BRAND NAME: Nebireb
INTERNATIONAL NONPROPRIETARY NAME:
Nebivolol
DRUG FORM: tablets 5 mg.
DESCRIPTION:
white or almost white color biconvex rounded tablets with a cross-shaped line on one side.
COMPOSITION:
1 tablet contains:
Active substance: Nebivolol – 5.0 mg (in a form of Nebivolol hydrochloride – 5.45 мг).
Excipients: microcrystalline cellulose, lactose monohydrate, corn starch, croscarmellose sodium, hypromellose, colloidal anhydrous silicon dioxide, magnesium stearate.
PHARMACOTHERAPEUTIC GROUP:
Selective β - adrenoreceptors agonists
ATC: С07АВ12
PHARMACOLOGICAL PROPERTIES:
PHARMACODYNAMICS:
Nebivolol is a mixture of two enantiomers, SRRR-Nebivolol (or D-Nebivolol) and RSSS-Nebivolol (or L-Nebivolol) and possesses the dual pharmacological action. Nebivolol is a competitive and selective β1-adrenergic receptor blocker: this effect is determined by SRRR-Nebivolol (or D-Nebivolol). Nebivolol also possesses mild vasodilating properties as a result of its exchange with L-arginine /nitric oxide.
Single and repeated doses of Nebivolol reduce heart rate and blood pressure both at rest and during exercises – in patients with normal blood pressure and in patients with hypertension. In a long-term treatment the hypotensive effect still persists.
α-adrenergic antagonism does not develop when the drug is used in therapeutic doses.
In patients with arterial hypertension systemic vascular resistance decreases when Nebivolol is used in short-term and long-term treatment. Despite the decrease in heart rate, the decrease in cardiac output at rest and during exercises is limited due to the increase in stroke volume. Clinical significance of these hemodynamic differences in comparison with other β-adrenergic receptor blockers has not been fully investigated yet.
In patients with hypertension Nebivolol increases the vascular response to acetylcholine mediated by nitrogen monoxide; in patients with endothelial dysfunction this response is reduced.
In placebo-controlled mortality-morbidity studies with 2128 patients aged ≥70 years old (at average age 75.2 y/o) suffered from the persistent chronic heart failure with a decrease in left ventricular ejection fraction (LVEF) or without it (mean LVEF 36 ± 12.3% with the following distribution: LVEF less than 35% in 56% of patients, LVEF 35% -45% in 25% of patients, LVEF higher than 45% in 19% of patients) which on average lasted for 20 months, Nebivolol, as an adjunct to standard therapy, significantly increased the time period before death or hospitalization due to cardiovascular disease (primary efficacy endpoint). The decrease in relative risk was 14% (absolute decrease - 4.2%). This reduction in risk was manifested after 6 months of treatment and remained so throughout the treatment period (on average - 18 months). Nebivolol effect was not related to age, sex or volume of left ventricular ejection fraction obtained in the study participants. The benefit of Nebivolol treatment in preventing death from any cause was statistically insignificant compared to placebo (absolute decrease - 2.3%).
Sudden death decrease in number was observed in patients treated with Nebivolol (4.1% versus 6.6%, relative decrease ratio 38%).
Animal studies in vitro and in vivo have shown that Nebivolol does not exhibit its own sympathomimetic activity; in pharmacological doses, it does not possess the membrane stabilizing effect.
In healthy research subjects Nebivolol did not significantly affect the potential of maximal physical activity or endurance.
Preclinical data based on generally accepted toxicity studies related to the genetic apparatus and carcinogenicity studies have not demonstrated any danger to humans.
PHARMACOKINETICS:
Following oral administration, both enantiomers of Nebivolol are absorbed rapidly. Food has no effect on Nebivolol absorption; so it can be taken with or without food.
Nebivolol undergoes comprehensive metabolism, partly followed by an active hydroxymetabolites formation. Nebivolol is metabolized by alicyclic and aromatic hydroxylation, N-dealkylation and glucuronidation; in addition, hydroxymetabolite glucuronides are formed. Nebivolol metabolism by aromatic hydroxylation depends on genetic oxidative polymorphism and CYP2D6.
Nebivolol oral dosage form bioavailability is, at average, 12% in individuals with a fast metabolism and is almost complete in those with a slow metabolism.
At a steady state and the same dosage plasma Cmax of unchanged Nebivolol in patients with a slow metabolism is approximately 23 times higher than in those with a fast metabolism. When analyzing the amount of unchanged substance and active metabolites, the difference in plasma Cmax is 1.3 - 1.4 times the value. Based on metabolic rate deviations, Nebivolol dose should always be adjusted to the patient individual needs: therefore, patients with a slow metabolism may require lower doses.
