • VenlaBlue XL (GB);
  • Venlafact SR (KR);
  • Venlalic XL (GB);
  • Venlasand (BE);
  • Venlax (BD, CL, LK);
  • Venlax Retard (CL);
  • Venlax XR (LB);
  • Venlaxer (UA);
  • Venlaxor (LV);
  • Venlifax (AU);
  • Venlift OD 75 (TZ);
  • Venlify OD (BH);
  • Venlor (HK, ZA);
  • Venorion (FI, NO);
  • Vensir XL (GB);
  • Ventaxin OR (KR);
  • Venxor (HK, MY);
  • Viepax (IL, SG);
  • Viepax XR (IL);
  • Xadevil (GR);
  • Zarelis (IT)


For country abbreviations used in Lexicomp (show table)

REFERENCES

  1. Abozguia K, Chudley S, Gammage M. Dose-dependent venlafaxine-induced sinus tachycardia. Int J Cardiol. 2006;113(1):E9-E10. doi:10.1016/j.ijcard.2006.01.072 [PubMed 16989912]
  2. Adan-Manes J, Novalbos J, López-Rodríguez R, Ayuso-Mateos JL, Abad-Santos F. Lithium and venlafaxine interaction: a case of serotonin syndrome. J Clin Pharm Ther. 2006;31(4):397-400. doi:10.1111/j.1365-2710.2006.00745.x [PubMed 16882112]
  3. Albert U, Aguglia E, Maina G, Bogetto F. Venlafaxine versus clomipramine in the treatment of obsessive-compulsive disorder: a preliminary single-blind, 12-week, controlled study. J Clin Psychiatry. 2002;63(11):1004-1009. [PubMed 12444814]
  4. American College of Obstetricians and Gynecologists, ACOG Practice Bulletin: Clinical Management Guidelines for Obstetricians-Gynecologists No. 92 April 2008 (Replaces Practice Bulletin Number 87, November 2007). Use of psychiatric medications during pregnancy and lactation. Obstet Gynecol, 2008, 111(4):1001-20. [PubMed 18378767]
  5. 2019 American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2019 updated AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2019;67(4):674-694. doi:10.1111/jgs.15767 [PubMed 30693946]
  6. American Psychiatric Association (APA). Practice guideline for the treatment of patients with major depressive disorder. 3rd ed. http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf Published October 2010. Accessed July 2020.
  7. American Psychological Association (APA). Clinical practice guideline for the treatment of depression across three age cohorts. https://www.apa.org/depression-guideline/guideline.pdf. Published February 16, 2019. Accessed April 21, 2021.
  8. Anderson PO, Sauberan JB. Modeling drug passage into human milk. Clin Pharmacol Ther. 2016;100(1):42-52. [PubMed 27060684]
  9. Andrade C, Sandarsh S, Chethan KB, Nagesh KS. Serotonin reuptake inhibitor antidepressants and abnormal bleeding: a review for clinicians and a reconsideration of mechanisms. J Clin Psychiatry. 2010;71(12):1565-1575. doi:10.4088/JCP.09r05786blu [PubMed 21190637]
  10. Attal N, Cruccu G, Baron R, et al; European Federation of Neurological Societies. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol. 2010;17(9):1113-e88. [PubMed 20402746]
  11. Baldessarini RJ, Faedda GL, Offidani E, et al. Antidepressant-associated mood-switching and transition from unipolar major depression to bipolar disorder: a review. J Affect Disord. 2013;148(1):129-135. doi:10.1016/j.jad.2012.10.033 [PubMed 23219059]
  12. Baldwin DS, Anderson IM, Nutt DJ, et al. Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: a revision of the 2005 guidelines from the British Association for Psychopharmacology. J Psychopharmacol. 2014;28(5):403-439. doi:10.1177/0269881114525674 [PubMed 24713617]
  13. Bandelow B, Sher L, Bunevicius R, et al; WFSBP Task Force on Mental Disorders in Primary Care; WFSBP Task Force on Anxiety Disorders, OCD and PTSD. Guidelines for the pharmacological treatment of anxiety disorders, obsessive-compulsive disorder and posttraumatic stress disorder in primary care [published corrections appear in: Int J Psychiatry Clin Pract. 2012;16(3):242; Int J Psychiatry Clin Pract. 2013;17(1):76.]. Int J Psychiatry Clin Pract. 2012;16(2):77-84. doi:10.3109/13651501.2012.667114 [PubMed 22540422]
  14. Bartlett D. Drug-induced serotonin syndrome. Crit Care Nurse. 2017;37(1):49-54. doi:10.4037/ccn2017169 [PubMed 28148614]
  15. Bauer M, Pfennig A, Severus E, et al; World Federation of Societies of Biological Psychiatry Task Force on Unipolar Depressive Disorders. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J Biol Psychiatry. 2013;14(5):334-385. [PubMed 23879318]
  16. Bauer M, Severus E, Köhler S, Whybrow PC, Angst J, Möller HJ; WFSBP Task Force on Treatment Guidelines for Unipolar Depressive Disorders. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders. Part 2: maintenance treatment of major depressive disorder-update 2015. World J Biol Psychiatry. 2015;16(2):76-95. doi:10.3109/15622975.2014.1001786 [PubMed 25677972]
  17. Bauer M, Whybrow PC, Anst J, et al. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders, Part 2: Maintenance treatment of major depressive disorder and treatment of chronic depressive disorders and subthreshold depressions. World J Biol Psychiatry. 2002;3(2):69-86. [PubMed 12479080]
  18. Benvenuti A, Rucci P, Miniati M, et al. Treatment-emergent mania/hypomania in unipolar patients. Bipolar Disord. 2008;10(6):726-732. doi:10.1111/j.1399-5618.2008.00613. [PubMed 18837867]
  19. Berle JO, Spigset O. Antidepressant use during breastfeeding. Curr Womens Health Rev. 2011;7(1):28-34. [PubMed 22299006]
  20. Bhatara VS, Magnus RD, Paul KL, Preskorn SH. Serotonin syndrome induced by venlafaxine and fluoxetine: a case study in polypharmacy and potential pharmacodynamic and pharmacokinetic mechanisms. Ann Pharmacother. 1998;32(4):432-436. doi:10.1345/aph.17041 [PubMed 9562139]
  21. Bixby AL, VandenBerg A, Bostwick JR. Clinical management of bleeding risk with antidepressants. Ann Pharmacother. 2019;53(2):186-194. doi:10.1177/1060028018794005 [PubMed 30081645]
  22. Botha VE, Bhikoo R, Merriman M. Venlafaxine-induced intraocular pressure rise in a patient with open angle glaucoma. Clin Exp Ophthalmol. 2016;44(8):734-735. doi:10.1111/ceo.12769 [PubMed 27131226]
  23. Boyd IW. Comment: hyponatremia with venlafaxine. Ann Pharmacother. 1998;32(9):981-982. doi:10.1177/106002809803200902 [PubMed 9762390]
  24. Boyer EW, Shannon M. The serotonin syndrome [published correction appears in N Engl J Med. 2007;356(23):2437] [published correction appears in N Engl J Med. 2009;361(17):1714]. N Engl J Med. 2005;352(11):1112-1120. doi:10.1056/NEJMra041867 [PubMed 15784664]
  25. Brent D, Emslie G, Clarke G, et al. Switching to another SSRI or to venlafaxine with or without cognitive behavioral therapy for adolescents with SSRI-resistant depression: the TORDIA randomized controlled trial. JAMA. 2008;299(8):901-913. doi:10.1001/jama.299.8.901 [PubMed 18314433]
  26. Bril V, England J, Franklin GM, et al; American Academy of Neurology; American Association of Neuromuscular and Electrodiagnostic Medicine; American Academy of Physical Medicine and Rehabilitation. Evidence-based guideline: Treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation [published correction appears in Neurology. 2011;77(6):603]. Neurology. 2011;76(20):1758-1765. [PubMed 21482920]
  27. Bulut S, Berilgen MS, Baran A, Tekatas A, Atmaca M, Mungen B. Venlafaxine versus amitriptyline in the prophylactic treatment of migraine: randomized, double-blind, crossover study. Clin Neurol Neurosurg. 2004;107(1):44-48. doi:10.1016/j.clineuro.2004.03.004 [PubMed 15567552]
  28. Bunchorntavakul C, Reddy KR. Drug hepatotoxicity: newer agents. Clin Liver Dis. 2017;21(1):115-134. doi:10.1016/j.cld.2016.08.009 [PubMed 27842767]
  29. Bushnell GA, Compton SN, Dusetzina SB, et al. Treating pediatric anxiety: initial use of SSRIs and other antianxiety prescription medications. J Clin Psychiatry. 2018;79(1):16m11415. doi:10.4088/JCP.16m11415 [PubMed 29099547]
  30. Cardona X, Avila A, Castellanos P. Venlafaxine-associated hepatitis. Ann Intern Med. 2000;132(5):417. doi:10.7326/0003-4819-132-5-200003070-00016 [PubMed 10691596]
  31. Carpenter JE, Fombi J, Udoka O, Holder-Perkins V. Venlafaxine-induced bruising: a case report. Prim Care Companion CNS Disord. 2016;18(3):10.4088/PCC.15l01886. doi:10.4088/PCC.15l01886 [PubMed 27722026]
  32. Carvalho AF, Sharma MS, Brunoni AR, Vieta E, Fava GA. The safety, tolerability and risks associated with the use of newer generation antidepressant drugs: a critical review of the literature. Psychother Psychosom. 2016;85(5):270-288. doi:10.1159/000447034 [PubMed 27508501]
  33. Casper RF, Yonkers KA. Treatment of premenstrual syndrome and premenstrual dysphoric disorder. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed February 13, 2020.
