Efevelon^® (Tablets) Instructions for Use

Marketing Authorization Holder

Actavis hf. (Iceland)

ATC Code

N06AX16 (Venlafaxine)

Active Substance

Venlafaxine (Rec.INN registered by WHO)

Dosage Forms

	Efevelon®	Film-coated tablets, 25 mg: 30 pcs.
		Film-coated tablets, 37.5 mg: 30 pcs.
		Film-coated tablets, 50 mg: 30 pcs.
		Film-coated tablets, 75 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets orange, round, biconvex, marked “V1” on one side.

Excipients: lactose monohydrate – 18.33 mg, microcrystalline cellulose – 45.89 mg, croscarmellose sodium – 3 mg, povidone K30 – 4 mg, magnesium stearate – 0.5 mg.

Shell composition Opadry 03B23319 orange (hypromellose – 1.875 mg, titanium dioxide – 0.908 mg, polyethylene glycol 400 (macrogol) – 0.188 mg, dye sunset yellow FCF – 0.03 mg) – 3 mg.

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

Film-coated tablets orange, round, biconvex, marked “V2” on one side.

Excipients: lactose monohydrate – 27.5 mg, microcrystalline cellulose – 68.83 mg, croscarmellose sodium – 4.5 mg, povidone K30 – 6 mg, magnesium stearate – 0.75 mg.

Shell composition Opadry 03B23319 orange (hypromellose – 2.813 mg, titanium dioxide – 1.362 mg, polyethylene glycol 400 (macrogol) – 0.282 mg, dye sunset yellow FCF – 0.045 mg) – 4.5 mg.

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

Film-coated tablets orange, round, biconvex, marked “V3” on one side.

Excipients: lactose monohydrate – 36.67 mg, microcrystalline cellulose – 91.77 mg, croscarmellose sodium – 6 mg, povidone K30 – 8 mg, magnesium stearate – 1 mg.

Shell composition Opadry 03B23319 orange (hypromellose – 3.75 mg, titanium dioxide – 1.815 mg, polyethylene glycol 400 (macrogol) – 0.375 mg, dye sunset yellow FCF – 0.06 mg) – 6 mg.

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

Film-coated tablets orange, round, biconvex, with notches on both sides, side notches and marked “V” on one side of the notch and “4” on the other side of the notch.

Excipients: lactose monohydrate – 55 mg, microcrystalline cellulose – 137.66 mg, croscarmellose sodium – 9 mg, povidone K30 – 12 mg, magnesium stearate – 1.5 mg.

Shell composition Opadry 03B23319 orange (hypromellose – 5.625 mg, titanium dioxide – 2.725 mg, polyethylene glycol 400 (macrogol) – 0.563 mg, dye sunset yellow FCF – 0.09 mg) – 9 mg.

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

Clinical-Pharmacological Group

Antidepressant

Pharmacotherapeutic Group

Antidepressant

Pharmacological Action

Antidepressant, chemically unrelated to any class of antidepressants (tricyclic, tetracyclic, or others), is a mixture 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 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 single administration and during continuous 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 dose of venlafaxine 25-150 mg, C_max in plasma reaches 33-172 ng/ml in approximately 2.4 hours. It undergoes intensive first-pass metabolism in the liver. Its main metabolite is O-desmethylvenlafaxine (ODV). C_max of ODV in plasma 61-325 ng/ml is reached approximately 4.3 hours after administration. 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 and metabolism

Plasma protein binding of venlafaxine and ODV is 27% and 30%, respectively.

With repeated administration, 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.

Venlafaxine undergoes intensive metabolism in the liver.

Excretion

T_1/2 of venlafaxine and ODV is 5 and 11 hours, respectively. ODV and other metabolites, as well as unmetabolized Venlafaxine, are excreted in the urine.

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

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

Indications

• Treatment of depression;
• Prevention of relapse of depression.

ICD codes

Dosage Regimen

The drug should be taken orally, preferably at the same time of day, with meals. The tablets should not be chewed and should be swallowed with liquid.

