Nebovolol-teva

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Nebivolol-Teva

Composition:

Active substance: nebivolol;

1 tablet contains 5.45 mg of nebivolol hydrochloride, equivalent to 5 mg of nebivolol;

Excipients: colloidal anhydrous silicon dioxide, magnesium stearate, sodium croscarmellose, polyethylene glycol 6000, lactose monohydrate.

Pharmaceutical form. Tablets.

Main physicochemical properties: round, white, convex tablets with a cross-score on one side and marked "N5" on the other side.

Pharmacotherapeutic group. Selective β-adrenoreceptor blockers. ATC code C07AB12.

Pharmacological properties.

Pharmacodynamics.

Nebivolol is a racemate consisting of two enantiomers: SRRR-nebivolol (D-nebivolol) and RSSS-nebivolol (L-nebivolol). It combines two pharmacological properties:

• nebivolol is a competitive and selective β1-adrenoceptor blocker due to the D-enantiomer;
• it exhibits mild vasodilatory effects resulting from metabolic interaction with L-arginine/nitric oxide.

After single and repeated administration, nebivolol reduces heart rate at rest and during exercise in both individuals with normal blood pressure and those with arterial hypertension. The antihypertensive effect is maintained during long-term treatment.

At therapeutic doses, α-adrenergic antagonism is not observed.

During short- and long-term treatment with nebivolol in patients with arterial hypertension, systemic vascular resistance decreases. Despite the reduction in heart rate, the decrease in cardiac output at rest and during exercise is limited due to an increase in stroke volume. The clinical significance of this hemodynamic difference compared to other β-adrenoceptor blockers has not yet been fully elucidated.

In patients with arterial hypertension, nebivolol enhances the vascular response to acetylcholine mediated by nitric oxide; this response is reduced in patients with endothelial dysfunction.

In a placebo-controlled study involving 2128 patients aged ≥70 years (mean age 75.2 years) with stable chronic heart failure with reduced or preserved left ventricular ejection fraction (LVEF) (mean LVEF 36±12.3%, with distribution: LVEF <35% in 56% of patients, LVEF 35–45% in 25%, LVEF >45% in 19%), lasting on average 20 months, the addition of nebivolol to standard therapy significantly prolonged the time to death or hospitalization due to cardiovascular events, reducing the relative risk by 14% (absolute reduction 4.2%). This risk reduction emerged after 6 months of treatment and persisted throughout the treatment period (mean duration 18 months). The effect of nebivolol was independent of age, sex, or left ventricular ejection fraction in study participants. Benefit regarding prevention of all-cause mortality compared to placebo did not reach statistical significance (absolute reduction 2.3%).

In patients receiving nebivolol, a reduction in the incidence of sudden cardiac death was observed (4.1% vs. 6.6%, relative reduction of 38%).

In vitro and in vivo experiments in animals showed that nebivolol has no intrinsic sympathomimetic activity.

In vitro and in vivo experiments in animals showed that nebivolol, at pharmacological doses, has no membrane-stabilizing effect. In healthy volunteers, nebivolol does not significantly affect maximal exercise tolerance or endurance. Available preclinical and clinical data do not indicate that nebivolol negatively affects erectile function in patients with hypertension.

Pharmacokinetics.

Absorption. After oral administration, both enantiomers of nebivolol are rapidly absorbed. Food does not affect the absorption of nebivolol; therefore, it can be taken independently of food intake.

Metabolism. Nebivolol is completely metabolized, partly forming active hydroxymetabolites. The metabolism of nebivolol occurs via aliphatic or aromatic hydroxylation, N-dealkylation, and glucuronidation; in addition, glucuronides of hydroxymetabolites are formed. The metabolism of nebivolol via hydroxylation is subject to genetic oxidative polymorphism dependent on CYP2D6. The bioavailability of orally administered nebivolol averages 12% in individuals with rapid metabolism and is nearly complete in individuals with slow metabolism. At steady state and with equal dosing, the maximum plasma concentration of unchanged nebivolol in individuals with slow metabolism is approximately 23 times higher than in those with rapid metabolism. When considering the sum of unchanged drug and its active metabolites, the difference in maximum plasma concentration ranges from 1.3 to 1.4 times. Due to differences in metabolic rate, nebivolol dosing should be individualized; individuals with slow metabolism may require lower doses.

