Bivotenz (Tablets) Instructions for Use

Marketing Authorization Holder

Atoll LLC (Russia)

Manufactured By

Ozon, LLC (Russia)

ATC Code

C07AB12 (Nebivolol)

Active Substance

Nebivolol (Rec.INN registered by WHO)

Dosage Form

Bivotenz

Tablets 5 mg: 7, 10, 14, 20, 21, 28, 30, 35, 40, 42, 50, 56, 60, 63, 70, 80, 84, 90, 100, 112, 120, 126, 140, 150, 160, 168, 180, 200, 240, 270, 300, or 360 pcs.

Dosage Form, Packaging, and Composition

Tablets are white or almost white, round, flat-cylindrical, with a cross-shaped score on one side and a bevel.

Excipients: lactose – 148 mg, microcrystalline cellulose – 20 mg, povidone K25 – 5 mg, croscarmellose sodium – 8 mg, colloidal silicon dioxide – 1.65 mg, magnesium stearate – 1.9 mg.

7 pcs. – contour cell packs (1) – cardboard packs.
7 pcs. – contour cell packs (2) – cardboard packs.
7 pcs. – contour cell packs (3) – cardboard packs.
7 pcs. – contour cell packs (4) – cardboard packs.
7 pcs. – contour cell packs (5) – cardboard packs.
7 pcs. – contour cell packs (8) – cardboard packs.
7 pcs. – contour cell packs (9) – cardboard packs.
7 pcs. – contour cell packs (10) – cardboard packs.
7 pcs. – contour cell packs (12) – cardboard packs.
10 pcs. – contour cell packs (1) – cardboard packs.
10 pcs. – contour cell packs (2) – cardboard packs.
10 pcs. – contour cell packs (3) – cardboard packs.
10 pcs. – contour cell packs (4) – cardboard packs.
10 pcs. – contour cell packs (5) – cardboard packs.
10 pcs. – contour cell packs (8) – cardboard packs.
10 pcs. – contour cell packs (9) – cardboard packs.
10 pcs. – contour cell packs (10) – cardboard packs.
10 pcs. – contour cell packs (12) – cardboard packs.
14 pcs. – contour cell packs (1) – cardboard packs.
14 pcs. – contour cell packs (2) – cardboard packs.
14 pcs. – contour cell packs (3) – cardboard packs.
14 pcs. – contour cell packs (4) – cardboard packs.
14 pcs. – contour cell packs (5) – cardboard packs.
14 pcs. – contour cell packs (8) – cardboard packs.
14 pcs. – contour cell packs (9) – cardboard packs.
14 pcs. – contour cell packs (10) – cardboard packs.
14 pcs. – contour cell packs (12) – cardboard packs.
20 pcs. – contour cell packs (1) – cardboard packs.
20 pcs. – contour cell packs (2) – cardboard packs.
20 pcs. – contour cell packs (3) – cardboard packs.
20 pcs. – contour cell packs (4) – cardboard packs.
20 pcs. – contour cell packs (5) – cardboard packs.
20 pcs. – contour cell packs (8) – cardboard packs.
20 pcs. – contour cell packs (9) – cardboard packs.
20 pcs. – contour cell packs (10) – cardboard packs.
20 pcs. – contour cell packs (12) – cardboard packs.
30 pcs. – contour cell packs (1) – cardboard packs.
30 pcs. – contour cell packs (2) – cardboard packs.
30 pcs. – contour cell packs (3) – cardboard packs.
30 pcs. – contour cell packs (4) – cardboard packs.
30 pcs. – contour cell packs (5) – cardboard packs.
30 pcs. – contour cell packs (8) – cardboard packs.
30 pcs. – contour cell packs (9) – cardboard packs.
30 pcs. – contour cell packs (10) – cardboard packs.
30 pcs. – contour cell packs (12) – cardboard packs.
7 pcs. – jars (1) – cardboard packs.
10 pcs. – jars (1) – cardboard packs.
14 pcs. – jars (1) – cardboard packs.
20 pcs. – jars (1) – cardboard packs.
28 pcs. – jars (1) – cardboard packs.
30 pcs. – jars (1) – cardboard packs.
40 pcs. – jars (1) – cardboard packs.
50 pcs. – jars (1) – cardboard packs.
100 pcs. – jars (1) – cardboard packs.