  34. Chand PK, Kalyani GS, Murthy P. Venlafaxine-associated hypomania in unipolar depression. Can J Psychiatry. 2004;49(7):496. doi:10.1177/070674370404900717 [PubMed 15362257]
  35. Chen VC, Ng MH, Chiu WC, et al. Effects of selective serotonin reuptake inhibitors on glaucoma: a nationwide population-based study. PLoS One. 2017;12(3):e0173005. doi:10.1371/journal.pone.0173005 [PubMed 28257449]
  36. Cheng YL, Hu HY, Lin XH, et al. Use of SSRI, but not SNRI, increased upper and lower gastrointestinal bleeding: a nationwide population-based cohort study in Taiwan. Medicine (Baltimore). 2015;94(46):e2022. doi:10.1097/MD.0000000000002022 [PubMed 26579809]
  37. Cheung AH, Zuckerbrot RA, Jensen PS, Laraque D, Stein REK; GLAD-PC Steering Group. Guidelines for Adolescent Depression in Primary Care (GLAD-PC): Part II. Treatment and ongoing management. Pediatrics. 2018;141(3):e20174082. doi:10.1542/peds.2017-4082 [PubMed 29483201]
  38. Chou PH, Chu CS, Chen YH, et al. Antidepressants and risk of cataract development: a population-based, nested case-control study. J Affect Disord. 2017;215:237-244. doi:10.1016/j.jad.2017.03.044 [PubMed 28342338]
  39. Christensen RC, Garces LK. Hepatotoxic effects with high-dose venlafaxine. Psychiatry (Edgmont). 2006;3(7):10-11. [PubMed 20975814]
  40. Cobin RH, Goodman NF; AACE Reproductive Endocrinology Scientific Committee. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on menopause-2017 update [published correction appears in Endocr Pract. 2017;23(12):1488]. Endocr Pract. 2017;23(7):869-880. doi:10.4158/EP171828.PS [PubMed 28703650]
  41. Cohen LS, Soares CN, Lyster A, Cassano P, Brandes M, Leblanc GA. Efficacy and tolerability of premenstrual use of venlafaxine (flexible dose) in the treatment of premenstrual dysphoric disorder. J Clin Psychopharmacol. 2004;24(5):540-543. doi:10.1097/01.jcp.0000138767.53976.10 [PubMed 15349012]
  42. Colucci VJ, Berry BD. Heart failure worsening and exacerbation after venlafaxine and duloxetine therapy. Ann Pharmacother. 2008;42(6):882-887. doi:10.1345/aph.1L031 [PubMed 18445706]
  43. Costagliola C, Parmeggiani F, Semeraro F, Sebastiani A. Selective serotonin reuptake inhibitors: a review of its effects on intraocular pressure. Curr Neuropharmacol. 2008;6(4):293-310. doi:10.2174/157015908787386104 [PubMed 19587851]
  44. Coupland CA, Dhiman P, Barton G, et al. A study of the safety and harms of antidepressant drugs for older people: a cohort study using a large primary care database. Health Technol Assess. 2011;15(28):1-iv. doi:10.3310/hta15280 [PubMed 21810375]
  45. Coupland C, Hill T, Morriss R, Arthur A, Moore M, Hippisley-Cox J. Antidepressant use and risk of suicide and attempted suicide or self harm in people aged 20 to 64: cohort study using a primary care database. BMJ. 2015;350:h517. doi:10.1136/bmj.h517 [PubMed 25693810]
  46. Daniels RJ. Serotonin syndrome due to venlafaxine overdose. J Accid Emerg Med. 1998;15(5):333-334. doi:10.1136/emj.15.5.333 [PubMed 9785164]
  47. Davidson J, Baldwin D, Stein DJ, et al. Treatment of posttraumatic stress disorder with venlafaxine extended release: a 6-month randomized controlled trial. Arch Gen Psychiatry. 2006a;63(10):1158-1165. doi:10.1001/archpsyc.63.10.1158 [PubMed 17015818]
  48. Davidson J, Rothbaum BO, Tucker P, Asnis G, Benattia I, Musgnung JJ. Venlafaxine extended release in posttraumatic stress disorder: a sertraline- and placebo-controlled study [published correction appears in: J Clin Psychopharmacol. 2006;26(5):473]. J Clin Psychopharmacol. 2006b;26(3):259-267. doi:10.1097/01.jcp.0000222514.71390.c1 [PubMed 16702890]
  49. de Abajo FJ, García-Rodríguez LA. Risk of upper gastrointestinal tract bleeding associated with selective serotonin reuptake inhibitors and venlafaxine therapy: interaction with nonsteroidal anti-inflammatory drugs and effect of acid-suppressing agents. Arch Gen Psychiatry. 2008;65(7):795-803. doi:10.1001/archpsyc.65.7.795 [PubMed 18606952]
  50. De Picker L, Van Den Eede F, Dumont G, Moorkens G, Sabbe BG. Antidepressants and the risk of hyponatremia: a class-by-class review of literature. Psychosomatics. 2014;55(6):536-547. doi:10.1016/j.psym.2014.01.010 [PubMed 25262043]
  51. Decoutere L, De Winter S, Vander Weyden L, et al. A venlafaxine and mirtazapine-induced serotonin syndrome confirmed by de- and re-challenge [published correction appears in Int J Clin Pharm. 2012;34(5):689]. Int J Clin Pharm. 2012;34(5):686-688. doi:10.1007/s11096-012-9666-7 [PubMed 22752315]
  52. Denys D, van der Wee N, van Megen HJ, Westenberg HG. A double blind comparison of venlafaxine and paroxetine in obsessive-compulsive disorder. J Clin Psychopharmacol. 2003;23(6):568-575. doi:10.1097/01.jcp.0000095342.32154.54 [PubMed 14624187]
  53. Denys D, van Megen HJ, van der Wee N, Westenberg HG. A double-blind switch study of paroxetine and venlafaxine in obsessive-compulsive disorder. J Clin Psychiatry. 2004;65(1):37-43. [PubMed 14744166]
  54. Depression in children and young people: identification and management. London: National Institute for Health and Care Excellence (UK); June 25, 2019. [PubMed 31577402]
  55. Detry O, Delwaide J, De Roover A, et al. Fulminant hepatic failure induced by venlafaxine and trazodone therapy: a case report. Transplant Proc. 2009;41(8):3435-3436. doi:10.1016/j.transproceed.2009.09.022 [PubMed 19857765]
  56. Dobson ET, Strawn JR. Pharmacotherapy for pediatric generalized anxiety disorder: a systematic evaluation of efficacy, safety and tolerability. Paediatr Drugs. 2016;18(1):45-53. doi:10.1007/s40272-015-0153-1 [PubMed 26660158]
  57. Douros A, Ades M, Renoux C. Risk of intracranial hemorrhage associated with the use of antidepressants inhibiting serotonin reuptake: a systematic review. CNS Drugs. 2018;32(4):321-334. doi:10.1007/s40263-018-0507-7 [PubMed 29536379]
  58. Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM. 2003;96(9):635-642. doi:10.1093/qjmed/hcg109 [PubMed 12925718]
