Newvelong (Tablets) Instructions for Use

Marketing Authorization Holder

Italfarmaco, S.p.A. (Italy)

Manufactured By

Laboratorios Liconsa, S.A. (Spain)

ATC Code

N06AX16 (Venlafaxine)

Active Substance

Venlafaxine (Rec.INN registered by WHO)

Dosage Forms

	Newvelong	Prolonged-release film-coated tablets 75 mg: 30 pcs.
		Prolonged-release film-coated tablets 150 mg: 30 pcs.
		Prolonged-release film-coated tablets 225 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Prolonged-release film-coated tablets white, round, biconvex, with an orifice on one side.

Excipients : mannitol – 10 mg, povidone K90 – 7 mg, macrogol 400 – 5 mg, microcrystalline cellulose – 70.34 mg, colloidal silicon dioxide – 1 mg, magnesium stearate – 1.8 mg.

Composition of coating A (osmotic) cellulose acetate 320S NF – 6.55 mg, cellulose acetate 398-10 NF – 9.58 mg, macrogol 400 – 0.88 mg.
Composition of coating B (cosmetic) Opadry^® Y-30-18037 (hypromellose, lactose monohydrate, silicon dioxide, triacetin) – 9 mg.

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

Prolonged-release film-coated tablets white, round, biconvex, with an orifice on one side.

Excipients : mannitol – 20 mg, povidone K90 – 14 mg, macrogol 400 – 10 mg, microcrystalline cellulose – 140.68 mg, colloidal silicon dioxide – 2 mg, magnesium stearate – 3.6 mg.

Composition of coating A (osmotic) cellulose acetate 320S NF – 9.9 mg, cellulose acetate 398-10 NF – 11 mg, macrogol 400 – 1.1 mg.
Composition of coating B (cosmetic) Opadry^® Y-30-18037 (hypromellose, lactose monohydrate, silicon dioxide, triacetin) – 15 mg.

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

Prolonged-release film-coated tablets white, round, biconvex, with an orifice on one side.

Excipients : mannitol – 30 mg, povidone K90 – 21 mg, macrogol 400 – 15 mg, microcrystalline cellulose – 211.02 mg, colloidal silicon dioxide – 3 mg, magnesium stearate – 5.4 mg.

Composition of coating A (osmotic) cellulose acetate 320S NF – 12.15 mg, cellulose acetate 398-10 NF – 13.5 mg, macrogol 400 – 1.35 mg.
Composition of coating B (cosmetic) Opadry^® Y-30-18037 (hypromellose, lactose monohydrate, silicon dioxide, triacetin) – 17 mg.

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

Clinical-Pharmacological Group

Antidepressant

Pharmacotherapeutic Group

Antidepressant

Pharmacological Action

Venlafaxine is a structurally novel antidepressant which is a racemate with two active enantiomers.

The mechanism of the antidepressant action of venlafaxine is associated with its potentiating effect on neurotransmitter activity 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 terms of serotonin reuptake inhibition, Venlafaxine is inferior to selective serotonin reuptake inhibitors.

Pharmacokinetics

Absorption is at least 92% of a single oral dose of venlafaxine. The absolute bioavailability of venlafaxine is about 45%. After a single dose of venlafaxine tablets, the C_max of venlafaxine and ODV in plasma is reached within 6.0±1.5 and 8.8±2.2 hours, respectively. The T_1/2 of the prolonged-release drug is 15±6 hours and is limited by the absorption rate.

Venlafaxine and ODV are 27% and 30% bound to plasma proteins, respectively.

Venlafaxine undergoes significant first-pass metabolism in the liver involving cytochrome P450 (isoenzyme CYP2D6) to form the active metabolite O-desmethylvenlafaxine. Venlafaxine is also metabolized by isoenzymes CYP3A3/4 to N-desmethylvenlafaxine and other metabolites. In patients with reduced activity of the CYP2D6 isoenzyme, there is a 2-3 times greater exposure to venlafaxine and a 2-3 times lower exposure to the active metabolite ODV.

