Nebivolol-NAN

Nebivolol

Tablets

Off-white, biconvex, cross-scored tablets, can be divided in equal quarters.

One tablet contains:
Active substance: 5 mg of nebivolol (as nebivolol hydrochloride);
Auxiliary substances: partially pregelatinized maize starch, low viscosity sodium carboxymethylcellulose, sodium croscarmellose, Kolliphor P188 micro poloxamer, lactose monohydrate, magnesium stearate, colloidal anhydrous silicon dioxide, microcrystalline cellulose.

Beta blocking agent, selective.

C07AB12

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

• It is a competitive and selective pi-adrenoceptor antagonist: this effect is attributed to the SRRR-nebivolol (D-nebivolol).
• It has mild vasodilating properties due to an interaction with the L-arginine/nitric oxide pathway.

Single and repeated doses of nebivolol reduce heart rate and blood pressure at rest and during exercise, both in normotensive subjects and in hypertensive patients. The antihypertensive effect is maintained during chronic treatment.

At therapeutic doses, nebivolol is devoid of alpha-adrenergic antagonism.
During acute and chronic treatment with nebivolol in hypertensive patients, systemic vascular resistance is decreased. Despite heart rate reduction, reduction in cardiac output during rest and exercise may be limited due to an increase in stroke volume. The clinical relevance of these haemodynamic differences as compared to other beta-adrenoreceptor antagonists has not been fully established.

In hypertensive patients, nebivolol increases the NO-mediated vascular response to acetylcholine which is reduced in patients with endothelial dysfunction.
Administration of nebivolol as an adjunct to the standard therapy of chronic heart failure with or without impaired left ventricular ejection fraction significantly prolonged the time to occurrence of deaths or hospitalizations for cardiovascular reasons. The effect of nebivolol was independent from age, gender, or left ventricular ejection fraction of the population on study.

A decrease in sudden death was observed in nebivolol treated patients.
Nebivolol has no intrinsic sympathicomimetic activity and it has no membrane stabilizing action at pharmacological doses.
In healthy volunteers, nebivolol has no significant effect on maximal exercise capacity or endurance.

Hypertension
Treatment of essential hypertension.

Chronic heart failure
Treatment of stable mild and moderate chronic heart failure in addition to standard therapies in elderly patients ≥ 70 years.

Tablets should be taken orally with a sufficient amount of water (for example, one glass of chilled boiled water) with or without meals.

Hypertension

Adults
The dose is one tablet (5 mg of nebivolol) daily, preferably at the same time of the day. The blood pressure lowering effect becomes evident after 1-2 weeks of treatment. Occasionally, the optimal effect is reached only after 4 weeks.

Combination with other antihypertensive agents
Beta-blockers can be used alone or concomitantly with other antihypertensive agents. To date, an additional antihypertensive effect has been observed only when nebivolol is combined with hydrochlorothiazide 12.5-25 mg.

Patients with renal impairment
In patients with renal impairment, the recommended starting dose is 2.5 mg daily. If needed, the daily dose may be increased to 5 mg.

Patients with hepatic impairment
Data in patients with hepatic impairment or impaired liver function are limited. Therefore, the use of nebivolol in these patients is contra-indicated.

Elderly patients
In patients over 65 years, the recommended starting dose is 2.5 mg daily. If needed, the daily dose may be increased to 5 mg. However, in view of the limited experience in patients above 75 years, caution must be exercised and these patients monitored closely.

Paediatric population
The efficacy and safety of nebivolol in children and adolescents aged below 18 years has not been established. Therefore, the use of nebivolol in children and adolescents of this age is not recommended.

Chronic heart failure
The treatment of stable chronic heart failure has to be initiated with a gradual uptitration of dosage until the optimal individual maintenance dose is reached.
Patients should be given nebivolol if they have stable chronic heart failure without acute failure during the past six weeks.
It is recommended that the treating physician should be experienced in the management of chronic heart failure.

For those patients receiving cardiovascular drug therapy including diuretics and/or digoxin and/or ACE inhibitors and/or angiotensin II antagonists, dosing of these drugs should be stabilized during the past two weeks prior to initiation of nebivolol treatment.

