PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Serotonin Norepinephrine Reuptake Inhibitor Antidepressants, SNRIs

    BOXED WARNING

    Children, growth inhibition, suicidal ideation

    Safety and efficacy of venlafaxine for the treatment of major depressive disorder (MDD) have not been established in children and adolescents less than 18 years of age. In a pooled analysis of placebo-controlled trials of antidepressants (n = 4,500 pediatrics and 77,000 adults), there was an increased risk for suicidal thoughts and behaviors in patients 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. The difference in absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. No suicides occurred in any of the pediatric trials. Nevertheless, the need for an antidepressant in children, adolescents, or young adults for any use must be weighed against the risk of suicidality; it is unknown if this risk extends to long-term use. All patients should be monitored for symptom worsening or suicidality, especially at treatment initiation or after dose changes. Caregivers and/or patients should immediately notify the prescriber of changes in behavior or suicidal ideation. A change to the treatment regimen or discontinuation of venlafaxine may be necessary in patients with emerging suicidality or worsening depression. Venlafaxine has been shown to lead to dose-dependent weight loss in children ages 6 to 17 years. In addition, growth inhibition has been noted in short and long-term studies in children. Clinicians should regularly monitor height and weight changes in pediatric patients receiving venlafaxine.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral serotonin norepinephrine reuptake inhibitor (SNRI) antidepressant
    Used in adults for major depression, generalized anxiety disorder, social anxiety disorder, and panic disorder; effective in women with hot flashes due to menopause or breast cancer treatment
    Increased risk of suicidality during the initial stages of treatment in pediatric and young adult patients

    COMMON BRAND NAMES

    Effexor, Effexor XR, Venlafaxine

    HOW SUPPLIED

    Effexor XR/Venlafaxine/Venlafaxine Hydrochloride Oral Cap ER: 37.5mg, 75mg, 150mg
    Effexor/Venlafaxine/Venlafaxine Hydrochloride Oral Tab: 25mg, 37.5mg, 50mg, 75mg, 100mg
    Venlafaxine/Venlafaxine Besylate/Venlafaxine Hydrochloride Oral Tab ER: 37.5mg, 75mg, 112.5mg, 150mg, 225mg

    DOSAGE & INDICATIONS

    For the treatment of major depression.
    Oral dosage (immediate-release)
    Adults

    75 mg/day PO divided in 2 or 3 doses, initially. May increase dose by 75 mg/day at intervals of at least every 4 days as needed. In outpatient settings, there was no evidence of usefulness of doses more than 225 mg/day for moderately depressed patients, but more severely depressed inpatients responded to a mean dose of 350 mg/day. Max: 375 mg/day in 3 divided doses.

    Oral dosage (extended-release)
    Adults

    75 mg PO once daily, initially. Alternatively, 37.5 mg PO once daily for 4 to 7 days to allow for tolerability before increasing to 75 mg PO once daily. May increase dose by 75 mg/day at intervals of at least every 4 days as needed. In outpatient settings, there was no evidence of usefulness of doses more than 225 mg/day for moderately depressed patients, but more severely depressed inpatients responded to a mean dose of 350 mg/day. Max: 375 mg/day.

    Children and Adolescents 7 to 17 years†

    The overall findings of published and manufacturer studies do not suggest that venlafaxine ER should be a first-line treatment for depression in pediatric patients. Two placebo-controlled studies in 766 pediatric patients have been conducted with venlafaxine XR, and the data were not sufficient to support efficacy in pediatric patients. Dosage used: 37.5 mg PO once daily initially, then titrated based on weight. Maximum dose in patients 50 kg or more: 225 mg/day PO.

    For the treatment of generalized anxiety disorder (GAD).
    Oral dosage (extended-release products, e.g., Effexor XR, Venbysi XR)
    Adults

    Initially, 75 mg PO once daily. Alternatively, 37.5 mg PO once daily can be given for 4 to 7 days to allow for tolerability before increasing to 75 mg PO once daily. If needed, may increase further by 75 mg/day at intervals of no less than every 4 days. Venlafaxine besylate ER tablets may be used in patients who have taken at least 75 mg/day for 4 or more days in order to provide 112.5 mg or 225 mg PO once daily dosage. Max: 225 mg/day PO. Anxiety disorders are often chronic conditions; consider continuation if a therapeutic response is demonstrated. Use lowest effective maintenance dosage and periodically reassess the need for continued treatment.

    Children† and Adolescents† 6 years and older

    Data are limited. Two placebo-controlled trials 793 pediatric patients with GAD have been conducted with venlafaxine XR, and the data were not sufficient to support a claim for use in pediatric patients. In 2 multicenter, randomized, placebo-controlled studies of 8 weeks duration, dosage was initiated at 37.5 mg PO once daily, and dose titration was determined by weight. For patients 25 to 33 kg, dosage was titrated to a maximum of 112.5 mg/day or a lower maximum tolerated dose. For patients 34 to 49 kg, dosage was titrated to a maximum of 150 mg/day or a lower maximum tolerated dose. For patients 50 kg or more, Max: 225 mg/day PO. The pediatric patients (age 6 to 17 years) met diagnostic criteria for generalized anxiety disorder (GAD) per the DSM-IV. The results of the data from the 2 trials were analyzed separately and also pooled. The overall results suggest that venlafaxine ER may be effective in the short-term treatment of GAD in children and adolescents. The primary efficacy measure was improvement in the specific anxiety-directed items of the Columbia Schedule for Affective Disorders and Schizophrenia for School-Age Children (Columbia K-SADS) On the nine delineated items of the Columbia K-SADS, the mean adjusted decrease in score was 17.4 for participants in the extended-release venlafaxine group, compared with 12.7 points for the placebo group. The results were statistically significant only for the first study. Clinical Global improvement score response rates for the venlafaxine ER and placebo groups were 69% and 48%, respectively. More study is needed, since GAD can be a chronic condition. The findings of these trials were not sufficient to establish the efficacy of venlafaxine ER in treating GAD in pediatric patients according to FDA requirements, namely, 2 trials with statistically significant positive results on the primary outcome measure. Treatment-emergent adverse events with an incidence 5% or more in the venlafaxine ER group and at least twice that of the placebo group were asthenia, pain, anorexia, and somnolence. In general, the adverse reaction profile in children and adolescents (ages 6 to 17) during controlled clinical trials was similar to that seen for adults. Decreased appetite, weight loss, increased blood pressure, and increased serum cholesterol were observed. Suicidal ideation was observed, as was abdominal pain, agitation, dyspepsia, ecchymosis, epistaxis, and myalgia. Close clinical monitoring for adverse events in pediatric patients is recommended, including treatment-emergent suicidality.

    For the treatment of social phobia (social anxiety disorder).
    Oral dosage (extended-release products, e.g., Effexor XR)
    Adults

    75 mg PO once daily. There was no evidence in clinical trials that higher doses confer additional clinical benefit. For some patients, it may be desirable to start at 37.5 mg PO once daily for 4 to 7 days to allow for adjustment to the medication before increasing to 75 mg PO once daily. Consider continuation in those demonstrating a therapeutic response. Use lowest effective maintenance dosage and periodically reassess the need for continued treatment.

    Children† and Adolescents† 8 years and older

    Data are limited. In one study (n = 293), dosage was initiated at 37.5 mg PO once daily, and dose titration was determined by weight. For patients 25 to 33 kg, dosage was titrated to a maximum of 112.5 mg/day or a lower maximum tolerated dose. For patients 34 to 49 kg, dosage was titrated to a maximum of 150 mg/day or a lower maximum tolerated dose. Finally, for patients 50 kg or more, the maximum dosage for titration was 225 mg/day PO. The pediatric patients (age 8 to 17 years) met diagnostic criteria for social anxiety disorder of the DSM-IV. The primary measures were the Social Anxiety Scale, child or adolescent version (SAS-CA) and for responder analysis, a (dichotomized) Clinical Global Impressions-Improvement (CGI-I) score. Compared with placebo, intent-to-treat random regression analyses indicated a statistically significant advantage for venlafaxine ER (p = 0.001) on the SAS-CA. On the CGI-I responder analysis, 56% (95% CI, 47% to 64%) of venlafaxine ER treated subjects responded, which was statistically superior to 37% with placebo (95% CI, 29% to 45%). Three venlafaxine ER and no placebo patients developed treatment-emergent suicidality; there were no completed suicides. The authors found venlafaxine effective and reasonably well-tolerated. As with other antidepressants, they recommend close clinical monitoring for adverse events in pediatric patients, including treatment-emergent suicidality.

    For the treatment of panic disorder (with or without agoraphobia).
    Oral dosage (extended-release products, e.g., Effexor XR)
    Adults

    Initially, 37.5 mg PO once daily for 7 days. After the first week, dose may be increased to 75 mg/day PO, with subsequent weekly dose increases of 37.5 mg/day to 75 mg/day PO. Although a dose-response relationship for effectiveness was not clearly established in fixed-dose studies for panic disorder, certain patients not responding to 75 mg/day PO may benefit from a higher dose. Max: 225 mg/day PO. In a randomized, placebo-controlled trial, venlafaxine ER was not associated with a greater number of patients free from full-symptom panic attacks. However, venlafaxine ER was associated with lower mean panic attack frequency and a greater number of patients free from limited-symptom panic attacks, higher response and remission rates, and improvements in anticipatory anxiety, fear, and avoidance. In 2 randomized, controlled, pivotal trials conducted by the manufacturer, the percentage of patients free of full-symptom panic attacks on the Panic and Anticipatory Anxiety Scale (PAAS) was found to be significant vs. placebo. Patients also exhibited a significantly longer time to relapse, defined as 1) having 2 or more full-symptom panic attacks per week for 2 consecutive weeks or 2) discontinuing the study due to loss of effectiveness as determined by the investigators.

    For the treatment of obsessive-compulsive disorder (OCD)†.
    Oral dosage (immediate-release tablets, e.g., Effexor)
    Adults

    Initially, 25 mg PO 3 times daily, then titrate weekly according to response and tolerance. According to the American Psychiatric Association treatment guidelines, venlafaxine is considered a second-line agent for patients with little or no response to first-line therapies (e.g., SSRIs, cognitive behavioral therapy) for OCD. A target range of 225 mg/day to 350 mg/day PO, given in divided doses, is supported by active comparator trials and open-label studies suggesting effectiveness of venlafaxine in treating OCD. In one comparison study with clomipramine, venlafaxine was initiated at 25 mg PO three times per day and titrated to 75 mg PO 3 times per day within 1 week for a minimum dose of 225 mg/day. Further titration up to a maximum of 350 mg/day was permitted at 2-week intervals based on response and tolerability. The mean total daily dosages achieved were venlafaxine 265 +/- 52.5 mg/day and clomipramine 168 +/- 29 mg/day. Total YBOCS (Yale-Brown Obsessive Compulsive Scale) scores and Obsessions and Compulsions sub-items significantly decreased with both treatment regimens over the 12-week trial period for an approximate 30% change in YBOCS from baseline scores. Change in YBOCS scores were evident from Week 4 onward with both agents. For the Obsessions and Compulsions sub-items, change was evident from Week 4 onward for Obsessions with both agents and for Compulsions with clomipramine. A significant reduction in Compulsions with venlafaxine treatment was evident from Week 8 onward.

    Oral dosage (extended-release products, e.g., Effexor XR)
    Adults

    Initially, 75 mg PO once daily and titrate weekly (and no more frequently than every 4 days) to response and tolerance. Some patients may require 37.5 mg PO once daily initially to allow for dose tolerance. If needed, may increase at intervals no more frequently than every 4 days. A target venlafaxine ER dose range of 225 mg to 300 mg PO once daily is supported by active comparator trials and open-label studies suggesting effectiveness of venlafaxine in treating OCD. According to the American Psychiatric Association treatment guidelines, venlafaxine is considered a second-line agent for patients with little or no response to first-line therapies (e.g., SSRIs, cognitive behavioral therapy). In one comparison study with paroxetine, venlafaxine ER was initiated at 75 mg PO once daily for 2 weeks, then 150 mg PO once daily for 2 weeks, then 225 mg PO once daily for 2 weeks, then 300 mg PO once daily thereafter. The Young Obsessive Compulsive Scale (YBOCS) score and Obsessions and Compulsions sub-item scores similarly decreased significantly from baseline over the 12-week trial period with both venlafaxine and paroxetine, with no difference between treatments, or between treatments over time. A significant reduction in Obsessions was observed at Week 5 with both agents. A significant reduction in Compulsions was observed at Week 3 with venlafaxine, and Week 5 for paroxetine. Reduction in YBOCS scores was significant at Week 3 with venlafaxine and Week 5 with paroxetine, and scores continued to significantly decrease with each assessment until Week 10, after which no further significant reductions were observed.

    For the treatment of hot flashes† due to menopause† or in women who have been treated for breast cancer.
    For women experiencing hot flashes† due to natural menopause†.
    Oral dosage (extended-release products, e.g., Effexor XR)
    Adult females

    37.5 mg PO once daily for 1 week, followed by titration to 75 mg PO once daily has been effective at decreasing the frequency and severity of hot flashes compared to placebo. Venlafaxine XR (75 mg/day PO) has also been compared to estradiol (0.5 mg/day PO) and placebo. Estradiol (52% reduction) or venlafaxine (47.6% reduction) treatment reduced vasomotor symptom frequency compared to placebo (28.6% reduction) and there was a significant reduction in hot flash severity compared to placebo. Clinical improvement at week 8 was significantly more common in the estradiol and venlafaxine groups compared to placebo (56.5%, 50.6%, and 30.7% respectively). Treatment satisfaction was highest with estradiol (70.3%), followed by venlafaxine (51.1%), and placebo (38.4%), although the only statistically significant difference was between estradiol and placebo (p less than 0.001). Venlafaxine is considered a first-line, effective alternative for women who cannot or do not wish to use hormone replacement therapy per the American College of Obstetricians and Gynecologists (ACOG) guidelines. The North American Menopause Society (NAMS) Guidelines for non-hormonal therapy indicate that venlafaxine is an effective choice for treating vasomotor symptoms of menopause when hormonal therapy is not desired or is contraindicated.

    For hot flashes† in women with a history of, or high risk of, breast cancer, including those receiving adjuvant treatments like tamoxifen.
    Oral dosage (extended-release products, e.g., Effexor XR)
    Adult females

    37.5 mg PO once daily initially, titrated up to 75 mg PO once daily for efficacy and as tolerated, is suggested. In a study of women with a history of breast cancer or fear of breast cancer due to hormone replacement therapy, the median decrease in hot flash scores was significantly greater in all 3 venlafaxine XR groups (37.5 mg PO once daily, 75 mg PO once daily, and 150 mg PO once daily) than with placebo. Between 45% and 63% of patients in the active treatment groups reported a reduction of 50% or more in hot flash activity versus 20% of those in the placebo group. A dose-response relationship was observed between 37.5 mg/day and 75 mg/day (45% vs. 63%), but not 75 mg/day to 150 mg/day (63% vs. 55%). More side effects occurred with 150 mg/day than 75 mg/day. Venlafaxine is considered a first-line, effective alternative for women who cannot or do not wish to use hormone replacement therapy per the American College of Obstetricians and Gynecologists (ACOG) guidelines. The North American Menopause Society (NAMS) Guidelines for non-hormonal therapy indicate that venlafaxine is an effective choice for treating vasomotor symptoms of menopause when hormonal therapy is not desired or is contraindicated.

    For the treatment of premenstrual dysphoric disorder (PMDD)†.
    Oral dosage (immediate release products)
    Adult Females

    In one flexible-dose study, venlafaxine 50 to 200 mg/day PO, administered in 2 divided doses, was compared to placebo for 4 menstrual cycles. Venlafaxine was significantly more effective than placebo in reducing PMDD symptoms as assessed by the Daily Symptom Report (DSR) scores. All patients randomized to venlafaxine received 25 mg PO twice daily during the first treatment cycle. If needed, the dose could be increased by a total of 50 mg/day at each subsequent treatment cycle. Maximum: 100 mg PO twice daily. Improvement of 50% or more occurred in 60% of the venlafaxine group versus 35% of the placebo group. Symptom remission was also significant for venlafaxine compared to placebo (43% vs 25%). Venlafaxine was superior to placebo for all statistically derived DSR factors (mood, function, pain, and physical symptoms). There was an approximate 80% symptom reduction in the first treatment cycle. The mean venlafaxine dose was 84 mg/day PO in cycle 2, 115 mg/day PO in cycle 3, and 130 mg/day PO in cycle 4. Adverse events such as nausea, insomnia, and dizziness were mild and transient. The potential for using cyclic luteal phase administration (i.e., during the 14 days prior to menses) has yet to be defined.

