Adult: Conventional tab: 75 mg daily in 2 divided doses, increased if necessary up to 375 mg daily. Extended-release: Initially, 75 mg once daily, increased if necessary up to 225 mg daily. All doses may be increased in increments of up to 75 mg at intervals of ≥2 weeks based on clinical evaluation. For severe cases, dose increases may be done at more frequent intervals of ≥4 days. Elderly: Initiate at lowest recommended dose.
Oral Anxiety
Adult: Extended-release: Initially, 75 mg once daily, may increase dose in increments of up to 75 mg at intervals of ≥2 weeks based on clinical evaluation. Max: 225 mg daily. Elderly: Initiate at lowest recommended dose.
Oral Panic disorder
Adult: Extended-release: Initially, 37.5 mg once daily for 7 days, then increase dose to 75 mg daily. Further increase in doses may be done, as necessary, in increments of up to 75 mg at intervals of ≥2 weeks based on clinical evaluation. Max: 225 mg daily. Elderly: Initiate at lowest recommended dose.
Special Patient Group
Venlafaxine is extensively metabolised in the liver by CYP2D6 to active metabolite, O-desmethylvenlafaxine, and to a lesser extent by CYP3A4 to a minor metabolite, N-desmethylvenlafaxine. CYP2D6 metabolism is the 1st and the most important phase of venlafaxine metabolism, a lack of CYP2D6 activity may result in a shift in the metabolic pathway via CYP3A4 leading to increased levels of minor metabolite. N-desmethylvenlafaxine has less pharmacological activity than the parent compound and may possibly display toxicological activity towards alternative targets. Genetic testing may be considered prior to initiation of therapy to determine genetic variation of CYP2D6.
CYP2D6 extensive metaboliser (carrier of 1 functional and 1 defective allele *1/*3, *4, *5)
Heterozygous extensive metabolisers have significantly higher formation of N-desmethylvenlafaxine than in homozygous extensive metabolisers. A higher risk of adverse effects and reduced response to venlafaxine were observed in these individuals. The prevalence of heterozygous extensive metabolisers in Caucasian population is approx 40%.
According to studies, the formation of O-desmethylvenlafaxine is significantly decreased in individuals homozygous for defective CYP2D6 alleles. Plasma concentration of N-desmethylvenlafaxine in CYP2D6 poor metabolisers is higher than in heterozygous extensive metabolisers. Increased adverse effects (e.g. gastrointestinal, hyponatraemia) and reduced response were observed in these individuals. Available studies suggest that dosage adjustment or switching to another antidepressant drug, which is not a CYP2D6 substrate, may be done to reduce risk of adverse effects. The prevalence of CYP2D6 poor metabolisers in Caucasians is approx 7%.
Renal Impairment
Severe (GFR <30 mL/min) and patients requiring haemodialysis: Reduce dose by 50%.
Hepatic Impairment
Mild to moderate (Child-Pugh class A and B): Reduce dose by 50%. Severe (Child-Pugh class C): Reduce dose by >50%.
Contraindications
Children. Concomitant use with MAOIs (including methylene blue, linezolid) or within 14 days of therapy. Avoid alcohol.
Special Precautions
Patient with CV disease (e.g. recent history of MI, unstable heart disease, cerebrovascular conditions or hyperthyroidism), bipolar disorder, diabetes, suicidal ideation/behaviour, at risk of acute narrow-angle glaucoma, history of convulsions, predisposing factors of bleeding. Volume-depleted or dehydrated patients. Renal and hepatic impairment. Elderly. Pregnancy and lactation. CYP2D6 extensive and poor metabolisers. Avoid abrupt discontinuation.
