Version November 2024
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.
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). Some experts suggest maintaining the initial therapeutic dose for 4 to 6 weeks to assess for efficacy before increasing further (Ref).
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 4 to 6 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 4 to 6 weeks are appropriate in less clinically urgent situations); usual dosage: 75 to 375 mg/day (Ref) (maximum dose: 375 mg/day).
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 (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 (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 (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: 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). Some experts maintain dose at 75 mg for 6 weeks before considering further dose increases. May require 6 weeks at maximally tolerated dose for adequate treatment trial (Ref).
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 (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: Oral: ER hydrochloride: Initial: 37.5 mg once daily; after 4 to 6 weeks at this dose, may increase to 75 mg/day, and then 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 (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: When discontinuing antidepressant treatment that has lasted for ≥4 weeks, gradually taper the dose (eg, over 2 to 4 weeks) to minimize withdrawal symptoms and detect reemerging symptoms (Ref). For brief treatment (eg, 2 to 3 weeks), may taper over 1 to 2 weeks; <2 weeks of treatment generally does not warrant tapering (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.
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).
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.
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.
(For additional information see "Venlafaxine: Pediatric drug information")
Dosage guidance:
Dosage form information: 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 (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: 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 (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.
There are no pediatric-specific recommendations; based on experience in adult patients, dosing adjustment suggested.
There are no pediatric-specific recommendations; based on experience in adult patients, dosing adjustment suggested.
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)
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 gastrointestinal 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)
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)
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)
Abnormal hepatic function tests may occur with use; increased serum alanine aminotransferase is usually modest and self-limiting. However, postmarketing cases of hepatotoxicity, including hepatitis, cholestatic hepatitis, and hepatic failure, 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. 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)
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)
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 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.
Venlafaxine is commonly associated with sexual disorder in both men and women. The following adverse reactions have been associated with use: Abnormal orgasm, 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).
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, 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 dose taper) or tapering the antidepressant too quickly (Ref)
• Drugs with a half-life <24 hours (eg, paroxetine, venlafaxine) (Ref)
• Higher doses (Ref)
• Longer duration of treatment (eg, ≥4 weeks) (Ref)
• Prior history of antidepressant withdrawal symptoms (Ref)
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: Asthenia (13%), dizziness (16%), drowsiness (15%), insomnia (17% to 24%)
1% to 10%:
Cardiovascular: Vasodilation (4%)
Endocrine & metabolic: Decreased libido (5%) (table 1), hypercholesterolemia (5%)
|
Drug (Venlafaxine) |
Placebo |
Dosage Form |
Number of Patients (Venlafaxine) |
Number of Patients (Placebo) |
|---|---|---|---|---|
|
5% |
2% |
Extended-release capsules |
3,558 |
2,197 |
Gastrointestinal: Constipation (9%), diarrhea (8%), vomiting (4%)
Genitourinary: Abnormal orgasm (males: ≤10%) (table 2), anorgasmia (2% to 4%) (table 3), ejaculatory disorder (≤10%), erectile dysfunction (5%)
|
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" |
|
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 |
Nervous system: Abnormal dreams (3%), nervousness (7% to 10%), paresthesia (2%), tremor (5%), yawning (4%)
Ophthalmic: Visual disturbance (4%)
<1%: Nervous system: Hypomania, manic reaction
Frequency not defined:
Cardiovascular: Hypotension, syncope, tachycardia
Dermatologic: Ecchymoses, pruritus, skin photosensitivity, skin rash, urticaria
Endocrine & metabolic: Heavy menstrual bleeding, increased serum triglycerides, weight gain
Gastrointestinal: Abdominal pain (children and adolescents), dysgeusia, dyspepsia (children and adolescents), gastrointestinal hemorrhage
Genitourinary: Abnormal uterine bleeding, urinary frequency
Nervous system: Agitation, chills, confusion, depersonalization, hallucination, headache, hypertonia, 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) (Ref), heart failure (including worsening of heart failure) (Ref), hypertension (Ref), hypertensive crisis (Ref), orthostatic hypotension (Ref), prolonged QT interval on ECG (Ref), sinus tachycardia (Ref), torsades de pointes (Ref), ventricular fibrillation, ventricular tachycardia
Dermatologic: Alopecia (Ref), erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis
Endocrine & metabolic: Galactorrhea not associated with childbirth (Ref), hyperprolactinemia (Ref), hypoglycemia (Ref), hyponatremia (literature suggests an incidence ranging from <1% to 39% and even as high as 70%) (Ref), lactic acidosis (Ref), SIADH (Ref)
Gastrointestinal: Bruxism (Ref), gingival hemorrhage (Ref), mucous membrane bleeding, pancreatitis (Ref)
Genitourinary: Postpartum hemorrhage (Ref), priapism (Ref), sexual disorder (Ref), urinary incontinence (Ref), urinary retention (Ref), vaginal hemorrhage (Ref)
Hematologic & oncologic: Agranulocytosis, aplastic anemia, bruise (Ref), neutropenia, pancytopenia, prolonged bleeding time, thrombocytopenia
Hepatic: Abnormal hepatic function tests (including increased serum alanine aminotransferase and increased serum aspartate aminotransferase) (Ref), cholestatic hepatitis (Ref), hepatic failure (Ref), hepatitis (Ref), hepatocellular hepatitis (Ref), hepatotoxicity (Ref)
Hypersensitivity: Anaphylaxis, angioedema (Ref)
Nervous system: Akathisia (Ref), anosmia (including hyposmia), apathy (Ref), ataxia, balance impairment, delirium, extrapyramidal reaction, hyperactive behavior (children and adolescents treated for ADHD) (Ref), kleptomania (Ref), myoclonus (Ref), neuroleptic malignant syndrome, serotonin syndrome (Ref), withdrawal syndrome (literature suggests an incidence ranging from 23% to 78%; can be severe, may include aggressive behavior, violent behavior, or blurred vision) (Ref)
Neuromuscular & skeletal: Dyskinesia, dystonia, rhabdomyolysis, tardive dyskinesia
Ophthalmic: Acute angle-closure glaucoma (Ref), increased intraocular pressure (open-angle glaucoma) (Ref)
Respiratory: Dyspnea, eosinophilic pneumonitis (Ref), interstitial lung disease (Ref), respiratory failure (Ref)
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 IV methylene blue.