    Oral dosage (extended-release products, e.g., Effexor XR)
    Adult Females

    An open label study assessed the effectiveness of continuous dosing of extended-release (ER) venlafaxine. Women (n = 30) received venlafaxine ER 37.5 mg PO once daily for the first cycle and could increase to 75 mg PO once daily for their second cycle. The main outcomes were a change in daily symptoms, assessed by Prospective Record of the Impact and Severity of Menstrual Symptomatology (PRISM). PRISM scores were significantly decreased compared to baseline and between cycles. Hamilton depression (HAM-D-21) scores also decreased. The most common side effects were insomnia, nausea, and dizziness. LUTEAL PHASE DOSING: Preliminary evidence suggests potential efficacy of intermittent venlafaxine ER dosing. In one small study, patients (n = 11) initiated treatment 14 days before the expected day of menses: venlafaxine ER 37.5 mg PO once daily for 2 days, then 75 mg PO once daily for 12 days or until the first day of menses, followed by 2 days of 37.5 mg PO once daily. Based on response and tolerability, the dose for the second cycle could be increased to 75 mg PO once daily for 2 days, then 112.5 mg PO once daily for 12 days or until first day of menses, followed by 2 days of 75 mg PO once daily. After 1 cycle of treatment, 4 of 11 subjects showed a significant response; the others increased the dose for the second cycle. The 11 study completers had a significant decrease in median luteal Daily Rating Severity of Problems (DRSP) total scores from baseline to endpoint. Changes in the luteal DRSP subscores for depression, physical symptoms, and anger were also significant. Nine subjects (81.8%) showed satisfactory response based on a Clinical Global Impression (CGI) score of 2 or less.

    For the treatment of fibromyalgia†.
    Oral dosage (extended-release products, e.g., Effexor XR)
    Adults

    Initially, 37.5 mg or 75 mg PO once per day; the lower dose may be useful for newer patients as they adjust to the medication prior to higher titration. The usual maximum dosage is 150 mg PO once daily. However, in some instances, higher dosages may be necessary and the dosage should be titrated to clinical response. Studies have been limited by small sample size and lack of blinding and proper controls, but there is suggestion of efficacy. Larger randomized controlled trials are needed.

    For the treatment of painful diabetic neuropathy†.
    Oral dosage (extended-release products, e.g., Effexor XR)
    Adults

    Initiate at 75 mg PO once daily and titrate to effectiveness and as tolerated. Effective daily dose range: 75 to 225 mg PO once daily. For some patients, it may be desirable to start at 37.5 mg PO once daily for 4 to 7 days to allow adjustment to the medication before increasing to 75 mg PO once daily. According to the American Academy of Neurology treatment guidelines, venlafaxine is probably effective and should be considered for the treatment of painful diabetic neuropathy (level B evidence). The recommendation is based on several trials showing improvements in Visual Analog Scale (VAS) and severity of pain scores compared to placebo, or when combined with other accepted therapies (e.g., gabapentin). In one study, only venlafaxine XR 150 mg or higher PO once daily led to statistically significant mean reductions in Visual Analog Scale-Pain Intensity (VAS-PI) scores at week 6 of treatment. In a comparison study of venlafaxine XR (150 mg/day) to carbamazepine (200 mg PO every 12 hours), or pregabalin (75 mg PO every 12 hours) pregabalin was superior to venlafaxine and carbamazepine, and no statistically significant differences in VAS-PI scores between venlafaxine and carbamazepine; all three treatments improved VAS-PI scores. Use of venlafaxine XR (75 mg PO twice daily) as an adjunct gabapentin resulted in significant improvement on an 11-point Likert Pain scale at 8 weeks compared to gabapentin plus placebo (18% more relief with adjunct venlafaxine XR compared to gabapentin and placebo). Common adverse events reported with venlafaxine in clinical trials include nausea, dizziness, dyspepsia, constipation, and somnolence.

    For migraine prophylaxis†.
    Oral dosage (extended-release products, e.g., Effexor XR)
    Adults

    37.5 mg PO once daily for 3 days, then 75 mg PO once daily for 3 days, followed by 150 mg PO once daily.[44244] [52575] Guidelines classify venlafaxine as probably effective for migraine prophylaxis.[57981] [64551]

    For the treatment of hot flashes† due to prostate cancer† and associated induced androgen deficiency† ('andropause†') in men who have had surgical or medication induced castration.
    Oral dosage
    Adult males

    Effectiveness has not been established. Venlafaxine has been studied in men suffering vasomotor flushing from androgen-deprivation therapy as an option to hormonal therapies, at varying dosage formulations and doses. An initial pilot open-label study reported that immediate-release venlafaxine 12.5 mg PO twice daily reduced the daily incidence of hot flashes by more than 50% in roughly 63% of patients. However, a 12-week double-blind trial in 301 men receiving leuprorelin, use of venlafaxine XR (75 mg PO once daily) was not as effective as medroxyprogesterone acetate or cyproterone acetate in reducing hot flashes. Another multicenter, randomized, controlled trial in 120 men studied 1) venlafaxine XR (75 mg PO once daily), 2) soy isoflavones 160 mg/day PO, 3) placebo, or 4) combined treatment with venlafaxine XR plus soy isoflavones. At week 12, there was no effect of venlafaxine or soy isoflavones, or the combined treatments on hot flash frequency or severity of symptoms, nor did the treatments improve quality of life, compared to placebo. There was a 28% decrease in the venlafaxine plus soy arm, a 35% decrease in the venlafaxine arm, a 31% decrease in the soy arm, and a 55% decrease in the placebo arm.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    For immediate release products: 225 mg/day PO is maximum recommended for outpatients; up to 375 mg/day PO for hospitalized inpatients. For venlafaxine XR: 225 mg/day is usual maximum; there is very limited experience with higher doses.

    Geriatric

    For immediate release products: 225 mg/day PO is maximum recommended for outpatients; up to 375 mg/day PO for hospitalized inpatients. For venlafaxine XR: 225 mg/day is usual maximum; there is very limited experience with higher doses.

    Adolescents

    Safety and efficacy have not been established. Clinical trials for off-label use of venlafaxine ER suggest the following maximum dosages based on weight for depression and anxiety disorders:
    25 to 33 kg: 112.5 mg/day PO
    34 to 49 kg: 150 mg/day PO
    50 kg or more: 225 mg/day PO.

    Children

    6 to 12 years: Safety and efficacy have not been established. Clinical trials for off-label use of venlafaxine ER suggest the following maximum dosages based on weight for depression and anxiety disorders:
    25 to 33 kg: 112.5 mg/day PO
    34 to 49 kg: 150 mg/day PO
    50 kg or more: 225 mg/day PO.
     
    1 to 5 years: Safety and efficacy have not been established.

    Infants

    Not indicated.

    Neonates

    Not indicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Mild to moderate hepatic impairment (Child-Pugh Class A and B): The total daily dose should be reduced by 50%. It may be necessary to choose a different dosage form in some cases to accomplish proper dosage adjustment.
    Severe hepatic impairment or hepatic cirrhosis (Child-Pugh Class C): The total daily dose should be reduced by at least 50%. Because there is a large variability in clearance of venlafaxine between patients with severe hepatic impairment or cirrhosis, a reduction of more than 50% may be needed on an individual basis. It may be necessary to choose a different dosage form in some cases to accomplish proper dosage adjustment.

    Renal Impairment

    Mild to moderate renal impairment (CrCl 30 to 89 mL/minute): Reduce total daily dose by 25% to 50%; doses should be individualized due to large interpatient variability in clearance.
    Severe renal impairment (CrCl less than 30 mL/minute): Reduce total daily dose by 50% or more; doses should be individualized due to large interpatient variability in clearance. It may be necessary to choose a different dosage form in some cases to accomplish proper dosage adjustment.
     
    Intermittent Hemodialysis
    Reduce total daily dose by 50% or more; doses should be individualized due to large interpatient variability in clearance. It may be necessary to choose a different dosage form in some cases to accomplish proper dosage adjustment.

    ADMINISTRATION

    Oral Administration

    All dosage forms: Administer with food to minimize gastrointestinal side effects.

    Oral Solid Formulations

    Extended-release capsules:
    Administer as a single dose with food either in the morning or evening at the same time each day.
    Have patient swallow the capsule whole with plenty of fluids. Do not divide, cut, chew, crush, or place the capsules in water.
    Alternatively, the dose may be administered by carefully opening the capsule and sprinkling the entire contents on a spoonful of applesauce. This drug/food mixture should be swallowed immediately without chewing and followed with a glass of water to ensure complete swallowing of the pellets.
     
    Extended-release tablets:
    Administer as a single dose with food either in the morning or in the evening at the same time each day.
    Each tablet should be swallowed whole with fluid and not divided, crushed, chewed, or placed in water.

    STORAGE

    Generic:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in a dry place
    Effexor:
    - Store between 68 to 77 degrees F
    - Store in a dry place
    Effexor XR:
    - Store between 68 to 77 degrees F
    - Store in a dry place
    Venlafaxine:
    - Avoid excessive humidity
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Some reports suggest that a false positive urine drug screen may occur for amphetamine or phencyclidine in patients who have received venlafaxine. False positive tests may be expected for several days following treatment discontinuation. Caution should be exercised when interpreting positive urine drug screens for amphetamine or phencyclidine, and confirmation by alternative tests such as gas chromatography/mass spectrometry should be considered.

    Desvenlafaxine hypersensitivity, venlafaxine hypersensitivity

    Venlafaxine is contraindicated in patients with a venlafaxine hypersensitivity or reaction to any other ingredient in the formulation. Cross-sensitivity can be expected in those exhibiting desvenlafaxine hypersensitivity, as desvenlafaxine is a single enantiomer of the racemic parent compound, venlafaxine.

    Abrupt discontinuation

    Abrupt discontinuation of venlafaxine should be avoided. Advise patients not to stop taking venlafaxine without talking to their healthcare provider and to be aware that discontinuation effects may occur if the drug is abruptly stopped. When discontinuing venlafaxine, tapering of the dose is recommended to minimize the risk of discontinuation symptoms. Individualize the dose taper; some patients may require several months of a tapered dosing regimen in order to minimize discontinuation symptoms. If intolerable symptoms occur following a dose decrease or upon discontinuation, the health care provider may resume the previous dose or continue a more gradual dose decrease. Withdrawal symptoms that have been reported with abrupt discontinuation or tapering of venlafaxine include abnormal dreams, headache, insomnia, dizziness, nausea/vomiting, paresthesia, irritability, fatigue, diarrhea, anxiety, decreased appetite, vertigo, hyperhidrosis, and tremors. Serious discontinuation symptoms have been reported and may include aggression, violent behavior, suicidal thoughts or completed suicide. Other adverse effects noted in these reports include changes in vision (such as blurry vision or trouble focusing) and increased blood pressure. Other adverse effects reported with the discontinuation of SNRIs (including venlafaxine) and SSRIs include irritability, fatigue, emotional lability, ringing of the ears, and convulsions. Patients should be carefully monitored if abrupt discontinuation of venlafaxine is necessary.

    Bipolar disorder, mania

    All effective antidepressants can transform depression into mania or hypomania in predisposed individuals. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Based on reports during use of venlafaxine, this drug may activate mania or hypomania. If a patient develops manic symptoms, venlafaxine should be withheld and appropriate therapy initiated to treat the manic symptoms. Additionally, depression may be the presenting symptom of a mixed/manic episode of bipolar disorder. Patients should be adequately screened for bipolar disorder prior to initiating an antidepressant. Such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Patients with depression or comorbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes. Caregivers should be advised to closely observe the patient on a daily basis and to communicate immediately with the prescriber the emergence of agitation, irritability, unusual changes in behavior, or suicidality. It should be noted that venlafaxine is not approved for use in treating bipolar depression.

    Children, growth inhibition, suicidal ideation

    Safety and efficacy of venlafaxine for the treatment of major depressive disorder (MDD) have not been established in children and adolescents less than 18 years of age. In a pooled analysis of placebo-controlled trials of antidepressants (n = 4,500 pediatrics and 77,000 adults), there was an increased risk for suicidal thoughts and behaviors in patients 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. The difference in absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. No suicides occurred in any of the pediatric trials. Nevertheless, the need for an antidepressant in children, adolescents, or young adults for any use must be weighed against the risk of suicidality; it is unknown if this risk extends to long-term use. All patients should be monitored for symptom worsening or suicidality, especially at treatment initiation or after dose changes. Caregivers and/or patients should immediately notify the prescriber of changes in behavior or suicidal ideation. A change to the treatment regimen or discontinuation of venlafaxine may be necessary in patients with emerging suicidality or worsening depression. Venlafaxine has been shown to lead to dose-dependent weight loss in children ages 6 to 17 years. In addition, growth inhibition has been noted in short and long-term studies in children. Clinicians should regularly monitor height and weight changes in pediatric patients receiving venlafaxine.

    MAOI therapy

    Venlafaxine is contraindicated for concomitant use in patients receiving MAOI therapy, due to the risk for serotonin syndrome. Venlafaxine is a serotonin norepinephrine reuptake inhibitor (SNRI) and should not be used concurrently with MAOI therapy or within 14 days of discontinuation of a MAOI intended to treat a psychiatric disorder. Similarly, treatment with such MAOIs should not be initiated for at least 7 days after stopping venlafaxine. In addition, do not start venlafaxine in a patient who is being treated with linezolid or intravenous methylene blue. Serotonin syndrome has been reported with SNRIs, including venlafaxine, both when taken alone, but especially when coadministered with other serotonergic agents (including other SNRIs, triptans, selective serotonin reuptake inhibitors or SSRIs, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John's Wort). If such symptoms occur, discontinue venlafaxine and initiate supportive treatment. Do not give venlafaxine with other SNRI treatments. If concomitant use of venlafaxine with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

    Electroconvulsive therapy (ECT), seizure disorder, seizures

    In pre-marketing studies of depression, venlafaxine was associated with a low incidence of seizures (0.3%). Use with caution in patients with a history of seizure disorder. If seizures develop during therapy, use of venlafaxine should be terminated. Venlafaxine's effects during electroconvulsive therapy (ECT) have not been evaluated in clinical studies.

    Dehydration, hyponatremia, hypovolemia

    Serotonin norepinephrine reuptake inhibitors (SNRIs), including venlafaxine, may cause hyponatremia, which is frequently the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In some cases, serum sodium levels less than 110 mmol/L have been reported; however, the adverse effect appeared reversible upon discontinuation of the causative SNRI. Older patients (65 years and older), those receiving diuretics or prone to dehydration, and those who are otherwise volume depleted (have hypovolemia) appear to be at greatest risk. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of the SNRI, as well as implementation of the appropriate medical interventions.

    Apheresis, AV block, bradycardia, cardiac disease, cardiomyopathy, celiac disease, cerebrovascular disease, females, fever, heart failure, human immunodeficiency virus (HIV) infection, hyperparathyroidism, hypocalcemia, hypokalemia, hypomagnesemia, hypothermia, hypothyroidism, long QT syndrome, myocardial infarction, pheochromocytoma, QT prolongation, rheumatoid arthritis, sickle cell disease, sleep deprivation, stroke, systemic lupus erythematosus (SLE)

    Patients receiving venlafaxine should have regular monitoring of blood pressure since increases in blood pressure were observed in clinical studies. Pre-existing hypertension should be controlled before initiating treatment. Caution should be exercised in treating patients with pre-existing hypertension, cardiac disease, or cerebrovascular disease, or other conditions that might be compromised by increases in blood pressure. Cases of elevated blood pressure requiring immediate treatment have been reported with venlafaxine. Sustained blood pressure increases could have adverse consequences. For patients who experience a sustained increase in blood pressure while receiving venlafaxine, either dose reduction or discontinuation should be considered. Venlafaxine is associated with a possible risk for QT prolongation and torsade de pointes (TdP). Avoid use in patients with a history of or a family history of long QT syndrome. Use venlafaxine with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, people 65 years and older, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation. Statistically significant and dose-dependent increases in heart rate have been observed on electrocardiograms (ECGs) during venlafaxine therapy. Doses ranging from 200 to 375 mg/day resulted in a mean increase of 4 beats per minute, while mean doses more than 300 mg/day resulted in a heart rate increase of roughly 8 beats per minute. Slight elevations of QTc from baseline (roughly 1 to 4 milliseconds) have been noted in clinical trials; however, the incidence of trial-emergent conduction abnormalities has not differed from placebo.