Clinical-Pharmacological Group

Third-generation beta₁-adrenoblocker with vasodilating properties

Pharmacotherapeutic Group

Selective beta1-adrenergic blocker

Pharmacological Action

Cardioselective beta₁-adrenergic blocker of the third generation with vasodilating properties. The active substance is a racemate consisting of two enantiomers: D-nebivolol and L-nebivolol. D-Nebivolol is a competitive and highly selective blocker of β₁-adrenergic receptors; L-Nebivolol has a mild vasodilating effect by modulating the release of a vasodilating factor (NO) from the vascular endothelium.

Nebivolol reduces heart rate and blood pressure at rest and during exercise, reduces left ventricular end-diastolic pressure, reduces total peripheral vascular resistance, improves diastolic heart function (reduces filling pressure), increases ejection fraction; causes an antianginal effect in patients with coronary artery disease.

The antihypertensive effect is also due to a decrease in the activity of the renin-angiotensin system (does not directly correlate with changes in plasma renin activity).

The antiarrhythmic effect is due to the suppression of pathological cardiac automatism (including in the pathological focus) and slowing of AV conduction.

A sustained antihypertensive effect develops after 1-2 weeks of regular use of the drug, and in some cases – after 4 weeks, a stable effect is noted after 1-2 months.

Pharmacokinetics

After oral administration, Nebivolol is rapidly absorbed from the gastrointestinal tract. Food intake does not affect absorption. Bioavailability averages 12% in individuals with rapid metabolism (first-pass effect through the liver) and is almost complete in individuals with slow metabolism.

In blood plasma, both enantiomers are predominantly bound to albumin. Plasma protein binding of D-nebivolol is 98.1%, L-nebivolol – 97.9%.

It is metabolized by acyclic and aromatic hydroxylation and partial N-dealkylation. The resulting hydroxy and amino derivatives conjugate with glucuronic acid and are excreted as O- and N-glucuronides.

Excreted by the kidneys (38%) and through the intestines (48%).

In individuals with rapid metabolism, the T_1/2 of hydroxymetabolites is 24 hours, enantiomers of nebivolol – 10 hours; in individuals with slow metabolism: hydroxymetabolites – 48 hours, enantiomers of nebivolol – 30-50 hours.

The excretion of unchanged nebivolol in urine is less than 0.5%.

Indications

Arterial hypertension.

Stable chronic heart failure of mild to moderate severity (as part of combination therapy) in patients over 70 years of age.

ICD codes

Dosage Regimen

Take orally once daily, with or without food.

For arterial hypertension, initiate therapy at 5 mg once daily. For elderly patients over 65 years or those with renal impairment, initiate at a 2.5 mg dose. Titrate the dose upwards to 10 mg if adequate blood pressure control is not achieved after 1-2 weeks.

For stable chronic heart failure, initiate treatment at 1.25 mg once daily. Increase the dose to 2.5 mg, then 5 mg, and finally to 10 mg once daily, using a titration interval of 1-2 weeks. Monitor patients for signs of worsening heart failure during titration.

Do not exceed the maximum daily dose of 10 mg.

In patients with severe renal impairment (CrCl <20 mL/min) or severe hepatic impairment, the use of Bivotenz is contraindicated. Use with caution in mild to moderate hepatic impairment.

Do not abruptly discontinue therapy. Gradually reduce the dose over 1-2 weeks under medical supervision.

For patients requiring dose adjustment, the 5 mg tablet features a functional score line and can be divided into equal halves.

Adverse Reactions

Immune system disorders: very rarely – angioedema, hypersensitivity reactions.

Psychiatric disorders: infrequently – depression, “nightmare” dreams, psychosis; very rarely – hallucinations, confusion.

Nervous system disorders: very often – dizziness; often – headache, dizziness, weakness, paresthesia; very rarely – fainting.

Eye disorders: infrequently – visual impairment; rarely – dry eyes.

Cardiovascular disorders: very often – bradycardia; often – worsening of chronic heart failure, first-degree AV block, orthostatic hypotension; infrequently – peripheral edema, bradycardia, heart failure, AV block, marked decrease in blood pressure, progression of concomitant “intermittent” claudication; very rarely – Raynaud’s syndrome.

Respiratory disorders: often – shortness of breath; infrequently – bronchospasm (including in the absence of a history of obstructive pulmonary diseases).

Gastrointestinal disorders: often – nausea, constipation, diarrhea; infrequently – dyspepsia, flatulence, vomiting.

Skin and subcutaneous tissue disorders: infrequently – erythematous skin rash, itching; very rarely – exacerbation of psoriasis, urticaria; frequency unknown – alopecia.

Other: often – increased fatigue; infrequently – photodermatosis, hyperhidrosis; erectile dysfunction; very rarely – coldness/cyanosis of the extremities.

