CLASSES

Serotonin Norepinephrine Reuptake Inhibitor Antidepressants, SNRIs

BOXED WARNING

Venlafaxine is not FDA approved for the treatment of major depressive disorder (MDD) in children. In October 2004, the FDA directed manufacturers of all antidepressants to add a boxed warning to their product labels detailing the risk of suicide 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 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. 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 with 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 pediatrics 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 during dose changes. It is unknown if the suicidality risk in children or young adults extends to longer-term therapy. The possibility of a suicide attempt is inherent in patients with depressive symptoms, whether these occur in primary depression or in association with another primary disorder. All patients with a history of suicidal ideation or behaviors and those with a prominence of suicidal ideation prior to treatment should be closely monitored during treatment with venlafaxine. In patients who exhibit worsening of depression or suicidality, a decision should be made to change or discontinue treatment. If discontinuing, the 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 to reduce the risk of overdose. Postmarketing 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. 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

Serotonin norepinephrine reuptake inhibitor (SNRI) class antidepressant
Used in adults for major depression, generalized anxiety disorder, social anxiety disorder, and panic disorder; effective in women with hot flashes due to menopause or breast cancer treatment
Boxed warning regarding increased risk of suicidality in pediatric and young adult patients at treatment initiation and dose changes

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

†Indicates off-label use

MAXIMUM DOSAGE

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.

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.

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.

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.

Not indicated.

DOSING CONSIDERATIONS

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.

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

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

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 between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

CONTRAINDICATIONS / PRECAUTIONS

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.

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.

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.

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.

Venlafaxine is not FDA approved for the treatment of major depressive disorder (MDD) in children. In October 2004, the FDA directed manufacturers of all antidepressants to add a boxed warning to their product labels detailing the risk of suicide 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 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. 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 with 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 pediatrics 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 during dose changes. It is unknown if the suicidality risk in children or young adults extends to longer-term therapy. The possibility of a suicide attempt is inherent in patients with depressive symptoms, whether these occur in primary depression or in association with another primary disorder. All patients with a history of suicidal ideation or behaviors and those with a prominence of suicidal ideation prior to treatment should be closely monitored during treatment with venlafaxine. In patients who exhibit worsening of depression or suicidality, a decision should be made to change or discontinue treatment. If discontinuing, the 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 to reduce the risk of overdose. Postmarketing 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. 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

There are no adequate and well-controlled studies regarding use of venlafaxine during human pregnancy. Venlafaxine should be used in pregnancy only when the benefit to the mother clearly outweighs any potential risk to the fetus.  Animal studies have failed to show an increased risk of teratogenic effects; however, other fetal toxicities have been observed. Consider the risks of untreated depression during pregnancy as well as the potential risks to the fetus from exposure to the drug. When treating a pregnant woman with a serotonin norepinephrine reuptake inhibitor (SNRI) or other serotonergic agent during the third trimester, discontinuation symptoms should be considered in the newborn at birth. Neonates exposed to serotonergic antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Symptoms have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with serotonin syndrome or possibly a drug discontinuation syndrome. 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. Exposure to SNRIs in mid to late pregnancy may increase the risk of eclampsia. Exposure to SNRIs near obstetric delivery may increase the risk for postpartum hemorrhage.

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

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

ADVERSE REACTIONS

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
heart failure / Delayed / 0-0.1
myocardial infarction / Delayed / 0-0.1
AV block / Early / 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
spontaneous fetal abortion / Delayed / 0-0.1
anuria / Delayed / 0-0.1
oliguria / Early / 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
ventricular tachycardia / Early / Incidence not known
cardiomyopathy / Delayed / Incidence not known
torsade de pointes / Rapid / Incidence not known
ventricular fibrillation / Early / Incidence not known
atrial 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
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / 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
anaphylactoid reactions / Rapid / Incidence not known
renal failure (unspecified) / Delayed / Incidence not known
neonatal abstinence syndrome / Early / Incidence not known

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
angina / Early / 0.1-1.0
peripheral vasoconstriction / Rapid / 0.1-1.0
phlebitis / Rapid / 0-1.0
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
urinary incontinence / Early / 0.1-1.0
vaginal bleeding / Delayed / 0.1-1.0
urinary retention / 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
flank pain / Delayed / 0-0.1
hypercalciuria / Delayed / 0-0.1
glycosuria / Early / 0-0.1
nephrolithiasis / Delayed / 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
chest pain (unspecified) / Early / 1.0
edema / Delayed / 1.0
vaginitis / Delayed / 1.0
prostatitis / Delayed / 1.0
delirium / Early / Incidence not known
dyskinesia / Delayed / Incidence not known
supraventricular tachycardia (SVT) / Early / Incidence not known
QT prolongation / Rapid / 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

