indication

For the management of major depressive disorder (MDD), generalized anxiety disorder (GAD), social anxiety disorder (social phobia), panic disorder with or without agoraphobia, and vasomotor symptoms in women with breast cancer and in postmenopausal women.

pharmacology

Venlafaxine, an antidepressant agent structurally and pharmacologically unrelated to other antidepressants and agents used to treat generalized anxiety disorder, is used to treat melancholia, generalized anxiety disorder (GAD), panic disorder, post-traumatic stress disorder, and hot flashes in breast cancer survivors.

mechanism of action

The exact mechanism of action of venlafaxine is unknown, but appears to be associated with the its potentiation of neurotrasmitter activity in the CNS. Venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), inhibit the reuptake of both serotonin and norepinephrine with a potency greater for the 5-HT than for the NE reuptake process. Both venlafaxine and the ODV metabolite have weak inhibitory effects on the reuptake of dopamine but, unlike the tricyclics and similar to SSRIs, they are not active at histaminergic, muscarinic, or alpha(1)-adrenergic receptors.

toxicity

Most patients overdosing with venlafaxine develop only mild symptoms. However, severe toxicity is reported with the most common symptoms being CNS depression, serotonin toxicity, seizure, or cardiac conduction abnormalities. Venlafaxine's toxicity appears to be higher than other SSRIs, with a fatal toxic dose closer to that of the tricyclic antidepressants than the SSRIs. Doses of 900 mg or more are likely to cause moderate toxicity. Deaths have been reported following large doses.

biotransformation

Undergoes extensive first pass metabolism in the liver to its major, active metabolite, ODV, and two minor, less active metabolites, N-desmethylvenlafaxine and N,O-didesmethylvenlafaxine. Formation of ODV is catalyzed by cytochrome P450 (CYP) 2D6, whereas N-demethylation is catalyzed by CYP3A4, 2C19 and 2C9. ODV possesses antidepressant activity that is comparable to that of venlfaxine.

absorption

Bioavailability is 45% following oral administration.

half life

5 hours

route of elimination

Renal elimination of venlafaxine and its metabolites is the primary route of excretion.

drug interactions

Almotriptan: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Amitriptyline: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Amoxapine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Amprenavir: Amprenavir, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Amprenavir is initiated, discontinued, or dose changed.

Atazanavir: Atazanavir, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Atazanavir is initiated, discontinued, or dose changed.

Bromocriptine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Buspirone: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Cabergoline: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Chlorpromazine: Chlorpromazine, a CYP2D6 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP2D6 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Chlorpromazine is initiated, discontinued, or dose changed.

Cinacalcet: Cinacalcet, a CYP2D6 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP2D6 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Cinacalcet is initiated, discontinued, or dose changed.

Citalopram: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Clarithromycin: Clarithromycin, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Clarithromycin is initiated, discontinued, or dose changed.

Clomipramine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Cocaine: Cocaine, a CYP2D6 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP2D6 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Cocaine is initiated, discontinued, or dose changed.

Conivaptan: Conivaptan, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Conivaptan is initiated, discontinued, or dose changed.

Darunavir: Darunavir, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Darunavir is initiated, discontinued, or dose changed.

Delavirdine: Delaviridine, a CYP2D6 and CYP3A4 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP2D6 and CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Delavirdine is initiated, discontinued, or dose changed.

Desipramine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Desvenlafaxine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Dexfenfluramine: Risk of serotoninergic syndrome

Dextromethorphan: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Diethylpropion: Risk of serotoninergic syndrome

Dihydroergotamine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Dipivefrin: Venlafaxine may increase the tachycardic and vasopressor effects of dipivefrin. Consider alternate therapy or monitor for increased sympathomimetic effects, such as increased blood pressure, chest pain and headache.

Doxepin: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Duloxetine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Eletriptan: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Ephedrine: Venlafaxine may increase the tachycardic and vasopressor effects of ephedrine. Consider alternate therapy or monitor for increased sympathomimetic effects, such as increased blood pressure, chest pain and headache.

Epinephrine: Venlafaxine may increase the tachycardic and vasopressor effects of epinephrine. Consider alternate therapy or monitor for increased sympathomimetic effects, such as increased blood pressure, chest pain and headache.

Ergoloid mesylate: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Ergonovine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Ergotamine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Escitalopram: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Fenfluramine: Risk of serotoninergic syndrome

Fluoxetine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Fluvoxamine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Fosamprenavir: Fosamprenavir, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Fosamprenavir is initiated, discontinued, or dose changed.

Frovatriptan: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Furazolidone: Increased risk of serotonin syndrome. Ensure adequate washout period between therapies to avoid toxicity. Concurrent therapy should be avoided.

