Velafax, tablets 75 mg 28 pcs.

Pharmacotherapeutic group: antidepressant

Code ATX: N06AX16

Pharmacological properties

Pharmacodynamics. An antidepressant that is not chemically related to any known class of antidepressants (tricyclic, tetracyclic or other). It is a racemate of two active enantiomers. The antidepressant effect of venlafaxine is related to its ability to potentiate nerve impulse transmission in the CNS. Venlafaxine and its main metabolite O-desmethylvenlafaxine (ODV) are potent inhibitors of serotonin and noradrenaline reuptake by neurons and weakly inhibit dopamine reuptake. Venlafaxine and EFA reduce CNS beta-adrenergic reactivity both after a single dose and with continuous administration.

Venlafaxine has no affinity for m-cholinergic, H1-histamine and α₁-adrenergic receptors in the brain. It does not inhibit the activity of MAOIs. The drug does not affect norepinephrine release from brain tissue.

Pharmacokinetics. After oral administration venlafaxine is well absorbed from the gastrointestinal tract. After a single dose of 25-150 mg, maximum plasma concentrations (C_max) are reached within approximately 2.4 hours and are 33-172 ng/mL. After taking the drug with meals, the time to reach maximum plasma concentrations is increased by 20-30 minutes, but the values of maximum concentration and absorption do not change.

Venlafaxine undergoes intensive metabolism during “first passage” through the liver. The main metabolite is O-desmethylvenlafaxine (ODV). Maximum plasma concentration of EFA is reached approximately 4.3 hours after administration and is 61-325 ng/ml. The pharmacokinetics of venlafaxine and EFAs are linear in the daily dose range of 75-450 mg.

The binding of venlafaxine and EFA to plasma proteins is 27% and 30%, respectively. Equilibrium concentrations (C_ss) of venlafaxine and EFA are reached within 3 days with multiple dosing.

The half-life (T_1/2) of venlafaxine and EFA are 5 and 11 h, respectively. EFA and other metabolites, as well as unchanged venlafaxine, are excreted by the kidneys.

In patients with cirrhosis, plasma concentrations of venlafaxine and EFA are elevated and their elimination rate is reduced. In moderate to severe renal failure (creatinine clearance (CK) less than 30 ml/min), total clearance of venlafaxine and EFA is decreased and the elimination half-life is prolonged.

The patient’s age and sex have no effect on the pharmacokinetics of the drug.

Indications

Active ingredient

Composition

How to take, the dosage

Velafax tablets® are taken orally with a meal, preferably at the same time, without chewing and with fluids.

For the treatment of depression, the recommended starting dose of Velafax® is 37.5 mg twice daily. If there is no significant improvement after several weeks of treatment, the dose may be increased to 150 mg daily – 75 mg twice daily.

If a higher dose is necessary for severe depressive disorder or other conditions requiring inpatient treatment, 75 mg 2 times daily may be prescribed immediately. Thereafter, the daily dose may be increased by 75 mg every 2-3 days until the desired therapeutic effect is achieved. The maximum daily dose of Velafax® is 375 mg. After achieving the desired therapeutic effect, the daily dose may be gradually reduced to the minimum effective level.

The maintenance treatment is continued for 6 months or longer. The drug is prescribed at the lowest effective dose used in the treatment of a depressive episode.

In mild renal failure (glomerular filtration rate greater than 30 ml/min), no dosing adjustment is required. In moderate renal insufficiency (glomerular filtration rate 10-30 ml/min) the dose should be reduced by 25-50%. Due to the prolonged elimination half-life of venlafaxine and its active metabolite (AML), such patients should take the entire dose once daily. In severe renal failure (glomerular filtration rate less than 10 ml/min), the use of Velafax® is not recommended because experience with such therapy is limited. Patients on hemodialysis may receive 50% of the usual daily dose of venlafaxine after completion of hemodialysis.

In mild hepatic impairment (prothrombin time (PV) less than 14 sec), no dosing adjustments are required. In moderate hepatic insufficiency (PV of 14 to 18 sec) the dose should be reduced by 50%. In severe hepatic impairment, the use of Velafax® is not recommended since experience with this therapy is limited.

Dose adjustment is not necessary in elderly patients, but (as with other medications) caution is required during treatment, e.g., due to the possibility of impaired renal function. Therefore, in elderly patients, the lowest effective dose of the drug should be used; close medical supervision is indicated if a higher dose is necessary.

