Nebipolex

INSTRUCTIONS for MEDICAL USE of the MEDICINAL PRODUCT NEBIPOLEX (NEBIPOLEX)

Composition:

Active ingredient: nebivolol (nebivolol);

One tablet contains nebivolol hydrochloride 10.9 mg, equivalent to 10 mg of nebivolol;

Excipients: lactose monohydrate, maize starch, sodium croscarmellose, hypromellose 2910 (15 mPa*s), polysorbate 80, microcrystalline cellulose (type 102), colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physical and chemical properties: white or almost white, round, biconvex tablets with four bevelled edges, with a cross-score on both sides, embossed with the letter "N" in each quarter on one side of the tablet, approximately 11 mm in diameter.

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 actions:

• it is a competitive and selective β-receptor antagonist, an effect mediated by the SRRR-enantiomer (d-enantiomer);
• it has mild vasodilatory properties due to interaction with L-arginine/nitric oxide.

Single and repeated doses of nebivolol reduce heart rate and blood pressure 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.

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

During short- and long-term treatment with nebivolol in patients with arterial hypertension, systemic vascular resistance is reduced. 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 (ACh), mediated by nitric oxide; in patients with endothelial dysfunction, this response is diminished.

In a placebo-controlled morbidity-mortality study involving 2128 patients aged ≥70 years (mean age 75.2 years) with stable chronic heart failure with or without reduced left ventricular ejection fraction (LVEF) (mean LVEF 36 ± 12.3%, distributed as follows: LVEF <35% in 56% of patients, LVEF 35–45% in 25%, LVEF >45% in 19%), which lasted on average 20 months, nebivolol as an add-on therapy to standard treatment significantly prolonged the time to death or hospitalization due to cardiovascular disease (primary efficacy endpoint), 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 the age, gender, or left ventricular ejection fraction of the study participants. The benefit of nebivolol in preventing all-cause mortality compared to placebo did not reach statistical significance (absolute reduction 2.3%).

In patients treated with nebivolol, a reduction in the incidence of sudden death was observed (4.1% vs 6.6%, relative reduction by 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 has no membrane-stabilizing effect at pharmacological doses.

In healthy volunteers, nebivolol has no significant effect on maximal exercise tolerance or endurance.

Available preclinical and clinical data have not shown that nebivolol negatively affects erectile function in patients with hypertension.

Pharmacokinetics

After oral administration, both enantiomers of nebivolol are rapidly absorbed. Food does not affect the absorption of nebivolol; therefore, it can be taken with or without food.

Nebivolol is completely metabolized, partly forming active hydroxymetabolites. The metabolism of nebivolol occurs via aliphatic or aromatic hydroxylation, N-dealkylation, and glucuronidation; glucuronides of hydroxymetabolites are also formed. The metabolism of nebivolol via hydroxylation is subject to genetic oxidative polymorphism dependent on CYP2D6. The oral bioavailability of nebivolol is 12% in individuals with rapid metabolism and is nearly complete in those with slow metabolism. At steady state and with the same dose, the maximum plasma concentration of unchanged nebivolol in individuals with slow metabolism is approximately 23 times higher than in those with rapid metabolism. The difference in maximum plasma concentration of unchanged drug and its active metabolites combined ranges from 1.3 to 1.4 times. Due to differences in the extent of metabolism, the dose of Nebipolex should always be adjusted according to individual patient needs, and lower doses may be required for individuals with slow metabolism.

In individuals with rapid metabolism, the mean elimination half-life of nebivolol enantiomers is approximately 10 hours. In individuals with slow metabolism, this value is 3–5 times higher. 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 rapid metabolism.

In individuals with rapid metabolism, the elimination half-life of hydroxymetabolites of both enantiomers averages 24 hours, while in individuals with slow metabolism, these values are approximately twice as high.

Steady-state plasma levels are achieved within 24 hours in most patients with rapid metabolism, and within several days for hydroxymetabolites.

Plasma concentrations ranging from 1 to 30 mg of nebivolol are dose-proportional. Age does not influence the pharmacokinetics of nebivolol.

In plasma, both enantiomers are predominantly bound to albumin. Protein binding in plasma is 98.1% for SRRR-nebivolol and 97.9% for RSSS-nebivolol.

One week after administration, 38% of the dose is excreted in urine and 48% in feces. Renal excretion of unchanged nebivolol is less than 0.5% of the dose.

Preclinical Safety Data

Preclinical data based on standard genotoxicity, reproductive toxicity, developmental toxicity, and carcinogenicity studies 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 other components of the medicinal product;
• hepatic insufficiency or hepatic dysfunction;
• acute heart failure, cardiogenic shock, or episodes of heart failure decompensation requiring intravenous administration of active substances with positive inotropic effect.

