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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 of suicidal thoughts and behavior in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. 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;
  • Effexor XR;
  • M-Venlafaxine XR;
  • PMS-Venlafaxine XR;
  • PMSC-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
Generalized anxiety disorder

Generalized anxiety disorder: Oral: Note: Do not initiate therapy, titrate by doses <112.5 mg, or taper treatment with ER besylate tablets. Use other ER products to initiate, titrate, administer doses <112.5 mg/day, and to taper during discontinuation of therapy.

ER besylate: Initial: 112.5 mg once daily in patients who have received ≥75 mg/day of another venlafaxine ER product for at least 4 days; may then be increased by ≤75 mg/day increments (using another venlafaxine ER product) at intervals ≥4 days as tolerated (maximum dose: 225 mg/day).

ER hydrochloride: 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: Note: Do not initiate therapy, titrate by doses <112.5 mg. or taper treatment with ER besylate tablets. Use other ER products to initiate, titrate, administer doses <112.5 mg/day, and to taper during discontinuation of therapy.

ER besylate: Initial: 112.5 mg once daily in patients who have received ≥75 mg/day of another venlafaxine ER product for at least 4 days; may then be increased by ≤75 mg/day increments (using another venlafaxine ER product) at intervals ≥4 days as tolerated (maximum dose: 225 mg/day).

ER hydrochloride: 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) (Ref). Some experts use more rapid titrations (every 2 to 3 days) in combination with an antipsychotic (eg, quetiapine) for patients with psychotic features (Ref).

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 (Ref) (maximum dose: 375 mg/day).

Migraine, prevention

Migraine, prevention (off-label use):

Note: An adequate trial for assessment of effect is considered to be at least 2 to 3 months at a therapeutic dose (Ref).

Oral: ER hydrochloride: Initial: 37.5 mg once daily for 1 week; may increase based on response and tolerability by 37.5 mg increments at weekly intervals to a target dose of 75 to 150 mg once daily (Ref).

Narcolepsy with cataplexy

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

Neuropathic pain associated with diabetes mellitus

Neuropathic pain associated with diabetes mellitus (off-label use): Oral: ER hydrochloride: 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 (Ref).

Obsessive-compulsive disorder

Obsessive-compulsive disorder (alternative agent) (off-label use): Note: Alternative for patients with limited or no response to SSRI therapy (Ref). Oral: IR and ER hydrochloride: Initial: 75 mg once daily for ER hydrochloride 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 (Ref).

Panic disorder

Panic disorder: Oral: ER hydrochloride: 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: ER hydrochloride: 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 (Ref).

Premenstrual dysphoric disorder

Premenstrual dysphoric disorder (alternative agent) (off-label use): Continuous daily dosing regimen: Oral: ER hydrochloride: 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 (Ref).

Social anxiety disorder

Social anxiety disorder: Oral: ER hydrochloride: Initial: 37.5 mg once daily; increase to 75 mg/day after 1 to 2 weeks (Ref). May continue to increase in increments of 75 mg each week based on response and tolerability up to 225 mg once daily (Ref); 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 (Ref). Oral: IR and ER hydrochloride: Initial: 37.5 mg once daily; may increase dose after ≥1 week based on response and tolerability to 75 mg once daily for ER hydrochloride or 75 mg/day in 2 to 3 divided doses for immediate release (Ref). 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 (Ref).

Dosing conversion: Patients treated with a therapeutic dose with venlafaxine immediate release may be switched to venlafaxine ER besylate at the nearest equivalent dose (mg/day) if the total dosage is either 112.5 mg/day or 225 mg/day or venlafaxine ER hydrochloride 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 (Ref). Reasons for a slower taper (eg, over 4 weeks) include history of antidepressant withdrawal symptoms or high doses of antidepressants (Ref). If intolerable withdrawal symptoms occur, resume the previously prescribed dose and/or decrease dose at a more gradual rate (Ref). Select patients (eg, those with a history of discontinuation syndrome) on long-term treatment (>6 months) may benefit from tapering over >3 months (Ref). The ER besylate tablet should not be used for tapering because the dosage strengths are not available below 112.5 mg. Evidence supporting ideal taper rates is limited (Ref).

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 (Ref).

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 (Ref).

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 (Ref):

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), a 25% to 50% reduction with CrCl 30 to 89 mL/minute (extended release), and a ≥50% reduction with CrCl <30 mL/minute (extended release), and the maximum recommended dose of venlafaxine ER besylate is 112.5 mg/day; 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 (Ref); 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 (Ref).

