Venlafaxine

Unless your doctor tells you otherwise, continue your normal diet.

Venlafaxine and Alcohol

Do not drink alcohol while taking venlafaxine, as alcohol can augment the sleepiness effect of the drug.

Venlafaxine and Other Interactions

Since venlafaxine can induce sleepiness or hinder your ability to think clearly or react quickly, do not drive or operate heavy machinery until you know how Effexor affects you.

Your doctor needs to know about all the medications you take, whether prescription or over-the-counter, vitamins, illegal or recreational drugs, and dietary or herbal supplements, as they can affect how Effexor works, and vice-versa.

Venlafaxine interacts with the following drugs, which should not be taken with Effexor or taken only under close medical supervision:

• Monoamine oxidase inhibitors (MAOIs), including phenelzine sulfate (Nardil), tranylcypromine sulfate (Parnate), isocarboxazid (Marplen), rasagline (Azilect), selegeline (Eldepryl, Emsam)
• Antidepressants, including amitriptyline (Elavil), citalopram (Celexa), fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), fluvoxamine (Luvox)
• Tripans (Imitrex, Imigran, Migriptan)
• Linezolid (Zyvox)
• Cimetidine (Tagamet, Tagamet HB)
• Ketoconazole (Nizoral)
• Ibuprofen (Advil, Motrin)
• Naproxen (Aleve, Naprosyn)
• Warfarin (Coumadin)
• Aspirin (Bayer)
• Lithium (Eskalith, LithoBid)
• Tramadol (Ultram, Ultracet)
• Tryptophan
• St. John's wort

Take venlafaxine exactly as your doctor prescribes it. Follow the directions on your prescription label carefully. The dose will depend on several factors including the condition being treated, response to the medicine, and how well the medicine is tolerated.

The usual starting dose is 75 mg per day (divided into two or three smaller doses for short-acting venlafaxine). Some patients will need to be started on 37.5 mg per day and after 4 to 7 days increased to 75 mg per day. Dose increases of up to 75 mg per day may be necessary.

The recommended maximum daily dose is 225 mg, although some patients may require as much as 350 mg per day.

If you will be taking venlafaxine for a long time, it is very important that your doctor check you at regular visits. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to take it.

Do not take venlafaxine with a monoamine oxidase (MAO) inhibitor (eg, isocarboxazid (Marplan®), phenelzine (Nardil®)], selegiline (Eldepryl®), tranylcypromine (Parnate®)). Do not start taking venlafaxine during the 2 weeks after you stop a MAO inhibitor and wait 1 week after stopping venlafaxine before you start taking a MAO inhibitor. If you take them together or do not wait the proper amount of time, you may develop confusion, agitation, restlessness, stomach or intestinal symptoms, a sudden high body temperature, an extremely high blood pressure, or severe convulsions.

Venlafaxine may cause a serious condition called serotonin syndrome if taken together with certain medicines. Do not use venlafaxine with buspirone (Buspar®), fentanyl (Abstral®, Duragesic®), linezolid (Zyvox®), lithium (Eskalith®, Lithobid®), methylene blue injection, tryptophan, St. John's wort, amphetamines, or some pain or migraine medicines (eg, rizatriptan, sumatriptan, tramadol, Frova®, Imitrex®, Maxalt®, Relpax®, Ultram®, Zomig®). Check with your doctor first before taking any other medicines with venlafaxine.

For some children, teenagers, and young adults, venlafaxine can increase thoughts of suicide. Tell your doctor right away if you start to feel more depressed and have thoughts about hurting yourself. Report any unusual thoughts or behaviors that trouble you, especially if they are new or get worse quickly. Make sure the doctor knows if you have trouble sleeping, get upset easily, have a big increase in energy, or start to act reckless. Also tell the doctor if you have sudden or strong feelings, such as feeling nervous, angry, restless, violent, or scared. Let the doctor know if you or anyone in your family has bipolar disorder (manic-depressive) or has tried to commit suicide.

Do not stop taking venlafaxine without checking first with your doctor. Your doctor may want you to gradually reduce the amount you are taking before stopping it completely. This will decrease the chance of side effects, such as agitation, confusion, headache, irritability, numbness or tingling feeling, restlessness, trouble sleeping, or unusual drowsiness or weakness.

venlafaxine may cause hyponatremia (low sodium in the blood). This is more common in elderly patients, those who take diuretic medicines, or those who have a low amount of fluid in the body due to severe diarrhea or vomiting. Check with your doctor right away if you have a headache, trouble concentrating, memory problems, confusion, weakness, or feel unsteady when standing.

Venlafaxine may increase your risk for bleeding problems. Make sure your doctor knows if you are also using other medicines that thin the blood, such as aspirin, NSAID pain or arthritis medicines (eg, diclofenac, ibuprofen, naproxen, Advil®, Aleve®, Celebrex®, Voltaren®), or warfarin (Coumadin®, Jantoven®).

Tell your doctor right away if you are having chest discomfort, a cough, or trouble breathing with venlafaxine. These might be symptoms of a serious lung problem.

Venlafaxine may cause some people to become drowsy or have blurred vision. Make sure you know how you react to venlafaxine before you drive, use machines, or do anything else that could be dangerous if you are not alert or able to see clearly. It is best to avoid alcohol with venlafaxine.

Before you have any medical tests, tell the medical doctor in charge that you are taking venlafaxine. The results of some tests may be affected by venlafaxine.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal (eg, St. John's wort) or vitamin supplements.

Pediatric Patients: During the eight week placebo-controlled GAD studies, Venlafaxine hydrochloride extended-release capsules-treated patients (ages 6 to 17) grew an average of 0.3 cm (n = 122), while placebo-treated patients grew an average of 1 cm (n = 132); p=0.041. This difference in height increase was most notable in patients younger than twelve. During the eight week placebo-controlled MDD studies, Venlafaxine hydrochloride extended-release capsules-treated patients grew an average of 0.8 cm (n = 146), while placebo-treated patients grew an average of 0.7 cm (n = 147). In the six month open-label study, children and adolescents had height increases that were less than expected based on data from age- and sex-matched peers. The difference between observed growth rates and expected growth rates was larger for children (< 12 years old) than for adolescents (> 12 years old).

Changes in Appetite

Adult Patients: Treatment-emergent anorexia was more commonly reported for Venlafaxine-treated (11%) than placebo-treated patients (2%) in the pool of short-term, doubleblind, placebo-controlled depression studies.

Decreased appetite has been observed in pediatric patients receiving Venlafaxine hydrochloride extended-release capsules. In the placebo-controlled trials for GAD and MDD, 10% of patients aged 6 to 17 treated with Venlafaxine hydrochloride extended-release capsules for up to eight weeks and 3% of patients treated with placebo reported treatment-emergent anorexia (decreased appetite). None of the patients receiving Venlafaxine hydrochloride extended-release capsules discontinued for anorexia or weight loss.

Activation of Mania/Hypomania

During Phase 2 and Phase 3 trials, hypomania or mania occurred in 0.5% of patients treated with Venlafaxine. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants. As with all antidepressants, Venlafaxine tablets should be used cautiously in patients with a history of mania.

