OD-Neb (Tablets) Instructions for Use

Marketing Authorization Holder

Edge Pharma Private Limited (India)

Contact Information

Edge Pharma Private Limited COO (India)

ATC Code

C07AB12 (Nebivolol)

Active Substance

Nebivolol (Rec.INN registered by WHO)

Dosage Form

OD-Neb

Tablets 5 mg: 10, 14, 28, or 30 pcs.

Dosage Form, Packaging, and Composition

Tablets are almost white in color, round, biconvex, with a cross-shaped score line on one side.

Excipients: lactose – 83.45 mg, corn starch – 18 mg, croscarmellose sodium – 5.4 mg, polysorbate 80 – 0.22 mg, hypromellose – 1.8 mg, colloidal silicon dioxide – 0.23 mg, microcrystalline cellulose – 30 mg, magnesium stearate – 0.45 mg.

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
14 pcs. – blisters (1) – cardboard packs.
14 pcs. – blisters (2) – cardboard packs.

Clinical-Pharmacological Group

Third-generation beta₁-adrenoblocker with vasodilating properties

Pharmacotherapeutic Group

Selective beta1-adrenergic blocker

Pharmacological Action

Nebivolol is a lipophilic, cardioselective third-generation beta₁-adrenoblocker with vasodilating properties. It has antihypertensive, antianginal, and antiarrhythmic effects. It reduces elevated blood pressure at rest, during physical exertion, and under stress. It competitively and selectively blocks synaptic and postsynaptic β₁-adrenoceptors, making them inaccessible to catecholamines, and modulates the release of the endothelial relaxing factor nitric oxide.

Nebivolol is a racemate consisting of two enantiomers: SRRR-nebivolol (D-nebivolol) and RSSS-nebivolol (L-nebivolol), combining two pharmacological actions

• D-Nebivolol is a competitive and highly selective blocker of β₁-adrenoceptors (affinity for β₁-adrenoceptors is 293 times higher than for β₂-adrenoceptors).
• L-Nebivolol has a vasodilating effect by modulating the release of the endothelial relaxing factor nitric oxide from the vascular endothelium. The antihypertensive effect develops within 2-5 days of treatment, with a stable effect noted after 1 month. This effect is maintained during long-term treatment. The antihypertensive effect is also due to a reduction in the activity of the renin-angiotensin-aldosterone system (does not directly correlate with changes in plasma renin activity).

The use of nebivolol improves systemic and intracardiac hemodynamic parameters. Nebivolol reduces heart rate at rest and during physical exertion, decreases left ventricular end-diastolic pressure, reduces total peripheral vascular resistance, improves diastolic heart function (reduces filling pressure), increases ejection fraction, and reduces myocardial mass and myocardial mass index.

By reducing myocardial oxygen demand (decreased heart rate, reduced preload and afterload), it reduces the number and severity of angina attacks and improves exercise tolerance.

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

Pharmacokinetics

Absorption and Distribution

After oral administration, Nebivolol is rapidly absorbed from the gastrointestinal tract. Food intake does not affect absorption, so Nebivolol can be taken regardless of meals.

Bioavailability averages 12% in patients with “rapid” metabolism and is almost complete in patients with “slow” metabolism. The efficacy of nebivolol does not depend on the metabolic rate.

Plasma clearance in most patients (with “rapid” metabolism) is achieved within 24 hours, and for hydroxymetabolites – after several days.

Plasma concentrations of 1-30 µg/L are dose-proportional.

Plasma protein binding (primarily to albumin) is 98.1% for D-nebivolol and 97.9% for L-nebivolol.

Metabolism and Excretion

Nebivolol is actively metabolized, partially forming active hydroxymetabolites. The rate of nebivolol metabolism via aromatic hydroxylation is genetically determined by oxidative polymorphism and depends on the CYP 2D6 isoenzyme.

After administration, 38% (the amount of unchanged active substance is less than 0.5%) of the dose is excreted by the kidneys and 48% via the intestines.

