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    Serotonin Norepinephrine Reuptake Inhibitor Antidepressants, SNRIs

    BOXED WARNING

    Children, growth inhibition, suicidal ideation

    Venlafaxine is not FDA approved for the treatment of depression in children. In October 2004, the FDA directed manufacturers of all antidepressants to include a boxed warning detailing the risk of suicide in pediatric patients. A causal role has been established for antidepressants in inducing suicidality in pediatric patients. The risk of suicidality for these drugs was identified in a pooled analysis of 24 placebo-controlled trials (n = 4,400) lasting up to 16 weeks in pediatric patients with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. The analysis showed a greater risk of suicidality during the first few months of treatment in those receiving antidepressants (SSRIs and others). The average risk of such events on drug was 4% and 2% for placebo; however, no suicides occurred in these trials. Pooled analysis of short-term clinical trials during early phase treatment of SSRIs and other antidepressants in young adults (18 to 24 years) also showed an increased risk of suicidal thinking and behavior. The clinical need for an antidepressant in children or young adults for any use must be weighed against the risk of increased suicidality; patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior, particularly within the first few months of starting therapy or at the time of dose increase or decrease; such observation would generally include at least weekly face-to-face contact with patients during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks; additional contact by telephone may be appropriate between visits. It is unknown if the suicidality risk in children and young adults extends to longer-term therapy (i.e., beyond several months). The possibility of a suicide attempt is inherent in all patients with depressive symptoms, whether these occur in primary depression or in association with another primary disorder such as OCD. All patients with a history of suicidal ideation or behaviors and those with a prominence of suicidal ideation prior to treatment are considered at an increased risk for suicidal ideation or attempts, and should be closely monitored during treatment with venlafaxine. Post-marketing data suggest that overdose with venlafaxine may result in more serious outcomes (i.e., fatalities) compared to selective serotonin reuptake inhibitors (SSRIs), but less than for tricyclic antidepressants (TCAs). Most reports of overdose have included ingestion of a combination of drugs, including alcohol. In patients who exhibit changes in symptoms, worsening of depression or emergent suicidality, a decision should be made to change or discontinue treatment. If discontinuing, medication should be tapered as rapidly as possible, but with recognition that abrupt discontinuation can also cause adverse symptoms. All antidepressants should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. 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 antidepressant closely related to SSRIs pharmacologically but not structurally; inhibits serotonin reuptake but also inhibits NE reuptake slightly; shares a drug interaction, ADR, and indication profile similar to the pure SSRIs; used for depression, generalized anxiety (GAD), panic disorder, and social anxiety disorder.

    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 Hydrochloride Oral Tab ER: 37.5mg, 75mg, 150mg, 225mg

    DOSAGE & INDICATIONS

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

    Initially, 75 mg/day PO given in 2 or 3 divided doses. If needed, the daily dose may be increased by 75 mg/day PO at intervals no less than every 4 days. Recommended Outpatient Max: 225 mg/day PO, in divided doses. In outpatient settings there was no evidence of usefulness of doses greater than 225 mg/day for moderately depressed patients, but more severely depressed inpatients responded to a mean dose of 350 mg/day (range 150 to 375 mg per day). Institutional Max: 375 mg/day PO, given in 3 divided doses.

    Oral dosage (extended-release products, e.g., Effexor 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. Recommended Max: 225 mg/day PO (outpatients). More severely depressed inpatients in one study of the development program for the immediate-release product responded to a mean dose of 350 mg/day (range of 150 to 375 mg per day). Whether or not higher doses of venlafaxine XR are needed for more severely depressed patients is unknown; however, the experience with venlafaxine XR doses higher than 225 mg/day is very limited.

    Children† and Adolescents† 7 years and older

    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 with have been conducted with venlafaxine XR, and the data were not sufficient to support a claim for use in pediatric patients. Dosage was initiated at 37.5 mg PO once daily, followed by titration to maximum doses based on weight, up to a maximum dose in patients 50 kg or more of 225 mg/day PO. In general, the adverse reaction profile in children and adolescents was similar to that seen for adults. Suicidal ideation was observed.

    For the treatment of generalized anxiety disorder (GAD).
    Oral dosage (extended-release products, e.g., Effexor 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. Max: 225 mg PO once daily. 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. Finally, for patients 50 kg or more, the maximum dosage for titration was 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. As with other antidepressants, 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, followed by 75 mg PO once daily for 3 days before increasing to 150 mg PO once daily is a suggested dose regimen. American Academy of Neurology and American Headache Society clinical practice guidelines classify venlafaxine as probably effective for migraine prophylaxis.

    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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Mild to moderate hepatic impairment (Child-Pugh Class A and B, score 5 to 9): The total daily dose should be reduced by 50%.
    Severe hepatic impairment or hepatic cirrhosis (Child-Pugh Class C, score 10 to 15): 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.

    Renal Impairment

    Because patients with renal impairment show considerable individual variability in clearance, doses should be individualized.
    Mild to moderate renal impairment (CrCl 30 to 89 mL/minute): Reduce total daily dose by 25% to 50%.
    Severe renal impairment (CrCl less than 30 mL/minute): Reduce total daily dose by 50% or more.
     
    Intermittent Hemodialysis
    Reduce total daily dose by 50% or more; doses should be individualized.

    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. 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:
    - Avoid excessive humidity
    - Protect from moisture
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Effexor:
    - Protect from light
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Effexor XR:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Venlafaxine:
    - Avoid excessive humidity
    - Protect from moisture
    - Store at 77 degrees F; excursions permitted to 59-86 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

    Avoid abrupt discontinuation of venlafaxine if possible. Advise patients not to stop taking venlafaxine without talking first with their healthcare professional. Patients should be aware that discontinuation effects may occur if the drug is abruptly discontinued. When discontinuing venlafaxine, it is generally recommended that the dose be tapered to minimize the risk of discontinuation symptoms. Individualization of tapering may be necessary. If intolerable symptoms occur following a decrease in the dose or upon discontinuation the physician may continue decreasing the dose but at a more gradual rate. Withdrawal symptoms have been reported with abrupt discontinuation or tapering with SNRIs have included abnormal dreams, headache, insomnia, dizziness, nausea/vomiting, paresthesia, irritability, fatigue, diarrhea, anxiety, vertigo, hyperhidrosis, and a small increase in recumbent heart rate. More severe symptoms such as confusion, hypomanic episode, and seizures have also been reported following discontinuation of other SNRIs and similar medications. Patients should be carefully monitored if abrupt discontinuation of venlafaxine becomes necessary. If the decision has been made to discontinue treatment more emergently, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms.

    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

    Venlafaxine is not FDA approved for the treatment of depression in children. In October 2004, the FDA directed manufacturers of all antidepressants to include a boxed warning detailing the risk of suicide in pediatric patients. A causal role has been established for antidepressants in inducing suicidality in pediatric patients. The risk of suicidality for these drugs was identified in a pooled analysis of 24 placebo-controlled trials (n = 4,400) lasting up to 16 weeks in pediatric patients with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. The analysis showed a greater risk of suicidality during the first few months of treatment in those receiving antidepressants (SSRIs and others). The average risk of such events on drug was 4% and 2% for placebo; however, no suicides occurred in these trials. Pooled analysis of short-term clinical trials during early phase treatment of SSRIs and other antidepressants in young adults (18 to 24 years) also showed an increased risk of suicidal thinking and behavior. The clinical need for an antidepressant in children or young adults for any use must be weighed against the risk of increased suicidality; patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior, particularly within the first few months of starting therapy or at the time of dose increase or decrease; such observation would generally include at least weekly face-to-face contact with patients during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks; additional contact by telephone may be appropriate between visits. It is unknown if the suicidality risk in children and young adults extends to longer-term therapy (i.e., beyond several months). The possibility of a suicide attempt is inherent in all patients with depressive symptoms, whether these occur in primary depression or in association with another primary disorder such as OCD. All patients with a history of suicidal ideation or behaviors and those with a prominence of suicidal ideation prior to treatment are considered at an increased risk for suicidal ideation or attempts, and should be closely monitored during treatment with venlafaxine. Post-marketing data suggest that overdose with venlafaxine may result in more serious outcomes (i.e., fatalities) compared to selective serotonin reuptake inhibitors (SSRIs), but less than for tricyclic antidepressants (TCAs). Most reports of overdose have included ingestion of a combination of drugs, including alcohol. In patients who exhibit changes in symptoms, worsening of depression or emergent suicidality, a decision should be made to change or discontinue treatment. If discontinuing, medication should be tapered as rapidly as possible, but with recognition that abrupt discontinuation can also cause adverse symptoms. All antidepressants should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. 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.

    Alcoholism, bradycardia, cardiac arrhythmias, cardiac disease, cerebrovascular disease, coronary artery disease, diabetes mellitus, females, heart failure, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, long QT syndrome, malnutrition, myocardial infarction, QT prolongation, thyroid disease

    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. Statistically significant and dose-dependent increases in heart rate have been observed on electrocardioagrams (ECGs) during venlafaxine therapy. Doses ranging 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 msec) in QTc have been noted in clinical trials; however, the incidence of trial-emergent conduction abnormalities has not differed from placebo. Use venlafaxine with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, elderly patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic impairment may also be at increased risk for QT prolongation.

    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 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.

    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.

    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

    A clinical study has shown that venlafaxine does not increase the impairment of mental and motor skills caused by ethanol. However, as with all central nervous system (CNS)-active drugs, patients should be advised to avoid ethanol ingestion while taking venlafaxine. 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.

    Neonates, pregnancy

    There are no adequate and well-controlled studies regarding use of venlafaxine during human pregnancy. Venlafaxine should be used in pregnancy only where the benefit to the mother clearly outweighs any potential risk to the fetus. Alternative agents should be considered. Animal studies (rats, rabbits) have failed to show an increased risk of fetal malformations. However, an increase in stillbirths, low birth-weight, and pup deaths postnatally has been noted when venlafaxine was given throughout gestation and continued during lactation in rats. These effects occurred at 2.5 times (mg/m2) the maximum human daily dose. The no effect dose for rat pup mortality was 0.25 times the human dose on a mg/m2 basis. Animal studies may not be predictive of human response. Non-teratogenic effects have been reported in humans. If the clinician and patient decide to continue venlafaxine during pregnancy, 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. Features are consistent with either a direct toxic effect of serotonergic agents or, possibly, a neonatal abstinence syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome. When treating a pregnant woman with an SNRI or other serotonergic agent during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. 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. Pregnant women using antidepressants are encouraged to register. For more information, contact the registry at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry or by phone 1-866-961-2388. The effects of venlafaxine on labor and delivery are unknown.

    Breast-feeding

    According to the manufacturer, 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 breast-fed by mothers taking venlafaxine. The majority of infants had measurable desvenlafaxine (active metabolite of venlafaxine) plasma concentrations. 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. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA

    Geriatric

    No differences in response or safety between geriatric patients and younger adults was demonstrated in preclinical trials of venlafaxine; however, greater sensitivity of older individuals to venlafaxine cannot be ruled out. No dose adjustment is recommended solely on the basis of 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 of venlafaxine. 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. According to the Beers Criteria, serotonin norepinephrine reuptake inhibitors (SNRIs) are considered potentially inappropriate medications (PIMs) in older adults and should be used cautiously because 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. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of antidepressants in residents of long-term care facilities. According to OBRA, the duration of therapy should be in accordance with pertinent literature for the condition being treated, including clinical practice guidelines. All residents being treated for depression with any antidepressant should be monitored closely for worsening of depression and/or suicidal behavior or thinking, especially during initiation of therapy and during dose changes. Antidepressants may cause dizziness, nausea, diarrhea, anxiety, nervousness, insomnia, somnolence, weight gain, anorexia, or increased appetite. Many of these effects can increase the risk for falls. Prior to discontinuation, many antidepressants may need a taper to avoid a withdrawal syndrome. Concurrent use of two or more antidepressants may increase the risk of side effects; in such cases there should be documentation of expected benefits that outweigh the associated risks and monitoring for any increase in side effects. Monitoring should consist of a review for continued need at least quarterly, and documentation of 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.