Adverse Reactions
Significant: Withdrawal symptoms (e.g. dizziness, sensory and sleep disturbances, agitation, nausea, vomiting, headache), anxiety, insomnia, nervousness, CNS depression, dyslipidaemia, bone fracture, hypertension, sexual dysfunction, weight loss and anorectic effect, mild pupillary dilation, suicidal thoughts and behaviour, mild pupillary dilation. Rarely, hyponatraemia, akathisia, interstitial lung disease, eosinophilic pneumonia, ventricular tachycardia. Cardiac disorders: Palpitations, dyspnoea. Ear and labyrinth disorders: Tinnitus. Eye disorders: Visual impairment, accommodation disorder. Gastrointestinal disorders: Nausea, constipation, vomiting, diarrhoea. General disorders and admin site conditions: Hyperhidrosis, asthenia, fatigue, chills. Investigations: Weight gain, increased heart rate, increased triglycerides. Metabolism and nutrition disorders: Decreased appetite. Musculoskeletal and connective tissue disorders: Hypertonia. Nervous system disorders: Dizziness, headache, sedation, tremor, paraesthesia, dysgeusia. Psychiatric disorders: Insomnia, confusional state, depersonalisation, anorgasmia, nervousness, abnormal dreams, agitation, anxiety. Renal and urinary disorders: Urinary retention, urinary frequency, dysuria, urinary incontinence. Reproductive system and breast disorders: Decreased libido, metrorrhagia, ejaculation disorder, menorrhagia, impotence. Skin and subcutaneous tissue disorders: Rash, pruritus. Vascular disorders: Hot flush, vasodilation, orthostatic hypotension, bleeding events (e.g. ecchymoses, hematomas, epistaxis, petechiae). Potentially Fatal: Serotonin syndrome (e.g. dizziness, agitation, hallucination, tachycardia, tremor, severe headache), cardiac arrhythmias.
PO: C, Z (Birth defects (e.g. cardiac) in early pregnancy use. Postpartum haemorrhage, persistent pulmonary hypertension in infant, neonatal withdrawal/toxicity in late pregnancy use. Monitor closely.)
Patient Counseling Information
This drug may impair judgement, thinking and motor skills, if affected, do not drive or operate machinery.
Monitoring Parameters
Monitor blood pressure, prior to therapy and regularly, thereafter, serum cholesterol levels (prolonged use). Observe signs of clinical worsening of depression, suicide ideation or unusual behavioural changes, signs and symptoms of serotonin syndrome (e.g. mental status changes, neuromuscular changes). Perform screening for bipolar disorder (e.g. psychiatric history). Reassess patient regularly.
Overdosage
Symptoms: Tachycardia, changes in level of consciousness, mydriasis, convulsion, vomiting, ECG changes (e.g. prolonged QT interval, QRS prolongation, bundle branch block), ventricular tachycardia, bradycardia, hypotension, vertigo, rhabdomyolysis and death. Management: Symptomatic and supportive treatment. Monitor cardiac rhythm and vital signs. In symptomatic patients, perform gastric lavage soon after ingestion. Administration of activated charcoal to reduce absorption.
Drug Interactions
Increased risk of hyponatraemia with diuretics. Altered glycaemic control of antidiabetic agents (e.g. insulin). Increased risk of QTc prolongation and/or ventricular arrhythmias with concomitant use of other QTc prolonging agents [e.g. class IA and III antiarrhythmics (e.g. quinidine, amiodarone, sotalol, dofetilide), antipsychotics (e.g. thioridazone), macrolides (e.g. erythromycin), quinolone antibiotics (e.g. moxifloxacin)]. Increased serum concentration with CYP3A4 inhibitors (e.g. atazanavir, clarithromycin, itraconazole). Increased serum or plasma concentrations of imipramine metabolite (2-hydroxydesipramine), haloperidol, risperidone, and metoprolol. Decreased serum concentration of indinavir. Increased risk of bleeding with antiplatelet agents (e.g. aspirin), anticoagulants (e.g. warfarin), and NSAIDs. Potentially Fatal: Increased risk of serotonin syndrome with concomitant use of other serotonergic agents (e.g. triptans, SSRIs, SNRIs, amphetamines, lithium, sibutramine, opioids), MAOI (including methylene blue, linezolid), serotonin precursors (e.g. tryptophan), antipsychotics or other dopamine antagonists.
