Venlafaxine Interactions

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 (C max ) 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 C max increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t 1/2 ) 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. Ketoconazole 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-desvenlafaxine (ODV) in most subjects following administration of ketoconazole. Venlafaxine C max increased by 26% in EM subjects and 48% in PM subjects. C max 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. CYP3A4 Inhibitors 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. Imipramine Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine. However, desipramine AUC, C max , and C min 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. Metoprolol 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 ). Risperidone 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). CYP3A4 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. Indinavir 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 C max . Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this finding is unknown. CYP1A2 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. CYP2C9 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. CYP2C19 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 CONTRAINDICATIONS and WARNINGS )

7 DRUG INTERACTIONS 7.1 Drugs Having Clinically Important Interactions with Venlafaxine Hydrochloride Extended-Release Capsules Table 15: Clinically Important Drug Interactions with Venlafaxine Hydrochloride Extended-Release Capsules Monoamine Oxidase Inhibitors (MAOI) Clinical Impact The concomitant use of SNRIs, including venlafaxine hydrochloride extended-release capsules, with MAOIs increases the risk of serotonin syndrome. Intervention Concomitant use of venlafaxine hydrochloride extended-release capsules is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Dosage and Administration (2.11) , Contraindications (4) and Warnings and Precautions (5.2) ]. Other Serotonergic Drugs Clinical Impact Concomitant use of venlafaxine hydrochloride extended-release capsules with other serotonergic drugs (including other SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St.John's Wort) increases the risk of serotonin syndrome. Intervention Monitor for symptoms of serotonin syndrome when venlafaxine hydrochloride extended-release capsules is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems. If serotonin syndrome occurs, consider discontinuation of venlafaxine hydrochloride extended-release capsules and/or concomitant serotonergic drugs [see Dosage and Administration (2.11) and Warnings and Precautions (5.2) ]. Drugs that Interfere with Hemostasis Clinical Impact Concomitant use of venlafaxine hydrochloride extended-release capsules with an antiplatelet or anticoagulant drug may potentiate the risk of bleeding. This may be due to the effect of venlafaxine hydrochloride extended-release capsules on the release of serotonin by platelets. Intervention Closely monitor for bleeding for patients receiving an antiplatelet or anticoagulant drug when venlafaxine hydrochloride extended-release capsules is initiated or discontinued [see Warnings and Precautions (5.4) ] . Effect of CYP3A Inhibitors Clinical Impact Concomitant use of a CYP3A inhibitor increases the C max and AUC of venlafaxine and O-desmethylvenlafaxine (ODV) [see Clinical Pharmacology (12.3) ] , which may increase the risk of toxicity of venlafaxine hydrochloride extended-release capsules. Intervention Consider reducing the dose of venlafaxine hydrochloride extended-release capsules. CYP2D6 Substrates Clinical Impact Concomitant use of venlafaxine hydrochloride extended-release capsules increases C max and AUC of a CYP2D6 substrate, which may increase the risk of toxicity of the CYP2D6 substrate [see Clinical Pharmacology (12.3) ] . Intervention Consider reduction in dose of concomitant CYP2D6 substrates. 7.2 Other Drug Interactions with Venlafaxine Hydrochloride Extended-Release Capsules Central Nervous System (CNS)-Active Drugs The risk of using venlafaxine concomitantly with other CNS-active drugs (including alcohol) has not been systematically evaluated. Consequently, caution is advised when venlafaxine hydrochloride extended-release capsules are taken concomitantly in combination with other CNS-active drugs. Weight Loss Agents Concomitant use of venlafaxine hydrochloride extended-release capsules and weight loss agents is not recommended. The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Venlafaxine hydrochloride extended-release capsules are not indicated for weight loss alone or in combination with other products. Laboratory Test Interference False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking venlafaxine 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.