Hyponatremia

Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Venlafaxine tablets. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower  than 110 mmol/L have been reported. Elderly patients may be at greater risk of  developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see PRECAUTIONS, Geriatric Use). Discontinuation of Venlafaxine tablets should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

Seizures

During premarketing testing, seizures were reported in 0.26% (8/3082) of Venlafaxine-treated patients. Most seizures (5 of 8) occurred in patients receiving doses of 150 mg/day or less. Venlafaxine tablets should be used cautiously in patients with a history of seizures. It should be discontinued in any patient who develops seizures.

Abnormal Bleeding

SSRIs and SNRIs, including Venlafaxine, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

Patients should be cautioned about the risk of bleeding associated with the concomitant use of Venlafaxine tablets and NSAIDs, aspirin, or other drugs that affect coagulation.

Serum Cholesterol Elevation

Clinically relevant increases in serum cholesterol were recorded in 5.3% of Venlafaxine-treated patients and 0% of placebo-treated patients treated for at least 3 months in placebo-controlled trials (see ADVERSE REACTIONS – Laboratory Changes) Measurement of serum cholesterol levels should be considered during long-term treatment.

Interstitial Lung Disease and Eosinophilic Pneumonia

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

Use in Patients with Concomitant Illness

Clinical experience with Venlafaxine tablets in patients with concomitant systemic illness is limited. Caution is advised in administering Venlafaxine tablets to patients with diseases or conditions that could affect hemodynamic responses or metabolism.

Venlafaxine tablets have not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many clinical studies during the product's premarketing testing. Evaluation of the electrocardiograms for 769 patients who received Venlafaxine tablets in 4 to 6 week doubleblind placebo-controlled trials, however, showed that the incidence of trial-emergent conduction abnormalities did not differ from that with placebo. The mean heart rate in Venlafaxine tablets-treated patients was increased relative to baseline by about 4 beats per minute.

The electrocardiograms for 357 patients who received Venlafaxine hydrochloride extended-release capsules and 285 patients who received placebo in 8 to 12 week doubleblind, placebo-controlled trials were analyzed. The mean change from baseline in corrected QT interval (QTc) for Venlafaxine hydrochloride extended-release capsules-treated patients was increased relative to that for placebo-treated patients (increase of 4.7 msec for Venlafaxine hydrochloride extended-release capsules and decrease of 1.9 msec for placebo). In these same trials, the mean change from baseline in heart rate for Venlafaxine hydrochloride extended-release capsules-treated patients was significantly higher than that for placebo (a mean increase of 4 beats per minute for Venlafaxine hydrochloride extended-release capsules and 1 beat per minute for placebo). In a flexible-dose study, with Venlafaxine tablets doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, Venlafaxine tablets-treated patients had a mean increase in heart rate of 8.5 beats per minute compared with 1.7 beats per minute in the placebo group.

As increases in heart rate were observed, caution should be exercised in patients whose underlying medical conditions might be compromised by increases in heart rate (e.g., patients with hyperthyroidism, heart failure, or recent myocardial infarction), particularly when using doses of Venlafaxine tablets above 200 mg/day.

In patients with renal impairment (GFR=10 to 70 mL/min) or cirrhosis of the liver, the clearances of Venlafaxine and its active metabolite were decreased, thus prolonging the elimination half-lives of these substances. A lower dose may be necessary (see DOSAGE AND ADMINISTRATION). Venlafaxine tablets, like all antidepressants, should be used with caution in such patients.

Information for Patients

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Venlafaxine tablets and should counsel them in its appropriate use. A patient Medication Guide about "Antidepressant Medicines, Depression and Other Serious Mental Illness, and Suicidal Thoughts or Actions" is available for Venlafaxine tablets. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Venlafaxine tablets.

Clinical Worsening and Suicide Risk

Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.

Interference with Cognitive and Motor Performance

Clinical studies were performed to examine the effects of Venlafaxine on behavioral performance of healthy individuals. The results revealed no clinically significant impairment of psychomotor, cognitive, or complex behavior performance. However, since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that Venlafaxine tablets therapy does not adversely affect their ability to engage in such activities.

Angle-Closure Glaucoma

Patients should be advised that taking Venlafaxine tablets can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.

Pregnancy

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.

Nursing

Patients should be advised to notify their physician if they are breastfeeding an infant.

Concomitant Medication

Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, including herbal preparations and nutritional supplements, since there is a potential for interactions.

Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Venlafaxine tablets and triptans, tramadol, tryptophan supplements or other serotonergic agents (see CONTRAINDICATIONSand WARNINGS, Serotonin Syndrome and PRECAUTIONS, Drug Interactions, CNS-Active Drugs, Serotonergic Drugs).

Patients should be cautioned about the concomitant use of Venlafaxine tablets and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding (see PRECAUTIONS, Abnormal Bleeding).

Alcohol

Although Venlafaxine tablets have not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking Venlafaxine tablets.

Allergic Reactions

Patients should be advised to notify their physician if they develop a rash, hives, or a related allergic phenomenon.

Laboratory Tests

There are no specific laboratory tests recommended.

Drug Interactions

As with all drugs, the potential for interaction by a variety of mechanisms is a possibility.

Alcohol

A single dose of ethanol (0.5 g/kg) had no effect on the pharmacokinetics of Venlafaxine or ODV when Venlafaxine was administered at 150 mg/day in 15 healthy male subjects. Additionally, administration of Venlafaxine in a stable regimen did not exaggerate the psychomotor and psychometric effects induced by ethanol in these same subjects when they were not receiving Venlafaxine.

Cimetidine

Concomitant administration of cimetidine and Venlafaxine in a steady-state study for both drugs resulted in inhibition of first-pass metabolism of Venlafaxine in 18 healthy subjects. The oral clearance of Venlafaxine was reduced by about 43%, and the exposure (AUC) and maximum concentration (Cmax) of the drug were increased by about 60%. However, coadministration of cimetidine had no apparent effect on the pharmacokinetics of ODV, which is present in much greater quantity in the circulation than is Venlafaxine. The overall pharmacological activity of Venlafaxine plus ODV is expected to increase only slightly, and no dosage adjustment should be necessary for most normal adults. However, for patients with preexisting hypertension, and for elderly patients or patients with hepatic dysfunction, the interaction associated with the concomitant use of Venlafaxine and cimetidine is not known and potentially could be more pronounced. Therefore, caution is advised with such patients.

Diazepam

Under steady-state conditions for Venlafaxine administered at 150 mg/day, a single 10 mg dose of diazepam did not appear to affect the pharmacokinetics of either Venlafaxine or ODV in 18 healthy male subjects. Venlafaxine also did not have any effect on the pharmacokinetics of diazepam or its active metabolite, desmethyldiazepam, or affect the psychomotor and psychometric effects induced by diazepam.

Haloperidol

Venlafaxine administered under steady-state conditions at 150 mg/day in 24 healthy subjects decreased total oral-dose clearance (Cl/F) of a single 2 mg dose of haloperidol by 42%, which resulted in a 70% increase in haloperidol AUC. In addition, the haloperidol Cmax increased 88% when coadministered with Venlafaxine, but the haloperidol elimination half-life (t1/2) was unchanged. The mechanism explaining this finding is unknown.