In individuals with rapid metabolism, the elimination half-life of nebivolol enantiomers averages 10 hours, while in individuals with slow metabolism, this value is 3–5 times longer. In individuals with rapid metabolism, the concentration of the RSSS-enantiomer is slightly higher than that of the SRRR-enantiomer. This difference is greater in individuals with slow metabolism. In individuals with rapid metabolism, the elimination half-life of hydroxymetabolites of both enantiomers averages 24 hours, while in individuals with slow metabolism, this value is approximately twice as long.

Steady-state plasma concentrations of nebivolol are reached within 24 hours in most patients (with rapid metabolism), while steady-state concentrations of hydroxymetabolites are achieved over several days. Plasma concentrations are dose-proportional within the dosage range of 1 to 30 mg of nebivolol. Age does not influence the pharmacokinetics of nebivolol.

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

Excretion. One week after administration, 38% of the dose is excreted in urine and 48% in feces. Less than 0.5% of the dose is excreted unchanged in urine.

Preclinical safety data.

Preclinical data based on conventional studies of genotoxicity, reproductive toxicity, developmental toxicity, and carcinogenicity revealed no hazard to humans. Adverse effects on reproductive function were observed only at high doses several times exceeding the maximum recommended human dose (see section "Use in pregnancy or breastfeeding").

Clinical characteristics.

Indications.

Arterial hypertension

Treatment of essential arterial hypertension.

Chronic heart failure (CHF)

Treatment of mild to moderate chronic heart failure, as an adjunct to standard therapy in patients aged 70 years and older.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients;
• hepatic insufficiency or hepatic dysfunction;
• acute heart failure, cardiogenic shock, or episodes of decompensated heart failure requiring intravenous administration of agents with positive inotropic effect.

Additionally, as with other β-blockers, Nebivolol-Teva is contraindicated in:

• sinus node dysfunction, including sinoatrial block;
• second- or third-degree atrioventricular (AV) block (without a pacemaker);
• bronchospasm and history of bronchial asthma;
• untreated pheochromocytoma;
• metabolic acidosis;
• bradycardia (heart rate less than 60 beats per minute prior to treatment initiation);
• arterial hypotension (systolic blood pressure less than 90 mm Hg);
• severe peripheral circulatory disorders.

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions

The following interactions are common to β-adrenoceptor blockers.

Concomitant use is not recommended:

• with Class I antiarrhythmic agents (quinidine, hydroquinidine, cibenzoline, flecainide, disopyramide, lidocaine, mexiletine, propafenone): may enhance effects on AV conduction and increase negative inotropic effect (see section "Special precautions");
• with calcium channel blockers of the verapamil and diltiazem type: negative effects on AV conduction and myocardial contractility; intravenous administration of verapamil to patients receiving β-blockers may lead to marked hypotension and AV block (see section "Special precautions");
• with centrally-acting antihypertensive agents (clonidine, guanfacine, moxonidine, methyldopa, rilmenidine): may lead to worsening of heart failure due to reduced central sympathetic tone (decreased heart rate and stroke volume, vasodilation) (see section "Special precautions"); abrupt withdrawal, particularly before discontinuation of β-adrenoblockers, may increase the likelihood of elevated blood pressure (withdrawal syndrome).

Caution is required when used concomitantly:

• with Class III antiarrhythmic agents (amiodarone): may enhance effects on AV conduction;
• with halogenated volatile anesthetics: may suppress reflex tachycardia and increase the risk of arterial hypotension (see section "Special precautions"); as a general rule, abrupt discontinuation of β-blocker therapy should be avoided; if the patient is taking Nebivolol-Teva, the anesthesiologist must be informed;
• with insulin and oral antidiabetic agents: although nebivolol does not affect blood glucose levels, when used concomitantly it may mask symptoms of hypoglycemia such as tachycardia and palpitations;
• with baclofen (antispastic agent) and amifostine (adjunct in antineoplastic therapy): concomitant use with antihypertensive agents may lead to significant reduction in blood pressure; therefore, the dose of antihypertensive agents should be appropriately adjusted.

