Venlafaxine

Venlafaxine is an antidepressant belonging to Selective serotonin and norepinephrine reuptake inhibitor (SNRI) class.

Venlafaxine is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) used for the treatment of major depression, generalized or social anxiety disorder, and panic disorder.

Venlafaxine is well absorbed from the gastrointestinal tract. Its Bioavailability is approximately 45%. Time taken to reach peak plasma concentrations for Immediate-release is Approximately 2 hours (Venlafaxine) and 6.3±2.3 hours for extended-release. Venlafaxine is having Volume of distribution of about 7.5±3.7 L/kg with Plasma protein binding of 27±2%. Venlafaxine Undergoes extensive first-pass metabolism in the liver by CYP2D6 to active metabolite, O-desmethyl Venlafaxine and to a lesser extent by CYP3A4 to N-desmethyl Venlafaxine, both metabolites are further metabolized to N, O-didesmethyl Venlafaxine, mainly excreted Via urine (approximately 87%; 5% as unchanged drug, 29% as unconjugated active metabolite, 26% as conjugated active metabolite, 27% as minor inactive metabolites).

Venlafaxine shows side effects like Drowsiness, weakness or tiredness, dizziness, headache, nightmares, nausea, vomiting, stomach pain, constipation, etc.

Venlafaxine is available in the form of oral tablet, oral capsule, extended release, oral tablet, extended release.

Venlafaxine is available in India, US, Italy, Spain, France, Malaysia, Canada, Europe, and South Africa.

Venlafaxine belongs to Selective serotonin and norepinephrine reuptake inhibitor (SNRI) class and acts as antidepressant.

The exact mechanism of the antidepressant action of venlafaxine in humans is unknown but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through inhibition of their reuptake. Non- clinical studies have demonstrated that venlafaxine and its active metabolite, ODV, are potent and selective inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake.

The Onset and Duration of action of Venlafaxine is not clinically established.

The Time to peak plasma concentration of Venlafaxine is approximately 2-12 hours.

Venlafaxine is available in the form of oral tablet and oral capsule.

Venlafaxine tablet and capsule is taken orally, usually once daily.

Venlafaxine is an effective drug to treat depression. Venlafaxine affects the level of certain chemicals in the brain that is unbalanced in people with depression.

Venlafaxine is an antidepressant belonging to Selective serotonin and norepinephrine reuptake inhibitor (SNRI) class.

Venlafaxine 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.

Venlafaxine is approved for use in the following clinical indications

• Depression
• Panic disorder
• Anxiety

• Depression
• Adult Oral dose: 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.

• Panic disorder

Adult Oral Dose: 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.

• Anxiety
• Adult Oral Dose: Extended release: Initially, 75 mg once daily, may increase dose, as necessary, in increments of up to 75 mg at intervals of ≥2 weeks based on clinical evaluation. Max: 225 mg daily.

Venlafaxine is available in various strengths as 25 mg; 50 mg; 75 mg; 100 mg; 37.5 mg; 150 mg; 225 mg and 112.5 mg.

Venlafaxine is available in the form of oral tablet, oral capsule, extended release, oral tablet, extended release.

• Dosage Adjustment in Kidney Patient

Severe (GFR <30 mL/min) and patients requiring hemodialysis: Reduce dose by 50%.

• Dosage Adjustment in Hepatic impairment Patient

Mild to moderate (Child-Pugh class A and B): Reduce dose by 50%. Severe (Child-Pugh class C): Reduce dose by >50%.

Venlafaxine is contraindicated in patients with

• Hypersensitivity

Hypersensitivity to Venlafaxine hydrochloride, Desvenlafaxine succinate or to any excipients in the formulation

• Concomitant Use with Monoamine Oxidase Inhibitors (MAOIs)

The use of MAOIs (intended to treat psychiatric disorders) concomitantly with Venlafaxine or within 7 days of discontinuing treatment with Venlafaxine is contraindicated because of an increased risk of serotonin syndrome. The use of Venlafaxine within 14 days of discontinuing treatment with an MAOI (intended to treat psychiatric disorders) is also contraindicated.

Starting Venlafaxine in a patient who is being treated with an MAOI such as linezolid or intravenous methylene blue is also contraindicated, because of an increased risk of serotonin syndrome.

• Suicidal thinking and behavior

Use of Venlafaxine may cause suicidal thought and change the behavior of the user. This risk is increasingly high in young patients. It is recommended to screen the patient for such behavior before starting the treatment. Any change in behavior and thought process after taking this medicine should be reported to the doctor immediately.