Lithium

The steady-state pharmacokinetics of Venlafaxine administered at 150 mg/day were not affected when a single 600 mg oral dose of lithium was administered to 12 healthy male subjects. O-desmethylVenlafaxine (ODV) also was unaffected. Venlafaxine had no effect on the pharmacokinetics of lithium (see also CNS-Active Drugs, below ).

Drugs Highly Bound to Plasma Protein

Venlafaxine is not highly bound to plasma proteins; therefore, administration of Venlafaxine tablets to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug.

Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)

Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when Venlafaxine is initiated or discontinued.

Drugs that Inhibit Cytochrome P450 Isoenzymes

CYP2D6 Inhibitors: In vitro and in vivo studies indicate that Venlafaxine is metabolized to its active metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the genetic polymorphism seen in the metabolism of many antidepressants. Therefore, the potential exists for a drug interaction between drugs that inhibit CYP2D6-mediated metabolism and Venlafaxine. However, although imipramine partially inhibited the CYP2D6-mediated metabolism of Venlafaxine, resulting in higher plasma concentrations of Venlafaxine and lower plasma concentrations of ODV, the total concentration of active compounds (Venlafaxine plus ODV) was not affected. Additionally, in a clinical study involving CYP2D6-poor and -extensive metabolizers, the total concentration of active compounds (Venlafaxine plus ODV), was similar in the two metabolizer groups. Therefore, no dosage adjustment is required when Venlafaxine is coadministered with a CYP2D6 inhibitor.

A pharmacokinetic study with ketoconazole 100 mg b.i.d. with a single dose of Venlafaxine 50 mg in extensive metabolizers (EM; n = 14) and 25 mg in poor metabolizers (PM; n = 6) of CYP2D6 resulted in higher plasma concentrations of both Venlafaxine and O-desmethylVenlafaxine (ODV) in most subjects following  administration of ketoconazole. Venlafaxine Cmax increased by 26% in EM subjects and 48% in PM subjects. Cmax values for ODV increased by 14% and 29% in EM and PM subjects, respectively.

Venlafaxine AUC increased by 21% in EM subjects and 70% in PM subjects (range in PMs - 2% to 206%), and AUC values for ODV increased by 23% and 33% in EM and PM subjects (range in PMs - 38% to 105%) subjects, respectively. Combined AUCs of Venlafaxine and ODV increased on average by approximately 23% in EMS and 53% in PMs (range in PMs – 4% to 134%).

Concomitant use of CYP3A4 inhibitors and Venlafaxine may increase levels of Venlafaxine and ODV. Therefore, caution is advised if a patient's therapy includes a CYP3A4 inhibitor and Venlafaxine concomitantly.

In vitro studies indicate that Venlafaxine is likely metabolized to a minor, less active metabolite, N-desmethylVenlafaxine, by CYP3A4. Because CYP3A4 is typically a minor pathway relative to CYP2D6 in the metabolism of Venlafaxine, the potential for a clinically significant drug interaction between drugs that inhibit CYP3A4-mediated metabolism and Venlafaxine is small.

The concomitant use of Venlafaxine with a drug treatment(s) that potently inhibits both CYP2D6 and CYP3A4, the primary metabolizing enzymes for Venlafaxine, has not been studied. Therefore, caution is advised should a patient's therapy include Venlafaxine and any agent(s) that produce potent simultaneous inhibition of these two enzyme systems.

Drugs Metabolized by Cytochrome P450 Isoenzymes

CYP2D6: In vitro studies indicate that Venlafaxine is a relatively weak inhibitor of CYP2D6. These findings have been confirmed in a clinical drug interaction study comparing the effect of Venlafaxine to that of fluoxetine on the CYP2D6-mediated metabolism of dextromethorphan to dextrorphan.

Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine. However, desipramine AUC, Cmax, and Cmin increased by about 35% in the presence of Venlafaxine. The 2-OH-desipramine AUCs increased by at least 2.5 fold (with Venlafaxine 37.5 mg q12h) and by 4.5 fold (with Venlafaxine 75 mg q12h). Imipramine did not affect the pharmacokinetics of Venlafaxine and ODV. The clinical significance of elevated 2-OH-desipramine levels is unknown.

Concomitant administration of Venlafaxine (50 mg every 8 hours for 5 days) and metoprolol (100 mg every 24 hours for 5 days) to 18 healthy male subjects in a pharmacokinetic interaction study for both drugs resulted in an increase of plasma concentrations of metoprolol by approximately 30 to 40% without altering the plasma concentrations of its active metabolite, α-hydroxymetoprolol. Metoprolol did not alter the pharmacokinetic profile of Venlafaxine or its active metabolite, O-desmethylVenlafaxine.

Venlafaxine appeared to reduce the blood pressure lowering effect of metoprolol in this study. The clinical relevance of this finding for hypertensive patients is unknown. Caution should be exercised with coadministration of Venlafaxine and metoprolol.

Venlafaxine treatment has been associated with dose-related increases in blood pressure in some patients. It is recommended that patients receiving Venlafaxine tablets have regular monitoring of blood pressure (see WARNINGS).

Venlafaxine administered under steady-state conditions at 150 mg/day slightly inhibited the CYP2D6-mediated metabolism of risperidone (administered as a single 1 mg oral dose) to its active metabolite, 9-hydroxyrisperidone, resulting in an approximate 32% increase in risperidone AUC. However, Venlafaxine coadministration did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone).

Venlafaxine did not inhibit CYP3A4 in vitro. This finding was confirmed in vivo by clinical drug interaction studies in which Venlafaxine did not inhibit the metabolism of several CYP3A4 substrates, including alprazolam, diazepam, and terfenadine.

In a study of 9 healthy volunteers, Venlafaxine administered under steady-state conditions at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir and a 36% decrease in indinavir Cmax. Indinavir did not affect the pharmacokinetics of Venlafaxine and ODV. The clinical significance of this finding is unknown.

Venlafaxine did not inhibit CYP1A2 in vitro. This finding was confirmed in vivo by a clinical drug interaction study in which Venlafaxine did not inhibit the metabolism of caffeine, a CYP1A2 substrate.

Venlafaxine did not inhibit CYP2C9 in vitro. In vivo, Venlafaxine 75 mg by mouth every 12 hours did not alter the pharmacokinetics of a single 500 mg dose of tolbutamide or the CYP2C9 mediated formation of 4-hydroxy-tolbutamide.

Venlafaxine did not inhibit the metabolism of diazepam which is partially metabolized by CYP2C19 (see Diazepam above).

Monoamine Oxidase Inhibitors

See CONTRAINDICATIONS.

