Alventa^® (Capsules) Instructions for Use

Marketing Authorization Holder

Krka d.d., Novo mesto (Slovenia)

ATC Code

N06AX16 (Venlafaxine)

Active Substance

Venlafaxine (Rec.INN registered by WHO)

Dosage Forms

	Alventa®	Extended-release capsules 37.5 mg: 14, 28, or 56 pcs.
		Extended-release capsules 75 mg: 14, 28, or 56 pcs.
		Extended-release capsules 150 mg: 14, 28, or 56 pcs.

Dosage Form, Packaging, and Composition

Extended-release capsules hard, gelatin, size #3, white body, brownish-pink cap; capsule contents – white or almost white pellets.

Excipients: sugar spheres¹[sucrose, starch syrup), hypromellose, povidone K30, ethylcellulose, dibutyl sebacate, talc.

Composition of hard gelatin capsules size #3:
Body: titanium dioxide (E171), gelatin.
Cap: iron oxide red (E172), titanium dioxide (E171), gelatin.

14 pcs. – blister packs (1) – cardboard cartons.
14 pcs. – blister packs (2) – cardboard cartons.
14 pcs. – blister packs (4) – cardboard cartons.

¹Composition of sugar spheres: sucrose, starch (corn), purified water.

Extended-release capsules hard, gelatin, size #1, light pink body and cap; capsule contents – white or almost white pellets.

Excipients: sugar spheres¹[sucrose, starch syrup), hypromellose, povidone K30, ethylcellulose, dibutyl sebacate, talc.

Composition of hard gelatin capsules size #1:
Body: titanium dioxide (E171), iron oxide red (E172), iron oxide yellow (E172), gelatin.
Cap: iron oxide red (E172), titanium dioxide (E171), iron oxide yellow (E172), gelatin.

14 pcs. – blister packs (1) – cardboard cartons.
14 pcs. – blister packs (2) – cardboard cartons.
14 pcs. – blister packs (4) – cardboard cartons.

¹Composition of sugar spheres: sucrose, starch (corn), purified water.

Modified-release capsules hard, gelatin, size #0, brownish-orange body and cap; capsule contents – white or almost white pellets.

Excipients: sugar spheres¹[sucrose, starch syrup), hypromellose, povidone K30, ethylcellulose, dibutyl sebacate, talc.

Composition of hard gelatin capsules size #0:
Body: titanium dioxide (E171), iron oxide red (E172), iron oxide yellow (E172), gelatin.
Cap: iron oxide red (E172), titanium dioxide (E171), iron oxide yellow (E172), gelatin.

14 pcs. – blister packs (1) – cardboard cartons.
14 pcs. – blister packs (2) – cardboard cartons.
14 pcs. – blister packs (4) – cardboard cartons.

¹Composition of sugar spheres: sucrose, starch (corn), purified water.

Clinical-Pharmacological Group

Antidepressant

Pharmacotherapeutic Group

Antidepressant

Pharmacological Action

Antidepressant, serotonin and norepinephrine reuptake inhibitor. According to its chemical structure, Venlafaxine 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 enhancement of neurotransmitter activity in the CNS. Venlafaxine and its primary 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.

Pharmacokinetics

After oral administration, Venlafaxine is well absorbed from the gastrointestinal tract. After a single dose of 25-150 mg, C_max in plasma is reached within approximately 2.4 hours and is 33-172 ng/ml. Venlafaxine undergoes intensive metabolism during the first pass through the liver. 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, Venlafaxine and ODV have linear kinetics. When 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.

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

The main metabolite is ODV. 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.

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 less than 30 ml/min.

Indications

Depression of various etiologies (treatment and prevention).

ICD codes

Dosage Regimen

Take orally. The recommended initial dose is 75 mg in 2 divided doses (37.5 mg twice daily) every day. If no significant improvement is observed after several weeks of treatment, the daily dose can be increased to 150 mg (75 mg twice daily). In severe depression or other conditions requiring inpatient treatment, 150 mg in 2 divided doses (75 mg twice daily) can be used immediately. Thereafter, the daily dose can be increased by 75 mg every 2-3 days until the desired therapeutic effect is achieved. Maximum dose – 375 mg/day.

After achieving the necessary therapeutic effect, the daily dose can be gradually reduced to the minimum effective level. The duration of the period required for dose reduction depends on the dose size, duration of therapy, and the individual sensitivity of the patient.

For maintenance therapy and relapse prevention, the minimum effective dose used during the treatment of the depressive episode is indicated.

In patients with renal failure with CrCl 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.

Patients on hemodialysis can receive 50% of the usual daily dose of venlafaxine after the hemodialysis session is completed.

In moderate hepatic insufficiency (prothrombin time from 14 to 18 seconds), the dose should be reduced by 50%.

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

At the end of treatment, it is recommended to gradually reduce the dose for at least a week and monitor the patient’s condition to minimize the risk associated with venlafaxine withdrawal. The duration of the period required for dose reduction depends on the dose size, duration of therapy, and the individual sensitivity of the patient.

Adverse Reactions

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

From the digestive system decreased appetite, constipation, nausea, vomiting, dry mouth; rarely – hepatitis.