Food Interaction
Increased risk of serotonin syndrome with St. John’s wort. Enhanced adverse effect with alcohol.
Lab Interference
False-positive results in urine immunoassay tests for phencyclidine and amphetamine.
Action
Description: Venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent serotonin and noradrenaline reuptake inhibitor (SNRI) and a weak dopamine reuptake inhibitor. The exact mechanism of action is unknown, but it is believed to be related to the potentiation of serotonin and norepinephrine in the CNS through inhibition of their reuptake. It also has minimal affinity for muscarinic, histamine, or α1-adrenergic receptors. Pharmacokinetics: Absorption: Well absorbed from the gastrointestinal tract. Bioavailability: Approx 45%. Approx 2 hours (venlafaxine), approx 4 hours (O-desmethylvenlafaxine); extended-release: 6.3±2.3 hours (venlafaxine), 11.6±2.9 hours (O-desmethylvenlafaxine). Distribution: Crosses placenta and present in breastmilk. Volume of distribution: 7.5±3.7 L/kg (venlafaxine); 5.7±1.8 L/kg (O-desmethylvenlafaxine). Plasma protein binding: 27±2% (venlafaxine); 30±12% (O-desmethylvenlafaxine). Metabolism: Undergoes extensive first-pass metabolism in the liver by CYP2D6 to active metabolite, O-desmethylvenlafaxine and to a lesser extent by CYP3A4 to N-desmethylvenlafaxine, both metabolites are further metabolised to N,O-didesmethylvenlafaxine. Excretion: Via urine (approx 87%; 5% as unchanged drug; 29% as unconjugated active metabolite; 26% as conjugated active metabolite; 27% as minor inactive metabolites). Elimination half-life: Immediate-release: 5±2 hours (venlafaxine), 11±2 hours (O-desmethylvenlafaxine); extended-release: 10.7±3.2 hours (venlafaxine), 12.5±3 hours (O-desmethylvenlafaxine).
Chemical Structure
Venlafaxine Source: National Center for Biotechnology Information. PubChem Database. Venlafaxine, CID=5656, https://pubchem.ncbi.nlm.nih.gov/compound/Venlafaxine (accessed on Jan. 23, 2020)
Storage
Store between 20-25°C. Protect from light and moisture.
N06AX16 - venlafaxine ; Belongs to the class of other antidepressants.
References
Hermann M, Hendset M, Fosaas K et al. Serum Concentrations of Venlafaxine and its Metabolites O-desmethylvenlafaxine and N-desmethylvenlafaxine in Heterozygous Carriers of the CYP2D6*3, *4 or *5 Allele. Eur J Clin Pharmaco. 2008;64:483-487. doi: 10.1007/s00228-007-0453-7. Accessed 02/08/2019Shams ME, Arneth B, Hiemke C et al. CYP2D6 Polymorphism and Clinical Effect of the Antidepressant Venlafaxine. Journal of Clinical Pharmacy and Therapeutics. 2006;31:493-502. Accessed 02/08/2019Anon. Venlafaxine. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 31/07/2019.Buckingham R (ed). Venlafaxine Hydrochloride. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 31/07/2019.Effexor XR (Wyeth Pharmaceuticals LLC). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 31/07/2019.Joint Formulary Committee. Venlafaxine. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 15/08/2019.McEvoy GK, Snow EK, Miller J et al (eds). Venlafaxine Hydrochloride. AHFS Drug Information (AHFS DI) [online]. American Society of Health-System Pharmacists (ASHP). https://www.medicinescomplete.com. Accessed 23/07/2014.Venlafaxine Tablet (Sun Pharmaceutical Industries, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 31/07/2019.Venlafaxine. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 02/08/2019.Wickersham RM. Venlafaxine. Facts and Comparisons [online]. St. Louis, MO. Wolters Kluwer Clinical Drug Information, Inc. https://www.wolterskluwercdi.com/facts-comparisons-online/. Accessed 23/07/2014.
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