Contraindications

Hypersensitivity to nebivolol; acute heart failure; chronic heart failure in the stage of decompensation (requiring intravenous administration of drugs with positive inotropic action); severe arterial hypotension (systolic blood pressure less than 90 mm Hg); sick sinus syndrome, including sinoatrial block; second and third degree AV block (without an artificial pacemaker); bradycardia (heart rate less than 60 beats/min); cardiogenic shock; pheochromocytoma (without simultaneous use of alpha-adrenergic blockers); metabolic acidosis; severe liver dysfunction; severe renal impairment (creatinine clearance less than 20 ml/min); bronchospasm and bronchial asthma in history; severe obliterating peripheral vascular diseases (intermittent claudication, Raynaud’s syndrome); myasthenia gravis; depression; simultaneous use with floctafenine, sultopride; breastfeeding period; children and adolescents under 18 years of age.

With caution renal impairment (creatinine clearance more than 20 ml/min); diabetes mellitus; hyperfunction of the thyroid gland; burdened allergic history; psoriasis; COPD; first-degree AV block; Prinzmetal’s angina; use in elderly patients (over 65 years of age); desensitizing therapy; liver dysfunction; mild or moderate peripheral circulatory disorders.

Use in Pregnancy and Lactation

Use during pregnancy is possible only for vital indications, when the expected benefit to the mother outweighs the potential risk to the fetus (due to the possibility of fetal growth retardation, intrauterine fetal death, premature birth, as well as the development of bradycardia, arterial hypotension, hypoglycemia and respiratory paralysis in the newborn).

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

Use in Hepatic Impairment

Contraindicated in severe liver dysfunction. It should be used with caution in patients with liver dysfunction.

Use in Renal Impairment

Contraindicated in severe renal impairment (creatinine clearance less than 20 ml/min). It should be used with caution in patients with renal impairment.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Use with caution in patients over 65 years of age. Monitoring of laboratory parameters of renal function in elderly patients should be carried out once every 4-5 months.

Special Precautions

Abrupt discontinuation of beta-adrenergic blockers is unacceptable (with abrupt cessation of treatment, “withdrawal” syndrome may develop), treatment should be discontinued gradually if possible.

Monitoring of patients taking beta-adrenergic blockers includes monitoring of heart rate and blood pressure (at the beginning of administration – daily, then once every 3-4 months).

In elderly patients, monitoring of renal function is necessary (once every 4-5 months).

In stable angina, the selected dose should provide a resting heart rate within 55-60 beats/min, during exercise – no more than 110 beats/min.

Beta-adrenergic blockers can cause bradycardia: the dose should be reduced if the heart rate is less than 50-55 beats/min.

Beta-adrenergic blockers should be used with caution in the following groups of patients: with peripheral circulatory disorders; with first-degree AV block, since beta-adrenergic blockers negatively affect the conduction time; with Prinzmetal’s angina due to unimpeded α-receptor-mediated coronary artery vasoconstriction: beta-adrenergic antagonists may increase the number and duration of angina attacks.

Beta-adrenergic blockers should be used with caution in patients with COPD, as bronchospasm may increase.

Beta-adrenergic blockers should not be used in patients with untreated chronic heart failure until the condition has stabilized.

Treatment of chronic heart failure with nebivolol is carried out against the background of stable cardiovascular parameters no earlier than 6 weeks after the end of the decompensation period. Nebivolol can be used for the treatment of chronic heart failure simultaneously with thiazide diuretics, digoxin, ACE inhibitors or angiotensin II receptor antagonists.

In smoking patients, the effectiveness of beta-adrenergic blockers is lower than in non-smokers.

Nebivolol does not affect the concentration of glucose in patients with diabetes mellitus, however, under the influence of nebivolol, signs of hypoglycemia (tachycardia, palpitations) caused by the use of hypoglycemic agents may be masked. In patients with diabetes mellitus, blood glucose concentration should be monitored once every 4-5 months.

Beta-adrenergic blockers should be used with caution in patients with hyperfunction of the thyroid gland because clinical signs of hyperthyroidism, such as tachycardia, may be masked under their influence. Abrupt withdrawal of nebivolol may cause an exacerbation of the symptoms of the disease and the development of a thyrotoxic crisis.

The use of nebivolol in patients with pheochromocytoma is possible only with the simultaneous use of alpha-adrenergic blockers.

Beta-adrenergic blockers may increase sensitivity to allergens and the severity of anaphylactic reactions. Nebivolol may cause a severe reaction to a number of allergens when prescribed to patients with a history of a severe anaphylactic reaction to these allergens. Such patients may not respond to the usual doses of epinephrine (adrenaline) used to treat anaphylactic shock.