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

Note: The manufacturer recommends a ≥50% dose reduction of ER capsules and tablets in patients undergoing hemodialysis.

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

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

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

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

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

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

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. The maximum recommended dose of venlafaxine ER besylate is 112.5 mg/day.

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. The maximum recommended dose of venlafaxine ER besylate is 112.5 mg/day.

Dosing: Pediatric

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

Note: Venlafaxine extended release is available in 2 different formulations: Hydrochloride salt (eg, Effexor XR) and besylate 24-hour tablet; use caution to ensure appropriate dosage form.

Attention-deficit/hyperactivity disorder

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 (Ref); venlafaxine has shown minor positive benefits for some outcomes in small trials (Ref); robust evidence is lacking (Ref).

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 (Ref).

Generalized anxiety disorder, social anxiety, separation anxiety, or panic disorder

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 (Ref).

Children ≥6 years and Adolescents: Oral: Extended-release capsule (hydrochloride salt; eg, Effexor XR): 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) (Ref).

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 (Ref).

Major depressive disorder

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) (Ref). Therapy should be initiated at a low dose and titrated every 1 to 2 weeks based on response and tolerability (Ref).

Children ≥12 years and Adolescents: Oral: Extended-release capsule (hydrochloride salt; eg, Effexor XR): 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%) (Ref).

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 (Ref). 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 (Ref).

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 (Ref). 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 (Ref).

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, as hydrochloride:

Effexor XR: 37.5 mg, 75 mg, 150 mg

Generic: 37.5 mg, 75 mg, 150 mg

Tablet, Oral, as hydrochloride:

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

Tablet Extended Release 24 Hour, Oral, as besylate:

Generic: 112.5 mg

Tablet Extended Release 24 Hour, Oral, as hydrochloride:

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, as hydrochloride:

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/2022/20699s112lbl.pdf#page=38

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

Venlafaxine besylate ER tablet: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215429s000lbl.pdf#page=31

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 (hydrochloride salt; eg, Effexor XR): 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 (ER hydrochloride capsules and ER besylate tablets only): Treatment of generalized anxiety disorder.

Major depressive disorder (unipolar): Treatment of unipolar major depressive disorder.

Panic disorder (ER hydrochloride capsules only): Treatment of panic disorder, with or without agoraphobia.

Social anxiety disorder (ER hydrochloride capsules and tablets only): Treatment of social anxiety disorder, also known as social phobia.

Use: Off-Label: Adult

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

Older Adult: 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)

• Female sex (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 monoamine oxidase inhibitors (MAOIs) (concurrently or within 14 days of discontinuing the MAOI); initiation of MAOI 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

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

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 hepatotoxic effect of Serotonin/Norepinephrine Reuptake Inhibitors. Particularly duloxetine and milnacipran. Management: Consider advising patients to avoid concomitant use of alcohol with SNRIs, particularly those using extended-release SNRI formulations, due to the risk of accelerated drug release. Heavy alcohol use has been associated with overdose and hepatotoxicity. 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

Caplacizumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Caplacizumab. Specifically, the risk of bleeding may be increased. Management: Avoid coadministration of caplacizumab with antiplatelets if possible. If coadministration is required, monitor closely for signs and symptoms of bleeding. Interrupt use of caplacizumab if clinically significant bleeding occurs. Risk D: Consider therapy modification

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

Metoclopramide: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Consider monitoring 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

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 ER 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; screen patients for personal or family history of bipolar disorder, mania, or hypomania prior to initiating therapy; 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), 6.8 ± 1.6 hours (ER besylate), 10.7 ± 3.2 hours (ER hydrochloride); ODV: 11 ± 2 hours (immediate-release), 11.3 ± 2.3 hours (ER besylate), 12.5 ± 3 hours (ER hydrochloride); 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.

ER besylate: Venlafaxine: 10 hours (range: 5 to 18 hours), ODV: 18 hours (range: 5 to 28 hours).

ER hydrochloride: 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

Altered kidney function: 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): $18.27

75 mg (per each): $20.47

150 mg (per each): $22.30

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 Besylate ER Oral)

112.5 mg (per each): $7.40

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): $1.94

37.5 mg (per each): $2.00

50 mg (per each): $2.06

75 mg (per each): $2.18

100 mg (per each): $2.31 - $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 code abbreviations (show table)
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