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 / 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
maculopapular rash / Early / 0.1-1.0
urticaria / Rapid / 0.1-1.0
alopecia / Delayed / 0.1-1.0
xerosis / Delayed / 0.1-1.0
pruritus / Rapid / 1.0-1.0
photosensitivity / Delayed / 0.1-1.0
hirsutism / Delayed / 0.1-1.0
urinary urgency / Early / 0.1-1.0
nocturia / Early / 0.1-1.0
polyuria / Early / 0.1-1.0
menorrhagia / Delayed / 0.1-1.0
amenorrhea / Delayed / 0.1-1.0
mastalgia / Delayed / 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
breast enlargement / Delayed / 0-0.1
gynecomastia / Delayed / 0-0.1
breast discharge / 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
restlessness / Early / Incidence not known
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; Butalbital; Caffeine; Codeine: (Moderate) Monitor for additive CNS effects, such as sedation, with use of these drugs together. Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during use of codeine with venlafaxine because of the potential risk of serotonin syndrome. Discontinue all serotonergic agents if serotonin syndrome is suspected. In theory, use of codeine with venlafaxine might also result in reduced codeine efficacy or symptoms of opioid withdrawal in patients at risk. Codeine is primarily metabolized by CYP2D6 to morphine. Venlafaxine is a weak inhibitor of CYP2D6.
Acetaminophen; Caffeine; Dihydrocodeine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of dihydrocodeine and venlafaxine because of the potential risk of serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Discontinue dihydrocodeine if serotonin syndrome is suspected. Additionally, concomitant use of dihydrocodeine with venlafaxine may decrease dihydrocodeine plasma concentrations resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of venlafaxine could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If venlafaxine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Venlafaxine is a weak inhibitor of CYP2D6.
Acetaminophen; 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: (Moderate) Use of venlafaxine with dextromethorphan may increase the risk of serotonin syndrome or other adverse effects of dextromethorphan. Venlafaxine is a serotonin norepinephrine reuptake inhibitor and also inhibits CYP2D6, the isozyme responsible for dextromethorphan metabolism. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Use of venlafaxine with dextromethorphan may increase the risk of serotonin syndrome or other adverse effects of dextromethorphan. Venlafaxine is a serotonin norepinephrine reuptake inhibitor and also inhibits CYP2D6, the isozyme responsible for dextromethorphan metabolism. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
Acetaminophen; Codeine: (Moderate) Monitor for additive CNS effects, such as sedation, with use of these drugs together. Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during use of codeine with venlafaxine because of the potential risk of serotonin syndrome. Discontinue all serotonergic agents if serotonin syndrome is suspected. In theory, use of codeine with venlafaxine might also result in reduced codeine efficacy or symptoms of opioid withdrawal in patients at risk. Codeine is primarily metabolized by CYP2D6 to morphine. Venlafaxine is a weak inhibitor of CYP2D6.
Acetaminophen; Dextromethorphan: (Moderate) Use of venlafaxine with dextromethorphan may increase the risk of serotonin syndrome or other adverse effects of dextromethorphan. Venlafaxine is a serotonin norepinephrine reuptake inhibitor and also inhibits CYP2D6, the isozyme responsible for dextromethorphan metabolism. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Use of venlafaxine with dextromethorphan may increase the risk of serotonin syndrome or other adverse effects of dextromethorphan. Venlafaxine is a serotonin norepinephrine reuptake inhibitor and also inhibits CYP2D6, the isozyme responsible for dextromethorphan metabolism. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Use of venlafaxine with dextromethorphan may increase the risk of serotonin syndrome or other adverse effects of dextromethorphan. Venlafaxine is a serotonin norepinephrine reuptake inhibitor and also inhibits CYP2D6, the isozyme responsible for dextromethorphan metabolism. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Use of venlafaxine with dextromethorphan may increase the risk of serotonin syndrome or other adverse effects of dextromethorphan. Venlafaxine is a serotonin norepinephrine reuptake inhibitor and also inhibits CYP2D6, the isozyme responsible for dextromethorphan metabolism. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Use of venlafaxine with dextromethorphan may increase the risk of serotonin syndrome or other adverse effects of dextromethorphan. Venlafaxine is a serotonin norepinephrine reuptake inhibitor and also inhibits CYP2D6, the isozyme responsible for dextromethorphan metabolism. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
Acetaminophen; Hydrocodone: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and venlafaxine because of the potential risk of serotonin syndrome. Discontinue hydrocodone if serotonin syndrome is suspected. Additionally, concomitant use of hydrocodone with venlafaxine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of venlafaxine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If venlafaxine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Venlafaxine is a weak inhibitor of CYP2D6.
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.
Aclidinium; 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.
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: (Moderate) Due to a possible risk for QT prolongation and torsade de pointes (TdP), alfuzosin and venlafaxine should be used together cautiously. Based on electrophysiology studies performed by the manufacturer, alfuzosin may prolong the QT interval in a dose-dependent manner. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with postmarketing use.
Aminosalicylate sodium, Aminosalicylic acid: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Amiodarone: (Major) 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.
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: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and serotonin norepinephrine reuptake inhibitors (SNRIs). At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
Anagrelide: (Major) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be instructed to monitor for signs and symptoms of bleeding while taking venlafaxine concurrently with a platelet inhibitor and to promptly report any bleeding events to the practitioner. Also, torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with anagrelide include venlafaxine.
Antithrombin III: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like antithrombin III. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Apixaban: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like apixaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Apomorphine: (Moderate) Exercise caution when administering apomorphine concomitantly with venlafaxine as concurrent use may increase the risk of QT prolongation. Limited data indicate that QT prolongation is possible with apomorphine administration; the change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
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: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like argatroban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Aripiprazole: (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 or Aristada Initio 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) Monitor for additive CNS effects, such as sedation, with use of these drugs together. Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during use of codeine with venlafaxine because of the potential risk of serotonin syndrome. Discontinue all serotonergic agents if serotonin syndrome is suspected. In theory, use of codeine with venlafaxine might also result in reduced codeine efficacy or symptoms of opioid withdrawal in patients at risk. Codeine is primarily metabolized by CYP2D6 to morphine. Venlafaxine is a weak inhibitor of CYP2D6. (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: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of dihydrocodeine and venlafaxine because of the potential risk of serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Discontinue dihydrocodeine if serotonin syndrome is suspected. Additionally, concomitant use of dihydrocodeine with venlafaxine may decrease dihydrocodeine plasma concentrations resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of venlafaxine could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If venlafaxine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Venlafaxine is a weak inhibitor of CYP2D6. (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Aspirin, ASA; Carisoprodol: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Monitor for additive CNS effects, such as sedation, with use of these drugs together. Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during use of codeine with venlafaxine because of the potential risk of serotonin syndrome. Discontinue all serotonergic agents if serotonin syndrome is suspected. In theory, use of codeine with venlafaxine might also result in reduced codeine efficacy or symptoms of opioid withdrawal in patients at risk. Codeine is primarily metabolized by CYP2D6 to morphine. Venlafaxine is a weak inhibitor of CYP2D6. (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Aspirin, ASA; Dipyridamole: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner. (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with a platelet inhibitor and to promptly report any bleeding events to the practitioner.
Aspirin, ASA; Omeprazole: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Aspirin, ASA; Oxycodone: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Aspirin, ASA; Pravastatin: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Atazanavir; Cobicistat: (Moderate) Monitor for adverse effects when administering venlafaxine with cobicistat. There is a potential for elevated venlafaxine and cobicistat concentrations if these drugs are given together. Venlafaxine and cobicistat are substrates and inhibitors of CYP2D6. In addition, venlafaxine is a substrate for CYP3A4; cobicistat is a strong inhibitor of CYP3A4.
Atomoxetine: (Moderate) The concomitant use of atomoxetine and venlafaxine may lead to additive 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: (Moderate) Use caution if venlafaxine is coadministered with azithromycin due to the potential for QT prolongation and torsade de pointes (TdP). Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with postmarketing use. Azithromycin has also been associated with postmarketing reports of QT prolongation and TdP.
Bedaquiline: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with venlafaxine. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Venlafaxine administration is also associated with a possible risk of QT prolongation; TdP has been reported with post-marketing use.
Benzhydrocodone; Acetaminophen: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of benzhydrocodone and venlafaxine because of the potential risk of serotonin syndrome. Discontinue benzhydrocodone if serotonin syndrome is suspected. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (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: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and serotonin norepinephrine reuptake inhibitors. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