    Dialysis, renal disease, renal failure, renal impairment

    Venlafaxine should be used cautiously in patients with renal disease. The clearance of venlafaxine is reduced in patients with renal impairment; therefore, dosage reductions are recommended in all stages of renal impairment, including those with renal failure who are undergoing dialysis.

    Hepatic disease

    Venlafaxine is extensively metabolized in the liver and should be used with caution in patients with hepatic disease (e.g., cirrhosis). Patients with hepatic impairment have an increase in plasma concentrations of venlafaxine compared to patients without hepatic impairment. Reduced dosages of venlafaxine are recommended in patients with mild to severe hepatic impairment.

    Anticoagulant therapy, bleeding, thrombolytic therapy

    Monitor patients taking venlafaxine for signs and symptoms of bleeding. Platelet aggregation may be impaired by serotonin and norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage). Concurrent use of aspirin, NSAIDs, anticoagulant therapy, thrombolytic therapy, or other medications that enhance bleeding potential may increase this risk. Patients taking venlafaxine should be instructed to promptly report any bleeding events to the practitioner. Patients who are taking warfarin should have coagulation lab values [e.g., INR, prothrombin time (PT)] monitored carefully when initiating, discontinuing, or changing doses of venlafaxine.

    Closed-angle glaucoma, increased intraocular pressure

    Caution is recommended when prescribing venlafaxine to patients with closed-angle glaucoma. The pupillary dilation that can occur with antidepressants may precipitate a closed-angle glaucoma attack in patients with anatomically narrow angles who do not have a patent iridectomy. An acute attack of closed-angle glaucoma is considered a medical emergency because the increased intraocular pressure is rapid and severe, and may quickly result in blindness if left untreated. Patients with untreated anatomically narrow angles should avoid use of antidepressants, including venlafaxine.

    Eosinophilic pneumonia

    Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine therapy have been rarely reported. The possibility of these adverse events should be considered in venlafaxine-treated patients who present with progressive dyspnea, cough or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of venlafaxine therapy should be considered.

    Driving or operating machinery, ethanol ingestion

    Consistent with other drugs that act on the CNS, patients taking venlafaxine should use caution when driving or operating machinery until the full effects of the drug are known. A clinical study has shown that venlafaxine does not increase the impairment of mental and motor skills caused by alcohol. However, as with all central nervous system (CNS)-active drugs, patients should be advised to avoid ethanol ingestion while taking venlafaxine, especially if they are taking extended-release dosage forms. In vitro studies have shown an increased release rate of venlafaxine from extended-release (ER) tablet and ER capsule formulations during ethanol ingestion, which increases venlafaxine maximal concentrations and exposure, and may increase the risk of serious side effects.

    Sexual dysfunction

    Sexual dysfunction can occur in individuals taking venlafaxine. For males, these effects may present as ejaculatory failure or delay, decreased libido, and/or erectile dysfunction. Females may experience decreased libido and delayed or absent orgasm. Prescribers should discuss sexual function prior to initiating treatment with venlafaxine and throughout treatment and obtain a detailed history and timeline of any changes in sexual function to determine whether the changes are medication-related or may be attributed to the underlying psychiatric disorder. Clinicians should also discuss management strategies and treatment options with patients.

    Eclampsia, neonates, obstetric delivery, pregnancy

    There are no adequate and well-controlled studies regarding use of venlafaxine during human pregnancy. Venlafaxine should be used in pregnancy only when the benefit to the mother clearly outweighs any potential risk to the fetus. Animal studies have failed to show an increased risk of teratogenic effects; however, other fetal toxicities have been observed. Consider the risks of untreated depression during pregnancy as well as the potential risks to the fetus from exposure to the drug. When treating a pregnant woman with a serotonin norepinephrine reuptake inhibitor (SNRI) or other serotonergic agent during the third trimester, discontinuation symptoms should be considered in the newborn at birth. Neonates exposed to serotonergic antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Symptoms have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with serotonin syndrome or possibly a drug discontinuation syndrome. In terms of maternal risk, exposure to SNRIs in mid to late pregnancy may increase the risk of eclampsia. Exposure to SNRIs near obstetric delivery may increase the risk for postpartum hemorrhage. If clinically feasible, gradual tapering of the medication prior to delivery may be considered. The National Pregnancy Registry for Psychiatric Medications is dedicated to evaluating the safety of psychiatric medications that may be taken by women during pregnancy to treat a wide range of mood, anxiety, or psychiatric disorders. The primary goal of this Registry is to determine the frequency of major malformations, such as heart defects, cleft lip, or neural tube defects, in babies exposed to various psychiatric drugs during pregnancy. The pregnancy exposure registry monitors outcomes in pregnant patients exposed to venlafaxine; information about the registry can be obtained at womensmentalhealth.org/research/pregnancyregistry or by calling 1-866-961-2388.

    Breast-feeding

    Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue venlafaxine. Venlafaxine and its active metabolite, desvenlafaxine (O-desmethylvenlafaxine), are both excreted in human breast milk. Data describing the clinical effects of infant exposure after maternal venlafaxine administration are not available. Several small case series have described infants who were breastfed by mothers taking venlafaxine. The majority of infants had measurable desvenlafaxine plasma concentrations. The estimated mean relative infant doses in these studies were 6.4% to 8.1% based on the sum of venlafaxine and desvenlafaxine. Consider if treatment alternatives are appropriate. Due to individual variability in response to antidepressants, it may be prudent to continue the existing regimen if ongoing treatment is deemed necessary during breast-feeding. However, because a pooled analysis found that maternal use of sertraline, along with nortriptyline and paroxetine, usually produced undetectable or low drug concentrations in infant serum, these agents may be the preferred antidepressants when initiating antidepressant therapy in a breast-feeding mother. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition.

    Geriatric

    No differences in response or safety between geriatric patients and younger adults were demonstrated in preclinical trials of venlafaxine; however, greater sensitivity of older individuals to venlafaxine cannot be ruled out. No dose adjustment is recommended solely based on age; adjust dose based on renal or hepatic function. Patients who are debilitated, geriatric, or who have body weights less than 45 kg may need more careful dosage titration. Venlafaxine produces a dose-dependent weight loss, which may be important in the older or debilitated patient. As with other antidepressants, several cases of hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been reported, usually in older adults. Geriatric patients may also be at increased risk for developing a prolonged QT interval with venlafaxine use.[28275] [33715]  According to the Beers Criteria, SNRIs are considered potentially inappropriate medications (PIMs) in older adults and should be avoided in elderly patients with a history of falls or fractures, unless safer alternatives are not available since SNRIs can produce ataxia, impaired psychomotor function, syncope, and additional falls. If venlafaxine must be used in an elderly patient with a history of falls or fractures, consider reducing the use of other CNS-active medications that increase the risk of falls and fractures and implement strategies to reduce fall risk. All SNRIs can cause or exacerbate hyponatremia and SIADH, and the elderly are at increased risk of developing these conditions. Sodium levels should be closely monitored when starting or changing dosages in older adults.[63923] The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of antidepressants in residents of long-term care facilities; the duration of therapy is determined by pertinent literature and clinical practice guidelines for the condition being treated. Monitor closely for worsening of depression and suicidal behavior or thinking, especially during initiation of therapy and during dose changes. Monitor for side effects of the antidepressant; some of these effects can increase the risk of falls. Review for continued need of the antidepressant at least quarterly and document the rationale for continuation. When the drug is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt to taper the medication as outlined in the OBRA guidelines, unless a taper is clinically contraindicated. Before discontinuation, many antidepressants, including SNRIs such as venlafaxine, need a taper to avoid a withdrawal/discontinuation syndrome.[60742]

    ADVERSE REACTIONS

    Severe

    peptic ulcer / Delayed / 0.1-1.0
    bradycardia / Rapid / 0-1.0
    laryngospasm / Rapid / 0.1-1.0
    exfoliative dermatitis / Delayed / 0.1-1.0
    seizures / Delayed / 0.2-0.3
    akinesia / Delayed / 0-0.1
    muscle paralysis / Delayed / 0-0.1
    stroke / Early / 0-0.1
    Guillain-Barre syndrome / Delayed / 0-0.1
    torticollis / Delayed / 0-0.1
    GI obstruction / Delayed / 0-0.1
    myocardial infarction / Delayed / 0-0.1
    AV block / Early / 0-0.1
    heart failure / Delayed / 0-0.1
    hematemesis / Delayed / 0-0.1
    tendon rupture / Delayed / 0-0.1
    cholecystitis / Delayed / 0-0.1
    pulmonary embolism / Delayed / 0-0.1
    apnea / Delayed / 0-0.1
    laryngeal edema / Rapid / 0-0.1
    anuria / Delayed / 0-0.1
    oliguria / Early / 0-0.1
    spontaneous fetal abortion / Delayed / 0-0.1
    hyperkalemia / Delayed / 0-0.1
    proteinuria / Delayed / 1.0
    prostatic hypertrophy / Delayed / 1.0
    tardive dyskinesia / Delayed / Incidence not known
    suicidal ideation / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    ventricular fibrillation / Early / Incidence not known
    cardiomyopathy / Delayed / Incidence not known
    atrial fibrillation / Early / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    torsade de pointes / Rapid / Incidence not known
    ocular hypertension / Delayed / Incidence not known
    serotonin syndrome / Delayed / Incidence not known
    neuroleptic malignant syndrome / Delayed / Incidence not known
    SIADH / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    eosinophilic pneumonia / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    aplastic anemia / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    neonatal abstinence syndrome / Early / Incidence not known

    Moderate

    ejaculation dysfunction / Delayed / 8.0-19.0
    constipation / Delayed / 8.0-15.0
    hypertension / Early / 0.5-13.0
    impotence (erectile dysfunction) / Delayed / 4.0-6.0
    blurred vision / Early / 4.0-6.0
    hypertonia / Delayed / 3.0-3.0
    depression / Delayed / 1.0-3.0
    confusion / Early / 2.0-2.0
    sinus tachycardia / Rapid / 2.0-2.0
    psychosis / Early / 0.1-1.0
    hostility / Early / 0.1-1.0
    hallucinations / Early / 0.1-1.0
    euphoria / Early / 0.1-1.0
    neuritis / Delayed / 0.1-1.0
    hyperesthesia / Delayed / 0.1-1.0
    peripheral neuropathy / Delayed / 0.1-1.0
    dysarthria / Delayed / 0.1-1.0
    akathisia / Delayed / 0.1-1.0
    hypotonia / Delayed / 0.1-1.0
    ataxia / Delayed / 0.1-1.0
    neuropathic pain / Delayed / 0.1-1.0
    oral ulceration / Delayed / 0.1-1.0
    colitis / Delayed / 0.1-1.0
    dysphagia / Delayed / 0.1-1.0
    glossitis / Early / 0.1-1.0
    esophagitis / Delayed / 0.1-1.0
    hemorrhoids / Delayed / 0.1-1.0
    gastritis / Delayed / 0.1-1.0
    stomatitis / Delayed / 0.1-1.0
    teeth grinding (bruxism) / Delayed / 0.1-1.0
    hypotension / Rapid / 0.1-1.0
    orthostatic hypotension / Delayed / 0.1-1.0
    phlebitis / Rapid / 0-1.0
    peripheral vasoconstriction / Rapid / 0.1-1.0
    angina / Early / 0.1-1.0
    conjunctivitis / Delayed / 0.1-1.0
    cataracts / Delayed / 0.1-1.0
    photophobia / Early / 0.1-1.0
    melena / Delayed / 0.1-1.0
    synovitis / Delayed / 0.1-1.0
    bone pain / Delayed / 0.1-1.0
    myasthenia / Delayed / 0.1-1.0
    hypercholesterolemia / Delayed / 0.1-1.0
    hyperlipidemia / Delayed / 0.1-1.0
    dysphonia / Delayed / 0.1-1.0
    thrombocytopenia / Delayed / 0.1-1.0
    anemia / Delayed / 0.1-1.0
    lymphadenopathy / Delayed / 0.1-1.0
    leukopenia / Delayed / 0.1-1.0
    contact dermatitis / Delayed / 0.1-1.0
    psoriasis / Delayed / 0.1-1.0
    urinary retention / Early / 0.1-1.0
    urinary incontinence / Early / 0.1-1.0
    vaginal bleeding / Delayed / 0.1-1.0
    hypokalemia / Delayed / 0.1-1.0
    hyperglycemia / Delayed / 0.1-1.0
    mania / Early / 0.3-0.5
    impulse control symptoms / Delayed / 0-0.1
    dystonic reaction / Delayed / 0-0.1
    nystagmus / Delayed / 0-0.1
    aphasia / Delayed / 0-0.1
    hyperreflexia / Delayed / 0-0.1
    paresis / Delayed / 0-0.1
    proctitis / Delayed / 0-0.1
    parotitis / Delayed / 0-0.1
    bundle-branch block / Early / 0-0.1
    hyponatremia / Delayed / 0-0.1
    prolonged bleeding time / Delayed / 0-0.1
    cholelithiasis / Delayed / 0-0.1
    hepatitis / Delayed / 0-0.1
    jaundice / Delayed / 0-0.1
    hypoventilation / Rapid / 0-0.1
    hypoxia / Early / 0-0.1
    hemoptysis / Delayed / 0-0.1
    lymphocytosis / Delayed / 0-0.1
    eosinophilia / Delayed / 0-0.1
    flank pain / Delayed / 0-0.1
    hypercalciuria / Delayed / 0-0.1
    glycosuria / Early / 0-0.1
    nephrolithiasis / Delayed / 0-0.1
    galactorrhea / Delayed / 0-0.1
    hypothyroidism / Delayed / 0-0.1
    hyperthyroidism / Delayed / 0-0.1
    goiter / Delayed / 0-0.1
    gout / Delayed / 0-0.1
    hyperphosphatemia / Delayed / 0-0.1
    diabetes mellitus / Delayed / 0-0.1
    hyperuricemia / Delayed / 0-0.1
    hypophosphatemia / Delayed / 0-0.1
    hypoglycemia / Early / 0-0.1
    amnesia / Delayed / 1.0
    trismus / Delayed / 1.0
    edema / Delayed / 1.0
    chest pain (unspecified) / Early / 1.0
    vaginitis / Delayed / 1.0
    prostatitis / Delayed / 1.0
    delirium / Early / Incidence not known
    dyskinesia / Delayed / Incidence not known
    QT prolongation / Rapid / Incidence not known
    supraventricular tachycardia (SVT) / Early / Incidence not known
    growth inhibition / Delayed / Incidence not known
    priapism / Early / Incidence not known
    bleeding / Early / Incidence not known
    platelet dysfunction / Delayed / Incidence not known
    steatosis / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    neutropenia / Delayed / Incidence not known
    hyperprolactinemia / Delayed / Incidence not known
    withdrawal / Early / Incidence not known

