Velafax^® (Tablets) Instructions for Use

Marketing Authorization Holder

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

ATC Code

N06AX16 (Venlafaxine)

Active Substance

Venlafaxine (Rec.INN registered by WHO)

Dosage Forms

	Velafax®	Tablets 37.5 mg: 28 or 56 pcs.
		Tablets 75 mg: 28 or 56 pcs.

Dosage Form, Packaging, and Composition

Tablets light yellow or yellow in color, oblong, with a score line on both sides.

Excipients: microcrystalline cellulose, corn starch, yellow iron oxide dye (E172), sodium carboxymethyl starch, talc, colloidal silicon dioxide, magnesium stearate.

14 pcs. – blisters (2) – cardboard packs.
14 pcs. – blisters (4) – cardboard packs.

Tablets light yellow or yellow in color, round, with a score line on one side and an engraving “PLIVA” on the other.

Excipients: microcrystalline cellulose, corn starch, yellow iron oxide dye (E172), sodium carboxymethyl starch, talc, colloidal silicon dioxide, magnesium stearate.

14 pcs. – blisters (2) – cardboard packs.
14 pcs. – blisters (4) – cardboard packs.

Clinical-Pharmacological Group

Antidepressant

Pharmacotherapeutic Group

Psychoanaleptics, antidepressants, other antidepressants

Pharmacological Action

An antidepressant, chemically unrelated to any class of antidepressants (tricyclic, tetracyclic, or others), is a racemate of two active enantiomers.

The mechanism of the antidepressant action of the drug is associated with its ability to potentiate nerve impulse transmission in the CNS. Venlafaxine and its primary metabolite O-desmethylvenlafaxine (ODV) are potent inhibitors of serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake.

In addition, Venlafaxine and ODV reduce beta-adrenergic reactivity both after single administration and during continuous use. Venlafaxine has no affinity for m-cholinergic, histamine H₁ receptors, and α₁-adrenoceptors of the brain. It does not inhibit MAO activity. The drug does not affect the release of norepinephrine from brain tissue.

Pharmacokinetics

Absorption

After oral administration, Venlafaxine is well absorbed from the gastrointestinal tract. After a single dose of 25-150 mg, C_max is reached within approximately 2.4 hours and is 33-172 ng/ml.

When the drug is taken with food, the time to reach C_max in plasma increases by 20-30 minutes, but the values of C_max and absorption do not change.

Distribution

The binding of venlafaxine and ODV to plasma proteins is 27% and 30%, respectively. With multiple doses, C_ss of venlafaxine and ODV are reached within 3 days.

Metabolism

It undergoes intensive metabolism during the “first pass” through the liver. The main metabolite is O-desmethylvenlafaxine.

C_max of ODV in plasma is reached approximately 4.3 hours after administration and is 61-325 ng/ml.

In the range of daily doses of 75-450 mg, the pharmacokinetics of venlafaxine and ODV are linear.

Excretion

T_1/2 of venlafaxine and ODV are 5 and 11 hours, respectively. ODV and other metabolites, as well as unchanged Venlafaxine, are excreted by the kidneys.

With multiple administrations, C_ss of venlafaxine and ODV are reached within 3 days.

Pharmacokinetics in special clinical cases

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

In moderate or severe renal failure (GFR less than 30 ml/min), the total clearance of venlafaxine and ODV decreases, and T_1/2 increases.

The age and sex of the patient do not affect the pharmacokinetics of the drug.

Indications

• Treatment of depressions of various etiologies, including depression accompanied by anxiety symptoms.

ICD codes

Dosage Regimen

Velafax^® tablets are recommended to be taken orally, with meals, preferably at the same time, without chewing and with liquid.

For treatment of depressions the recommended initial dose is 37.5 mg twice daily.

If no significant improvement is observed after several weeks of treatment, the dose can be increased to 150 mg/day – 75 mg twice daily.

