Venlaxor^® (Tablets) Instructions for Use

Marketing Authorization Holder

Grindeks, JSC (Latvia)

Contact Information

Grindeks, JSC (Latvia)

ATC Code

N06AX16 (Venlafaxine)

Active Substance

Venlafaxine (Rec.INN registered by WHO)

Dosage Forms

	Venlaxor®	Tablets 37.5 mg: 30 pcs.
		Tablets 75 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Tablets light pink with dark pink specks, flat-cylindrical, with a bevel and a score on one side.

Excipients : anhydrous calcium hydrogen phosphate, anhydrous lactose, sodium carboxymethyl starch, magnesium stearate, anhydrous colloidal silicon dioxide, iron oxide red dye (E172).

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

Clinical-Pharmacological Group

Antidepressant

Pharmacotherapeutic Group

Antidepressant

Pharmacological Action

Antidepressant.

Venlafaxine does not belong by its chemical structure to any class of antidepressants (tricyclic, tetracyclic, or others) and is a racemate of two active enantiomers.

The mechanism of the antidepressant action of the drug is associated with its ability to potentiate the transmission of nerve impulses in the CNS.

Venlafaxine and its main 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 a single administration and with constant use.

Venlafaxine and ODV are equally effective in influencing neurotransmitter reuptake.

Venlafaxine has no affinity for m-cholinergic receptors, histamine H₁ receptors, and α₁-adrenergic receptors of the brain.

Venlafaxine does not inhibit MAO activity.

It has no affinity for opioid, benzodiazepine, phencyclidine, or NMDA receptors.

Pharmacokinetics

Absorption

Venlafaxine is well absorbed from the gastrointestinal tract.

After a single oral administration in doses of 25-150 mg, C_max in blood plasma is 33-172 ng/ml and is reached within approximately 2.4 hours.

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

Distribution and Metabolism

It undergoes intensive metabolism during the “first pass” through the liver.

Its main metabolite is O-desmethylvenlafaxine (ODV).

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

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

With repeated administration, C_ss in plasma 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.

Elimination

T_1/2 of venlafaxine and ODV is 5 and 11 hours, respectively.

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

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, the total clearance of venlafaxine and ODV decreases, and T_1/2 increases.

The decrease in total clearance is mainly observed in patients with CrCl below 30 ml/min.

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

Indications

• Depression of various etiologies (treatment and prevention).

ICD codes

Dosage Regimen

Tablets are recommended to be taken with meals.

The recommended initial dose is 75 mg in 2 doses (37.5 mg 2 times/day) daily.

If no significant improvement is observed after several weeks of treatment, the daily dose can be increased to 150 mg (75 mg 2 times/day).

If a higher dose is needed (severe depressive disorder or other conditions requiring inpatient treatment), 150 mg in 2 doses (75 mg 2 times/day) 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 the drug Venlaxor^® is 375 mg.

After achieving the necessary therapeutic effect, the daily dose can be gradually reduced to the minimum effective level.

Maintenance treatment may continue for 6 months or longer.

The minimum effective doses used in the treatment of the depressive episode are prescribed.

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 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 a day.

It is not recommended to use Venlafaxine in severe renal failure (GFR less than 10 ml/min), since reliable data on such therapy are not available.

Patients on hemodialysis are prescribed 50% of the usual daily dose of venlafaxine after hemodialysis is completed.

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

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

It is not recommended to use Venlafaxine in severe hepatic impairment, since reliable data on such therapy are not available.

Elderly patients do not require a dose change, but caution is necessary, 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.

Discontinuation of Venlaxor^®

Upon completion of taking Venlaxor^®, it is recommended to gradually reduce the dose of the drug for at least a week and monitor the patient’s condition in order to minimize the risk associated with drug withdrawal.

The period required for complete discontinuation of the drug depends on its dose, duration of the course of treatment, and individual characteristics of the patient.

Adverse Reactions

Most side effects 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.

Definition of frequency of adverse effects: common (>1%), uncommon (0.1-1%), rare (0.01-0.1%), very rare (<0.01%).

From the CNS common – dizziness, asthenia, insomnia, nightmares, increased nervous excitability, paresthesia, muscle hypertonia, tremor, sedative effect; uncommon – apathy, hallucinations, myoclonus, fainting; rare – convulsions, manic disorders, NMS.