CNS-Active Drugs

The risk of using Venlafaxine in combination with other CNS-active drugs has not been systematically evaluated (except in the case of those CNS-active drugs noted above). Consequently, caution is advised if the concomitant administration of Venlafaxine and such drugs is required. (see CONTRAINDICATIONSand WARNINGS)

Based on the mechanism of action of Venlafaxine and the potential for serotonin syndrome, caution is advised when Venlafaxine is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, SSRIs, other SNRIs, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, amphetamines or St. John's Wort and methylene blue (see CONTRAINDICATIONS and WARNINGS, Serotonin Syndrome). If concomitant treatment of Venlafaxine tablets with these drugs is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see CONTRAINDICATIONS, WARNINGS, Serotonin Syndrome). The concomitant use of Venlafaxine tablets with tryptophan supplements is not recommended (see CONTRAINDICATIONS, WARNINGS, Serotonin Syndrome).

There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Venlafaxine tablets with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome).

Drug-Laboratory Test Interactions

False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking Venlafaxine. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of Venlafaxine therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish Venlafaxine from PCP and amphetamine.

Electroconvulsive Therapy

There are no clinical data establishing the benefit of electroconvulsive therapy combined with Venlafaxine tablets treatment.

Postmarketing Spontaneous Drug Interaction Reports

See ADVERSE REACTIONS, Postmarketing Reports.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Venlafaxine was given by oral gavage to mice for 18 months at doses up to 120 mg/kg per day, which was 16 times, on a mg/kg basis, and 1.7 times on a mg/m2 basis, the maximum recommended human dose. Venlafaxine was also given to rats by oral gavage for 24 months at doses up to 120 mg/kg per day. In rats receiving the 120 mg/kg dose, plasma levels of Venlafaxine were 1 times (male rats) and 6 times (female rats) the plasma levels of patients receiving the maximum recommended human dose. Plasma levels of the O-desmethyl metabolite were lower in rats than in patients receiving the maximum recommended dose. Tumors were not increased by Venlafaxine treatment in mice or rats.

Mutagenicity

Venlafaxine and the major human metabolite, O-desmethylVenlafaxine (ODV), were not mutagenic in the Ames reverse mutation assay in Salmonella bacteria or the CHO/HGPRT mammalian cell forward gene mutation assay. Venlafaxine was also not mutagenic in the in vitro BALB/c-3T3 mouse cell transformation assay, the sister chromatid exchange assay in cultured CHO cells, or the in vivo chromosomal aberration assay in rat bone marrow. ODV was not mutagenic in the in vitro CHO cell chromosomal aberration assay. There was a clastogenic response in the in vivo chromosomal aberration assay in rat bone marrow in male rats receiving 200 times, on a mg/kg basis, or 50 times, on a mg/m2 basis, the maximum human daily dose. The no effect dose was 67 times (mg/kg) or 17 times (mg/m2) the human dose.

Impairment of Fertility

Reproduction and fertility studies of Venlafaxine in rats showed no adverse effects on male or female fertility at oral doses of up to 2 times the maximum recommended human dose of 225 mg/day on a mg/m2 basis.

However, reduced fertility was observed in a study in which male and female rats were treated with O-desmethylVenlafaxine (ODV), the major human metabolite of Venlafaxine, prior to and during mating and gestation. This occurred at an ODV exposure (AUC) approximately 2 to 3 times that associated with a human Venlafaxine dose of 225 mg/day.

Pregnancy

Teratogenic EffectsPregnancy Category C

Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 11 times (rat) or 12 times (rabbit) the maximum recommended human daily dose on a mg/kg basis, or 2.5 times (rat) and 4 times (rabbit) the human daily dose on a mg/m2 basis. However, in rats, there was a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known. These effects occurred at 10 times (mg/kg) or 2.5 times (mg/m2) the maximum human daily dose. The no effect dose for rat pup mortality was 1.4 times the human dose on a mg/kg basis or 0.25 times the human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Non-teratogenic Effects

Neonates exposed to Venlafaxine tablets, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin Reuptake Inhibitors), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings 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 either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see PRECAUTIONS-Drug Interactions- CNS-Active Drugs). When treating a pregnant woman with Venlafaxine tablets during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION).

Labor and Delivery

The effect of Venlafaxine tablets on labor and delivery in humans is unknown.

Nursing Mothers

Venlafaxine and ODV have been reported to be excreted in humanmilk. Because of the potential for serious adverse reactions in nursing infants from Venlafaxine tablets, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Two placebo-controlled trials in 766 pediatric patients with MDD and two placebo-controlled trials in 793 pediatric patients with GAD have been conducted with Venlafaxine hydrochloride extended-release capsules, and the data were not sufficient to support a claim for use in pediatric patients.

Anyone considering the use of Venlafaxine tablets in a child or adolescent must balance the potential risks with the clinical need.

Although no studies have been designed to primarily assess Venlafaxine hydrochloride extended-release capsule's impact on the growth, development, and maturation of children and adolescents, the studies that have been done suggest that Venlafaxine hydrochloride extended-release capsules may adversely affect weight and height (see PRECAUTIONS , General,Changes in Height and Changes in Weight). Should the decision be made to treat a pediatric patient with Venlafaxine tablets, regular monitoring of weight and height is recommended during treatment, particularly if it is to be continued long term. The safety of Venlafaxine hydrochloride extended-release capsules treatment for pediatric patients has not been systematically assessed for chronic treatment longer than six months in duration.

In the studies conducted in pediatric patients (ages 6 to 17), the occurrence of blood pressure and cholesterol increases considered to be clinically relevant in pediatric patients was similar to that observed in adult patients. Consequently, the precautions for adults apply to pediatric patients (see WARNINGS, Sustained Hypertension, and PRECAUTIONS, General, Serum Cholesterol Elevation).

Geriatric Use

Of the 2,897 patients in Phase 2 and Phase 3 depression studies with Venlafaxine tablets, 12% (357) were 65 years of age or over. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience generally has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including Venlafaxine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see PRECAUTIONS, Hyponatremia).

The pharmacokinetics of Venlafaxine and ODV are not substantially altered in the elderly (see CLINICAL PHARMACOLOGY). No dose adjustment is recommended for the elderly on the basis of age alone, although other clinical circumstances, some of which may be more common in the elderly, such as renal or hepatic impairment, may warrant a dose reduction (see DOSAGE AND ADMINISTRATION).

• Venlafaxine HCl

• Antidepressant, Serotonin/Norepinephrine Reuptake Inhibitor

Elimination half-life is prolonged and clearance is reduced.

Mild to moderate impairment (Child-Pugh class A and B): Reduce total daily dose by 50%. There is variability in clearance for patients with cirrhosis; therefore, a reduction in total daily dose of more than 50% may be necessary.

Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer’s labeling; however, a reduction in total daily dose of at least 50% or more is prudent in patients with cirrhosis.