If it is necessary to use the drug at a higher dose for severe depressive disorder or other conditions requiring inpatient treatment, 75 mg twice daily can be prescribed immediately.

After that, the daily dose can 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 necessary therapeutic effect, the daily dose can be gradually reduced to the minimum effective level. Maintenance therapy and relapse prevention continues for 6 months or more. The drug is prescribed at the minimum effective dose used in the treatment of the depressive episode.

In mild renal impairment (GFR greater than 30 ml/min) no dosage adjustment is required.

In moderate renal impairment (GFR 10-30 ml/min) the dose should be reduced by 25-50%.

Due to the prolongation of T_1/2 of venlafaxine and its active metabolite (ODV), such patients should take the entire dose once daily.

In severe renal impairment (GFR less than 10 ml/min) the use of Velafax^® is not recommended, as experience with such therapy is limited. Patients on hemodialysis can receive 50% of the usual daily dose of venlafaxine after hemodialysis is completed.

In mild hepatic impairment (prothrombin time /PT/ less than 14 sec) no dosage adjustment is required.

In moderate hepatic impairment (PT from 14 to 18 sec) the dose should be reduced by 50%.

In severe hepatic impairment the use of Velafax^® is not recommended, as experience with such therapy is limited.

Elderly patients do not require dose adjustment, however (as with the prescription of other drugs) caution is required during treatment, for example, due to the possibility of impaired renal function.

In elderly patients, the drug should be prescribed at the lowest effective dose. When increasing the dose, the patient should be under close medical supervision.

Discontinuation of Velafax^® at the end of treatment, the dose is recommended to be reduced gradually.

When used at a dose equal to or exceeding 75 mg, for a course of 7 days or more, the drug is discontinued over at least a week, gradually reducing the dose.

When used in high doses for more than 6 weeks, the period required for complete discontinuation of the drug is at least 2 weeks.

The appearance of symptoms of disease recurrence during the withdrawal period of Velafax^® requires the prescription of the initial dose of the drug or a more gradual and prolonged reduction.

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.

Frequency of adverse reactions: very common (≥10%), common (≥1%, but <10%), uncommon (≥0.1%, but <1%), rare (≥0.01%, but <0.1%), very rare (<0.01%), including isolated cases.

From the digestive system common – decreased appetite, constipation, nausea, vomiting, dry mouth, dyspepsia, abdominal pain; uncommon – bruxism, increased activity of liver transaminases; rare – hepatitis; in isolated cases – pancreatitis.

From the metabolism common – increased serum cholesterol levels (especially after long-term use or use of the drug in high doses), decrease or increase in body weight; uncommon – hyponatremia, syndrome of inappropriate antidiuretic hormone secretion (SIADH); in isolated cases – increased plasma prolactin levels.

From the cardiovascular system common – increased blood pressure, skin hyperemia; uncommon – decreased blood pressure, postural hypotension, syncope, arrhythmia, tachycardia; very rare – torsades de pointes arrhythmia, QT interval prolongation, ventricular tachycardia, ventricular fibrillation.

From the central and peripheral nervous system common – dizziness, asthenia, nightmares, weakness, dizziness, insomnia, drowsiness, increased nervous excitability, paresthesia, stupor, muscle hypertonia, tremor, yawning, sedative effect; uncommon – apathy, hallucinations, myoclonus, syncope; rare – convulsions, ataxia with impaired balance and coordination of movement, speech impairment, mania or hypomania, serotonin syndrome, symptoms resembling neuroleptic malignant syndrome, epileptic seizures; in isolated cases – delirium, extrapyramidal disorders, including dyskinesia and dystonia, tardive dyskinesia, psychomotor restlessness/akathisia.

From the mental status frequency not established – depression, emergence of suicidal thoughts and suicidal behavior during therapy and after drug withdrawal.

From the hematopoietic and lymphatic system uncommon – skin hemorrhages (ecchymoses) and mucous membranes, thrombocytopenia, prolonged bleeding time, hemorrhagic syndrome; in isolated cases – agranulocytosis, aplastic anemia, neutropenia and pancytopenia.