The initial uptitration should be done according to the following steps at 1-2 weekly intervals based on patient tolerability:
1.25 mg nebivolol, to be increased to 2.5 mg nebivolol once daily, then to 5 mg once daily and then to 10 mg once daily.
The maximum recommended dose is 10 mg nebivolol once daily.

Initiation of therapy and every dose increase should be done under the supervision of an experienced physician over a period of at least 2 hours to ensure that the clinical status (especially as regards blood pressure, heart rate, conduction disturbances, signs of worsening of heart failure) remains stable.

Occurrence of adverse events may prevent all patients being treated with the maximum recommended dose. If necessary, the dose reached can also be decreased step by step and reintroduced as appropriate.

During the titration phase, in case of worsening of the heart failure or intolerance, it is recommended first to reduce the dose of nebivolol, or to stop it immediately if necessary (in case of severe hypotension, worsening of heart failure with acute pulmonary oedema, cardiogenic shock, symptomatic bradycardia or AV block).
Treatment of stable chronic heart failure with nebivolol is generally a long-term treatment.

The treatment with nebivolol is not recommended to be stopped abruptly since this might lead to a transitory worsening of heart failure. If discontinuation is necessary, the dose should be gradually decreased divided into halves weekly.

Patients with renal impairment
No dose adjustment is required in mild to moderate renal insufficiency since uptitration to the maximum tolerated dose is individually adjusted. There is no experience in patients with severe renal insufficiency (serum creatinine ≥ 250 μmol/L). Therefore, the use of nebivolol in these patients is not recommended.

Patients with hepatic impairment
Data in patients with hepatic insufficiency are limited. Therefore, the use of nebivolol in these patients is contra-indicated.

Elderly patients
No dose adjustment is required in elderly patients since uptitration to the maximum tolerated dose is individually adjusted.

Paediatric population
The efficacy and safety of nebivolol in children and adolescents aged below 18 years has not been established. Therefore, the use of Nebivolol-NAN in this age group is not recommended.

Do not skip taking Nebivolol-NAN. If you forget a dose of the Nebivolol-NAN, but remember a little later on that you should have taken it, take that missed dose, the next day’s dose should be taken as usual. However, if a long delay has occurred (e.g., several hours), so that the next due dose is near, skip the forgotten dose and take the next, scheduled, normal dose at the usual time. Do not take a double dose. Repeated skipping, however, should be avoided.

Do not take a larger dose than prescribed for you by your physician. If you accidentally took more than the prescribed number of tablets, which may lead to symptoms of overdose, inform your doctor immediately (see also Section Overdose). You can take activated charcoal (if it is available at your medicine chest) while you wait for the arrival of the doctor.

It is not recommended to stop taking Nebivolol-NAN without consulting your doctor. You should not stop the treatment abruptly as this can temporarily make your heart failure worse. If it is necessary to stop Nebivolol-NAN treatment for chronic heart failure, the daily dose should be decreased gradually, by halving the dose, at weekly intervals.

Adverse events are listed separately for hypertension and CHF because of differences in the background diseases. The incidence of adverse events: very common (≥ 1/10), common (≥ 1/100, but < 1/10), uncommon (≥ 1/1000, but < 1/100), rare (≥ 1/10000, but < 1/1000), not known (cannot be estimated based on available data).

Hypertension
The adverse reactions reported, which are in most of the cases of mild to moderate intensity, are tabulated below, classified by system organ class and ordered by frequency:

Immune system disorders: not known – angioneurotic oedema, hypersensitivity.

Psychiatric disorders: uncommon – nightmares, depression.

Nervous system disorders: common – headache, dizziness, paraesthesia; very rare – syncope.

Eye disorders: uncommon – impaired vision.

Cardiac disorders: uncommon – bradycardia, heart failure, slowed AV conduction/AV-block.

Vascular disorders: uncommon – hypotension, increase of intermittent claudication.

Respiratory, thoracic and mediastinal disorders: common – dysponoea; uncommon – bronchospasm.

Gastrointestinal disorders: common – constipation, nausea, diarrhoea; uncommon – dyspepsia, flatulence, vomiting.