Betrixaban: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like betrixaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) 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: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like bivalirudin. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
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.
Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Use of venlafaxine with dextromethorphan may increase the risk of serotonin syndrome or other adverse effects of dextromethorphan. Venlafaxine is a serotonin norepinephrine reuptake inhibitor and also inhibits CYP2D6, the isozyme responsible for dextromethorphan metabolism. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and venlafaxine because of the potential risk of serotonin syndrome. Discontinue hydrocodone if serotonin syndrome is suspected. Additionally, concomitant use of hydrocodone with venlafaxine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of venlafaxine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If venlafaxine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Venlafaxine is a weak inhibitor of CYP2D6.
Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and venlafaxine because of the potential risk of serotonin syndrome. Discontinue hydrocodone if serotonin syndrome is suspected. Additionally, concomitant use of hydrocodone with venlafaxine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of venlafaxine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If venlafaxine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Venlafaxine is a weak inhibitor of CYP2D6.
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, caution should be observed when coadministering drugs that have serotonergic properties such as buspirone 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. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be initiated.
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: (Moderate) Use of venlafaxine with dextromethorphan may increase the risk of serotonin syndrome or other adverse effects of dextromethorphan. Venlafaxine is a serotonin norepinephrine reuptake inhibitor and also inhibits CYP2D6, the isozyme responsible for dextromethorphan metabolism. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and venlafaxine because of the potential risk of serotonin syndrome. Discontinue hydrocodone if serotonin syndrome is suspected. Additionally, concomitant use of hydrocodone with venlafaxine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of venlafaxine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If venlafaxine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Venlafaxine is a weak inhibitor of CYP2D6.
Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and venlafaxine because of the potential risk of serotonin syndrome. Discontinue hydrocodone if serotonin syndrome is suspected. Additionally, concomitant use of hydrocodone with venlafaxine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of venlafaxine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If venlafaxine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Venlafaxine is a weak inhibitor of CYP2D6.
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) Avoid coadministration of ceritinib with venlafaxine if possible due to the risk of QT prolongation; plasma concentrations of venlafaxine may also increase. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Monitor for venlafaxine-related adverse reactions. Venlafaxine is a CYP3A4 substrate that is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has been reported with postmarketing use. Ceritinib is a strong CYP3A4 inhibitor that causes concentration-dependent QT prolongation.
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; Codeine: (Moderate) Monitor for additive CNS effects, such as sedation, with use of these drugs together. Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during use of codeine with venlafaxine because of the potential risk of serotonin syndrome. Discontinue all serotonergic agents if serotonin syndrome is suspected. In theory, use of codeine with venlafaxine might also result in reduced codeine efficacy or symptoms of opioid withdrawal in patients at risk. Codeine is primarily metabolized by CYP2D6 to morphine. Venlafaxine is a weak inhibitor of CYP2D6.
Chlorpheniramine; Dextromethorphan: (Moderate) Use of venlafaxine with dextromethorphan may increase the risk of serotonin syndrome or other adverse effects of dextromethorphan. Venlafaxine is a serotonin norepinephrine reuptake inhibitor and also inhibits CYP2D6, the isozyme responsible for dextromethorphan metabolism. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Use of venlafaxine with dextromethorphan may increase the risk of serotonin syndrome or other adverse effects of dextromethorphan. Venlafaxine is a serotonin norepinephrine reuptake inhibitor and also inhibits CYP2D6, the isozyme responsible for dextromethorphan metabolism. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of dihydrocodeine and venlafaxine because of the potential risk of serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Discontinue dihydrocodeine if serotonin syndrome is suspected. Additionally, concomitant use of dihydrocodeine with venlafaxine may decrease dihydrocodeine plasma concentrations resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of venlafaxine could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If venlafaxine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Venlafaxine is a weak inhibitor of CYP2D6.
Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of dihydrocodeine and venlafaxine because of the potential risk of serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Discontinue dihydrocodeine if serotonin syndrome is suspected. Additionally, concomitant use of dihydrocodeine with venlafaxine may decrease dihydrocodeine plasma concentrations resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of venlafaxine could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If venlafaxine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Venlafaxine is a weak inhibitor of CYP2D6.
Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and venlafaxine because of the potential risk of serotonin syndrome. Discontinue hydrocodone if serotonin syndrome is suspected. Additionally, concomitant use of hydrocodone with venlafaxine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of venlafaxine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If venlafaxine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Venlafaxine is a weak inhibitor of CYP2D6.
Chlorpheniramine; Hydrocodone: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and venlafaxine because of the potential risk of serotonin syndrome. Discontinue hydrocodone if serotonin syndrome is suspected. Additionally, concomitant use of hydrocodone with venlafaxine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of venlafaxine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If venlafaxine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Venlafaxine is a weak inhibitor of CYP2D6.
Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and venlafaxine because of the potential risk of serotonin syndrome. Discontinue hydrocodone if serotonin syndrome is suspected. Additionally, concomitant use of hydrocodone with venlafaxine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of venlafaxine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If venlafaxine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Venlafaxine is a weak inhibitor of CYP2D6.
Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and venlafaxine because of the potential risk of serotonin syndrome. Discontinue hydrocodone if serotonin syndrome is suspected. Additionally, concomitant use of hydrocodone with venlafaxine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of venlafaxine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If venlafaxine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Venlafaxine is a weak inhibitor of CYP2D6.
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.
Clofazimine: (Major) Monitor ECGs for QT prolongation when clofazimine is administered with venlafaxine. QT prolongation and torsade de pointes (TdP) have been reported in patients receiving clofazimine in combination with QT prolonging medications. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has been reported with postmarketing use.
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) Carefully monitor patients for signs and symptoms of bleeding during coadministration of venlafaxine and clopidogrel. Serotonin-norepinephrine reuptake inhibitors (SNRIs) affect platelet activation; therefore, concomitant use may increase the risk of bleeding.
Clozapine: (Major) Venlafaxine is associated with a possible risk of QT prolongation and clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. In addition, venlafaxine is a weak inhibitor of CYP2D6. Clozapine is a substrate of CYP1A2, CYP2D6, or CYP3A4 and elevated plasma concentrations of clozapine occurring through CYP inhibition may increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP2D6 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary. Post-marketing reports have indicated there may be the potential for seizure activity if venlafaxine is added to established clozapine therapy. Clozapine serum concentrations have risen temporally following the addition of venlafaxine.
Cobicistat: (Moderate) Monitor for adverse effects when administering venlafaxine with cobicistat. There is a potential for elevated venlafaxine and cobicistat concentrations if these drugs are given together. Venlafaxine and cobicistat are substrates and inhibitors of CYP2D6. In addition, venlafaxine is a substrate for CYP3A4; cobicistat is a strong inhibitor of CYP3A4.
Cocaine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as cocaine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
Codeine: (Moderate) Monitor for additive CNS effects, such as sedation, with use of these drugs together. Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during use of codeine with venlafaxine because of the potential risk of serotonin syndrome. Discontinue all serotonergic agents if serotonin syndrome is suspected. In theory, use of codeine with venlafaxine might also result in reduced codeine efficacy or symptoms of opioid withdrawal in patients at risk. Codeine is primarily metabolized by CYP2D6 to morphine. Venlafaxine is a weak inhibitor of CYP2D6.
Codeine; Guaifenesin: (Moderate) Monitor for additive CNS effects, such as sedation, with use of these drugs together. Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during use of codeine with venlafaxine because of the potential risk of serotonin syndrome. Discontinue all serotonergic agents if serotonin syndrome is suspected. In theory, use of codeine with venlafaxine might also result in reduced codeine efficacy or symptoms of opioid withdrawal in patients at risk. Codeine is primarily metabolized by CYP2D6 to morphine. Venlafaxine is a weak inhibitor of CYP2D6.