  59. Effexor XR (venlafaxine) [prescribing information]. Philadelphia, PA: Wyeth Pharmaceuticals LLC; September 2021.
  60. Emslie GJ, Mayes T, Porta G, et al. Treatment of resistant depression in adolescents (TORDIA): week 24 outcomes. Am J Psychiatry. 2010;167(7):782-791. doi:10.1176/appi.ajp.2010.09040552 [PubMed 20478877]
  61. Erie JC, Brue SM, Chamberlain AM, Hodge DO. Selective serotonin reuptake inhibitor use and increased risk of cataract surgery: a population-based, case-control study. Am J Ophthalmol. 2014;158(1):192-197.e1. doi:10.1016/j.ajo.2014.03.006 [PubMed 24631758]
  62. Etminan M, Mikelberg FS, Brophy JM. Selective serotonin reuptake inhibitors and the risk of cataracts: a nested case-control study. Ophthalmology. 2010;117(6):1251-1255. doi:10.1016/j.ophtha.2009.11.042 [PubMed 20207418]
  63. Evans ML, Pritts E, Vittinghoff E, McClish K, Morgan KS, Jaffe RB. Management of postmenopausal hot flushes with venlafaxine hydrochloride: a randomized, controlled trial. Obstet Gynecol. 2005;105(1):161-166. doi:10.1097/01.AOG.0000147840.06947.46 [PubMed 15625158]
  64. Evers S, Afra J, Frese A, et al; European Federation of Neurological Societies. EFNS guideline on the drug treatment of migraine—revised report of an EFNS task force. Eur J Neurol. 2009;16(9):968-981. doi:10.1111/j.1468-1331.2009.02748.x [PubMed 19708964]
  65. Ezra DG, Storoni M, Whitefield LA. Simultaneous bilateral acute angle closure glaucoma following venlafaxine treatment. Eye (Lond). 2006;20(1):128-129. doi:10.1038/sj.eye.6701815 [PubMed 15746956]
  66. Fava GA, Benasi G, Lucente M, Offidani E, Cosci F, Guidi J. Withdrawal symptoms after serotonin-noradrenaline reuptake inhibitor discontinuation: systematic review. Psychother Psychosom. 2018;87(4):195-203. doi:10.1159/000491524 [PubMed 30016772]
  67. Fava GA, Gatti A, Belaise C, Guidi J, Offidani E. Withdrawal symptoms after selective serotonin reuptake inhibitor discontinuation: a systematic review. Psychother Psychosom. 2015;84(2):72-81. doi:10.1159/000370338 [PubMed 25721705]
  68. Feighner JP. Cardiovascular safety in depressed patients: focus on venlafaxine. J Clin Psychiatry. 1995;56(12):574-579. [PubMed 8530334]
  69. Fenske JN, Schwenk TL. Obsessive compulsive disorder: diagnosis and management. Am Fam Physician. 2009;80(3):239-245. [PubMed 19621834]
  70. Fernández-Ferreiro A, Pose-Reino A, Martinez-Bahamonde F, et al. Serotonin syndrome, rhabdomyolysis and convulsion associated with drug interaction between venlafaxine and amoxicillin/clavulanic acid. Actas Esp Psiquiatr. 2016;44(5):193-202. [PubMed 27644102]
  71. Findling RL, Greenhill LL, McNamara NK, et al. Venlafaxine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2007;17(4):433-445. doi:10.1089/cap.2007.0119 [PubMed 17822339]
  72. Fisher AA, Davis MW. Serotonin syndrome caused by selective serotonin reuptake-inhibitors-metoclopramide interaction. Ann Pharmacother. 2002;36(1):67-71. doi:10.1345/aph.1A161 [PubMed 11816261]
  73. Fleisch MC, Blauer F, Gubler JG, Kuhn M, Scherer TA. Eosinophilic pneumonia and respiratory failure associated with venlafaxine treatment [published correction appears in Eur Respir J. 2000;15(3):627]. Eur Respir J. 2000;15(1):205-208. doi:10.1183/09031936.00.15120500 [PubMed 10678647]
  74. Freeman EW, Rickels K, Yonkers KA, Kunz NR, McPherson M, Upton GV. Venlafaxine in the treatment of premenstrual dysphoric disorder. Obstet Gynecol. 2001;98(5, pt 1):737-744. doi: 10.1016/s0029-7844(01)01530-7 [PubMed 11704162]
  75. Friedman RA, Leon AC. Expanding the black box - depression, antidepressants, and the risk of suicide. N Engl J Med. 2007;356(23):2343-2346. doi:10.1056/NEJMp078015 [PubMed 17485726]
  76. Gabriel M, Sharma V. Antidepressant discontinuation syndrome. CMAJ. 2017;189(21):E747. doi:10.1503/cmaj.160991 [PubMed 28554948]
  77. Gandhi S, Shariff SZ, Al-Jaishi A, et al. Second-generation antidepressants and hyponatremia risk: a population-based cohort study of older adults. Am J Kidney Dis. 2017;69(1):87-96. doi:10.1053/j.ajkd.2016.08.020 [PubMed 27773479]
  78. Goodman NF, Cobin RH, Ginzburg SB, Katz IA, Woode DE; American Association of Clinical Endocrinologists. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of menopause: executive summary of recommendations. Endocr Pract. 2011;17(6):949-954. [PubMed 22193145]
  79. Griffin H, Pearson S, Linnebur S, Fixen D. A case of venlafaxine-induced angioedema in an older adult. SAGE Open Med Case Rep. 2021;9:2050313X211050465. doi:10.1177/2050313X211050465 [PubMed 34616557]
  80. Grossman A, Messerli FH, Grossman E. Drug induced hypertension--an unappreciated cause of secondary hypertension. Eur J Pharmacol. 2015;763(Pt A):15-22. doi:10.1016/j.ejphar.2015.06.027 [PubMed 26096556]
  81. Grover S, Somaiya M, Ghormode D. Venlafaxine-associated hyponatremia presenting with catatonia. J Neuropsychiatry Clin Neurosci. 2013;25(2):E11-E12. doi:10.1176/appi.neuropsych.12030070 [PubMed 23686044]
  82. Gupta AK, Saravay SM. Venlafaxine-induced hyponatremia. J Clin Psychopharmacol. 1997;17(3):223-225. doi:10.1097/00004714-199706000-00014 [PubMed 9169969]
  83. Haddad PM. Antidepressant discontinuation syndromes. Drug Saf. 2001;24(3):183-197. [PubMed 11347722]
  84. Halperin D, Reber G. Influence of antidepressants on hemostasis. Dialogues Clin Neurosci. 2007;9(1):47-59. [PubMed 17506225]
  85. Hammad TA, Laughren T, Racoosin J. Suicidality in pediatric patients treated with antidepressant drugs. Arch Gen Psychiatry. 2006;63(3):332-339. doi:10.1001/archpsyc.63.3.332 [PubMed 16520440]
  86. Hanley GE, Smolina K, Mintzes B, Oberlander TF, Morgan SG. Postpartum hemorrhage and use of serotonin reuptake inhibitor antidepressants in pregnancy. Obstet Gynecol. 2016;127(3):553-561. doi:10.1097/AOG.0000000000001200 [PubMed 26855096]
  87. Harvey AT, Rudolph RL, Preskorn SH. Evidence of the dual mechanism of action of venlafaxine. Arch Gen Psychiatry. 2000;57(5):503-509. [PubMed 10807491]
  88. Hathaway EE, Walkup JT, Strawn JR. Antidepressant Treatment Duration in Pediatric Depressive and Anxiety Disorders: How Long is Long Enough? Curr Probl Pediatr Adolesc Health Care. 2018;48(2):31-39. [PubMed 29337001]
  89. Hetrick SE, McKenzie JE, Cox GR, Simmons MB, Merry SN. Newer generation antidepressants for depressive disorders in children and adolescents. Cochrane Database Syst Rev. 2012;11:CD004851. doi:10.1002/14651858.CD004851.pub3 [PubMed 23152227]
  90. Higgins A, Nash M, Lynch AM. Antidepressant-associated sexual dysfunction: impact, effects, and treatment. Drug Healthc Patient Saf. 2010;2:141-150. doi:10.2147/DHPS.S7634 [PubMed 21701626]
  91. Hirsch M, Birnbaum RJ. Discontinuing antidepressant medications in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed June 29, 2021a.
