Venlafaxine Guide: Pharmacology, Indications, Dosing Guidelines and Adverse Effects

In a nutshell

• Dose-dependent effects:
  • Venlafaxine’s efficacy increases with higher doses, but this comes at the cost of decreased acceptability and tolerability¹.
  • Higher doses are associated with elevated blood pressure.
• Efficacy for anhedonia and fatigue:
  • Venlafaxine may help patients with anhedonia and fatigue, likely due to its effects on norepinephrine and dopamine pathways².
• High risk of discontinuation syndrome:
  • Venlafaxine has a higher risk of discontinuation syndrome than other antidepressants³.

Pharmacodynamics and mechanism of action

• Venlafaxine’s mechanism of action appears to be dose-dependent:
  • At lower doses (37.5-75 mg/day): serotonin reuptake inhibition.
  • At moderate doses (150−225 mg/day): dual mechanism agent affecting serotonin and norepinephrine^4,5.

Pharmacokinetics

Metabolism

Venlaxafine is metabolized to O-desmethylvenlafaxine (ODV)

• Venlafaxine is primarily metabolized to its active metabolite, O-desmethylvenlafaxine (ODV), via CYP2D6.
• CYP3A4 is involved in the metabolism of venlafaxine, though to a lesser extent than CYP2D6.⁶

Venlafaxine is a weak inhibitor of CYP2D6

• Venlafaxine is a weak inhibitor of CYP2D6
  • It may increase the concentrations of CYP2D6 substrates
  • Caution when used with other drugs metabolized by CYP2D6
• Drug interactions:
  • Contraindicated with MAOIs
  • CYP3A4 inhibitors may increase venlafaxine and ODV levels

Half-life

• Venlafaxine and its active metabolite O-desmethylvenlafaxine (ODV) have different half-lives.
  • Venlafaxine: 5 hours
  • O-desmethylvenlafaxine (ODV): 11 hours

Dosage forms

• Immediate-release:
  • Tablets:
    • 25 mg, 37.5 mg, 50 mg, 75 mg, 100 mg
    • Generic
• Extended-release:
  • Capsules:
    • 37.5 mg, 75 mg, 150 mg
    • Generic, Effexor XR
  • Tablets:
    • 37.5 mg, 75 mg, 150 mg, 225 mg
    • Generic
  • Tablets (besylate salt):
    • 112.5 mg
    • Generic

Indications

FDA-Approved Indications

Major depressive disorder

• Guidelines recommend venlafaxine-XR as a first-line pharmacotherapy for major depression⁷.
• Dose-dependent action:
  • At lower doses (37.5 –75 mg/day), venlafaxine can be considered to act as an SSRI primarily.
  • At higher doses (150-225 mg/day), its noradrenergic effects can help treat the anhedonia/fatigue symptom cluster.
• Venlafaxine is an option to switch to if patients do not adequately respond to the initial antidepressant prescribed⁸.
• Dosing
  • Starting dose: 37.5 –75 mg/day.
  • For most patients, 75 mg/day.
  • Target dose: 75 mg/day
  • Increments: no faster than 75 mg every 4 days.
  • Maximum recommended dose: 225 mg/day
• Formulation considerations:
  • XR capsules and tablets: taken once daily, with food.
  • IR tablets can be divided into 2-3 daily doses.
  • If XR formulations are broken, the extended-release properties will be altered.

Generalized anxiety disorder

• SSRIs and SNRIs are first-line pharmacotherapies for GAD⁹.
• Dosing:
  • Starting dose:
    • For most patients, 75 mg/day
    • For some patients, 37.5 mg/day
  • Target dose: 75 mg/day
  • Increments: no faster than 75 mg every 4 days.
  • Maximum recommended dose: 225 mg/day

Social anxiety disorder

• Venlafaxine is a first-line drug for the treatment of SAD .
• Venlafaxine and paroxetine are similarly effective, according to a comparison trial¹⁰.
  • Similar discontinuation rates, but paroxetine had better tolerability, with fewer adverse events requiring dose adjustment.
• Dosing:
  • Starting dose: 75 mg/day
  • Target dose: 75 mg/day
  • Maximum dose: 75 mg/day (no benefit at higher doses)

Panic disorder

• Venlafaxine and SSRIs are first-line pharmacotherapies for panic disorder .
• Dosing
  • Starting dose: 37.5 mg/day for 7 days
  • Target dose: 75 mg/day
  • Maximum dose: 225 mg/day

Off-label uses

PTSD

• When pharmacotherapy is needed, guidelines recommend starting with SSRIs such as sertraline or citalopram¹¹.
• SNRIs such as venlafaxine are considered a reasonable first-line option¹².