Codeine; Phenylephrine; Promethazine: (Moderate) Monitor for additive CNS effects, such as sedation, with use of these drugs together. Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during use of codeine with venlafaxine because of the potential risk of serotonin syndrome. Discontinue all serotonergic agents if serotonin syndrome is suspected. In theory, use of codeine with venlafaxine might also result in reduced codeine efficacy or symptoms of opioid withdrawal in patients at risk. Codeine is primarily metabolized by CYP2D6 to morphine. Venlafaxine is a weak inhibitor of CYP2D6. (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 additive CNS effects, such as sedation, with use of these drugs together. Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during use of codeine with venlafaxine because of the potential risk of serotonin syndrome. Discontinue all serotonergic agents if serotonin syndrome is suspected. In theory, use of codeine with venlafaxine might also result in reduced codeine efficacy or symptoms of opioid withdrawal in patients at risk. Codeine is primarily metabolized by CYP2D6 to morphine. Venlafaxine is a weak inhibitor of CYP2D6. (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) Avoid coadministration of crizotinib with venlafaxine due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib 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) was 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.
Cyproheptadine: (Moderate) Cyproheptadine is a serotonin and histamine antagonist. Cyproheptadine may interfere with serotonin-enhancing antidepressants, including the selective serotonin reuptake inhibitors (SSRIs) and drugs with similar activity, such as venlafaxine. Cyproheptadine has been used for the management of orgasm dysfunction caused by the SSRIs and for the adjunctive treatment of SSRI or venlafaxine overdose (i.e., serotonin syndrome) in emergency situations; however, a reversal of antidepressant effects may occur when cyproheptadine is given in a routine manner along with the SSRIs due to the serotonin antagonistic effects of cyproheptadine.
Dabigatran: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like dabigatran. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Dacomitinib: (Moderate) Monitor for increased toxicity of venlafaxine if coadministered with dacomitinib. Coadministration may increase serum concentrations of venlafaxine. Venlafaxine is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor.
Dalteparin: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like dalteparin. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Danaparoid: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like danaparoid. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Darunavir; Cobicistat: (Moderate) Monitor for adverse effects when administering venlafaxine with cobicistat. There is a potential for elevated venlafaxine and cobicistat concentrations if these drugs are given together. Venlafaxine and cobicistat are substrates and inhibitors of CYP2D6. In addition, venlafaxine is a substrate for CYP3A4; cobicistat is a strong inhibitor of CYP3A4.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for adverse effects when administering venlafaxine with cobicistat. There is a potential for elevated venlafaxine and cobicistat concentrations if these drugs are given together. Venlafaxine and cobicistat are substrates and inhibitors of CYP2D6. In addition, venlafaxine is a substrate for CYP3A4; cobicistat is a strong inhibitor of CYP3A4.
Dasatinib: (Moderate) Monitor for evidence of QT prolongation and torsade de pointes (TdP) during concurrent use of dasatinib and venlafaxine. In vitro studies have shown that dasatinib has the potential to prolong the QT interval. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with postmarketing use.
Degarelix: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving venlafaxine as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval. Venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has reported with post-marketing use.
Delavirdine: (Moderate) Delavirdine is a potent inhibitor of cytochrome P450 2D6 and might decrease venlafaxine metabolism leading to increased adverse reactions.
Desipramine: (Major) 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: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like desirudin. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Desvenlafaxine: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, coadministration of venlafaxine and desvenlafaxine should be avoided. Also, because desvenlafaxine is the active metabolite of venlafaxine and both agents are serotonin norepinephrine reuptake inhibitors (SNRIs), coadministration is considered duplicative therapy. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SNRI to another SNRI.
Deutetrabenazine: (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: (Moderate) Use of venlafaxine with dextromethorphan may increase the risk of serotonin syndrome or other adverse effects of dextromethorphan. Venlafaxine is a serotonin norepinephrine reuptake inhibitor and also inhibits CYP2D6, the isozyme responsible for dextromethorphan metabolism. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
Dexmethylphenidate: (Moderate) 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. 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: (Moderate) Use of venlafaxine with dextromethorphan may increase the risk of serotonin syndrome or other adverse effects of dextromethorphan. Venlafaxine is a serotonin norepinephrine reuptake inhibitor and also inhibits CYP2D6, the isozyme responsible for dextromethorphan metabolism. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Use of venlafaxine with dextromethorphan may increase the risk of serotonin syndrome or other adverse effects of dextromethorphan. Venlafaxine is a serotonin norepinephrine reuptake inhibitor and also inhibits CYP2D6, the isozyme responsible for dextromethorphan metabolism. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
Dextromethorphan; Guaifenesin: (Moderate) Use of venlafaxine with dextromethorphan may increase the risk of serotonin syndrome or other adverse effects of dextromethorphan. Venlafaxine is a serotonin norepinephrine reuptake inhibitor and also inhibits CYP2D6, the isozyme responsible for dextromethorphan metabolism. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Use of venlafaxine with dextromethorphan may increase the risk of serotonin syndrome or other adverse effects of dextromethorphan. Venlafaxine is a serotonin norepinephrine reuptake inhibitor and also inhibits CYP2D6, the isozyme responsible for dextromethorphan metabolism. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Moderate) Use of venlafaxine with dextromethorphan may increase the risk of serotonin syndrome or other adverse effects of dextromethorphan. Venlafaxine is a serotonin norepinephrine reuptake inhibitor and also inhibits CYP2D6, the isozyme responsible for dextromethorphan metabolism. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Use of venlafaxine with dextromethorphan may increase the risk of serotonin syndrome or other adverse effects of dextromethorphan. Venlafaxine is a serotonin norepinephrine reuptake inhibitor and also inhibits CYP2D6, the isozyme responsible for dextromethorphan metabolism. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
Dextromethorphan; 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. (Moderate) Use of venlafaxine with dextromethorphan may increase the risk of serotonin syndrome or other adverse effects of dextromethorphan. Venlafaxine is a serotonin norepinephrine reuptake inhibitor and also inhibits CYP2D6, the isozyme responsible for dextromethorphan metabolism. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
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. (Moderate) Use of venlafaxine with dextromethorphan may increase the risk of serotonin syndrome or other adverse effects of dextromethorphan. Venlafaxine is a serotonin norepinephrine reuptake inhibitor and also inhibits CYP2D6, the isozyme responsible for dextromethorphan metabolism. 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.
Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of dihydrocodeine and venlafaxine because of the potential risk of serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Discontinue dihydrocodeine if serotonin syndrome is suspected. Additionally, concomitant use of dihydrocodeine with venlafaxine may decrease dihydrocodeine plasma concentrations resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of venlafaxine could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If venlafaxine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Venlafaxine is a weak inhibitor of CYP2D6.
Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and venlafaxine because of the potential risk of serotonin syndrome. Discontinue hydrocodone if serotonin syndrome is suspected. Additionally, concomitant use of hydrocodone with venlafaxine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of venlafaxine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If venlafaxine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Venlafaxine is a weak inhibitor of CYP2D6.
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 a Serotonin norepinephrine reuptake inhibitor (SNRI) may be at greater risk of developing hyponatremia and/or the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH may occur during therapy with SNRIs. Cases involving serum sodium levels lower than 110 mmol/L have been reported. Discontinuation of the SNRI should be considered in patients who develop symptomatic hyponatremia.
Dofetilide: (Major) Coadministration of dofetilide and venlafaxine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has been reported with postmarketing use.
Dolasetron: (Moderate) Administer dolasetron with caution in combination with venlafaxine as concurrent use may increase the risk of QT prolongation. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
Dolutegravir; Rilpivirine: (Moderate) Caution is advised when administering rilpivirine with venlafaxine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Venlafaxine administration is also associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
Donepezil: (Moderate) Use donepezil with caution in combination with venlafaxine. Both drugs have been associated with a risk of QT prolongation and torsade de pointes.
Donepezil; Memantine: (Moderate) Use donepezil with caution in combination with venlafaxine. Both drugs have been associated with a risk of QT prolongation and torsade de pointes.
Doxepin: (Major) 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.
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: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, coadministration of venlafaxine and duloxetine should be avoided. Also, because both venlafaxine and duloxetine are serotonin norepinephrine reuptake inhibitors (SNRIs), coadministration is considered duplicative therapy. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SNRI to another SNRI.
Edoxaban: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like edoxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Efavirenz: (Moderate) Consider alternatives to efavirenz when coadministering with venlafaxine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
Efavirenz; Emtricitabine; Tenofovir: (Moderate) Consider alternatives to efavirenz when coadministering with venlafaxine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Consider alternatives to efavirenz when coadministering with venlafaxine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
