Active ingredients: Nebivolol
NEBILOX 5 mg Tablets
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01.0 NAME OF THE MEDICINAL PRODUCT
NEBILOX 5 MG TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each NEBILOX tablet contains 5 mg of nebivolol (as nebivolol hydrochloride): 2.5 mg of SRRR-nebivolol (or d-nebivolol) and 2.5 mg of RSSS-nebivolol (or l-nebivolol).
Excipients with known effect: each tablet contains 141.75 mg of lactose monohydrate (see sections 4.4 and 6.1).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Tablet.
White, round, double-barred tablet. The tablet can be divided into four equal parts.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Hypertension
Treatment of essential hypertension.
Chronic heart failure
Treatment of stable mild and moderate chronic heart failure as an adjunct to standard therapies in elderly patients aged 70 years.
04.2 Posology and method of administration
Dosage
Hypertension
Adults
The dose is 1 tablet (5 mg) per day, preferably always at the same time. The antihypertensive effect is evident after 1-2 weeks of treatment. Occasionally the optimal effect is achieved only after 4 weeks of treatment.
Association with other antihypertensive drugs
Beta blockers can be used alone or in combination with other antihypertensive drugs. To date, an additional antihypertensive effect has been observed only by combining NEBILOX 5 mg with hydrochlorothiazide 12.5-25 mg.
Patients with renal insufficiency
In patients with renal insufficiency the recommended starting dose is 2.5 mg per day. If necessary, the daily dose can be increased to 5 mg.
Patients with hepatic insufficiency
There are limited data on the use of nebivolol in patients with hepatic insufficiency or hepatic impairment. Therefore the administration of NEBILOX in these patients is contraindicated.
Older people
In patients over the age of 65, the recommended starting dose is 2.5 mg per day. If necessary, the daily dose can be increased to 5 mg.
However, there are limited data regarding the use of nebivolol in patients over 75 years of age. Therefore the administration of nebivolol should be undertaken with caution and patients should be carefully monitored.
Pediatric population
The safety and efficacy of NEBILOX in children and adolescents aged below 18 years have not been established. No data are available. Therefore, use in children and adolescents is not recommended.
Chronic heart failure
Treatment of stable chronic heart failure should begin with a gradual increase in dosage until the optimal maintenance dose for the individual patient is achieved.
Patients must have stable chronic heart failure without exacerbations for the previous six weeks. It is recommended that the treating physician has experience in the treatment of chronic heart failure.
In patients being treated with cardiovascular drugs, including diuretics and / or digoxin and / or ACE inhibitors and / or angiotensin II antagonists, the dosage of these drugs should be stabilized during the previous two weeks before starting treatment with NEBILOX.
The initial dose increase should be done at 1-2 week intervals based on patient tolerability as follows: 1.25 mg nebivolol, to be increased to 2.5 mg nebivolol once daily, then to 5 mg once daily and 10 mg once daily thereafter.
The maximum recommended dose is 10 mg nebivolol once daily.
The initiation of therapy and any dose increase should take place under the supervision of an experienced physician for a period of at least two hours to ensure that the clinical condition (particularly with regard to blood pressure, heart rate, conduction disturbances, signs of deterioration heart failure) remain stable.
The maximum recommended dose may not be reached by all patients due to the occurrence of adverse effects. If necessary, the achieved dosage can also be gradually decreased and reintroduced appropriately.
During the titration phase, in case of worsening of heart failure or intolerance, it is first recommended to reduce the dose of nebivolol or to discontinue it immediately if necessary (in case of severe hypotension, worsening of heart failure with acute pulmonary edema, cardiogenic shock, symptomatic bradycardia or atrioventricular block).
Treatment of stable chronic heart failure with nebivolol is generally a long-term treatment.
Nebivolol treatment should not be stopped abruptly as this could lead to temporary worsening of heart failure. If an interruption is necessary, the dosage should be gradually reduced by halving the dose weekly.
Patients with renal insufficiency
No dosage adjustment is necessary in mild to moderate renal impairment, as titration to the maximum tolerated dose is individually adjusted. There is no experience in patients with severe renal impairment (serum creatinine 250micromol / L). Therefore, administration of nebivolol in these patients is not recommended.
Patients with hepatic insufficiency
There are limited data on the use of nebivolol in patients with hepatic insufficiency. Therefore, the administration of NEBILOX in these patients is contraindicated.