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Consider therapy modification

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the antiplatelet effect of other Agents with Antiplatelet Properties. Monitor therapy

Alcohol (Ethyl): May enhance the adverse/toxic effect of Serotonin/Norepinephrine Reuptake Inhibitors. Specifically, risks of psychomotor impairment may be enhanced. Alcohol (Ethyl) may enhance the hepatotoxic effect of Serotonin/Norepinephrine Reuptake Inhibitors. Particularly duloxetine and milnacipran. Management: Patients receiving serotonin/norepinephrine reuptake inhibitors (SNRIs) should be advised to avoid alcohol. Monitor for increased psychomotor impairment and hepatotoxicity in patients who consume alcohol during treatment with SNRIs. Consider therapy modification

Alpha-/Beta-Agonists: Serotonin/Norepinephrine Reuptake Inhibitors may enhance the tachycardic effect of Alpha-/Beta-Agonists. Serotonin/Norepinephrine Reuptake Inhibitors may enhance the vasopressor effect of Alpha-/Beta-Agonists. Consider therapy modification

Alpha2-Agonists: Serotonin/Norepinephrine Reuptake Inhibitors may diminish the antihypertensive effect of Alpha2-Agonists. Exceptions: Apraclonidine. Monitor therapy

Analgesics (Opioid): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Anticoagulants: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Antipsychotic Agents: Serotonin Modulators may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Apixaban: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Apixaban. Specifically, the risk for bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely. Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

ARIPiprazole: CYP2D6 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Aspirin: Serotonin/Norepinephrine Reuptake Inhibitors may enhance the antiplatelet effect of Aspirin. Monitor therapy

Asunaprevir: May increase the serum concentration of CYP2D6 Substrates. Consider therapy modification

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Cephalothin: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Cephalothin. Specifically, the risk for bleeding may be increased. Monitor therapy

Collagenase (Systemic): Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Monitor therapy

CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Consider therapy modification

Dabigatran Etexilate: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Dabigatran Etexilate. Agents with Antiplatelet Properties may increase the serum concentration of Dabigatran Etexilate. This mechanism applies specifically to clopidogrel. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dapoxetine: May enhance the adverse/toxic effect of Serotonin Modulators. Avoid combination

Dasatinib: May enhance the anticoagulant effect of Agents with Antiplatelet Properties. Monitor therapy

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Deoxycholic Acid: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Monitor therapy

Edoxaban: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Glucosamine: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Consider therapy modification

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Ibritumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Imatinib: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Indinavir: Venlafaxine may decrease the serum concentration of Indinavir. Monitor therapy

Iobenguane I 123: Serotonin/Norepinephrine Reuptake Inhibitors may diminish the therapeutic effect of Iobenguane I 123. Avoid combination

Ioflupane I 123: Serotonin/Norepinephrine Reuptake Inhibitors may diminish the diagnostic effect of Ioflupane I 123. Monitor therapy

Limaprost: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Linezolid: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Avoid combination

MAO Inhibitors: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This may cause serotonin syndrome. While methylene blue and linezolid are expected to interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to monographs specific to those agents for details. Exceptions: Linezolid; Methylene Blue; Tedizolid. Avoid combination

Metaxalone: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Methylene Blue: Serotonin/Norepinephrine Reuptake Inhibitors may enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Avoid combination

Methylene Blue: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Avoid combination

Methylphenidate: May enhance the adverse/toxic effect of Serotonin Modulators. Specifically, the risk of serotonin syndrome or serotonin toxicity may be increased. Monitor therapy

Metoclopramide: May enhance the adverse/toxic effect of Serotonin/Norepinephrine Reuptake Inhibitors. Management: Seek alternatives to this combination when possible. Monitor patients receiving metoclopramide with serotonin/norepinephrine reuptake inhibitors for signs of extrapyramidal symptoms, neuroleptic malignant syndrome, and serotonin syndrome. Consider therapy modification

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Multivitamins/Fluoride (with ADE): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with AE, No Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

NSAID (Nonselective): Serotonin/Norepinephrine Reuptake Inhibitors may enhance the antiplatelet effect of NSAID (Nonselective). Monitor therapy

Obinutuzumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Monitor therapy

Omega-3 Fatty Acids: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Panobinostat: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of sensitive CYP2D6 substrates when possible, particularly those substrates with a narrow therapeutic index. Consider therapy modification

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Monitor therapy

Pentoxifylline: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Perhexiline: CYP2D6 Inhibitors (Weak) may increase the serum concentration of Perhexiline. Monitor therapy

Perhexiline: CYP2D6 Substrates may increase the serum concentration of Perhexiline. Perhexiline may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Propafenone: May increase the serum concentration of Venlafaxine. Management: Monitor for increased venlafaxine levels/adverse effects (e.g., hallucinations, agitation, confusion) with propafenone initiation/dose increase. Conversely, monitor for decreased venlafaxine levels with profapenone discontinuation/dose decrease. Monitor therapy

Prostacyclin Analogues: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Rivaroxaban: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Rivaroxaban. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Monitor therapy

Salicylates: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Exceptions: Nicergoline; Tedizolid. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tedizolid: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Thrombolytic Agents: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tositumomab and Iodine I 131 Tositumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse events may be increased. Monitor therapy

TraMADol: Serotonin Modulators may enhance the adverse/toxic effect of TraMADol. The risk of seizures may be increased. TraMADol may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

TraZODone: Venlafaxine may enhance the serotonergic effect of TraZODone. This could result in serotonin syndrome. Consider therapy modification

Urokinase: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Urokinase. Avoid combination

Vitamin E (Systemic): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Venlafaxine may enhance the adverse/toxic effect of Vitamin K Antagonists. Specifically, the risk for bleeding may be increased. Monitor therapy

Voriconazole: May enhance the adverse/toxic effect of Venlafaxine. Voriconazole may increase the serum concentration of Venlafaxine. Monitor therapy

May interfere with urine detection of phencyclidine and amphetamine (false-positives).

Actual frequency may be dependent upon formulation and/or indication.

>10%:

Central nervous system: Insomnia (18%), dizziness (16%), drowsiness (15%)

Dermatologic: Diaphoresis (11%)

Gastrointestinal: Nausea (30%), xerostomia (15%)

Neuromuscular & skeletal: Weakness (13%)

1% to 10%:

Cardiovascular: Vasodilation (4%), hypotension (<2%), orthostatic hypotension (<2%), syncope (<2%), tachycardia (<2%), increased blood pressure (1%)

Central nervous system: Nervousness (7%), yawning (4%), anorgasmia (2% to 4%), abnormal dreams (3%), paresthesia (2%), agitation (<2%), akathisia (<2%), apathy (<2%), chills (<2%), confusion (<2%), depersonalization (<2%), hallucination (<2%), hypertonia (<2%), manic reaction (<2%), myoclonus (<2%), seizure (<2%)

Dermatologic: Alopecia (<2%), ecchymoses (<2%), pruritus (<2%), skin photosensitivity (<2%), skin rash (<2%), urticaria (<2%)

Endocrine & metabolic: Orgasm abnormal (men: ≤10%), decreased libido (5%), hypercholesterolemia (5%), hypermenorrhea (<2%), weight gain (<2%), weight loss (<2%)

Gastrointestinal: Anorexia (10%), constipation (9%), diarrhea (8%), vomiting (4%), bruxism (<2%), dysgeusia (<2%), gastrointestinal hemorrhage (<2%)

Genitourinary: Ejaculatory disorder (≤10%), impotence (5%), abnormal uterine bleeding (<2%), urinary frequency (<2%), urinary incontinence (<2%), urinary retention (<2%), urination disorder (<2%)