Elbasvir; Grazoprevir: (Moderate) Administering venlafaxine with elbasvir; grazoprevir may result in elevated venlafaxine plasma concentrations. Venlafaxine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Eliglustat: (Major) 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.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for adverse effects when administering venlafaxine with cobicistat. There is a potential for elevated venlafaxine and cobicistat concentrations if these drugs are given together. Venlafaxine and cobicistat are substrates and inhibitors of CYP2D6. In addition, venlafaxine is a substrate for CYP3A4; cobicistat is a strong inhibitor of CYP3A4.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for adverse effects when administering venlafaxine with cobicistat. There is a potential for elevated venlafaxine and cobicistat concentrations if these drugs are given together. Venlafaxine and cobicistat are substrates and inhibitors of CYP2D6. In addition, venlafaxine is a substrate for CYP3A4; cobicistat is a strong inhibitor of CYP3A4.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Caution is advised when administering rilpivirine with venlafaxine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Venlafaxine administration is also associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering rilpivirine with venlafaxine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Venlafaxine administration is also associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
Encorafenib: (Major) Avoid coadministration of encorafenib and venlafaxine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
Enoxaparin: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like enoxaparin. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Entrectinib: (Major) Avoid coadministration of entrectinib with venlafaxine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
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 and QT prolongation, escitalopram, a selective serotonin reuptake inhibitor (SSRI) should generally not be administered with venlafaxine, a serotonin norepinephrine reuptake inhibitor (SNRI).
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: (Moderate) Use caution during concurrent use of ezogabine and venlafaxine as concurrent use may increase the risk of QT prolongation. Ezogabine has been associated with QT prolongation. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
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.
Fedratinib: (Moderate) Although no dosage adjustment of venlafaxine is required during concomitant use of fedratinib, venlafaxine exposure may increase resulting in increased adverse effects. Venlafaxine is a sensitive CYP2D6 substrate and venlafaxine is a moderate CYP2D6 inhibitor.
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: (Moderate) Exercise caution when administering fingolimod concomitantly with venlafaxine as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
Flecainide: (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: (Moderate) Use caution if venlafaxine is coadministered with fluconazole due to the potential for QT prolongation and torsade de pointes (TdP). Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with postmarketing use. Fluconazole has been associated with QT prolongation and rare cases of TdP.
Fluoxetine: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, selective serotonin reuptake inhibitors (SSRIs) should generally not be administered with serotonin norepinephrine reuptake inhibitors like venlafaxine. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued. Also, both fluoxetine and venlafaxine have been associated with QT prolongation and torsade de pointes (TdP), which could theoretically result in additive effects on the QT interval.
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. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued. Also, both fluoxetine and venlafaxine have been associated with QT prolongation and torsade de pointes (TdP), which could theoretically result in additive effects on the QT interval. (Moderate) Venlafaxine is associated with a possible risk of QT prolongation. Atypical antipsychotics associated with a risk for QT prolongation and TdP that should be used cautiously with venlafaxine include olanzapine. In addition, venlafaxine is a weak inhibitor of CYP2D6. Atypical antipsychotics with partial metabolism via CYP2D6 include olanzapine. Monitor patients for potential adverse effects if these drugs are co-prescribed.
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: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like fondaparinux. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
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.
Gemifloxacin: (Moderate) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering venlafaxine with gemifloxacin. Venlafaxine is associated with a possible risk of QT prolongation; TdP has been reported with post-marketing use. Gemifloxacin may also prolong the QT interval in some patients, with the maximal change in the QTc interval occurring approximately 5 to 10 hours following oral administration. The likelihood of QTc prolongation may increase with increasing dose of gemifloxacin; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
Gemtuzumab Ozogamicin: (Major) 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.
Gilteritinib: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and venlafaxine is necessary. Gilteritinib has been associated with QT prolongation. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
Givosiran: (Major) Avoid concomitant use of givosiran and venlafaxine due to the risk of increased venlafaxine-related adverse reactions. If use is necessary, consider reducing the venlafaxine dose. Venlafaxine is a sensitive CYP2D6 substrate. Givosiran may moderately reduce hepatic CYP2D6 enzyme activity because of its pharmacological effects on the hepatic heme biosynthesis pathway.
Glasdegib: (Major) Avoid coadministration of glasdegib with venlafaxine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has 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) Consider whether the benefits of androgen deprivation therapy (i.e., goserelin) outweigh the potential risks of QT prolongation in patients receiving venlafaxine. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use. Androgen deprivation therapy (i.e., goserelin) may also prolong the QT/QTc interval.
Granisetron: (Moderate) Use granisetron with caution in combination with venlafaxine due to increased risk for QT prolongation and serotonin syndrome. If serotonin syndrome is suspected, discontinue granisetron and concurrent serotonergic agents and initiate appropriate medical treatment. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use. Granisetron has been associated with QT prolongation.
Guaifenesin; Hydrocodone: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and venlafaxine because of the potential risk of serotonin syndrome. Discontinue hydrocodone if serotonin syndrome is suspected. Additionally, concomitant use of hydrocodone with venlafaxine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of venlafaxine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If venlafaxine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Venlafaxine is a weak inhibitor of CYP2D6.
Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and venlafaxine because of the potential risk of serotonin syndrome. Discontinue hydrocodone if serotonin syndrome is suspected. Additionally, concomitant use of hydrocodone with venlafaxine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of venlafaxine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If venlafaxine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Venlafaxine is a weak inhibitor of CYP2D6.
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: (Moderate) Caution is advisable when combining haloperidol concurrently with venlafaxine as concurrent use may increase the risk of QT prolongation and haloperidol-related adverse effects. A haloperidol dose reduction may be necessary. Mild to moderately increased haloperidol concentrations have been reported when haloperidol was given concomitantly with venlafaxine. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
Heparin: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like heparin. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Histrelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving venlafaxine. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
Homatropine; Hydrocodone: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and venlafaxine because of the potential risk of serotonin syndrome. Discontinue hydrocodone if serotonin syndrome is suspected. Additionally, concomitant use of hydrocodone with venlafaxine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of venlafaxine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If venlafaxine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Venlafaxine is a weak inhibitor of CYP2D6.
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: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and venlafaxine because of the potential risk of serotonin syndrome. Discontinue hydrocodone if serotonin syndrome is suspected. Additionally, concomitant use of hydrocodone with venlafaxine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of venlafaxine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If venlafaxine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Venlafaxine is a weak inhibitor of CYP2D6.
Hydrocodone; Ibuprofen: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and venlafaxine because of the potential risk of serotonin syndrome. Discontinue hydrocodone if serotonin syndrome is suspected. Additionally, concomitant use of hydrocodone with venlafaxine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of venlafaxine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If venlafaxine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Venlafaxine is a weak inhibitor of CYP2D6. (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
Hydrocodone; Phenylephrine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and venlafaxine because of the potential risk of serotonin syndrome. Discontinue hydrocodone if serotonin syndrome is suspected. Additionally, concomitant use of hydrocodone with venlafaxine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of venlafaxine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If venlafaxine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Venlafaxine is a weak inhibitor of CYP2D6.
Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and venlafaxine because of the potential risk of serotonin syndrome. Discontinue hydrocodone if serotonin syndrome is suspected. Additionally, concomitant use of hydrocodone with venlafaxine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of venlafaxine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If venlafaxine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Venlafaxine is a weak inhibitor of CYP2D6.
Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and venlafaxine because of the potential risk of serotonin syndrome. Discontinue hydrocodone if serotonin syndrome is suspected. Additionally, concomitant use of hydrocodone with venlafaxine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of venlafaxine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If venlafaxine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Venlafaxine is a weak inhibitor of CYP2D6.
Hydrocodone; Pseudoephedrine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and venlafaxine because of the potential risk of serotonin syndrome. Discontinue hydrocodone if serotonin syndrome is suspected. Additionally, concomitant use of hydrocodone with venlafaxine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of venlafaxine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If venlafaxine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Venlafaxine is a weak inhibitor of CYP2D6.