In addition, as with other β-blockers, Nebipolox 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/min 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 information below refers to general interactions associated with β-adrenoceptor antagonists.

Concomitant use not recommended

Class I antiarrhythmic drugs (quinidine, hydroquinidine, cibenzoline, flecainide, disopyramide, lidocaine, mexiletine, propafenone): the effect on atrioventricular conduction may be enhanced and the negative inotropic effect may be increased (see section "Special precautions for use").

Calcium antagonists of the verapamil/diltiazem type: negative effects on contractility and atrioventricular conduction. Intravenous administration of verapamil to patients receiving β-blockers may lead to severe arterial hypotension and atrioventricular block (see section "Special precautions for use").

Centrally-acting antihypertensive agents (clonidine, guanfacine, moxonidine, methyldopa, rilmenidine): concomitant use of centrally-acting antihypertensive agents may exacerbate heart failure due to reduced central sympathetic tone (decreased heart rate and stroke volume, vasodilation) (see section "Special precautions for use"). Upon abrupt discontinuation, particularly before stopping β-blocker therapy, the risk of increased blood pressure may rise (withdrawal syndrome).

Combination use requiring caution

Class III antiarrhythmic drugs (amiodarone): the effect on atrioventricular conduction may be enhanced.

Halogenated volatile anesthetics: concomitant use of β-blockers and anesthetics may suppress reflex tachycardia and increase the risk of hypotension (see section "Special precautions for use"). As a general rule, abrupt discontinuation of β-blocker therapy should be avoided. If the patient is taking Nebipolox, the anesthesiologist should be informed.

Insulin and oral antidiabetic agents: although nebivolol does not affect blood glucose levels, concomitant use may mask certain symptoms of hypoglycemia (palpitations, tachycardia). Concurrent use of β-blockers with sulfonylurea derivatives may increase the risk of severe hypoglycemia (see section "Special precautions for use").

Baclofen (antispastic agent), amifostine (adjunct in anticancer therapy): concomitant use with antihypertensive agents may lead to a significant decrease in blood pressure; therefore, the dose of antihypertensive agents should be adjusted accordingly.

Information to consider during concomitant use

Cardiac glycosides (digitalis group): concomitant use may increase atrioventricular conduction time. No signs of this interaction were observed in clinical studies. Nebivolol does not affect digoxin kinetics.

Calcium antagonists of the dihydropyridine type (amlodipine, felodipine, lacidipine, nifedipine, nicardipine, nimodipine, nitrendipine): concomitant use may increase the risk of hypotension, and in patients with heart failure, a worsening of ventricular pump function cannot be excluded.

Antipsychotics, antidepressants (tricyclic antidepressants, barbiturates, and phenothiazine derivatives): concomitant use may enhance the antihypertensive effect (additive effect).

Nonsteroidal anti-inflammatory drugs (NSAIDs): do not affect the antihypertensive effect of nebivolol.

Sympathomimetics: concomitant use may counteract the antihypertensive effect of β-blockers. Active substances with β-adrenergic activity may enhance α-adrenergic activity of sympathomimetics possessing both α- and β-adrenergic effects (risk of arterial hypertension, severe bradycardia, and heart block).

Pharmacokinetic interactions

Since the CYP2D6 isoenzyme is involved in the metabolism of nebivolol, concomitant use of medicinal products that inhibit this enzyme (e.g., paroxetine, fluoxetine, thioridazine, quinidine) may increase plasma levels of nebivolol and thereby increase the risk of pronounced bradycardia and adverse reactions.

Concomitant use with cimetidine increases plasma levels of nebivolol but does not alter the clinical efficacy of nebivolol. Concomitant use with ranitidine does not affect the pharmacokinetics of nebivolol. Provided Nebipolox is taken with food and the antacid is taken between meals, both medicinal products may be administered simultaneously.

When nebivolol is used concomitantly with nicardipine, plasma concentrations of both drugs are slightly increased without changes in clinical efficacy.

Concomitant use of alcohol, furosemide, or hydrochlorothiazide does not affect the pharmacokinetics of nebivolol. Nebivolol does not affect the pharmacokinetics or pharmacodynamics of warfarin.

Special precautions for use

The following warnings and precautions are common to β-adrenoblockers.

Anesthesia

Continuation of β-blockade reduces the risk of cardiac rhythm disturbances during induction of anesthesia and intubation. If β-blockade needs to be discontinued prior to surgery, β-adrenoreceptor blockers should be withdrawn at least 24 hours beforehand.

Caution is required when using certain anesthetics that cause myocardial depression. Vagal reactions in patients can be prevented by intravenous administration of atropine.

Cardiovascular system

β-adrenoreceptor blockers should generally not be prescribed to patients with untreated chronic heart failure (CHF) until their condition becomes stable.