Neuromuscular & skeletal: Tremor (5%)

Ophthalmic: Visual disturbance (4%), accommodation disturbance (<2%), mydriasis (<2%)

Otic: Tinnitus (<2%)

Frequency not defined:

Cardiovascular: Hypertension, increased pulse

Central nervous system: Suicidal ideation

Endocrine & metabolic: Increased serum triglycerides

Hematologic & oncologic: Hematoma, petechia

Respiratory: Epistaxis

<1%, postmarketing, and/or case reports: Abnormal hepatic function tests, agranulocytosis, anaphylaxis, angioedema, angle-closure glaucoma, aplastic anemia, ataxia, delirium, dyspnea, eosinophilic pneumonitis, erythema multiforme, extrapyramidal reaction (including dystonia, dyskinesia), hepatitis, hypomania, hyponatremia, increased intraocular pressure (open-angle glaucoma) (Botha 2016), increased serum prolactin, interstitial pulmonary disease, mucous membrane bleeding, neuroleptic malignant syndrome, neutropenia, pancreatitis, pancytopenia, prolonged bleeding time, prolonged Q-T Interval on ECG, rhabdomyolysis, serotonin syndrome, SIADH, Stevens-Johnson syndrome, tardive dyskinesia, thrombocytopenia, toxic epidermal necrolysis, ventricular fibrillation, ventricular tachycardia (including torsades de pointes), withdrawal syndrome

Major psychiatric warnings:

• Suicidal thinking/behavior: [US Boxed Warning]: Antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults (18 to 24 years of age) in short-term studies of major depressive disorder (MDD) and other psychiatric disorders; consider risk prior to prescribing. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥65 years. Closely monitor patients of all ages for clinical worsening, suicidality, or unusual changes in behavior, particularly during the first few months of therapy or during periods of dosage adjustments (increases or decreases); the patient’s family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. A medication guide concerning the use of antidepressants in children and teenagers should be dispensed with each prescription. Venlafaxine is not approved for use in pediatric patients.

• The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy.

• Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their health care provider if any of these symptoms or worsening depression or psychosis occur.

Concerns related to adverse effects:

• Anxiety/insomnia: May cause increase in anxiety, nervousness, and insomnia.

• Bleeding risk: May impair platelet aggregation resulting in increased risk of bleeding events, particularly if used concomitantly with aspirin, NSAIDs, warfarin, or other anticoagulants. Bleeding related to SSRI or SNRI use has been reported to range from relatively minor bruising and epistaxis to life-threatening hemorrhage.

• CNS depression: Has a low potential to impair cognitive or motor performance; caution operating hazardous machinery or driving.

• Dyslipidemia: May cause significant increases in serum total cholesterol and triglycerides; monitor during long-term treatment.

• Fractures: Bone fractures have been associated with antidepressant treatment. Consider the possibility of a fragility fracture if an antidepressant-treated patient presents with unexplained bone pain, point tenderness, swelling, or bruising (Rabenda, 2013; Rizzoli, 2012).

• Hypertension: Dose-related increases in systolic and diastolic blood pressure have been documented. Monitor blood pressure regularly, and if sustained increases noted, consider dose reduction or discontinuation.

• Ocular effects: May cause mild pupillary dilation which in susceptible individuals can lead to an episode of narrow-angle glaucoma. Consider evaluating patients who have not had an iridectomy for narrow-angle glaucoma risk factors.

• Pulmonary events: Interstitial lung disease and eosinophilic pneumonia have been rarely reported. May present as progressive dyspnea, cough, and/or chest pain. Prompt evaluation and possible discontinuation of therapy may be necessary.

• Serotonin syndrome: Potentially life-threatening serotonin syndrome (SS) has occurred with serotonergic agents (eg, SSRIs, SNRIs), particularly when used in combination with other serotonergic agents (eg, triptans, TCAs, fentanyl, lithium, tramadol, buspirone, St John’s wort, tryptophan) or agents that impair metabolism of serotonin (eg, MAO inhibitors intended to treat psychiatric disorders, other MAO inhibitors [ie, linezolid and intravenous methylene blue]). Monitor patients closely for signs of SS such as mental status changes (eg, agitation, hallucinations, delirium, coma); autonomic instability (eg, tachycardia, labile blood pressure, diaphoresis); neuromuscular changes (eg, tremor, rigidity, myoclonus); GI symptoms (eg, nausea, vomiting, diarrhea); and/or seizures. Discontinue treatment (and any concomitant serotonergic agent) immediately if signs/symptoms arise.

• Sexual dysfunction: May cause or exacerbate sexual dysfunction.

• SIADH and hyponatremia: SSRIs and SNRIs have been associated with the development of SIADH; hyponatremia has been reported rarely (including severe cases with serum sodium <110 mmol/L). Age (the elderly), volume depletion, and/or concurrent use of diuretics likely increases risk. Discontinue treatment in patients with symptomatic hyponatremia.

• Weight loss and anorectic effects: Dose-dependent weight loss has been observed in both pediatric and adult patients; weight loss was not limited to those experiencing reduced appetite.

Disease-related concerns:

• Cardiovascular disease: May cause sustained increase in blood pressure or tachycardia. Control pre-existing hypertension prior to initiation of venlafaxine. Use caution in patients with recent history of MI, unstable heart disease, cerebrovascular conditions, or hyperthyroidism. Hypertensive effect is dose related and increases are generally modest (12 to 15 mm Hg diastolic).

• Hepatic impairment: Use caution; clearance is decreased and plasma concentrations are increased; dosage reduction recommended.

• Mania/hypomania: May precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Patients presenting with depressive symptoms should be screened for bipolar disorder, including details regarding family history of suicide, bipolar disorder, and depression. Venlafaxine is not FDA approved for the treatment of bipolar depression.

• Renal impairment: Use caution; clearance is decreased and plasma concentrations are increased; dosage reduction recommended.

• Seizure disorders: Use caution in patients with a previous seizure disorder; discontinue in any patient who develops seizures.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Use with caution in the elderly; may have a higher risk of SIADH or hyponatremia.

• Pediatric: Small differences in height and weight have been observed in pediatric patients receiving venlafaxine, particularly those <12 years of age, compared to placebo.

Other warnings/precautions:

• Discontinuation syndrome: Abrupt discontinuation or interruption of antidepressant therapy has been associated with a discontinuation syndrome. Symptoms arising may vary with antidepressant however commonly include nausea, vomiting, diarrhea, headaches, lightheadedness, dizziness, diminished appetite, sweating, chills, tremors, paresthesias, fatigue, somnolence, and sleep disturbances (eg, vivid dreams, insomnia). Less common symptoms include electric shock-like sensations, cardiac arrhythmias (more common with tricyclic antidepressants), myalgias, parkinsonism, arthralgias, and balance difficulties. Psychological symptoms may also emerge such as agitation, anxiety, akathisia, panic attacks, irritability, aggressiveness, worsening of mood, dysphoria, mood lability, hyperactivity, mania/hypomania, depersonalization, decreased concentration, slowed thinking, confusion, and memory or concentration difficulties. Greater risks for developing a discontinuation syndrome have been associated with antidepressants with shorter half-lives, longer durations of treatment, and abrupt discontinuation. For antidepressants of short or intermediate half-lives, symptoms may emerge within 2 to 5 days after treatment discontinuation and last 7 to 14 days (APA 2010; Fava 2006; Haddad 2001; Shelton 2001; Warner 2006).