From the cardiovascular system common – increased blood pressure, skin hyperemia; uncommon – decreased blood pressure, postural hypotension, tachycardia; very rare – QT interval change, ventricular fibrillation, ventricular tachycardia (including ventricular flutter).

From the digestive system common – decreased appetite, nausea, vomiting; uncommon – bruxism (involuntary teeth grinding), increased activity of hepatic transaminases; rare – hepatitis.

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

From the reproductive system common – decreased libido, impaired erection and/or ejaculation, anorgasmia, menorrhagia; uncommon – impaired orgasm in women.

From the sensory organs common – accommodation disorder, mydriasis, vision disorder; uncommon – taste perception disorder.

From the hematopoietic system frequency unknown – agranulocytosis, aplastic anemia, neutropenia, pancytopenia.

Allergic reactions uncommon – rash, photosensitivity; very rare – multiforme exudative erythema (including Stevens-Johnson syndrome), anaphylaxis.

Laboratory parameters uncommon – thrombocytopenia; rare – increased bleeding time, hyponatremia; with long-term administration and use in high doses – hypercholesterolemia.

Other common – weight loss, sweating (including night sweats); uncommon – ecchymosis, weight gain; rare – syndrome of inappropriate ADH secretion, serotonin syndrome (nausea, vomiting, abdominal pain, diarrhea, flatulence, psychomotor agitation, tachycardia, hyperthermia, muscle rigidity, convulsions, myoclonus, sweating, depression of consciousness of varying severity).

Upon withdrawal syndrome occurrence dizziness, headache, asthenia, increased fatigue, sleep disorders (change in the nature of dreams, drowsiness or insomnia, difficulty falling asleep), hypomania, anxiety, increased nervous excitability, confusion, paresthesia, increased sweating, dry mouth, decreased appetite, nausea, vomiting, diarrhea (most of these reactions are mild and do not require treatment).

Contraindications

• Severe renal impairment (GFR less than 10 ml/min);
• Severe hepatic impairment;
• Concomitant use of MAO inhibitors;
• Age under 18 years (safety and efficacy for this category of patients have not been proven);
• Established or suspected pregnancy;
• Lactation period (breastfeeding);
• Hypersensitivity to the components of the drug.

With caution the drug should be prescribed for recently suffered myocardial infarction, unstable angina, arterial hypertension, tachycardia, history of convulsive syndrome, increased intraocular pressure, angle-closure glaucoma, history of manic states, predisposition to bleeding from the skin and mucous membranes, initially reduced body weight, hyponatremia, hypovolemia, concomitant use of diuretics, suicidal tendencies, renal or hepatic insufficiency.

Use in Pregnancy and Lactation

The safety of venlafaxine use during pregnancy has not been proven, therefore the use of the drug during pregnancy (or suspected pregnancy) is contraindicated.

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

Women of childbearing age should use appropriate methods of contraception while taking venlafaxine.

If the mother’s treatment was completed shortly before delivery, the newborn may experience symptoms of drug withdrawal.

Venlafaxine and its metabolite ODV are excreted in breast milk.

The safety of these substances for newborn children has not been proven, therefore taking venlafaxine during breastfeeding is not recommended.

If it is necessary to take the drug during lactation, the issue of stopping breastfeeding should be decided.

Use in Hepatic Impairment

The use of the drug is contraindicated in severe hepatic impairment.

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

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

Use in Renal Impairment

The use of the drug is contraindicated in severe renal impairment (GFR less than 10 ml/min).

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 25-50%.

Due to the prolongation of the half-life of venlafaxine and its active metabolite ODV, such patients should take the entire dose once a day.

It is not recommended to use Venlafaxine in severe renal failure (GFR less than 10 ml/min), since reliable data on such therapy are not available.

Patients on hemodialysis are prescribed 50% of the usual daily dose of venlafaxine after hemodialysis is completed.

Pediatric Use

The use of the drug is contraindicated under the age of 18 years (safety and efficacy for this category of patients have not been proven).

Geriatric Use

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

Elderly patients do not require a dose change, but caution is necessary, 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

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

The duration of the period required for dose reduction depends on the dose size, duration of therapy, as well as the individual sensitivity of the patient.