Cessation of Velafax®: It is recommended that the dose be reduced gradually at the end of treatment. When used at a dose equal to or greater than 75 mg, for a course of 7 days or more, the drug should be withdrawn for at least a week, gradually reducing the dose. When used in high doses with a course of more than 6 weeks, the period required for complete cessation of the drug is at least 2 weeks. The onset of relapse symptoms during withdrawal of Velafax® requires the initial dose of the drug or a more gradual and prolonged reduction.

Interaction

MAO inhibitors

Unreversible non-selective MAOI inhibitors

. Venlafaxine should not be taken in combination with irreversible non-selective MAO inhibitors, and the interval between discontinuation of MAO inhibitor therapy and initiation of venlafaxine therapy should be at least 14 days. Therapy with venlafaxine should be discontinued at least 7 days before starting therapy with MAO inhibitors.

Retractable selective MAO inhibitors (moclobemide)

Because of the risk of serotonin syndrome, the combination of venlafaxine with reversible and selective MAO inhibitors such as moclobemide is not recommended. After treatment with reversible MAO inhibitors, an interval of less than 14 days may be allowed before starting venlafaxine therapy. It is recommended that venlafaxine therapy be discontinued at least 7 days before starting therapy with reversible MAO inhibitors.

Reversible non-selective MAOI inhibitors (linezolid)

The antibiotic linezolid is a weakly reversible and non-selective MAOI inhibitor and should not be prescribed in patients taking venlafaxine.

Serious adverse reactions have been reported in patients who discontinued MAO inhibitor therapy shortly before starting venlafaxine and in those who started a course of MAO inhibitors immediately after starting venlafaxine. These side effects included tremors, myoclonus, sweating, nausea, vomiting, redness with fever, dizziness, and hyperthermia with symptoms similar to those of malignant neuroleptic syndrome, as well as seizures and death.

Serotonin Syndrome

. Venlafaxine may affect the pharmacodynamics of other drugs acting at the level of the serotonergic neurotransmitter system, so caution should be exercised when prescribing it concurrently with triptans, other selective serotonin reuptake inhibitors and lithium drugs.

When treating venlafaxine concomitantly with selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRIs) or serotonin receptor antagonists, close monitoring of the patient is recommended, especially at the beginning of therapy and when increasing the dose of the drug.

The co-administration of venlafaxine with serotonin precursors, such as tryptophan supplements, is not recommended.

Medications acting on the central nervous system (CNS)

The risk of using venlafaxine in combination with other CNS-acting agents has not been studied. Caution should be exercised during therapy with venlafaxine in combination with other CNS agents.

Ethanol

The concomitant administration of ethanol and venlafaxine was not associated with decreased mental or motor performance. Despite this (as with other CNS medications), ethanol use is not recommended during therapy with venlafaxine.

Drugs that prolong the interval QT

. Co-administration of venlafaxine with other QT interval prolonging drugs increases the risk of QT interval prolongation and/or ventricular arrhythmias. Concomitant use of these drugs should be avoided.

The medications that prolong the QT interval include:

Special Instructions

The risk of suicidal thoughts and suicide attempts increases with depression. This risk persists until sustained remission occurs. Because improvement may not occur during the first few weeks of treatment or more, patients must be under constant medical observation throughout this period until sustained improvement occurs. The risk of suicide attempts is highest immediately after starting the drug, but also increases again during the initial period of recovery.

Venlafaxine should not be used when treating children or adolescents under 18 years of age.

In patients with a history of suicidal behavior or a tendency to have suicidal thoughts before starting treatment, as well as in young adult patients, the risk of suicidal thoughts or suicide attempts is highest. Placebo-controlled clinical trials of antidepressants in adult patients with psychiatric disorders have shown an increased likelihood of suicidal behavior (suicide attempts and suicidal ideation) in individuals under 25 years of age receiving antidepressants, including venlafaxine.

Patients and caregivers should be warned to watch for suicidal ideation and seek medical attention immediately if symptoms occur.

As with other serotonergic agents, treatment with venlafaxine may result in potentially life-threatening serotonin syndrome or reactions similar to malignant neuroleptic syndrome (see

Patients receiving concomitant therapy with venlafaxine and other agents that may affect the serotonergic and/or dopaminergic neurotransmitter systems should be closely monitored.

Simultaneous use of venlafaxine with serotonin precursors is not recommended.

As with other antidepressants, abrupt discontinuation of venlafaxine therapy – especially after using high doses of the drug – may cause “withdrawal” symptoms, so it is recommended that the dose be gradually reduced before withdrawing the drug. The risk of withdrawal symptoms depends on the dose, the duration of therapy, and the individual sensitivity of the patient. Hypomanic or manic states may occur in patients with affective disorders during treatment with antidepressants (including venlafaxine). Venlafaxine (like other antidepressants) should be prescribed with caution in patients with a history of mania (these patients need medical monitoring).