In patients with a rapid metabolism, at average, Nebivolol enantiomers half-life is 10 hours. In patients with a slow metabolism these value is 3-5 times higher. In patients with a rapid metabolism the RSSS enantiomer plasma concentration is slightly higher than that of the SRRR enantiomer. In patients with a slow metabolism this difference will be greater. In patients with a fast metabolism both hydroxymetabolites enantiomers half-life is 24 hours, on average, while in those with a slow metabolism these value will be approximately twice higher.
The steady state of Nebivolol plasma level in most patients (people with fast metabolism) is achieved within 24 hours, for hydroxymetabolites - in a few days period.
For Nebivolol dosage from 1 to 30 mg plasma concentration is dose-proportional. Age has no effect on Nebivolol pharmacokinetics.
In plasma both enantiomers are mainly bound to albumin. Plasma protein binding to SRRR-Nebivolol is 98.1%, and to RSSS-Nebivolol – 97.9%. In one week of the drug administration 38% of the dose is excreted through the kidneys and 48% with the feces. Renal excretion of unchanged Nebivolol is less than 0.5% of the dose intake.
INDICATION FOR USE
Nebireb is used for treatment:
- essential arterial hypertension;
- persistent chronic heart failure of mild to moderate severity as an addition to standard treatment in elderly patients ≥70 years.
DOSAGE AND ADMINISTRATION:
If you want to stop treatment with Nebireb
Always consult your doctor before you want to stop the treatment with Nebireb, whether you take it in case of high blood pressure or chronic heart failure.
You should not stop the treatment suddenly, as that could worsen your heart condition.
If it is necessary to stop treatment with Nebireb which is used in treatment of chronic heart failure, then the daily dose should be reduced gradually, reducing the dose by half with an interval of one week.
If you have any further questions about this drug product medical use, please ask your doctor or a pharmacist.
If you forgot to take Nebireb or took too little dose of it:
If you missed the next dose of the drug product then you should take it as soon as you remembered about it but with a little delay. If you took the missed dose almost at the time of the next dose, you should skip the missed dose and follow the previous dosing regimen, you should not double the dose to compensate for the missed dose.
Arterial hypertension
Adults:
One dose is 1 tablet (5 mg of Nebivolol) per day; it is advisable to take it always at the same time. The drug product can be taken together with a meal.
Antihypertensive effect is observed in 1-2 weeks of the treatment. An optimal effect sometimes might be achieved only in 4 weeks of the treatment.
Combination with other antihypertensive drugs:
Β-adrenergic receptor blockers can be used both as a monotherapy and in combination with other antihypertensive drugs. Until today an additional antihypertensive effect has been observed only in case of Nebivolol combination with 12.5 - 25 mg of hydrochlorothiazide.
Patients with renal failure:
For patients with renal failure the recommended initial dose is 2.5 mg per day. If necessary, the daily dose can be increased to 5 mg.
Patients with hepatic failure
Only limited data are available on the drug use in patients with hepatic failure or impaired liver function. For that reason, the use of Nebivolol in this group of patients is contraindicated.
Elderly patients:
In patients above 65 years old the recommended starting dose is 2.5 mg per day. If necessary, the daily dose can be increased to 5 mg. However, due to the lack of experience in this drug administration in patients above 75 years old, caution and careful monitoring is required when prescribed for this group of patients.
Children and adolescents:
Studies on the use of this drug in children and adolescents (under 18 years old) have not been conducted yet. For that reason, the use of Nebivolol in this group of patients is not recommended.
Chronic heart failure
The treatment of persistent chronic heart failure should begin with slow dose titration until the patient’s optimal maintenance dose is reached.
This drug product is prescribed for such patients in case they have persistent chronic heart failure without episodes of its acute decompensation during the last 6 weeks.
The attending doctor should have experience in chronic heart failure treatment.
In patients on other cardiovascular drugs therapy, including diuretics and/ or digoxin and/ or ACE inhibitors and/ or angiotensin II receptor antagonists, before starting the treatment with Nebivolol, the adjusted dose of these drugs should be stable for the last 2 weeks.
The initial dose titration should be carried out according to the following scheme, while maintaining intervals of one to two weeks and focusing on the patient's dose tolerance: 1.25 mg of Nebivolol once/day can be increased to 2.5 mg once/day then – up to 5 mg once/day and then – up to 10 mg once/day.
Maximum recommended dose is 10 mg of Nebivolol once a day.
At the beginning of the treatment and at each dose increase the patient should be under an experienced doctor supervision for at least 2 hours to make sure that the clinical condition remains stable (especially blood pressure, heart rate, conduction disorders and heart failure aggravation).