Older people
No dosage adjustment is necessary as titration to the maximum tolerated dose is adjusted individually.
Pediatric population
The safety and efficacy of NEBILOX in children and adolescents below 18 years of age have not been established. Therefore, use in children and adolescents is not recommended. No data are available.
Method of administration
Oral use.
The tablets can be taken with meals.
04.3 Contraindications
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
- Hepatic failure or impaired liver function
- Acute heart failure, cardiogenic shock or acute heart failure episodes requiring intravenous inotropic therapy.
Furthermore, as with other beta blockers, NEBILOX is contraindicated in case of
- sick sinus node, including sino-atrial block
- second and third degree heart block (without pacemaker)
- history of bronchospasm and bronchial asthma
- untreated pheochromocytoma
- metabolic acidosis
- bradycardia (heart rate
- hypotension (systolic blood pressure
- severe peripheral circulatory disorders
04.4 Special warnings and appropriate precautions for use
See also section 4.8 Undesirable effects.
The following warnings and precautions for use reflect those generally applicable to beta-adrenergic antagonist drugs.
Anesthesia
Maintaining beta blockade reduces the risk of arrhythmias during induction and intubation. If, in anticipation of surgery, it is decided to interrupt the beta receptor blockade, therapy with beta-adrenergic antagonists should be stopped at least 24 hours beforehand.
Particular care should be taken in the use of certain anesthetic drugs that cause myocardial depression. The patient can be protected against vagal reactions by intravenous administration of atropine.
Cardiovascular system
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 ischemic heart disease, treatment with beta-adrenergic antagonists should be discontinued gradually, i.e. over 1-2 weeks. If necessary, replacement therapy should be started at the same time to prevent an "exacerbation of" angina pectoris.
Beta adrenergic antagonists can induce bradycardia: if the heart rate falls below 50-55 bpm at rest and / or the patient exhibits symptoms attributable to bradycardia, the dosage should be reduced.
Beta adrenergic antagonists should be used with caution in:
- patients with peripheral circulatory diseases (Raynaud's syndrome or disease, intermittent claudication), as worsening of these disorders may occur;
- patients with first degree heart block due to the negative effect of beta-blockers on conduction time;
- patients with Prinzmetal's angina due to coronary vasoconstriction due to non-contrasted alpha-adrenergic stimulation: beta-adrenergic antagonists can increase the number and duration of angina attacks.
Administration of nebivolol in combination with calcium channel blockers of the verapamil and diltiazem type, with Class I antiarrhythmic drugs and centrally acting antihypertensive drugs is generally not recommended, for details see section 4.5.
Metabolism and the endocrine system
NEBILOX, in diabetic patients, does not interfere with blood sugar. However, it should be used with caution in diabetic patients as nebivolol can mask some symptoms of hypoglycemia (tachycardia, palpitations).
Beta-adrenergic antagonist drugs may mask the symptoms of tachycardia in hyperthyroidism. Abrupt discontinuation of treatment may intensify these symptoms.
Respiratory system
In patients with chronic obstructive pulmonary disorders beta-adrenergic antagonists should be used with caution as airway constriction may be aggravated.
Others
In patients with a history of psoriasis beta-adrenergic antagonists should only be administered after careful consideration.
Beta adrenergic antagonists may increase sensitivity to allergens and the severity of anaphylactic reactions.
Initiation of chronic heart failure treatment with nebivolol requires regular monitoring. For posology and method of administration, see section 4.2. Treatment should not be stopped abruptly unless explicitly indicated. For further information, see section 4.2.
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
04.5 Interactions with other medicinal products and other forms of interaction
Pharmacodynamic interactions:
The following interactions reflect those that are generally described for beta-adrenergic antagonists.
Combinations not recommended:
Class I antiarrhythmics (quinidine, hydroquinidine, cibenzoline, flecainide, disopyramide, lidocaine, mexiletine, propafenone): the effect on atrioventricular conduction time can be potentiated and the negative inotropic effect can be enhanced (see section 4.4.).
Calcium channel blockers such as verapamil / diltiazem: negative effect on contractility and atrioventricular conduction. Intravenous administration of verapamil in patients treated with beta blockers may lead to profound hypotension and atrioventricular block (see section 4.4).