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: (Moderate) Use caution if venlafaxine is coadministered with hydroxyzine due to the potential for QT prolongation and torsade de pointes (TdP). Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with postmarketing use. Postmarketing data indicate that hydroxyzine causes QT prolongation and TdP.
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.
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.
Iobenguane I 131: (Major) Discontinue serotonin norepinephrine reuptake inhibitors for at least 5 half-lives before the administration of the dosimetry dose or a therapeutic dose of iobenguane I-131. Do not restart serotonin norepinephrine reuptake inhibitors until at least 7 days after each iobenguane I-131 dose. Drugs that reduce catecholamine uptake or deplete catecholamine stores, such as serotonin norepinephrine reuptake inhibitors, may interfere with iobenguane I-131 uptake into cells and interfere with dosimetry calculations resulting in altered iobenguane I-131 efficacy.
Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with venlafaxine may result in increased serum concentrations of venlafaxine. Venlafaxine is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
Isoniazid, INH: (Major) Due to the risk of serotonin syndrome, concurrent use of venlafaxine and medications with MAO-like activity, such as isoniazid, INH, should be avoided if possible. Isoniazid is chemically related to iproniazid, a drug that was known to possess MAO inhibiting activity. Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO and may possess enough MAO inhibiting activity to produce clinical symptoms consistent with serotonergic excess when combined with serotonin norepinephrine reuptake inhibitors. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Due to the risk of serotonin syndrome, concurrent use of venlafaxine and medications with MAO-like activity, such as isoniazid, INH, should be avoided if possible. Isoniazid is chemically related to iproniazid, a drug that was known to possess MAO inhibiting activity. Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO and may possess enough MAO inhibiting activity to produce clinical symptoms consistent with serotonergic excess when combined with serotonin norepinephrine reuptake inhibitors. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
Isoniazid, INH; Rifampin: (Major) Due to the risk of serotonin syndrome, concurrent use of venlafaxine and medications with MAO-like activity, such as isoniazid, INH, should be avoided if possible. Isoniazid is chemically related to iproniazid, a drug that was known to possess MAO inhibiting activity. Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO and may possess enough MAO inhibiting activity to produce clinical symptoms consistent with serotonergic excess when combined with serotonin norepinephrine reuptake inhibitors. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued.
Itraconazole: (Moderate) Caution is advised when administering itraconazole with venlafaxine due to the potential for additive effects on the QT interval and increased exposure to venlafaxine. Both venlafaxine and itraconazole are associated with QT prolongation; coadministration may increase this risk. In addition, venlafaxine is a substrate of CYP2D6 (major) and CYP3A4 (minor). In patients who are poor CYP2D6 metabolizers, the CYP3A4 pathway for venlafaxine may become more important. Administration of venlafaxine and itraconazole (a potent CYP3A4 inhibitor) to patients identified as CYP2D6 poor metabolizers may significantly increase venlafaxine plasma concentrations.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with venlafaxine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
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: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with venlafaxine. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with postmarketing use.
Lefamulin: (Major) Avoid coadministration of lefamulin with venlafaxine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
Lenvatinib: (Major) Avoid coadministration of lenvatinib with venlafaxine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
Lepirudin: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like lepirudin. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Letermovir: (Moderate) An increase in the plasma concentration of venlafaxine may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Venlafaxine is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Leuprolide: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving venlafaxine. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
Leuprolide; Norethindrone: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving venlafaxine. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
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: (Moderate) Levofloxacin should be used cautiously with other agents, such as venlafaxine, that may prolong the QT interval or increase the risk of torsade de pointes (TdP). Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has been reported with postmarketing use. Levofloxacin has been associated with a risk of QT prolongation and TdP. Although extremely rare, TdP has been reported during postmarketing surveillance of levofloxacin.
Levomilnacipran: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, coadministration of venlafaxine and levomilnacipran should be avoided. Also, because both venlafaxine and levomilnacipran are serotonin norepinephrine reuptake inhibitors (SNRIs), coadministration is considered duplicative therapy. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SNRI to another SNRI.
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: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and serotonin norepinephrine reuptake inhibitors (SNRIs). At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
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.
Lofexidine: (Moderate) Monitor the ECG for QT prolongation during concurrent use of lofexidine and venlafaxine. Lofexidine may prolong the QT interval, and torsade de pointes (TdP) has been reported during postmarketing use. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has been reported with postmarketing use.
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.
Lorcaserin: (Major) Based on the mechanism of action of lorcaserin and the theoretical potential for serotonin syndrome, use with extreme caution in combination with other drugs that may affect the serotonergic neurotransmitter systems, including, serotonin norepinephrine reuptake inhibitors. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or Neuroleptic Malignant Syndrome (NMS) like signs and symptoms.
Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as venlafaxine. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
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 of maprotiline and venlafaxine may increase the risk for QT prolongation and torsade de pointes (TdP). Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with postmarketing use.
Meclofenamate Sodium: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
Mefenamic Acid: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
Mefloquine: (Moderate) Mefloquine should be used with caution in patients receiving venlafaxine as concurrent use may increase the risk of QT prolongation. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
Meloxicam: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
Meperidine: (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: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as methamphetamine and serotonin norepinephrine reuptake inhibitors. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (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: (Moderate) 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 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 and SNRI. It is unclear if the reaction was the result of a drug interaction. 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.
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: (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 of mifepristone should always be used. Drugs with a possible risk for QT prolongation and TdP include venlafaxine.
Milnacipran: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, coadministration of venlafaxine and milnacipran should be avoided. Also, because both venlafaxine and milnacipran are serotonin norepinephrine reuptake inhibitors (SNRIs), coadministration is considered duplicative therapy. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SNRI to another SNRI.
Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as venlafaxine may be increased when co-administered with mirabegron. Venlafaxine is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
Mirtazapine: (Major) Concomitant use of mirtazapine and venlafaxine may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes. 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: (Moderate) 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). Morphine and the SNRI should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
Morphine; Naltrexone: (Moderate) 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). 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, Fosnetupitant; Palonosetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as venlafaxine. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Nilotinib: (Major) Avoid coadministration of nilotinib with venlafaxine due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of venlafaxine may also be increased resulting in increase in treatment-related adverse reactions. Nilotinib is a moderate CYP3A4 inhibitor; sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Venlafaxine is a CYP3A4 substrate that is also associated with a possible risk of QT prolongation; TdP has reported with postmarketing use. Concomitant use may increase the risk for QT prolongation.
Nonsteroidal antiinflammatory drugs: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
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) Use octreotide with caution in combination with venlafaxine. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of TdP, the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval.
Ofloxacin: (Moderate) Ofloxacin should be used cautiously with venlafaxine as concurrent use may increase the risk of QT prolongation. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has been reported with postmarketing use. Quinolones have been associated with a risk of QT prolongation and TdP. Although extremely rare, TdP has been reported during postmarketing surveillance of ofloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
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.
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) Avoid coadministration of venlafaxine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Venlafaxine administration is associated with a possible risk of QT prolongation; 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) Coadministration of paliperidone and venlafaxine should be avoided if possible due to a potential increased risk of QT prolongation. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of paliperidone overdose. According to the manufacturer of paliperidone, the drug should be avoided in combination with other agents also known to cause QT prolongation. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with postmarketing use. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