7 DRUG INTERACTIONS MAOI's: concomitant use contraindicated ( 4 ). Avoid MAOI's 14 days before starting venlafaxine and 7 days after stopping venlafaxine ( 5.2 ). Cimetidine: Caution in patients with pre-existing hypertension, in elderly patients and patients with hepatic dysfunction. ( 7.2 ) Haloperidol: Increase in Haloperidol AUC and C max . ( 7.4 ) Ketoconazole: Increase in venlafaxine and O-desmethylvenlafaxine AUC and C max . Caution when using venlafaxine with substances that inhibit both CYP2D6 and CYP3A4. ( 7.7 ) Metoprolol: Possibly reduced blood-pressure lowering effect despite increased metoprolol plasma levels. Caution should be exercised with co-administration of venlafaxine and metoprolol. ( 7.8 ) CNS-active drugs: Caution when using venlafaxine with such drugs. ( 7.10 ) Serotonergic drugs (e.g., triptans, SSRIs, other SNRIs, linezolid, lithium, tramadol, or St. John's Wort): Potential for serotonin syndrome. Careful patient observation advised. ( 7.10 ) Tryptophan supplements: Concomitant use not recommended. ( 7.10 ) 7.1 Alcohol A single dose of ethanol (0.5 g/kg) had no effect on the pharmacokinetics of venlafaxine or O-desmethylvenlafaxine (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. 7.2 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 (C max ) 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 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 pre-existing 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. 7.3 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. 7.4 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 C max increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t 1/2 ) was unchanged. The mechanism explaining this finding is unknown. 7.5 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. ODV also was unaffected. Venlafaxine had no effect on the pharmacokinetics of lithium (see also CNS-Active Drugs, below). 7.6 Drugs Highly Bound to Plasma Proteins Venlafaxine is not highly bound to plasma proteins; therefore, administration of venlafaxine extended-release tablets to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug. 7.7 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 of venlafaxine, reducing the metabolism of venlafaxine to ODV, resulting in increased plasma concentrations of venlafaxine and decreased concentrations of the active metabolite. CYP2D6 inhibitors such as quinidine would be expected to do this, but the effect would be similar to what is seen in patients who are genetically CYP2D6 poor metabolizers [ see Clinical Pharmacology ( 12.3 ) ]. Therefore, no dosage adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor. Ketoconazole: 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 C max increased by 26% in EM subjects and 48% in PM subjects. C max 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 PM's -2% to 206%), and AUC values for ODV increased by 23% and 33% in EM and PM (range in PM's 38% to 105%) subjects, respectively. Combined AUC's of venlafaxine and ODV increased on average by approximately 23% in EM's and 53% in PM's, (range in PM's 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. 7.8 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 with that of fluoxetine on the CYP2D6-mediated metabolism of dextromethorphan to dextrorphan. Imipramine - Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine. However, desipramine AUC, C max , and C min increased by about 35% in the presence of venlafaxine. The 2-OH-desipramine AUC's 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. Metoprolol - 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 30-40% 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 co-administration 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 extended-release tablets have regular monitoring of blood pressure [ see Warnings and Precautions ( 5.3 ) ]. Risperidone - 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). CYP3A4 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. Indinavir - 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 C max . Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this finding is unknown. CYP1A2 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. CYP2C9 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. CYP2C19 Venlafaxine did not inhibit the metabolism of diazepam, which is partially metabolized by CYP2C19 (see Diazepam above). 7.9 Monoamine Oxidase Inhibitors (MAOIs) [See Dosage and Administration ( 2.6 and 2.7 ), Contraindications ( 4.1 ), and Warnings and Precautions ( 5.2 ) .] 7.10 Other Serotonergic Drugs The concomitant use of serotonergic drugs (including other SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John’s Wort) with venlafaxine extended-release tablets increases the risk of serotonin syndrome. Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of venlafaxine extended-release tablets and/or concomitant serotonergic drugs [ see Warnings and Precautions (5.2) ] 7.11 Drugs that Interfere with Hemostasis (e.g., NSAID's, 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. These studies 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 SSRI's and SNRI's are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when venlafaxine extended-release tablets are initiated or discontinued [s ee Warnings and Precautions ( 5.13 ) ]. 7.12 Electroconvulsive Therapy There are no clinical data establishing the benefit of electroconvulsive therapy combined with venlafaxine extended-release tablets treatment. 7.13 Postmarketing Spontaneous Drug Interaction Reports There have been reports of elevated clozapine levels that were temporally associated with adverse reactions, including seizures, following the addition of venlafaxine. There have been reports of increases in prothrombin time, partial thromboplastin time, or INR when venlafaxine was given to patients receiving warfarin therapy. 7.14 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.