Centrally acting antihypertensives (clonidine, guanfacine, moxonidine, methyldopa, rilmenidine): concomitant use of centrally acting antihypertensives may aggravate heart failure by decreasing central sympathetic tone (reduced heart rate and cardiac output, vasodilation) (see section 4.4). Sudden withdrawal, particularly if prior to discontinuation of the beta blocker, may increase the risk of "rebound arterial hypertension".
Combinations to be used with caution
Class III antiarrhythmics (amiodarone): it may potentiate the effect on atrioventricular conduction time.
Halogenated volatile anesthetics: concomitant use of beta-adrenergic antagonists and anesthetic drugs may attenuate reflex tachycardia and increase the risk of hypotension (see section 4.4). In general, abrupt discontinuation of beta-blocker treatment should be avoided.
The anesthetist should be informed about the patient's use of NEBILOX.
Insulin and oral antidiabetic drugs: although NEBILOX has no influence on glycaemia, concomitant use can mask certain symptoms of hypoglycemia (palpitations, tachycardia).
Baclofen (an antispasmodic agent), amifostine (in addition to antineoplastics ): concomitant use with antihypertensives may increase the fall in blood pressure, therefore the dosage of the antihypertensive drug should be adjusted accordingly.
Associations to be taken into consideration
Digitalis glycosides: concomitant use may increase atrioventricular conduction time. Clinical studies with nebivolol have provided no clinical evidence of interaction. Nebivolol has no effect on 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 increase in the risk of further deterioration of ventricular pump function cannot be excluded.
Antipsychotics, antidepressants (tricyclics, barbiturates and phenothiazines): concomitant use may potentiate the hypotensive effect of beta blockers (additive effect).
Non-steroidal anti-inflammatory drugs (NSAIDs): no interference on the hypotensive effect of nebivolol.
Sympathomimetic drugs: concomitant use may counteract the effect of beta-adrenergic antagonists. Beta adrenergic drugs can lead to non-counteracted alpha adrenergic activity of sympathomimetic drugs with both alpha and beta adrenergic effects (risk of hypertension, severe bradycardia and cardiac arrest).
Pharmacokinetic interactions:
Since the CYP2D6 isoenzyme is involved in the metabolism of nebivolol, concomitant administration of substances that inhibit this enzyme, particularly paroxetine, fluoxetine, thioridazine and quinidine, may lead to increased plasma levels of nebivolol, associated with an increased risk of excessive bradycardia and adverse events.
Concomitant administration of cimetidine increased the plasma levels of nebivolol without changing the clinical effect. Concomitant administration of ranitidine did not affect the pharmacokinetics of nebivolol.
If NEBILOX is taken during meals and antacid drugs are taken between meals, the two treatments can be prescribed at the same time.
The combination of nebivolol with nicardipine weakly increased the plasma levels of both drugs without changing the clinical effect.Concomitant intake of alcohol, furosemide or hydrochlorothiazide had no effect on the pharmacokinetics of nebivolol.
Nebivolol has no effect on the pharmacokinetics and pharmacodynamics of warfarin.
04.6 Pregnancy and lactation
Pregnancy
Nebivolol has pharmacological effects which may be harmful to pregnancy and / or the fetus / newborn. In general, beta blockers reduce placental perfusion and this has been associated with growth retardation, intrauterine death, miscarriage or premature birth. Adverse effects (e.g. hypoglycaemia and bradycardia) may occur in the fetus and neonate. If treatment with beta blockers is deemed necessary, selective beta1 blockers should be used.
Nebivolol should not be used during pregnancy unless absolutely necessary. If treatment with nebivolol is deemed necessary, uteroplacental blood flow and fetal growth should be monitored. In the case of harmful effects on pregnancy or the fetus alternative treatment should be considered. Newborns must be carefully monitored. Symptoms of hypoglycemia and bradycardia are usually expected in the first 3 days.
Feeding time
Animal studies have shown that nebivolol is excreted in breast milk. It is not known whether this drug is excreted in human breast milk.
Most beta blockers, particularly lipophilic compounds such as nebivolol and its active metabolites, pass into breast milk albeit in a variable manner. Breastfeeding is therefore not recommended during administration of nebivolol.
04.7 Effects on ability to drive and use machines
No studies on the ability to drive and use machines have been performed. Pharmacodynamic studies have shown that NEBILOX 5 mg has no effect on psychomotor function.