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: (Moderate) Use caution when using pasireotide in combination with venlafaxine as concurrent use may increase the risk of QT prolongation. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses. Venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has reported with post-marketing use.
Pazopanib: (Major) Coadministration of pazopanib and other drugs that prolong the QT interval is not advised; pazopanib has been reported to prolong the QT interval. Venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has reported with post-marketing use. If pazopanib and venlafaxine must be continued, closely monitor the patient for QT interval prolongation. In addition, pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and venlafaxine, a CYP3A4 substrate, may cause an increase in systemic concentrations of venlafaxine. Use caution when concurrent administration is necessary.
Peginterferon Alfa-2b: (Moderate) Monitor for adverse effects associated with increased exposure to venlafaxine if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP2D6 inhibitor, while venlafaxine is a CYP2D6 substrate.
Pentamidine: (Major) 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: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and pentosan, which has weak anticoagulant properties. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Perphenazine: (Moderate) Caution is advisable during concurrent use of perphenazine and serotonin norepinephrine reuptake inhibitors (SNRIs) since elevations in plasma concentrations of perphenazine may occur. Phenothiazines are CYP2D6 substrates, and SNRIs including duloxetine and venlafaxine are CYP2D6 inhibitors. In addition, both venlafaxine and perphenazine are associated with a possible risk of QT prolongation; therefore, additive cardiac effects are possible. Although clinical studies have shown that desvenlafaxine does not have a clinically relevant effect on CYP2D6 inhibition at doses of 100 mg/day, the manufacturer recommends that doses of medications that are primary substrates of CYP2D6 be reduced by one-half during co-administration of desvenlafaxine doses of 400 mg/day.
Perphenazine; Amitriptyline: (Major) 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.
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.
Pitolisant: (Major) Avoid coadministration of pitolisant with venlafaxine as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
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: (Moderate) Exercise caution when administering primaquine in combination with venlafaxine as concurrent use may increase the risk of QT prolongation. Primaquine is associated with QT prolongation. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
Procainamide: (Major) 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.
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 is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Venlafaxine is a CYP3A4 substrate that is also associated with a possible risk of QT prolongation; TdP has reported with postmarketing use. Concomitant use may increase the risk for QT prolongation.
Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with venlafaxine due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of venlafaxine may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Venlafaxine is a CYP3A4 substrate that is also associated with a possible risk of QT prolongation; TdP has reported with postmarketing use. Concomitant use may increase the risk for QT prolongation.
Rilpivirine: (Moderate) Caution is advised when administering rilpivirine with venlafaxine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Venlafaxine administration is also associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
Risperidone: (Moderate) Use risperidone and venlafaxine together with caution due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Risperidone has been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with postmarketing use.
Rivaroxaban: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like rivaroxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
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 is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
Romidepsin: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with venlafaxine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has been reported with postmarketing use.
Safinamide: (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: (Moderate) 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 serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and serotonin norepinephrine reuptake inhibitors. Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose increases. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Sertraline: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, selective serotonin reuptake inhibitors (SSRIs) should generally not be administered with serotonin norepinephrine reuptake inhibitors like venlafaxine. If serotonin syndrome is suspected, venlafaxine and concurrent serotonergic agents should be discontinued. Also, both sertraline and venlafaxine have been associated with QT prolongation, which could theoretically result in additive effects on the QT interval.
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.
Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving venlafaxine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes has been reported with postmarketing use.
Solifenacin: (Moderate) Solifenacin has been associated dose-dependent prolongation of the QT interval. Torsades de pointes (TdP) has been reported with post-marketing use, although causality was not determined. This should be taken into consideration when prescribing solifenacin to patients taking other drugs that are associated with QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with solifenacin include venlafaxine.
Solriamfetol: (Moderate) Monitor blood pressure and heart rate during coadministration of solriamfetol, a norepinephrine and dopamine reuptake inhibitor, and antidepressants that are serotonin norepinephrine reuptake inhibitors. Concurrent use of solriamfetol and other medications that increase blood pressure and/or heart rate may increase the risk of such effects. Coadministration of solriamfetol with other drugs that increase blood pressure or heart rate has not been evaluated.
Sorafenib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of sorafenib with venlafaxine is necessary; correct any electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib has been associated with QT prolongation. Venlafaxine administration is also associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing 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) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as St. John's wort 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. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be initiated.
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: (Moderate) Monitor for evidence of QT prolongation if sunitinib is administered with venlafaxine. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use. Sunitinib can prolong the QT interval.
Tacrolimus: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with venlafaxine. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has been reported with postmarketing use.
Tamoxifen: (Moderate) 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 been described when tamoxifen is used at lower doses. Venlafaxine administration is also 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: (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering telavancin with venlafaxine. Telavancin has been associated with QT prolongation. Venlafaxine is associated with a possible risk of QT prolongation and TdP has been reported with post-marketing use.
Telithromycin: (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering telithromycin with venlafaxine. Telithromycin is associated with QT prolongation and TdP. Venlafaxine is also associated with a possible risk of QT prolongation; TdP has reported with post-marketing use.
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) Avoid coadministration of tetrabenazine and venlafaxine due to an increased risk for QT prolongation. Tetrabenazine causes a small increase in the corrected QT interval (QTc). Venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has reported with postmarketing 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: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like tinzaparin. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
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.
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) Avoid coadministration of venlafaxine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
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 QT prolongation and torsade de pointes (TdP), the manufacturer of trazodone recommends avoiding trazodone in patients receiving other drugs that cause QT prolongation and TdP. Venlafaxine has a possible risk for QT prolongation and TdP. In addition, coadministration of trazodone and venlafaxine may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue venlafaxine and trazodone and initiate symptomatic treatment if serotonin syndrome occurs.
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) Consider whether the benefits of androgen deprivation therapy (i.e., triptorelin) outweigh the potential risks of QT prolongation in patients receiving venlafaxine. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use. Androgen deprivation therapy (i.e., triptorelin) may also prolong the QT/QTc interval.
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) Avoid coadministration of vandetanib with venlafaxine due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. 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.
Vardenafil: (Moderate) Use vardenafil with caution in combination with venlafaxine due to increased risk of QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Venlafaxine administration is also associated with a possible risk of QT prolongation; torsade de pointes has been reported with postmarketing use.
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 strong CYP3A4 inhibitor) to patients identified as CYP2D6 poor metabolizers may significantly increase venlafaxine plasma concentrations. If these drugs are given together, closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
Vorinostat: (Moderate) Venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has been reported with post-marketing use. Vorinostat therapy is associated with a risk of QT prolongation. Vorinostat should be used with caution if given with other agents that may prolong the QT interval including venlafaxine.
Vortioxetine: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, vortioxetine should generally not be administered with serotonin norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine, desvenlafaxine, duloxetine, and milnacipran. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, vortioxetine and concurrent serotonergic agents should be discontinued.
Warfarin: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of venlafaxine and warfarin. Carefully monitor patients receiving warfarin therapy if venlafaxine is initiated or discontinued. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Ziprasidone: (Major) Concomitant use of ziprasidone and venlafaxine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with postmarketing use.
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