In patients with “rapid” metabolism, the T_1/2 of nebivolol enantiomers from plasma averages 10 hours. In patients with “slow” metabolism, these values increase by 3-5 times.

In patients with “rapid” metabolism, the T_1/2 of hydroxymetabolites of both enantiomers from plasma averages 24 hours; in patients with “slow” metabolism, these values approximately double.

The pharmacokinetics of nebivolol are not influenced by the age and sex of patients.

Indications

• Arterial hypertension;
• Coronary artery disease: prevention of stable angina attacks;
• Chronic heart failure (as part of combination therapy).

ICD codes

Dosage Regimen

The drug OD-Neb should be taken orally at the same time of day, regardless of meals, without chewing, and with a sufficient amount of liquid.

Arterial Hypertension and Coronary Artery Disease

The average daily dose for the treatment of arterial hypertension and coronary artery disease is 5 mg (1 tablet) once a day. The optimal effect becomes pronounced after 1-2 weeks of treatment, and in some cases – after 4 weeks. The drug can be used in monotherapy or as part of combination therapy.

If necessary, the daily dose can be increased to 10 mg (2 tablets of 5 mg taken at one time). The maximum daily dose is 10 mg.

In patients with renal insufficiency, as well as in patients over 65 years of age, the initial dose is 2.5 mg/day (1/2 tablet of 5 mg). If necessary, the dose can be increased to 5 mg.

In cases of severe renal impairment (creatinine clearance less than 20 ml/min) and in patients with severe liver disease, the maximum daily dose is 10 mg.

Dose increases in such patients should be carried out with particular caution.

Chronic Heart Failure

Treatment of chronic heart failure should begin with a gradual dose increase until an individual optimal maintenance dose is achieved.

The dose selection at the beginning of treatment should be carried out according to the following scheme, maintaining two-week intervals and based on the patient’s tolerance of this dose: a dose of 1.25 mg of OD-Neb (1/4 tablet of 5 mg) once a day can be increased first to 2.5-5 mg of OD-Neb (1/2 tablet of 5 mg – 1 tablet), and then to 10 mg (2 tablets of 5 mg) once a day. The patient should be under medical supervision for 2 hours after taking the first dose of the drug, and after each subsequent dose increase. Each dose increase should be made no less than 2 weeks apart. The maximum recommended dose for CHF therapy is 10 mg of OD-Neb once a day. During titration, regular monitoring of blood pressure, heart rate, and symptoms of CHF severity is recommended.

During the titration phase, in case of worsening chronic heart failure or drug intolerance, it is recommended to reduce the dose of OD-Neb or, if necessary, immediately discontinue its use (in case of pronounced arterial hypotension, worsening CHF with acute pulmonary edema, in case of cardiogenic shock, symptomatic bradycardia, or AV block).

Adverse Reactions

Nervous system disorders: headache, dizziness, increased fatigue, paresthesia, depression, decreased ability to concentrate, drowsiness, insomnia, nightmares, hallucinations, confusion, fainting.

Digestive system disorders: nausea, constipation, flatulence, diarrhea, dry oral mucosa.

Cardiovascular system disorders: bradycardia, heart failure, AV block, orthostatic hypotension, peripheral circulation disorders, dyspnea, cardiac arrhythmias, Raynaud’s syndrome, peripheral edema, cardialgia, worsening of CHF¹.

Skin and subcutaneous tissue disorders: skin itching, erythematous rash.

Respiratory system disorders: bronchospasm (including in the absence of a history of obstructive pulmonary diseases), bronchospasm in patients with a history of bronchial asthma or airway obstruction, rhinitis.

Allergic reactions: angioedema, urticaria, allergic vasculitis.

Other: photodermatosis, hyperhidrosis, exacerbation of psoriasis, dry eye mucosa.

¹– this adverse reaction occurs predominantly during drug dose titration.