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

For moderate depression the recommended daily dose is 225 mg (75 mg 3 times/day). If necessary, the dose can be increased at intervals of at least 4 days by 75 mg/day. 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 it is necessary to use the drug in a higher dose – severe depressive disorder or other conditions requiring inpatient treatment, – the drug can be immediately prescribed at a daily dose of 150 mg (75 mg 2 times/day). 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 Efevelon^® 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 (glomerular filtration rate /GFR/ greater than 30 ml/min) no dose 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 a day. In severe renal impairment (GFR less than 10 ml/min) the use of venlafaxine 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 dose 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 Efevelon^® 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.

Upon discontinuation of the drug Efevelon^® it is recommended to reduce the dose gradually, for at least one 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 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.

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

From the body as a whole common – asthenia, increased fatigue.

From the digestive system common – decreased appetite, constipation, nausea, vomiting, dry mouth; uncommon – changes in liver function tests; rare – hepatitis.

From the metabolism: common – increased blood cholesterol, weight loss; uncommon – hyponatremia, syndrome of inappropriate ADH secretion.

From the cardiovascular system common – arterial hypertension, flushing; uncommon – postural hypotension, tachycardia.

From the CNS and peripheral nervous system common – unusual dreams, dizziness, insomnia, increased excitability, stupor, increased muscle tone, paresthesia, tremor; uncommon – apathy, hallucinations, muscle spasms, serotonin syndrome; rare – epileptic seizures, manic reactions, as well as symptoms resembling NMS.

From the senses common – accommodation disturbances, mydriasis, vision disorders; uncommon – taste perversion.

From the urinary system common – dysuria (mainly difficulty initiating urination); uncommon – urinary retention.

From the reproductive system common – ejaculation disorders, erectile dysfunction, anorgasmia; uncommon – decreased libido, menorrhagia.

From the hematopoietic system: uncommon – hemorrhages in the skin (ecchymoses) and mucous membranes, thrombocytopenia; rare – prolonged bleeding time.

Dermatological reactions common – increased sweating; uncommon – photosensitivity; rare – erythema multiforme, Stevens-Johnson syndrome.

Allergic reactions uncommon – skin rash; very rare – anaphylaxis.

After abrupt discontinuation of the drug or reduction of its dose fatigue, drowsiness, headache, nausea, vomiting, anorexia, dry mouth, dizziness, diarrhea, insomnia, anxiety, increased irritability, disorientation, hypomania, paresthesia, sweating are possible. 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.

Contraindications

• Concomitant use of MAO inhibitors;
• Severe renal impairment (GFR<10 ml/min);
• Severe hepatic impairment;
• Children and adolescents under 18 years of age (safety and efficacy not proven);
• Established or suspected pregnancy;
• Lactation period;
• Hypersensitivity to the components of the drug.

With caution the drug should be used 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, predisposition to bleeding of the skin and mucous membranes, 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.

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

Women of childbearing age should use appropriate contraceptive methods while taking venlafaxine. In case of pregnancy or planning pregnancy during treatment with the drug, women of childbearing age should be warned that they should immediately consult a doctor.

Venlafaxine and its metabolite ODV are excreted in breast milk. The safety of these substances for newborn infants has not been proven, so 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

In mild hepatic impairment (prothrombin time /PT/ less than 14 sec) no dose 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 Efevelon^® is not recommended, as experience with such therapy is limited.

Use in Renal Impairment

In mild renal impairment (glomerular filtration rate greater than 30 ml/min) no dose adjustment is required. In moderate renal impairment (glomerular filtration rate 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. In severe renal impairment (glomerular filtration rate less than 10 ml/min) the use of venlafaxine 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

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

As with treatment with other antidepressants, abrupt discontinuation of venlafaxine therapy, especially after use in high doses, may cause withdrawal symptoms, therefore it is recommended to gradually reduce the dose of the drug before discontinuation. The duration of the period required for dose reduction depends on the dose, duration of therapy, and individual sensitivity of the patient.

When prescribing Efevelon^® to patients with lactose intolerance, the lactose content should be taken into account (56.62 mg in each 25 mg tablet, 84.93 mg in each 37.5 mg tablet, 113.24 mg in each 50 mg tablet, 169.86 mg in each 75 mg tablet).

In patients with depressive disorders, the possibility of suicide attempts should be considered before starting any drug therapy. 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, treatment with antidepressants, including venlafaxine, may cause hypomanic or manic states. 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. Treatment with venlafaxine should be discontinued if epileptic seizures occur.