Skin and subcutaneous tissue disorders: uncommon – pruritus, rash erythematous; very rare – psoriasis aggravated.

Reproductive system and breast disorders: uncommon – impotence.

General disorders and administration site conditions: common – tiredness, oedema.

The following adverse reactions have also been reported with some beta-adrenergic antagonists: hallucinations, psychoses, confusion, cold/cyanotic extremities, Raynaud phenomenon, dry eyes, and oculo-mucocutaneous toxicity of the practolol-type.

Chronic heart failure
Data on adverse reactions in CHF patients are available from one placebo-controlled clinical trial. The most commonly reported adverse reactions in nebivolol patients were bradycardia and dizziness, both occurring in approximately 11% of patients.

The following incidences were reported for adverse reactions (at least possibly nebivolol-related) which are considered specifically relevant in the treatment of chronic heart failure:

• Aggravation of cardiac failure occurred in 5.8 % of nebivolol patients compared to 5.2% of placebo patients.
• Postural hypotension was reported in 2.1% of nebivolol patients compared to 1.0% of placebo patients.
• Intolerance to medication occurred in 1.6% of nebivolol patients compared to 0.8% of placebo patients.
• First degree atrio-ventricular block occurred in 1.4% of nebivolol patients compared to 0.9% of placebo patients.
• Oedema of the lower limb were reported by 1.0% of nebivolol patients compared to 0.2% of placebo patients.

In case of adverse reactions, including those not specified in the instruction for medical use, consult a doctor.

• Hypersensitivity to the active substance or to any of the auxiliary substances.
• Liver insufficiency or liver function impairment.
• Acute heart failure, cardiogenic shock or episodes of heart failure decompensation requiring i.v. inotropic therapy.

In addition, as with other beta-blockers, nebivolol is contra-indicated in the following diseases and conditions:

• sick sinus syndrome, including sino-atrial block.
• second- and third-degree AV block (without a pacemaker).
• history of bronchospasm and bronchial asthma.
• untreated phaeochromocytoma.
• metabolic acidosis.
• bradycardia (heart rate < 60b pm prior to start therapy).
• hypotension (systolic blood pressure < 90 mm Hg).
• severe peripheral circulatory disturbances.
• children and adolescents under 18 years of age (safety and administration efficiency in children under 18 years is not established).

If taking a larger dose than prescribed by your doctor, immediately contact specialists to provide timely medical care!
No data are available on overdosage with nebivolol.

Symptoms: symptoms of overdosage with beta-blockers are bradycardia, hypotension, bronchospasm and acute cardiac insufficiency.

Treatment: In case of overdosage or hypersensitivity, the patient should be kept under close supervision and be treated in an intensive care ward. Blood glucose levels should be checked. Absorption of any medication residues still present in the gastro-intestinal tract can be prevented by gastric lavage and the administration of activated charcoal and a laxative. Artificial respiration may be required. Bradycardia or extensive vagal reactions should be treated by administering atropine or methylatropine.

Hypotension and shock should be treated with plasma/plasma substitutes and, if necessary, catecholamines. The beta-blocking effect can be counteracted by slow intravenous administration of isoprenaline hydrochloride, starting with a dose of approximately 5 μg/minute, or dobutamine, starting with a dose of 2.5 μg/minute, until the required effect has been obtained. In refractory cases isoprenaline can be combined with dopamine. If this does not produce the desired effect either, intravenous administration of glucagon 50-100 μg/kg i.v. may be considered. If required, the injection should be repeated within one hour, to be followed -if required- by an i.v. infusion of glucagon 70 μg/kg/h. In extreme cases of treatment-resistant bradycardia, a pacemaker may be inserted.

Pharmacodynamic interactions
The following interactions apply to beta-adrenergic antagonists in general.

Concomitant use not recommended:

Class I antiarrhythmics (quinidine, hydroquinidine, cibenzoline, flecainide, disopyramide, lidocaine, mexiletine, propafenone): Effect on atrio-ventricular conduction time may be potentiated and negative inotropic effect increased.

Calcium channel antagonists of verapamil/diltiazem type: Negative influence on contractility and atrio-ventricular conduction. Intravenous administration of verapamil in patients with ß-blocker treatment may lead to profound hypotension and atrio-ventricular block.