The plasma clearance of venlafaxine is 1.3 L/h/kg, and for the active metabolite ODV it is 0.4 L/h/kg. The T_1/2 of venlafaxine is 15 hours and of ODV is 11 hours.

Special patient groups

Gender and age do not significantly affect the pharmacokinetics of venlafaxine. No accumulation of venlafaxine or ODV was observed during long-term administration in healthy subjects. In moderate to severe hepatic and renal impairment, a decrease in venlafaxine metabolism and ODV excretion was noted, leading to an increase in C_max, a decrease in clearance, and a prolongation of T_1/2. The decrease in total drug clearance is most pronounced in patients with creatinine clearance (CrCl) below 30 ml/min. Taking venlafaxine with food does not affect the absorption of venlafaxine or the subsequent formation of ODV.

Indications

• Depression (treatment, prevention of relapse).

ICD codes

Dosage Regimen

Venlafaxine should be taken orally with food, without chewing and with liquid, once a day, preferably at the same time, in the morning or evening.

The effective dose for the treatment of depression is usually between 75 mg and 225 mg. Treatment should be started with 75 mg once a day. A noticeable effect will appear after 2-4 weeks of treatment with a standard adequate dose. If the clinical result is unsatisfactory, the dose may be increased to 150 mg, then to 225 mg. The maximum allowable daily dose is 375 mg, however, it should be noted that the use of high doses is not sufficiently studied. In all cases, high doses should be used under close medical supervision. Doses may be increased at intervals of about 2 weeks or more, with a minimum of 4 days between each increase. If no positive dynamics are observed after 2-4 weeks, treatment should be discontinued.

Maintenance treatment

It is generally accepted that acute episodes of major depression require 4-6 months of therapy. Some patients may require longer treatment. The physician should periodically reassess the usefulness of long-term treatment with Venlafaxine for each individual patient.

Discontinuation of the drug should be gradual to avoid withdrawal syndrome: for a course of treatment lasting 6 weeks or more, the period of gradual withdrawal should be at least 2 weeks and depends on the dose, duration of therapy and individual patient characteristics.

In renal impairment (glomerular filtration rate – 10-70 ml/min) the daily dose should be reduced by 25-50%.

In hemodialysis the daily dose should be reduced by 50%, the drug should be taken after the end of the hemodialysis session.

In patients with moderate hepatic impairment the daily dose should be reduced by 50% or more.

Adverse Reactions

It is often difficult to distinguish adverse effects from symptoms of depression. The severity of most side effects is dose-dependent. Frequency assessment

Very common: >1/10;

Common: > 1/100 < 1/10;

Uncommon: > 1/1000 < 1/100;

Rare: > 1/10,000 < 1/1000;

Very rare: < 1/10,000 including isolated reports;

From the hematopoietic system rare – thrombocytopenia; very rare – impaired hematopoiesis (including agranulocytosis, aplastic anemia, neutropenia and pancytopenia).

From the immune system uncommon – photosensitivity; very rare – anaphylaxis.

From the endocrine system very rare – hyperprolactinemia.

Metabolism and nutrition disorders: common – hypercholesterolemia (especially associated with long-term treatment and possibly with the use of high doses), weight loss; uncommon – hyponatremia, weight gain; rare – syndrome of inappropriate antidiuretic hormone secretion.

From the nervous system common – dizziness, headache, increased muscle tone, paresthesia, sedation, tremor, insomnia, drowsiness, nervousness, aggression, abnormal dreams, orgasm disorders (men), yawning, decreased appetite, anorexia, weakness, fatigue, asthenia; uncommon – myoclonus, apathy, hallucinations, agitation, orgasm disorders (women); rare – serotonin syndrome, neuroleptic malignant syndrome, seizures, akathisia, mania or hypomania; very rare – extrapyramidal reactions (including dystonia and dyskinesia), tardive dyskinesia, delirium.