Contraindications

• Severe liver dysfunction;
• Acute heart failure;
• Cardiogenic shock;
• Chronic heart failure in the decompensation stage (requiring inotropic therapy);
• Sick sinus syndrome, including sinoatrial block;
• Second and third-degree AV block (without an artificial pacemaker);
• Bronchospasm and severe forms of bronchial asthma;
• Pheochromocytoma (without simultaneous use of alpha-blockers)
• Depression;
• Metabolic acidosis;
• Severe bradycardia (heart rate less than 50 beats/min);
• Arterial hypotension;
• Severe peripheral circulation disorders (“intermittent” claudication, Raynaud’s syndrome);
• Age under 18 years;
• Lactose intolerance, lactase deficiency, or glucose-galactose malabsorption (the drug contains lactose);
• Concomitant use with floctafenine, sultopride;
• Hypersensitivity to nebivolol or one of the components of the drug.

Use with caution in cases of severe renal failure (creatinine clearance less than 20 ml/min), mild to moderate liver dysfunction, diabetes mellitus, hyperthyroidism, desensitizing therapy, psoriasis, first-degree AV block, Prinzmetal’s angina, chronic obstructive pulmonary disease, and in elderly patients (over 65 years of age).

Use in Pregnancy and Lactation

During pregnancy, the drug is prescribed only for strict indications, when the benefit to the mother outweighs the risk to the fetus (due to the possible development of bradycardia, arterial hypotension, hypoglycemia, and respiratory paralysis in the newborn). Treatment should be discontinued 48-72 hours before delivery. In cases where this is not possible, strict monitoring of the newborn for 48-72 hours after delivery is necessary.

There are no data on the excretion of nebivolol into breast milk. Therefore, the use of OD-Neb is not recommended for women during breastfeeding. If the use of OD-Neb during lactation is necessary, breastfeeding should be discontinued.

Use in Hepatic Impairment

In patients with severe liver disease, the maximum daily dose is 10 mg.

Contraindicated in severe liver dysfunction. Use with caution in mild to moderate liver dysfunction.

Use in Renal Impairment

In patients with renal insufficiency, the initial dose is 2.5 mg/day (1/2 tablet of 5 mg). If necessary, the dose can be increased to 5 mg.

In cases of severe renal impairment (creatinine clearance less than 20 ml/min), the maximum daily dose is 10 mg.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

In patients over 65 years of age, the initial dose is 2.5 mg/day (1/2 tablet of 5 mg). If necessary, the dose can be increased to 5 mg.

Special Precautions

Discontinuation of beta-adrenergic blockers should be gradual, over 10 days (up to 2 weeks in patients with coronary artery disease).

Monitoring of blood pressure and heart rate at the beginning of drug administration should be daily.

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

In exertional angina, the drug dose should provide a resting heart rate within 55-60 beats/min, and 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.

When deciding on the use of OD-Neb in patients with psoriasis, the expected benefit of using the drug and the possible risk of exacerbation of psoriasis should be carefully weighed.

Patients using contact lenses should consider that beta-adrenergic blockers may reduce tear fluid production.

Before surgery, the anesthesiologist should be informed that the patient is taking Nebivolol.

OD-Neb does not affect plasma glucose concentration in patients with diabetes mellitus. Nevertheless, caution should be exercised when treating these patients, as Nebivolol may mask certain symptoms of hypoglycemia (e.g., tachycardia) caused by the use of hypoglycemic agents. Plasma glucose concentration should be monitored once every 4-5 months (in patients with diabetes mellitus).

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

In hyperfunction of the thyroid gland, the drug mitigates tachycardia.

Beta-adrenergic blockers may increase sensitivity to allergens and the severity of anaphylactic reactions. Such patients may be unresponsive to the usual doses of epinephrine used to treat them.

The effectiveness of beta-adrenergic blockers in smoking patients is lower than in non-smoking patients.