As with other antidepressants, venlafaxine should be prescribed with caution in patients with a history of epileptic seizures. Treatment with venlafaxine should be interrupted if epileptic seizures occur. The drug should not be administered to patients with uncontrolled epilepsy, and patients with controlled epilepsy need close monitoring.

The use of venlafaxine may be associated with the development of psychomotor restlessness, which is clinically similar to akathisia and characterized by subjectively unpleasant and distressing anxiety with a need to move, often combined with an inability to sit or stand still. This condition is most commonly observed during the first few weeks of treatment. If these symptoms occur, increasing the dose may have an adverse effect and continuation of venlafaxine should be considered.

Patients should be warned to seek immediate medical attention if rash, urticaria, or other allergic reactions occur.

In some patients, a dose-dependent increase in blood pressure has been noted while taking venlafaxine; therefore, regular monitoring of blood pressure is recommended, especially during dosage adjustment or increase.

Heart rate may increase during treatment with the drug, especially when taken in high doses. Caution should be exercised when using the drug in patients with a tendency to tachycardia.

Patients, especially elderly patients, should be warned about the possibility of dizziness and impaired sense of balance (orthostatic hypotension).

In patients taking venlafaxine, changes in ECG parameters (prolongation of PR interval, extension of QRS complex, prolongation of QT interval) have rarely been observed.

Patients with recent myocardial infarction and unstable angina should use venlafaxine with caution because the safety of this group of patients has not been studied.

Like other serotonin reuptake inhibitors, venlafaxine may increase the risk of skin and mucosal bleeding. Caution is necessary when treating patients who are predisposed to these conditions.

Hyponatremia and/or insufficient antidiuretic hormone secretion syndrome may occur while taking venlafaxine, especially in conditions of dehydration or reduced circulating blood volume (including elderly patients and patients taking diuretics).

Mydriasis may be seen while taking the drug; therefore it is recommended to monitor the intraocular pressure in patients who are prone to elevated eye pressure or with closed-angle glaucoma.

It is not recommended to combine venlafaxine with agents that reduce body weight (including phentermine.

To date, no clinical studies have shown a tolerance to, or dependence on, venlafaxine. However, the clinician should monitor patients closely for signs of abuse (as with other CNS medications). Patients with a history of drug abuse require special monitoring.

Serum cholesterol levels should be monitored when using venlafaxine for an extended period of time.

With caution, the drug should be prescribed if liver or renal function is impaired. Dose reduction may sometimes be necessary.

Particular caution should be used with venlafaxine during administration of electroconvulsive therapy, as there is no experience with venlafaxine in these settings.

Alcohol consumption is not recommended during treatment.

A small number of patients who have received antidepressants, including venlafaxine, have experienced aggression. This has been reported at initiation of venlafaxine therapy, dose changes, and discontinuation of treatment.

As with other antidepressants, venlafaxine should be used with caution in patients with a history of aggression.

Dry mouths may occur while taking the drug, which may increase the risk of tooth decay. Patients should therefore be advised of the importance of oral hygiene.

In patients with diabetes, treatment with SSRIs or venlafaxine may result in altered glycemic control. Adjustments in insulin dose and/or oral antidiabetic medication may be necessary.

SIOZS/IOSS may cause symptoms of sexual dysfunction. Prolonged sexual dysfunction has been reported in which symptoms persisted despite discontinuation of SSRI/ISOZN therapy.

Effects on driving and operating ability

Venlafaxine has little effect on psychomotor and cognitive function. However, given the possibility of significant adverse effects on the central nervous system, during treatment with venlafaxine, caution should be exercised when driving motor vehicles and engaging in potentially hazardous activities requiring increased concentration and rapid psychomotor reactions.

Synopsis

Contraindications

Individual intolerance to venlafaxine and other components of the drug; concomitant use of MAOI inhibitors (see section “Interaction with other medicinal products”); age under 18 years; severe renal (CKR less than 10 ml/min) and/or hepatic function impairment; pregnancy and lactation.

With caution

. Recent myocardial infarction, unstable angina pectoris, arterial hypertension, tachycardia, history of seizures, increased intraocular pressure, closed-angle glaucoma, history of manic state, hyponatremia, hypovolemia, dehydration, concomitant use of diuretics, suicidal tendencies, predisposition to bleeding of the skin and mucous membranes, with initially low body weight.

Side effects

Unwanted reactions are systematized with respect to each of the organ systems according to frequency of occurrence using the World Health Organization classification: very common (≥1/10), frequent (≥1/100 and < 1/10), not common (≥1/1000 and < 1/100), rare (≥1/10000 and < 1/1000), very rarely (< 1/10000), frequently unknown – cannot be estimated based on available data.