Note: Although venlafaxine is contraindicated per the manufacturer labeling when used in combination with linezolid, new evidence suggests that the combination is unlikely to cause serotonin syndrome (0.06% to 3% risk), and therefore these agents can be administered concomitantly when necessary. Monitor patients on this combination; average duration of serotonin toxicity is ~4 days; however, risks may be greater with longer durations of concurrent therapy. Educate patients on the signs and symptoms of serotonin syndrome (Bai 2022; Butterfield 2012; Karkow 2017; Kufel 2023; Narita 2007; Taylor 2006).
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
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.
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
Yes
Capsule ER 24 Hour Therapy Pack (Effexor XR Oral)
37.5 mg (per each): $20.52
75 mg (per each): $23.00
150 mg (per each): $25.05
Capsule ER 24 Hour Therapy Pack (Venlafaxine HCl ER Oral)
37.5 mg (per each): $0.48 - $6.18
75 mg (per each): $0.53 - $6.92
150 mg (per each): $0.59 - $7.54
Tablet, 24-hour (Venlafaxine Besylate ER Oral)
112.5 mg (per each): $7.77
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.
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
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.
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.
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/2023/020699s118lbl.pdf#page=41
Venlafaxine ER tablet: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/022104s023lbl.pdf#page=35
Venlafaxine besylate ER tablet: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/215429s001lbl.pdf#page=33
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.
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
Effexor may be confused with Effexor XR
Effexor XR may be confused with Enablex
Venlafaxine may be confused with Venclexta, venetoclax
Beers Criteria: Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) (venlafaxine) 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 2023]).
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)
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 drug interactions program by clicking on the “Launch drug interactions program” link above.
Abrocitinib: Serotonin/Norepinephrine Reuptake Inhibitors may enhance the antiplatelet effect of Abrocitinib. 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
Anagrelide: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. 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
Antiplatelet Agents (P2Y12 Inhibitors): Serotonin/Norepinephrine Reuptake Inhibitors may enhance the antiplatelet effect of Antiplatelet Agents (P2Y12 Inhibitors). 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
Epinephrine (Racemic): Serotonin/Norepinephrine Reuptake Inhibitors may enhance the adverse/toxic effect of Epinephrine (Racemic). Risk X: Avoid combination
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
Gepirone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. 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
Lecanemab: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Specifically, the risk of hemorrhage may be increased. 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
Pirtobrutinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Propafenone: May increase the serum concentration of Venlafaxine. Venlafaxine may increase the serum concentration of Propafenone. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Psilocybin: Antidepressants may diminish the therapeutic effect of Psilocybin. 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
Selective Serotonin Reuptake Inhibitors: May enhance the antiplatelet effect of Venlafaxine. Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of Venlafaxine. 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
Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors): Venlafaxine may enhance the antiplatelet effect of Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors). Venlafaxine may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors). This could result in serotonin syndrome. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may decrease serum concentrations of the active metabolite(s) of Venlafaxine. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may increase the serum concentration of Venlafaxine. 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
Volanesorsen: May enhance the antiplatelet effect of Agents with Antiplatelet Effects. 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
Venlafaxine is approved for the treatment of major depressive disorder. If treatment for major depressive disorder is initiated for the first time in patients planning to become pregnant, agents other than venlafaxine are preferred (Larsen 2015).