• Serotonin syndrome

Use of Venlafaxine with other medicines to treat depression may cause nausea, agitation, seizures, and hallucinations (symptoms of serotonin syndrome).

• Neuroleptic malignant syndrome

Use of Venlafaxine may cause Neuroleptic malignant syndrome characterized by high fever, muscle stiffness, extreme changes in blood pressure, excessive sweating, and salivation. The use of this medicine should be stopped as soon as these side effects are experienced.

• Hypertension

Use of Venlafaxine is associated with a sharp increase in blood pressure levels. It is recommended to control hypertension using appropriate medicines before starting the treatment with venlafaxine.

• Bleeding disorders

Use of Venlafaxine may cause unusual bleeding and bruising and hence should be used with caution in patients suffering from bleeding disorders. Use of medicines that are known to cause gastrointestinal bleeding, (example: aspirin, paracetamol, ibuprofen etc.), should be avoided while taking desvenlafaxine.

• Glaucoma

Venlafaxine should be used with caution in patients suffering from angle closure glaucoma. The symptoms of this disease may worsen upon using desvenlafaxine and hence caution is advised.

• Seizure disorder

Use of Venlafaxine may cause seizures and hence should be used with caution in patients suffering from epilepsy.

• Manic episodes

Use of Venlafaxine may cause agitation and aggressive behavior in some patients. The patient should be screened for bipolar disorder before starting the treatment course with this medicine.

• Heart disease

Venlafaxine should be used with caution in patients suffering from a heart or blood vessel disorder.

• Hyponatremia

Venlafaxine may decrease the sodium levels in the body and hence should be used with caution in patients taking diuretic medicines.

• Bone fractures

Use of Venlafaxine has been associated with an increase in the incidence of bone fractures. Report any incidence of bone pain to the doctor while taking venlafaxine.

• Drowsiness and cognitive impairment

Use of Venlafaxine has been associated with drowsiness and impairment of cognition. It is advised to refrain from driving vehicles or operating heavy machinery while taking this medicine.

• Sexual dysfunction

Use of Venlafaxine may cause sexual dysfunction. These dysfunctions may include a decrease in libido, erectile disorders, or unusual orgasm.

• Withdrawal symptoms

Use of Venlafaxine should not be discontinued abruptly. It is advised to gradually reduce the dose of this medicine.

• Monoamine oxidase inhibitor drugs

Venlafaxine should be used at least 14 days after stopping the use of MOAI drugs. Use venlafaxine should stop at least 7 days before using the other medicine.

Venlafaxine and ODV have been reported to be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Venlafaxine extended release, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Common

Withdrawal symptoms (e.g. dizziness, sensory and sleep disturbances, agitation, nausea, vomiting, headache), anxiety, insomnia, nervousness, CNS depression, dyslipidemia, bone fracture, hypertension, sexual dysfunction, weight loss and anorectic effect, mild pupillary dilation, suicidal thoughts and behavior, mild pupillary dilation. Rarely, hyponatraemia, akathisia, interstitial lung disease, eosinophilic pneumonia, ventricular tachycardia, Palpitations, dyspnea, Tinnitus, Visual impairment, accommodation disorder, Nausea, constipation, vomiting, diarrhea, ,Hyperhidrosis, asthenia, fatigue, chills, Weight gain, increased heart rate, increased triglycerides , Decreased appetite, ,Hypertonia, Dizziness, headache, sedation, tremor, paranesthesia, dysgeusia, , Insomnia, confusional state, depersonalization, anorgasmia, nervousness, abnormal dreams, agitation, anxiety, Urinary retention, urinary frequency, dysuria, urinary incontinence, Decreased libido, metrorrhagia, ejaculation disorder, menorrhagia, impotence, Rash, pruritus, Hot flush, vasodilation, orthostatic hypotension, bleeding events (e.g. ecchymoses, hematomas, epistaxis, petechiae).

Rare

Serotonin syndrome (e.g. dizziness, agitation, hallucination, tachycardia, tremor, severe headache), cardiac arrhythmias.

Central Nervous System (CNS)-Active Drugs

The risk of using Venlafaxine in combination with other CNS-active drugs has not been systematically evaluated. Consequently, caution is advised when Venlafaxine is taken in combination with other CNS active drugs.