  92. Hirsch M, Birnbaum RJ. Switching antidepressant medications in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed March 9, 2021b.
  93. Horsmans Y, De Clercq M, Sempoux C. Venlafaxine-associated hepatitis. Ann Intern Med. 1999;130(11):944. doi:10.7326/0003-4819-130-11-199906010-00014 [PubMed 10375350]
  94. Huybrechts KF, Bateman BT, Pawar A, et al. Maternal and fetal outcomes following exposure to duloxetine in pregnancy: cohort study. BMJ. 2020;368:m237. doi:10.1136/bmj.m237 [PubMed 32075794]
  95. Ignaszewski MJ, Waslick B. Update on randomized placebo-controlled trials in the past decade for treatment of major depressive disorder in child and adolescent patients: a systematic review. J Child Adolesc Psychopharmacol. 2018;28(10):668-675. doi:10.1089/cap.2017.0174 [PubMed 30063169]
  96. Ito S. Drug therapy for breast-feeding women. N Engl J Med. 2000;343(2):118-126. [PubMed 10891521]
  97. Jacob S, Spinler SA. Hyponatremia associated with selective serotonin-reuptake inhibitors in older adults. Ann Pharmacother. 2006;40(9):1618-1622. doi:10.1345/aph.1G293 [PubMed 16896026]
  98. Jagadheesan K, Sandil R, Ram D. Venlafaxine-induced mania. Indian J Psychiatry. 2001;43(4):357-359. [PubMed 21407889]
  99. Jha MK, Rush AJ, Trivedi MH. When discontinuing SSRI antidepressants is a challenge: management tips. Am J Psychiatry. 2018;175(12):1176-1184. doi:10.1176/appi.ajp.2018.18060692 [PubMed 30501420]
  100. Jiang HY, Xu LL, Li YC, Deng M, Peng CT, Ruan B. Antidepressant use during pregnancy and risk of postpartum hemorrhage: a systematic review and meta-analysis. J Psychiatr Res. 2016;83:160-167. doi:10.1016/j.jpsychires.2016.09.001 [PubMed 27637098]
  101. Jing E, Straw-Wilson K. Sexual dysfunction in selective serotonin reuptake inhibitors (SSRIs) and potential solutions: a narrative literature review. Ment Health Clin. 2016;6(4):191-196. doi:10.9740/mhc.2016.07.191 [PubMed 29955469]
  102. Jung YE, Jun TY, Kim KS, Bahk WM. Hyponatremia associated with selective serotonin reuptake inhibitors, mirtazapine, and venlafaxine in Korean patients with major depressive disorder. Int J Clin Pharmacol Ther. 2011;49(7):437-443. doi:10.5414/cp201500 [PubMed 21726494]
  103. Kadiroglu AK, Sit D, Kayabasi H, Tuzcu AK, Tasdemir N, Yilmaz ME. The effect of venlafaxine HCl on painful peripheral diabetic neuropathy in patients with type 2 diabetes mellitus. J Diabetes Complications. 2008;22(4):241-245. [PubMed 18413214]
  104. Katzman MA, Bleau P, Blier P, et al; Canadian Anxiety Guidelines Initiative Group. Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders. BMC Psychiatry. 2014;14(suppl 1):S1. doi:10.1186/1471-244X-14-S1-S [PubMed 25081580]
  105. Kelsey JE. Dose-response relationship with venlafaxine. J Clin Psychopharmacol. 1996;16(3 suppl 2):21S-26S. [PubMed 8784645]
  106. Kennedy SH, Eisfeld BS, Dickens SE, Bacchiochi JR, Bagby RM. Antidepressant-induced sexual dysfunction during treatment with moclobemide, paroxetine, sertraline, and venlafaxine. J Clin Psychiatry. 2000;61(4):276-281. doi:10.4088/jcp.v61n0406 [PubMed 10830148]
  107. Khan A, Khan S, Kolts R, Brown WA. Suicide rates in clinical trials of SSRIs, other antidepressants, and placebo: analysis of FDA reports. Am J Psychiatry. 2003;160(4):790-792. doi:10.1176/appi.ajp.160.4.790 [PubMed 12668373]
  108. Khan S, Sivananthan M, Bacon O. Serotonin sensitivity and withdrawal with low-dose venlafaxine. Prim Care Companion CNS Disord. 2019;21(1):18l02334. doi:10.4088/PCC.18l02334 [PubMed 30817861]
  109. Khanassov V, Hu J, Reeves D, van Marwijk H. Selective serotonin reuptake inhibitor and selective serotonin and norepinephrine reuptake inhibitor use and risk of fractures in adults: a systematic review and meta-analysis. Int J Geriatr Psychiatry. 2018;33(12):1688-1708. doi:10.1002/gps.4974 [PubMed 30247774]
  110. Khurana RN, Baudendistel TE. Hypertensive crisis associated with venlafaxine. Am J Med. 2003;115(8):676-677. doi:10.1016/s0002-9343(03)00472-8 [PubMed 14656626]
  111. Kirby D, Harrigan S, Ames D. Hyponatraemia in elderly psychiatric patients treated with selective serotonin reuptake inhibitors and venlafaxine: a retrospective controlled study in an inpatient unit. Int J Geriatr Psychiatry. 2002;17(3):231-237. doi:10.1002/gps.591 [PubMed 11921151]
  112. Kirkham J, Seitz D. Evidence of ocular side effects of SSRIs and new warnings. Evid Based Ment Health. 2017;20(1):27. doi:10.1136/eb-2016-102528 [PubMed 27993931]
  113. Klier CM, Mossaheb N, Saria A, et al, "Pharmacokinetics and Elimination of Quetiapine, Venlafaxine, and Trazodone During Pregnancy and Postpartum," J Clin Psychopharmacol, 2007, 27(6):720-2. [PubMed 18004149]
  114. Kohn S, Labbate LA. Venlafaxine and ecchymosis. Can J Psychiatry. 1997;42(1):91. doi:10.1177/070674379704200126 [PubMed 9040933]
  115. Koran LM, Hanna GL, Hollander E, Nestadt G, Simpson HB; American Psychiatric Association. Practice guideline for the treatment of patients with obsessive-compulsive disorder. Am J Psychiatry. 2007;164(7)(suppl):5-53. [PubMed 17849776]
  116. Kwok CSN, Lim LEC. Mania following antidepressant discontinuation in depression: two case reports. Australas Psychiatry. 2017;25(6):617-621. doi:10.1177/1039856217732470 [PubMed 28976215]
  117. Lahon K, Shetty HM, Paramel A, Sharma G. Sexual dysfunction with the use of antidepressants in a tertiary care mental health setting - a retrospective case series. J Pharmacol Pharmacother. 2011;2(2):128-131. doi:10.4103/0976-500X.81913 [PubMed 21772780]
  118. Larsen ER, Damkier P, Pedersen LH, et al. Use of psychotropic drugs during pregnancy and breast-feeding. Acta Psychiatr Scand Suppl. 2015;(445):1-28. [PubMed 26344706]
  119. Leon AC. The revised warning for antidepressants and suicidality: unveiling the black box of statistical analyses. Am J Psychiatry. 2007;164(12):1786-1789. doi:10.1176/appi.ajp.2007.07050775 [PubMed 18056231]