    Mild

    nausea / Early / 21.0-58.0
    weight loss / Delayed / 4.0-47.0
    headache / Early / 25.0-38.0
    drowsiness / Early / 12.0-23.0
    insomnia / Early / 18.0-23.0
    xerostomia / Early / 12.0-22.0
    dizziness / Early / 11.0-20.0
    hyperhidrosis / Delayed / 6.7-19.3
    weakness / Early / 8.0-19.0
    anorexia / Delayed / 8.0-18.0
    asthenia / Delayed / 8.0-15.0
    yawning / Early / 3.0-8.0
    diarrhea / Early / 8.0-8.0
    libido decrease / Delayed / 2.0-8.0
    dyspepsia / Early / 5.0-7.0
    anxiety / Delayed / 6.0-6.0
    vomiting / Early / 3.0-6.0
    infection / Delayed / 2.2-6.0
    tremor / Early / 4.0-5.0
    orgasm dysfunction / Delayed / 2.0-5.0
    flushing / Rapid / 3.0-4.0
    agitation / Early / 2.0-3.0
    paresthesias / Delayed / 2.0-3.0
    flatulence / Early / 3.0-3.0
    rash / Early / 3.0-3.0
    increased urinary frequency / Early / 3.0-3.0
    chills / Rapid / 1.1-3.0
    emotional lability / Early / 0.1-1.0
    hyperkinesis / Delayed / 0.1-1.0
    restlessness / Early / 0.1-1.0
    gingivitis / Delayed / 0.1-1.0
    syncope / Early / 0.1-1.0
    diplopia / Early / 0.1-1.0
    xerophthalmia / Early / 0.1-1.0
    muscle cramps / Delayed / 0.1-1.0
    arthralgia / Delayed / 0.1-1.0
    epistaxis / Delayed / 0.1-1.0
    laryngitis / Delayed / 0.1-1.0
    hyperventilation / Early / 0.1-1.0
    leukocytosis / Delayed / 0.1-1.0
    hirsutism / Delayed / 0.1-1.0
    photosensitivity / Delayed / 0.1-1.0
    pruritus / Rapid / 1.0-1.0
    acne vulgaris / Delayed / 0.1-1.0
    urticaria / Rapid / 0.1-1.0
    maculopapular rash / Early / 0.1-1.0
    alopecia / Delayed / 0.1-1.0
    xerosis / Delayed / 0.1-1.0
    polyuria / Early / 0.1-1.0
    menorrhagia / Delayed / 0.1-1.0
    mastalgia / Delayed / 0.1-1.0
    nocturia / Early / 0.1-1.0
    urinary urgency / Early / 0.1-1.0
    amenorrhea / Delayed / 0.1-1.0
    fever / Early / 0-1.0
    paranoia / Early / 0-0.1
    hyporeflexia / Delayed / 0-0.1
    cheilitis / Delayed / 0-0.1
    hypersalivation / Early / 0-0.1
    tongue discoloration / Delayed / 0-0.1
    pallor / Early / 0-0.1
    petechiae / Delayed / 0-0.1
    purpura / Delayed / 0-0.1
    breast enlargement / Delayed / 0-0.1
    gynecomastia / Delayed / 0-0.1
    breast discharge / Delayed / 0-0.1
    vertigo / Early / 1.0
    eructation / Early / 1.0
    dysgeusia / Early / 1.0
    mydriasis / Early / 1.0
    menstrual irregularity / Delayed / 1.0
    night sweats / Early / Incidence not known
    ecchymosis / Delayed / Incidence not known
    cough / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abciximab: (Moderate) Monitor closely for signs and symptoms of bleeding during concurrent use of venlafaxine and abciximab. Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) like venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving abciximab.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Acetaminophen; Aspirin: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Acetaminophen; Caffeine; Dihydrocodeine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of dihydrocodeine and venlafaxine because of the potential risk of serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Discontinue dihydrocodeine if serotonin syndrome is suspected. Additionally, concomitant use of dihydrocodeine with venlafaxine may decrease dihydrocodeine plasma concentrations resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of venlafaxine could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If venlafaxine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Venlafaxine is a weak inhibitor of CYP2D6.
    Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with venlafaxine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with venlafaxine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with venlafaxine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with venlafaxine may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of venlafaxine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If venlafaxine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. venlafaxine is a weak inhibitor of CYP2D6. Also, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Acetaminophen; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with venlafaxine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with venlafaxine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with venlafaxine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
    Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with venlafaxine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with venlafaxine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with venlafaxine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with venlafaxine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of venlafaxine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If venlafaxine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Venlafaxine is a weak inhibitor of CYP2D6. Also, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Acetaminophen; Oxycodone: (Moderate) If concomitant use of oxycodone and serotonin norepinephrine reuptake inhibitors is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Acetaminophen; Pentazocine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Alfentanil: (Moderate) If concomitant use of alfentanil and venlafaxine is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Alfuzosin: (Moderate) Due to a possible risk for QT prolongation and torsade de pointes (TdP), alfuzosin and venlafaxine should be used together cautiously. Based on electrophysiology studies performed by the manufacturer, alfuzosin may prolong the QT interval in a dose-dependent manner. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with postmarketing use.
    Aminosalicylate sodium, Aminosalicylic acid: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Amiodarone: (Major) Concomitant use of amiodarone and venlafaxine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
    Amisulpride: (Major) Concomitant use of venlafaxine and amisulpride increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Amitriptyline: (Major) The combination of venlafaxine and tricyclic antidepressants may lead to serotonin syndrome and increased plasma concentrations of TCAs. Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Venlafaxine is an inhibitor of CYP2D6, and many TCAs are metabolized by this isozyme. One case report documented a first-time seizure in a patient receiving venlafaxine and trimipramine at therapeutic dosages.
    Amlodipine; Celecoxib: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Concomitant use of venlafaxine and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Amphetamine; Dextroamphetamine Salts: (Moderate) Coadministration of amphetamines with serotonin norepinephrine reuptake inhibitors (SNRIs) may increase the risk of serotonin syndrome. At high doses, amphetamines can increase serotonin release and act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
    Anagrelide: (Major) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be instructed to monitor for signs and symptoms of bleeding while taking venlafaxine concurrently with a platelet inhibitor and to promptly report any bleeding events to the practitioner. Also, torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with anagrelide include venlafaxine.
    Antithrombin III: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like antithrombin III. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Apixaban: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like apixaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Apomorphine: (Moderate) Exercise caution when administering apomorphine concomitantly with venlafaxine since concurrent use may increase the risk of QT prolongation. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes has reported with postmarketing use. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if venlafaxine and aprepitant, fosaprepitant are used concurrently and monitor for an increase in venlafaxine-related adverse effects for several days after administration of a multi-day aprepitant regimen. Venlafaxine is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of venlafaxine. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Argatroban: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like argatroban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Aripiprazole: (Major) Concomitant use of aripiprazole and venlafaxine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. Monitor for aripiprazole-related adverse reactions during concurrent use. Reduce the oral aripiprazole dosage to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response in patients also receiving a CYP3A inhibitor. Adults receiving a combination of a CYP3A inhibitor and venlafaxine for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP2D6 inhibitor alone. Aripiprazole is a substrate for CYP2D6 and CYP3A; venlafaxine is a weak CYP2D6 inhibitor.
    Arsenic Trioxide: (Major) Concomitant use of venlafaxine and arsenic trioxide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Artemether; Lumefantrine: (Major) Concomitant use of venlafaxine and lumefantrine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Asenapine: (Major) Venlafaxine is associated with a possible risk of QT prolongation. Other atypical antipsychotics associated with a risk for QT prolongation and torsades de pointes (TdP) that should be used cautiously with venlafaxine include asenapine. In addition, venlafaxine is a weak inhibitor of CYP2D6, and increases in plasma concentrations of antipsychotics primarily metabolized via CYP2D6, such as risperidone, may occur. Atypical antipsychotics with partial metabolism via CYP2D6 include asenapine.
    Aspirin, ASA: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with venlafaxine may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of venlafaxine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If venlafaxine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. venlafaxine is a weak inhibitor of CYP2D6. Also, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Aspirin, ASA; Caffeine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Aspirin, ASA; Carisoprodol: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with venlafaxine may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of venlafaxine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If venlafaxine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. venlafaxine is a weak inhibitor of CYP2D6. Also, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Aspirin, ASA; Dipyridamole: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner. (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with a platelet inhibitor and to promptly report any bleeding events to the practitioner.
    Aspirin, ASA; Omeprazole: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Aspirin, ASA; Oxycodone: (Moderate) If concomitant use of oxycodone and serotonin norepinephrine reuptake inhibitors is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Aspirin, ASA; Pravastatin: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Atazanavir; Cobicistat: (Moderate) Monitor for adverse effects when administering venlafaxine with cobicistat. There is a potential for elevated venlafaxine and cobicistat concentrations if these drugs are given together. Venlafaxine and cobicistat are substrates and inhibitors of CYP2D6. In addition, venlafaxine is a substrate for CYP3A4; cobicistat is a strong inhibitor of CYP3A4.
    Atomoxetine: (Moderate) The concomitant use of atomoxetine and venlafaxine may lead to additive effects on blood pressure, heart rate, or QT interval prolongation. Venlafaxine is a serotonin norepinephrine reuptake inhibitor (SNRI) and atomoxetine selectively inhibits norepinephrine reuptake; the drugs have some additive pharmacology that may lead to increases in blood pressure or heart rate. Venlafaxine is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has been reported with postmarketing use. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Contraindicated) Concurrent use of methylene blue and serotonin norepinephrine reuptake inhibitors (SNRIs) (e.g., venlafaxine, duloxetine, desvenlafaxine, milnacipran) should generally be avoided due to the potential for serotonin syndrome. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with serotonergic agents such as SNRIs may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, SNRIs, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case report suggests that serotonin toxicity may have occurred post-operatively following administration of standard infusions of methylene blue in a patient receiving duloxetine. The patient experienced disorientation, a mildly elevated temperature, tachycardia, elevated blood pressure, mild agitation, and nystagmus. In a separate case, a patient who had been receiving venlafaxine developed expressive aphasia, confusion, and disinhibition following a methylene blue infusion. The authors concluded that methylene blue toxicity had occurred; however, they did not exclude the possibility of a drug interaction based upon previous reports of an interaction between injectable methylene blue and selective serotonin reuptake inhibitors (SSRIs). Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. If emergent treatment with methylene blue is required in a patient receiving an SNRI, the SNRI must be stopped immediately and the patient should be monitored for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, the SNRI should be stopped at least 2 weeks prior to methylene blue treatment, but also taking into consideration the half-life of the SNRI being discontinued. (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Azithromycin: (Major) Concomitant use of azithromycin and venlafaxine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Bedaquiline: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with venlafaxine. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Venlafaxine administration is also associated with a possible risk of QT prolongation; TdP has been reported with post-marketing use.
    Benzhydrocodone; Acetaminophen: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of benzhydrocodone and venlafaxine because of the potential risk of serotonin syndrome. Discontinue benzhydrocodone if serotonin syndrome is suspected. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Contraindicated) Concurrent use of methylene blue and serotonin norepinephrine reuptake inhibitors (SNRIs) (e.g., venlafaxine, duloxetine, desvenlafaxine, milnacipran) should generally be avoided due to the potential for serotonin syndrome. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with serotonergic agents such as SNRIs may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, SNRIs, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case report suggests that serotonin toxicity may have occurred post-operatively following administration of standard infusions of methylene blue in a patient receiving duloxetine. The patient experienced disorientation, a mildly elevated temperature, tachycardia, elevated blood pressure, mild agitation, and nystagmus. In a separate case, a patient who had been receiving venlafaxine developed expressive aphasia, confusion, and disinhibition following a methylene blue infusion. The authors concluded that methylene blue toxicity had occurred; however, they did not exclude the possibility of a drug interaction based upon previous reports of an interaction between injectable methylene blue and selective serotonin reuptake inhibitors (SSRIs). Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. If emergent treatment with methylene blue is required in a patient receiving an SNRI, the SNRI must be stopped immediately and the patient should be monitored for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, the SNRI should be stopped at least 2 weeks prior to methylene blue treatment, but also taking into consideration the half-life of the SNRI being discontinued. (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Benzphetamine: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and serotonin norepinephrine reuptake inhibitors. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Betrixaban: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like betrixaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and venlafaxine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Bismuth Subsalicylate: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and venlafaxine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Bivalirudin: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like bivalirudin. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with venlafaxine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
    Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with venlafaxine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
    Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with venlafaxine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
    Bupivacaine; Meloxicam: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Buprenorphine: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of venlafaxine and buprenorphine is necessary. Venlafaxine may cause QT interval prolongation and a risk for torsade de pointes (TdP); buprenorphine caused QT prolongation in some patients during clinical trials. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as SNRIs, has resulted in serotonin syndrome in some cases. Patients should be carefully observed, particularly during treatment initiation and during dose adjustments. Discontinue the serotonergic medications if serotonin syndrome is suspected.
    Buprenorphine; Naloxone: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of venlafaxine and buprenorphine is necessary. Venlafaxine may cause QT interval prolongation and a risk for torsade de pointes (TdP); buprenorphine caused QT prolongation in some patients during clinical trials. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as SNRIs, has resulted in serotonin syndrome in some cases. Patients should be carefully observed, particularly during treatment initiation and during dose adjustments. Discontinue the serotonergic medications if serotonin syndrome is suspected.
    Buspirone: (Moderate) Coadministration of buspirone with serotonin norepinephrine reuptake inhibitors (SNRIs) may increase the risk of serotonin syndrome. Both types of medications have serotonergic properties. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, all serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with venlafaxine may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of venlafaxine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If venlafaxine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. venlafaxine is a weak inhibitor of CYP2D6. Also, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Cabotegravir; Rilpivirine: (Moderate) Caution is advised when administering rilpivirine with venlafaxine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Venlafaxine administration is also associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Capsaicin; Metaxalone: (Moderate) Concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and metaxalone may increase the risk for serotonin syndrome. Monitor patients for serotonin syndrome if concomitant use is necessary.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with venlafaxine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
    Celecoxib: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Celecoxib; Tramadol: (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with venlafaxine is necessary. If venlafaxine is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and venlafaxine is a CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Ceritinib: (Major) Avoid coadministration of ceritinib with venlafaxine if possible due to the risk of QT prolongation; plasma concentrations of venlafaxine may also increase. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Monitor for venlafaxine-related adverse reactions. Venlafaxine is a CYP3A4 substrate that is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has been reported with postmarketing use. Ceritinib is a strong CYP3A4 inhibitor that causes concentration-dependent QT prolongation.
    Chlordiazepoxide; Amitriptyline: (Major) The combination of venlafaxine and tricyclic antidepressants may lead to serotonin syndrome and increased plasma concentrations of TCAs. Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Venlafaxine is an inhibitor of CYP2D6, and many TCAs are metabolized by this isozyme. One case report documented a first-time seizure in a patient receiving venlafaxine and trimipramine at therapeutic dosages.
    Chloroquine: (Major) Concomitant use of venlafaxine and chloroquine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with venlafaxine may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of venlafaxine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If venlafaxine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. venlafaxine is a weak inhibitor of CYP2D6. Also, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Chlorpheniramine; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with venlafaxine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with venlafaxine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
    Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with venlafaxine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of dihydrocodeine and venlafaxine because of the potential risk of serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Discontinue dihydrocodeine if serotonin syndrome is suspected. Additionally, concomitant use of dihydrocodeine with venlafaxine may decrease dihydrocodeine plasma concentrations resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of venlafaxine could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If venlafaxine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Venlafaxine is a weak inhibitor of CYP2D6.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with venlafaxine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of venlafaxine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If venlafaxine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Venlafaxine is a weak inhibitor of CYP2D6. Also, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Chlorpromazine: (Major) Chlorpromazine is associated with a possible risk of QT prolongation and should be used cautiously with venlafaxine since venlafaxine is also associated with a possible risk of QT prolongation. In addition, venlafaxine is an inhibitor of CYP2D6, and concurrent use with CYP2D6 substrates, such as phenothiazines, may result in increased plasma concentrations of such antipsychotics. In one case report, the initiation of venlafaxine in a patient taking trifluoperazine resulted in symptoms consistent with neuroleptic malignant syndrome (NMS). After discontinuation of all psychiatric medications and treatment for NMS, the patient recovered and was able to reinitiate trifluoperazine without further problems. Venlafaxine was not administered a second time.
    Choline Salicylate; Magnesium Salicylate: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Cilostazol: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with a platelet inhibitor and to promptly report any bleeding events to the practitioner.
    Cinacalcet: (Minor) Cinacalcet, a strong in vitro inhibitor of the CYP2D6 cytochrome P450 enzyme, may theoretically increase serum concentrations of other drugs metabolized by this enzyme, including venlafaxine.
    Ciprofloxacin: (Moderate) Concomitant use of ciprofloxacin and venlafaxine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Cisapride: (Contraindicated) Avoid concomitant use of venlafaxine and cisapride due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Citalopram: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, selective serotonin reuptake inhibitors (SSRIs) should generally not be administered with serotonin norepinephrine reuptake inhibitors like venlafaxine. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued. In addition, venlafaxine and citalopram are associated with a possible risk of QT prolongation and torsade de pointes (TdP) and combination therapy should be avoided if possible.
    Clarithromycin: (Major) Concomitant use of venlafaxine and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Clofazimine: (Moderate) Concomitant use of clofazimine and venlafaxine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Clomipramine: (Major) The combination of venlafaxine and tricyclic antidepressants may lead to serotonin syndrome and increased plasma concentrations of TCAs. Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Venlafaxine is an inhibitor of CYP2D6, and many TCAs are metabolized by this isozyme. One case report documented a first-time seizure in a patient receiving venlafaxine and trimipramine at therapeutic dosages.
    Clopidogrel: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of venlafaxine and clopidogrel. Serotonin-norepinephrine reuptake inhibitors (SNRIs) affect platelet activation; therefore, concomitant use may increase the risk of bleeding.
    Clozapine: (Major) Venlafaxine is associated with a possible risk of QT prolongation and clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. In addition, venlafaxine is a weak inhibitor of CYP2D6. Clozapine is a substrate of CYP1A2, CYP2D6, or CYP3A4 and elevated plasma concentrations of clozapine occurring through CYP inhibition may increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP2D6 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary. Post-marketing reports have indicated there may be the potential for seizure activity if venlafaxine is added to established clozapine therapy. Clozapine serum concentrations have risen temporally following the addition of venlafaxine.
    Cobicistat: (Moderate) Monitor for adverse effects when administering venlafaxine with cobicistat. There is a potential for elevated venlafaxine and cobicistat concentrations if these drugs are given together. Venlafaxine and cobicistat are substrates and inhibitors of CYP2D6. In addition, venlafaxine is a substrate for CYP3A4; cobicistat is a strong inhibitor of CYP3A4.
