Nolet

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NOLET (NOLET)

Composition:

Active substance: nebivolol;

One tablet contains nebivolol (as nebivolol hydrochloride) 5 mg;

Excipients: lactose monohydrate; corn starch; microcrystalline cellulose type 102; sodium croscarmellose; hypromellose 15 cP; polysorbate 80; colloidal anhydrous silicon dioxide; magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white, round, biconvex tablets with a cross-shaped score line on one 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 actions:

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

Single and repeated doses of nebivolol reduce heart rate and arterial 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.

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 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 placebo-controlled morbidity-mortality studies 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 the following distribution: LVEF <35% in 56% of patients, LVEF 35–45% in 25% of patients, LVEF >45% in 19% of patients), which lasted on average 20 months, nebivolol as a primary medicinal product within standard therapy 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 remained consistent 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. The benefit in preventing mortality from all causes compared to placebo did not reach statistical significance (absolute reduction – 2.3%).

In patients treated with nebivolol, a reduction in mortality rate was observed (4.1% vs 6.6%, relative reduction by 38%).

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

In vitro and in vivo animal experiments showed that nebivolol at pharmacological doses has no membrane-stabilizing effect.

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 hypertensive disease.

Pharmacokinetics.

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.

Nebivolol is completely metabolized, partly forming active hydroxymetabolites. The metabolism of nebivolol occurs via alicyclic or aromatic hydroxylation, N-dealkylation, and glucuronidation, and 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. 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 the extent of metabolism, the dose of the medicinal product Nolet should always be adjusted according to individual patient needs; therefore, individuals with slow metabolism may require lower doses.

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 mean elimination half-life of hydroxymetabolites of both enantiomers is approximately 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 concentration is proportional to the dose within the range of 1 to 30 mg of nebivolol. Age does not affect the pharmacokinetics of nebivolol.

In plasma, both enantiomers are predominantly bound to albumin. Plasma protein binding 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.

Safety Preclinical 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 lactation").

Clinical characteristics.

Indications.

Arterial hypertension

Treatment of essential arterial hypertension.

Chronic heart failure (CHF).

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

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product;
• 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.

In addition, as with other β-blockers, Noleth is contraindicated in:

• sinus node dysfunction, including sinoatrial block;
• II–III degree AV block (without a pacemaker);
• bronchospasm and history of bronchial asthma;
• untreated pheochromocytoma;
• metabolic acidosis;
• bradycardia (prior to treatment, heart rate less than 60 beats/min);
• arterial hypotension (systolic blood pressure < 90 mm Hg);
• severe peripheral circulatory disorders.

Interaction with other medicinal products and other forms of interactions.

Pharmacodynamic interactions:

The information below refers to general interactions with β-adrenoreceptor antagonists.

Co-administration not recommended:

Class I antiarrhythmic agents (quinidine, hydroquinidine, cibenzoline, flecainide, disopyramide, lidocaine, mexiletine, propafenone): effects on atrioventricular conduction may be enhanced and negative inotropic effect may increase (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 marked 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 reduction in 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).

Caution required during combination therapy:

Class III antiarrhythmic agents (amiodarone): effects 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 arterial hypotension (see section "Special precautions for use"). As a general rule, avoid abrupt withdrawal of β-blocker therapy. If a patient is taking Noleth, 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 beta-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 significantly reduce blood pressure; therefore, the dose of antihypertensive agents should be adjusted accordingly.

Consider during co-administration:

Cardiac glycosides (digitalis group): concomitant use may increase atrioventricular conduction time. No clinical 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, an increased risk of further deterioration of ventricular pump function cannot be excluded.

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

Nonsteroidal anti-inflammatory drugs do not affect the antihypertensive action of nebivolol.

Sympathomimetics: concomitant use may counteract the antihypertensive effect of β-adrenoblockers. Agents with β-adrenergic activity may unmask 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 nebivolol metabolism, concomitant use of medicinal products that inhibit this enzyme (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 nebivolodol. Concomitant use with ranitidine does not affect the pharmacokinetics of nebivolol. Provided Noleth is taken with food and antacid agents are taken between meals, both medicinal products may be administered simultaneously.

When nebivolol is used in combination 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 and pharmacodynamics of warfarin.

Special precautions for use.

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

Anesthesia.

Continuation of beta-blockade reduces the risk of cardiac rhythm disturbances 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.

Use of certain anesthetics that cause myocardial depression requires caution. Vagal reactions in the patient can be prevented by intravenous administration of atropine.

Cardiovascular system.

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

Discontinuation of beta-blocker 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 exacerbation of angina.

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

Beta-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 exacerbation of these conditions may occur;

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

c) patients with Prinzmetal’s (variant) angina, due to unopposed α-adrenoceptor-mediated vasoconstriction of coronary arteries: beta-adrenoreceptor blockers may increase the frequency and duration of angina attacks.

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

Metabolic/endocrine disorders.