Imatinib: Imatinib, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Imatinib is initiated, discontinued, or dose changed.

Imipramine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Indinavir: Indinavir, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Indinavir is initiated, discontinued, or dose changed.

Isocarboxazid: Increased risk of serotonin syndrome. Ensure adequate washout period between therapies to avoid toxicity. Concurrent therapy should be avoided.

Isoniazid: Isoniazid, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Isoniazid is initiated, discontinued, or dose changed.

Itraconazole: Itraconaole, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Itraconazole is initiated, discontinued, or dose changed.

Ketoconazole: Ketoconazole, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Ketoconazole is initiated, discontinued, or dose changed.

Linezolid: Increased risk of serotonin syndrome. Ensure adequate washout period between therapies to avoid toxicity. Concurrent therapy should be avoided.

Lithium: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Lopinavir: Lopinavir, a CYP2D6 and CYP3A4 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP2D6 and CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Lopinavir is initiated, discontinued, or dose changed.

Maprotiline: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Mazindol: Risk of serotoninergic syndrome

Meperidine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Methylergonovine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Metoclopramide: Possible serotoninergic syndrome with this combination

Miconazole: Miconazole, a CYP2D6 and CYP3A4 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP2D6 and CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Miconazole is initiated, discontinued, or dose changed.

Milnacipran: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Mirtazapine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Moclobemide: Increased risk of serotonin syndrome. Ensure adequate washout period between therapies to avoid toxicity. Concurrent therapy should be avoided.

Naratriptan: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Nefazodone: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Nelfinavir: Nelfinavir, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Nelfinavir is initiated, discontinued, or dose changed.

Nicardipine: Nicardipine, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Nicardipine is initiated, discontinued, or dose changed.

Norepinephrine: Venlafaxine may increase the tachycardic and vasopressor effects of Norepinephrine. Consider alternate therapy or monitor for increased sympathomimetic effects, such as increased blood pressure, chest pain and headache.

Nortriptyline: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Paroxetine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Pergolide: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Phenelzine: Increased risk of serotonin syndrome. Ensure adequate washout period between therapies to avoid toxicity. Concurrent therapy should be avoided.

Phentermine: Risk of serotoninergic syndrome

Phenylpropanolamine: Risk of serotoninergic syndrome

Posaconazole: Posaconazole, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Posaconazole is initiated, discontinued, or dose changed.

Procarbazine: Increased risk of serotonin syndrome. Ensure adequate washout period between therapies to avoid toxicity. Concurrent therapy should be avoided.

Promethazine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Propafenone: Propafenone increases the effect and toxicity of venlafaxine

Protriptyline: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Pseudoephedrine: Venlafaxine may increase the tachycardic and vasopressor effects of Pseudoephedrine. Consider alternate therapy or monitor for increased sympathomimetic effects, such as increased blood pressure, chest pain and headache.

Quinidine: Quinidine, a CYP2D6 and CYP3A4 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP2D6 and CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Quinidine is initiated, discontinued, or dose changed.

Quinupristin: This combination presents an increased risk of toxicity

Rasagiline: Increased risk of serotonin syndrome. Ensure adequate washout period between therapies to avoid toxicity. Concurrent therapy should be avoided.

Ritonavir: Ritonavir, a CYP2D6 and CYP3A4 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP2D6 and CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Ritonavir is initiated, discontinued, or dose changed.

Rizatriptan: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

S-Adenosylmethionine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Saquinavir: Saquinavir, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Saquinavir is initiated, discontinued, or dose changed.

Selegiline: Increased risk of serotonin syndrome. Ensure adequate washout period between therapies to avoid toxicity. Concurrent therapy should be avoided.

Sertraline: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Sibutramine: Increased risk of serotonin syndrome. Concurrent therapy should be avoided.

St. John's Wort: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Sumatriptan: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Telithromycin: Telithromycin, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Telithromycin is initiated, discontinued, or dose changed.

Terbinafine: Terbinafine, a CYP2D6 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP2D6 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Terbinafine is initiated, discontinued, or dose changed.

Tramadol: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Tranylcypromine: Increased risk of serotonin syndrome. Concomitant therapy should be avoided. A significant washout period, dependent on the half-lives of the agents, should be employed between therapies.

Trazodone: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Trimipramine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Triprolidine: The CNS depressants, Triprolidine and Venlafaxine, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of venlafaxine by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of venlafaxine if voriconazole is initiated, discontinued or dose changed.

Zolmitriptan: Use of two serotonin modulators, such as zolmitriptan and venlafaxine, may increase the risk of serotonin syndrome. Consider alternate therapy or monitor for serotonin syndrome during concomitant therapy.