From the urinary system common – urination disorder; uncommon – urinary retention.

From the reproductive system common – decreased libido, erectile and/or ejaculation disorders, anorgasmia in men, menorrhagia; uncommon – menstrual cycle disorders, anorgasmia in women.

From the senses common – accommodation disturbances, mydriasis, vision disturbances, noise or ringing in the ears; uncommon – taste disturbances.

From the skin and its appendages common – increased sweating (including night sweats); uncommon – alopecia.

From the respiratory system uncommon – dyspnea; in isolated cases – pulmonary eosinophilia.

From the endocrine system rare – galactorrhea; in isolated cases – increased prolactin levels.

Allergic reactions uncommon – skin rash (including maculopapular), itching, photosensitivity, angioedema, urticaria; rare – erythema multiforme exudativum, Stevens-Johnson syndrome; in isolated cases – anaphylactic reactions.

From the musculoskeletal system common – arthralgia, myalgia; uncommon – muscle cramps; in isolated cases – rhabdomyolysis.

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

Contraindications

• Severe impairment of renal (GFR less than 10 ml/min) and/or liver function;
• Childhood and adolescence under 18 years;
• Pregnancy;
• Lactation period (breastfeeding);
• Concomitant use of MAO inhibitors;
• Individual intolerance to venlafaxine and other components of the drug.

With caution use in case of recent myocardial infarction, with unstable angina, arterial hypertension, tachycardia, history of convulsive syndrome, increased intraocular pressure, angle-closure glaucoma, history of manic state, hyponatremia, hypovolemia, dehydration, concomitant use of diuretics, suicidal tendencies, predisposition to bleeding (from the skin and mucous membranes), with initially reduced body weight.

Use in Pregnancy and Lactation

During pregnancy (including before childbirth) Venlafaxine is contraindicated, because the safety of its use during this period has not been determined.

Venlafaxine and the ODV metabolite are excreted in breast milk. The safety of these substances for newborn infants has not been proven, therefore, if it is necessary to take the drug during lactation, breastfeeding should be discontinued for the duration of treatment.

Use in Hepatic Impairment

In mild hepatic impairment (prothrombin time /PT/ less than 14 sec) no dosage adjustment is required.

In moderate hepatic impairment (PT from 14 to 18 sec) the dose should be reduced by 50%.

In severe hepatic impairment the use of Velafax^® is not recommended, as experience with such therapy is limited.

Use in Renal Impairment

In mild renal impairment (GFR greater than 30 ml/min) no dosage adjustment is required.

In moderate renal impairment (GFR 10-30 ml/min) the dose should be reduced by 25-50%.

Due to the prolongation of T_1/2 of venlafaxine and its active metabolite (ODV), such patients should take the entire dose once daily.

In severe renal impairment (GFR less than 10 ml/min) the use of Velafax^® is not recommended, as experience with such therapy is limited. Patients on hemodialysis can receive 50% of the usual daily dose of venlafaxine after hemodialysis is completed.

Pediatric Use

The drug is contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Elderly patients do not require dose adjustment, however (as with the prescription of other drugs) caution is required during treatment, for example, due to the possibility of impaired renal function.

In elderly patients, the drug should be prescribed at the lowest effective dose. 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.

Since improvement may not occur during the first few weeks of treatment or longer, patients should be under constant medical supervision throughout this period until stable improvement occurs.

The risk of suicide attempts is highest immediately after starting the drug, but also increases again in the early stages of recovery, Velafax^® should not be used in the treatment of children and 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.

In placebo-controlled clinical trials of antidepressants in adult patients with mental disorders, an increased likelihood of suicidal behavior (suicide attempt and suicidal thoughts) was shown in persons under 25 years of age receiving antidepressants, including Venlafaxine.

Patients and people caring for patients should be warned to monitor for the emergence of suicidal thoughts and to seek immediate medical attention if such symptoms appear.