Discontinuation of β-adrenoblocker therapy in patients with ischemic heart disease should be gradual, over a period of 1–2 weeks. If necessary, replacement therapy should be initiated simultaneously to prevent angina exacerbation.

β-adrenoreceptor blockers may cause bradycardia. If resting pulse rate decreases to 50–55 beats per minute and/or symptoms of bradycardia develop, dose reduction is recommended.

β-adrenoreceptor blockers should be used with caution in the treatment of:

a) patients with peripheral circulatory disorders (Raynaud's disease or syndrome, intermittent claudication), as these conditions may worsen;

b) patients with first-degree atrioventricular block due to the negative effect of β-adrenoreceptor blockers on conduction;

c) patients with Prinzmetal's (vasospastic) angina due to unopposed α-adrenoreceptor-mediated coronary artery vasoconstriction: β-adrenoreceptor blockers may increase the frequency and duration of angina attacks.

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

Metabolism and endocrine system

Nebipolex does not affect blood glucose levels in patients with diabetes mellitus. Nevertheless, caution is required when administering it to patients in this category, as nebivolol may mask some symptoms of hypoglycemia (tachycardia, palpitations). β-adrenoreceptor blockers may additionally increase the risk of severe hypoglycemia when used concomitantly with sulfonylurea derivatives. Patients with diabetes mellitus should be advised to carefully monitor their blood glucose levels (see section "Interaction with other medicinal products and other forms of interaction"). β-adrenoreceptor blockers may mask symptoms of tachycardia in hyperthyroidism. Abrupt discontinuation of therapy may exacerbate these symptoms.

Respiratory system

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

Other

β-adrenoreceptor blockers should be prescribed to patients with a history of psoriasis only after careful consideration.

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

Regular monitoring of the patient's condition is required at the beginning of chronic heart failure treatment with nebivolol. For information on dosage and administration, see section "Dosage and administration".

Abrupt discontinuation of treatment should be avoided unless urgently necessary (see section "Dosage and administration"). For additional information, see section "Dosage and administration".

Excipients

This medicinal product contains lactose monohydrate (244.3 mg per tablet); therefore, if the patient has been diagnosed with intolerance to certain sugars, consultation with a physician is necessary before using this medicinal product.

This medicinal product contains 24 mg/dose (tablet) of sodium. Caution is advised when administering to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding

Pregnancy

Nebivolol has pharmacological effects that may adversely affect pregnancy and/or the fetus/neonate. In general, β-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 β-blocker therapy is necessary, β1-selective β-adrenoblockers are preferred.

Nebivolol must not be used during pregnancy. Use of this medicinal product in pregnant women is permitted only if there is unquestionable 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 observed, alternative therapy should be considered. The newborn should be closely monitored. Symptoms of hypoglycemia and bradycardia are generally expected within the first three days.

Lactation (breastfeeding)

Animal studies have shown that nebivolol passes into breast milk. It is unknown whether this substance passes into human breast milk. Most β-blockers, particularly lipophilic compounds such as nebivolol and its active metabolites, pass into breast milk to varying degrees. Risk to the newborn/infant 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 affect 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 at a dose of 5 mg does not affect psychomotor function. However, dizziness and fatigue may occasionally occur, which should be taken into account when driving or operating machinery.

Method of Administration and Dosage

Method of Administration

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

Dosage Regimen

Arterial Hypertension

Adults

The dose is 5 mg of nebivolol (half a tablet) once daily; it is advisable to take it at the same time each day. The antihypertensive effect becomes apparent within 1–2 weeks of treatment, but optimal effect may sometimes only be observed after 4 weeks.

Combination with Other Antihypertensive Agents

β-blockers can be used as monotherapy or in combination with other antihypertensive medicinal products. To date, an additional antihypertensive effect has only been observed with the combination of 5 mg nebivolol and 12.5–25 mg hydrochlorothiazide.

Patients with Renal Impairment

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

Patients with Hepatic Impairment

Data on the use of the medicinal product in patients with hepatic impairment or impaired liver function are limited. Therefore, the use of Nebipolex in such patients is contraindicated.

Elderly Patients

For patients aged over 65 years, the recommended initial dose is 2.5 mg once daily. This dose may be increased to 5 mg if necessary. However, due to limited experience with use in patients aged over 75 years, caution and close monitoring are required.

Chronic Heart Failure

Treatment of chronic heart failure should begin with slow dose titration to achieve the individual optimal maintenance dose. This medicinal product should be prescribed to patients who have chronic heart failure without episodes of acute decompensation during the past 6 weeks. It is recommended that the physician has experience in treating chronic heart failure. Patients who are taking other cardiovascular agents, 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 the past 2 weeks before starting therapy with Nebipolex.

