Venlafaxine

Uses

Venlafaxine tablets is used for the treatment of major depressive disorder.

The efficacy of venlafaxine tablets, in the treatment of major depressive disorder was established in 6 week controlled trials of adult outpatients whose diagnoses corresponded most closely to the DSM-III or DSM-III-R category of major depression and in a 4 week controlled trial of inpatients meeting diagnostic criteria for major depression with melancholia

A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation.

The efficacy of venlafaxine hydrochloride extended-release capsules in maintaining an antidepressant response for up to 26 weeks following 8 weeks of acute treatment was demonstrated in a placebocontrolled trial. The efficacy of venlafaxine tablets in maintaining an antidepressant response in patients with recurrent depression who had responded and continued to be improved during an initial 26 weeks of treatment and were then followed for a period of up to 52 weeks was demonstrated in a second placebo-controlled trial (see Clinical Trials). Nevertheless, the physician who elects to use venlafaxine tablets / extended-release capsules for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Venlafaxine is also used to associated treatment for these conditions: Generalized Anxiety Disorder (GAD), Major Depressive Disorder (MDD), Migraine, Neuropathic Pain, Panic Disorder, Social Anxiety Disorder (SAD), Vasomotor Symptoms Associated With Menopause

How Venlafaxine works

The exact mechanism of action of venlafaxine is unknown, but appears to be associated with the potentiation of neurotransmitter 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.

Dosage

Venlafaxine dosage

Initial Treatment: The recommended starting dose for venlafaxine tablets is 75 mg/day, administered in two or three divided doses, taken with food. Depending on tolerability and the need for further clinical effect, the dose may be increased to 150 mg/day. If needed, the dose should be further increased up to 225 mg/day. When increasing the dose, increments of up to 75 mg/day should be made at intervals of no less than 4 days. Inoutpatientsettings there was no evidence of usefulness of doses greater than 225 mg/day for moderately depressed patients, but more severely depressed inpatients responded to a mean dose of 350 mg/day. Certain patients, including more severely depressed patients, may therefore respond more to higher doses, up to a maximum of 375 mg/day, generally in three divided doses

Dosage For Elderly Patients: No dose adjustment is recommended for elderly patients on the basis of age. As with any antidepressant, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose.

Maintenance Treatment: It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacological therapy beyond response to the acute episode. In one study, in which patients responding during 8 weeks of acute treatment with venlafaxine hydrochloride extendedrelease capsules were assignedrandomlyto placebo or to the same dose of venlafaxine hydrochloride extended-release capsules (75, 150, or 225 mg/day, qAM) during 26 weeks of maintenance treatment as they had received during the acute stabilization phase, longer-term efficacy was demonstrated. A second longer-term study has demonstrated the efficacy of venlafaxine tablets in maintaining an antidepressant response in patients with recurrent depression who had responded and continued to be improved during an initial 26 weeks of treatment and were then randomly assigned to placebo or venlafaxine tablets for periods of up to 52 weeks on the same dose (100 to 200 mg/day, on ab.i.d.schedule) (seeClinical Trials). Based on these limited data, it is not known whether or not the dose of venlafaxine tablets / extended-release capsules needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment.

Discontinuing Venlafaxine Tablet: Symptoms associated with discontinuation of venlafaxine tablets, other SNRIs, and SSRIs, have been reported. Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.

Side Effects

Changes in behaviour, suicidal ideation, agitation, tremor, nervousness, anxiety, insomnia, confusions, abnormal dreams, HTN, nausea, headache, asthenia, somnolence, dizziness, dry mouth, vomiting, constipation, diarrhoea, dyspepsia, abdominal pain, anorexia, sexual dysfunction, urinary frequency, visual disturbances, mydriasis, vasodilatation, paraesthesia, hypertonia, chills or fever, palpitations, wt gain or loss, arthralgia, myalgia, tinnitus, pruritus, dyspnoea, yawning, rashes, sweating, increased serum cholesterol, may impair platelet aggregation.

Toxicity

Overdose of venlafaxine is typically associated with 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.

Precaution

History of MI or unstable cardiac disease, seizure; hypomania or mania, increased intraocular pressure or at risk of acute narrow-angle galaucoma, at risk of bleeding. Renal and hepatic impairment. Gradual dose reduction is recommended rather than abrupt withdrawal. Pregnancy and lactation. Patient Counselling May impair ability to drive or operate machinery.