PMDD

• Venlafaxine has shown efficacy for the treatment of PMDD:
  • as a continuous dosing strategy (open-label trial)¹³
  • as luteal phase dosing strategy¹⁴

Side Effects

Most common side effects

Gastrointestinal

Gastrointestinal side effects

• Anorexia
• Dry mouth
• Nausea
  • Reassure your patient that it is not dangerous and usually improves over time.
  • Recommend ginger root in some form to alleviate nausea^15.
  • Start low, with half the intended dose
• Constipation

Other side effects

• Discontinuation syndrome
  • Increased incidence at higher dosages, possibly related to noradrenergic effects.
  • SNRIs, paroxetine, and mirtazapine have the highest risk among antidepressants.
• Antidepressant-induced sexual dysfunction
  • Ranking of risk: SSRIs and venlafaxine > tricyclics > other SNRIs¹⁶.
• Headache
• Dizziness
• Nervousness
• Sleep alterations
  • Decrease in REM sleep¹⁷.
  • Somnolence
  • Insomnia
• Sweating
  • Dose-related side effect
  • If antidepressant dose reduction is clinically feasible, it should be tried¹⁸.

Serious side effects

• Dose-related hypertension
  • The extended-release formulation has a lower risk of diastolic hypertension¹⁹.
    • Immediate-release: 10-15% of patients.
    • Extended-release: almost 6% of patients.
  • Chronic venlafaxine treatment can facilitate the occurrence of hypertensive crises in normotensive patients.
• Hyponatremia
  • Ranking of risk:
    • MAOIs > SNRIs > SSRIs > TCAs > Mirtazapine²⁰
  • For hyponatremia-prone patients:
    • Mirtazapine should be considered the antidepressant of choice.
    • SNRIs should be prescribed more cautiously than SSRIs

Use in special populations

Breastfeeding

• Infants’ exposure through breastmilk²¹
  • Infants receive venlafaxine.
  • Side effects in breastfed infants have rarely been reported.
• Breastfed infants should be monitored for:
  • Excessive sedation
  • Adequate weight gain
• A safety scoring system finds venlafaxine use to be possible during breastfeeding²².
  • However, some experts do not recommend venlafaxine during nursing²³.

Hepatic impairment

• Mild (Child-Pugh Class A, score 5-6)
  • Reduce total daily dose by 50%
• Moderate (Child-Pugh Class B, score 7-8)
  • Reduce total daily dose by 50%
• Severe (Child-Pugh Class C, score 10-15) or cirrhosis
  • Reduce the total daily dose by 50% or more

Renal impairment

• Mild (CLcr 60–89 mL/min)
  • Reduce total daily dose by 25-50%
• Moderate (CLcr 30–59 mL/min)
  • Reduce total daily dose by 25-50%
• Severe (CLcr <30 mL/min) or undergoing hemodialysis
  • Reduce the total daily dose by 50% or more

Elderly

No dose adjustment is needed.

Brand names

• US: Effexor XR
• Canada: Effexor XR
• Other countries/regions: Alventa, Arafaxina, Argofan, Conervin, Deprevix, Dislaven, Dobupal, Duofaxin, Eduxon, Efectin, Efexor, Efevel, Elafax, Elify, Faxine, Faxipaw, Faxiprol, Flavix, Ganavax, Idixor, Jarvis, Lafaxin, Lanvexin, Laroxin, Maxibral, Melocin, Niztec, Norafexine, Norezor, Norpilen, Politid, Pracet, Pramina, Psiseven, Quilarex, Senexon, Serosmine, Sesaren, Sunvex, Tifaxin, Trevilor, Vandral, Vaxor, Velafax, Velaxin, Velostad, Velpine, Vendep, Venexor, Veniba, Veniz, Venlalic, Venxin, Venxor, Viepax, Vilfax, Voxafen, Voxatin, Zacalen, Zarelis, Zaxine

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