    Cocaine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as cocaine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Codeine: (Moderate) Concomitant use of codeine with venlafaxine may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of venlafaxine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If venlafaxine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. venlafaxine is a weak inhibitor of CYP2D6. Also, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with venlafaxine may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of venlafaxine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If venlafaxine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. venlafaxine is a weak inhibitor of CYP2D6. Also, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with venlafaxine may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of venlafaxine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If venlafaxine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. venlafaxine is a weak inhibitor of CYP2D6. Also, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with venlafaxine may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of venlafaxine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If venlafaxine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. venlafaxine is a weak inhibitor of CYP2D6. Also, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) Concomitant use of promethazine and venlafaxine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Codeine; Promethazine: (Moderate) Concomitant use of codeine with venlafaxine may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of venlafaxine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If venlafaxine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. venlafaxine is a weak inhibitor of CYP2D6. Also, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) Concomitant use of promethazine and venlafaxine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Crizotinib: (Major) Concomitant use of venlafaxine and crizotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Cyclobenzaprine: (Major) Cautious use of cyclobenzaprine and drugs that increase serotonin concentrations such as serotonin norepinephrine reuptake inhibitors (SNRIs) is advised because of the possibility of serotonin syndrome. If these drugs must be used together, closely monitor the patient for signs and symptoms of serotonin syndrome. If such a reaction develops, immediately discontinue cyclobenzaprine and the SSRI. A suspected case of serotonin syndrome was noted in a man who took duloxetine, opiates, and cyclobenzaprine. The man developed worsening confusion, hallucinations, diaphoresis, tachycardia, tremors, marked agitation, spontaneous sustained clonus, and multifocal myoclonus.but recovered after duloxetine and cyclobenzaprine discontinuation and cyproheptadine initiation.
    Cyproheptadine: (Moderate) Cyproheptadine is a serotonin and histamine antagonist. Cyproheptadine may interfere with serotonin-enhancing antidepressants, including the selective serotonin reuptake inhibitors (SSRIs) and drugs with similar activity, such as venlafaxine. Cyproheptadine has been used for the management of orgasm dysfunction caused by the SSRIs and for the adjunctive treatment of SSRI or venlafaxine overdose (i.e., serotonin syndrome) in emergency situations; however, a reversal of antidepressant effects may occur when cyproheptadine is given in a routine manner along with the SSRIs due to the serotonin antagonistic effects of cyproheptadine.
    Dabigatran: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like dabigatran. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Dacomitinib: (Moderate) Monitor for increased toxicity of venlafaxine if coadministered with dacomitinib. Coadministration may increase serum concentrations of venlafaxine. Venlafaxine is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor.
    Dalteparin: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like dalteparin. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Darunavir; Cobicistat: (Moderate) Monitor for adverse effects when administering venlafaxine with cobicistat. There is a potential for elevated venlafaxine and cobicistat concentrations if these drugs are given together. Venlafaxine and cobicistat are substrates and inhibitors of CYP2D6. In addition, venlafaxine is a substrate for CYP3A4; cobicistat is a strong inhibitor of CYP3A4.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for adverse effects when administering venlafaxine with cobicistat. There is a potential for elevated venlafaxine and cobicistat concentrations if these drugs are given together. Venlafaxine and cobicistat are substrates and inhibitors of CYP2D6. In addition, venlafaxine is a substrate for CYP3A4; cobicistat is a strong inhibitor of CYP3A4.
    Dasatinib: (Moderate) Monitor for evidence of QT prolongation and torsade de pointes (TdP) during concurrent use of dasatinib and venlafaxine. In vitro studies have shown that dasatinib has the potential to prolong the QT interval. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with postmarketing use.
    Degarelix: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving venlafaxine as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval. Venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has reported with post-marketing use.
    Delavirdine: (Moderate) Delavirdine is a potent inhibitor of cytochrome P450 2D6 and might decrease venlafaxine metabolism leading to increased adverse reactions.
    Desipramine: (Major) The combination of venlafaxine and tricyclic antidepressants may lead to serotonin syndrome and increased plasma concentrations of TCAs. Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Venlafaxine is an inhibitor of CYP2D6, and many TCAs are metabolized by this isozyme. One case report documented a first-time seizure in a patient receiving venlafaxine and trimipramine at therapeutic dosages.
    Desirudin: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like desirudin. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Desvenlafaxine: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, coadministration of venlafaxine and desvenlafaxine should be avoided. Also, because desvenlafaxine is the active metabolite of venlafaxine and both agents are serotonin norepinephrine reuptake inhibitors (SNRIs), coadministration is considered duplicative therapy. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SNRI to another SNRI.
    Deutetrabenazine: (Moderate) The risk of QT prolongation may be increased with coadministration of deutetrabenazine and venlafaxine. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has been reported with postmarketing use.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with venlafaxine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
    Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with venlafaxine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
    Dextromethorphan; Bupropion: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with venlafaxine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with venlafaxine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
    Dextromethorphan; Guaifenesin: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with venlafaxine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with venlafaxine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with venlafaxine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with venlafaxine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
    Dextromethorphan; Quinidine: (Contraindicated) Quinidine administration is associated with QT prolongation and torsades de pointes (TdP). Quinidine inhibits CYP2D6 and has QT-prolonging actions; quinidine is contraindicated with other drugs that prolong the QT interval and are metabolized by CYP2D6 as the effects on the QT interval may be increased during concurrent use of these agents. Drugs that prolong the QT and are substrates for CYP2D6 that are contraindicated with quinidine includes venlafaxine. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with venlafaxine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
    Diclofenac: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Diclofenac; Misoprostol: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Diflunisal: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Diphenhydramine; Ibuprofen: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Diphenhydramine; Naproxen: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Dipyridamole: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with a platelet inhibitor and to promptly report any bleeding events to the practitioner.
    Disopyramide: (Major) Concomitant use of venlafaxine and disopyramide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Diuretics: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and serotonin norepinephrine reuptake inhibitor (SNRI) use; consider discontinuing the SNRI if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
    Dofetilide: (Major) Concomitant use of venlafaxine and dofetilide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Dolasetron: (Moderate) Administer dolasetron with caution in combination with venlafaxine as concurrent use may increase the risk of QT prolongation. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
    Dolutegravir; Rilpivirine: (Moderate) Caution is advised when administering rilpivirine with venlafaxine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Venlafaxine administration is also associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Donepezil: (Moderate) Use donepezil with caution in combination with venlafaxine. Both drugs have been associated with a risk of QT prolongation and torsade de pointes.
    Donepezil; Memantine: (Moderate) Use donepezil with caution in combination with venlafaxine. Both drugs have been associated with a risk of QT prolongation and torsade de pointes.
    Doxepin: (Major) The combination of venlafaxine and tricyclic antidepressants may lead to serotonin syndrome and increased plasma concentrations of TCAs. Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Venlafaxine is an inhibitor of CYP2D6, and many TCAs are metabolized by this isozyme. One case report documented a first-time seizure in a patient receiving venlafaxine and trimipramine at therapeutic dosages.
    Dronedarone: (Contraindicated) Avoid concomitant use of venlafaxine and dronedarone due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Droperidol: (Major) Concomitant use of venlafaxine and droperidol increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Duloxetine: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, coadministration of venlafaxine and duloxetine should be avoided. Also, because both venlafaxine and duloxetine are serotonin norepinephrine reuptake inhibitors (SNRIs), coadministration is considered duplicative therapy. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SNRI to another SNRI.
    Edoxaban: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like edoxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Efavirenz: (Moderate) Consider alternatives to efavirenz when coadministering with venlafaxine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Consider alternatives to efavirenz when coadministering with venlafaxine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Consider alternatives to efavirenz when coadministering with venlafaxine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Elbasvir; Grazoprevir: (Moderate) Administering venlafaxine with elbasvir; grazoprevir may result in elevated venlafaxine plasma concentrations. Venlafaxine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eliglustat: (Major) Concomitant use of venlafaxine and eliglustat increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for adverse effects when administering venlafaxine with cobicistat. There is a potential for elevated venlafaxine and cobicistat concentrations if these drugs are given together. Venlafaxine and cobicistat are substrates and inhibitors of CYP2D6. In addition, venlafaxine is a substrate for CYP3A4; cobicistat is a strong inhibitor of CYP3A4.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for adverse effects when administering venlafaxine with cobicistat. There is a potential for elevated venlafaxine and cobicistat concentrations if these drugs are given together. Venlafaxine and cobicistat are substrates and inhibitors of CYP2D6. In addition, venlafaxine is a substrate for CYP3A4; cobicistat is a strong inhibitor of CYP3A4.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Caution is advised when administering rilpivirine with venlafaxine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Venlafaxine administration is also associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering rilpivirine with venlafaxine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Venlafaxine administration is also associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Encorafenib: (Major) Concomitant use of venlafaxine and encorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Enoxaparin: (Major) Whenever possible, discontinue agents which may enhance the risk of hemorrhage, including serotonin norepinephrine reuptake inhibitors (SNRIs), before initiation of enoxaparin therapy. If coadministration is essential, conduct close clinical and laboratory monitoring.
    Entrectinib: (Major) Concomitant use of venlafaxine and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Eptifibatide: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with a platelet inhibitor and to promptly report any bleeding events to the practitioner.
    Ergot alkaloids: (Moderate) Because of the potential risk and severity of serotonin syndrome, use caution when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties, such as the ergot alkaloids. Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been coadministered with serotonin reuptake inhibitors, which may be indicative of serotonin excess. Inform patients of the potential risk and monitor for serotonin syndrome. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
    Eribulin: (Major) Concomitant use of venlafaxine and eribulin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Erythromycin: (Major) Concomitant use of erythromycin and venlafaxine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Escitalopram: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome and QT prolongation, escitalopram, a selective serotonin reuptake inhibitor (SSRI) should generally not be administered with venlafaxine, a serotonin norepinephrine reuptake inhibitor (SNRI).
    Ethanol: (Major) Advise patients to avoid alcohol while taking some dosage forms (e.g., venlafaxine extended-release capsules and tablets) of venlafaxine. Consumption of alcohol while taking such dosage forms may result in a more rapid release of the dose of venlafaxine which may potentially lead to serious side effects.
    Etodolac: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Everolimus: (Moderate) Monitor for an increase in venlafaxine-related adverse reactions if coadministration with everolimus is necessary. Venlafaxine is a sensitive CYP2D6 substrate and everolimus is a CYP2D6 inhibitor; concomitant use may increase plasma concentrations of venlafaxine.
    Fedratinib: (Moderate) Although no dosage adjustment of venlafaxine is required during concomitant use of fedratinib, venlafaxine exposure may increase resulting in increased adverse effects. Venlafaxine is a sensitive CYP2D6 substrate and venlafaxine is a moderate CYP2D6 inhibitor.
    Fenfluramine: (Moderate) Use fenfluramine and serotonin norepinephrine reuptake inhibitors with caution due to an increased risk of serotonin syndrome. Monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Fenoprofen: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Fentanyl: (Moderate) If concomitant use of fentanyl and venlafaxine is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Fingolimod: (Moderate) Exercise caution when administering fingolimod concomitantly with venlafaxine as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Flecainide: (Major) Concomitant use of flecainide and venlafaxine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Fluconazole: (Moderate) Concomitant use of fluconazole and venlafaxine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Fluoxetine: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, selective serotonin reuptake inhibitors (SSRIs) should generally not be administered with serotonin norepinephrine reuptake inhibitors like venlafaxine. If serotonin syndrome is suspected, all serotonergic agents should be discontinued. Also, both fluoxetine and venlafaxine have been associated with QT prolongation and torsade de pointes (TdP), which could theoretically result in additive effects on the QT interval.
    Fluphenazine: (Moderate) Caution is advisable during concurrent use of fluphenazine and serotonin norepinephrine reuptake inhibitors (SNRIs) since elevations in plasma concentrations of fluphenazine may occur. Phenothiazines are CYP2D6 substrates and SNRIs including venlafaxine are CYP2D6 inhibitors. In addition, both venlafaxine and fluphenazine are associated with a possible risk of QT prolongation; therefore, additive cardiac effects are possible.
    Flurbiprofen: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Fluvoxamine: (Major) Concomitant use of fluvoxamine and venlafaxine may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes (TdP). Both venlafaxine and fluvoxamine are associated with reports of QT prolongation and TdP. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Fondaparinux: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like fondaparinux. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Foscarnet: (Major) Concomitant use of venlafaxine and foscarnet increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Fostemsavir: (Moderate) Use venlafaxine and fostemsavir together with caution due to the potential for QT prolongation. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
    Gemifloxacin: (Moderate) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering venlafaxine with gemifloxacin. Venlafaxine is associated with a possible risk of QT prolongation; TdP has been reported with post-marketing use. Gemifloxacin may also prolong the QT interval in some patients, with the maximal change in the QTc interval occurring approximately 5 to 10 hours following oral administration. The likelihood of QTc prolongation may increase with increasing dose of gemifloxacin; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
    Gemtuzumab Ozogamicin: (Major) Concomitant use of venlafaxine and gemtuzumab ozogamicin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Gilteritinib: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and venlafaxine is necessary. Gilteritinib has been associated with QT prolongation. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Givosiran: (Major) Avoid concomitant use of givosiran and venlafaxine due to the risk of increased venlafaxine-related adverse reactions. If use is necessary, consider reducing the venlafaxine dose. Venlafaxine is a sensitive CYP2D6 substrate. Givosiran may moderately reduce hepatic CYP2D6 enzyme activity because of its pharmacological effects on the hepatic heme biosynthesis pathway.
    Glasdegib: (Major) Concomitant use of venlafaxine and glasdegib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Goserelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., goserelin) outweigh the potential risks of QT prolongation in patients receiving venlafaxine. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use. Androgen deprivation therapy (i.e., goserelin) may also prolong the QT/QTc interval.
    Granisetron: (Moderate) Use granisetron with caution in combination with venlafaxine due to increased risk for QT prolongation and serotonin syndrome. If serotonin syndrome is suspected, discontinue granisetron and concurrent serotonergic agents and initiate appropriate medical treatment. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use. Granisetron has been associated with QT prolongation.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with venlafaxine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of venlafaxine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If venlafaxine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Venlafaxine is a weak inhibitor of CYP2D6. Also, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with venlafaxine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of venlafaxine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If venlafaxine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Venlafaxine is a weak inhibitor of CYP2D6. Also, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Halogenated Anesthetics: (Major) Concomitant use of venlafaxine and halogenated anesthetics increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Haloperidol: (Moderate) Caution is advisable when combining haloperidol concurrently with venlafaxine as concurrent use may increase the risk of QT prolongation and haloperidol-related adverse effects. A haloperidol dose reduction may be necessary. Mild to moderately increased haloperidol concentrations have been reported when haloperidol was given concomitantly with venlafaxine. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Heparin: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like heparin. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Histrelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving venlafaxine. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with venlafaxine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of venlafaxine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If venlafaxine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Venlafaxine is a weak inhibitor of CYP2D6. Also, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Hydrocodone: (Moderate) Concomitant use of hydrocodone with venlafaxine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of venlafaxine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If venlafaxine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Venlafaxine is a weak inhibitor of CYP2D6. Also, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with venlafaxine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of venlafaxine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If venlafaxine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Venlafaxine is a weak inhibitor of CYP2D6. Also, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with venlafaxine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of venlafaxine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If venlafaxine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Venlafaxine is a weak inhibitor of CYP2D6. Also, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Hydromorphone: (Moderate) If concomitant use of hydromorphone and venlafaxine is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Hydroxychloroquine: (Major) Concomitant use of hydroxychloroquine and venlafaxine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Hydroxyzine: (Moderate) Concomitant use of hydroxyzine and venlafaxine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Contraindicated) Concurrent use of methylene blue and serotonin norepinephrine reuptake inhibitors (SNRIs) (e.g., venlafaxine, duloxetine, desvenlafaxine, milnacipran) should generally be avoided due to the potential for serotonin syndrome. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with serotonergic agents such as SNRIs may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, SNRIs, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case report suggests that serotonin toxicity may have occurred post-operatively following administration of standard infusions of methylene blue in a patient receiving duloxetine. The patient experienced disorientation, a mildly elevated temperature, tachycardia, elevated blood pressure, mild agitation, and nystagmus. In a separate case, a patient who had been receiving venlafaxine developed expressive aphasia, confusion, and disinhibition following a methylene blue infusion. The authors concluded that methylene blue toxicity had occurred; however, they did not exclude the possibility of a drug interaction based upon previous reports of an interaction between injectable methylene blue and selective serotonin reuptake inhibitors (SSRIs). Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. If emergent treatment with methylene blue is required in a patient receiving an SNRI, the SNRI must be stopped immediately and the patient should be monitored for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, the SNRI should be stopped at least 2 weeks prior to methylene blue treatment, but also taking into consideration the half-life of the SNRI being discontinued. (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Ibuprofen: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Ibuprofen; Famotidine: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Ibuprofen; Oxycodone: (Moderate) If concomitant use of oxycodone and serotonin norepinephrine reuptake inhibitors is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Ibuprofen; Pseudoephedrine: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Ibutilide: (Major) Concomitant use of venlafaxine and ibutilide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with venlafaxine, a CYP3A substrate, as venlafaxine toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Iloperidone: (Major) Venlafaxine is associated with a possible risk of QT prolongation. Other atypical antipsychotics associated with a risk for QT prolongation and torsades de pointes (TdP) that should be used cautiously with venlafaxine include iloperidone. In addition, venlafaxine is a weak inhibitor of CYP2D6, and increases in plasma concentrations of antipsychotics primarily metabolized via CYP2D6, such as risperidone, may occur. Atypical antipsychotics with partial metabolism via CYP2D6 include iloperidone.
    Imatinib: (Moderate) Imatinib, STI-571 is a potent inhibitor of cytochrome P450 2D6 and might decrease venlafaxine metabolism leading to increased adverse reactions.
    Imipramine: (Major) The combination of venlafaxine and tricyclic antidepressants may lead to serotonin syndrome and increased plasma concentrations of TCAs. Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Venlafaxine is an inhibitor of CYP2D6, and many TCAs are metabolized by this isozyme. One case report documented a first-time seizure in a patient receiving venlafaxine and trimipramine at therapeutic dosages.
    Indinavir: (Minor) Serum concentrations of indinavir may decrease when coadministered with venlafaxine. In a study of 9 healthy volunteers, coadministration resulted in a 28% decrease in the AUC of indinavir and a 36% decrease in indinavir Cmax. Indinavir did not affect the pharmacokinetics of venlafaxine or its metabolite (i.e., ODV). The clinical significance of this interaction is unknown.
    Indomethacin: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Inotuzumab Ozogamicin: (Major) Concomitant use of venlafaxine and inotuzumab increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Iobenguane I 131: (Major) Discontinue serotonin norepinephrine reuptake inhibitors for at least 5 half-lives before the administration of the dosimetry dose or a therapeutic dose of iobenguane I-131. Do not restart serotonin norepinephrine reuptake inhibitors until at least 7 days after each iobenguane I-131 dose. Drugs that reduce catecholamine uptake or deplete catecholamine stores, such as serotonin norepinephrine reuptake inhibitors, may interfere with iobenguane I-131 uptake into cells and interfere with dosimetry calculations resulting in altered iobenguane I-131 efficacy.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with venlafaxine may result in increased serum concentrations of venlafaxine. Venlafaxine is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isoniazid, INH: (Major) Due to the risk of serotonin syndrome, concurrent use of venlafaxine and medications with MAO-like activity, such as isoniazid, INH, should be avoided if possible. Isoniazid is chemically related to iproniazid, a drug that was known to possess MAO inhibiting activity. Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO and may possess enough MAO inhibiting activity to produce clinical symptoms consistent with serotonergic excess when combined with serotonin norepinephrine reuptake inhibitors. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Due to the risk of serotonin syndrome, concurrent use of venlafaxine and medications with MAO-like activity, such as isoniazid, INH, should be avoided if possible. Isoniazid is chemically related to iproniazid, a drug that was known to possess MAO inhibiting activity. Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO and may possess enough MAO inhibiting activity to produce clinical symptoms consistent with serotonergic excess when combined with serotonin norepinephrine reuptake inhibitors. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