Side effects can result in failure to treat all patients with the highest recommended doses. If necessary, the already used dose can be gradually reduced or, accordingly, returned to an initial value again.
In case of heart failure aggravation or drug intolerance at the titration phase, it is firstly recommended to reduce the dose of Nebivolol or, if necessary, to stop it immediately (in case of severe hypotension, heart failure aggravated with acute pulmonary edema, cardiogenic shock development, symptomatic bradycardia or AV- blockade).
Generally, persistent chronic heart failure treatment with Nebivolol is a long-term treatment.
Nebivolol treatment should not be suddenly discontinued, as that may lead to the temporarily heart failure aggravation. If it is necessary to withdraw the drug, then the dose should be reduced gradually by half a week.
Patients with kidney failure:
Since the dose titration to the maximal tolerated dose should be carried out individually, its adjustment in patients with renal failure of mild to moderate severity is not required.
There is no experience of the drug treatment in patients with severe renal failure (serum creatinine ≥250 μmol/l). Therefore, Nebivolol administration in this group of patients is not recommended.
Patients with liver failure:
Only limited data are available on the drug use in patients with hepatic impairment. Therefore, Nebivolol administration in this group of patients is contraindicated.
Elderly patients:
As the dose titration to the maximal tolerated dose should be carried out individually, its adjustment in elderly patients is not required.
Children and adolescents:
Studies on the drug administration in children and adolescents (under 18 years old) have not been conducted yet. Therefore, Nebivolol administration in this group of patients is not recommended.
SIDE EFFECT
Adverse reactions are classified by frequency of occurrence: very often (≥1 / 10), often (≥1 / 100, <1/10), infrequently (≥1 / 1000, <1/100), rarely (≥1 / 10000, < 1/1000), very rare (<1/10 000) and unknown frequency (frequency that cannot be established according to the data available).
Adverse events in case of arterial hypertension and chronic heart failure are indicated separately due to differences in diseases determined these conditions.
Arterial hypertension
Side effects observed, in most cases represented in a form of mild to moderate severity, classified by organ systems and frequency, are listed below:
Immune system disorders: unknown frequency - angioedema, hypersensitivity.
Mental disorders: infrequently - nightmares, depression.
Nervous system disorders: often - headaches, dizziness, paresthesia; very rarely syncope.
Eye disorders: infrequently - visual disturbance.
Cardiac disorders: infrequently - bradycardia, heart failure, delayed atrioventricular conduction /AV block.
Vascular disorders: infrequently - hypotension, Charcot syndrome aggravation.
Respiratory system, chest and mediastinal organs disorders: often - dyspnea; infrequently - bronchospasm.
Gastrointestinal tract disorders: often - constipation, nausea, diarrhea; infrequently - dyspepsia, flatulence, vomiting.
Skin and subcutaneous tissue disorders: infrequently - itching, erythematous nature skin rash; very rare – psoriasis aggravation; unknown frequency - urticaria.
Genital organs and mammary glands disorders: infrequently - impotence.
General disorders and the injection site disorders: often - fatigue, edema.
In addition, the following side effects have been reported in case of some β-blockers administration: hallucinations, psychosis, confusion, extremities coldness/cyanosis, Raynaud's syndrome, dry eyes, and practolol-induced oculomucocutaneous syndrome.
Chronic heart failure
Data on side effects in chronic heart failure have been obtained in placebo-controlled clinical trials where 1,067 patients received Nebivolol and 1,061 patients received placebo. In this study a total of 449 patients taken Nebivolol (42.1%) and 334 patients taken placebo (31.5%) experienced adverse reactions, possibly drug-related. The most common side effects reported by patients taken Nebivolol were bradycardia and dizziness occurred in approximately 11% of the patients. The corresponding incidence in patients taken placebo was approximately 2% and 7%.
The following incidence of side effects, potentially related to the drug intake and considered as characteristic and significant in the chronic heart failure treatment has been reported:
- heart failure aggravation was observed in 5.8% of patients taken Nebivolol and in 5.2% of patients taken placebo;
- orthostatic hypotension occurred in 2.1% of patients taken Nebivolol and 1.0% of patients taken placebo;
- drug intolerance was observed in 1.6% of patients taken Nebivolol and 0.8% of patients taken placebo;
- Grade I AV block occurred in 1.4% of patients taken Nebivolol and 0.9% of patients taken placebo;
- the lower extremities edema occurred in 1.0% of patients taken Nebivolol and 0.2% of patients taken placebo.
Patients should be informed about the need to consult the doctor in case of any adverse reactions, including those not specified in this instruction.
