Venlafaxine

Generic Name

Venlafaxine

Brand Names

Effexor

Effexor XR

Efexor

Trevilor

Elafax

Ventab

Venlor

Viepax

Drug Class

Serotonin-norepinephrine reuptake inhibitor SNRI

Antidepressant

Mechanism of Action

Venlafaxine inhibits the reuptake of both serotonin 5HT and norepinephrine NE in the central nervous system

At low doses it acts primarily as a selective serotonin reuptake inhibitor SSRI

At moderate to high doses it also inhibits norepinephrine reuptake

At very high doses it may weakly inhibit dopamine reuptake

It does not exhibit significant affinity for muscarinic cholinergic histaminergic or alpha1-adrenergic receptors

This profile contributes to its antidepressant anxiolytic and pain-modulating effects

Indications

Major depressive disorder MDD

Generalized anxiety disorder GAD

Social anxiety disorder SAD

Panic disorder

Off-label uses include

Hot flashes associated with menopause or breast cancer

Attention deficit hyperactivity disorder ADHD

Post-traumatic stress disorder PTSD

Obsessive-compulsive disorder OCD

Diabetic neuropathy and fibromyalgia

Dosage and Administration

Immediate-release formulation

Initial dose 375 mg orally two or three times daily

Usual maintenance dose 75 mg to 225 mg daily

Maximum recommended dose is 375 mgday

Extended-release formulation

Initial dose 375 mg once daily with food

Titrated every 4 days in increments of 75 mg

Usual effective dose range 75 mg to 225 mgday

Doses above 225 mg should be used only when benefit outweighs risk

Dosage in renal or hepatic impairment should be reduced

In patients with creatinine clearance 10 to 70 mLmin reduce total daily dose by 25 to 50 percent

For end-stage renal disease reduce by 50 percent and administer after dialysis

Taper gradually over weeks to avoid discontinuation syndrome

Pharmacokinetics

Bioavailability is approximately 45 percent due to extensive first-pass metabolism

Peak plasma concentrations occur within 2 hours for immediate-release and 5 to 7 hours for extended-release

Half-life of venlafaxine is about 5 hours

Its active metabolite O-desmethylvenlafaxine ODV has a half-life of 11 hours

Metabolized mainly in the liver by CYP2D6 to ODV

Excretion is mainly renal

Approximately 87 percent excreted in urine within 48 hours as parent drug and metabolites

Highly protein bound ~27 percent

Contraindications

Hypersensitivity to venlafaxine or any component

Use with monoamine oxidase inhibitors MAOIs or within 14 days of discontinuing an MAOI

Concomitant use with linezolid or intravenous methylene blue

Uncontrolled narrow-angle glaucoma due to norepinephrine-related mydriasis

Caution in patients with bipolar disorder seizure disorders or bleeding risk

Warnings and Precautions

Increased risk of suicidal thoughts and behaviors in children adolescents and young adults

Monitor closely during initiation and dosage adjustments

Can increase blood pressure especially at higher doses

Monitor blood pressure regularly

May increase heart rate

QT interval prolongation may occur especially at high doses

May cause hyponatremia especially in elderly or patients on diuretics

Risk of serotonin syndrome with serotonergic drugs

Discontinuation syndrome may include agitation nausea dysphoria tremor paresthesia and insomnia

Taper dosage gradually to prevent withdrawal symptoms

Risk of mania or hypomania in patients with bipolar disorder

Caution in patients with angle-closure glaucoma

May affect platelet aggregation and increase bleeding risk especially with NSAIDs aspirin anticoagulants

Adverse Effects

Very common

Nausea

Dry mouth

Somnolence

Dizziness

Insomnia

Headache

Common

Hypertension

Anorexia

Tremor

Nervousness

Abnormal ejaculation in males

Sweating

Constipation

Blurred vision

Uncommon

Hyponatremia

Increased cholesterol

Urinary hesitation or retention

Menstrual disorders

Rare

Seizures

QT prolongation

Serotonin syndrome

Stevens-Johnson syndrome

Closed-angle glaucoma

Overdose

Symptoms

Tachycardia

Seizures

Drowsiness

Coma

Mydriasis

Vomiting

QT prolongation

Fatalities can occur especially with mixed overdoses

Management

Supportive care

Monitor cardiac rhythm and vital signs

Activated charcoal may be considered if early presentation

No specific antidote available

Drug Interactions

MAO inhibitors can lead to serotonin syndrome fatal interactions possible

SSRIs SNRIs triptans tramadol increase risk of serotonin syndrome

Antipsychotics and antiarrhythmics may enhance QT prolongation

CYP2D6 inhibitors paroxetine fluoxetine bupropion may increase venlafaxine levels

Alcohol may enhance CNS depression

Increased bleeding risk when used with NSAIDs aspirin warfarin

Lithium and St John’s Wort increase serotonergic effects

Concomitant use with drugs that increase blood pressure may cause additive hypertensive effects

Use in Special Populations

Pregnancy

Category C

May cause withdrawal symptoms in neonates if used in third trimester

Limited evidence suggests potential for cardiac malformations

Use only if potential benefit outweighs risk

Lactation

Excreted in breast milk

Use with caution

Infant should be monitored for irritability and feeding issues

Pediatrics

Not approved for use in children or adolescents with depression

Suicide risk is increased

Geriatrics

Increased risk of hyponatremia and SIADH

Dose should be started low and titrated slowly

Renal impairment

Requires dose adjustment

Hepatic impairment

Metabolism may be reduced and drug may accumulate

Dose reduction recommended

Monitoring Parameters

Blood pressure especially at doses above 200 mg

Heart rate

Signs of suicidal ideation

Serum sodium in elderly

Symptoms of serotonin syndrome when combined with serotonergic agents

ECG in patients with risk of QT prolongation

Lipid profile during long-term use due to potential increase in serum cholesterol

Eye examination in patients at risk of narrow-angle glaucoma

Comparative Pharmacology

Compared to SSRIs venlafaxine may be more effective in severe depression

More likely to cause dose-dependent blood pressure elevation

Has faster onset than many SSRIs

Compared to duloxetine both are SNRIs

Duloxetine has more balanced serotonin and norepinephrine effects at lower doses

Venlafaxine's noradrenergic activity increases at higher doses

Venlafaxine has a shorter half-life than duloxetine

Compared to tricyclic antidepressants venlafaxine is safer in overdose and has fewer anticholinergic effects

More activating than sedating compared to mirtazapine or trazodone

Formulations Available

Immediate-release tablets 25 mg 37.5 mg 75 mg

Extended-release capsules 37.5 mg 75 mg 150 mg

Extended-release tablets 37.5 mg 75 mg 150 mg 225 mg

Generic versions available globally

Regulatory and Legal Status

Prescription-only medicine

Approved by FDA EMA and other regulatory bodies

Not classified as a controlled substance

Included in WHO Model List of Essential Medicines