    Isoniazid, INH; Rifampin: (Major) Due to the risk of serotonin syndrome, concurrent use of venlafaxine and medications with MAO-like activity, such as isoniazid, INH, should be avoided if possible. Isoniazid is chemically related to iproniazid, a drug that was known to possess MAO inhibiting activity. Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO and may possess enough MAO inhibiting activity to produce clinical symptoms consistent with serotonergic excess when combined with serotonin norepinephrine reuptake inhibitors. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
    Itraconazole: (Moderate) Caution is advised when administering itraconazole with venlafaxine due to the potential for additive effects on the QT interval and increased exposure to venlafaxine. Both venlafaxine and itraconazole are associated with QT prolongation; coadministration may increase this risk. In addition, venlafaxine is a substrate of CYP2D6 (major) and CYP3A4 (minor). In patients who are poor CYP2D6 metabolizers, the CYP3A4 pathway for venlafaxine may become more important. Administration of venlafaxine and itraconazole (a potent CYP3A4 inhibitor) to patients identified as CYP2D6 poor metabolizers may significantly increase venlafaxine plasma concentrations.
    Ivosidenib: (Major) Concomitant use of venlafaxine and ivosidenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and venlafaxine due to an increased risk for QT/QTc prolongation and torsade de pointes (TdP).
    Ketoprofen: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Ketorolac: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Lansoprazole; Amoxicillin; Clarithromycin: (Major) Concomitant use of venlafaxine and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Lansoprazole; Naproxen: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Lapatinib: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with venlafaxine. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with postmarketing use.
    Lasmiditan: (Moderate) Serotonin syndrome may occur during coadministration of lasmiditan and serotonin norepinephrine reuptake inhibitors. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Lefamulin: (Major) Concomitant use of venlafaxine and lefamulin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Lenvatinib: (Major) Concomitant use of venlafaxine and lenvatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Lepirudin: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like lepirudin. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Letermovir: (Moderate) An increase in the plasma concentration of venlafaxine may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Venlafaxine is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
    Leuprolide: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving venlafaxine. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
    Leuprolide; Norethindrone: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving venlafaxine. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
    Levofloxacin: (Moderate) Concomitant use of levofloxacin and venlafaxine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Levoketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and venlafaxine due to an increased risk for QT/QTc prolongation and torsade de pointes (TdP).
    Levomilnacipran: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, coadministration of venlafaxine and levomilnacipran should be avoided. Also, because both venlafaxine and levomilnacipran are serotonin norepinephrine reuptake inhibitors (SNRIs), coadministration is considered duplicative therapy. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SNRI to another SNRI.
    Levorphanol: (Moderate) If concomitant use of levorphanol and venlafaxine is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Linezolid: (Contraindicated) The use of linezolid with serotonin norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine is contraindicated due to the potential for serotonin syndrome. Linezolid is an antibiotic that also possesses weak non-selective MAO-inhibiting activity which could have additive effects with SNRIs on central serotonin activity. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. In a patient who requires urgent treatment of a psychiatric condition, interventions other than an SNRI, including hospitalization, should be considered. In some cases, a patient already receiving venlafaxine may require urgent treatment with linezolid. If acceptable alternatives to linezolid are not available and the potential benefits of linezolid are determined to outweigh the risks of serotonin syndrome in an individual patient, venlafaxine should be stopped promptly, and linezolid can be administered. The patient should be monitored for symptoms of serotonin syndrome for 7 days or until 24 hours after the last dose of linezolid, whichever comes first. Therapy with venlafaxine may be resumed 24 hours after the last dose of linezolid.
    Lisdexamfetamine: (Major) Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation or dosage increase, during concomitant lisdexamfetamine and serotonin norepinephrine reuptake inhibitor use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk of serotonin syndrome.
    Lithium: (Moderate) Concomitant use of lithium and venlafaxine may increase the risk of serotonin syndrome or QT/QTc prolongation and torsade de pointes (TdP) in some patients. Monitor for serotonin syndrome, particularly during therapy initiation and dose increases. If serotonin syndrome occurs, consider discontinuation of lithium and/or venlafaxine. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Lofexidine: (Major) Concomitant use of venlafaxine and lofexidine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Loperamide: (Moderate) Concomitant use of loperamide and venlafaxine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Loperamide; Simethicone: (Moderate) Concomitant use of loperamide and venlafaxine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Lopinavir; Ritonavir: (Major) Concomitant use of venlafaxine and lopinavir increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Lorcaserin: (Major) Based on the mechanism of action of lorcaserin and the theoretical potential for serotonin syndrome, use with extreme caution in combination with other drugs that may affect the serotonergic neurotransmitter systems, including, serotonin norepinephrine reuptake inhibitors. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or Neuroleptic Malignant Syndrome (NMS) like signs and symptoms.
    Macimorelin: (Major) Concomitant use of venlafaxine and macimorelin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Magnesium Salicylate: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Maprotiline: (Major) Concomitant use of venlafaxine and maprotiline increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Meclofenamate Sodium: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Mefenamic Acid: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Mefloquine: (Moderate) Mefloquine should be used with caution in patients receiving venlafaxine as concurrent use may increase the risk of QT prolongation. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Meloxicam: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Meperidine: (Moderate) If concomitant use of meperidine and serotonin norepinephrine reuptake inhibitors is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Meperidine; Promethazine: (Moderate) Concomitant use of promethazine and venlafaxine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) If concomitant use of meperidine and serotonin norepinephrine reuptake inhibitors is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Metaxalone: (Moderate) Concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and metaxalone may increase the risk for serotonin syndrome. Monitor patients for serotonin syndrome if concomitant use is necessary.
    Methadone: (Major) Concomitant use of venlafaxine and methadone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Methamphetamine: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as methamphetamine and serotonin norepinephrine reuptake inhibitors. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Contraindicated) Concurrent use of methylene blue and serotonin norepinephrine reuptake inhibitors (SNRIs) (e.g., venlafaxine, duloxetine, desvenlafaxine, milnacipran) should generally be avoided due to the potential for serotonin syndrome. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with serotonergic agents such as SNRIs may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, SNRIs, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case report suggests that serotonin toxicity may have occurred post-operatively following administration of standard infusions of methylene blue in a patient receiving duloxetine. The patient experienced disorientation, a mildly elevated temperature, tachycardia, elevated blood pressure, mild agitation, and nystagmus. In a separate case, a patient who had been receiving venlafaxine developed expressive aphasia, confusion, and disinhibition following a methylene blue infusion. The authors concluded that methylene blue toxicity had occurred; however, they did not exclude the possibility of a drug interaction based upon previous reports of an interaction between injectable methylene blue and selective serotonin reuptake inhibitors (SSRIs). Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. If emergent treatment with methylene blue is required in a patient receiving an SNRI, the SNRI must be stopped immediately and the patient should be monitored for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, the SNRI should be stopped at least 2 weeks prior to methylene blue treatment, but also taking into consideration the half-life of the SNRI being discontinued.
    Methenamine; Sodium Salicylate: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Methylene Blue: (Contraindicated) Concurrent use of methylene blue and serotonin norepinephrine reuptake inhibitors (SNRIs) (e.g., venlafaxine, duloxetine, desvenlafaxine, milnacipran) should generally be avoided due to the potential for serotonin syndrome. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with serotonergic agents such as SNRIs may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, SNRIs, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case report suggests that serotonin toxicity may have occurred post-operatively following administration of standard infusions of methylene blue in a patient receiving duloxetine. The patient experienced disorientation, a mildly elevated temperature, tachycardia, elevated blood pressure, mild agitation, and nystagmus. In a separate case, a patient who had been receiving venlafaxine developed expressive aphasia, confusion, and disinhibition following a methylene blue infusion. The authors concluded that methylene blue toxicity had occurred; however, they did not exclude the possibility of a drug interaction based upon previous reports of an interaction between injectable methylene blue and selective serotonin reuptake inhibitors (SSRIs). Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. If emergent treatment with methylene blue is required in a patient receiving an SNRI, the SNRI must be stopped immediately and the patient should be monitored for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, the SNRI should be stopped at least 2 weeks prior to methylene blue treatment, but also taking into consideration the half-life of the SNRI being discontinued.
    Methylphenidate Derivatives: (Moderate) Caution should be observed when coadministering methylphenidate derivatives and serotonin norepinephrine reuptake inhibitors (SNRIs). There are postmarketing reports of serotonin syndrome during concurrent use of methylphenidate derivatives with other serotonergic medications. There is also a case of a neuroleptic malignant syndrome-like reaction occurring in a child on chronic methylphenidate therapy after ingesting methylphenidate with an SNRI. It is unclear if the reaction was the result of a drug interaction. Monitor patients for the emergence of serotonin syndrome. If serotonin syndrome occurs, serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Metoclopramide: (Moderate) Concomitant use of metoclopramide and serotonin and norepinephrine reuptake inhibitors (SNRIs) may increase the risk for serotonin syndrome. Monitor patients for serotonin syndrome if concomitant use is necessary. In rare cases postmarketing, NMS-like symptoms, which may overlap with serotonin syndrome symptoms, have been reported with metoclopramide when used with serotonergic agents.
    Metoprolol: (Moderate) Monitor blood pressure and heart rate during concomitant metoprolol and venlafaxine use. Concomitant use may increase metoprolol exposure.
    Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure and heart rate during concomitant metoprolol and venlafaxine use. Concomitant use may increase metoprolol exposure.
    Metronidazole: (Moderate) Concomitant use of metronidazole and venlafaxine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Midostaurin: (Major) Concomitant use of venlafaxine and midostaurin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Mifepristone: (Major) Concomitant use of mifepristone and venlafaxine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Milnacipran: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, coadministration of venlafaxine and milnacipran should be avoided. Also, because both venlafaxine and milnacipran are serotonin norepinephrine reuptake inhibitors (SNRIs), coadministration is considered duplicative therapy. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SNRI to another SNRI.
    Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as venlafaxine may be increased when co-administered with mirabegron. Venlafaxine is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Mirtazapine: (Major) Concomitant use of mirtazapine and venlafaxine may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes. Both medications are associated with a possible risk of QT prolongation and torsade de pointes (TdP). Cases of serotonin syndrome have been reported between mirtazapine and other serotonin-enhancing antidepressants. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Mitotane: (Moderate) Use caution if mitotane and venlafaxine are used concomitantly, and monitor for decreased efficacy of venlafaxine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and venlafaxine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of venlafaxine.
    Mobocertinib: (Major) Concomitant use of mobocertinib and venlafaxine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Monoamine oxidase inhibitors: (Contraindicated) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with serotonin norepinephrine reuptake inhibitors (SNRIs). MAOIs should not be used within 5 days of discontinuing treatment with duloxetine or milnacipran or within 7 days of discontinuing treatment with other SNRIs. Conversely, SNRIs should not be initiated within 14 days of stopping an MAOI. Monitor the patient for serotonin-related effects during therapy transitions.
    Morphine: (Moderate) If concomitant use of morphine and serotonin norepinephrine reuptake inhibitors is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Morphine; Naltrexone: (Moderate) If concomitant use of morphine and serotonin norepinephrine reuptake inhibitors is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Moxifloxacin: (Major) Concomitant use of venlafaxine and moxifloxacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Nabumetone: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Nalbuphine: (Moderate) If concomitant use of nalbuphine and venlafaxine is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Naproxen: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Naproxen; Esomeprazole: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Naproxen; Pseudoephedrine: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Nefazodone: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as nefazodone. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Netupitant, Fosnetupitant; Palonosetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as venlafaxine. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Nilotinib: (Major) Avoid coadministration of nilotinib with venlafaxine due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of venlafaxine may also be increased resulting in increase in treatment-related adverse reactions. Nilotinib is a moderate CYP3A4 inhibitor; sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Venlafaxine is a CYP3A4 substrate that is also associated with a possible risk of QT prolongation; TdP has reported with postmarketing use. Concomitant use may increase the risk for QT prolongation.
    Nonsteroidal antiinflammatory drugs: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Nortriptyline: (Major) The combination of venlafaxine and tricyclic antidepressants may lead to serotonin syndrome and increased plasma concentrations of TCAs. Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Venlafaxine is an inhibitor of CYP2D6, and many TCAs are metabolized by this isozyme. One case report documented a first-time seizure in a patient receiving venlafaxine and trimipramine at therapeutic dosages.
    Octreotide: (Moderate) Use octreotide with caution in combination with venlafaxine. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of TdP, the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval.
    Ofloxacin: (Moderate) Concomitant use of ofloxacin and venlafaxine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Olanzapine: (Moderate) Venlafaxine is associated with a possible risk of QT prolongation. Atypical antipsychotics associated with a risk for QT prolongation and TdP that should be used cautiously with venlafaxine include olanzapine. In addition, venlafaxine is a weak inhibitor of CYP2D6. Atypical antipsychotics with partial metabolism via CYP2D6 include olanzapine. Monitor patients for potential adverse effects if these drugs are co-prescribed.
    Olanzapine; Fluoxetine: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, selective serotonin reuptake inhibitors (SSRIs) should generally not be administered with serotonin norepinephrine reuptake inhibitors like venlafaxine. If serotonin syndrome is suspected, all serotonergic agents should be discontinued. Also, both fluoxetine and venlafaxine have been associated with QT prolongation and torsade de pointes (TdP), which could theoretically result in additive effects on the QT interval. (Moderate) Venlafaxine is associated with a possible risk of QT prolongation. Atypical antipsychotics associated with a risk for QT prolongation and TdP that should be used cautiously with venlafaxine include olanzapine. In addition, venlafaxine is a weak inhibitor of CYP2D6. Atypical antipsychotics with partial metabolism via CYP2D6 include olanzapine. Monitor patients for potential adverse effects if these drugs are co-prescribed.
    Olanzapine; Samidorphan: (Moderate) Venlafaxine is associated with a possible risk of QT prolongation. Atypical antipsychotics associated with a risk for QT prolongation and TdP that should be used cautiously with venlafaxine include olanzapine. In addition, venlafaxine is a weak inhibitor of CYP2D6. Atypical antipsychotics with partial metabolism via CYP2D6 include olanzapine. Monitor patients for potential adverse effects if these drugs are co-prescribed.
    Oliceridine: (Moderate) If concomitant use of oliceridine and venlafaxine is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Ondansetron: (Major) Concomitant use of ondansetron and venlafaxine increases the risk of QT/QTc prolongation, torsade de pointes (TdP), and serotonin syndrome. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. If concomitant use is necessary, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, and monitor for serotonin syndrome.
    Oritavancin: (Moderate) Venlafaxine is metabolized by CYP3A4 and CYP2D6; oritavancin is a weak CYP3A4 and CYP2D6 inducer. Plasma concentrations and efficacy of venlafaxine may be reduced if these drugs are administered concurrently.
    Osilodrostat: (Moderate) Monitor ECGs in patients receiving osilodrostat with venlafaxine. Osilodrostat is associated with dose-dependent QT prolongation. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes has been reported with postmarketing use.
    Osimertinib: (Major) Concomitant use of venlafaxine and osimertinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Oxaliplatin: (Major) Concomitant use of venlafaxine and oxaliplatin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Oxaprozin: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Oxycodone: (Moderate) If concomitant use of oxycodone and serotonin norepinephrine reuptake inhibitors is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Oxymorphone: (Moderate) If concomitant use of oxymorphone and serotonin norepinephrine reuptake inhibitors is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Ozanimod: (Major) In general, do not initiate ozanimod in patients taking venlafaxine due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). Additionally, there is a potential for hypertensive crisis and serotonergic effects. If treatment initiation is considered, seek advice from a cardiologist and monitor for hypertension and serotonin-related adverse effects. An active metabolite of ozanimod inhibits MAO-B, which may increase the potential for hypertensive crisis. Ozanimod may also result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Venlafaxine increases serotonin and norepinephrine concentrations and is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Pacritinib: (Major) Concomitant use of pacritinib and venlafaxine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Paliperidone: (Major) Concomitant use of venlafaxine and paliperidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Palonosetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as venlafaxine. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Panobinostat: (Major) The co-administration of panobinostat with venlafaxine is not recommended; QT prolongation has been reported with both agents. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of venlafaxine toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and venlafaxine is a CYP2D6 substrate. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
    Paroxetine: (Moderate) Monitor patients for an increase in paroxetine-related adverse reactions and signs and symptoms of serotonin syndrome during concomitant use of paroxetine and venlafaxine, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and venlafaxine is a weak CYP2D6 inhibitor.
    Pasireotide: (Moderate) Use caution when using pasireotide in combination with venlafaxine as concurrent use may increase the risk of QT prolongation. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses. Venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has reported with post-marketing use.
    Pazopanib: (Major) Coadministration of pazopanib and other drugs that prolong the QT interval is not advised; pazopanib has been reported to prolong the QT interval. Venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has reported with post-marketing use. If pazopanib and venlafaxine must be continued, closely monitor the patient for QT interval prolongation. In addition, pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and venlafaxine, a CYP3A4 substrate, may cause an increase in systemic concentrations of venlafaxine. Use caution when concurrent administration is necessary.
    Peginterferon Alfa-2b: (Moderate) Monitor for adverse effects associated with increased exposure to venlafaxine if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP2D6 inhibitor, while venlafaxine is a CYP2D6 substrate.
    Pentamidine: (Major) Concomitant use of venlafaxine and pentamidine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Pentazocine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Pentazocine; Naloxone: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Pentosan: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and pentosan, which has weak anticoagulant properties. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Perphenazine: (Moderate) Caution is advisable during concurrent use of perphenazine and serotonin norepinephrine reuptake inhibitors (SNRIs) since elevations in plasma concentrations of perphenazine may occur. Phenothiazines are CYP2D6 substrates, and SNRIs including duloxetine and venlafaxine are CYP2D6 inhibitors. In addition, both venlafaxine and perphenazine are associated with a possible risk of QT prolongation; therefore, additive cardiac effects are possible. Although clinical studies have shown that desvenlafaxine does not have a clinically relevant effect on CYP2D6 inhibition at doses of 100 mg/day, the manufacturer recommends that doses of medications that are primary substrates of CYP2D6 be reduced by one-half during co-administration of desvenlafaxine doses of 400 mg/day.
    Perphenazine; Amitriptyline: (Major) The combination of venlafaxine and tricyclic antidepressants may lead to serotonin syndrome and increased plasma concentrations of TCAs. Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Venlafaxine is an inhibitor of CYP2D6, and many TCAs are metabolized by this isozyme. One case report documented a first-time seizure in a patient receiving venlafaxine and trimipramine at therapeutic dosages. (Moderate) Caution is advisable during concurrent use of perphenazine and serotonin norepinephrine reuptake inhibitors (SNRIs) since elevations in plasma concentrations of perphenazine may occur. Phenothiazines are CYP2D6 substrates, and SNRIs including duloxetine and venlafaxine are CYP2D6 inhibitors. In addition, both venlafaxine and perphenazine are associated with a possible risk of QT prolongation; therefore, additive cardiac effects are possible. Although clinical studies have shown that desvenlafaxine does not have a clinically relevant effect on CYP2D6 inhibition at doses of 100 mg/day, the manufacturer recommends that doses of medications that are primary substrates of CYP2D6 be reduced by one-half during co-administration of desvenlafaxine doses of 400 mg/day.
    Phentermine: (Moderate) Use phentermine and serotonin norepinephrine reuptake inhibitors (SNRIs) together with caution due to a potential for serotonin syndrome. Monitor weight, cardiovascular status, and for potential serotonergic adverse effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome when combined with serotonergic agents. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses and some large controlled clinical studies have allowed patients to start phentermine-based therapy for obesity along with their SNRI as long as the antidepressant dose had been stable for at least 3 months prior. Such therapy was generally well-tolerated, especially at lower phentermine doses. Because depression and obesity often coexist, the study data may be important to providing optimal co-therapies.