Adverse events have been observed in some animal reproduction studies. Venlafaxine and its active metabolite ODV cross the human placenta. An increased risk of teratogenic effects following venlafaxine exposure during pregnancy has not been observed, based on available data. The risk of spontaneous abortion may be increased. Neonatal seizures and neonatal abstinence syndrome have been noted in case reports following maternal use of venlafaxine during pregnancy. Nonteratogenic effects in the newborn following SSRI/SNRI exposure late in the third trimester include respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hyper- or hypotonia, hyper-reflexia, jitteriness, irritability, constant crying, and tremor. Symptoms may be due to the toxicity of the SNRI or a discontinuation syndrome and may be consistent with serotonin syndrome associated with treatment. The long-term effects of in utero SNRI/SSRI exposure on infant development and behavior are not known.

Due to pregnancy-induced physiologic changes, some pharmacokinetic parameters of venlafaxine may be altered. Women should be monitored for decreased efficacy. The ACOG recommends that therapy with SSRIs or SNRIs during pregnancy be individualized; treatment of depression during pregnancy should incorporate the clinical expertise of the mental health clinician, obstetrician, primary health care provider, and pediatrician. According to the American Psychiatric Association (APA), the risks of medication treatment should be weighed against other treatment options and untreated depression. For women who discontinue antidepressant medications during pregnancy and who may be at high risk for postpartum depression, the medications can be restarted following delivery. Treatment algorithms have been developed by the ACOG and the APA for the management of depression in women prior to conception and during pregnancy.

Pregnant women exposed to antidepressants during pregnancy are encouraged to enroll in the National Pregnancy Registry for Antidepressants (NPRAD). Women 18 to 45 years of age or their health care providers may contact the registry by calling 844-405-6185. Enrollment should be done as early in pregnancy as possible.

Applies to venlafaxine: oral capsule extended release, oral tablet, oral tablet extended release

Gastrointestinal

Very common (10% or more): Nausea (up to 35%), dry mouth ( up to 17%), constipation (12%)
Common (1% to 10%): Vomiting, abdominal pain, diarrhea, dyspepsia, flatulence, eructation
Uncommon (0.1% to 1%): Bruxism, colitis, dysphagia, tongue edema, esophagitis, gastritis, gastroenteritis, gastrointestinal ulcer, gingivitis, glossitis, rectal hemorrhage, hemorrhoids, melena, stomatitis, mouth ulceration
Rare (less than 0.1%): Cheilitis, cholecystitis, cholelithiasis, duodenitis, esophageal spasm, hematemesis, gastrointestinal hemorrhage, gum hemorrhage, ileitis, intestinal obstruction, parotitis, periodontitis, proctitis, increased salivation, soft stools, tongue discoloration
Postmarketing reports: Pancreatitis[Ref]

Nervous system

Very common (10% or more): Headache (up to 38%), dizziness (up to 20%), somnolence (up to 20%), fatigue (11%), nervousness (up to 10%)
Common (1% to 10%): Tremor, paraesthesia, twitching, hypertonia, migraine, trismus, vertigo
Uncommon (0.1% to 1%): Myoclonus, dysgeusia, akathisia, apathy, ataxia, circumoral paraesthesia, CNS stimulation, emotional lability, euphoria, hallucinations, hostility, hyperesthesia, hyperkinesia, hypotonia, incoordination, neuralgia, neuropathy, seizure, abnormal speech, stupor
Rare (less than 0.1%): Akinesia, alcohol abuse, aphasia, bradykinesia, buccoclusal syndrome, cerebrovascular accident, loss of consciousness, dementia, dystonia, facial paralysis, feeling drunk, abnormal gait, Guillain-Barre Syndrome, hyperchlorhydria, hypokinesia, impulse control difficulties, neuritis, paresis, torticollis
Frequency not reported: Neuroleptic malignant syndrome (NMS), serotonergic syndrome, extrapyramidal reactions (including dystonia, and dyskinesia), tardive dyskinesia[Ref]

Cardiovascular

Common (1% to 10%): Hypertension, vasodilatation (mostly hot flashes/flushes), palpitation, chest pain
Uncommon (0.1% to 1%): Hypotension, postural hypotension, syncope, angina pectoris, arrhythmia, extrasystoles, peripheral vascular disorder (mainly cold feet and/or cold hands), thrombophlebitis
Rare (less than 0.1%): Aortic aneurysm, arteritis, first-degree atrioventricular block, bigeminy, bradycardia, bundle branch block, capillary fragility, cardiovascular disorder (mitral valve and circulatory disturbance), coronary artery disease, congestive heart failure, heart arrest, mucocutaneous hemorrhage, myocardial infarct, pallor
Postmarketing reports: QT prolongation, ventricular fibrillation, ventricular tachycardia (including torsades de pointes)[Ref]

Genitourinary

Very common (10% or more): Abnormal ejaculation (up to 16%)
Common (1% to 10%): Impotence, decreased libido, anorgasmia, erectile dysfunction, impaired urination, dysuria, metrorrhagia, prostatic disorder (prostatitis and enlarged prostate), vaginitis
Uncommon (0.1% to 1%): Menorrhagia, urinary retention, pelvic pain, cystitis, hematuria, leukorrhea, nocturia, bladder pain, breast pain, polyuria, pyuria, urinary incontinence, urinary urgency, vaginal hemorrhage
Rare (less than 0.1%): BUN increased, creatinine increased, glucosuria, balanitis, breast discharge, breast engorgement, breast enlargement, endometriosis, fibrocystic breast, calcium crystalluria, cervicitis, ovarian cyst, gynecomastia (male), kidney calculus, kidney pain, mastitis, menopause, oliguria, orchitis, pyelonephritis, salpingitis, urolithiasis, uterine spasm, vaginal dryness
Postmarketing reports: Menstrual disorders associated with
increased bleeding or increased irregular bleeding, proteinuria[Ref]

Dermatologic

Very common (10% or more): Sweating (up to 14%)
Uncommon (0.1% to 1%): Photosensitivity, rash, acne, alopecia, brittle nails, contact dermatitis, dry skin, eczema, skin hypertrophy, maculopapular rash, psoriasis, urticaria
Rare (less than 0.1%): Erythema nodosum, exfoliative dermatitis, lichenoid dermatitis, hair discoloration, skin discoluration, furunculosis, leukoderma, petechial rash, pustular rash, vesiculobullous rash, seborrhea, skin atrophy, skin striae
Postmarketing reports: Night sweats, erythema multiforme, Stevens-Johnson syndrome, pruritus, toxic epidermal necrolysis[Ref]