    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 / 0.3-0.3
    muscle paralysis / Delayed / 0-0.1
    Guillain-Barre syndrome / Delayed / 0-0.1
    torticollis / Delayed / 0-0.1
    akinesia / Delayed / 0-0.1
    stroke / Early / 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
    laryngeal edema / Rapid / 0-0.1
    apnea / Delayed / 0-0.1
    oliguria / Early / 0-0.1
    anuria / Delayed / 0-0.1
    fetal abortion / Delayed / 0-0.1
    hyperkalemia / Delayed / 0-0.1
    prostatic hypertrophy / Delayed / 1.0
    proteinuria / Delayed / 1.0
    tardive dyskinesia / Delayed / Incidence not known
    suicidal ideation / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    atrial fibrillation / Early / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    torsade de pointes / Rapid / Incidence not known
    ventricular fibrillation / Early / 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 failure / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    eosinophilic pneumonia / Delayed / Incidence not known
    aplastic anemia / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / 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
    blurred vision / Early / 4.0-6.0
    impotence (erectile dysfunction) / Delayed / 4.0-5.0
    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
    hostility / Early / 0.1-1.0
    hallucinations / Early / 0.1-1.0
    psychosis / Early / 0.1-1.0
    euphoria / Early / 0.1-1.0
    peripheral neuropathy / Delayed / 0.1-1.0
    akathisia / Delayed / 0.1-1.0
    ataxia / Delayed / 0.1-1.0
    neuropathic pain / Delayed / 0.1-1.0
    dysarthria / Delayed / 0.1-1.0
    neuritis / Delayed / 0.1-1.0
    hyperesthesia / Delayed / 0.1-1.0
    hypotonia / Delayed / 0.1-1.0
    gastritis / Delayed / 0.1-1.0
    stomatitis / Delayed / 0.1-1.0
    hemorrhoids / Delayed / 0.1-1.0
    colitis / Delayed / 0.1-1.0
    oral ulceration / Delayed / 0.1-1.0
    glossitis / Early / 0.1-1.0
    dysphagia / Delayed / 0.1-1.0
    esophagitis / 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
    angina / Early / 0.1-1.0
    peripheral vasoconstriction / Rapid / 0.1-1.0
    photophobia / Early / 0.1-1.0
    conjunctivitis / Delayed / 0.1-1.0
    cataracts / Delayed / 0.1-1.0
    melena / Delayed / 0.1-1.0
    bone pain / Delayed / 0.1-1.0
    myasthenia / Delayed / 0.1-1.0
    synovitis / Delayed / 0.1-1.0
    hyperlipidemia / Delayed / 0.1-1.0
    hypercholesterolemia / 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
    psoriasis / Delayed / 0.1-1.0
    contact dermatitis / Delayed / 0.1-1.0
    vaginal bleeding / Delayed / 0.1-1.0
    urinary retention / Early / 0.1-1.0
    urinary incontinence / Early / 0.1-1.0
    hypokalemia / Delayed / 0.1-1.0
    hyperglycemia / Delayed / 0.1-1.0
    withdrawal / Early / 0.1-1.0
    mania / Early / 0.3-0.5
    impulse control symptoms / Delayed / 0-0.1
    dystonic reaction / Delayed / 0-0.1
    paresis / Delayed / 0-0.1
    aphasia / Delayed / 0-0.1
    hyperreflexia / Delayed / 0-0.1
    nystagmus / Delayed / 0-0.1
    parotitis / Delayed / 0-0.1
    proctitis / Delayed / 0-0.1
    bundle-branch block / Early / 0-0.1
    hyponatremia / Delayed / 0-0.1
    prolonged bleeding time / Delayed / 0-0.1
    hepatitis / Delayed / 0-0.1
    jaundice / Delayed / 0-0.1
    cholelithiasis / Delayed / 0-0.1
    hypoventilation / Rapid / 0-0.1
    hemoptysis / Delayed / 0-0.1
    hypoxia / Early / 0-0.1
    lymphocytosis / Delayed / 0-0.1
    eosinophilia / Delayed / 0-0.1
    hypercalciuria / Delayed / 0-0.1
    flank pain / Delayed / 0-0.1
    nephrolithiasis / Delayed / 0-0.1
    glycosuria / Early / 0-0.1
    hyperthyroidism / Delayed / 0-0.1
    galactorrhea / Delayed / 0-0.1
    goiter / Delayed / 0-0.1
    hypothyroidism / Delayed / 0-0.1
    hypophosphatemia / Delayed / 0-0.1
    diabetes mellitus / Delayed / 0-0.1
    hyperuricemia / Delayed / 0-0.1
    hyperphosphatemia / Delayed / 0-0.1
    hypoglycemia / Early / 0-0.1
    gout / Delayed / 0-0.1
    amnesia / Delayed / 1.0
    trismus / Delayed / 1.0
    edema / Delayed / 1.0
    chest pain (unspecified) / Early / 1.0
    prostatitis / Delayed / 1.0
    vaginitis / 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
    elevated hepatic enzymes / Delayed / Incidence not known
    steatosis / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    neutropenia / Delayed / Incidence not known
    hyperprolactinemia / Delayed / Incidence not known