    Phentermine; Topiramate: (Moderate) Use phentermine and serotonin norepinephrine reuptake inhibitors (SNRIs) together with caution due to a potential for serotonin syndrome. Monitor weight, cardiovascular status, and for potential serotonergic adverse effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome when combined with serotonergic agents. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses and some large controlled clinical studies have allowed patients to start phentermine-based therapy for obesity along with their SNRI as long as the antidepressant dose had been stable for at least 3 months prior. Such therapy was generally well-tolerated, especially at lower phentermine doses. Because depression and obesity often coexist, the study data may be important to providing optimal co-therapies.
    Pimavanserin: (Major) Concomitant use of venlafaxine and pimavanserin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Pimozide: (Contraindicated) Avoid concomitant use of venlafaxine and pimozide due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Piroxicam: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Pitolisant: (Major) Concomitant use of venlafaxine and pitolisant increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Ponesimod: (Major) In general, do not initiate ponesimod in patients taking venlafaxine due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Venlafaxine is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Posaconazole: (Contraindicated) Concurrent use of posaconazole and venlafaxine is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of venlafaxine. These drugs used in combination may result in elevated venlafaxine plasma concentrations, causing an increased risk for venlafaxine-related adverse events, such as QT prolongation. Additionally, posaconazole has been associated with prolongation of the QT interval as well as rare cases of TdP; avoid use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as venlafaxine.
    Prasugrel: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with a platelet inhibitor and to promptly report any bleeding events to the practitioner.
    Primaquine: (Moderate) Exercise caution when administering primaquine in combination with venlafaxine as concurrent use may increase the risk of QT prolongation. Primaquine is associated with QT prolongation. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Procainamide: (Major) Concomitant use of venlafaxine and procainamide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Procarbazine: (Major) Concurrent use of procarbazine and serotonin norepinephrine reuptake inhibitors (SNRIs) should be avoided if possible. Procarbazine is a weak monoamine oxidase inhibitor (MAOI). Since monoamine oxidase type A deaminates serotonin, administration of a non-selective MAO inhibitor concurrently with an SNRI can lead to serious reactions including serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If combination therapy is necessary, patients should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Prochlorperazine: (Moderate) Caution is advisable during concurrent use of prochlorperazine and serotonin norepinephrine reuptake inhibitors (SNRIs) since elevations in plasma concentrations of prochlorperazine may occur. Phenothiazines are CYP2D6 substrates, and SNRIs including duloxetine and venlafaxine are CYP2D6 inhibitors. In addition, both venlafaxine and prochlorperazine are associated with a possible risk of QT prolongation; therefore, additive cardiac effects are possible. Although clinical studies have shown that desvenlafaxine does not have a clinically relevant effect on CYP2D6 inhibition at doses of 100 mg/day, the manufacturer recommends that doses of medications that are primary substrates of CYP2D6 be reduced by one-half during co-administration of desvenlafaxine doses of 400 mg/day.
    Promethazine: (Moderate) Concomitant use of promethazine and venlafaxine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Promethazine; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with venlafaxine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated. (Moderate) Concomitant use of promethazine and venlafaxine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Promethazine; Phenylephrine: (Moderate) Concomitant use of promethazine and venlafaxine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Propafenone: (Major) Concomitant use of propafenone and venlafaxine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Protriptyline: (Major) The combination of venlafaxine and tricyclic antidepressants may lead to serotonin syndrome and increased plasma concentrations of TCAs. Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Venlafaxine is an inhibitor of CYP2D6, and many TCAs are metabolized by this isozyme. One case report documented a first-time seizure in a patient receiving venlafaxine and trimipramine at therapeutic dosages.
    Quetiapine: (Major) Avoid coadministration of venlafaxine and quetiapine due to the potential for QT prolongation. Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Quinidine: (Contraindicated) Quinidine administration is associated with QT prolongation and torsades de pointes (TdP). Quinidine inhibits CYP2D6 and has QT-prolonging actions; quinidine is contraindicated with other drugs that prolong the QT interval and are metabolized by CYP2D6 as the effects on the QT interval may be increased during concurrent use of these agents. Drugs that prolong the QT and are substrates for CYP2D6 that are contraindicated with quinidine includes venlafaxine.
    Quinine: (Moderate) Quinine inhibits CYP2D6 and may theoretically increase concentrations of other drugs metabolized by this enzyme. Caution is recommended when administering quinine with other CYP2D6 substrates that have a narrow therapeutic range or where large increases in serum concentrations may be associated with severe adverse reactions, such as venlafaxine.
    Ranolazine: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include venlafaxine. In addition, ranolazine and/or metabolites are moderate inhibitors of CYP2D6 isoenzymes. Based on drug interaction studies with metoprolol, a CYP2D6 substrate, ranolazine may theoretically increase plasma concentrations of CYP2D6 substrates, such as venlafaxine, and could lead to toxicity for drugs that have a narrow therapeutic range.
    Rasagiline: (Major) It is recommended to avoid concurrent use of rasagiline and antidepressants, including serotonin norepinephrine reuptake inhibitors (SNRIs). Severe CNS toxicity with hyperpyrexia has been reported during concurrent use of antidepressants and selective or non-selective MAOIs. During post-marketing use of rasagiline, non-fatal cases of serotonin syndrome have been reported during concomitant antidepressant administration. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. At least 2 weeks should elapse between stopping rasagiline treatment and beginning therapy with any antidepressant. Conversely, when discontinuing the antidepressant, it is advisable to wait the length of 4 to 5 half lives of the individual agent being discontinued prior to initiation with rasagiline.
    Relugolix: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving other QT prolonging agents. Androgen deprivation therapy (i.e., relugolix) may prolong the QT/QTc interval. Venlafaxine administration is also associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Relugolix; Estradiol; Norethindrone acetate: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving other QT prolonging agents. Androgen deprivation therapy (i.e., relugolix) may prolong the QT/QTc interval. Venlafaxine administration is also associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Remifentanil: (Moderate) If concomitant use of remifentanil and serotonin norepinephrine reuptake inhibitors is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Ribociclib: (Major) Avoid coadministration of ribociclib with venlafaxine due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of venlafaxine may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Venlafaxine is a CYP3A4 substrate that is also associated with a possible risk of QT prolongation; TdP has reported with postmarketing use. Concomitant use may increase the risk for QT prolongation.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with venlafaxine due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of venlafaxine may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Venlafaxine is a CYP3A4 substrate that is also associated with a possible risk of QT prolongation; TdP has reported with postmarketing use. Concomitant use may increase the risk for QT prolongation.
    Rilpivirine: (Moderate) Caution is advised when administering rilpivirine with venlafaxine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Venlafaxine administration is also associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Risperidone: (Moderate) Use risperidone and venlafaxine together with caution due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Risperidone has been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with postmarketing use.
    Rivaroxaban: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like rivaroxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Rolapitant: (Major) Use caution if venlafaxine and rolapitant are used concurrently, and monitor for venlafaxine-related adverse effects. Venlafaxine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Romidepsin: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with venlafaxine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has been reported with postmarketing use.
    Safinamide: (Contraindicated) Safinamide is contraindicated for use with serotonin norepinephrine reuptake inhibitors (SNRIs) due to the risk of serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. At least 14 days should elapse between the discontinuation of safinamide and the initiation of an SNRI.
    Salicylates: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Salsalate: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Saquinavir: (Major) Concurrent use of venlafaxine and saquinavir should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Venlafaxine is also associated with a possible risk of QT prolongation; TdP has been reported with post-marketing use.
    Selegiline: (Contraindicated) Serotonin norepinephrine reuptake inhibitors (SNRIs) are contraindicated for use with selegiline, a selective monoamine oxidase type B inhibitor (MAO-B inhibitor). At least 14 days should elapse between discontinuation of selegiline and initiation of treatment with an SNRI. After stopping treatment with an SNRI, a time period equal to 4 to 5 half-lives of the SNRI or any active metabolite should elapse before starting therapy with selegiline. Serotonin syndrome has occurred in patients receiving selective MAO-B inhibitors and serotonin-augmenting antidepressants simultaneously. Monitor for serotonergic side effects during therapy transitions.
    Selpercatinib: (Major) Concomitant use of venlafaxine and selpercatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Serotonin-Receptor Agonists: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant venlafaxine and serotonin-receptor agonist use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
    Sertraline: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, selective serotonin reuptake inhibitors (SSRIs) should generally not be administered with serotonin norepinephrine reuptake inhibitors like venlafaxine. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued. Also, both sertraline and venlafaxine have been associated with QT prolongation, which could theoretically result in additive effects on the QT interval.
    Sibutramine: (Major) Sibutramine is a serotonin reuptake inhibitor. Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering sibutramine with other drugs that have serotonergic properties such as serotonin norepinephrine reuptake inhibitors (SNRIs). Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving sibutramine in combination with an SNRI should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Siponimod: (Major) Concomitant use of venlafaxine and siponimod increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Sodium Stibogluconate: (Moderate) Concomitant use of sodium stibogluconate and venlafaxine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Solifenacin: (Moderate) Solifenacin has been associated dose-dependent prolongation of the QT interval. Torsades de pointes (TdP) has been reported with post-marketing use, although causality was not determined. This should be taken into consideration when prescribing solifenacin to patients taking other drugs that are associated with QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with solifenacin include venlafaxine.
    Solriamfetol: (Moderate) Monitor blood pressure and heart rate during coadministration of solriamfetol, a norepinephrine and dopamine reuptake inhibitor, and antidepressants that are serotonin norepinephrine reuptake inhibitors. Concurrent use of solriamfetol and other medications that increase blood pressure and/or heart rate may increase the risk of such effects. Coadministration of solriamfetol with other drugs that increase blood pressure or heart rate has not been evaluated.
    Sorafenib: (Major) Concomitant use of venlafaxine and sorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Sotalol: (Major) Concomitant use of sotalol and venlafaxine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    St. John's Wort, Hypericum perforatum: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering St. John's wort and serotonin norepinephrine reuptake inhibitors (SNRIs). Inform the patient of the increased risk and monitor for the emergence of serotonin syndrome, particularly at treatment initiation or with dose increases. If serotonin syndrome occurs, serotonergic agents should be discontinued and appropriate medical treatment should be initiated.
    Sufentanil: (Moderate) If concomitant use of sufentanil and venlafaxine is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Sulindac: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Sumatriptan; Naproxen: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Sunitinib: (Moderate) Monitor for evidence of QT prolongation if sunitinib is administered with venlafaxine. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use. Sunitinib can prolong the QT interval.
    Tacrolimus: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with venlafaxine. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has been reported with postmarketing use.
    Tamoxifen: (Moderate) Concomitant use of tamoxifen and venlafaxine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Tapentadol: (Moderate) If concomitant use of tapentadol and serotonin norepinephrine reuptake inhibitors is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Tedizolid: (Minor) Use caution with the concurrent use of tedizolid and serotonin norepinephrine reuptake inhibitors (SNRIs) due to the theoretical risk of serotonin sydrome. Animal studies did not predict serotonergic effects; however, patients on concurrent SNRIs were excluded from clinical trials. Additionally, tedizolid is an antibiotic that is also a weak reversible, non-selective MAO inhibitor and monoamine oxidase type A deaminates serotonin; therefore, coadministration theoretically could lead to serious reactions including serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Telavancin: (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering telavancin with venlafaxine. Telavancin has been associated with QT prolongation. Venlafaxine is associated with a possible risk of QT prolongation and TdP has been reported with post-marketing use.
    Telithromycin: (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering telithromycin with venlafaxine. Telithromycin is associated with QT prolongation and TdP. Venlafaxine is also associated with a possible risk of QT prolongation; TdP has reported with post-marketing use.
    Terbinafine: (Moderate) In vitro studies have shown systemic terbinafine to inhibit hepatic isoenzyme CYP2D6, and thus may inhibit the clearance of drugs metabolized by this isoenzyme, such as venlafaxine.
    Tetrabenazine: (Major) Concomitant use of venlafaxine and tetrabenazine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Thiethylperazine: (Moderate) Venlafaxine is an inhibitor of CYP2D6, and concurrent use with CYP2D6 substrates, such as the phenothiazines, may result in increased plasma concentrations, and potential increased risk for phenothiazine-related side effects.
    Thioridazine: (Contraindicated) Venlafaxine is contraindicated for use with thioridazine. Venlafaxine is associated with a possible risk of QT prolongation. Thioridazine has an established risk of QT prolongation and torsades de pointes (TdP). In addition, venlafaxine impairs the activity of CYP2D6, and the use of thioridazine concomitantly with CYP2D6 inhibitors is contraindicated due to the theoretical risk of prolongation of QTc interval and subsequent arrhythmias due to elevated serum concentrations of thioridazine.
    Thrombolytic Agents: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered concurrently with venlafaxine.
    Ticagrelor: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with a platelet inhibitor and to promptly report any bleeding events to the practitioner.
    Ticlopidine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with a platelet inhibitor and to promptly report any bleeding events to the practitioner.
    Tirofiban: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with a platelet inhibitor and to promptly report any bleeding events to the practitioner.
    Tolmetin: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Tolterodine: (Moderate) Venlafaxine may inhibit the CYP2D6 metabolism of tolterodine in extensive metabolizers. In addition, tolterodine is associated with dose-dependent prolongation of the QT interval, especially in poor metabolizers of CYP2D6. Venlafaxine is also associated with QT prolongation. Use tolterodine and venlafaxine concomitantly with caution.
    Toremifene: (Major) Concomitant use of venlafaxine and toremifene increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Tramadol: (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with venlafaxine is necessary. If venlafaxine is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and venlafaxine is a CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Tramadol; Acetaminophen: (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with venlafaxine is necessary. If venlafaxine is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and venlafaxine is a CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Trazodone: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of trazodone and venlafaxine is necessary. Both drugs may cause QT interval prolongation and a risk for torsade de pointes (TdP). In addition, concurrent use of trazodone with other drugs that modulate serotonergic function, such as venlafaxine, has resulted in serotonin syndrome in some cases. Patients should be carefully observed, particularly during treatment initiation and during dose adjustments. Discontinue the serotonergic medications if serotonin syndrome is suspected.
    Triclabendazole: (Moderate) Concomitant use of triclabendazole and venlafaxine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Tricyclic antidepressants: (Major) The combination of venlafaxine and tricyclic antidepressants may lead to serotonin syndrome and increased plasma concentrations of TCAs. Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Venlafaxine is an inhibitor of CYP2D6, and many TCAs are metabolized by this isozyme. One case report documented a first-time seizure in a patient receiving venlafaxine and trimipramine at therapeutic dosages.
    Trifluoperazine: (Moderate) Caution is advisable during concurrent use of trifluoperazine and serotonin norepinephrine reuptake inhibitors (SNRIs) since elevations in plasma concentrations of trifluoperazine may occur. Phenothiazines are CYP2D6 substrates, and SNRIs including duloxetine and venlafaxine are CYP2D6 inhibitors. In addition, both venlafaxine and trifluoperazine are associated with a possible risk of QT prolongation; therefore, additive cardiac effects are possible. Although clinical studies have shown that desvenlafaxine does not have a clinically relevant effect on CYP2D6 inhibition at doses of 100 mg/day, the manufacturer recommends that doses of medications that are primary substrates of CYP2D6 be reduced by one-half during co-administration of desvenlafaxine doses of 400 mg/day.
    Trimipramine: (Major) The combination of venlafaxine and tricyclic antidepressants may lead to serotonin syndrome and increased plasma concentrations of TCAs. Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Venlafaxine is an inhibitor of CYP2D6, and many TCAs are metabolized by this isozyme. One case report documented a first-time seizure in a patient receiving venlafaxine and trimipramine at therapeutic dosages.
    Triptorelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., triptorelin) outweigh the potential risks of QT prolongation in patients receiving venlafaxine. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use. Androgen deprivation therapy (i.e., triptorelin) may also prolong the QT/QTc interval.
    Tryptophan, 5-Hydroxytryptophan: (Major) The manufacturer of venlafaxine recommends against concurrent use with tryptophan when possible. Since tryptophan is converted to serotonin (5-hydroxytryptamine), the use of tryptophan in patients receiving venlafaxine could lead to serotonin excess and serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Valdecoxib: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Valerian, Valeriana officinalis: (Moderate) The German Commission E and other groups warn that any substances that act on the CNS, including psychopharmacologic agents like venlafaxine, may interact with the phytomedicinal valerian, Valeriana officinalis. These interactions are probably pharmacodynamic in nature, or result from additive mechanisms of action.
    Vandetanib: (Major) Concomitant use of venlafaxine and vandetanib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Vardenafil: (Moderate) Concomitant use of vardenafil and venlafaxine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Vemurafenib: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as venlafaxine, that is associated with a possible risk for QT prolongation and torsade de pointes must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, venlafaxine is a substrate of CYP2D6 and 3A4, while vemurafenib is a weak CYP2D6 inhibitor and CYP3A4 substrate/inducer. Therefore, altered concentrations of venlafaxine may occur. Monitor the patient for toxicity and efficacy.
    Vilazodone: (Major) Due to possible additive effects on serotonin concentrations, it is advisable to avoid combining serotonin norepinephrine reuptake inhibitors (SNRIs) with vilazodone. Interactions between vilazodone and serotonergic agents can lead to serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Patients receiving vilazodone and an SNRI should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. Vilazodone and the SNRI should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Viloxazine: (Moderate) Monitor for an increase in venlafaxine-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase venlafaxine exposure; viloxazine is a weak CYP2D6 inhibitor and venlafaxine is a CYP2D6 substrate. Since both drugs may increase blood pressure via blocking of norepinephrine reuptake, blood pressure and heart rate should be monitored periodically.
    Voclosporin: (Moderate) Concomitant use of voclosporin and venlafaxine may increase the risk of QT prolongation. Consider interventions to minimize the risk of progression to torsades de pointes (TdP), such as ECG monitoring and correcting electrolyte abnormalities, particularly in patients with additional risk factors for TdP. Voclosporin has been associated with QT prolongation at supratherapeutic doses. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Vonoprazan; Amoxicillin; Clarithromycin: (Major) Concomitant use of venlafaxine and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Vorapaxar: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with a platelet inhibitor and to promptly report any bleeding events to the practitioner.
    Voriconazole: (Major) Caution is advised when administering voriconazole with venlafaxine due to the potential for additive effects on the QT interval and increased exposure to venlafaxine. Both drugs are associated with QT prolongation; coadministration may increase this risk. Voriconazole has also been associated with rare cases of torsades de pointes, cardiac arrest, and sudden death. In addition, venlafaxine is a substrate of CYP2D6 (major) and CYP3A4 (minor). In patients who are poor CYP2D6 metabolizers, the CYP3A4 pathway for venlafaxine may become more important. Administration of venlafaxine and voriconazole (a strong CYP3A4 inhibitor) to patients identified as CYP2D6 poor metabolizers may significantly increase venlafaxine plasma concentrations. If these drugs are given together, closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
    Vorinostat: (Moderate) Venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has been reported with post-marketing use. Vorinostat therapy is associated with a risk of QT prolongation. Vorinostat should be used with caution if given with other agents that may prolong the QT interval including venlafaxine.
    Vortioxetine: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, vortioxetine should generally not be administered with serotonin norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine, desvenlafaxine, duloxetine, and milnacipran. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, vortioxetine and concurrent serotonergic agents should be discontinued.
    Warfarin: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of venlafaxine and warfarin. Carefully monitor patients receiving warfarin therapy, including coagulation parameters such as the INR and/or prothrombin time, if venlafaxine is initiated or discontinued. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Ziprasidone: (Major) Concomitant use of ziprasidone and venlafaxine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Zolpidem: (Moderate) Disorientation, delusions, or hallucinations have been reported rarely during co-administration of zolpidem and antidepressants. The duration of the visual hallucinations has ranged from 30 minutes to 7 hours. The interaction is thought to be pharmacodynamic in nature; therefore, a similar reaction is possible with venlafaxine. Data from a clinical study in which SSRI-treated patients were given immediate-release zolpidem revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n = 95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction.