Centrally-acting antihypertensives (clonidine, guanfacin, moxonidine, methyldopa, rilmenidine): Concomitant use of centrally acting antihypertensive drugs may worsen heart failure by a decrease in the central sympathetic tonus (reduction of heart rate and cardiac output, vasodilation). Abrupt withdrawal, particularly if prior to beta-blocker discontinuation, may increase risk of elevation in blood pressure (rebound hypertension).

Combinations to be used with caution

Class III antiarrhythmic drugs (Amiodarone): Effect on atrio-ventricular conduction time may be potentiated.

Anaesthetics – volatile halogenated: Concomitant use of beta-adrenergic antagonists and anaesthetics may attenuate reflex tachycardia and increase the risk of hypotension. As a general rule, avoid sudden withdrawal of beta-blocker treatment. The anaesthesiologist should be informed when the patient is receiving nebivolol.

Insulin and oral antidiabetic drugs: Although nebivolol does not affect glucose level, concomitant use may mask certain symptoms of hypoglycaemia (palpitations, tachycardia).

Baclofen (antispastic myorelaxing agent), amifostine (antineoplastic adjunct): Concomitant use with antihypertensives is likely to increase the fall in blood pressure, therefore the dosage of the antihypertensive medication should be adjusted accordingly.

Combinations to be considered:

Digitalis glycosides: Concomitant use may increase atrio-ventricular conduction time. Clinical trials with nebivolol have not shown any clinical evidence of an interaction. Nebivolol does not influence the kinetics of digoxin.

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

Antipsychotics, antidepressants (tricyclics, barbiturates and phenothiazines): Concomitant use may enhance the hypothensive effect of the beta-blockers (additive effect).

Non-steroidal anti-inflammatory drugs (NSAID): No effect on the blood pressure lowering effect of nebivolol.

Sympathicomimetic agents: Concomitant use may counteract the effect of beta-adrenergic antagonists. Beta-adrenergic agents may lead to unopposed alpha-adrenergic activity of sympathicomimetic agents with both alpha- and beta-adrenergic effects (risk of hypertension, severe bradycardia and heart block).

Pharmacokinetic interactions
As nebivolol metabolism involves the CYP2D6 isoenzyme, co-administration with substances inhibiting this enzyme, especially paroxetine, fluoxetine, thioridazine and quinidine may lead to increased plasma levels of nebivolol associated with an increased risk of excessive bradycardia and adverse events. Co-administration of cimetidine increased the plasma levels of nebivolol, without changing the clinical effect. Co-administration of ranitidine did not affect the pharmacokinetics of nebivolol. Provided nebivolol is taken with the meal, and an antacid between meals, the two treatments can be co-prescribed.

Combining nebivolol with nicardipine slightly increased the plasma levels of both medications, without changing the clinical effect. Co-administration of alcohol, furosemide or hydrochlorothiazide did not affect the pharmacokinetics of nebivolol. Nebivolol does not affect the pharmacokinetics and pharmacodynamics of warfarin.

Inform your doctor about all medications you are taking. Consult your doctor before you start taking any medication during treatment with Nebivolol-NAN.

The following warnings and precautions apply to beta-adrenergic antagonists in general.

Anaesthesia
Continuation of beta-blockade reduces the risk of arrhythmias during induction and intubation. If beta-blockade is interrupted in preparation for surgery, the beta-adrenergic antagonist should be discontinued at least 24 hours beforehand.
Caution should be observed with certain anaesthetics that cause myocardial depression. The patient can be protected against vagal reactions by intravenous administration of atropine.

Cardiovascular
In general, beta-adrenergic antagonists should not be used in patients with untreated congestive heart failure, unless their condition has been stabilized.
In patients with ischaemic heart disease, treatment with a beta-adrenergic antagonist should be discontinued gradually, i.e., over 1-2 weeks. If necessary, replacement therapy should be initiated at the same time, to prevent exacerbation of angina pectoris.
Beta-adrenergic antagonists may induce bradycardia. If the pulse rate drops below 50-55 bpm at rest and/or the patient experiences symptoms that are suggestive of bradycardia, the dosage should be reduced.