    Mild

    nausea / Early / 21.0-58.0
    weight loss / Delayed / 4.0-47.0
    headache / Early / 25.0-38.0
    insomnia / Early / 18.0-23.0
    drowsiness / Early / 12.0-23.0
    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 / 6.0-6.0
    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 (unspecified) / Early / 3.0-3.0
    increased urinary frequency / Early / 3.0-3.0
    chills / Rapid / 3.0-3.0
    emotional lability / Early / 0.1-1.0
    hyperkinesis / Delayed / 0.1-1.0
    gingivitis / Delayed / 0.1-1.0
    syncope / Early / 0.1-1.0
    xerophthalmia / Early / 0.1-1.0
    diplopia / Early / 0.1-1.0
    arthralgia / Delayed / 0.1-1.0
    muscle cramps / Delayed / 0.1-1.0
    epistaxis / Delayed / 0.1-1.0
    hyperventilation / Early / 0.1-1.0
    laryngitis / Delayed / 0.1-1.0
    leukocytosis / Delayed / 0.1-1.0
    acne vulgaris / Delayed / 0.1-1.0
    photosensitivity / Delayed / 0.1-1.0
    pruritus / Rapid / 1.0-1.0
    maculopapular rash / Early / 0.1-1.0
    urticaria / Rapid / 0.1-1.0
    hirsutism / Delayed / 0.1-1.0
    alopecia / Delayed / 0.1-1.0
    xerosis / Delayed / 0.1-1.0
    mastalgia / Delayed / 0.1-1.0
    menorrhagia / Delayed / 0.1-1.0
    nocturia / Early / 0.1-1.0
    polyuria / Early / 0.1-1.0
    amenorrhea / Delayed / 0.1-1.0
    urinary urgency / Early / 0.1-1.0
    fever / Early / 0-1.0
    paranoia / Early / 0-0.1
    hyporeflexia / Delayed / 0-0.1
    tongue discoloration / Delayed / 0-0.1
    cheilitis / Delayed / 0-0.1
    hypersalivation / Early / 0-0.1
    pallor / Early / 0-0.1
    petechiae / Delayed / 0-0.1
    purpura / Delayed / 0-0.1
    gynecomastia / Delayed / 0-0.1
    breast discharge / Delayed / 0-0.1
    breast enlargement / Delayed / 0-0.1
    vertigo / Early / 1.0
    dysgeusia / Early / 1.0
    eructation / 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; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (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; Phenyltoloxamine; Salicylamide: (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; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering venlafaxine with other drugs that have serotonergic properties such as dextromethorphan. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. Dextromethorphan should be used in lower doses in patients receiving serotonin-potentiating medications, such as venlafaxine, which are inhibitors of CYP2D6, the isoenzyme responsible for metabolism of dextromethorphan. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering venlafaxine with other drugs that have serotonergic properties such as dextromethorphan. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. Dextromethorphan should be used in lower doses in patients receiving serotonin-potentiating medications, such as venlafaxine, which are inhibitors of CYP2D6, the isoenzyme responsible for metabolism of dextromethorphan. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
    Acetaminophen; Dextromethorphan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering venlafaxine with other drugs that have serotonergic properties such as dextromethorphan. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. Dextromethorphan should be used in lower doses in patients receiving serotonin-potentiating medications, such as venlafaxine, which are inhibitors of CYP2D6, the isoenzyme responsible for metabolism of dextromethorphan. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
    Acetaminophen; Dextromethorphan; Doxylamine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering venlafaxine with other drugs that have serotonergic properties such as dextromethorphan. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. Dextromethorphan should be used in lower doses in patients receiving serotonin-potentiating medications, such as venlafaxine, which are inhibitors of CYP2D6, the isoenzyme responsible for metabolism of dextromethorphan. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering venlafaxine with other drugs that have serotonergic properties such as dextromethorphan. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. Dextromethorphan should be used in lower doses in patients receiving serotonin-potentiating medications, such as venlafaxine, which are inhibitors of CYP2D6, the isoenzyme responsible for metabolism of dextromethorphan. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering venlafaxine with other drugs that have serotonergic properties such as dextromethorphan. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. Dextromethorphan should be used in lower doses in patients receiving serotonin-potentiating medications, such as venlafaxine, which are inhibitors of CYP2D6, the isoenzyme responsible for metabolism of dextromethorphan. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering venlafaxine with other drugs that have serotonergic properties such as dextromethorphan. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. Dextromethorphan should be used in lower doses in patients receiving serotonin-potentiating medications, such as venlafaxine, which are inhibitors of CYP2D6, the isoenzyme responsible for metabolism of dextromethorphan. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
    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.
    Acetaminophen; Tramadol: (Major) 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 tramadol. 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. In one case, the addition of tramadol to extended-release venlafaxine (300 mg/day) and mirtazapine (30 mg/day) likely caused serotonin syndrome. A patient developed agitation, confusion, severe shivering, diaphoresis, myoclonus, hyperreflexia, mydriasis, tachycardia, and fever within 7 weeks of taking tramadol 400 mg daily. He had taken 300 mg tramadol without difficulty. Discontinuation of the 3 drugs and rehydration led to symptom resolution over 36 hours. Reinstitution of the antidepressants 3 days after patient presentation was uneventful. Also, duloxetine and venlafaxine may inhibit the formation of the active M1 metabolite of tramadol by inhibiting CYP2D6. The inhibition of this metabolite may decrease the analgesic effectiveness of tramadol but increase the level of the parent compound, which has more serotonergic activity than the metabolite The risk for serious adverse effects such as seizures and serotonin syndrome may be increased. Patients receiving tramadol in combination with an SNRI should be monitored for the emergence of serotonin syndrome or other adverse effects.
    Albuterol: (Minor) Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has been reported with post-marketing use. Drugs with a possible risk for QT prolongation that should be used cautiously with venlafaxine include the beat-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Albuterol; Ipratropium: (Minor) Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has been reported with post-marketing use. Drugs with a possible risk for QT prolongation that should be used cautiously with venlafaxine include the beat-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Alfuzosin: (Major) 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. Coadministration may increase the risk of QT prolongation.
    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) Venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has reported with post-marketing use. The concomitant use of amiodarone and other drugs known to prolong the QT interval should only be done after careful assessment of risks versus benefits, especially when the coadministered agent might decrease the metabolism of amiodarone. If possible, avoid coadministration of amiodarone and drugs known to prolong the QT interval. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Amitriptyline: (Major) 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. Clinicians should also be alert for pharmacokinetic interactions between tricyclic antidepressants and SNRIs. Duloxetine and venlafaxine are inhibitors of CYP2D6, and many TCAs are metabolized by this isozyme. Duloxetine increased the maximum plasma concentration (Cmax) of desipramine 1.7-fold and the AUC 2.9-fold in one study. One case report documented a first-time seizure in a patient receiving venlafaxine and trimipramine at therapeutic dosages. Patients receiving these combinations should be monitored for the emergence of serotonin syndrome or other adverse effects. In addition, venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has been reported with post-marketing use. Venlafaxine should be used cautiously with other drugs with a possible risk of QT prolongation and TdP including TCAs.
    Amitriptyline; Chlordiazepoxide: (Major) 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. Clinicians should also be alert for pharmacokinetic interactions between tricyclic antidepressants and SNRIs. Duloxetine and venlafaxine are inhibitors of CYP2D6, and many TCAs are metabolized by this isozyme. Duloxetine increased the maximum plasma concentration (Cmax) of desipramine 1.7-fold and the AUC 2.9-fold in one study. One case report documented a first-time seizure in a patient receiving venlafaxine and trimipramine at therapeutic dosages. Patients receiving these combinations should be monitored for the emergence of serotonin syndrome or other adverse effects. In addition, venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has been reported with post-marketing use. Venlafaxine should be used cautiously with other drugs with a possible risk of QT prolongation and TdP including TCAs.
    Amoxapine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering venlafaxine with other drugs that have central serotonergic properties such as amoxapine. 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.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with venlafaxine. Clarithromycin is associated with an established risk for QT prolongation and TdP, while venlafaxine is associated with a possible risk of QT prolongation; TdP has reported with post-marketing use of venlafaxine.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with venlafaxine. Clarithromycin is associated with an established risk for QT prolongation and TdP, while venlafaxine is associated with a possible risk of QT prolongation; TdP has reported with post-marketing use of venlafaxine.
    Amphetamine; Dextroamphetamine Salts: (Major) 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 amphetamines. 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. In addition, the MAOI activity of amphetamines may be of concern with the use of drugs that have serotonergic activity. A man developed marked agitation, anxiety, diaphoresis, shivering, tachycardia, tremor, generalized hypertonia, hyperreflexia, 1 to 2 beats of inducible ankle clonus, frequent myoclonic jerking, and tonic spasm of the right side of his orbicularis oris muscle while taking dexamphetamine and venlafaxine. Cessation of both drugs and administration of cyproheptadine led to a stepwise heart rate reduction and complete symptom resolution. Patients receiving SNRIs and amphetamines should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. The SNRI and amphetamine should be discontinued if serotonin syndrome occurs and supportive symptomatic 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.
    Anticoagulants: (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 anticoagulants. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. Monitor INR levels when venlafaxine is added to or discontinued from warfarin therapy. Patients should be instructed to monitor for signs and symptoms of bleeding while taking venlafaxine concurrently with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Antithrombin III: (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 anticoagulants. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. Monitor INR levels when venlafaxine is added to or discontinued from warfarin therapy. Patients should be instructed to monitor for signs and symptoms of bleeding while taking venlafaxine concurrently with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Apixaban: (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 anticoagulants. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. Monitor INR levels when venlafaxine is added to or discontinued from warfarin therapy. Patients should be instructed to monitor for signs and symptoms of bleeding while taking venlafaxine concurrently with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Apomorphine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering venlafaxine with apomorphine. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with post-marketing use. Limited data indicate that QT prolongation is also possible with apomorphine administration. The change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines; however, large increases (> 60 msecs from pre-dose) have occurred in two patients receiving 6 mg doses. Doses <= 6 mg SC are associated with minimal increases in QTc; doses > 6 mg SC do not provide additional clinical benefit and are not recommended.
    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.
    Arformoterol: (Moderate) Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has been reported with post-marketing use. Drugs with a possible risk for QT prolongation that should be used cautiously with venlafaxine include the beat-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Argatroban: (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 anticoagulants. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. Monitor INR levels when venlafaxine is added to or discontinued from warfarin therapy. Patients should be instructed to monitor for signs and symptoms of bleeding while taking venlafaxine concurrently with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Aripiprazole: (Moderate) Because both venlafaxine and aripiprazole are associated with a possible risk for QT prolongation and torsade de pointes (TdP), this combination should be used cautiously and with close monitoring. In addition, venlafaxine is a mild inhibitor of CYP2D6 and aripiprazole is a partial CYP2D6 substrate. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. Because aripiprazole is also metabolized by CYP3A4, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor 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 during use of a mild to moderate CYP2D6 inhibitor. Aripiprazole dosage adjustments are not required when aripiprazole is added as adjunctive treatment to antidepressants for major depressive disorder provided that the manufacturer's dosing guidelines for this indication are followed.
    Arsenic Trioxide: (Major) If possible, drugs that are known to prolong the QT interval should be discontinued prior to initiating arsenic trioxide therapy. QT prolongation should be expected with the administration of arsenic trioxide. Torsade de pointes (TdP) and complete atrioventricular block have been reported. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with arsenic trioxide include venlafaxine.
    Artemether; Lumefantrine: (Major) Artemether; lumefantrine is an inhibitor of and venlafaxine is metabolized by the CYP2D6 isoenzyme; therefore, coadministration may lead to increased venlafaxine concentrations. Furthermore, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with drugs that may prolong the QT interval, such as venlafaxine, should be avoided. Consider ECG monitoring if venlafaxine must be used with or after artemether; lumefantrine treatment.
    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) 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; Dihydrocodeine: (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) 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) 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) Caution is warranted when cobicistat is administered with venlafaxine as there is a potential for elevated venlafaxine and cobicistat concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Venlafaxine and cobicistat are substrates and inhibitors of CYP2D6. In addition, venlafaxine is a substrate for CYP3A4; cobicistat inhibit CYP3A4.
    Atomoxetine: (Moderate) The concomitant use of atomoxetine and venlafaxine may lead to additive QT interval prolongation. Venlafaxine is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has been reported with post-marketing use. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. In addition, 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.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Severe) 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) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering venlafaxine with azithromycin. Venlafaxine is associated with a possible risk of QT prolongation; TdP has been reported with postmarketing use. Azithromycin has also been associated with postmarketing reports of QT prolongation and TdP. Concurrent use may increase the risk of QT prolongation.
    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.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Severe) 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: (Major) 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 amphetamines. 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 addition, the MAOI activity of amphetamines may be of concern with the use of drugs that have serotonergic activity. A man developed marked agitation, anxiety, diaphoresis, shivering, tachycardia, tremor, generalized hypertonia, hyperreflexia, 12 beats of inducible ankle clonus, frequent myoclonic jerking, and tonic spasm of the right side of his orbicularis oris muscle while taking dexamphetamine and venlafaxine. Cessation of both drugs and administration of cyproheptadine led to a stepwise heart rate reduction and complete symptom resolution. Patients receiving an SNRI and an amphetamine should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. The SNRI and amphetamine should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Betrixaban: (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 anticoagulants. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. Monitor INR levels when venlafaxine is added to or discontinued from warfarin therapy. Patients should be instructed to monitor for signs and symptoms of bleeding while taking venlafaxine concurrently with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Coadministration of metronidazole and venlafaxine may increase the risk for QT prolongation and torsade de pointes (TdP). Potential QT prolongation has been reported in limited case reports with metronidazole. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    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) Coadministration of metronidazole and venlafaxine may increase the risk for QT prolongation and torsade de pointes (TdP). Potential QT prolongation has been reported in limited case reports with metronidazole. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use. (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: (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 anticoagulants. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. Monitor INR levels when venlafaxine is added to or discontinued from warfarin therapy. Patients should be instructed to monitor for signs and symptoms of bleeding while taking venlafaxine concurrently with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering venlafaxine with boceprevir due to an increased potential for venlafaxine-related adverse events. If venlafaxine dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of venlafaxine. Venlafaxine is partially metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in elevated venlafaxine plasma concentrations.
    Bromocriptine: (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 bromocriptine. 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 these combinations should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering venlafaxine with other drugs that have serotonergic properties such as dextromethorphan. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. Dextromethorphan should be used in lower doses in patients receiving serotonin-potentiating medications, such as venlafaxine, which are inhibitors of CYP2D6, the isoenzyme responsible for metabolism of dextromethorphan. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
    Budesonide; Formoterol: (Moderate) Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has been reported with post-marketing use. Drugs with a possible risk for QT prolongation that should be used cautiously with venlafaxine include the beat-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    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. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Venlafaxine also has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as SNRIs (e.g., desvenlafaxine, duloxetine, milnacipran, levomilnacipran, venlafaxine), has resulted in serotonin syndrome in some cases. 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 combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine 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. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Venlafaxine also has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as SNRIs (e.g., desvenlafaxine, duloxetine, milnacipran, levomilnacipran, venlafaxine), has resulted in serotonin syndrome in some cases. 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 combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected.
    Buspirone: (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 buspirone. 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 these combinations should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Cabergoline: (Moderate) 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 cabergoline. Cabergoline has minimal affinity for serotonin receptors, possibly reducing the risk of this interaction compared to the chemically related ergot alkaloids. However, patients receiving cabergoline with an SNRI should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering venlafaxine with other drugs that have serotonergic properties such as dextromethorphan. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. Dextromethorphan should be used in lower doses in patients receiving serotonin-potentiating medications, such as venlafaxine, which are inhibitors of CYP2D6, the isoenzyme responsible for metabolism of dextromethorphan. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