When driving vehicles or using machines it should be borne in mind that occasionally dizziness and fatigue may occur.
04.8 Undesirable effects
Adverse events are listed separately for hypertension and chronic heart failure due to the differences between the diseases.
Hypertension
The table below, grouped by system organ class and listed in order of frequency, lists the adverse reactions which are mostly mild or moderate in intensity.
In addition, the following adverse reactions may be observed with some beta-adrenergic antagonists: hallucinations, psychosis, confusion, cold / cyanotic extremities, Raynaud's phenomenon, dry eyes and oculo-mucocutaneous toxicity like practolol.
Reward cardiac chronic
Data on adverse reactions in patients with chronic heart failure are derived from a placebo-controlled clinical study involving 1067 patients treated with nebivolol and 1061 patients treated with placebo. In this study, a total of 449 nebivolol-treated patients (42.1%) compared with 334 patients in the placebo group (31.5%) reported at least possibly drug-related adverse reactions. The most commonly reported adverse reactions in nebivolol-treated patients were bradycardia and dizziness, both occurring in approximately 11% of patients. The corresponding frequency in placebo-treated patients was approximately 2% and 7%, respectively.
Adverse reactions (at least possibly drug related) considered specifically relevant in the treatment of chronic heart failure have been reported with the following incidences:
- Heart failure aggravated in 5.8% of nebivolol-treated patients compared with 5.2% of placebo-treated patients.
- Postural hypotension was reported in 2.1% of nebivolol-treated patients compared with 1.0% of placebo-treated patients.
- Drug intolerance occurred in 1.6% of nebivolol-treated patients compared with 0.8% of placebo-treated patients.
- First degree atrioventricular block occurred in 1.4% of patients treated with nebivolol compared to 0.9% of patients treated with placebo.
- Lower limb edema was reported by 1.0% of nebivolol-treated patients compared with 0.2% of placebo-treated patients.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "inidrizzo www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
There are no data on overdose with NEBILOX.
Symptoms
Symptoms of overdose with beta-blockers are: bradycardia, hypotension, bronchospasm and acute heart failure.
Treatment
In the event of an overdose or hypersensitivity the patient should be kept under close surveillance and should be treated in an intensive care unit. Blood glucose levels should be checked. Absorption of any drug residues still present in the gastrointestinal tract can be prevented by gastric lavage and 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 with catecholamines. The beta blocking effect can be counteracted by slow intravenous administration of isoprenaline hydrochloride, starting with a dose of about 5 microg / minute, or of dobutamine with an initial dose of 2.5 microg / minute until the effect is achieved. required. In refractory cases, isoprenaline may be associated with dopamine. If this does not produce the desired effect, intravenous administration of 50-100 microg / kg i.v. should be considered. of glucagon. If necessary, the injection must be repeated within one "hour to be followed - if necessary - by an IV infusion of glucagon 70 microg / kg / h. In extreme cases of treatment-resistant bradycardia, a pacemaker can be applied. .
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: beta blocker, selective.
ATC code C07AB12.
Nebivolol is a racemate of two enantiomers, SRRR-nebivolol (or d-nebivolol) and RSSS-nebivolol (or l-nebivolol). It is a drug with dual pharmacological activity:
- it is a competitive and selective antagonist of beta-receptors; this effect is attributed to the SRRR enantiomer (d-enantiomer).
- it has mild vasodilatory properties due to the interaction with the L-arginine / nitric oxide pathway.
Nebivolol given in single and repeated doses reduces heart rate and blood pressure, at rest and during exercise, in both normotensive and hypertensive patients.
The antihypertensive effect is maintained during chronic treatment.
At therapeutic doses, nebivolol is devoid of alpha-adrenergic antagonism.
Systemic vascular resistance decreases during acute and chronic treatment with nebivolol in hypertensive patients. The reduction in cardiac output at rest or under exertion can be contained, despite the reduction in heart rate, due to an increase in systolic output.
The clinical relevance of these haemodynamic differences relative to other beta-1 antagonists has not been fully established.
In hypertensive patients nebivolol increases the nitroxide-mediated vascular response to acetylcholine (Ach) which is reduced in patients with endothelial dysfunction.