  120. Leong C, Alessi-Severini S, Enns MW, et al. Cerebrovascular, cardiovascular, and mortality events in new users of selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors: a propensity score-matched population-based study. J Clin Psychopharmacol. 2017;37(3):332-340. doi:10.1097/JCP.0000000000000701 [PubMed 28383363]
  121. Leth-Møller KB, Hansen AH, Torstensson M, et al. Antidepressants and the risk of hyponatremia: a Danish register-based population study. BMJ Open. 2016;6(5):e011200. doi:10.1136/bmjopen-2016-011200 [PubMed 27194321]
  122. Lewis JD, Strom BL, Localio AR, et al. Moderate and high affinity serotonin reuptake inhibitors increase the risk of upper gastrointestinal toxicity. Pharmacoepidemiol Drug Saf. 2008;17(4):328-335. doi:10.1002/pds.1546 [PubMed 18188866]
  123. Liebowitz MR, Gelenberg AJ, Munjack D. Venlafaxine extended release vs placebo and paroxetine in social anxiety disorder. Arch Gen Psychiatry. 2005;62(2):190-198. [PubMed 15699296]
  124. Linnebur SA, Saseen JJ, Pace WD. Venlafaxine-associated vaginal bleeding. Pharmacotherapy. 2002;22(5):652-655. doi:10.1592/phco.22.8.652.33219 [PubMed 12013367]
  125. LiverTox: clinical and research information on drug-induced liver injury. National Center for Biotechnology Information. Updated March 6, 2020. Accessed July 2, 2020. https://www.ncbi.nlm.nih.gov/books/NBK548799/
  126. Loibl S, Schwedler K, von Minckwitz G, Strohmeier R, Mehta KM, Kaufmann M. Venlafaxine is superior to clonidine as treatment of hot flashes in breast cancer patients—a double-blind, randomized study. Ann Oncol. 2007;18(4):689-693. [PubMed 17229772]
  127. Loprinzi CL, Kugler JW, Sloan JA, et al. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Lancet. 2000;356(9247):2059-2063. [PubMed 11145492]
  128. Loprinzi CL, Levitt R, Barton D, et al. Phase III comparison of depomedroxyprogesterone acetate to venlafaxine for managing hot flashes: North Central Cancer Treatment Group trial N99C7. J Clin Oncol. 2006;24(9):1409-1414. [PubMed 16505409]
  129. MacQueen GM, Frey BN, Ismail Z, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 6. Special populations: youth, women, and the elderly. Can J Psychiatry. 2016;61(9):588-603. [PubMed 27486149]
  130. Mannesse CK, Jansen PA, Van Marum RJ, et al. Characteristics, prevalence, risk factors, and underlying mechanism of hyponatremia in elderly patients treated with antidepressants: a cross-sectional study. Maturitas. 2013;76(4):357-363. doi:10.1016/j.maturitas.2013.08.010 [PubMed 24094459]
  131. Martin A, Young C, Leckman JF, Mukonoweshuro C, Rosenheck R, Leslie D. Age effects on antidepressant-induced manic conversion. Arch Pediatr Adolesc Med. 2004;158(8):773-780. doi:10.1001/archpedi.158.8.773 [PubMed 15289250]
  132. Masood GR, Karki SD, Patterson WR. Hyponatremia with venlafaxine. Ann Pharmacother. 1998;32(1):49-51. doi:10.1345/aph.17117 [PubMed 9475820]
  133. Mawardi G, Markman TM, Muslem R, et al. SSRI/SNRI therapy is associated with a higher risk of gastrointestinal bleeding in LVAD patients. Heart Lung Circ. 2019;S1443-9506(19)31374-5. doi:10.1016/j.hlc.2019.07.011 [PubMed 31635997]
  134. Meynaar IA, Peeters AJ, Mulder AH, Ottervanger JP. Syndrome of inappropriate ADH secretion attributed to the serotonin re-uptake inhibitors, venlafaxine and paroxetine. Neth J Med. 1997;50(6):243-245. doi:10.1016/s0300-2977(97)00005-3 [PubMed 9232089]
  135. Mines D, Hill D, Yu H, Novelli L. Prevalence of risk factors for suicide in patients prescribed venlafaxine, fluoxetine, and citalopram. Pharmacoepidemiol Drug Saf. 2005;14(6):367-372. doi:10.1002/pds.1095 [PubMed 15883980]
  136. Montejo AL, Llorca G, Izquierdo JA, Rico-Villademoros F. Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction. J Clin Psychiatry. 2001;62 Suppl 3:10-21. [PubMed 11229449]
  137. Moura C, Bernatsky S, Abrahamowicz M, et al. Antidepressant use and 10-year incident fracture risk: the population-based Canadian Multicentre Osteoporosis Study (CaMoS). Osteoporos Int. 2014;25(5):1473-1481. doi:10.1007/s00198-014-2649-x [PubMed 24566587]
  138. Mullen S. Major depressive disorder in children and adolescents. Ment Health Clin. 2018;8(6):275-283. doi:10.9740/mhc.2018.11.275 [PubMed 30397569]
  139. Mullish BH, Kabir MS, Thursz MR, Dhar A. Review article: depression and the use of antidepressants in patients with chronic liver disease or liver transplantation. Aliment Pharmacol Ther. 2014;40(8):880-892. doi:10.1111/apt.12925 [PubMed 25175904]
  140. Murphy RM, Bakir B, O'Brien C, Wiggs JL, Pasquale LR. Drug-induced bilateral secondary angle-closure glaucoma: a literature synthesis. J Glaucoma. 2016;25(2):e99-e105. doi:10.1097/IJG.0000000000000270 [PubMed 25943730]
  141. Nagler EV, Webster AC, Vanholder R, Zoccali C. Antidepressants for depression in stage 3-5 chronic kidney disease: a systematic review of pharmacokinetics, efficacy and safety with recommendations by European Renal Best Practice (ERBP). Nephrol Dial Transplant. 2012;27(10):3736-3745. doi:10.1093/ndt/gfs295 [PubMed 22859791]
  142. National Collaborating Centre for Mental Health (NCCMH). Depression: The Treatment and Management of Depression in Adults (Updated Edition). National Institute for Health & Clinical Excellence (NICE). 2010. [PubMed 22132433]
  143. National Institute for Health and Care Excellence (NICE). Attention deficit hyperactivity disorder: diagnosis and management. NICE clinical guideline NG87. London, UK: National Institute for Health and Care Excellence. https://www.nice.org.uk/guidance/ng87/chapter/recommendations. Published March 14, 2018a. Accessed January 25, 2021.
  144. National Institute for Health and Care Excellence (NICE). Attention deficit hyperactivity disorder (update). NICE clinical guideline NG87. London, UK: National Institute for Health and Care Excellence. https://www.nice.org.uk/guidance/ng87/evidence/c-pharmacological-efficacy-and-sequencing-pdf-4783686303. Published March 2018b. Accessed January 25, 2021.