    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.
    Ceritinib: (Major) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and venlafaxine; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Venlafaxine administration is also associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Cevimeline: (Minor) Cevimeline is metabolized by cytochrome P450 3A4 and CYP2D6. Venlafaxine is a mild inhibitor of CYP2D6 and could lead to an increase in cevimeline plasma concentrations.
    Chloroquine: (Major) Coadminister chloroquine with other drugs known to prolong the QT interval, such as venlafaxine, with caution. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); fatalities have been reported. The risk of QT prolongation is increased with higher chloroquine doses. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has been reported with postmarketing use.
    Chlorpheniramine; Dextromethorphan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering venlafaxine with other drugs that have serotonergic properties such as dextromethorphan. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. Dextromethorphan should be used in lower doses in patients receiving serotonin-potentiating medications, such as venlafaxine, which are inhibitors of CYP2D6, the isoenzyme responsible for metabolism of dextromethorphan. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering venlafaxine with other drugs that have serotonergic properties such as dextromethorphan. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. Dextromethorphan should be used in lower doses in patients receiving serotonin-potentiating medications, such as venlafaxine, which are inhibitors of CYP2D6, the isoenzyme responsible for metabolism of dextromethorphan. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
    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.
    Cimetidine: (Moderate) The metabolism of venlafaxine may be inhibited to some degree by cimetidine. No dosage adjustments are recommended in normal patients, but caution should be observed in the elderly and in patients with preexisting hypertension and/or hepatic disease or impairment because the results of this interaction can be more pronounced.
    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) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering venlafaxine with ciprofloxacin. Both venlafaxine and ciprofloxacin are associated with a possible risk of QT prolongation; TdP has been reported with post-marketing use.
    Cisapride: (Severe) Venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has reported with postmarketing use. Because of the potential for TdP, use of cisapride with venlafaxine is contraindicated.
    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. 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, venlafaxine and concurrent serotonergic agents should be discontinued. In addition, venlafaxine and SSRIs including fluoxetine, citalopram, and escitalopram are associated with a possible risk of QT prolongation and torsade de pointes (TdP) and combination therapy should be avoided if possible.
    Clarithromycin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with venlafaxine. Clarithromycin is associated with an established risk for QT prolongation and TdP, while venlafaxine is associated with a possible risk of QT prolongation; TdP has reported with post-marketing use of venlafaxine.
    Clobazam: (Moderate) A dosage reduction of CYP2D6 substrates, such as venlafaxine, may be necessary during co-administration of clobazam. Limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. If these agents are used in combination, it is advisable to monitor the patient for adverse reactions related to venlafaxine.
    Clomipramine: (Major) 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. Clinicians should also be alert for pharmacokinetic interactions between tricyclic antidepressants and SNRIs. Duloxetine and venlafaxine are inhibitors of CYP2D6, and many TCAs are metabolized by this isozyme. Duloxetine increased the maximum plasma concentration (Cmax) of desipramine 1.7-fold and the AUC 2.9-fold in one study. One case report documented a first-time seizure in a patient receiving venlafaxine and trimipramine at therapeutic dosages. Patients receiving these combinations should be monitored for the emergence of serotonin syndrome or other adverse effects. In addition, venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has been reported with post-marketing use. Venlafaxine should be used cautiously with other drugs with a possible risk of QT prolongation and TdP including TCAs.
    Clopidogrel: (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.
    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) Caution is warranted when cobicistat is administered with venlafaxine as there is a potential for elevated venlafaxine and cobicistat concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Venlafaxine and cobicistat are substrates and inhibitors of CYP2D6. In addition, venlafaxine is a substrate for CYP3A4; cobicistat inhibit CYP3A4.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when cobicistat is administered with venlafaxine as there is a potential for elevated venlafaxine and cobicistat concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Venlafaxine and cobicistat are substrates and inhibitors of CYP2D6. In addition, venlafaxine is a substrate for CYP3A4; cobicistat inhibit CYP3A4.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is warranted when cobicistat is administered with venlafaxine as there is a potential for elevated venlafaxine and cobicistat concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Venlafaxine and cobicistat are substrates and inhibitors of CYP2D6. In addition, venlafaxine is a substrate for CYP3A4; cobicistat inhibit CYP3A4.
    Codeine; Phenylephrine; Promethazine: (Moderate) Monitor for evidence of QT prolongation if promethazine is coadministered with venlafaxine. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Codeine; Promethazine: (Moderate) Monitor for evidence of QT prolongation if promethazine is coadministered with venlafaxine. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Crizotinib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with venlafaxine. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Venlafaxine administration is also associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    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. In addition, cyclobenzaprine is structurally similar to tricyclic antidepressants (TCAs) and like TCAs, is associated with a possible risk of QT prolongation and torsades de pointes (TdP), particularly in the event of acute overdose. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with cyclobenzaprine include venlafaxine and potentially other SNRIs.
    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: (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 anticoagulants. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. Monitor INR levels when venlafaxine is added to or discontinued from warfarin therapy. Patients should be instructed to monitor for signs and symptoms of bleeding while taking venlafaxine concurrently with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Dalteparin: (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 anticoagulants. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. Monitor INR levels when venlafaxine is added to or discontinued from warfarin therapy. Patients should be instructed to monitor for signs and symptoms of bleeding while taking venlafaxine concurrently with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Danaparoid: (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 anticoagulants. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. Monitor INR levels when venlafaxine is added to or discontinued from warfarin therapy. Patients should be instructed to monitor for signs and symptoms of bleeding while taking venlafaxine concurrently with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Darunavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with venlafaxine as there is a potential for elevated venlafaxine and cobicistat concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Venlafaxine and cobicistat are substrates and inhibitors of CYP2D6. In addition, venlafaxine is a substrate for CYP3A4; cobicistat inhibit CYP3A4.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Ritonavir may be expected to decrease the metabolism of venlafaxine; ritonavir is a potent inhibitor of CYP3A4 and 2D6, and venlafaxine is a substrate for both of these enzymes. In addition, venlafaxine can inhibit the CYP2D6 metabolism of ritonavir. The risk of elevated plasma concentrations and toxicity may be greater when ritonavir is given with venlafaxine. In addition, both ritonavir and venlafaxine are associated with QT prolongation; concomitant use increases the risk of QT prolongation.
    Dasatinib: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), dasatinib and venlafaxine should be used together cautiously. In vitro studies have shown that dasatinib has the potential to prolong cardiac ventricular repolarization (prolong QT interval). Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has been reported with postmarketing use.
    Daunorubicin: (Moderate) Venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has been reported with post-marketing use and should be used cautiously with other drugs with a possible risk for QT prolongation and TdP including daunorubicin and doxorubicin. Acute cardiotoxicity can occur during administration of daunorubicin or doxorubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Degarelix: (Major) Venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has reported with post-marketing use. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with venlafaxine include degarelix.
    Delavirdine: (Moderate) Delavirdine is a potent inhibitor of cytochrome P450 2D6 and might decrease venlafaxine metabolism leading to increased adverse reactions.
    Desipramine: (Major) 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. Clinicians should also be alert for pharmacokinetic interactions between tricyclic antidepressants and SNRIs. Duloxetine and venlafaxine are inhibitors of CYP2D6, and many TCAs are metabolized by this isozyme. Duloxetine increased the maximum plasma concentration (Cmax) of desipramine 1.7-fold and the AUC 2.9-fold in one study. One case report documented a first-time seizure in a patient receiving venlafaxine and trimipramine at therapeutic dosages. Patients receiving these combinations should be monitored for the emergence of serotonin syndrome or other adverse effects. In addition, venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has been reported with post-marketing use. Venlafaxine should be used cautiously with other drugs with a possible risk of QT prolongation and TdP including TCAs.
    Desirudin: (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 anticoagulants. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. Monitor INR levels when venlafaxine is added to or discontinued from warfarin therapy. Patients should be instructed to monitor for signs and symptoms of bleeding while taking venlafaxine concurrently with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Desvenlafaxine: (Severe) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, serotonin norepinephrine reuptake inhibitors (SNRIs) including venlafaxine, desvenlafaxine, duloxetine, levomilnacipran, and milnacipran should not be coadministered with each other. 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. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SNRI to another SNRI.
    Deutetrabenazine: (Major) For patients taking a deutetrabenazine dosage more than 24 mg/day with venlafaxine, assess the QTc interval before and after increasing the dosage of either medication. Clinically relevant QTc prolongation may occur with deutetrabenazine. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has been reported with postmarketing use.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering venlafaxine with other drugs that have serotonergic properties such as dextromethorphan. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. Dextromethorphan should be used in lower doses in patients receiving serotonin-potentiating medications, such as venlafaxine, which are inhibitors of CYP2D6, the isoenzyme responsible for metabolism of dextromethorphan. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
    Dexmethylphenidate: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dexmethylphenidate and serotonin norepinephrine reuptake inhibitors (SNRIs). There are rare reports of serotonin syndrome occurring during use of other serotonergic antidepressants (i.e., SSRIs) and methylphenidate, a racemic compound containing dexmethylphenidate. There is also a case of a neuroleptic malignant syndrome-like reaction occurring in a child on chronic methylphenidate therapy 45 minutes after ingesting a dose of venlafaxine. It is unclear if the reaction was the result of a drug interaction. 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 this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Dextromethorphan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering venlafaxine with other drugs that have serotonergic properties such as dextromethorphan. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. Dextromethorphan should be used in lower doses in patients receiving serotonin-potentiating medications, such as venlafaxine, which are inhibitors of CYP2D6, the isoenzyme responsible for metabolism of dextromethorphan. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering venlafaxine with other drugs that have serotonergic properties such as dextromethorphan. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. Dextromethorphan should be used in lower doses in patients receiving serotonin-potentiating medications, such as venlafaxine, which are inhibitors of CYP2D6, the isoenzyme responsible for metabolism of dextromethorphan. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
    Dextromethorphan; Guaifenesin: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering venlafaxine with other drugs that have serotonergic properties such as dextromethorphan. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. Dextromethorphan should be used in lower doses in patients receiving serotonin-potentiating medications, such as venlafaxine, which are inhibitors of CYP2D6, the isoenzyme responsible for metabolism of dextromethorphan. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering venlafaxine with other drugs that have serotonergic properties such as dextromethorphan. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. Dextromethorphan should be used in lower doses in patients receiving serotonin-potentiating medications, such as venlafaxine, which are inhibitors of CYP2D6, the isoenzyme responsible for metabolism of dextromethorphan. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering venlafaxine with other drugs that have serotonergic properties such as dextromethorphan. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. Dextromethorphan should be used in lower doses in patients receiving serotonin-potentiating medications, such as venlafaxine, which are inhibitors of CYP2D6, the isoenzyme responsible for metabolism of dextromethorphan. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering venlafaxine with other drugs that have serotonergic properties such as dextromethorphan. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. Dextromethorphan should be used in lower doses in patients receiving serotonin-potentiating medications, such as venlafaxine, which are inhibitors of CYP2D6, the isoenzyme responsible for metabolism of dextromethorphan. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
    Dextromethorphan; Promethazine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering venlafaxine with other drugs that have serotonergic properties such as dextromethorphan. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. Dextromethorphan should be used in lower doses in patients receiving serotonin-potentiating medications, such as venlafaxine, which are inhibitors of CYP2D6, the isoenzyme responsible for metabolism of dextromethorphan. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued. (Moderate) Monitor for evidence of QT prolongation if promethazine is coadministered with venlafaxine. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Dextromethorphan; Quinidine: (Severe) 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. (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering venlafaxine with other drugs that have serotonergic properties such as dextromethorphan. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. Dextromethorphan should be used in lower doses in patients receiving serotonin-potentiating medications, such as venlafaxine, which are inhibitors of CYP2D6, the isoenzyme responsible for metabolism of dextromethorphan. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
    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) Venlafaxine should be used cautiously and with close monitoring with disopyramide. Disopyramide administration is associated with QT prolongation and torsades de pointes (TdP). Venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has reported with post-marketing use.
    Diuretics: (Moderate) Patients receiving a diuretic during treatment with venlafaxine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH may occur during therapy with SNRIs, including venlafaxine. Cases involving serum sodium levels lower than 110 mmol/l have been reported. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of the SNRI should be considered in patients who develop symptomatic hyponatremia.
    Dofetilide: (Severe) Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with post-marketing use. Because of the potential for TdP, use of venlafaxine with dofetilide is contraindicated.
    Dolasetron: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), dolasetron and venlafaxine should be used together cautiously. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with post-marketing use. Concurrent use may further increase the risk for QT prolongation.
    Dolutegravir; Rilpivirine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with venlafaxine. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with post-marketing use. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also been associated with prolongation of the QT interval.
    Donepezil: (Major) Monitor for evidence of QT prolongation and torsade de pointes (TdP) if coadministration of donepezil and venlafaxine is necessary. Both drugs have been associated with a risk of QT prolongation and TdP. Concurrent use may further increase this risk.
    Donepezil; Memantine: (Major) Monitor for evidence of QT prolongation and torsade de pointes (TdP) if coadministration of donepezil and venlafaxine is necessary. Both drugs have been associated with a risk of QT prolongation and TdP. Concurrent use may further increase this risk.
    Doxepin: (Major) 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. Clinicians should also be alert for pharmacokinetic interactions between tricyclic antidepressants and SNRIs. Duloxetine and venlafaxine are inhibitors of CYP2D6, and many TCAs are metabolized by this isozyme. Duloxetine increased the maximum plasma concentration (Cmax) of desipramine 1.7-fold and the AUC 2.9-fold in one study. One case report documented a first-time seizure in a patient receiving venlafaxine and trimipramine at therapeutic dosages. Patients receiving these combinations should be monitored for the emergence of serotonin syndrome or other adverse effects. In addition, venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has been reported with post-marketing use. Venlafaxine should be used cautiously with other drugs with a possible risk of QT prolongation and TdP including TCAs.
    Doxorubicin: (Major) Venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has been reported with post-marketing use and should be used cautiously with other drugs with a possible risk for QT prolongation and TdP including daunorubicin and doxorubicin. Acute cardiotoxicity can occur during administration of daunorubicin or doxorubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Dronedarone: (Severe) Concurrent use of dronedarone and venlafaxine is contraindicated. Venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has reported with post-marketing use. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Droperidol: (Major) Droperidol should be administered with extreme caution to patients receiving other agents that may prolong the QT interval. Droperidol administration is associated with an established risk for QT prolongation and torsades de pointes (TdP). Any drug known to have potential to prolong the QT interval should not be coadministered with droperidol. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with droperidol include venlafaxine.
    Duloxetine: (Severe) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, serotonin norepinephrine reuptake inhibitors (SNRIs) including venlafaxine, desvenlafaxine, duloxetine, levomilnacipran, and milnacipran should not be coadministered. 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. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SNRI to another SNRI.
