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Active ingredient: Venlafaxine - Brands, Medical Use, Clinical Data

Brands, Medical Use, Clinical Data

Drug Category

  • Antidepressants
  • Analgesics
  • Antidepressants

Dosage Forms

  • Capsule (sustained-release)

Brands / Synonyms

Effexor; Effexor XR; Elafax; Venlafaxina [Inn-Spanish]; Venlafaxine [Inn:Ban]; Venlafaxinum [Inn-Latin]

Indications

For the treatment of severe depression

Pharmacology

Venlafaxine, an antidepressant agent structurally unrelated to other antidepressants, 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

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.

Absorption

Not Available

Toxicity

Not Available

Biotrnasformation / Drug Metabolism

Not Available

Contraindications

Hypersensitivity to venlafaxine hydrochloride or to any excipients in the formulation.

Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated.

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 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.

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 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.

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 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. ODV also was unaffected. Venlafaxine had no effect on the pharmacokinetics of lithium.

Drugs Highly Bound to Plasma Proteins: Venlafaxine is not highly bound to plasma proteins; therefore, administration of Effexor XR to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug.

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. Therefore, no dosage adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor.

The concomitant use of venlafaxine with drug treatment(s) that potentially 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 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 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, Cmax, and Cmin 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.

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 Cmax. 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.

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. Based on the mechanism of action of venlafaxine and the potential for serotonin syndrome, caution is advised when venlafaxine is co-administered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, serotonin reuptake inhibitors (SRIs), or lithium.

Electroconvulsive Therapy: There are no clinical data establishing the benefit of electroconvulsive therapy combined with Effexor XR (venlafaxine hydrochloride) extended-release capsules treatment.

*Based on the number of men and women as appropriate.

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