Beta-adrenergic antagonists should be used with caution:

• in patients with peripheral circulatory disorders (Raynaud’s disease or syndrome, intermittent claudication), as aggravation of these disorders may occur;
• in patients with first degree heart block, because of the negative effect of beta-blockers on conduction time;
• in patients with Prinzmetal’s angina due to unopposed alphareceptor mediated coronary artery vasoconstriction: beta-adrenergic antagonists may increase the number and duration of anginal attacks.

Combination of nebivolol with calcium channel antagonists of the verapamil and diltiazem type, with Class I antiarrhythmic drugs, and with centrally acting antihypertensive medicinal products is generally not recommended (see Section Drug-to-drug interactions).

Metabolic/Endocrinological
Nebivolol does not affect glucose levels in diabetic patients. Care should be taken in diabetic patients however, as nebivolol may mask certain symptoms of hypoglycaemia (tachycardia, palpitations).
Beta-adrenergic blocking agents may mask tachycardic symptoms in hyperthyroidism. Abrupt withdrawal may intensify symptoms.

Respiratory
In patients with chronic obstructive pulmonary disorders, beta-adrenergic antagonists should be used with caution as airway constriction may be aggravated.

Other
Patients with a history of psoriasis should take beta-adrenergic antagonists only after careful consideration as they may increase the sensitivity to allergens and the severity of anaphylactic reactions.
The initiation of chronic heart failure treatment with nebivolol necessitates regular monitoring. Treatment discontinuation should not be done abruptly unless clearly indicated.

Auxiliary substances
Nebivolol-NAN contains lactose, so patients with rare hereditary problems of galactose intolerance, the Lapp-lactase deficiency or glucose-galactose malapsorption should not take Nebivolol-NAN.
Nebivolol-NAN contains sodium in an amount of less than 1 mmol (23 mg) / dose, i.e., practically “does not contain sodium”.

If you have one of the diseases or conditions listed above, be sure to consult your doctor before taking Nebivolol-NAN.

Pregnancy
Nebivolol has pharmacological effects that may cause harmful effects on pregnancy and/or the foetus/newborn. In general, beta-adrenoceptor blockers reduce placental perfusion, which has been associated with growth retardation, intrauterine death, abortion or early labour. Adverse effects (e.g., hypoglycaemia and bradycardia) may occur in the foetus and newborn infant. If treatment with beta-adrenoceptor blockers is necessary, beta1-selective adrenoceptor blockers are preferable.

Nebivolol should not be used during pregnancy unless clearly necessary. If treatment with nebivolol is considered necessary, the uteroplacental blood flow and the foetal growth should be monitored. In case of harmful effects on pregnancy or the foetus alternative treatment should be considered. The newborn infant must be closely monitored. Symptoms of hypoglycaemia and bradycardia are generally to be expected within the first 3 days.

Breast-feeding
Animal studies have shown that nebivolol is excreted in breast milk. It is not known whether nebivolol is excreted in human milk. Most beta-blockers, particularly lipophilic compounds like nebivolol and its active metabolites, pass into breast milk although to a variable extent. Therefore, mothers receiving nebivolol should not breast feed.

No studies on the effects on the ability to drive and use machines have been performed. Pharmacodynamic studies have shown that nebivolol does not affect psychomotor function. When driving vehicles or operating machines it should be taken into account that dizziness and fatigue may occasionally occur during antihypertensive treatment.

15 tablets in a blister made of PVC film as per GOST 25250-88 or three-layer film (PVC/PE/PVDC) as per CS-0500-2-037 and flexible packing based on aluminum foil as per TS 1811-002-45094918-97. 1 or 2 blisters with a patient information leaflet, packed in a carton.

Protect from light and moisture, at a temperature not above 25°C.
Keep away from children.

2 years. Do not use after the expiration date indicated on the packing.

State enterprise ACADEMPHARM
220141, 5/3 Kuprevicha Street, Minsk, Belarus,
Phone / Fax +375 17 268 63 64
production@academpharm.by
To report adverse reactions use the electronic application form on the manufacturer’s website: https://academpharm.by/en