Venlafaxine is effective for prevention of migraines. In general, preventive treatment for migraine in patients trying to become pregnant should be avoided. Options for patients planning a pregnancy should be considered as part of a shared decision-making process. Nonpharmacologic interventions should be considered initially. When needed, preventive treatment should be individualized considering the available safety data and needs of the patient should pregnancy occur. A gradual discontinuation of preventive medications is generally preferred when the decision is made to stop treatment prior to conception (ACOG 2022; AHS [Ailani 2021]).
Venlafaxine and its active metabolite O-desmethylvenlafaxine (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, hyperreflexia, 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. Pregnant patients 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 2013; Reis 2010).
Untreated or inadequately treated psychiatric illness may lead to poor adherence with prenatal care and adverse pregnancy outcomes. Therapy with antidepressants during pregnancy should be individualized; treatment with antidepressant medication is recommended for pregnant patients with severe major depressive disorder (ACOG 2008; CANMAT [MacQueen 2016]). Patients treated for major depression and who are euthymic prior to pregnancy are more likely to experience a relapse when medication is discontinued (68%) compared to pregnant patients who continue taking antidepressant medications (26%) (Cohen 2006). If treatment for major depressive disorder is initiated for the first time during pregnancy, agents other than venlafaxine are preferred (CANMAT [MacQueen 2016]; Larsen 2015). Patients effectively treated with venlafaxine prior to pregnancy may continue treatment (Larsen 2015).
In general, preventive treatment for migraine should be avoided during pregnancy. Options for pregnant patients should be considered as part of a shared decision-making process. Nonpharmacologic interventions should be considered initially. When needed, preventive treatment should be individualized considering the available safety data, the potential for adverse maternal and fetal events, and needs of the patient (ACOG 2022; AHS [Ailani 2021]). Efficacy of venlafaxine for migraine prevention in pregnancy is limited and use is not recommended (ACOG 2022; CHS [Pringsheim 2012]).
Patients exposed to antidepressants during pregnancy are encouraged to enroll in the National Pregnancy Registry for Antidepressants (NPRAD). Patients 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.
Venlafaxine and the active metabolite O-desmethylvenlafaxine (ODV) are present in breast milk.
Data related to the presence of venlafaxine in breast milk are available from multiple sources (Berle 2004; Ilett 1998; Ilett 2002; Misri 2006; Newport 2009; Schoretsanitis 2019; Weissman 2003).
• In 1 study, the transfer of venlafaxine and ODV into breast milk was evaluated in 13 mother-infant pairs. All patients in the study had been taking venlafaxine for >2 weeks (mean dose: 194 mg/day; range: 37.5 to 300 mg/day). All but 2 were using the extended-release dosage form. Milk samples were obtained over 24 hours. Mean breast milk concentrations were 469.8 ng/mL (venlafaxine) and 919 ng/mL (ODV). The maximum venlafaxine milk concentration reported was 2,759 ng/mL (maternal dose 187.5 mg/day) and the maximum ODV milk concentration reported was 3,146 ng/mL (maternal venlafaxine dose 225 mg/day). The mean theoretical infant dose (venlafaxine + ODV) was 0.21 mg/kg/day (range: 0.071 to 0.375 mg/kg/day). The mean relative infant dose (RID) was calculated to be 8.1% of the maternal dose (range: 5% to 13%). The amount of ODV in breast milk increased over time and was greater 12 hours after the dose than earlier in the sampling interval. In 6 mother-infant pairs, maternal and infant serum samples were taken. In the breastfeeding infants, mean plasma concentrations were 2.5 ng/mL (venlafaxine) and 58.7 ng/mL (ODV) and mean maternal plasma concentrations were 71.6 ng/mL (venlafaxine) and 245.6 ng/mL (ODV). Adverse effects were not reported in the 13 breastfeeding infants, all generally healthy at delivery (mean age: 20.9 weeks, range: 6.4 to 60 weeks) (Newport 2009).
• 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).
Infants of mothers using psychotropic medications should be monitored daily for changes in sleep, feeding patterns, and behavior (WFSBP [Bauer 2013]) as well as infant growth and neurodevelopment (ABM [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.
Psychotherapy or other nonmedication therapies are recommended for the initial treatment of mild depression in breastfeeding patients; antidepressant medication is recommended when psychotherapy is not an option or symptoms are moderate to severe. When first initiating an antidepressant in a breastfeeding patient, agents other than venlafaxine are preferred (ABM [Sriraman 2015]; CANMAT [MacQueen 2016]; Larsen 2015). A patient already stabilized on a serotonin/norepinephrine reuptake inhibitor during pregnancy may continue that medication while breastfeeding (ABM [Sriraman 2015]).
In general, preventive treatment for migraine in breastfeeding patients should be avoided. When needed, therapy should be individualized considering the available safety data and needs of the patient (AHS [Ailani 2021]). Agents other than venlafaxine are recommended when preventive therapy is needed in patients who are lactating (CHS [Pringsheim 2012]).
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); 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).
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).
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 2023a]); 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 2023a]; WFSBP [Bandelow 2023b]).
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%.
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).
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