    Edoxaban: (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 anticoagulants. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. Monitor INR levels when venlafaxine is added to or discontinued from warfarin therapy. Patients should be instructed to monitor for signs and symptoms of bleeding while taking venlafaxine concurrently with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Efavirenz: (Major) Coadministration of efavirenz and venlafaxine may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with post-marketing use. In addition, efavirenz may induce the CYP3A4 metabolism of venlafaxine; potentially reducing the efficacy of venlafaxine by decreasing its systemic exposure.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Coadministration of efavirenz and venlafaxine may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with post-marketing use. In addition, efavirenz may induce the CYP3A4 metabolism of venlafaxine; potentially reducing the efficacy of venlafaxine by decreasing its systemic exposure.
    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) Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with eliglustat include venlafaxine.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with venlafaxine. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with post-marketing use. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also been associated with prolongation of the QT interval.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with venlafaxine. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with post-marketing use. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also been associated with prolongation of the QT interval.
    Enoxaparin: (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 anticoagulants. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. Monitor INR levels when venlafaxine is added to or discontinued from warfarin therapy. Patients should be instructed to monitor for signs and symptoms of bleeding while taking venlafaxine concurrently with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Epirubicin: (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering venlafaxine with epirubicin. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has been reported with post-marketing use. Acute cardiotoxicity can also occur during administration of epirubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    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: (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 ergot alkaloids. 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 these combinations should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Eribulin: (Major) Eribulin has been associated with QT prolongation. If eribulin and another drug that prolongs the QT interval, such as venlafaxine, must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
    Erythromycin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering erythromycin with venlafaxine. Erythromycin is associated with prolongation of the QT interval and TdP. Venlafaxine administration is also associated with a possible risk of QT prolongation; TdP has reported with post-marketing use.
    Erythromycin; Sulfisoxazole: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering erythromycin with venlafaxine. Erythromycin is associated with prolongation of the QT interval and TdP. Venlafaxine administration is also associated with a possible risk of QT prolongation; TdP has reported with post-marketing use.
    Escitalopram: (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. 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, venlafaxine and concurrent serotonergic agents should be discontinued. In addition, venlafaxine and SSRIs including fluoxetine, citalopram, and escitalopram are associated with a possible risk of QT prolongation and torsade de pointes (TdP) and combination therapy should be avoided if possible.
    Esomeprazole; 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.
    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.
    Ezogabine: (Major) Venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has reported with post-marketing use. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with venlafaxine include ezogabine.
    Famotidine; 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.
    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: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering venlafaxine with other drugs that have serotonergic properties such as fentanyl. 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. Careful monitoring is recommended during co-administration of fentanyl and venlafaxine for signs and symptoms of serotonin syndrome or other serious effects.
    Fingolimod: (Major) Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). 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. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with fingolimod include venlafaxine. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with post-marketing use.
    Flecainide: (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering venlafaxine with flecainide. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with post-marketing use. Flecainide, a Class IC antiarrhythmic, is also associated with a possible risk for QT prolongation and/or TdP; flecainide increases the QT interval, but largely due to prolongation of the QRS interval.
    Fluconazole: (Severe) The concomitant administration of fluconazole and venlafaxine is contraindicated. Fluconazole has been associated with QT prolongation and is contraindicated for use with other drugs that both prolong the QT interval and are CYP3A4 substrates, such as venlafaxine. Coadministration of fluconazole with venlafaxine may result in elevated plasma concentrations of venlafaxine, causing an increased risk for adverse events, such as QT prolongation. Venlafaxine is a substrate of the hepatic CYP450 isoenzyme CYP2D6 (major) and CYP3A4 (minor). Venlafaxine is likely metabolized to a minor, less active metabolite by CYP3A4 and, normally, the potential for clinically significant drug interactions between CYP3A4 inhibitors and venlafaxine is small. However, in patients who are poor CYP2D6 metabolizers, the CYP3A4 pathway may become more important and administration of potent CYP3A4 inhibitors can result in elevated venlafaxine plasma concentrations.
    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. 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, venlafaxine and concurrent serotonergic agents should be discontinued. In addition, venlafaxine and SSRIs including fluoxetine are associated with a possible risk of QT prolongation and torsade de pointes (TdP) and combination therapy should be avoided if possible.
    Fluoxetine; Olanzapine: (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. 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, venlafaxine and concurrent serotonergic agents should be discontinued. In addition, venlafaxine and SSRIs including fluoxetine are associated with a possible risk of QT prolongation and torsade de pointes (TdP) and combination therapy should be avoided if possible. (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.
    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.
    Fluticasone; Salmeterol: (Moderate) Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has been reported with post-marketing use. Drugs with a possible risk for QT prolongation that should be used cautiously with venlafaxine include the beat-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has been reported with post-marketing use. Drugs with a possible risk for QT prolongation that should be used cautiously with venlafaxine include the beat-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fluticasone; Vilanterol: (Moderate) Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has been reported with post-marketing use. Drugs with a possible risk for QT prolongation that should be used cautiously with venlafaxine include the beat-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    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: (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 anticoagulants. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. Monitor INR levels when venlafaxine is added to or discontinued from warfarin therapy. Patients should be instructed to monitor for signs and symptoms of bleeding while taking venlafaxine concurrently with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Formoterol: (Moderate) Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has been reported with post-marketing use. Drugs with a possible risk for QT prolongation that should be used cautiously with venlafaxine include the beat-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Formoterol; Mometasone: (Moderate) Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has been reported with post-marketing use. Drugs with a possible risk for QT prolongation that should be used cautiously with venlafaxine include the beat-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as venlafaxine. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Venlafaxine administration is also associated with a possible risk of QT prolongation; TdP has reported with postmarketing use. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
    Gefitinib: (Moderate) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and venlafaxine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; venlafaxine is a weak CYP2D6 inhibitor. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with CYP2D6 inhibitors, in patients with poor CYP2D6 metabolism, the mean exposure to gefitinib was 2-fold higher when compared to extensive metabolizers; the contribution of drugs that inhibit CYP2D6 on gefitinib exposure has not been evaluated. Additionally, at high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of venlafaxine. In patients with solid tumors, exposure to metoprolol, another CYP2D6 substrate, was increased by 30% when given on day 15 of gefitinib dosing (500 mg daily); the effect of gefitinib on CYP2D6-dependent drugs is only likely to be clinically relevant when given with CYP2D6 substrates with a narrow therapeutic index or that are individually dose titrated such as venlafaxine.
    Gemifloxacin: (Major) 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) Use gemtuzumab ozogamicin and venlafaxine together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has also been reported with postmarketing use.
    Glycopyrrolate; Formoterol: (Moderate) Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has been reported with post-marketing use. Drugs with a possible risk for QT prolongation that should be used cautiously with venlafaxine include the beat-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Goserelin: (Moderate) Androgen deprivation therapy (e.g., goserelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with goserelin include venlafaxine.
    Granisetron: (Moderate) Because of the potential risk and severity of serotonin syndrome or QT prolongation, use caution and monitor closely when administering granisetron with other drugs that have serotonergic properties or may prolong the QT interval, such as venlafaxine. If serotonin syndrome is suspected, discontinue granisetron 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. In addition, granisetron has been associated with QT prolongation. According to the product labeling, use of granisetron in patients concurrently treated with drugs known to prolong the QT interval and/or are arrhythmogenic, may result in clinical consequences.
    Halogenated Anesthetics: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with venlafaxine. Halogenated anesthetics can 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.
    Haloperidol: (Major) Caution is advisable during concurrent use of venlafaxine and haloperidol since both agents are associated with a possible risk of QT prolongation. In addition, venlafaxine is an inhibitor of CYP2D6, and concurrent use with CYP2D6 substrates, such as haloperidol, may result in increased plasma concentrations of such antipsychotics. In one case report, venlafaxine administered at 150 mg/day in 24 subjects decreased total oral clearance of a 2 mg dose of haloperidol by 42%, which resulted in a 70% increase in haloperidol AUC. In addition, the haloperidol Cmax increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life was unchanged.
    Heparin: (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 anticoagulants. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. Monitor INR levels when venlafaxine is added to or discontinued from warfarin therapy. Patients should be instructed to monitor for signs and symptoms of bleeding while taking venlafaxine concurrently with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Concurrent administration of therapeutic doses of metoprolol and venlafaxine for 5 days resulted in increased metoprolol plasma concentrations; however, the antihypertensive effect of metoprolol was reduced. The clinical significance of these findings in hypertensive patients is unknown. Because venlafaxine treatment has been associated with hypertension in some patients, regular monitoring of blood pressure is recommended.
    Hydrocodone; 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.
    Hydroxychloroquine: (Major) Avoid coadministration of hydroxychloroquine and venlafaxine. Hydroxychloroquine increases the QT interval and should not be administered with other drugs known to prolong the QT interval. Ventricular arrhythmias and torsade de pointes (TdP) have been reported with the use of hydroxychloroquine. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has been reported with postmarketing use.
    Hydroxyzine: (Major) Post-marketing data indicate that hydroxyzine causes QT prolongation and Torsade de Pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with hydroxyzine include venlafaxine.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Severe) 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; Oxycodone: (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) Venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has reported with post-marketing use. Ibutilide administration can cause QT prolongation and torsades de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval, such as venlafaxine.
    Idarubicin: (Moderate) Venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has been reported with post-marketing use and should be used cautiously with other drugs with a possible risk for QT prolongation and TdP including daunorubicin, doxorubicin, epirubicin, and idarubicin. Acute cardiotoxicity can occur during administration of daunorubicin or doxorubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    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) 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. Clinicians should also be alert for pharmacokinetic interactions between tricyclic antidepressants and SNRIs. Duloxetine and venlafaxine are inhibitors of CYP2D6, and many TCAs are metabolized by this isozyme. Duloxetine increased the maximum plasma concentration (Cmax) of desipramine 1.7-fold and the AUC 2.9-fold in one study. One case report documented a first-time seizure in a patient receiving venlafaxine and trimipramine at therapeutic dosages. Patients receiving these combinations should be monitored for the emergence of serotonin syndrome or other adverse effects. In addition, venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has been reported with post-marketing use. Venlafaxine should be used cautiously with other drugs with a possible risk of QT prolongation and TdP including TCAs.
    Indacaterol: (Moderate) Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has been reported with post-marketing use. Drugs with a possible risk for QT prolongation that should be used cautiously with venlafaxine include the beat-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Indacaterol; Glycopyrrolate: (Moderate) Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has been reported with post-marketing use. Drugs with a possible risk for QT prolongation that should be used cautiously with venlafaxine include the beat-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    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) Avoid coadministration of inotuzumab ozogamicin with venlafaxine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has also been reported with postmarketing use.
    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: (Major) 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. If itraconazole therapy is stopped, it may be prudent to continue close monitoring for up to 2 weeks after discontinuing itraconazole. Once discontinued, the plasma concentration of itraconazole decreases to almost undetectable concentrations within 7 to 14 days. The decline in plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors.
    Ivacaftor: (Minor) Use caution when administering ivacaftor and venlafaxine concurrently. Ivacaftor is an inhibitor of CYP3A and venlafaxine is partially metabolized by CYP3A. Venlafaxine is likely metabolized to a minor, less active metabolite by CYP3A4 and, normally, the potential for clinically significant drug interactions between CYP3A4 inhibitors and venlafaxine is small.
    Kava Kava, Piper methysticum: (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 kava kava. This interactions are probably pharmacodynamic in nature, or result from additive mechanisms of action.
    Ketoconazole: (Major) Caution is advised when administering ketoconazole with venlafaxine due to the potential for additive effects on the QT interval and increased exposure to venlafaxine. Both venlafaxine and ketoconazole 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 ketoconazole (a potent CYP3A4 inhibitor) to patients identified as CYP2D6 poor metabolizers resulted in a significant increase in venlafaxine mean AUC; there was no effect on venlafaxine half-life.
    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; 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: (Major) In vitro, lapatinib, at clinically relevant concentrations, inhibits CYP3A4 and CYP2C8. If lapatinib will be coadministered with a CYP3A4 substrate, exercise caution and consider dose reduction of the concomitant substrate drug, especially for drugs that have a narrow therapeutic index. Several CYP3A4 substrates can prolong the QT interval, and lapatinib can also prolong the QT interval. Use lapatinib with extreme caution, if at all, in patients taking CYP3A4 substrates that also have potential to induce QT prolongation such as venlafaxine.
    Lenvatinib: (Major) Venlafaxine should be used cautiously and with close monitoring with lenvatinib. Venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has reported with post-marketing use. QT prolongation was reported in patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) in a double-blind, randomized, placebo-controlled clinical trial after receiving lenvatinib daily at the recommended dose; the QT/QTc interval was not prolonged, however, after a single 32 mg dose (1.3 times the recommended daily dose) in healthy subjects.
    Lepirudin: (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 anticoagulants. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. Monitor INR levels when venlafaxine is added to or discontinued from warfarin therapy. Patients should be instructed to monitor for signs and symptoms of bleeding while taking venlafaxine concurrently with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Leuprolide: (Moderate) Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with leuprolide include venlafaxine.
    Leuprolide; Norethindrone: (Moderate) Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with leuprolide include venlafaxine.
    Levalbuterol: (Minor) Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has been reported with post-marketing use. Drugs with a possible risk for QT prolongation that should be used cautiously with venlafaxine include the beat-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Levobupivacaine: (Minor) Levobupivacaine is metabolized by CYP3A4 and 1A2. Known inhibitors of either CYP3A4 or CYP1A2, such as venlafaxine, may result in increased systemic levels of levobupivacaine when given concurrently, with potential for toxicity.
    Levofloxacin: (Major) Concurrent use of venlafaxine and levofloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Levofloxacin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Additionally, rare cases of TdP have been spontaneously reported during postmarketing surveillance in patients receiving levofloxacin. Venlafaxine is associated with a possible risk of QT prolongation, and TdP has been reported with postmarketing use.
    Levomilnacipran: (Severe) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, serotonin norepinephrine reuptake inhibitors (SNRIs) such as levomilnacipran and venlafaxine should not be coadministered. 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. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SNRI to another SNRI.
    Linezolid: (Severe) 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) 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 lisdexamfetamine. 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 addition, the MAOI activity of amphetamines may be of concern with the use of drugs that have serotonergic activity. A man developed marked agitation, anxiety, diaphoresis, shivering, tachycardia, tremor, generalized hypertonia, hyperreflexia, 1 to 2 beats of inducible ankle clonus, frequent myoclonic jerking, and tonic spasm of the right side of his orbicularis oris muscle while taking dexamphetamine and venlafaxine. Cessation of both drugs and administration of cyproheptadine led to a stepwise heart rate reduction and complete symptom resolution. Patients receiving SNRIs and amphetamines should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. The SNRI and amphetamine should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Lithium: (Major) Lithium is an effective augmenting agent to antidepressants in treatment-resistant depression; however, lithium has been associated with QT prolongation and should be used cautiously and with close monitoring with other drugs having the potential to prolong the QT interval such as venlafaxine. In addition, lithium has been reported to have central serotonin-enhancing effects and may interact pharmacodynamically with venlafaxine to cause 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 should be informed of the possible increased risk of serotonin syndrome. If serotonin syndrome occurs, venlafaxine and lithium should be discontinued and symptomatic treatment should be initiated. One systematic review and meta-analysis of lithium augmentation of tricyclic and second generation antidepressants in major depression found no difference in discontinuation rate due to adverse events between the lithium and placebo groups. However, some data indicate that the elderly may have increased susceptibility to neurotoxicity (e.g., fine tremor, ataxia, severe memory impairment, and/or gait disturbances) from concurrent use of lithium and antidepressants, despite therapeutic lithium concentrations. There appears to be no pharmacokinetic interaction between venlafaxine and lithium.