In a placebo-controlled mortality-morbidity study in 2,128 patients aged 70 years (median age: 75.2 years) with stable chronic heart failure, with or without impairment of left ventricular ejection fraction (mean LVEF: 36 12.3%, with the following distribution: in 56% of LVEF patients less than 35%, in 25% of LVEF patients between 35% and 45% and in 19% of LVEF patients greater than 45%), followed for a mean period of 20 months, nebivolol, in addition to standard therapy, has been shown to significantly prolong the time interval until death or hospitalization from cardiovascular causes (primary efficacy endpoint) with a relative risk reduction of 14% ( absolute reduction: 4.2%). This risk reduction was evident after 6 months of treatment and was maintained for the entire duration of treatment (median duration: 18 months). The effect of nebivolol was independent of age, gender, or left ventricular ejection fraction of the study subjects. The all-cause benefit of mortality did not reach statistical significance compared to placebo (absolute reduction: 2.3%).
A decrease in sudden death cases was observed in patients treated with nebivolol (4.1% versus 6.6%, relative reduction of 38%).
Experimental in vitro and in vivo animal studies have shown that nebivolol is devoid of intrinsic sympathomimetic activity.
In vitro and in vivo experimental studies on animals have shown that nebivolol does not possess membrane stabilizing activity at pharmacological doses.
In healthy volunteers, nebivolol has no significant effect on maximal exercise capacity or endurance.
05.2 "Pharmacokinetic properties
Both enantiomers of nebivolol are rapidly absorbed after oral administration. Absorption of nebivolol is not affected by concomitant food intake; nebivolol can be taken with or without food.
Nebivolol is extensively metabolised, partly to active hydroxy metabolites. Nebivolol is metabolised via aromatic and alicyclic hydroxylation, N-dealkylation and glucuronidation with further formation of glucuronides of the hydroxy metabolites. The metabolism of nebivolol by aromatic hydroxylation is subject to CYP2D6 dependent oxidative genetic polymorphism. The oral bioavailability of nebivolol averages 12% in extensive metabolisers and is practically complete in poor metabolisers. At steady-state and at the same dose level, the peak plasma concentration of unchanged nebivolol is approximately 23-fold higher in poor metabolisers than in extensive metabolisers. When the sum of the concentrations of the parent drug and the active metabolites are considered, the difference in plasma concentrations at the peak is 1.3-1.4 times. Due to the variability in the rate of metabolism, the dose of NEBILOX must always be individually adapted to the needs of the individual patient: poor metabolisers, therefore, may require lower doses.
In rapid metabolisers, the elimination half-lives of the enantiomers of nebivolol average 10 hours. In slow metabolisers they are 3-5 times longer. In rapid metabolisers, plasma levels of the RSSS enantiomer are slightly higher than those of the SRRR enantiomer. In slow metabolisers this difference is greater. In rapid metabolisers, the elimination half-lives of hydroxymetabolites of both enantiomers average 24 hours and are approximately twice as long in subjects with slow metabolism.
In most subjects (extensive metabolisers) steady state is achieved within 24 hours for nebivolol and within a few days for the hydroxy metabolites.
Plasma concentrations are dose proportional in the range of 1 to 30 mg. The pharmacokinetics of nebivolol are not affected by age.
In plasma, both enantiomers of nebivolol are predominantly bound to albumin.
The plasma protein binding is 98.1% for SRRR-nebivolol and 97.9% for RSSS-nebivolol. After one week of administration, 38% of the dose is excreted in the urine and 48% in the faeces. The urinary excretion of unchanged nebivolol is less than 0.5% of the dose.
05.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of genotoxicity and carcinogenic potential.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Polysorbate 80, hypromellose, lactose monohydrate, corn starch, croscarmellose sodium, microcrystalline cellulose, colloidal anhydrous silica, magnesium stearate.
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
The tablets are supplied in blisters (PVC / Al). Packs of 7, 14, 28, 30, 50, 56, 90,100, 500 tablets
Not all pack sizes may be marketed
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
GlaxoSmithKline S.p.A. - Via A. Fleming 2 - Verona
Under license from Menarini International O.L. SA, 1, Avenue de la Gare, L-1611 Luxembourg
08.0 MARKETING AUTHORIZATION NUMBER
A.I.C. n. 032209013 - "5 mg tablets" 28 tablets in PVC / AL blister
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
First authorization: January 1997
Renewal 18 October 2010