When deciding on the prescription of the drug to patients with psoriasis, the expected benefit from the use of nebivolol and the possible risk of exacerbation of psoriasis should be carefully weighed.

Patients using contact lenses should take into account that during treatment with beta-adrenergic blockers, a decrease in the production of tear fluid is possible.

If a patient requires surgery during therapy with nebivolol, the surgeon-anesthesiologist must be informed about the nature of the therapy being carried out. Continuation of beta-adrenergic blockade reduces the risk of arrhythmia during anesthesia and intubation. If preparation for surgery involves interruption of beta-adrenergic blockade, beta-adrenergic antagonists should be discontinued at least 24 hours before surgery.

Anesthetics that cause myocardial depression should be used with caution.

Vagal reactions in a patient can be prevented by intravenous administration of atropine.

Effect on the ability to drive vehicles and mechanisms

Nebivolol does not affect the speed of psychomotor reactions. Against the background of taking nebivolol, dizziness and a feeling of fatigue are sometimes possible, so patients taking Nebivolol should refrain from engaging in potentially hazardous activities.

Drug Interactions

Concomitant use with floctafenine is contraindicated. Nebivolol can prevent compensatory reactions of the cardiovascular system associated with arterial hypotension or shock, which can be caused by floctafenine.

Concomitant use of nebivolol and sultopride is contraindicated, since their simultaneous use is associated with an increased risk of ventricular arrhythmia, especially polymorphic ventricular tachycardia of the “torsades de pointes” type.

With simultaneous use with class I antiarrhythmic drugs (quinidine, hydroquinidine, flecainide, cibenzoline, disopyramide, lidocaine, mexiletine, propafenone), an increase in the negative inotropic effect and prolongation of the excitation conduction time through the AV node is possible.

With simultaneous use of beta-adrenergic blockers with slow calcium channel blockers (verapamil and diltiazem), the negative effect on myocardial contractility and AV conduction is enhanced. Intravenous administration of verapamil against the background of nebivolol intake is contraindicated.

With simultaneous use with centrally acting antihypertensive agents (clonidine, guanfacine, moxonidine, methyldopa, rilmenidine), a worsening of the course of heart failure is possible due to a decrease in sympathetic tone (decrease in heart rate and cardiac output, symptoms of vasodilation). In case of abrupt withdrawal of these drugs, especially before the withdrawal of nebivolol, “rebound” arterial hypertension (“withdrawal” syndrome) may develop.

With simultaneous use with class III antiarrhythmic drugs (amiodarone), the effect on conduction time through the AV node may be enhanced.

With simultaneous use of nebivolol with insulin and oral hypoglycemic agents, symptoms of hypoglycemia (palpitations, tachycardia) may be masked.

Concomitant use of nebivolol and general anesthetics may suppress reflex tachycardia and increase the risk of arterial hypotension.

Concomitant use of nebivolol with baclofen, amifostine, with antihypertensive drugs can cause a significant drop in blood pressure, so dose adjustment of antihypertensive drugs is required.

With simultaneous use of nebivolol with cardiac glycosides, slowing of AV conduction is possible. Nebivolol does not affect the pharmacokinetic parameters of digoxin.

Concomitant use of nebivolol and slow calcium channel blockers of the dihydropyridine series (amlodipine, felodipine, lacidipine, nifedipine, nicardipine, nimodipine, nitrendipine) may increase the risk of arterial hypotension. An increase in the risk of further decrease in myocardial contractility in patients with heart failure cannot be excluded.

With simultaneous use of nebivolol with antihypertensive agents, nitroglycerin, severe arterial hypotension may develop (special caution is necessary when combined with prazosin).

Concomitant use of tricyclic antidepressants, barbiturates and phenothiazine derivatives, anxiolytics, and hypnotic drugs may enhance the antihypertensive effect of nebivolol.

No clinically significant interaction between nebivolol and NSAIDs has been established. Acetylsalicylic acid as an antiplatelet agent can be used concomitantly with nebivolol. When used concomitantly, sympathomimetic agents may suppress the activity of beta-blockers.

When nebivolol is used in combination with drugs that inhibit serotonin reuptake or other drugs metabolized with the participation of the CYP2D6 isoenzyme (e.g., paroxetine, fluoxetine, thioridazine, quinidine), the metabolism of nebivolol is slowed down, and the plasma concentration of nebivolol increases, which may lead to a risk of bradycardia and other side effects.

Rifampicin enhances the metabolism of nebivolol.

With the simultaneous use of nebivolol with nicardipine, the plasma concentrations of the active substances slightly increase without changing the clinical effect.

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.