Initial dose titration should follow the scheme below, with intervals of 1 to 2 weeks between dose increases, guided by patient tolerance: 1.25 mg nebivolol once daily (this dose cannot be achieved with Nebipolex 10 mg tablets; therefore, other medicinal products or Nebipolex 5 mg tablets, which can be divided into four 1.25 mg doses, should be used) may be increased to 2.5 mg nebivolol once daily, then to 5 mg once daily, and subsequently to 10 mg once daily. The maximum recommended dose is 10 mg nebivolol once daily. At the start of treatment and after each dose increase, an experienced physician should monitor the patient for at least 2 hours to ensure clinical stability (particularly regarding blood pressure, heart rate, myocardial conduction disturbances, and worsening of heart failure symptoms). The occurrence of adverse reactions may prevent all patients from reaching the maximum recommended dose. If necessary, a previously achieved dose may be gradually reduced or readjusted.

If heart failure symptoms worsen or the medicinal product is not tolerated during the titration phase, the nebivolol dose should first be reduced, or, if necessary, the medicinal product should be discontinued immediately (in cases of severe hypotension, worsening heart failure symptoms with acute pulmonary edema, cardiogenic shock, symptomatic bradycardia, or atrioventricular block).

Generally, treatment of stable chronic heart failure with nebivolol is long-term.

Nebivolol treatment should not be stopped 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 every week.

Patients with Renal Impairment

Since dose titration to the maximum 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 medicinal product in patients with severe renal impairment (serum creatinine ≥ 250 μmol/L); therefore, the use of nebivolol in such patients is not recommended.

Patients with Hepatic Impairment

Limited data are available regarding the use of the medicinal product in patients with hepatic impairment. Therefore, the use of Nebipolex in these patients is contraindicated.

Elderly Patients

Since dose titration to the maximum tolerated dose is individualized, dose adjustment is not required.

Children

Studies on the efficacy and safety of Nebipolex in children (under 18 years of age) have not been conducted. Data are unavailable.

Therefore, use in children (under 18 years of age) is not recommended.

Overdose

Data regarding overdose with Nebipolex are lacking.

Symptoms

Symptoms of β-blocker overdose include bradycardia, hypotension, bronchospasm, and acute heart failure.

Treatment

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 medicinal product remaining in the gastrointestinal tract. Mechanical ventilation may also be necessary. For treatment of bradycardia or increased vagal tone, administration of atropine or methylatropine is recommended. Treatment of hypotension and shock should be performed using plasma/plasma substitutes and, if necessary, catecholamines.

β-blocking effects can be reversed by slow intravenous infusion of isoprenaline hydrochloride, starting at a dose of 5 μg/min, or dobutamine, starting at 2.5 μg/min, until the desired effect is achieved. In case of resistance, isoprenaline may be combined with dopamine. If this is ineffective, intravenous glucagon may be administered at a dose of 50–100 μg/kg. If necessary, the injection should be repeated within one hour, followed, if needed, by intravenous infusion of glucagon at 70 μg/kg/hour. In extreme cases of therapy-resistant bradycardia, a temporary pacemaker may be implanted.

Adverse Reactions

Adverse events in arterial hypertension and chronic heart failure are listed separately due to differences in the underlying pathophysiological processes associated with these conditions.

Arterial Hypertension

The adverse reactions, which in most cases were of mild to moderate severity, are presented in the table below and are classified by organ system and frequency of occurrence.

In addition, the following adverse reactions have been reported with some β-blockers: hallucinations, psychosis, 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 heart failure was obtained from placebo-controlled clinical trials in which 1067 patients received nebivolol and 1061 patients received placebo. In this study, a total of 449 patients (42.1%) taking nebivolol 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 frequency in the placebo group was approximately 2% and 7%, respectively.

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

• Worsening of heart failure was observed in 5.8% of patients receiving nebivolol and in 5.2% of patients receiving placebo;
• Orthostatic hypotension was observed in 2.1% of patients receiving nebivolol and in 1% of patients receiving placebo;
• Drug intolerance was observed in 1.6% of patients receiving nebivolol and in 0.8% of patients receiving placebo;
• First-degree AV block was observed in 1.4% of patients receiving nebivolol and in 0.9% of patients receiving placebo;
• Edema of the lower extremities occurred in 1.0% of patients receiving nebivolol and in 0.2% of patients receiving placebo.

Reporting of adverse reactions

Reporting of adverse reactions after drug authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua/.

Shelf life

2 years.

Storage conditions

No special storage conditions required. Keep out of reach and sight of children.

Packaging

14 tablets in a blister pack. 2 blisters per cardboard box.

Prescription status

Prescription only.

Manufacturer

Pharmaceutical Plant "POLPHARMA" S.A.

Manufacturer's address and location of operations

Production site in Nowa Dęba, ul. Metalowca 2, 39-460 Nowa Dęba, Poland

and

ul. Pelplińska 19, 83-200 Starogard Gdański, Poland.