  145. Nelson JC, Devanand DP. A systematic review and meta-analysis of placebo-controlled antidepressant studies in people with depression and dementia. J Am Geriatr Soc. 2011;59(4):577-585. [PubMed 21453380]
  146. Nevatte T, O'Brien PM, Bäckström T, et al; Consensus Group of the International Society for Premenstrual Disorders. ISPMD consensus on the management of premenstrual disorders. Arch Womens Ment Health. 2013;16(4):279-291. doi:10.1007/s00737-013-0346-y [PubMed 23624686]
  147. Newport DJ, Ritchie JC, Knight BT, et al, "Venlafaxine in Human Breast Milk and Nursing Infant Plasma: Determination of Exposure," J Clin Psychiatry, 2009, 70(9):1304-10. [PubMed 19607765]
  148. Ng B, Sanbrook GM, Malouf AJ, Agarwal SA. Venlafaxine and bilateral acute angle closure glaucoma. Med J Aust. 2002;176(5):241. [PubMed 11999245]
  149. Norman TR, Olver JS. Duloxetine in the treatment of generalized anxiety disorder. Neuropsychiatr Dis Treat. 2008;4(6):1169-1180. doi:10.2147/ndt.s2820 [PubMed 19337457]
  150. North American Menopause Society (NAMS). Nonhormonal management of menopause-associated vasomotor symptoms: 2015 position statement of the North American Menopause Society. Menopause. 2015;22(11):1155-1172. doi:10.1097/GME.0000000000000546 [PubMed 26382310]
  151. Ogle NR, Akkerman SR. Guidance for the discontinuation or switching of antidepressant therapies in adults. J Pharm Pract. 2013;26(4):389-396. doi:10.1177/0897190012467210 [PubMed 23459282]
  152. Oh S, Cha SI, Kim H, et al. A case of venlafaxine-induced interstitial lung disease. Tuberc Respir Dis (Seoul). 2014;77(2):81-84. doi:10.4046/trd.2014.77.2.81 [PubMed 25237379]
  153. Olvera RL, Pliszka SR, Luh J, Tatum R. An open trial of venlafaxine in the treatment of attention-deficit/hyperactivity disorder in children and adolescents. J Child Adolesc Psychopharmacol. 1996;6(4):241-250. [PubMed 9231317]
  154. Opatrny L, Delaney JA, Suissa S. Gastro-intestinal haemorrhage risks of selective serotonin receptor antagonist therapy: a new look. Br J Clin Pharmacol. 2008;66(1):76-81. doi:10.1111/j.1365-2125.2008.03154.x [PubMed 18460039]
  155. Osuagwu FC, Bradley R. Delayed sinus tachycardia associated with venlafaxine administration: a unique case report and discussion. J Clin Psychopharmacol. 2019;39(6):689-690. doi:10.1097/JCP.0000000000001140 [PubMed 31688406]
  156. Ozyalcin SN, Talu GK, Kiziltan E, Yucel B, Ertas M, Disci R. The efficacy and safety of venlafaxine in the prophylaxis of migraine. Headache. 2005;45(2):144-152. doi:10.1111/j.1526-4610.2005.05029.x [PubMed 15705120]
  157. Palmsten K, Hernández-Díaz S, Huybrechts KF, et al. Use of antidepressants near delivery and risk of postpartum hemorrhage: cohort study of low income women in the United States. BMJ. 2013;347:f4877. [PubMed 23965506]
  158. Pan JJ, Shen WW. Serotonin syndrome induced by low-dose venlafaxine. Ann Pharmacother. 2003;37(2):209-211. doi:10.1177/106002800303700209 [PubMed 12549949]
  159. Panganiban B, Kinder B, Litner J. A painful urologic emergency. JAAPA. 2014;27(5):54-55. doi:10.1097/01.JAA.0000446226.77930.5f [PubMed 24758982]
  160. Papakostas GI, Perlis RH, Scalia MJ, Petersen TJ, Fava M. A meta-analysis of early sustained response rates between antidepressants and placebo for the treatment of major depressive disorder. J Clin Psychopharmacol. 2006;26(1):56-60. doi:10.1097/01.jcp.0000195042.62724.76 [PubMed 16415707]
  161. Pardal PK, John TR, Rathee SP. Venlafaxine induced hypertension:a case report. Indian J Psychiatry. 2001;43(4):360-361. [PubMed 21407890]
  162. Park SH, Ishino R. Liver injury associated with antidepressants. Curr Drug Saf. 2013;8(3):207-223. doi:10.2174/1574886311308030011 [PubMed 23914755]
  163. Park SH, Wackernah RC, Stimmel GL. Serotonin syndrome: is it a reason to avoid the use of tramadol with antidepressants?. J Pharm Pract. 2014;27(1):71-78. doi:10.1177/0897190013504957 [PubMed 24153222]
  164. Patel R, Reiss P, Shetty H, et al. Do antidepressants increase the risk of mania and bipolar disorder in people with depression? A retrospective electronic case register cohort study. BMJ Open. 2015;5(12):e008341. doi:10.1136/bmjopen-2015-008341 [PubMed 26667012]
  165. Perrotta C, Giordano F, Colombo A, et al. Postpartum bleeding in pregnant women receiving SSRIs/SNRIs: new insights from a descriptive observational study and an analysis of data from the FAERS database. Clin Ther. 2019;41(9):1755-1766. doi:10.1016/j.clinthera.2019.06.008 [PubMed 31371035]
  166. Pollack MH, Van Ameringen M, Simon NM, et al. A double-blind randomized controlled trial of augmentation and switch strategies for refractory social anxiety disorder. Am J Psychiatry. 2014;171(1):44-53. [PubMed 24399428]
  167. Pop-Busui R, Boulton AJ, Feldman EL, et al. Diabetic neuropathy: a position statement by the American Diabetes Association. Diabetes Care. 2017;40(1):136-154. doi:10.2337/dc16-2042 [PubMed 27999003]
  168. Posternak MA, Zimmerman M. Is there a delay in the antidepressant effect? A meta-analysis. J Clin Psychiatry. 2005;66(2):148-158. doi:10.4088/jcp.v66n0201 [PubMed 15704999]
  169. Pringsheim T, Davenport W, Mackie G, et al; Canadian Headache Society Prophylactic Guidelines Development Group. Canadian Headache Society guideline for migraine prophylaxis. Can J Neurol Sci. 2012;39(2)(suppl 2):S1-S59. [PubMed 22683887]
  170. Rajapakse S, Abeynaike L, Wickramarathne T. Venlafaxine-associated serotonin syndrome causing severe rhabdomyolysis and acute renal failure in a patient with idiopathic Parkinson disease. J Clin Psychopharmacol. 2010;30(5):620-622. doi:10.1097/JCP.0b013e3181ee2ae7 [PubMed 20814334]
  171. Rampono J, Simmer K, Ilett KF, et al, "Placental Transfer of SSRI and SNRI Antidepressants and Effects on the Neonate," Pharmacopsychiatry, 2009, 42(3):95-100. [PubMed 19452377]
  172. Rauma PH, Pasco JA, Berk M, et al. The association between major depressive disorder, use of antidepressants and bone mineral density (BMD) in men. J Musculoskelet Neuronal Interact. 2015;15(2):177-185. [PubMed 26032210]