From the sensory organs: common – accommodation disturbances, mydriasis, perception abnormalities; uncommon – tinnitus

From the cardiovascular system: common – increased BP, vasodilation (very common feeling of hot flush), ecchymosis, mucosal bleeding; uncommon – arrhythmias (including tachycardia), decreased BP, postural hypotension, syncope; rare – hemorrhage (including cerebral hemorrhage), gastrointestinal bleeding; very rare – QT interval prolongation and QRS complex widening, ventricular fibrillation, ventricular tachycardia (including torsade de pointes), decompensation of heart failure, heart failure.

From the respiratory system: very rare – pulmonary eosinophilia with respiratory impairment, chest pain.

From the digestive system: common – constipation, decreased appetite, nausea, vomiting, dry mouth, dyspepsia; uncommon – bruxism, taste perversion, diarrhea; impaired liver function tests; rare – hepatitis; very rare – pancreatitis.

From the skin: common – increased sweating (including night profuse sweating); uncommon – dermatitis, alopecia, photosensitivity, rash; very rare – erythema multiforme exudativum, Stevens-Johnson syndrome, pruritus, prurigo, urticaria.

From the musculoskeletal system very rare – rhabdomyolysis.

From the genitourinary system: common – urination disorders (most often intermittent urination), ejaculation disorders, erectile dysfunction, decreased libido; uncommon – urinary retention, menorrhagia, female orgasm disorder.

Changes in laboratory parameters rare – increased bleeding time.

Upon occurrence of withdrawal syndrome dizziness, headache, asthenia, increased fatigue, sleep disorders (change in dream nature, 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

• Concomitant use with MAO inhibitors;
• Lactase deficiency;
• Lactose intolerance;
• Glucose-galactose malabsorption;
• Pregnancy;
• Lactation period;
• Age under 18 years;
• Hypersensitivity to venlafaxine or any other component of the drug;

With caution: recent myocardial infarction, unstable angina, arterial hypertension, tachycardia, history of seizures, intraocular hypertension, angle-closure glaucoma, history of manic states, hyponatremia, hypovolemia, dehydration, concomitant use of diuretics, suicidal tendencies, predisposition to bleeding from the skin and mucous membranes, renal/hepatic impairment.

Use in Pregnancy and Lactation

Contraindicated during pregnancy and lactation.

Use in Hepatic Impairment

Use with caution in hepatic impairment.

In patients with moderate hepatic impairment, the daily dose should be reduced by 50% or more.

Use in Renal Impairment

Use with caution in renal impairment.

In renal impairment (glomerular filtration rate – 10-70 ml/min) the daily dose should be reduced by 25-50%.

In hemodialysis the daily dose should be reduced by 50%, the drug should be taken after the end of the hemodialysis session.

Pediatric Use

Contraindicated under 18 years of age.

Special Precautions

In patients (under 24 years) with depression or other mental disorders, antidepressants, compared to placebo, increase the risk of suicidal thoughts and suicidal behavior. Therefore, when prescribing venlafaxine to patients under 24 years of age, the risk of suicide and the benefit of their use should be weighed. In short-term studies in people over 24 years of age, the risk of suicide was not increased, and in people over 65 years of age it was somewhat reduced. Any depressive disorder itself increases the risk of suicide. Therefore, during treatment with antidepressants, all patients should be monitored for early detection of behavioral disturbances or changes, as well as suicidal tendencies.

For patients with diabetes, treatment with SSRIs/SNRIs (selective norepinephrine reuptake inhibitors) may affect glucose levels. The dose of insulin and/or oral antidiabetic agents should be adjusted.

During treatment, patients with hypovolemia or dehydrated patients (including elderly patients and those taking diuretics) may develop hyponatremia and/or syndrome of inappropriate antidiuretic hormone secretion.

