Velafax^® MV (Capsules) Instructions for Use

Marketing Authorization Holder

Pliva Hrvatska, d.o.o. (Croatia)

Manufactured By

Cipla Ltd. (India)

ATC Code

N06AX16 (Venlafaxine)

Active Substance

Venlafaxine (Rec.INN registered by WHO)

Dosage Forms

	Velafax® MV	Prolonged-release capsules 75 mg: 30 pcs.
		Prolonged-release capsules 150 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Prolonged-release capsules hard gelatin, size No. 1, with a yellow cap and a transparent body; capsule contents – pellets of white or almost white color.

Excipients: sucrose, hypromellose, talc.

Isolating coating composition hypromellose (6cps), talc.
Active substance release-regulating coating composition hypromellose (E-15), Surelease E-7-7050 (a complex component consisting of water, ethylcellulose (20cp), ammonia water 28%, dibutyl sebacate, butyric acid, colloidal silicon dioxide).
Capsule shell composition dye sunset yellow, dye quinoline yellow, titanium dioxide, sodium lauryl sulfate, gelatin.

10 pcs. – blisters (3) – cardboard packs.

Prolonged-release capsules hard gelatin, size No. 0, with a dark yellow cap and a transparent body; capsule contents – pellets of white or almost white color.

Excipients: sucrose, hypromellose, talc.

Isolating coating composition hypromellose (6cps), talc.
Active substance release-regulating coating composition hypromellose (E-15), Surelease E-7-7050 (a complex component consisting of water, ethylcellulose (20cp), ammonia water 28%, dibutyl sebacate, butyric acid, colloidal silicon dioxide).
Capsule shell composition dye sunset yellow, dye quinoline yellow, dye patent blue, titanium dioxide, sodium lauryl sulfate, gelatin.

10 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Antidepressant

Pharmacotherapeutic Group

Antidepressant

Pharmacological Action

Antidepressant. Its chemical structure cannot be attributed to any known class of antidepressants (tricyclic, tetracyclic, or others). It has two active enantiomeric racemic forms.

The antidepressant effect of venlafaxine is associated with an increase in neurotransmitter activity in the CNS. Venlafaxine and its main metabolite O-desmethylvenlafaxine (ODV) are potent inhibitors of serotonin and norepinephrine reuptake and weakly inhibit dopamine reuptake by neurons. Venlafaxine and ODV are equally effective in influencing neurotransmitter reuptake. Venlafaxine and ODV reduce beta-adrenergic responses.

Venlafaxine has no affinity for m-cholinergic receptors, histamine H₁ receptors, and α-adrenergic receptors of the brain. Venlafaxine does not inhibit MAO activity. It has no affinity for opioid, benzodiazepine, phencyclidine, and NMDA receptors.

Pharmacokinetics

Absorption

After taking Velafax MV, C_max of venlafaxine and ODV in plasma are reached within 6.0±1.5 h and 8.8±2.2 h, respectively. When the drug is taken with food, the time to reach C_max in blood plasma increases by 20-30 min, but the values of maximum concentration and absorption do not change.

Distribution

The binding of venlafaxine and ODV to plasma proteins is 27% and 30%, respectively.

With multiple administrations, C_ss of venlafaxine and ODV are achieved within 3 days. In the range of daily doses of 75-450 mg, Venlafaxine and ODV have linear kinetics.

Metabolism and excretion

ODV and other metabolites, as well as unchanged Venlafaxine, are excreted by the kidneys.

The absorption rate of venlafaxine from prolonged-release capsules is lower than its elimination rate. Therefore, the T_1/2 of venlafaxine after administration of Velafax MB is 15±6 h and actually represents the T_1/2 of absorption, rather than the T_1/2 of distribution (5±2 h), which is noted after administration of the drug Velafax in tablet form.

Pharmacokinetics in special clinical cases

In patients with liver cirrhosis, plasma concentrations of venlafaxine and ODV are increased, and their excretion rate is decreased.

In moderate or severe renal failure, the total clearance of venlafaxine and ODV decreases, and T_1/2 is prolonged. The decrease in total clearance is mainly observed in patients with CrCl less than 30 ml/min.

Age and sex do not affect the pharmacokinetics of the drug.

Indications

• Treatment and prevention of relapse of depression (including with anxiety).

ICD codes

Dosage Regimen

Velafax MB should be taken with food.