Monoamine Oxidase Inhibitors

Adverse reactions, some of which were serious, have been reported in patients who have recently been discontinued from an MAOI and started on antidepressants with pharmacological properties similar to Venlafaxine (SNRIs or SSRIs), or who have recently had SNRI or SSRI therapy discontinued prior to initiation of an MAOI.

Serotonergic Drugs

Based on the mechanism of action of Venlafaxine and the potential for serotonin syndrome, caution is advised when Venlafaxine is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, SSRIs, other SNRIs, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John’s wort. If concomitant treatment with Venlafaxine and these drugs is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of Venlafaxine with tryptophan supplements is not recommended.

Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)

Serotonin released by platelets plays an important role in hemostasis. The use of psychotropic drugs that interfere with serotonin reuptake is associated with the occurrence of upper gastrointestinal bleeding and concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when Venlafaxine is initiated or discontinued.

Weight Loss Agents

The safety and efficacy of Venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Coadministration of Venlafaxine and weight loss agents is not recommended. Venlafaxine is not indicated for weight loss alone or in combination with other products.

The common side effects of Venlafaxine include the following

Common side effects

Drowsiness, weakness or tiredness, dizziness, headache, nightmares, nausea, vomiting, stomach pain, constipation, diarrhoea, gas, heartburn, burping, dry mouth, change in ability to taste food, loss of appetite, weight loss, uncontrollable shaking of a part of the body, pain, burning, numbness, or tingling in part of the body, yawning, sweating, hot flashes or flushing, frequent urination, difficulty urinating, sore throat, chills, or other signs of infection, ringing in the ears, sexual problems in males; decreased sex drive, inability to get or keep an erection, or delayed or absent ejaculation, sexual problems in females; decreased sex drive, or delayed orgasm or unable to have an orgasm, enlarged pupils (black circles in the middle of the eyes).

Rare side effects

Rash, hives, itching, difficulty breathing or swallowing, chest pain, fast, pounding, or irregular heartbeat, seizures, unusual bruising or bleeding, small purple spots on the skin, fever, sweating, confusion, fast or irregular heartbeat, severe muscle stiffness or twitching, nausea, vomiting, or diarrhea, problems with coordination, hallucinations (seeing things or hearing voices that do not exist), coma (loss of consciousness for a period of time).

• Pregnancy

Pregnancy Category C

Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

• Nursing Mothers

Venlafaxine and ODV have been reported to be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Effexor XR, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

• Pediatric Use

In general, the adverse reaction profile of venlafaxine (in placebo-controlled clinical studies) in children and adolescents (ages 6 to 17) was like that seen for adults. As with adults, decreased appetite, weight loss, increased blood pressure, and increased serum cholesterol were observed.

• Geriatric Use

No overall differences in effectiveness or safety were observed between geriatric patients and younger patients, and other reported clinical experience generally has not identified differences in response between the elderly and younger patients. However, the greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including Effexor XR, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event.

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 In symptomatic patients, perform gastric lavage soon after ingestion. Administration of activated charcoal to reduce absorption.

• Pharmacodynamic

Venlafaxine is an antidepressant agent that works to ameliorate the symptoms of various psychiatric disorders by increasing the level of neurotransmitters in the synapse. Venlafaxine does not mediate muscarinic, histaminergic, or adrenergic effects.

• Pharmacokinetics

Absorption

Venlafaxine is well absorbed from the gastrointestinal tract. Its Bioavailability is approximately 45%. Time taken to reach peak plasma concentrations for Immediate-release is Approximately 2 hours (Venlafaxine) and 6.3±2.3 hours for extended-release.

Distribution

Venlafaxine is having Volume of distribution of about 7.5±3.7 L/kg with Plasma protein binding of 27±2%.

Metabolism and Excretion

Venlafaxine Undergoes extensive first-pass metabolism in the liver by CYP2D6 to active metabolite, O-desmethyl Venlafaxine and to a lesser extent by CYP3A4 to N-desmethyl Venlafaxine, both metabolites are further metabolized to N, O-didesmethyl Venlafaxine, mainly excreted Via urine (approximately 87%; 5% as unchanged drug, 29% as unconjugated active metabolite, 26% as conjugated active metabolite, 27% as minor inactive metabolites).

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020699s107lbl.pdf
• https://www.drugs.com/pregnancy/Venlafaxinee.html
• https://go.drugbank.com/drugs/DB00285
• https://medlineplus.gov/druginfo/meds/a694020.html
• https://www.rxlist.com/venlafaxine/generic-drug.htm