It should be noted that when used concomitantly:

• with cardiac glycosides (digitalis group): may increase atrioventricular conduction time; however, no signs of this interaction were observed in clinical studies; nebivolol does not affect digoxin kinetics;
• with dihydropyridine-type calcium antagonists (amlodipine, felodipine, lacidipine, nifedipine, nicardipine, nimodipine, nitrendipine): may increase the risk of hypotension, and in patients with heart failure, a worsening of ventricular pump function cannot be excluded;
• with antipsychotics, antidepressants (tricyclic antidepressants, barbiturates, phenothiazine derivatives), organic nitrates, and other antihypertensive agents: may enhance the hypotensive effect of β-blockers (additive effect);
• with nonsteroidal anti-inflammatory drugs: no effect on the antihypertensive action of nebivolol;
• with sympathomimetics: may counteract the antihypertensive effect of β-blockers; agents with β-adrenergic activity may lead to unopposed α-adrenergic activity of sympathomimetics possessing both α- and β-adrenergic effects (risk of developing arterial hypertension, severe bradycardia, and heart block).

Pharmacokinetic interactions:

• since the CYP2D6 isoenzyme is involved in nebivolol metabolism, concomitant use of drugs that inhibit this enzyme (paroxetine, fluoxetine, thioridazine, quinidine, terbinafine, bupropion, chloroquine, and levomepromazine) may increase plasma levels of nebivolol, thereby increasing the risk of excessive bradycardia and other adverse reactions;
• cimetidine increases plasma levels of nebivolol without altering clinical efficacy; ranitidine does not affect the pharmacokinetics of nebivolol;
• if nebivolol is taken with food and antacids are taken between meals, these drugs may be co-administered;
• concomitant use of nebivolol and nicardipine slightly increases plasma concentrations of both drugs without affecting clinical efficacy;
• concomitant use of alcohol, furosemide, or hydrochlorothiazide does not affect the pharmacokinetics of nebivolol;
• nebivolol does not affect the pharmacodynamics or pharmacokinetics of warfarin.

Special precautions for use.

The following warnings and precautions are common to beta-adrenoreceptor blockers.

Anesthesia

Maintaining beta-adrenoreceptor blockade reduces the risk of cardiac arrhythmias during induction of anesthesia and intubation. If beta-blockade needs to be discontinued prior to surgery, beta-adrenoreceptor blockers should be withdrawn at least 24 hours beforehand. Caution is required when using certain anesthetics that may cause myocardial depression. Vagal reactions in the patient can be prevented by intravenous administration of atropine.

Cardiovascular system

Beta-adrenoreceptor blockers are generally not prescribed for patients with untreated chronic heart failure until their condition becomes stable.

Beta-adrenoreceptor blocker therapy should be discontinued gradually over 1–2 weeks in patients with ischemic heart disease. If necessary, to prevent disease exacerbation, concomitant initiation of alternative treatment is recommended.

Beta-adrenoreceptor blockers may cause bradycardia. If resting heart rate decreases to 50–55 beats per minute and/or symptoms indicative of bradycardia develop, the dose should be reduced.

Beta-adrenoreceptor blockers should be used with caution in treating:

• Patients with peripheral circulatory disorders (Raynaud's disease or syndrome, intermittent claudication), as exacerbation of these conditions may occur;
• Patients with first-degree atrioventricular block due to the negative effect of beta-adrenoreceptor blockers on conduction;
• Patients with Prinzmetal's angina due to unopposed α-adrenoreceptor-mediated vasoconstriction of coronary arteries: beta-adrenoreceptor blockers may increase the frequency and duration of angina attacks.

Combination of nebivolol with calcium channel blockers of the verapamil and diltiazem type, with antiarrhythmic agents of Class I, and with centrally acting antihypertensive agents is generally not recommended (see section "Interaction with other medicinal products and other forms of interaction" for detailed information).

Metabolism and endocrine system

Nebivolol does not affect blood glucose levels in diabetic patients. Nevertheless, caution is required when using it in this patient group, as nebivolol may mask certain signs of hypoglycemia, such as tachycardia and palpitations.

Beta-adrenoreceptor blockers may mask symptoms of tachycardia associated with hyperthyroidism. These symptoms may intensify following abrupt discontinuation of therapy.

Respiratory system

Beta-adrenoblockers should be used with caution in patients with chronic obstructive airway diseases, as bronchoconstriction may be exacerbated.

Other recommendations

Beta-adrenoblockers should be prescribed to patients with a history of psoriasis only after careful consideration.

Beta-adrenoreceptor blockers may increase sensitivity to allergens and the severity of anaphylactic reactions.

Beta-adrenoreceptor blockers may cause reduced tear production (information for contact lens wearers).

Regular monitoring of the patient is required at the beginning of treatment with nebivolol for chronic heart failure. Treatment should not be abruptly discontinued without urgent need (see section "Dosage and administration").