  173. Reeves RR, Ladner ME. Antidepressant-induced suicidality: an update. CNS Neurosci Ther. 2010;16(4):227-234. doi:10.1111/j.1755-5949.2010.00160.x [PubMed 20553304]
  174. Reis M, Källén B. Delivery outcome after maternal use of antidepressant drugs in pregnancy: an update using Swedish data. Psychol Med. 2010;40(10):1723-1733. [PubMed 20047705]
  175. Rizzoli R, Cooper C, Reginster JY, et al. Antidepressant medications and osteoporosis. Bone. 2012;51(3):606-613. [PubMed 22659406]
  176. Romero S, Pintor L, Serra M, et al. Syndrome of inappropriate secretion of antidiuretic hormone due to citalopram and venlafaxine. Gen Hosp Psychiatry. 2007;29(1):81-84. doi:10.1016/j.genhosppsych.2006.11.001 [PubMed 17189754]
  177. Rowbotham MC, Goli V, Kunz NR, Lei D. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study [published correction appears in Pain. 2005;113(1-2):248]. Pain. 2004;110(3):697-706. [PubMed 15288411]
  178. Rudroju N, Bansal D, Talakokkula ST, et al. Comparative efficacy and safety of six antidepressants and anticonvulsants in painful diabetic neuropathy: a network meta-analysis [published correction appears in Pain Physician. 2014;17(2):203]. Pain Physician. 2013;16(6):E705-E714. [PubMed 24284851]
  179. Runowicz CD, Leach CR, Henry NL, et al. American Cancer Society/American Society of Clinical Oncology breast cancer survivorship care guideline. J Clin Oncol. 2016;34(6):611-635. doi: 10.1200/JCO.2015.64.3809. [PubMed 26644543]
  180. Rynn MA, Riddle MA, Yeung PP, Kunz NR. Efficacy and safety of extended-release venlafaxine in the treatment of generalized anxiety disorder in children and adolescents: two placebo-controlled trials. Am J Psychiatry. 2007;164(2):290-300. doi:10.1176/ajp.2007.164.2.290 [PubMed 17267793]
  181. Sabljić V, Ružić K, Rakun R. Venlafaxine withdrawal syndrome. Psychiatr Danub. 2011;23(1):117-119. [PubMed 21448114]
  182. Sachs HC, Committee On Drugs. The transfer of drugs and therapeutics into human breast milk: an update on selected topics. Pediatrics. 2013;132(3):e796-809. [PubMed 23979084]
  183. Safarinejad MR. Safety and efficacy of venlafaxine in the treatment of premature ejaculation: a double-blind, placebo-controlled, fixed-dose, randomised study. Andrologia. 2008;40(1):49-55. doi:10.1111/j.1439-0272.2008.00813.x [PubMed 18211302]
  184. Sakurada K, Nibuya M, Yamada K, Nakagawa S, Suzuki E. Kleptomania induced by venlafaxine. Case Rep Psychiatry. 2021;2021:8470045. doi:10.1155/2021/8470045 [PubMed 34540303]
  185. Samuel RZ. Priapism associated with venlafaxine use. J Am Acad Child Adolesc Psychiatry. 2000;39(1):16-17. doi:10.1097/00004583-200001000-00010 [PubMed 10638063]
  186. Sato S, Sodeyama N, Matsuzaki A, Shiratori Y. Apathy symptoms induced by low-dose venlafaxine: Two cases. Neuropsychopharmacol Rep. 2020;40(2):196-197. doi:10.1002/npr2.12104 [PubMed 32267090]
  187. Scammell TE. Treatment of narcolepsy in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed July 23, 2021.
  188. Schäfer W, Princk C, Kollhorst B, Schink T. Antidepressants and the risk of hemorrhagic stroke in the elderly: a nested case-control study. Drug Saf. 2019;42(9):1081-1089. doi:10.1007/s40264-019-00837-y [PubMed 31165430]
  189. Schatzberg AF, Blier P, Delgado PL, et al. Antidepressant discontinuation syndrome: consensus panel recommendations for clinical management and additional research. J Clin Psychiatry. 2006;67(Suppl 4):27-30. [PubMed 16683860]
  190. Sencan I, Sahin I, Ozcetin A. Low-dose venlafaxine-associated liver toxicity in chronic hepatitis. Ann Pharmacother. 2004;38(2):352-353. doi:10.1345/aph.1D205 [PubMed 14742779]
  191. Sevastru S, Wakatsuki M, Fennell J, Grocott MP. Plasma exchange in the management of a case of hypertriglyceridaemic pancreatitis triggered by venlafaxine. BMJ Case Rep. 2012;2012:bcr1120115208. doi:10.1136/bcr.11.2011.5208 [PubMed 22892234]
  192. Sharma T, Guski LS, Freund N, Gøtzsche PC. Suicidality and aggression during antidepressant treatment: systematic review and meta-analyses based on clinical study reports. BMJ. 2016;352:i65. doi:10.1136/bmj.i65 [PubMed 26819231]
  193. Shea ML, Garfield LD, Teitelbaum S, et al. Serotonin-norepinephrine reuptake inhibitor therapy in late-life depression is associated with increased marker of bone resorption. Osteoporos Int. 2013;24(5):1741-1749. doi:10.1007/s00198-012-2170-z [PubMed 23358607]
  194. Shelton, RC. Steps following attainment of remission: discontinuation of antidepressant therapy. Prim Care Companion J Clin Psychiatry. 2001;3(4):168-174. [PubMed 15014601]
  195. Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E; Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1337-1345. doi:10.1212/WNL.0b013e3182535d20 [PubMed 22529202]
  196. Smischney NJ, Pollard EM, Nookala AU, Olatoye OO. Serotonin syndrome in the perioperative setting. Am J Case Rep. 2018;19:833-835. doi:10.12659/AJCR.909497 [PubMed 30008467]
  197. Sobieraj DM, Baker WL, Martinez BK, et al. Adverse Effects of Pharmacologic Treatments of Major Depression in Older Adults. Rockville (MD): Agency for Healthcare Research and Quality (US); 2019. [PubMed 30964616]
  198. Sriraman NK, Melvin K, Meltzer-Brody S. ABM clinical protocol #18: use of antidepressants in breastfeeding mothers. Breastfeed Med. 2015;10(6):290-299. [PubMed 26204124]
  199. Stadlmann S, Portmann S, Tschopp S, Terracciano LM. Venlafaxine-induced cholestatic hepatitis: case report and review of literature. Am J Surg Pathol. 2012;36(11):1724-1728. doi:10.1097/PAS.0b013e31826af296 [PubMed 23073329]
  200. Stahl SM. Mechanism of action of serotonin selective reuptake inhibitors. Serotonin receptors and pathways mediate therapeutic effects and side effects. J Affect Disord. 1998;51(3):215-235. doi:10.1016/s0165-0327(98)00221-3 [PubMed 10333979]
  201. Stein MB. Pharmacotherapy for social anxiety disorder in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed August 6, 2018.