From the metabolism increased serum cholesterol levels, weight loss; sometimes – impaired liver function tests, hyponatremia, syndrome of inappropriate ADH secretion.

From the cardiovascular system arterial hypertension, skin flushing; sometimes – postural hypotension, tachycardia.

From the nervous system unusual dreams, dizziness, insomnia, nervous excitability, paresthesia, stupor, increased muscle tone, tremor, yawning; sometimes – apathy, hallucinations, muscle spasms, serotonin syndrome; rarely – epileptic seizures, manic reactions, as well as symptoms resembling neuroleptic malignant syndrome.

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

From the reproductive system ejaculation disorders, erection disorders, anorgasmia; sometimes – decreased libido, menorrhagia.

From the sensory organs accommodation disturbances, mydriasis, vision disturbances; sometimes – taste disturbance.

Dermatological reactions sweating; sometimes – photosensitivity.

From the hematopoietic system sometimes – skin hemorrhages (ecchymoses) and mucous membranes, thrombocytopenia; rarely – prolonged bleeding time.

Allergic reactions sometimes – skin rash; rarely – erythema multiforme, Stevens-Johnson syndrome; very rarely – anaphylactic reactions.

Other weakness, fatigue.

After abrupt withdrawal or dose reduction fatigue, drowsiness, headache, nausea, vomiting, anorexia, dry mouth, dizziness, diarrhea, insomnia, restlessness, anxiety, nervous irritability, disorientation, hypomania, paresthesia, sweating may occur. These symptoms are usually mild and resolve without treatment.

Contraindications

Severe renal failure (CrCl < 10 ml/min); severe liver dysfunction; simultaneous use of MAO inhibitors; children and adolescents under 18 years of age; established or suspected pregnancy; lactation period (breastfeeding); hypersensitivity to venlafaxine.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and during lactation (breastfeeding).

Women of childbearing age should use reliable methods of contraception during treatment and immediately consult a doctor in case of pregnancy or pregnancy planning.

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

Use in Hepatic Impairment

Contraindicated in severe liver dysfunction.

In moderate hepatic insufficiency (prothrombin time from 14 to 18 seconds), the dose should be reduced by 50%.

Use in Renal Impairment

Contraindicated in severe renal failure (CrCl < 10 ml/min).

In patients with renal failure with CrCl 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.

Patients on hemodialysis can receive 50% of the usual daily dose of venlafaxine after the hemodialysis session is completed.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

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

Elderly patients should be warned about the possibility of dizziness and impaired balance. During venlafaxine use, especially under conditions of dehydration or reduced blood volume, elderly patients may experience hyponatremia and/or syndrome of inappropriate ADH secretion.

Special Precautions

Venlafaxine should be used with caution after a recent myocardial infarction, in decompensated heart failure, in unstable angina, arterial hypertension, tachycardia, tachyarrhythmia, history of seizures, increased intraocular pressure, angle-closure glaucoma, history of manic states, predisposition to bleeding from the skin and mucous membranes, initially low body weight.

In patients with depressive disorders, before starting any drug therapy, the possibility of suicide attempts should be considered. Therefore, to reduce the risk of overdose at the beginning of treatment, Venlafaxine should be used in the minimum effective dose whenever possible, and the patient should be under close medical supervision.

In patients with affective disorders during treatment 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.

If epileptic seizures occur, treatment should be discontinued.

The risk of tachycardia increases with the use of venlafaxine in high doses.

Regular blood pressure monitoring is recommended during treatment, especially during dose adjustment or increase.

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

During venlafaxine use, especially under 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 use, mydriasis may be observed, in connection with which intraocular pressure control is recommended in patients prone to its increase or suffering from angle-closure glaucoma.

As with treatment with other drugs acting on the CNS, the physician should establish careful observation of patients to detect signs of venlafaxine abuse. Careful control and observation are necessary for patients with a history of such symptoms.

During venlafaxine use, special care should be taken when performing electroconvulsive therapy, as experience with venlafaxine under these conditions is lacking.

Alcohol consumption should be avoided during treatment.

Effect on ability to drive vehicles and operate machinery

Although Venlafaxine does not affect psychomotor and cognitive functions, it should be considered that any drug therapy with psychoactive drugs can impair thinking processes and reduce the ability to perform motor functions. The patient should be warned about this before starting treatment. If such disorders occur, the degree and duration of restrictions should be established by the doctor.

Drug Interactions

Venlafaxine administration can be started no less 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 less than 7 days after discontinuation of the venlafaxine drug.

Concomitant use of venlafaxine with lithium may increase the plasma concentration of the latter.

Enhancement of haloperidol effects is possible due to an increase in its blood concentration when used concomitantly with venlafaxine.

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

The main route of elimination of venlafaxine involves metabolism with the participation of CYP2D6 and CYP3A4, so special caution should be exercised when prescribing venlafaxine in combination with drugs that are inhibitors of both of these enzymes. The nature of this interaction has not yet been studied.

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).

With simultaneous use with warfarin, an enhancement of its anticoagulant effect is possible.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.