The product contains lactose monohydrate and therefore should not be used in patients with hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e. it is essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy

Nebivolol has pharmacological effects that may negatively affect pregnancy and/or the fetus/newborn. In general, beta-adrenoblockers reduce placental blood flow, which has been associated with growth retardation, intrauterine death, abortion, and premature delivery. Adverse effects (e.g., hypoglycemia and bradycardia) may occur in the fetus and newborn. If beta-blocker therapy is necessary, β1-selective beta-adrenoblockers are preferred.

Nebivolol should not be used during pregnancy except in cases of extreme necessity. If treatment with nebivolol is considered necessary, uteroplacental blood flow and fetal growth should be monitored. If harmful effects on pregnancy or the fetus are detected, alternative therapy should be considered. Newborns should be closely observed. Hypoglycemia and bradycardia are generally expected within the first 3 days.

Breastfeeding period

Animal studies have shown that nebivolol passes into breast milk. It is unknown whether this substance passes into human breast milk. Most beta-blockers, particularly lipophilic compounds such as nebivolol and its active metabolites, pass into breast milk to varying degrees. Risk to newborns/infants cannot be excluded. Therefore, mothers receiving nebivolol should not breastfeed.

Fertility

Nebivolol did not affect fertility in rats, except at doses several times higher than the maximum recommended human dose, where adverse effects on reproductive organs of male and female rats and mice were observed. The effect of nebivolol on human fertility is unknown.

Ability to influence reaction speed when driving or operating machinery.

Studies on the effect on reaction speed when driving or operating machinery have not been conducted. Pharmacodynamic studies have shown that nebivolol does not affect psychomotor function. However, when driving or operating machinery, it should be considered that dizziness and fatigue may occasionally occur (see section "Adverse reactions").

Method of Administration and Dosage

Administer orally. Swallow the tablet or part of the tablet with sufficient liquid (e.g., one glass of water). The drug may be taken independently of food intake.

Essential Arterial Hypertension

Adult patients should take 1 tablet (5 mg) of Nebivolol-Teva once daily, preferably at the same time each day. The antihypertensive effect becomes evident within 1–2 weeks of treatment, although in some cases optimal effect may only be observed after 4 weeks.

Combination with other antihypertensive agents. Nebivolol-Teva can be used as monotherapy or in combination with other antihypertensive agents. To date, additional antihypertensive effects have only been observed when the drug is combined with 12.5–25 mg hydrochlorothiazide.

Patients with renal impairment. The recommended initial dose is 2.5 mg once daily. If necessary, the daily dose may be increased to 5 mg.

Patients with hepatic impairment. Experience with the use of this drug in such patients is limited; therefore, nebivolol is contraindicated.

Elderly patients (over 65 years of age). For this patient group, the recommended initial dose is 2.5 mg once daily, which may be increased to 5 mg if necessary. Due to limited experience with patients over 75 years of age, use of the drug requires caution and careful monitoring.

Chronic Heart Failure

Treatment of chronic heart failure should begin with gradual dose titration until the individual optimal maintenance dose is reached. This drug should be prescribed to patients who have chronic heart failure without episodes of acute decompensation during the preceding 6 weeks. It is recommended that the prescribing physician has experience in the treatment of chronic heart failure.

Patients currently receiving other cardiovascular medications (including diuretics and/or digoxin and/or angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor antagonists) should have stable doses of these medications for at least 2 weeks before initiating nebivolol therapy. Initial dose titration should follow the schedule below, with intervals of 1 to 2 weeks between dose increases, based on patient tolerability: start with 1.25 mg nebivolol once daily, increase to 2.5 mg once daily, then to 5 mg once daily, and subsequently to 10 mg once daily. The maximum recommended dose is 10 mg once daily.

At the beginning of treatment and with each dose increase, the patient should remain under the supervision of an experienced physician for at least 2 hours to ensure clinical stability (particularly with regard to blood pressure, heart rate, myocardial conduction disturbances, and worsening of heart failure symptoms).

Adverse effects may prevent some patients from reaching the maximum recommended dose. If necessary, the achieved dose may be reduced stepwise or readjusted later.

If heart failure symptoms worsen or the drug is not tolerated during the titration phase, it is recommended to first reduce the dose of nebivolol or, if necessary, discontinue the drug immediately (in cases of severe hypotension, worsening heart failure symptoms with acute pulmonary edema, cardiogenic shock, symptomatic bradycardia, or AV block).