  202. Stein MB, Pollack MH, Bystritsky A, Kelsey JE, Mangano RM. Efficacy of low and higher dose extended-release venlafaxine in generalized social anxiety disorder: a 6-month randomized controlled trial. Psychopharmacology(Berl). 2005;177(3):280-288. [PubMed 15258718]
  203. Strawn JR, Welge JA, Wehry AM, Keeshin B, Rynn MA. Efficacy and tolerability of antidepressants in pediatric anxiety disorders: a systematic review and meta-analysis. Depress Anxiety. 2015;32(3):149-157. doi:10.1002/da.22329 [PubMed 25449861]
  204. Stuenkel CA, Davis SR, Gompel A, et al. Treatment of symptoms of the menopause: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015;100(11):3975-4011. doi:10.1210/jc.2015-2236 [PubMed 26444994]
  205. Sun-Edelstein C, Tepper SJ, Shapiro RE. Drug-induced serotonin syndrome: a review. Expert Opin Drug Saf. 2008;7(5):587-596. doi:10.1517/14740338.7.5.587 [PubMed 18759711]
  206. Szegedi A, Jansen WT, van Willigenburg AP, van der Meulen E, Stassen HH, Thase ME. Early improvement in the first 2 weeks as a predictor of treatment outcome in patients with major depressive disorder: a meta-analysis including 6562 patients. J Clin Psychiatry. 2009;70(3):344-353. doi:10.4088/jcp.07m03780 [PubMed 19254516]
  207. Tarlaci S. Escitalopram and venlafaxine for the prophylaxis of migraine headache without mood disorders. Clin Neuropharmacol. 2009;32(5):254-258. doi:10.1097/WNF.0b013e3181a8c84f [PubMed 19667978]
  208. ter Horst PG, Larmené-Beld KH, Bosman J, van der Veen EL, Wieringa A, Smit JP. Concentrations of venlafaxine and its main metabolite O-desmethylvenlafaxine during pregnancy. J Clin Pharm Ther. 2014;39(5):541-544. [PubMed 24989434]
  209. Thase ME. Effects of venlafaxine on blood pressure: a meta-analysis of original data from 3744 depressed patients. J Clin Psychiatry. 1998;59(10):502-508. doi:10.4088/jcp.v59n1002 [PubMed 9818630]
  210. Tondo L, Vázquez G, Baldessarini RJ. Mania associated with antidepressant treatment: comprehensive meta-analytic review. Acta Psychiatr Scand. 2010;121(6):404-414. doi:10.1111/j.1600-0447.2009.01514.x [PubMed 19958306]
  211. Troy SM, Schultz RW, Parker VD, Chiang ST, Blum RA. The effect of renal disease on the disposition of venlafaxine. Clin Pharmacol Ther. 1994;56(1):14-21. doi:10.1038/clpt.1994.95 [PubMed 8033490]
  212. Tully PJ, Cardinal T, Bennetts JS, Baker RA. Selective serotonin reuptake inhibitors, venlafaxine and duloxetine are associated with in hospital morbidity but not bleeding or late mortality after coronary artery bypass graft surgery. Heart Lung Circ. 2012;21(4):206-214. doi:10.1016/j.hlc.2011.12.002 [PubMed 22285303]
  213. US Department of Veterans Affairs/Department of Defense. VA/DoD clinical practice guideline for the management of posttraumatic stress disorder and acute stress disorder. https://www.healthquality.va.gov/guidelines/MH/ptsd/VADoDPTSDCPGFinal082917.pdf. Published June 2017. Accessed December 6, 2017.
  214. Venlafaxine tablets, USP [prescribing information]. Ahmedabad, India: BluePoint Laboratories; June 2021.
  215. Venlafaxine tablets, USP [prescribing information]. BluePoint Laboratories; March 2021.
  216. Venlafaxine Hydrochloride extended-release tablets [prescribing information]. Bridgewater, NJ: Vertical Pharmaceuticals LLC; July 2021.
  217. Venlafaxine: A New Dimension in Antidepressant Pharmacotherapy. J Clin Psychiatry. 1993;54(3):119-126. [PubMed 8468312]
  218. Viramontes TS, Truong H, Linnebur SA. Antidepressant-induced hyponatremia in older adults. Consult Pharm. 2016;31(3):139-150. doi:10.4140/TCP.n.2016.139 [PubMed 26975593]
  219. Voican CS, Corruble E, Naveau S, Perlemuter G. Antidepressant-induced liver injury: a review for clinicians. Am J Psychiatry. 2014;171(4):404-415. doi:10.1176/appi.ajp.2013.13050709 [PubMed 24362450]
  220. Wadhwa R, Kumar M, Talegaonkar S, Vohora D. Serotonin reuptake inhibitors and bone health: a review of clinical studies and plausible mechanisms. Osteoporos Sarcopenia. 2017;3(2):75-81. doi:10.1016/j.afos.2017.05.002 [PubMed 30775508]
  221. Walter HJ, Bukstein OG, Abright AR, et al. Clinical practice guideline for the assessment and treatment of children and adolescents with anxiety disorders. J Am Acad Child Adolesc Psychiatry. 2020;59(10):1107-1124. doi:10.1016/j.jaac.2020.05.005 [PubMed 32439401]
  222. Wang CY, Fu SH, Wang CL, Chen PJ, Wu FL, Hsiao FY. Serotonergic antidepressant use and the risk of fracture: a population-based nested case-control study. Osteoporos Int. 2016;27(1):57-63. doi:10.1007/s00198-015-3213-z [PubMed 26126579]
  223. Wang Z, Whiteside S, Sim L, et al. Anxiety in Children. Comparative Effectiveness Review No. 192. (Prepared by the Mayo Clinic Evidence-based Practice Center under Contract No. 290-2015-00013-I.) AHRQ Publication No. 17-EHC023-EF. Rockville, MD: Agency for Healthcare Research and Quality; August 2017. Erratum July 2018. doi:10.23970/AHRQEPCCER192
  224. Warner, CH, Bobo W, Warner C, Reid S, Rachal J. Antidepressant discontinuation syndrome. Am Fam Physician. 2006;74(3):449-456. [PubMed 16913164]
  225. Weiler S, Offinger A, Exadaktylos AK. Shaking head means "no". BMJ Case Rep. 2013;2013:bcr2013200796. doi:10.1136/bcr-2013-200796 [PubMed 24022904]
  226. Werneke U, Northey S, Bhugra D. Antidepressants and sexual dysfunction [published correction appears in Acta Psychiatr Scand. 2007;115(3):255]. Acta Psychiatr Scand. 2006;114(6):384-397. doi:10.1111/j.1600-0447.2006.00890.x [PubMed 17087787]
  227. Westin AA, Brekke M, Molden E, Skogvoll E, Spigset O. Selective serotonin reuptake inhibitors and venlafaxine in pregnancy: changes in drug disposition. PLoS One. 2017;12(7):e0181082. [PubMed 28708853]
  228. Wiciński M, Kaluzny BJ, Liberski S, Marczak D, Seredyka-Burduk M, Pawlak-Osińska K. Association between serotonin-norepinephrine reuptake inhibitors and acute angle closure: What is known?. Surv Ophthalmol. 2019;64(2):185-194. doi:10.1016/j.survophthal.2018.09.006 [PubMed 30278181]
  229. Wijkstra J, Burger H, van den Broek WW, et al. Treatment of unipolar psychotic depression: a randomized, double-blind study comparing imipramine, venlafaxine, and venlafaxine plus quetiapine. Acta Psychiatr Scand. 2010;121(3):190-200. doi:10.1111/j.1600-0447.2009.01464.x [PubMed 19694628]
  230. Wolraich ML, Hagan JF Jr, Allan C, et al. Clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics. 2019;144(4):e20192528. [PubMed 31570648]
  231. Yavasoglu I, Kadikoylu G, Bolaman Z. Gingival bleeding due to venlafaxine. Ann Pharmacother. 2008;42(1):144-145. doi:10.1345/aph.1K180 [PubMed 18029426]
  232. Yildirim B, Tuncer C, Ergun M, Unal S. Venlafaxine-induced hepatotoxicity in a patient with ulcerative colitis. Ann Hepatol. 2009;8(3):271-272. [PubMed 19841512]
  233. Young JB, Singh TD, Rabinstein AA, Fugate JE. SSRI/SNRI use is not associated with increased risk of delayed cerebral ischemia after aSAH. Neurocrit Care. 2016;24(2):197-201. doi:10.1007/s12028-015-0190-1 [PubMed 26264066]
  234. Zarinara AR, Mohammadi MR, Hazrati N, et al. Venlafaxine versus methylphenidate in pediatric outpatients with attention deficit hyperactivity disorder: a randomized, double-blind comparison trial. Hum Psychopharmacol. 2010;25(7-8):530-535. doi:10.1002/hup.1148 [PubMed 20860068]
  235. Zhou N, Zhao JX, Zhu YN, Zhang P, Zuo Y. Acute angle-closure glaucoma caused by venlafaxine. Chin Med J (Engl). 2018;131(12):1502-1503. doi:10.4103/0366-6999.233952 [PubMed 29893371]
  236. Zimmer B, Kant R, Zeiler D, Brilmyer M. Antidepressant efficacy and cardiovascular safety of venlafaxine in young vs old patients with comorbid medical disorders. Int J Psychiatry Med. 1997;27(4):353-364. doi:10.2190/UDRD-99CB-T6KH-EDKP [PubMed 9565731]
Topic 10042 Version 584.0