While taking Efevelon^®, special caution should be exercised during electroconvulsive therapy, as there is no experience with the use of venlafaxine under these conditions.

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

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

An increase in heart rate may occur, especially during high-dose administration. Caution is advised in patients with tachyarrhythmia.

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

Mydriasis may be observed during treatment with the drug; therefore, intraocular pressure monitoring is recommended for patients prone to its increase or those suffering from angle-closure glaucoma.

There is insufficient data on the use of venlafaxine in patients who have recently had a myocardial infarction and those suffering from decompensated heart failure. The drug should be prescribed to such patients with caution.

Clinical trials conducted to date have not revealed tolerance to or dependence on venlafaxine. Despite this, as with treatment with other drugs acting on the CNS, the physician should establish careful monitoring of patients to detect signs of drug abuse. Careful control and monitoring are necessary for patients with a history of such symptoms.

Although Venlafaxine does not affect psychomotor and cognitive functions, it should be considered that any drug therapy with psychoactive drugs can 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 determined by the physician. Alcohol consumption is also not recommended.

Overdose

Symptoms ECG changes (prolongation of the QT interval, bundle branch block, QRS complex widening), sinus or ventricular tachycardia, bradycardia, hypotension, convulsive states, altered consciousness (decreased level of wakefulness). Fatal outcome has been reported with venlafaxine overdose when taken concomitantly with alcohol and/or other psychotropic drugs.

Treatment Symptomatic therapy is performed. Specific antidotes are unknown. Continuous monitoring of vital functions (respiration and circulation) is recommended. Administration of activated charcoal is indicated to reduce drug absorption. Inducing vomiting is not recommended due to the risk of aspiration. Venlafaxine and O-desmethylvenlafaxine (ODV) are not eliminated by dialysis.

Drug Interactions

Concomitant use of MAO inhibitors and venlafaxine is contraindicated. Administration of Efevelon^® 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 Efevelon^®.

Venlafaxine does not affect the pharmacokinetics of lithium.

Concomitant use with imipramine does not alter the pharmacokinetics of venlafaxine or its metabolite ODV.

Concomitant use with haloperidol increases its plasma concentration and enhances its effects.

Concomitant use of Efevelon^® with diazepam does not significantly alter the pharmacokinetics of either active substance or their main metabolites. No effect on the psychomotor and psychometric effects of diazepam was found.

Concomitant use with clozapine may lead to an increase in its plasma levels and the development of adverse effects (e.g., seizures).

Concomitant use with risperidone (despite an increase in the AUC of risperidone) did not significantly alter the pharmacokinetics of the sum of active components (risperidone and its active metabolite).

Efevelon^® enhances the effect of alcohol on psychomotor reactions.

CYP2D6 converts Venlafaxine into the active metabolite ODV. Unlike many other antidepressants, the dose of venlafaxine does not need to be reduced when co-administered with inhibitors of the CYP2D6 isoenzyme, or in patients with a genetically determined reduction in CYP2D6 isoenzyme activity, because the total concentration of the active substance and metabolite (venlafaxine and ODV) will not change. The main route of venlafaxine elimination involves metabolism by the CYP2D6 and CYP3A4 isoenzymes. Therefore, particular caution should be exercised when prescribing Efevelon^® in combination with inhibitors of these isoenzymes. Such drug interaction has not yet been studied.

Venlafaxine is a relatively weak inhibitor of the CYP2D6 isoenzyme and does not suppress the activity of the CYP1A2, CYP2C9, and CYP3A4 isoenzymes; therefore, 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. Only a slight increase in the overall pharmacological activity of venlafaxine and ODV is expected in most patients (more pronounced in elderly patients and in cases of impaired liver function).

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

Efevelon^® does not affect the plasma concentration of drugs that are highly protein-bound.

Concomitant use with warfarin may enhance its anticoagulant effect.

Concomitant use with indinavir alters the pharmacokinetics of the latter (decrease in AUC by 28% and C_max by 36%), while the pharmacokinetics of venlafaxine and ODV remain unchanged. The clinical significance of these changes 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

The shelf life is 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.