Chronic heart failure treatment with nebivolol is generally long-term. Nebivolol therapy should not be discontinued abruptly, as this may lead to a temporary worsening of heart failure. If discontinuation is necessary, the dose should be gradually reduced by halving it each week.

Patients with renal impairment. Since dose titration to the maximally tolerated dose is individualized, dose adjustment is not required in patients with mild to moderate renal impairment. There is no experience with the use of the drug in patients with severe renal impairment (serum creatinine level ≥250 µmol/L); therefore, use of nebivolol in such patients is not recommended.

Patients with hepatic impairment. Nebivolol is contraindicated in patients with hepatic impairment due to limited experience with its use.

Elderly patients. Dose adjustment is not required, as titration to the maximally tolerated dose is performed individually.

Children.

Studies on the use of the drug in children under 18 years of age have not been conducted; therefore, use of the drug is not recommended in this age group.

Overdose.

There are no available data on nebivolol overdose.

Symptoms. In cases of β-blocker overdose, symptoms may include bradycardia, arterial hypotension, bronchospasm, and acute heart failure.

Treatment of overdose. In case of overdose or development of hypersensitivity reactions, continuous patient monitoring and treatment in an intensive care unit are required. Blood glucose levels should be monitored. Gastric lavage, activated charcoal, and laxatives may prevent absorption of any remaining drug in the gastrointestinal tract. Mechanical ventilation may also be necessary. For bradycardia or increased vagal tone, atropine or methylatropine should be administered. For hypotension and shock, intravenous plasma or plasma substitutes should be administered; catecholamines may be added if necessary.

The β-blocking effect can be counteracted by slow intravenous infusion of isoprenaline hydrochloride, starting at a dose of 5 µg/min, or dobutamine, starting at 2.5 µg/min, adjusted to achieve the desired effect. In refractory cases, isoprenaline may be combined with dopamine. If the above measures are ineffective, intravenous glucagon may be administered at a dose of 50–100 µg/kg. The injection may be repeated within one hour if needed, and if required, a continuous intravenous glucagon infusion may be initiated at a rate of 70 µg/kg/hour. In extreme cases, when bradycardia is unresponsive to treatment, implantation of an artificial pacemaker may be necessary.

Adverse reactions.

Adverse reactions are listed separately for arterial hypertension and chronic heart failure due to the differences in underlying diseases.

Arterial hypertension

The adverse reactions, which in most cases were of mild to moderate severity, are listed in the table below; they are classified according to system organ classes and frequency of occurrence.

Also reported were the following adverse reactions caused by some β-adrenoblockers: hallucinations, psychoses, confusion, cold extremities/cyanosis, Raynaud's syndrome, dry eyes, and ocular-mucocutaneous toxicity of the practolol type.

Chronic heart failure

Information on adverse reactions in patients with chronic heart failure was obtained from a placebo-controlled clinical trial in which 1067 patients received nebivolol and 1061 patients received placebo. In this study, a total of 449 patients taking nebivolol (42.1%) and 334 patients (31.5%) taking placebo reported adverse reactions possibly related to the drug. The most commonly reported adverse reactions in patients treated with nebivolol were bradycardia and dizziness, occurring in approximately 11% of patients. The corresponding incidence in patients receiving placebo was approximately 2% and 7%, respectively.

The following adverse reactions, considered at least potentially related to drug administration and regarded as relevant and significant in the treatment of chronic heart failure, have been reported:

• Worsening of heart failure was observed in 5.8% of patients treated with nebivolol and in 5.2% of patients receiving placebo;
• Orthostatic hypotension occurred in 2.1% of patients treated with nebivolol and in 1.0% of patients receiving placebo;
• Drug intolerance was observed in 1.6% of patients treated with nebivolol and in 0.8% of patients receiving placebo;
• First-degree AV block occurred in 1.4% of patients receiving nebivolol and in 0.9% of patients receiving placebo;
• Lower limb edema occurred in 1.0% of patients receiving nebivolol and in 0.2% of patients receiving placebo.

Suspected adverse reactions reporting

Reporting of suspected adverse reactions during the post-marketing period of the medicinal product is important. This allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

10 tablets in a blister, 2 or 3 blisters in a cardboard box.

14 tablets in a blister, 2 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturers.

Actavis Ltd.

Balkanpharma-Dupnitsa AD.

Manufacturers' addresses and locations of their operations.

VBL015, VBL016 Bulbebel Industrial Building, Zeitun ZTN 3000, Malta.

3 Samokovsko Shose Str., Dupnitsa, 2600, Bulgaria.