Effect on the ability to drive vehicles and operate machinery

Research has shown that Nebivolol does not affect the speed of psychomotor reactions. For pilots with grade I arterial hypertension (cleared for flight duties), the drug is prescribed at an initial dose of 2.5 mg. Subsequently (no earlier than 2 weeks later), with good treatment tolerance and adequate blood pressure control, the dose may be increased by 2.5 mg. The recommended dose is 5 mg/day. Some patients may experience side effects, most often dizziness, due to reduced blood pressure. If such effects occur, the patient should not drive vehicles or engage in potentially hazardous activities requiring special attention and quick psychomotor reactions. These effects most often occur immediately after the start of treatment or when the dose is increased.

Overdose

Symptoms: nausea, vomiting, cyanosis, pronounced decrease in blood pressure, severe bradycardia, bronchospasm, AV block, cardiogenic shock, acute heart failure, loss of consciousness, coma, cardiac arrest.

Treatment: gastric lavage, administration of activated charcoal. In case of a pronounced decrease in blood pressure, the patient should be placed in a horizontal position with legs elevated; if necessary, intravenous plasma-substituting solutions and vasopressors are administered.

In case of severe bradycardia, 0.5-2 mg of atropine is administered intravenously; if there is no positive effect, placement of a transvenous artificial pacemaker may be considered.

In case of AV block (grades II-III), intravenous administration of beta-adrenergic agonists is recommended; if they are ineffective, placement of an artificial pacemaker should be considered. In heart failure, treatment begins with the administration of cardiac glycosides and diuretics; if there is no effect, the administration of dopamine, dobutamine, or vasodilators is advisable. For bronchospasm, beta-adrenergic agonists are administered intravenously. For ventricular extrasystole – lidocaine (class IA antiarrhythmic agents should not be administered).

Drug Interactions

Floctafenine: in case of shock or arterial hypotension caused by floctafenine, beta-adrenergic blockers weaken the compensatory mechanisms of the cardiovascular system.

Sultopride: increased risk of ventricular arrhythmia, especially torsades de pointes.

When beta-adrenergic blockers are used concomitantly with slow calcium channel blockers (verapamil and diltiazem), the negative effect on myocardial contractility and AV conduction is enhanced. Intravenous administration of verapamil is contraindicated while taking nebivolol. When combined with antihypertensive agents, nitroglycerin, or slow calcium channel blockers, pronounced arterial hypotension may develop (special caution is necessary when combined with prazosin).

When used concomitantly with class I antiarrhythmic agents and with amiodarone, an enhancement of the negative inotropic effect and prolongation of atrial conduction time are possible.

Concomitant use of nebivolol with cardiac glycosides did not reveal an enhanced effect on slowing AV conduction.

Concomitant use of nebivolol and drugs for general anesthesia can suppress reflex tachycardia and increase the risk of arterial hypotension.

No clinically significant interaction between nebivolol and NSAIDs has been established. Acetylsalicylic acid as an antiplatelet agent can be used concomitantly with nebivolol.

Concomitant use of tricyclic antidepressants, barbiturates, and phenothiazine derivatives may enhance the hypotensive effect of nebivolol.

Pharmacokinetic Interaction

When used concomitantly with drugs that inhibit serotonin reuptake, or other agents biotransformed with the participation of the CYP 2D6 isoenzyme, the metabolism of nebivolol is slowed down.

Concomitant use of Nebivolol did not affect the pharmacokinetic parameters of digoxin.

When used concomitantly with cimetidine, the plasma concentration of nebivolol increases (data on the effect on the pharmacological effects of the drug are lacking). Concomitant use of ranitidine did not affect the pharmacokinetic parameters of nebivolol.

When nebivolol is used concomitantly with nicardipine, the plasma concentrations of the active substances increase somewhat, but this is not of clinical significance.

Concomitant administration of ethanol, furosemide, or hydrochlorothiazide did not affect the pharmacokinetics of nebivolol.

No clinically significant interaction between nebivolol and warfarin has been established.

When used concomitantly, sympathomimetic agents suppress the activity of nebivolol.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°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.