Each capsule should be swallowed whole and washed down with liquid. Capsules should not be divided, crushed, chewed, or placed in water. The daily dose should be taken in one dose (morning or evening) each time at approximately the same time.

For the treatment of depression, the recommended initial dose is 75 mg once/day. If it is necessary to use the drug at a higher dose (severe depressive disorder or other conditions requiring inpatient treatment), 150 mg once/day can be prescribed immediately. Subsequently, the daily dose can be increased by 75 mg at intervals of 2 weeks or more (but not more often than every 4 days) until the desired therapeutic effect is achieved. The maximum daily dose is 350 mg. After achieving the necessary therapeutic effect, the daily dose can be gradually reduced to the minimum effective level.

Maintenance therapy and relapse prevention

Treatment of depression should continue for at least 6 months. For stabilizing therapy, as well as therapy for the prevention of relapse or new episodes of depression, the drug is used in doses that were effective in the treatment of depression.

The effectiveness of long-term therapy with Velafax MB should be regularly monitored (at least once every 3 months).

When transferring patients from Velafax in tablet form to Velafax^® MV, an equivalent dose should be prescribed once/day. However, individual dose adjustment may be required.

In mild renal impairment (GFR more than 30 ml/min), no adjustment of the dosage regimen is required. In moderate renal impairment (GFR 10-30 ml/min), the dose should be reduced by 50%. Due to the prolongation of T_1/2 of venlafaxine and its active metabolite (ODV), such patients should take the entire dose once/day. The use of Venlafaxine is not recommended in severe renal failure (GFR less than 10 ml/min), since reliable data on such therapy are not available. Patients on hemodialysis can be prescribed 50% of the usual daily dose of venlafaxine after completion of the hemodialysis procedure.

In mild hepatic impairment (prothrombin time less than 14 sec), no adjustment of the dosage regimen is required. In moderate hepatic impairment (prothrombin time from 14 sec to 18 sec), the dose should be reduced by 50%. The use of Venlafaxine is not recommended in severe hepatic impairment, since reliable data on such therapy are not available.

When prescribing the drug to elderly patients, no dose changes are required, however (as with the prescription of other drugs), caution is required when treating elderly patients, for example, due to the possibility of impaired renal function. The lowest effective dose should be used. When increasing the dose, the patient should be under close medical supervision.

With abrupt discontinuation of Velafax (especially in high doses), withdrawal symptoms may occur. Therefore, before complete discontinuation of the drug, a gradual dose reduction is recommended. If high doses have been used for more than 6 weeks, it is recommended to reduce the doses over at least 2 weeks. The duration of the period required for dose reduction depends on the dose size, duration of therapy, and the patient’s reactions.

Adverse Reactions

Most of the side effects listed below are dose-dependent. With long-term treatment, the severity and frequency of most of these effects decrease, and there is no need to discontinue therapy.

The frequency of adverse reactions is presented according to the following gradation: common (<1/10 and >1/100); uncommon (<1/100 and >1/1000); rare (<1/1000); very rare (<1/10,000).

General disorders: asthenia, fatigue, headache, abdominal pain, chills, increased body temperature.

Digestive system disorders: decreased appetite, constipation, nausea, vomiting, dry mouth; uncommon – teeth grinding during sleep, reversible increase in liver enzyme activity; rare – gastrointestinal bleeding; very rare – hepatitis, pancreatitis.

Central and peripheral nervous system disorders dizziness, insomnia, agitation, drowsiness; common – unusual dreams, anxiety, confusion, increased muscle tone, paresthesia, tremor; uncommon – apathy, hallucinations, myoclonus; rare – ataxia, speech disorders (including dysarthria), mania or hypomania, manifestations resembling NMS, seizures, serotonin syndrome, extrapyramidal disorders (including dyskinesia and dystonia, akathisia); very rare – delirium.

Cardiovascular system disorders: arterial hypertension, vasodilation (flushing), palpitations; uncommon – orthostatic hypotension, syncope, arrhythmias (including tachycardia); very rare – torsades de pointes, QT interval prolongation, ventricular tachycardia, ventricular fibrillation.

Special senses disorders: accommodation disturbances, mydriasis, vision impairment, tinnitus; uncommon – taste perversion.

Hematopoietic system disorders: uncommon – skin hemorrhages (ecchymoses) and mucous membranes; rare – thrombocytopenia, prolonged bleeding time; very rare – agranulocytosis, aplastic anemia, neutropenia, pancytopenia.