    Long-acting beta-agonists: (Moderate) Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has been reported with post-marketing use. Drugs with a possible risk for QT prolongation that should be used cautiously with venlafaxine include the beat-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Loperamide: (Moderate) Loperamide should be used cautiously and with close monitoring with venlafaxine. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with post-marketing use. Coadministration may increase the risk for QT prolongation and TdP. In addition, the plasma concentrations of loperamide, a CYP2D6 substrate, may be increased when administered concurrently with venlafaxine, a weak CYP2D6 inhibitor, further increasing the risk of toxicity. If these drugs are used together, monitor for cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest) and other loperamide-associated adverse reactions, such as CNS effects.
    Loperamide; Simethicone: (Moderate) Loperamide should be used cautiously and with close monitoring with venlafaxine. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with post-marketing use. Coadministration may increase the risk for QT prolongation and TdP. In addition, the plasma concentrations of loperamide, a CYP2D6 substrate, may be increased when administered concurrently with venlafaxine, a weak CYP2D6 inhibitor, further increasing the risk of toxicity. If these drugs are used together, monitor for cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest) and other loperamide-associated adverse reactions, such as CNS effects.
    Lopinavir; Ritonavir: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering lopinavir; ritonavir with venlafaxine. Lopinavir; ritonavir is associated with QT prolongation. Venlafaxine is also associated with a possible risk of QT prolongation; TdP has been reported with post-marketing use. In addition, lopinavir; ritonavir inhibits CYP3A4 and venlafaxine is a CYP3A4 substrate. Coadministration may increase the serum concentrations of venlafaxine. (Major) Ritonavir may be expected to decrease the metabolism of venlafaxine; ritonavir is a potent inhibitor of CYP3A4 and 2D6, and venlafaxine is a substrate for both of these enzymes. In addition, venlafaxine can inhibit the CYP2D6 metabolism of ritonavir. The risk of elevated plasma concentrations and toxicity may be greater when ritonavir is given with venlafaxine. In addition, both ritonavir and venlafaxine are associated with QT prolongation; concomitant use increases the risk of QT prolongation.
    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.
    Lumacaftor; Ivacaftor: (Minor) Use caution when administering ivacaftor and venlafaxine concurrently. Ivacaftor is an inhibitor of CYP3A and venlafaxine is partially metabolized by CYP3A. Venlafaxine is likely metabolized to a minor, less active metabolite by CYP3A4 and, normally, the potential for clinically significant drug interactions between CYP3A4 inhibitors and venlafaxine is small.
    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) Coadministration may increase the risk for QT prolongation and torsade de pointes. Also monitor for an increase in CNS effects and drug toxicity, such as serotonin syndrome. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with maprotiline include venlafaxine. In addition, additive CNS and other effects are possible; one case of serotonin syndrome has been reported when maprotiline was used in combination with venlafaxine and a selective norepinephrine antidepressant.
    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: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering venlafaxine with mefloquine. There is evidence that the use of halofantrine after mefloquine causes significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation; however due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval. Venlafaxine is associated with a possible risk of QT prolongation; TdP has reported with post-marketing 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: (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 meperidine. 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.
    Meperidine; Promethazine: (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 meperidine. 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. (Moderate) Monitor for evidence of QT prolongation if promethazine is coadministered with venlafaxine. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Mesoridazine: (Severe) Mesoridazine has an established risk of QT prolongation and torsade de pointes (TdP) and is generally contraindicated for use with agents that may prolong the QT interval such as venlafaxine. In addition, phenothiazines are CYP2D6 substrates, and venlafaxine is a CYP2D6 inhibitor.
    Metaproterenol: (Minor) Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has been reported with post-marketing use. Drugs with a possible risk for QT prolongation that should be used cautiously with venlafaxine include the beat-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Methadone: (Major) The need to coadminister methadone with venlafaxine should be done with extreme caution and a careful assessment of treatment risks versus benefits. Venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has reported with post-marketing use. Methadone is considered to be associated with an increased risk for QT prolongation and torsades de pointes (TdP), especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). Laboratory studies, both in vivo and in vitro, have demonstrated that methadone inhibits cardiac potassium channels and prolongs the QT interval. Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
    Methamphetamine: (Major) 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 amphetamines. 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 addition, the MAOI activity of amphetamines may be of concern with the use of drugs that have serotonergic activity. A man developed marked agitation, anxiety, diaphoresis, shivering, tachycardia, tremor, generalized hypertonia, hyperreflexia, 1 to 2 beats of inducible ankle clonus, frequent myoclonic jerking, and tonic spasm of the right side of his orbicularis oris muscle while taking dexamphetamine and venlafaxine. Cessation of both drugs and administration of cyproheptadine led to a stepwise heart rate reduction and complete symptom resolution. Patients receiving an SNRI and an amphetamine should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. The SNRI and amphetamine should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Severe) 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.
    Methylene Blue: (Severe) 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: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and serotonin norepinephrine reuptake inhibitors (SNRIs). Serotonin syndrome has been reported during concurrent use of other serotonergic antidepressants (i.e., SSRIs) and methylphenidate. There is also a case of a neuroleptic malignant syndrome-like reaction occurring in a child on chronic methylphenidate therapy 45 minutes after ingesting a dose of venlafaxine. It is unclear if the reaction was the result of a drug interaction. 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 this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Metoclopramide: (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 are dopamine antagonists such as metoclopramide. 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. In addition, metoclopramide may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, or tardive dyskinesia) and is contraindicated with other drugs that are likely to cause extrapyramidal effects. Dystonia, akathisia, trismus, torticollis, dyskinesia, tardive dyskinesia, pseudo-parkinsonism, and/or extrapyramidal disorder (unspecified) have been reported during use of SNRIs; however, these effects appear uncommon. Patients receiving concurrent treatment with dopamine antagonists may be more predisposed to these reactions. Case reports documenting an interaction between metoclopramide and other serotonergic agents (i.e., SSRIs) suggest that serotonin syndrome and/or movement disorders are possible during combined use of metoclopramide and SNRIs. Patients receiving SNRIs and metoclopramide should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
    Metoprolol: (Moderate) Concurrent administration of therapeutic doses of metoprolol and venlafaxine for 5 days resulted in increased metoprolol plasma concentrations; however, the antihypertensive effect of metoprolol was reduced. The clinical significance of these findings in hypertensive patients is unknown. Because venlafaxine treatment has been associated with hypertension in some patients, regular monitoring of blood pressure is recommended.
    Metronidazole: (Moderate) Coadministration of metronidazole and venlafaxine may increase the risk for QT prolongation and torsade de pointes (TdP). Potential QT prolongation has been reported in limited case reports with metronidazole. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Midostaurin: (Major) The concomitant use of midostaurin and venlafaxine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. QT prolongation occurred in patients who received venlafaxine in clinical trials; additionally, QT prolongation and torsade de pointes have been reported in postmarketing surveillance of venlafaxine.
    Mifepristone, RU-486: (Moderate) Due to a possible risk for QT prolongation and torsade de pointes (TdP), mifepristone and venlafaxine should be used together cautiously. Mifepristone has been associated with dose-dependent prolongation of the QT interval. There is no experience with high exposure or concomitant use with other QT prolonging drugs. To minimize the risk of QT prolongation, the lowest effective dose should always be used. Drugs with a possible risk for QT prolongation and torsades de pointes that should be used cautiously with mifepristone include venlafaxine.
    Milnacipran: (Severe) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, serotonin norepinephrine reuptake inhibitors (SNRIs) including venlafaxine, desvenlafaxine, duloxetine, levomilnacipran, and milnacipran should not be coadministered with each other. 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. It is advisable to monitor for signs and symptoms of serotonin syndrome during 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. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with postmarketing use. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during use of mirtazapine, primarily after overdose or in patients with risk factors for QT prolongation (e.g., concurrent use of other medications associated with QT prolongation). Both mirtazapine and venlafaxine have central serotonin-enhancing effects. Cases of serotonin syndrome have been reported between mirtazapine and other antidepressants such as selective serotonin reuptake inhibitors (SSRIs). 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.
    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.
    Monoamine oxidase inhibitors: (Severe) 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 within 7 days of discontinuing treatment with other SNRIs. Conversely, SNRIs should not be initiated within 14 days of stopping an MAOI. 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.
    Morphine: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering drugs that have serotonergic properties such as morphine and serotonin norepinephrine reuptake inhibitors (SNRIs). 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. Morphine and the SNRI should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Morphine; Naltrexone: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering drugs that have serotonergic properties such as morphine and serotonin norepinephrine reuptake inhibitors (SNRIs). 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. Morphine and the SNRI should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Moxifloxacin: (Major) Concurrent use of venlafaxine and moxifloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with post-marketing use. Moxifloxacin has also been associated with prolongation of the QT interval. Additionally, post-marketing surveillance has identified very rare cases of ventricular arrhythmias including TdP, usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded.
    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.
    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; 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.
    Naproxen; Sumatriptan: (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; 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 the concomitant use of nilotinib with other agents that prolong the QT interval, such as venlafaxine. Nilotinib is a CYP3A4 and CYP2D6 inhibitor and venlafaxine is a substrate of CYP3A4 and CYP2D6; administering these drugs together may result in increased venlafaxine levels. If the use of venlafaxine is necessary, hold nilotinib therapy. If these drugs are used together, consider a venlafaxine dose reduction and monitor patients for toxicity (e.g., QT interval 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.
    Norfloxacin: (Moderate) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering venlafaxine with norfloxacin. Venlafaxine is associated with a possible risk of QT prolongation; TdP has been reported with post-marketing use. Quinolones have also been associated with QT prolongation and TdP. For norfloxacin specifically, extremely rare cases of TdP were reported during post-marketing surveillance. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Nortriptyline: (Major) 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. Clinicians should also be alert for pharmacokinetic interactions between tricyclic antidepressants and SNRIs. Duloxetine and venlafaxine are inhibitors of CYP2D6, and many TCAs are metabolized by this isozyme. Duloxetine increased the maximum plasma concentration (Cmax) of desipramine 1.7-fold and the AUC 2.9-fold in one study. One case report documented a first-time seizure in a patient receiving venlafaxine and trimipramine at therapeutic dosages. Patients receiving these combinations should be monitored for the emergence of serotonin syndrome or other adverse effects. In addition, venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has been reported with post-marketing use. Venlafaxine should be used cautiously with other drugs with a possible risk of QT prolongation and TdP including TCAs.
    Octreotide: (Moderate) Administer octreotide cautiously in patients receiving drugs that prolong the QT interval. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy, warranting more cautious monitoring during octreotide administration in higher risk patients with cardiac disease. 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. Until further data are available, it is suggested to use octreotide cautiously in patients receiving drugs which prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with octreotide include venlafaxine.
    Ofloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering venlafaxine with ofloxacin. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with post-marketing use. Some quinolones, including ofloxacin, have also been associated with QT prolongation. Additionally, post-marketing surveillance for ofloxacin has identified very rare cases of 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.
    Olodaterol: (Moderate) Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has been reported with post-marketing use. Drugs with a possible risk for QT prolongation that should be used cautiously with venlafaxine include the beat-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Ritonavir may be expected to decrease the metabolism of venlafaxine; ritonavir is a potent inhibitor of CYP3A4 and 2D6, and venlafaxine is a substrate for both of these enzymes. In addition, venlafaxine can inhibit the CYP2D6 metabolism of ritonavir. The risk of elevated plasma concentrations and toxicity may be greater when ritonavir is given with venlafaxine. In addition, both ritonavir and venlafaxine are associated with QT prolongation; concomitant use increases the risk of QT prolongation.
    Ondansetron: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), ondansetron and venlafaxine should be used together cautiously. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of TdP. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with post-marketing use.
    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.
    Osimertinib: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of venlafaxine with osimertinib is necessary; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Venlafaxine administration is also associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Oxaliplatin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of venlafaxine with oxaliplatin is necessary; correct electrolyte abnormalities prior to administration of oxaliplatin. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use. QT prolongation and ventricular arrhythmias including fatal TdP have also been reported with oxaliplatin use in postmarketing experience.
    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.
    Paliperidone: (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 paliperidone. 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 paliperidone.
    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: (Major) Due to similarity of pharmacology and the potential for serotonin syndrome, selective serotonin reuptake inhibitors (SSRIs) should generally not be administered with serotonin norepinephrine reuptake inhibitors like venlafaxine. 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 is suspected, venlafaxine, paroxetine, and concurrent serotonergic agents should be discontinued. In addition, because venlafaxine is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events.
    Pasireotide: (Major) Venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has reported with post-marketing use. Use caution close monitoring with pasireotide as coadministration may have additive effects on the prolongation of the QT interval.
    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) Pentamidine has been associated with QT prolongation. Drugs with a possible risk for QT prolongation and torsades de pointes (TdP) that should be used cautiously with pentamidine include venlafaxine. Venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has reported with post-marketing use.
    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: (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 anticoagulants. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. Monitor INR levels when venlafaxine is added to or discontinued from warfarin therapy. Patients should be instructed to monitor for signs and symptoms of bleeding while taking venlafaxine concurrently with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    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) 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. Clinicians should also be alert for pharmacokinetic interactions between tricyclic antidepressants and SNRIs. Duloxetine and venlafaxine are inhibitors of CYP2D6, and many TCAs are metabolized by this isozyme. Duloxetine increased the maximum plasma concentration (Cmax) of desipramine 1.7-fold and the AUC 2.9-fold in one study. One case report documented a first-time seizure in a patient receiving venlafaxine and trimipramine at therapeutic dosages. Patients receiving these combinations should be monitored for the emergence of serotonin syndrome or other adverse effects. In addition, venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has been reported with post-marketing use. Venlafaxine should be used cautiously with other drugs with a possible risk of QT prolongation and TdP including TCAs. (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 selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) together with caution; use together may be safe and efficacious for some patients based on available data, provided the patient is on a stable antidepressant regimen and receives close clinical monitoring. Regular appointments to assess the efficacy of the weight loss treatment, the emergence of adverse events, and blood pressure monitoring are recommended. Watch for excessive serotonergic effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome or cardiovascular or pulmonary effects when combined with serotonergic agents. One case report describes adverse reactions with phentermine and fluoxetine. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses, and that phentermine does not additionally increase plasma serotonin levels when combined with other serotonergic agents. In large controlled clinical studies, patients were allowed to start therapy with phentermine or phentermine; topiramate extended-release for obesity along with their antidepressants (e.g., SSRIs or SNRIs, but not MAOIs or TCAs) as long as the antidepressant dose had been stable for at least 3 months prior to the initiation of phentermine, and the patient did not have suicidal ideation or more than 1 episode of major depression documented. In analyses of the results, therapy was generally well tolerated, especially at lower phentermine doses, based on discontinuation rates and reported adverse events. Because depression and obesity often coexist, the study data may be important to providing optimal therapies.