7 DRUG INTERACTIONS 7.1 Drugs Having Clinically Important Interactions with Venlafaxine Hydrochloride Extended-Release Capsules Table 15: Clinically Important Drug Interactions with Venlafaxine Hydrochloride Extended-Release Capsules Monoamine Oxidase Inhibitors (MAOI) Clinical Impact The concomitant use of SNRIs, including venlafaxine hydrochloride extended-release capsules, with MAOIs increases the risk of serotonin syndrome. Intervention Concomitant use of venlafaxine hydrochloride extended-release capsules is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Dosage and Administration (2.11) , Contraindications (4) and Warnings and Precautions (5.2) ]. Other Serotonergic Drugs Clinical Impact Concomitant use of venlafaxine hydrochloride extended-release capsules with other serotonergic drugs (including other SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort) increases the risk of serotonin syndrome. Intervention Monitor for symptoms of serotonin syndrome when venlafaxine hydrochloride extended-release capsules is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems. If serotonin syndrome occurs, consider discontinuation of venlafaxine hydrochloride extended-release capsules and/or concomitant serotonergic drugs [see Dosage and Administration (2.11) and Warnings and Precautions (5.2) ]. Drugs that Interfere with Hemostasis Clinical Impact Concomitant use of venlafaxine hydrochloride extended-release capsules with an antiplatelet or anticoagulant drug may potentiate the risk of bleeding. This may be due to the effect of venlafaxine hydrochloride extended-release capsules on the release of serotonin by platelets. Intervention Closely monitor for bleeding for patients receiving an antiplatelet or anticoagulant drug when venlafaxine hydrochloride extended-release capsules are initiated or discontinued [see Warnings and Precautions (5.4) ] . Effect of CYP3A Inhibitors Clinical Impact Concomitant use of a CYP3A inhibitor increases the C max and AUC of venlafaxine and O-desmethylvenlafaxine (ODV) [see Clinical Pharmacology (12.3) ] , which may increase the risk of toxicity of venlafaxine hydrochloride extended-release capsules. Intervention Consider reducing the dose of venlafaxine hydrochloride extended-release capsules. CYP2D6 Substrates Clinical Impact Concomitant use of venlafaxine hydrochloride extended-release capsules increases C max and AUC of a CYP2D6 substrate, which may increase the risk of toxicity of the CYP2D6 substrate [see Clinical Pharmacology (12.3) ] . Intervention Consider reduction in dose of concomitant CYP2D6 substrates. 7.2 Other Drug Interactions with Venlafaxine Hydrochloride Extended-Release Capsules Central Nervous System (CNS)-Active Drugs The risk of using venlafaxine concomitantly with other CNS-active drugs (including alcohol) has not been systematically evaluated. Consequently, caution is advised when venlafaxine hydrochloride extended-release capsules are taken concomitantly in combination with other CNS-active drugs. Weight Loss Agents Concomitant use of venlafaxine hydrochloride extended-release capsules and weight loss agents is not recommended. The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Venlafaxine hydrochloride extended-release capsules are not indicated for weight loss alone or in combination with other products. Laboratory Test Interference False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking venlafaxine 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.

7 DRUG INTERACTIONS 7.1 Drugs Having Clinically Important Interactions with Venlafaxine Hydrochloride Extended-Release Capsules Table 15: Clinically Important Drug Interactions with Venlafaxine Hydrochloride Extended-Release Capsules Monoamine Oxidase Inhibitors (MAOI) Clinical Impact The concomitant use of SNRIs, including venlafaxine hydrochloride extended-release capsules, with MAOIs increases the risk of serotonin syndrome. Intervention Concomitant use of venlafaxine hydrochloride extended-release capsules are contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Dosage and Administration ( 2.11 ), Contraindications ( 4 ) and Warnings and Precautions ( 5.2 )] Other Serotonergic Drugs Clinical Impact Concomitant use of venlafaxine hydrochloride extended-release capsules with other serotonergic drugs increases the risk of serotonin syndrome. Intervention Monitor for symptoms of serotonin syndrome when venlafaxine hydrochloride extended-release capsules are used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems. If serotonin syndrome occurs, consider discontinuation of venlafaxine hydrochloride extended-release capsules and/or concomitant serotonergic drugs [see Dosage and Administration ( 2.11 ) and Warnings and Precautions ( 5.2 )]. Drugs that Interfere with Hemostasis Clinical Impact Concomitant use of venlafaxine hydrochloride extended-release capsules with an antiplatelet or anticoagulant drug may potentiate the risk of bleeding. This may be due to the effect of venlafaxine hydrochloride extended-release capsules on the release of serotonin by platelets. Intervention Closely monitor for bleeding for patients receiving an antiplatelet or anticoagulant drug when venlafaxine hydrochloride extended-release capsules are initiated or discontinued [see Warnings and Precautions ( 5.4 )] . Effect of CYP3A Inhibitors Clinical Impact Concomitant use of a CYP3A inhibitor increases the C max and AUC of venlafaxine and O-desmethylvenlafaxine (ODV) [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of toxicity of venlafaxine hydrochloride extended-release capsules Intervention Consider reducing the dose of venlafaxine hydrochloride extended-release capsules. CYP2D6 Substrates Clinical Impact Concomitant use of venlafaxine hydrochloride extended-release capsules increases C max and AUC of a CYP2D6 substrate, which may increase the risk of toxicity of the CYP2D6 substrate [see Clinical Pharmacology ( 12.3 )] . Intervention Consider reduction in dose of concomitant CYP2D6 substrates. 7.2 Other Drug Interactions with Venlafaxine Hydrochloride Extended-Release Capsules Central Nervous System (CNS)-Active Drugs The risk of using venlafaxine concomitantly with other CNS-active drugs (including alcohol) has not been systematically evaluated. Consequently, caution is advised when venlafaxine hydrochloride extended-release capsules are taken concomitantly in combination with other CNS-active drugs. Weight Loss Agents Concomitant use of venlafaxine hydrochloride extended-release capsules and weight loss agents is not recommended. The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Venlafaxine hydrochloride extended-release capsules are not indicated for weight loss alone or in combination with other products. Laboratory Test Interference False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking venlafaxine 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.