Most of the side effects listed below are dose-dependent. Their severity and frequency decreases with long-term treatment, and there is usually no need to discontinue therapy.

Blood and lymphatic system disorders: Rarely, agranulocytosis, aplastic anemia, neutropenia, pancytopenia; very rarely, thrombocytopenia.

Disorders of the immune system: rarely – anaphylactic reactions.

Endocrine system disorders: frequently – insufficient secretion of antidiuretic hormone; very rarely – increased blood plasma prolactin levels.

Disorders of metabolism and nutrition: frequently – decreased appetite; rarely – hyponatremia.

Mental disorders: very often – insomnia; often – confusion, depersonalization, anorgasmia, unusual dreams, decreased libido, increased nervous excitability, agitation; infrequent – mania, hypomanic state, hallucinations, derealization, orgasm disturbance, apathy, bruxism; rare – delirium; frequency unknown – aggression, occurrence of suicidal thoughts and suicidal behavior during therapy and after drug withdrawal.

Nervous system disorders: very frequently, dizziness, headache, sedation; frequently, psychomotor restlessness/akathisia, tremor, paresthesia, dysgeusia; infrequently, syncope, myoclonus, balance disorder, coordination disorder, dyskinesia; rarely, seizures, dystonia, serotonin syndrome, malignant neuroleptic syndrome; very rarely, tardive dyskinesia.

Visual disorders: frequently – visual impairment, accommodation spasm, mydriasis, worsening of visual acuity; rarely – closed-angle glaucoma.

Hearing organ and labyrinth disorders: frequent – tinnitus or ringing in the ears; frequency unknown – dizziness.

Cardiac disorders: frequently – palpitations, tachycardia; rarely – ventricular fibrillation, ventricular tachycardia.

Vascular disorders: frequent – increased blood pressure, vasodilation (mainly hot flashes); infrequent – orthostatic collapse, hypotension.

Disorders of the respiratory system, thoracic and mediastinal organs: frequent – yawning, shortness of breath; rarely – interstitial lung disease, pulmonary eosinophilia.

Gastrointestinal tract disorders: very frequently – nausea, dry mouth, constipation; frequently – dyspepsia, vomiting diarrhea; infrequently – bleeding from the gastrointestinal tract; rarely – pancreatitis.

Hepatic and biliary tract disorders: frequently – liver dysfunction; rarely – hepatitis.

Dermatological and subcutaneous tissue disorders: very often – increased sweating (including Nocturnal); frequently – rash, itching; infrequently – alopecia, photosensitization, angioedema (Quincke’s edema), urticaria, bruises; rarely – erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Muscular and connective tissue disorders:often – hypertonicity; rarely – rhabdomyolysis.

Renal and urinary tract disorders:frequent – rapid urination, pollicuria, urinary retention; infrequent – urinary incontinence.

Gender and mammary gland disorders: frequently – disorders of erection and/or ejaculation, menorrhagia, metrorrhagia.

General disorders and disorders at the injection site: frequently – asthenia, fatigue, chills; very rarely – mucous membrane bleeding.

Laboratory and instrumental findings: frequent – elevated blood cholesterol, increased body weight, decreased body weight; rare – prolongation of QT intervals; very rare – prolonged bleeding time.

. After abrupt withdrawal of venlafaxine or dose reduction, increased fatigue, somnolence, asthenia, headache, nausea, vomiting, anorexia, dry mouth, dizziness, diarrhea, insomnia, unusual dreams, difficulty falling asleep restlessness, anxiety, irritability and emotional lability, paresthesias, confusion, disorientation, hypomania, tremor, increased sweating, tachycardia, seizures, tinnitus or tinnitus, refusal of food. To prevent the development of withdrawal symptoms, it is very important to gradually reduce the dose of the drug, especially after taking high doses.

Overdose

Symptoms (often occurs with simultaneous administration of ethanol):dizziness, decreased blood pressure, ECG changes (QT interval prolongation, Gis bundle leg block, QRS complex extension), sinus and ventricular tachycardia or bradycardia, disorders of consciousness (from drowsiness to coma), seizures, death.

Treatment is symptomatic, under continuous control of ECG and vital organ functions. It is not recommended to induce vomiting due to the risk of aspiration. It is recommended to ensure airway patency, adequate pulmonary ventilation and oxygenation. Hemodialysis is ineffective – venlafaxine and OD are not excreted by dialysis. Specific antidotes are not known.

Pregnancy use

Similarities