When prescribing Venlaxor^® to patients with lactose intolerance, it should be taken into account that each 37.5 mg tablet contains 30 mg of lactose, and each 75 mg tablet contains 60 mg of lactose.

In patients with depressive disorders, before starting any drug therapy, the likelihood of suicide attempts should be considered.

Therefore, to reduce the risk of overdose, the initial dose of the drug should be as low as possible, and the patient should be under close medical supervision.

In patients with affective disorders, when treated with antidepressants (including venlafaxine), hypomanic or manic states may occur.

Like other antidepressants, Venlafaxine 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.

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

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

The drug should be prescribed with caution in tachyarrhythmia, because an increase in heart rate is possible, especially when taking high doses.

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

Like other serotonin reuptake inhibitors, Venlafaxine may increase the risk of hemorrhages in the skin and mucous membranes.

Caution is necessary when treating patients predisposed to such conditions.

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

During drug intake, mydriasis may be observed, therefore control of intraocular pressure is recommended in patients prone to its increase or with angle-closure glaucoma.

The use of venlafaxine has not been studied in patients who have recently had a myocardial infarction and with decompensated heart failure.

Such patients should be prescribed the drug with caution.

It is necessary to establish observation of patients to identify signs of drug abuse, especially for patients with a history of such symptoms.

Effect on ability to drive vehicles and mechanisms

Although Venlafaxine does not affect psychomotor and cognitive functions, it should be taken into account that any drug therapy with psychoactive drugs may reduce the ability to make judgments, 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 established by the doctor.

Alcohol consumption is also not recommended.

Overdose

Symptoms ECG changes (QT interval prolongation, bundle branch block, QRS complex widening), sinus or ventricular tachycardia, bradycardia, hypotension, convulsive states, altered consciousness (decreased level of wakefulness).

In case of venlafaxine overdose with simultaneous intake of alcohol and/or other psychotropic drugs, a fatal outcome has been reported.

Treatment symptomatic therapy is carried out.

Specific antidotes are unknown.

Activated charcoal is prescribed to reduce drug absorption.

Inducing vomiting is not recommended due to the risk of aspiration.

Continuous monitoring of vital functions (respiration and circulation) is recommended.

Venlafaxine and its metabolite ODV are not removed by dialysis.

Drug Interactions

Concomitant use of MAO inhibitors and venlafaxine is contraindicated.

Administration of Venlaxor^® can be started no less than 14 days after the end of therapy with MAO inhibitors.

If a reversible MAO inhibitor (moclobemide) was used, this interval may be shorter (24 hours).

Therapy with MAO inhibitors can be started no less than 7 days after discontinuation of Venlaxor^®.

Venlafaxine does not affect the pharmacokinetics of lithium.

With simultaneous use with imipramine, the pharmacokinetics of venlafaxine and its metabolite O-desmethylvenlafaxine (ODV) do not change.

With simultaneous use with haloperidol, the effect of the latter may be enhanced due to an increase in its blood concentration.

With simultaneous use 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.

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

Venlaxor^® enhances the effect of ethanol on psychomotor reactions.

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

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 administered concomitantly with drugs that suppress CYP2D6 activity, or in patients with genetically determined reduced CYP2D6 activity, since the total concentration of venlafaxine and its metabolite ODV will not change. The main route of elimination of venlafaxine involves metabolism by CYP2D6 and CYP3A4; 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 the CYP1A2, CYP2C9 and CYP3A4 isoenzymes; therefore, its interaction with other drugs metabolized by these hepatic enzymes is not expected.

Cimetidine inhibits the first-pass metabolism of venlafaxine in 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 its metabolite ODV is expected (more pronounced in elderly patients and with impaired liver function).

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

Protein binding is 27% for venlafaxine and 30% for ODV. Therefore, no effect on the plasma concentration of drugs that are highly protein-bound has been noted.

With simultaneous use with warfarin, the anticoagulant effect of the latter may be enhanced.

With simultaneous use with indinavir, the pharmacokinetics of indinavir change (AUC decreases by 28%, C_max by 36%), while the pharmacokinetics of venlafaxine and its metabolite ODV do not change. However, the clinical significance of this effect is unknown.

Storage Conditions

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

Shelf Life

The shelf life is 3 years. Do not use after the expiration date printed on the package.

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.