    Phentermine; Topiramate: (Moderate) Use phentermine and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) together with caution; use together may be safe and efficacious for some patients based on available data, provided the patient is on a stable antidepressant regimen and receives close clinical monitoring. Regular appointments to assess the efficacy of the weight loss treatment, the emergence of adverse events, and blood pressure monitoring are recommended. Watch for excessive serotonergic effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome or cardiovascular or pulmonary effects when combined with serotonergic agents. One case report describes adverse reactions with phentermine and fluoxetine. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses, and that phentermine does not additionally increase plasma serotonin levels when combined with other serotonergic agents. In large controlled clinical studies, patients were allowed to start therapy with phentermine or phentermine; topiramate extended-release for obesity along with their antidepressants (e.g., SSRIs or SNRIs, but not MAOIs or TCAs) as long as the antidepressant dose had been stable for at least 3 months prior to the initiation of phentermine, and the patient did not have suicidal ideation or more than 1 episode of major depression documented. In analyses of the results, therapy was generally well tolerated, especially at lower phentermine doses, based on discontinuation rates and reported adverse events. Because depression and obesity often coexist, the study data may be important to providing optimal therapies.
    Phenylephrine; Promethazine: (Moderate) Monitor for evidence of QT prolongation if promethazine is coadministered with venlafaxine. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Pimavanserin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known 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. Coadministration may increase the risk for QT prolongation.
    Pimozide: (Severe) Venlafaxine is contraindicated for use with pimozide. Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Venlafaxine is associated with a possible risk of QT prolongation. Serotonin syndrome or neuroleptic malignant syndrome-like reactions are also possible. 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 these combinations should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
    Pirbuterol: (Minor) Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has been reported with post-marketing use. Drugs with a possible risk for QT prolongation that should be used cautiously with venlafaxine include the beat-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    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.
    Posaconazole: (Severe) 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: (Major) Due to the potential for QT interval prolongation with primaquine, caution is advised with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with primaquine include venlafaxine.
    Procainamide: (Major) Venlafaxine should be used cautiously and with close clinical monitoring with procainamide. Procainamide is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with post-marketing use.
    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) Monitor for evidence of QT prolongation if promethazine is coadministered with venlafaxine. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Propafenone: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with venlafaxine. Propafenone is a Class IC antiarrhythmic which increases the QT interval largely due to prolongation of the QRS interval. Venlafaxine is also associated with a possible risk of QT prolongation; TdP has been reported with post-marketing use. In addition, an elderly women exhibited psychosis 2 weeks after an increase in her dose of venlafaxine from 225 to 300 mg/day and initiation of propafenone at 600 mg/day. Upon evaluation it was found that her serum concentrations of venlafaxine had increased > 6-fold. Although the mechanism of this interaction has not been described, it is possible that strong inhibition of CYP2D6 by propafenone led to elevated serum concentrations of venlafaxine, a CYP2D6 substrate. Additionally, propafenone is also a substrate for CYP2D6, and competitive inhibition may have played a role. Serum concentrations of venlafaxine and the clinical response to therapy should be monitored if adding propafenone to the regimen.
    Protriptyline: (Major) 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. Clinicians should also be alert for pharmacokinetic interactions between tricyclic antidepressants and SNRIs. Duloxetine and venlafaxine are inhibitors of CYP2D6, and many TCAs are metabolized by this isozyme. Duloxetine increased the maximum plasma concentration (Cmax) of desipramine 1.7-fold and the AUC 2.9-fold in one study. One case report documented a first-time seizure in a patient receiving venlafaxine and trimipramine at therapeutic dosages. Patients receiving these combinations should be monitored for the emergence of serotonin syndrome or other adverse effects. In addition, venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has been reported with post-marketing use. Venlafaxine should be used cautiously with other drugs with a possible risk of QT prolongation and TdP including TCAs.
    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: (Severe) 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.
    Regadenoson: (Moderate) Regadenoson has been associated with QT prolongation. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with regadenoson include venlafaxine.
    Remifentanil: (Moderate) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    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 has been shown to prolong the QT interval in a concentration-dependent manner. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with postmarketing use. Concomitant use may increase the risk for QT prolongation. Ribociclib is also a moderate CYP3A4 inhibitor and venlafaxine is a CYP3A4 substrate.
    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 has been shown to prolong the QT interval in a concentration-dependent manner. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with postmarketing use. Concomitant use may increase the risk for QT prolongation. Ribociclib is also a moderate CYP3A4 inhibitor and venlafaxine is a CYP3A4 substrate.
    Rilpivirine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with venlafaxine. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with post-marketing use. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also been associated with prolongation of the QT interval.
    Risperidone: (Major) Because both venlafaxine and risperidone are associated with a possible risk of QT prolongation, caution is advisable during coadministration.
    Ritonavir: (Major) Ritonavir may be expected to decrease the metabolism of venlafaxine; ritonavir is a potent inhibitor of CYP3A4 and 2D6, and venlafaxine is a substrate for both of these enzymes. In addition, venlafaxine can inhibit the CYP2D6 metabolism of ritonavir. The risk of elevated plasma concentrations and toxicity may be greater when ritonavir is given with venlafaxine. In addition, both ritonavir and venlafaxine are associated with QT prolongation; concomitant use increases the risk of QT prolongation.
    Rivaroxaban: (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 anticoagulants. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. Monitor INR levels when venlafaxine is added to or discontinued from warfarin therapy. Patients should be instructed to monitor for signs and symptoms of bleeding while taking venlafaxine concurrently with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Rofecoxib: (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.
    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 lasts for at least 7 days, and may last longer after single dose administration. The Cmax and AUC of another CYP2D6 substrate, dextromethorphan, were increased by 120% and 160%, respectively, on day 1 with rolapitant, and by 180% and 230%, respectively, on day 8 after rolapitant administration.
    Romidepsin: (Major) Romidepsin 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 romidepsin and venlafaxine must be coadministered, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Safinamide: (Severe) 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.
    Salmeterol: (Moderate) Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has been reported with post-marketing use. Drugs with a possible risk for QT prolongation that should be used cautiously with venlafaxine include the beat-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    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.
    Serotonin-Receptor Agonists: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering a selective serotonin norepinephrine reuptake inhibitor (SNRI) like venlafaxine with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan) because of the potential risk and severity of serotonin syndrome. Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SNRI or the addition of other serotonergic medications to an existing SNRI regimen.
    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. 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, venlafaxine and concurrent serotonergic agents should be discontinued.
    Short-acting beta-agonists: (Minor) Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has been reported with post-marketing use. Drugs with a possible risk for QT prolongation that should be used cautiously with venlafaxine include the beat-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    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.
    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.
    Sorafenib: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering sorafenib with venlafaxine. If these drugs must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Sorafenib has been associated with QT prolongation. Venlafaxine is also associated with a possible risk of QT prolongation; TdP has been reported with post-marketing use.
    Sotalol: (Major) Sotalol administration is associated with QT prolongation and torsades de pointes (TdP). Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has been reported with post-marketing use and should be used cautiously with sotalol.
    St. John's Wort, Hypericum perforatum: (Major) Due to possible additive effects on serotonin concentrations, it is advisable to avoid combinations of St. John's wort, Hypericum perforatum with serotonin norepinephrine reuptake inhibitors (SNRIs). Interactions between SNRIs and serotonergic agents 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.
    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.
    Sunitinib: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), sunitinib and venlafaxine should be used together cautiously. Sunitinib can prolong the QT interval. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with postmarketing use.
    Tacrolimus: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), tacrolimus and venlafaxine should be used together cautiously. Tacrolimus causes QT prolongation. Venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has reported with post-marketing use.
    Tamoxifen: (Moderate) Caution is advised with the concomitant use of tamoxifen and venlafaxine due to an increased risk of QT prolongation and torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has been reported with postmarketing use.
    Tapentadol: (Major) Caution is advised when tapentadol is coadministered with serotonin norepinephrine reuptake inhibitors as this combination may result in excessive concentrations of serotonin and/or norepinephrine and increase the potential for adverse cardiac events and serotonin syndrome development. If concomitant treatment is clinically warranted, careful observation of the patient is advised, especially during initiation of the second therapy and after dosage adjustments (increases) of either agent.
    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.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering venlafaxine with telaprevir due to an increased potential for venlafaxine-related adverse events. If venlafaxine dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of venlafaxine. Venlafaxine is partially metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated venlafaxine plasma concentrations.
    Telavancin: (Major) 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: (Major) 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. Additionally, telithromycin is a strong inhibitor of CYP3A4 and may affect the metabolism of venlafaxine. This could potentially result in increased plasma concentrations of venlafaxine.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and venlafaxine is necessary, as the systemic exposure of venlafaxine may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of venlafaxine; consider increasing the dose of venlafaxine if necessary. Venlafaxine is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    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.
    Terbutaline: (Minor) Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has been reported with post-marketing use. Drugs with a possible risk for QT prolongation that should be used cautiously with venlafaxine include the beat-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Tetrabenazine: (Major) etrabenazine causes a small increase in the corrected QT interval (QTc). The manufacturer recommends avoiding concurrent use of tetrabenazine with other drugs known to prolong QTc such as venlafaxine. Venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has reported with post-marketing use.
    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: (Severe) 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.
    Tinzaparin: (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 anticoagulants. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. Monitor INR levels when venlafaxine is added to or discontinued from warfarin therapy. Patients should be instructed to monitor for signs and symptoms of bleeding while taking venlafaxine concurrently with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Tiotropium; Olodaterol: (Moderate) Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has been reported with post-marketing use. Drugs with a possible risk for QT prolongation that should be used cautiously with venlafaxine include the beat-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    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.
    Tizanidine: (Moderate) Tizanidine should be used cautiously and with close monitoring with venlafaxine. Tizanidine administration may result in QT prolongation. Venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has reported with post-marketing use. Coadministration increases the risk for QT prolongation and torsade de pointes.
    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) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with toremifene include venlafaxine.
    Tramadol: (Major) 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 tramadol. 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. In one case, the addition of tramadol to extended-release venlafaxine (300 mg/day) and mirtazapine (30 mg/day) likely caused serotonin syndrome. A patient developed agitation, confusion, severe shivering, diaphoresis, myoclonus, hyperreflexia, mydriasis, tachycardia, and fever within 7 weeks of taking tramadol 400 mg daily. He had taken 300 mg tramadol without difficulty. Discontinuation of the 3 drugs and rehydration led to symptom resolution over 36 hours. Reinstitution of the antidepressants 3 days after patient presentation was uneventful. Also, duloxetine and venlafaxine may inhibit the formation of the active M1 metabolite of tramadol by inhibiting CYP2D6. The inhibition of this metabolite may decrease the analgesic effectiveness of tramadol but increase the level of the parent compound, which has more serotonergic activity than the metabolite The risk for serious adverse effects such as seizures and serotonin syndrome may be increased. Patients receiving tramadol in combination with an SNRI should be monitored for the emergence of serotonin syndrome or other adverse effects.
    Trazodone: (Major) Due to the risk of serotonin syndrome, concurrent use of trazodone and venlafaxine, should be avoided if possible. If concomitant use is clinically warranted, patients should be informed of the increased risk of serotonin syndrome, particularly during treatment initiation and during dose increases. 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. Treatment with trazodone and any concomitant serotonergic agents should be discontinued immediately if signs and symptoms of serotonin syndrome occur, and supportive symptomatic treatment should be initiated. Tthe manufacturer of trazodone recommends avoiding trazodone in patients receiving other drugs that increase the QT interval due to reports of QT prolongation and torsade de pointes (TdP) during treatment with trazodone. Venlafaxine has a possible risk for QT prolongation and TdP.
    Tricyclic antidepressants: (Major) 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. Clinicians should also be alert for pharmacokinetic interactions between tricyclic antidepressants and SNRIs. Duloxetine and venlafaxine are inhibitors of CYP2D6, and many TCAs are metabolized by this isozyme. Duloxetine increased the maximum plasma concentration (Cmax) of desipramine 1.7-fold and the AUC 2.9-fold in one study. One case report documented a first-time seizure in a patient receiving venlafaxine and trimipramine at therapeutic dosages. Patients receiving these combinations should be monitored for the emergence of serotonin syndrome or other adverse effects. In addition, venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has been reported with post-marketing use. Venlafaxine should be used cautiously with other drugs with a possible risk of QT prolongation and TdP including TCAs.
    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) 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. Clinicians should also be alert for pharmacokinetic interactions between tricyclic antidepressants and SNRIs. Duloxetine and venlafaxine are inhibitors of CYP2D6, and many TCAs are metabolized by this isozyme. Duloxetine increased the maximum plasma concentration (Cmax) of desipramine 1.7-fold and the AUC 2.9-fold in one study. One case report documented a first-time seizure in a patient receiving venlafaxine and trimipramine at therapeutic dosages. Patients receiving these combinations should be monitored for the emergence of serotonin syndrome or other adverse effects. In addition, venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has been reported with post-marketing use. Venlafaxine should be used cautiously with other drugs with a possible risk of QT prolongation and TdP including TCAs.
    Triptorelin: (Moderate) Androgen deprivation therapy (e.g., triptorelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with triptorelin include venlafaxine.
    Umeclidinium; Vilanterol: (Moderate) Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has been reported with post-marketing use. Drugs with a possible risk for QT prolongation that should be used cautiously with venlafaxine include the beat-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    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) The manufacturer of vandetanib recommends avoiding coadministration with other drugs that prolong the QT interval due to an increased risk of QT prolongation and torsade de pointes (TdP). Vandetanib can prolong the QT interval in a concentration-dependent manner. TdP and sudden death have been reported in patients receiving vandetanib. Venlafaxine administration is also associated with a possible risk of QT prolongation; TdP has reported with postmarketing use. If coadministration is necessary, an ECG is needed, as well as more frequent monitoring of the QT interval. If QTcF is greater than 500 msec, interrupt vandetanib dosing until the QTcF is less than 450 msec; then, vandetanib may be resumed at a reduced dose.
    Vardenafil: (Major) Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produces an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). When vardenafil (10 mg) was given with gatifloxacin (400 mg), an additive effect on the QT interval was observed. The effect of vardenafil on the QT interval should be considered when prescribing the drug. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with vardenafil include venlafaxine.
    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.
    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 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: (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 anticoagulants. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. Monitor INR levels when venlafaxine is added to or discontinued from warfarin therapy. Patients should be instructed to monitor for signs and symptoms of bleeding while taking venlafaxine concurrently with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Ziprasidone: (Severe) Venlafaxine is contraindicated for use with ziprasidone. Venlafaxine is associated with a possible risk of QT prolongation and ziprasidone has an established risk of QT prolongation and torsades de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation. In one study, ziprasidone increased the QT interval 10 msec more than placebo at the maximum recommended dosage. Comparative data with other antipsychotics have shown that the mean QTc interval prolongation occurring with ziprasidone exceeds that of haloperidol, quetiapine, olanzapine, and risperidone, but is less than that which occurs with thioridazine.
    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