As with treatment with other antidepressants, abrupt discontinuation of venlafaxine therapy – especially after high doses of the drug – can cause withdrawal symptoms, therefore it is recommended to gradually reduce the dose before discontinuing the drug.

The risk of withdrawal symptoms depends on the dose, duration of therapy, and individual patient sensitivity.

In patients with affective disorders during treatment with antidepressants (including venlafaxine), hypomanic or manic states may occur. Velafax^® (like other antidepressants) should be prescribed with caution to patients with a history of mania (such patients require medical supervision).

Like other antidepressants, Venlafaxine should be prescribed with caution to patients with a history of epileptic seizures.

Venlafaxine treatment should be interrupted if epileptic seizures occur. The drug should not be prescribed to patients with uncontrolled epilepsy, and patients with controlled epilepsy require careful monitoring.

The use of venlafaxine may be associated with the development of psychomotor restlessness, which clinically resembles akathisia and is characterized by subjectively unpleasant and distressing restlessness with a need to move, often combined with an inability to sit or stand still.

This condition is most often observed during the first few weeks of treatment. If such symptoms occur, increasing the dose may have an adverse effect and the advisability of continuing venlafaxine should be considered.

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

In some patients during venlafaxine use, a dose-dependent increase in blood pressure has been noted, therefore regular monitoring of blood pressure is recommended, especially during dose selection or increase.

During treatment with the drug, an increase in heart rate is possible, especially when taken in high doses. Caution should be exercised when using the drug in patients prone to tachycardia.

Patients, especially the elderly, 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 the PR interval, widening of the QRS complex, prolongation of the QT interval) have been rarely observed.

Venlafaxine should be prescribed with caution to patients who have recently had a myocardial infarction and with unstable angina, as the safety of the drug in this category of patients has not been studied.

Like other serotonin reuptake inhibitors, Venlafaxine may increase the risk of hemorrhages in the skin and mucous membranes. Caution is required when treating patients predisposed to such conditions.

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

During the use of the drug, mydriasis may be observed, in connection with which it is recommended to control intraocular pressure in patients prone to its increase or with angle-closure glaucoma.

It is not recommended to combine venlafaxine with weight loss agents (including phentermine) due to the lack of data on efficacy and safety.

Clinical studies conducted to date have not revealed tolerance to or dependence on venlafaxine. Despite this, the physician should establish careful monitoring of patients to identify signs of drug abuse (as with the treatment with other drugs acting on the CNS). Patients with a history of drug dependence require special monitoring.

When using venlafaxine for a long period of time, monitoring of serum cholesterol levels is required.

The drug should be prescribed with caution in case of impaired liver or kidney function. Sometimes a dose reduction may be required.

During the use of venlafaxine, special care should be taken when performing electroconvulsive therapy, as there is no experience with the use of venlafaxine under these conditions.

Alcohol consumption is not recommended during the treatment period.

Effect on the ability to drive vehicles and operate machinery

Venlafaxine has practically no effect on psychomotor and cognitive functions. However, given the possibility of significant side effects from the CNS, during treatment with venlafaxine, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms (often occur with simultaneous ethanol intake) dizziness, decreased blood pressure, ECG changes (QT interval prolongation, bundle branch block, QRS complex widening), sinus and ventricular tachycardia or bradycardia, impaired consciousness (from drowsiness to coma), seizures, death.

Treatment: symptomatic therapy is carried out under continuous monitoring of ECG and functions of vital organs. Inducing vomiting is not recommended due to the risk of aspiration. It is recommended to ensure airway patency, adequate pulmonary ventilation and oxygenation. Hemodialysis is ineffective, as Venlafaxine and ODV are not removed by dialysis. Specific antidotes are unknown.