Nolét does not affect blood glucose levels in diabetic patients. Nevertheless, caution is required when using it in this patient group, since nebivolol may mask some symptoms of hypoglycemia (tachycardia, palpitations). Beta-blockers may additionally increase the risk of severe hypoglycemia when used concomitantly with sulfonylurea derivatives. Diabetic patients should be advised to monitor blood glucose levels carefully (see section "Interaction with other medicinal products and other forms of interaction"). Beta-adrenoreceptor blockers may mask symptoms of tachycardia associated with hyperthyroidism. Abrupt discontinuation of therapy may exacerbate these symptoms.

Respiratory system.

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

Other.

Beta-adrenoreceptor blockers 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.

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

Treatment should not be abruptly discontinued without urgent need (see section "Dosage and administration"). For additional information, see section "Dosage and administration".

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

This medicinal product contains less than 1 mmol of sodium (in the form of sodium croscarmellose – 11.5 mg) per tablet, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

Nebivolol has pharmacological effects that may adversely affect pregnancy and/or the fetus/newborn. In general, beta-adrenoblockers reduce placental blood flow, which has been associated with intrauterine 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, beta1-selective beta-adrenoblockers are preferred.

Nebivolol should not be used during pregnancy unless clearly necessary. 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. Newborns should be carefully monitored. Hypoglycemia and bradycardia are generally expected within the first three days of life.

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. Therefore, breastfeeding during treatment with nebivolol is not recommended.

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 Nolét 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.

Dosage Regimen

Arterial Hypertension.

Adults:

The dose is 1 tablet (5 mg of nebivolol) once daily, preferably taken at the same time each day. The antihypertensive effect becomes evident within 1–2 weeks of treatment, although optimal efficacy may only be observed after 4 weeks.

Combination with other antihypertensive agents.

β-blockers can be used as monotherapy or in combination with other antihypertensive drugs. To date, an additional antihypertensive effect has been observed only when the medicinal product Nolex 5 mg is combined with 12.5–25 mg of hydrochlorothiazide.

Patients with renal impairment.

For 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.

Data on the use of the medicinal product in patients with hepatic impairment or liver function disorders are limited; therefore, its use in such patients is contraindicated.

Elderly patients.

For patients aged 65 years and older, the recommended initial dose is 2.5 mg once daily. If necessary, the dose may be increased to 5 mg. However, due to limited experience with the drug in patients aged 75 years and older, its use in this population requires caution and careful monitoring.

Chronic Heart Failure (CHF).

Treatment of CHF should begin with gradual dose titration until the individual optimal maintenance dose is achieved. 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 prescribing physician has experience in the treatment of CHF. Patients who are 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 the previous 2 weeks before initiating therapy with the medicinal product Nolex.

Initial dose titration should follow the scheme below, with intervals of 1 to 2 weeks between dose increases, based on patient tolerance: starting with 1.25 mg of nebivolol once daily, increasing 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 of nebivolol once daily. At the beginning of treatment and after each dose increase, the patient should remain under the supervision of an experienced physician 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 effects may prevent all patients from reaching the maximum recommended dose. If necessary, the achieved dose may be reduced stepwise or readjusted.

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

Treatment of stable CHF with nebivolol is typically 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 every week over a period of 1 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 level ≥ 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 the medicinal product Nolex in these patients is contraindicated.

Elderly patients.

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

Method of Administration.

Oral use.

Tablets may be taken with or without food.

Children.

The efficacy and safety of the medicinal product Nolex in children and adolescents (under 18 years of age) have not been studied. Data are unavailable. Therefore, use in children and adolescents (under 18 years of age) is not recommended.

Overdose.

Data regarding overdose with the medicinal product Nolex are lacking.

Symptoms.

Symptoms of β-blocker overdose include bradycardia, arterial 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 further absorption of any drug remaining in the gastrointestinal tract. Mechanical ventilation may also be necessary. For the treatment of bradycardia or increased vagal tone, administration of atropine or methylatropine is recommended. Treatment of arterial hypotension and shock should be performed using plasma/plasma substitutes and, if necessary, catecholamines.

β-blocking effects may 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, titrated to the desired effect. In case of resistance, isoprenaline may be combined with dopamine. If this does not achieve the desired effect, glucagon may be administered intravenously at a dose of 50–100 µg/kg. If necessary, the injection may be repeated within one hour, followed by continuous intravenous infusion of glucagon at 70 µg/kg/hour. In extreme cases of therapy-resistant bradycardia, temporary cardiac pacing may be required.

Adverse reactions.

Adverse events for arterial hypertension and chronic heart failure are listed separately due to differences in the underlying pathological 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 according to system organ classes 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 that might have been related to the drug. The most commonly reported adverse reactions in patients taking nebivolol were bradycardia and dizziness, occurring in approximately 11% of patients. The corresponding incidence in the placebo group was approximately 2% and 7%, respectively.

The following adverse reactions, considered at least potentially related to the drug and regarded as relevant and significant in the treatment of CHF, 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;
• Lower limb edema occurred in 1% of patients receiving nebivolol and in 0.2% of patients receiving placebo.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization of the medicinal product is important. It allows continued 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. Keep out of reach of children.

Packaging.

10 tablets per blister, 3 blisters per cardboard pack.

Prescription status. Prescription only.

Manufacturer.

ANTIBIOTICS S.A.

Manufacturer's location and address of its business site.

1 Valea Lupului Street, Iasi 707410, Romania.