Careful dosing and regular monitoring are used in the following cases

• Narrow-angle glaucoma, increased intraocular pressure (since Venlafaxine has a weak m-cholinolytic effect),
• Cardiovascular diseases (conduction disorders, angina pectoris, recent myocardial infarction, ventricular arrhythmia, arterial hypertension or hypotension).

During long-term treatment with venlafaxine, serum cholesterol concentration should be monitored. If hypercholesterolemia occurs, switching to another antidepressant should be considered.

Patients taking Venlafaxine may have an increased risk of skin or mucosal bleeding.

During treatment with the drug, it is recommended to refrain from drinking alcohol.

Effect on driving and operating machinery

During treatment with venlafaxine, caution should be exercised when driving vehicles or performing work that requires increased concentration and speed of psychomotor reactions.

Overdose

Symptoms: (often occur with simultaneous ethanol intake): impaired consciousness (from drowsiness to coma), as well as agitation, gastrointestinal disorders such as vomiting, diarrhea; tremor, electrocardiogram (ECG) changes (QT interval prolongation, bundle branch block, QRS complex widening), sinus and ventricular tachycardia or bradycardia, decreased or (slight) increased BP, epileptic seizures, rhabdomyolysis, mydriasis.

Treatment symptomatic; monitoring of ECG and vital organ functions; vomiting is not recommended if there is a risk of aspiration; gastric lavage (if overdose occurred recently, or overdose symptoms persist); activated charcoal. Forced diuresis, dialysis, hemoperfusion, or exchange transfusion are not effective. There is no specific antidote.

Drug Interactions

Concomitant use of venlafaxine with monoamine oxidase (MAO) inhibitors is unacceptable. Use of venlafaxine is possible no earlier than 14 days after discontinuation of MAO inhibitor therapy and should be discontinued at least 7 days before starting any MAO inhibitor due to the risk of increased side effects.

Enhances the effect of ethanol on psychomotor reactions.

When taken orally, it reduces the total clearance of haloperidol by 42%, increases its AUC by 70% and C_max by 88%.

Venlafaxine does not affect the metabolism of imipramine and its metabolite 2-hydroxy-imipramine, although the total renal clearance of 2-hydroxydesipramine decreases, and AUC and C_max increase by approximately 35%.

Cimetidine inhibits the first-pass metabolism of venlafaxine but does not affect the pharmacokinetics of O-desmethylvenlafaxine (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 of venlafaxine with antidepressants (selective serotonin reuptake inhibitors) (SSRIs), prolonged seizures have been noted.

The risk of increased side effects, including seizures, is increased with simultaneous use of venlafaxine with clozapine, due to increased blood concentration of clozapine.

Venlafaxine should be used with caution in patients simultaneously taking medications that increase the risk of bleeding, such as anticoagulants, salicylic acid derivatives and NSAIDs.

When used concomitantly with warfarin, an increase in prothrombin time, partial thromboplastin time or international normalized ratio was observed.

Caution is required when using venlafaxine concomitantly with inhibitors of the CYP2D6 isoenzyme (e.g., quinidine, paroxetine, fluoxetine, perphenazine, haloperidol, levomepromazine), since Venlafaxine may interfere with the action of other substrates of the CYP2D6 isoenzyme, increasing their plasma concentration.

A high concentration of venlafaxine may be observed in patients with low activity of the CYP2D6 isoenzyme.

When used concomitantly with drugs that are inhibitors of the CYP3A3/4 isoenzyme (ketoconazole, itraconazole, ritonavir), the plasma concentration of venlafaxine may be increased.

It does not interact with lithium preparations, nor with drugs metabolized by the CYP3A4, CYP1A2, and CYP2C9 isoenzymes (including alprazolam, caffeine, carbamazepine, diazepam, tolbutamide).

It does not affect the plasma concentration of drugs that are highly protein-bound.

Storage Conditions

Store the drug in a dry place at a temperature not exceeding 30°C (86°F). Keep out of the reach of children.

Shelf Life

The shelf life is 3 years. Do not use the drug after the expiration date.

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.