Drug Interactions

Concomitant use of MAO inhibitors and venlafaxine is contraindicated. Venlafaxine can be started no earlier than 14 days after the end of MAO inhibitor therapy. If a reversible MAO inhibitor (moclobemide) was used, this interval may be shorter (24 hours). MAO inhibitor therapy can be started no earlier than 7 days after discontinuation of venlafaxine.

With the simultaneous use of venlafaxine with lithium preparations, an increase in the level of lithium in the blood is possible.

With simultaneous use with imipramine, the pharmacokinetics of venlafaxine and its metabolite ODV do not change. Venlafaxine does not affect the metabolism of imipramine and its metabolite 2-hydroxyimipramine, but increases the AUC and C_max of desipramine (the main metabolite of imipramine) in plasma, and also reduces the renal clearance of 2-hydroxydesipramine. The clinical significance of this phenomenon is unknown.

With simultaneous use with antipsychotics, symptoms resembling neuroleptic malignant syndrome may appear.

Venlafaxine reduces the renal clearance of haloperidol by 42%, while the AUC and C_max increase by 70% and 88%, respectively. Enhancement of haloperidol effects is possible.

With simultaneous use with diazepam, the pharmacokinetics of the drugs and their main metabolites do not change significantly.

With simultaneous use with clozapine, an increase in its plasma level and the development of side effects (for example, epileptic seizures) may be observed.

With simultaneous use with risperidone, despite an increase in the AUC of the drug, the pharmacokinetics of the sum of active components (risperidone and its active metabolite) did not change significantly.

Simultaneous intake of ethanol and venlafaxine was not accompanied by a decrease in mental and motor activity. Despite this (as with the use of other drugs affecting the CNS), the use of ethanol is not recommended during venlafaxine therapy.

Cimetidine inhibits the metabolism of venlafaxine during the “first pass” through the liver 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 (more pronounced in elderly patients and with impaired liver function). In elderly patients and patients with impaired liver function, the simultaneous use of cimetidine and venlafaxine should be carried out under medical supervision.

No clinically significant interaction of venlafaxine with antihypertensive (including beta-blockers, ACE inhibitors and diuretics) and hypoglycemic drugs has been found.

Since the binding to plasma proteins of venlafaxine and ODV is 27% and 30%, respectively, drug interaction due to competitive release of other drugs from plasma protein binding is not expected.

The metabolism of venlafaxine occurs with the participation of the cytochrome P450 system, isoenzymes CYP2D6 and CYP3A4. Taking the drug with inhibitors of the CYP2D6 isoenzyme or in patients with genetically determined reduced activity of the CYP2D6 isoenzyme was not accompanied by significant changes in the concentration of the active substance and metabolite (venlafaxine and ODV), which allows not to reduce the dose of the antidepressant. However, simultaneous administration with inhibitors of the CYP3A4 isoenzyme is accompanied by an increase in the plasma concentration of venlafaxine. Therefore, special caution should be exercised when prescribing venlafaxine with drugs that are inhibitors of the CYP3A4 isoenzyme (ketoconazole, erythromycin) or both isoenzymes (CYP2D6 and CYP3A4).

Venlafaxine is a relatively weak inhibitor of the CYP2D6 isoenzyme and does not inhibit the activity of the CYP1A2, CYP2C9 and CYP3A4 isoenzymes. In vivo studies did not reveal the effect of venlafaxine on the metabolism of alprazolam (CYP3A4 isoenzyme), caffeine (CYP1A2 isoenzyme), carbamazepine (CYP3A4 isoenzyme) and diazepam (CYP3A4 and CYP2C19 isoenzymes).

With simultaneous use with warfarin, an increase in its anticoagulant effect is possible, while the prothrombin time, expressed as INR, is prolonged.

With simultaneous administration with indinavir, a decrease in the AUC of indinavir by 28% and a decrease in its C_max in plasma by 36% are observed, while the pharmacokinetic parameters of venlafaxine and ODV do not change. The clinical significance of this effect is unknown.

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 simultaneously with triptans, other selective serotonin reuptake inhibitors and lithium preparations.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 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.