Dermatological reactions: sweating, skin itching and rash; uncommon – photosensitivity, angioedema, maculopapular eruptions, urticaria; rare – alopecia, erythema multiforme, Stevens-Johnson syndrome.

Reproductive system disorders: ejaculation disorders, erection disorders, orgasm disorders; uncommon – decreased libido, impotence, menstrual cycle disorders, menorrhagia; rare – galactorrhea.

Urinary system disorders increased frequency of urination; uncommon – urinary retention.

Metabolic disorders: increased serum cholesterol levels (in some cases with long-term use and possibly with high doses), increased or decreased body weight; uncommon – hyponatremia, syndrome of inappropriate ADH secretion; very rare – increased prolactin levels.

Musculoskeletal system disorders: arthralgia, myalgia; uncommon – muscle spasm; very rare – rhabdomyolysis.

After abrupt withdrawal of venlafaxine or dose reduction: possible – fatigue, drowsiness, headache, nausea, vomiting, anorexia, dry mouth, dizziness, lightheadedness, diarrhea, insomnia, nightmares, restlessness, anxiety, disorientation, hypomania, weakness, coordination disorders, ringing in the ears, tremor, convulsions, paresthesias, sweating. These symptoms are usually mild and resolve without treatment. Due to the likelihood of these symptoms, it is very important to gradually reduce the dose of the drug (like any other antidepressant), especially after taking high doses. The duration of the period required for dose reduction depends on the dose size, duration of therapy, and individual sensitivity.

Contraindications

• Concomitant use of MAO inhibitors;
• Severe impairment of renal (GFR less than 10 ml/min) and/or hepatic function (prothrombin time more than 18 sec);
• Age under 18 years (safety and efficacy not established);
• Pregnancy or suspected pregnancy;
• Lactation period (insufficient data from controlled studies);
• Hypersensitivity to the components of the drug.

With caution the drug should be used after a recent myocardial infarction, with unstable angina, heart failure, coronary artery disease, ECG changes (including QT interval prolongation), electrolyte imbalance, arterial hypertension, tachycardia, history of seizures, with intraocular hypertension, closed-angle glaucoma, history of manic states, predisposition to bleeding from the skin and mucous membranes, suicidal tendencies, with concomitant use of diuretics, with initially reduced body weight.

Use in Pregnancy and Lactation

The safety of venlafaxine use during pregnancy has not been proven, so use during pregnancy (or suspected pregnancy) is possible only if the potential benefit to the mother outweighs the possible risk to the fetus.

Women of childbearing age should be informed about this before starting treatment and warned about the need to consult a doctor in case of pregnancy or planning pregnancy during treatment with the drug.

Venlafaxine and its metabolite (ODV) are excreted in breast milk. The safety of these substances for newborn infants has not been proven, so the use of venlafaxine during breastfeeding is not recommended. If it is necessary to take the drug during lactation, the issue of discontinuing breastfeeding should be decided. If the mother’s treatment was completed shortly before delivery, the newborn may experience drug withdrawal symptoms.

Use in Hepatic Impairment

In mild hepatic impairment (prothrombin time less than 14 sec), no adjustment of the dosage regimen is required. In moderate hepatic impairment (prothrombin time from 14 sec to 18 sec), the dose should be reduced by 50%. In severe hepatic impairment, it is not recommended to prescribe Venlafaxine, since reliable data on the use of the drug in this category of patients are not available.

Use in Renal Impairment

In mild renal impairment (GFR more than 30 ml/min), no adjustment of the dosage regimen is required. In moderate renal impairment (GFR 10-30 ml/min), the dose should be reduced by 50%.

Due to the prolongation of T_1/2 of venlafaxine and its active metabolite (ODV), such patients should take the entire dose once/day. In severe renal impairment (GFR less than 10 ml/min), it is not recommended to prescribe Venlafaxine since reliable data on the use of the drug in this category of patients are not available.

Patients on hemodialysis can be prescribed 50% of the usual daily dose of venlafaxine after completion of the hemodialysis procedure.

Pediatric Use

Contraindication: age under 18 years (safety and efficacy not established).

Geriatric Use

When prescribing the drug to elderly patients, no dose changes are required, however (as with the prescription of other drugs), caution is required when treating elderly patients, for example, due to the possibility of impaired renal function. The lowest effective dose should be used. When increasing the dose, the patient should be under close medical supervision.