Other

Very common (10% or more): Asthenia (up to 19%)
Common (1% to 10%): Accidental injury, trauma
Uncommon (0.1% to 1%): Face edema, malaise, intentional injury
Postmarketing reports: Chills[Ref]

Hepatic

Uncommon (0.1% to 1%): Abnormal liver function tests
Rare (less than 0.1%): Hepatitis, jaundice, bilirubinemia[Ref]

Psychiatric

Very common (10% or more): Insomnia (up to 25%)
Common (1% to 10%): Abnormal dreams, depression, agitation, anxiety
Uncommon (0.1% to 1%): Hallucination, derealization, apathy, hypomania
Rare (less than 0.1%): Mania
Frequency not reported: Suicidal ideation, suicidal behaviors, delirium, aggression
Postmarketing reports: Confusion, depersonalization[Ref]

Hematologic

Uncommon (0.1% to 1%): Ecchymosis, mucous membrane bleeding, anemia, leukocytosis, leukopenia, lymphadenopathy, thrombocythemia, thrombocytopenia
Rare (less than 0.1%): Prolonged bleeding time, basophilia, cyanosis, eosinophilia, lymphocytosis, multiple myeloma, purpura
Postmarketing reports: Blood dyscrasias (including agranulocytosis, aplastic anemia, neutropenia, pancytopenia)[Ref]

Musculoskeletal

Common (1% to 10%): Neck pain
Uncommon (0.1% to 1%): Neck rigidity, arthritis, arthrosis, bone pain, bone spurs, bursitis, leg cramps, myasthenia, tenosynovitis
Rare (less than 0.1%): Pathological fracture, myopathy, osteoporosis, osteosclerosis, plantar fasciitis, rheumatoid arthritis, tendon rupture
Postmarketing reports: Rhabdomyolysis[Ref]

Ocular

Common (1% to 10%): Abnormal vision, abnormality of accommodation, mydriasis
Uncommon (0.1% to 1%): Cataract, conjunctivitis, corneal lesion, diplopia, dry eyes, eye pain, photophobia, visual field defect
Rare (less than 0.1%): Blepharitis, chromatopsia, conjunctival edema, exophthalmos, angle-closure glaucoma, retinal hemorrhage, subconjunctival hemorrhage, keratitis, miosis, papilledema, decreased pupillary reflex, scleritis, uveitis[Ref]

Metabolic

Common (1% to 10%): Increased serum cholesterol , weight loss, decreased appetite, anorexia
Uncommon (0.1% to 1%): Hyponatremia, weight gain, increased alkaline phosphatase, dehydration, hyperglycemia, hyperlipemia, hypokalemia
Rare (less than 0.1%): Syndrome of inappropriate antidiuretic hormone secretion (SIADH), alcohol intolerance, diabetes mellitus, gout, hemochromatosis, hypercalcinuria, hyperkalemia, hyperuricemia, hypocholesteremia, hypoglycemia, hypophosphatemia, hypoproteinemia, uremia[Ref]

Respiratory

Common (1% to 10%): Pharyngitis, yawning, bronchitis, dyspnea
Uncommon (0.1% to 1%): Asthma, chest congestion, epistaxis, hyperventilation, laryngismus, laryngitis, pneumonia, voice alteration
Rare (less than 0.1%): Atelectasis, hemoptysis, hypoventilation, hypoxia, larynx edema, pleurisy, pulmonary embolus, sleep apnea
Postmarketing reports: Pulmonary eosinophilia[Ref]

Hypersensitivity

Very rare (less than 0.1%): Anaphylaxis[Ref]

Immunologic

Common (1% to 10%): Infection
Uncommon (0.1% to 1%): Moniliasis
Rare (less than 0.1%): Appendicitis, bacteremia, cellulitis[Ref]

Endocrine

Rare (less than 0.1%): Goiter, hyperthyroidism, hypothyroidism, thyroid nodule, thyroiditis
Postmarketing reports: Increased prolactin[Ref]

General

The most commonly reported side effects were headache, dizziness, somnolence, insomnia, and nausea.[Ref]

Oncologic

Rare (less than 0.1%): Carcinoma[Ref]

Some side effects of venlafaxine may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

US BOXED WARNINGS:
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS
-Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older.
-Patients of all ages who are started on antidepressant therapy should be monitored closely for clinical worsening and emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber.
-This drug is not approved for use in pediatric patients.

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

If you are between the ages of 18 and 60, take no other medication or have no other medical conditions, side effects you are more likely to experience include:

• Nausea, headache, sedation, dry mouth, dizziness, insomnia, nervousness, constipation, and sweating are some of the more commonly reported side effects. May also cause weight loss, cholesterol elevation, sexual dysfunction, and several other side effects.
• May be associated with a sustained moderate increase in blood pressure (about 10-15mm Hg) in some people; regular monitoring of blood pressure may be required.
• As with other antidepressants, venlafaxine may increase the risk of suicidal thoughts or behavior in young adults. Not generally recommended for people under the age of 18.
• May impair judgment or cause drowsiness and affect a person's ability to drive or operate machinery. Avoid alcohol.
• In susceptible people, pupil dilation may lead to an episode of angle-closure glaucoma.
• Interaction or overdosage may cause serotonin syndrome (symptoms include mental status changes [eg, agitation, hallucinations, coma, delirium], fast heart rate, dizziness, flushing, muscle tremor or rigidity and stomach symptoms [including nausea, vomiting, and diarrhea]).
• May increase the risk of bleeding, especially if used with other drugs that also increase bleeding risk.
• May precipitate a manic episode in people with undiagnosed bipolar disorder.
• May cause a lowering of sodium levels in the body (this is called hyponatremia). Elderly people or people taking diuretics or who are already dehydrated may be more at risk.
• May cause a discontinuation syndrome if abruptly stopped; symptoms include flu-like symptoms, irritability, low mood, dizziness, electric shock sensations, a headache, and confusion.
• Rarely causes seizures.
• May interact with some other medications, including other antidepressants and those metabolized through CYP3A4 or CYP2D6 enzymes, although the degree of interaction appears smaller than with some other antidepressants.

Notes: In general, seniors or children, people with certain medical conditions (such as liver or kidney problems, heart disease, diabetes, seizures) or people who take other medications are more at risk of developing a wider range of side effects. For a complete list of all side effects, click here.

Taking this medicine with other drugs that make you sleepy can worsen this effect. Ask your doctor before taking venlafaxine with a sleeping pill, narcotic pain medicine, muscle relaxer, or medicine for anxiety, depression, or seizures.

Many drugs can interact with venlafaxine. Not all possible interactions are listed here. Tell your doctor about all your current medicines and any you start or stop using, especially:

• any other antidepressant;

• cimetidine;

• St. John's wort;

• tramadol;

• tryptophan (sometimes called L-tryptophan);

• a blood thinner--warfarin, Coumadin, Jantoven;

• medicine to treat mood disorders, thought disorders, or mental illness--buspirone, lithium, and many others; or

• migraine headache medicine--sumatriptan, zolmitriptan, and others.

This list is not complete and many other drugs can interact with venlafaxine. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.