Interaction

Increased risk of serotonin syndrome with TCA, SSRI, SNRI, lithium, sibutramine, tramadol. May increase serum levels with CYP3A4 inhibitors (e.g. ketoconazole, atazanavir, clarithromycin). May increase serum levels of haloperidol. May decrease serum levels of indinavir. May increase bleeding risk with aspirin, NSAIDs, warfarin and other anticoagulants.

Food Interaction

• Avoid alcohol. Prescribing information recommends the avoidance of alcohol during therapy.
• Avoid St. John's Wort. Co-administration of St. John's Wort may lead to additive serotonergic activity and an increased risk of serotonin syndrome.
• Take with food. Co-administration with food helps to alleviate/mitigate GI upset.

[Moderate] GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents.

Use in combination may result in additive central nervous system depression and
MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol.

Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

Venlafaxine Hypertension interaction

[Moderate] Selective serotonin and norepinephrine reuptake inhibitor antidepressants (SNRIs) have been associated with sustained increases in blood pressure.

Therapy with SNRI antidepressants should be administered cautiously in patients with preexisting hypertension.

Blood pressure should be assessed prior to initiating treatment and monitored regularly.

The dose should be reduced or discontinued if necessary.

Venlafaxine Drug Interaction

Major: amphetamine / dextroamphetamine, lisdexamfetamineModerate: aripiprazole, aspirin, aspirin, diphenhydramine, pregabalin, acetaminophen / hydrocodone, albuterol, quetiapine, alprazolam, cetirizineUnknown: omega-3 polyunsaturated fatty acids, metoprolol, metoprolol, levothyroxine, acetaminophen, cyanocobalamin, ascorbic acid, cholecalciferol

Venlafaxine Disease Interaction

Major: depression, renal disease, renal/liver diseaseModerate: mania, glaucoma, hypertension, hyponatremia, mania, seizures, urinary tract obstructionMinor: weight loss

Volume of Distribution

• 7.5 ± 3.7 L/kg venlafaxine
• 5.7 ± 1.8 L/kg O-desmethylvenlafaxine(active metabolite)

Elimination Route

Venlafaxine is well absorbed, with at least 92% of a single dose absorbed on the basis of mass balance studies . Food does not affect the absorption of venlafaxine or its subsequent metabolism into ODV. Bioavailability is 45% following oral administration. Time to steady state = 3 days.

Half Life

5 hours

Clearance

Steady state plasma clearance, venlafaxine = 1.3 ± 0.6 L/h/kg; Steady state plasma clearance, ODV = 0.4 ± 0.2 L/h/kg.

Elimination Route

Renal elimination of venlafaxine and its metabolites is the primary route of excretion. Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as either unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%).

Pregnancy & Breastfeeding use

Treatment Of Pregnant Women During The Third TrimesterNeonates exposed to venlafaxine tablets, USP, other SNRIs, or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. When treating pregnant women with venlafaxine tablets during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.

Contraindication

Concomitant use with MAOIs or within 14 days of discontinuing the MAOI. Use with linezolid or IV methylene blue.

Special Warning

Dosage For Patients With Hepatic Impairment: Given the decrease in clearance and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with hepatic cirrhosis and mild and moderate hepatic impairment compared to normal subjects, it is recommended that the total daily dose be reduced by 50% in patients with mild to moderate hepatic impairment. Since there was much individual variability in clearance between subjects with cirrhosis, it may be necessary to reduce the dose even more than 50%, and individualization of dosing may be desirable in some patients.

Dosage For Patients With Renal Impairment: Given the decrease in clearance for venlafaxine and the increase in elimination half-life for both venlafaxine and ODV that is observed in patients with renal impairment (GFR = 10 to 70 mL/min) compared to normals, it is recommended that the total daily dose be reduced by 25% in patients with mild to moderate renal impairment. It is recommended that the total daily dose be reduced by 50% in patients undergoing hemodialysis. Since there was much individual variability in clearance between patients with renal impairment, individualization of dosing may be desirable in some patients.

Acute Overdose

Symptoms: Sweating, dizziness, somnolence, mydriasis, convulsions, vomiting, ECG changes, cardiac arrhythmias and seizures.

Management: Symptomatic and supportive treatment. Ensure adequate airway, oxygenation and ventilation. Initiate gastric lavage immediately after ingestion. Admin activated charcoal to reduce absorption. Monitor cardiac rhythm and vital signs.

Storage Condition

Store between 20-25° C.

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