Special Precautions

In depression, the risk of suicidal thoughts and suicide attempts increases. This risk persists until stable remission occurs. Therefore, patients require constant medical supervision and should be given only a small number of capsules of the drug to reduce the risk of possible abuse and/or overdose.

Aggressive behavior has been reported during venlafaxine use (especially at the beginning of the course of treatment and after discontinuation of the drug).

The use of venlafaxine may cause psychomotor agitation, which clinically resembles akathisia, characterized by restlessness with a need to move, often combined with an inability to sit or stand still. This is most often observed during the first few weeks of treatment. If these symptoms occur, increasing the dose may have an adverse effect and the advisability of continuing the drug should be considered.

Like all antidepressants, the drug should be prescribed with caution to patients with a history of mania and/or hypomania, as the drug may enhance their signs. In these cases, medical supervision is necessary.

Caution should be exercised when treating patients with a history of seizures. If seizures occur or their frequency increases, treatment with venlafaxine should be discontinued.

Like selective serotonin reuptake inhibitors, Velafax^® MV should be prescribed with caution when taking antipsychotic drugs concomitantly, as symptoms resembling NMS may develop.

Patients should be warned to consult a doctor immediately if a rash, urticaria, or other allergic reactions occur.

In some patients during venlafaxine use, a dose-dependent increase in blood pressure has been noted, so regular blood pressure monitoring is recommended, especially at the beginning of the course of treatment or when increasing the dose.

During the use of venlafaxine, isolated cases of orthostatic hypotension have been described.

Patients, especially the elderly, should be warned about the possibility of dizziness and impaired sense of balance.

Venlafaxine may cause an increase in heart rate, especially when taken in high doses. Special caution should be exercised when prescribing the drug to patients with conditions that may be exacerbated by an increase in heart rate.

There have been insufficient studies on the use of venlafaxine in patients with a recent myocardial infarction or with decompensated heart failure, so this drug should be used with caution in such cases.

Like other serotonin reuptake inhibitors, Venlafaxine may increase the risk of hemorrhages in the skin and mucous membranes, therefore caution is necessary when treating patients predisposed to bleeding.

During the use of venlafaxine, especially in conditions of dehydration or decreased blood volume (including in elderly patients and patients taking diuretics), hyponatremia and/or the syndrome of inappropriate antidiuretic hormone secretion may be observed.

Cases of mydriasis have been noted during the use of venlafaxine, so patients with a predisposition to increased intraocular pressure or at risk of angle-closure glaucoma require careful medical supervision.

The safety and efficacy of using venlafaxine with weight-reducing agents, including phentermine, have not been established, so their simultaneous use (as well as the use of venlafaxine as monotherapy for weight loss) is not recommended.

A clinically significant increase in serum cholesterol levels has been noted in some patients receiving Venlafaxine for at least 4 months. Therefore, with long-term use of the drug, it is advisable to monitor serum cholesterol levels.

Discontinuation of the drug, especially abrupt, often leads to withdrawal symptoms. The risk of withdrawal symptoms may depend on several factors, including the duration of the course and dose, as well as the rate of dose reduction.

Withdrawal symptoms, such as dizziness, sensory disturbances (including paresthesia and electric shock sensations), sleep disturbances (including insomnia and unusual dreams), agitation or anxiety, nausea and/or vomiting, tremor, sweating, headache, diarrhea, rapid and intensified heartbeat, and emotional lability, are usually mild to moderate, but in some patients they can be severe. They are usually observed in the first few days after discontinuation of the drug, although there have been isolated reports of such symptoms in patients who accidentally missed a single dose. Usually these phenomena resolve on their own within 2 weeks; however, in some patients they may be more prolonged (2-3 months or longer). Therefore, before discontinuing venlafaxine, it is recommended to gradually reduce its dose over several weeks or months depending on the patient’s condition.

Use in Pediatrics

Velafax^® MV is contraindicated for the treatment of children and adolescents under 18 years of age. An increased likelihood of suicidal behavior (suicide attempt and suicidal thoughts), as well as hostility, was more frequently observed in clinical trials among children and adolescents receiving antidepressants compared to groups receiving placebo.

Effect on the Ability to Drive Vehicles and Operate Machinery

It should be taken into account that any drug therapy with psychoactive drugs may reduce the ability to concentrate, think, or perform motor functions. The patient should be warned about this before starting treatment. If such effects occur, the degree and duration of restrictions should be determined by the physician.