There are no adequate and well-controlled studies regarding use of venlafaxine during human pregnancy. Venlafaxine should be used in pregnancy only when the benefit to the mother clearly outweighs any potential risk to the fetus.  Animal studies have failed to show an increased risk of teratogenic effects; however, other fetal toxicities have been observed. Consider the risks of untreated depression during pregnancy as well as the potential risks to the fetus from exposure to the drug. When treating a pregnant woman with a serotonin norepinephrine reuptake inhibitor (SNRI) or other serotonergic agent during the third trimester, discontinuation symptoms should be considered in the newborn at birth. Neonates exposed to serotonergic antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Symptoms have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with serotonin syndrome or possibly a drug discontinuation syndrome. 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. Exposure to SNRIs in mid to late pregnancy may increase the risk of eclampsia. Exposure to SNRIs near obstetric delivery may increase the risk for postpartum hemorrhage.

MECHANISM OF ACTION

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

PHARMACOKINETICS

Venlafaxine is administered orally. Protein binding is approximately 27% for venlafaxine and 30% for the active metabolite O-desmethylvenlafaxine (ODV). Both venlafaxine and ODV are excreted into human breastmilk. Venlafaxine is well absorbed and extensively metabolized in the liver. Venlafaxine is a substrate of CYP2D6 (major) and O-desmethylvenlafaxine (ODV) is the major active metabolite. Venlafaxine is likely metabolized to a minor, less active metabolite by CYP3A4, but the metabolite is not clinically significant. Elimination occurs primarily via the urine as unchanged drug, conjugated ODV, ODV, and inactive metabolites. The elimination half-lives of venlafaxine and ODV are 5 and 11 hours, respectively.
 
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP2D6, CYP3A4
Venlafaxine is 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.