    There are no adequate and well-controlled studies regarding use of venlafaxine during human pregnancy. Venlafaxine should be used in pregnancy only where the benefit to the mother clearly outweighs any potential risk to the fetus. Alternative agents should be considered. Animal studies (rats, rabbits) have failed to show an increased risk of fetal malformations. However, an increase in stillbirths, low birth-weight, and pup deaths postnatally has been noted when venlafaxine was given throughout gestation and continued during lactation in rats. These effects occurred at 2.5 times (mg/m2) the maximum human daily dose. The no effect dose for rat pup mortality was 0.25 times the human dose on a mg/m2 basis. Animal studies may not be predictive of human response. Non-teratogenic effects have been reported in humans. If the clinician and patient decide to continue venlafaxine during pregnancy, 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. Features are consistent with either a direct toxic effect of serotonergic agents or, possibly, a neonatal abstinence syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome. When treating a pregnant woman with an SNRI or other serotonergic agent during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. 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. Pregnant women using antidepressants are encouraged to register. For more information, contact the registry at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry or by phone 1-866-961-2388. The effects of venlafaxine on labor and delivery are unknown.

    MECHANISM OF ACTION

    Mechanism of Action: Like the tricyclics, venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), exert their antidepressant effects by inhibiting the reuptake of both serotonin and norepinephrine. In vivo, venlafaxine blocks both reuptake processes, with a potency greater for the 5-HT than for the NE reuptake process. Like the SSRI's, venlafaxine appears to act preferentially on certain serotonin receptors in vivo, but mechanisms have not been precisley defined. Both venlafaxine and the ODV metabolite have weak inhibitory effects on the reuptake of dopamine. Unlike the tricyclics and similar to SSRIs, venlafaxine and ODV do not exert activity at histaminergic, muscarinic, or alpha1-adrenergic receptors in vitro, which accounts for its lack of anticholinergic, sedative, and cardiovascular side effects frequently observed with the tricyclic antidepressants. However, despite the claims of minimal muscarinic receptor activity, anticholinergic-related side effects may still occur with venlafaxine. Neither parent nor metabolite possess monoamine oxidase inhibiting activity.

    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 primarily a substrate of CYP2D6, and metabolism occurs through CYP3A4 to a minor extent. Venlafaxine is a weak inhibitor of CYP2D6 in vivo. Venlafaxine does not appear to inhibit other CYP hepatic isoenzymes, including CYP3A4, CYP2C9, CYP2C19 or CYP1A2, based on in vitro studies. In studies of CYP2D6-poor metabolizers (PMs) and -extensive metabolizers, the total concentration of active compounds (venlafaxine plus the ODV metabolite), was similar in the two metabolizer groups; however, CYP2D6 PMs had increased levels of venlafaxine and reduced levels of ODV compared to the extensive metabolizers (those with normal CYP2D6 activity). No dosage adjustment is required when venlafaxine is given to patients who are CYP2D6 PMs in the absence of other risk factors for reduced metabolism. However, drugs that inhibit CYP2D6 may result in elevated venlafaxine plasma concentrations, particularly in patients who are CYP2D6 PMs. A drug that inhibits CYP3A4 alone is unlikely to cause cliinically significant drug interactions. Drugs that potently inhibit both CYP2D6 and CYP3A4 may increase the risk for venlafaxine toxicity.

    Oral Route

    Venlafaxine is well absorbed from the gastrointestinal tract, with food having no significant effect on its absorption or the formation of its active metabolite, O-desmethylvenlafaxine (ODV). After administration of an immediate-release tablet, time to peak serum concentration occurs at approximately 2 and 4 hours for venlafaxine and ODV, respectively; administration of the extended-release formulation results in later times to peak serum concentration (5.5 hours for venlafaxine and 9 hours for ODV).