Overdose

Symptoms: ECG changes (QT interval prolongation, bundle branch block, QRS complex widening), sinus or ventricular tachycardia, bradycardia, arterial hypotension, convulsive states, depression of consciousness, especially with venlafaxine overdose in combination with alcohol or other psychotropic drugs.

A fatal outcome has been reported with an overdose of venlafaxine and simultaneous use with alcohol and/or other psychotropic drugs.

Treatment: administration of activated charcoal to reduce drug absorption. Inducing vomiting is not recommended due to the risk of aspiration. Symptomatic therapy should be carried out. Specific antidotes are unknown. Adequate oxygenation and lung ventilation should be ensured. Continuous monitoring of heart rhythm and vital functions is recommended. Venlafaxine and ODV are not eliminated by dialysis.

Drug Interactions

Simultaneous use of MAO inhibitors and venlafaxine is contraindicated. Treatment with Velafax MB can be started no less than 14 days after the end of MAO inhibitor therapy. MAO inhibitor therapy can be started no less than 7 days after discontinuation of Velafax MB.

Theoretically, interaction of venlafaxine with drugs affecting the serotonin neurotransmitter system (such as triptans, selective serotonin reuptake inhibitors, lithium) is possible, so caution should be exercised when co-administering with these drugs. Simultaneous use of venlafaxine with lithium does not affect the plasma concentration of the latter.

When used concomitantly with imipramine/desipramine, the pharmacokinetics of venlafaxine and its metabolite (ODV) do not change. At the same time, the effects of desipramine, the main metabolite of imipramine, and its other metabolite 2-OH-imipramine are enhanced when combined, although the clinical significance of this phenomenon is unknown.

When used concomitantly, Venlafaxine increases the plasma concentration of haloperidol and enhances its effects.

When used concomitantly with diazepam, the pharmacokinetics of the drugs and their main metabolites do not change significantly. No effect on the psychomotor and psychometric effects of diazepam was found.

When used concomitantly with clozapine, an increase in its plasma concentration and the development of side effects (for example, seizures) are possible.

When used concomitantly with risperidone (despite an increase in the AUC of risperidone), the pharmacokinetics of the sum of active components (risperidone and its active metabolite) do not change significantly.

The decrease in mental and motor activity under the influence of ethanol was not enhanced after taking venlafaxine. Despite this, as with the use of other drugs affecting the central nervous system, alcohol consumption is not recommended during venlafaxine therapy.

Special caution should be exercised during electroconvulsive therapy while taking venlafaxine, as there is no experience with the use of venlafaxine under these conditions.

Drugs Metabolized by Cytochrome P450 Isoenzymes

The CYP2D6 isoenzyme converts Venlafaxine into the active metabolite ODV. Unlike many other antidepressants, the dose of venlafaxine does not need to be reduced when used concomitantly with drugs that suppress CYP2D6 activity, or in patients with a genetically determined decrease in the activity of this isoenzyme, since the total concentration of venlafaxine and ODV will not change.

The main route of elimination of venlafaxine involves metabolism with the participation of CYP2D6 and CYP3A4 isoenzymes, therefore special caution should be exercised when prescribing venlafaxine in combination with drugs that inhibit both of these enzymes. Such drug interaction has not yet been studied.

Venlafaxine is a relatively weak inhibitor of CYP2D6 and does not suppress the activity of CYP1A2, CYP2C9 and CYP3A4 isoenzymes, so its interaction with other drugs metabolized by these isoenzymes is not expected.

Cimetidine inhibits the first-pass metabolism of venlafaxine and does not affect the pharmacokinetics of ODV. In most patients, only a slight increase in the overall pharmacological activity of venlafaxine and ODV is expected (but in elderly patients and with impaired liver function, this is more pronounced, and medical supervision is recommended).

When taken concomitantly with warfarin, an enhancement of its anticoagulant effect is possible, with prolongation of prothrombin time and an increase in INR.

When taken concomitantly with indinavir, the pharmacokinetics of indinavir change (a 28% decrease in AUC and a 36% decrease in C_max), while the pharmacokinetics of venlafaxine and ODV do not change. The clinical significance of this effect is unknown.

Storage Conditions

The drug should be stored out of the reach of children, in a dry place at a temperature not exceeding 30°C (86°F).

Shelf Life

Shelf life is 2 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.