    PREGNANCY AND LACTATION

    Pregnancy

    Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue venlafaxine. Venlafaxine and its active metabolite, desvenlafaxine (O-desmethylvenlafaxine), are both excreted in human breast milk. Data describing the clinical effects of infant exposure after maternal venlafaxine administration are not available. Several small case series have described infants who were breastfed by mothers taking venlafaxine. The majority of infants had measurable desvenlafaxine plasma concentrations. The estimated mean relative infant doses in these studies were 6.4% to 8.1% based on the sum of venlafaxine and desvenlafaxine. Consider if treatment alternatives are appropriate. Due to individual variability in response to antidepressants, it may be prudent to continue the existing regimen if ongoing treatment is deemed necessary during breast-feeding. However, because a pooled analysis found that maternal use of sertraline, along with nortriptyline and paroxetine, usually produced undetectable or low drug concentrations in infant serum, these agents may be the preferred antidepressants when initiating antidepressant therapy in a breast-feeding mother. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition.

    MECHANISM OF ACTION

    Venlafaxine is a serotonin norepinephrine reuptake inhibitor (SNRI), and along with its active metabolite O-desmethylvenlafaxine (ODV), is thought to exert its therapeutic effects in part by inhibiting the central reuptake of serotonin and norepinephrine. Because of the delay in therapeutic response, it is theorized that long-term neurotransmitter receptor modulation is an important mechanism of effect. Venlafaxine has a 30-fold higher affinity for the reuptake inhibition of serotonin compared to norepinephrine, which is the highest serotonin to norepinephrine affinity ratio of all of the SNRIs. Both venlafaxine and ODV have weak inhibitory effects on the central reuptake of dopamine. All SNRIs inhibit serotonin uptake in human platelets, which has been associated with an increased risk of bleeding events. In addition, SNRIs can increase blood pressure and heart rate; cases of elevated blood pressure requiring immediate treatment have been reported. Venlafaxine and ODV do not have significant affinity for histaminergic, muscarinic, or alpha-1 adrenergic receptors and do not inhibit monoamine oxidase. However, despite in vitro evidence suggesting insignificant muscarinic receptor affinity, anticholinergic-related side effects have been observed with the use of venlafaxine.

    PHARMACOKINETICS

    Venlafaxine is administered orally. Protein binding is approximately 27% for venlafaxine and 30% for the active metabolite O-desmethylvenlafaxine (ODV). Both venlafaxine and ODV are excreted into human breastmilk. Venlafaxine is well absorbed and extensively metabolized in the liver. Venlafaxine is a substrate of CYP2D6 (major) and O-desmethylvenlafaxine (ODV) is the major active metabolite. Venlafaxine is likely metabolized to a minor, less active metabolite by CYP3A4, but the metabolite is not clinically significant. Elimination occurs primarily via the urine as unchanged drug, conjugated ODV, ODV, and inactive metabolites. The elimination half-lives of venlafaxine and ODV are 5 and 11 hours, respectively.
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP2D6, CYP3A4
    Venlafaxine is a weak inhibitor of CYP2D6 in vivo. Venlafaxine does not appear to inhibit other CYP isoenzymes, including CYP3A4, CYP2C9, CYP2C19 or CYP1A2, based on in vitro studies. Because venlafaxine is primarily metabolized by CYP2D6, drugs that inhibit CYP2D6 may result in elevated venlafaxine plasma concentrations, particularly in patients who are CYP2D6 poor metabolizers (PMs). A drug that inhibits CYP3A4 alone is unlikely to cause clinically significant drug interactions, as this is a minor metabolic route for venlafaxine. Drugs that potently inhibit both CYP2D6 and CYP3A4 may increase the risk of venlafaxine toxicity.

    Oral Route

    Venlafaxine is well absorbed (at least 92% after a single dose) from the gastrointestinal tract, with food having no significant effect on its absorption. The absolute bioavailability of venlafaxine is approximately 45%. After administration of an immediate-release tablet, time to peak serum concentration occurs at approximately 2 and 3 hours for venlafaxine and O-desmethylvenlafaxine (ODV), respectively; administration of the extended-release capsule results in later times to peak serum concentration (5.5 hours for venlafaxine and 9 hours for ODV). The extended-release capsule provides a slower rate of absorption, but the same extent of absorption as the immediate-release tablet; however, the exposure to both venlafaxine and ODV is similar for the two treatments. After multiple-dose therapy with the immediate-release formulation, steady-state concentrations of both venlafaxine and ODV in plasma were attained within 3 days.