Healthcare professionals are encouraged to send information about any suspected adverse reactions and drug inefficiencies to:
Republican Unitary Enterprise “Center for Expertise and Testing in Health Care”, 2a, Tovarishchensky lane, 220037, Republic of Belarus, e-mail: rcpl@rceth.by.
Interaction with other drug products
Pharmacodynamic drug Interactions
The following interactions are considered to be common for β-blockers.
Combined use is not recommended
Group I antiarrhythmic drugs (quinidine, hydroquinidine, cybenzoline, flecainide, disopyramide, lidocaine, mexiletine, propafenone): atrioventricular conduction effect may be potentiated and the negative inotropic effect may increase. Calcium antagonists such as verapamil/diltiazem: adverse effects on contractility and atrioventricular conduction. Intravenous administration of verapamil to patients taken β-blockers may lead to severe arterial hypotension and AV block.
Central-acting antihypertensive drugs (clonidine, guanfacine, moxonidine, methyldopa, rilmenidine): combined use with centrally acting antihypertensive drugs may - due to a decrease in the tone of the central sympathetic nervous system (decrease in heart rate and stroke volume, vasodilation) - lead to the heart failure aggravation. In case of sudden withdrawal, in particular, before the end of therapy with β-blockers, an increase in blood pressure (withdrawal syndrome) is possible.
When prescribed together, special care is required
Group III antiarrhythmic drugs (amiodarone): atrioventricular conduction effect can be potentiated.
Halogenated volatile anesthetics: Concomitant use of β-blockers and anesthetics may cause suppression of reflex tachycardia and increase the risk of hypotension. Sudden withdrawal of β-blocker therapy should always be avoided. Anesthesiologist should be informed, if the patient is on Nebivolol therapy
Insulin and oral antidiabetic drugs: Although Nebivolol does not affect the glucose level in combined use it may mask certain symptoms of hypoglycemia (palpitations, tachycardia).
When prescribed together, it is necessary to consider:
Digitalis group glycosides: when taken together, atrioventricular conductivity may be slowed down. However, clinical studies of Nebivolol found no indication of this interaction. Nebivolol does not affect the kinetics of digoxin.
Calcium antagonists such as dihydropyridine (such as amlodipine, felodipine, lacidipine, nifedipine, nicardipine, nimodipine, nitrendipine): Co-administration may increase the risk of hypotension. In patients with heart failure an increased risk of further impairment of ventricular pumping cannot be excluded. Antipsychotic, antidepressant drugs (tricyclic antidepressants, barbiturates and phenothiazine derivatives): when used together, the hypotensive effect of β-blockers can be enhanced due to cumulative effects. Non-steroidal anti-inflammatory drugs (NSAIDs): They have no influence on Nebivolol hypotensive effect.
Sympathomimetics: when used together, they can counteract the β-blockers activity. Active substances with β-adrenergic effect can lead to unimpeded α-adrenergic activity of sympathomimetics presented both α- and β-adrenergic effects (the risk of arterial hypertension development, severe bradycardia and heart block).
Pharmacokinetic drug interactions
Since the isoenzyme CYP2D6 is involved in Nebivolol metabolism, the combined use with drugs that inhibit this enzyme, in particular Paroxetine, Fluoxetine, Thioridazine and Quinidine, may increase Nebivolol plasma level in plasma and thus increase the risk of excessive bradycardia and other side effects.
Concomitant administration of Cimetidine increased Nebivolol plasma concentration, however, without change in clinical efficacy. Concomitant administration of ranitidine had no effect on Nebivolol pharmacokinetics.
Nebivolol when taken together with a meal and an antacid - taken between meals, they can be prescribed together.
Nebivolol combination with Nicardipine may slightly increase plasma concentration of both drugs without any change in clinical efficacy. Concurrently taken alcohol, furosemide or hydrochlorothiazide did not affect Nebivolol pharmacokinetics. Nebivolol does not affect pharmacokinetics and pharmacodynamics of Warfarin.
Contraindications
- hypersensitivity to the drug active substance or one of the other components;
- liver failure or decrease in liver function;
- acute heart attack, cardiogenic shock or episodes of cardiac decompensation that required i/v administration of active substances with an inotropic effect.
In addition, in case of other β-blockers administration, Nebireb is contraindicated in:
- sick sinus syndrome (sick-sinus-syndrome), including sinoauricular block;
- AV blockade of II and III degrees (without an artificial pacemaker);
- bronchospasm and bronchial asthma in history;
- untreated pheochromocytoma;
- metabolic acidosis;
- bradycardia (heart rate – less than 60 per minute before the treatment);
- arterial hypotension (systolic blood pressure <90 mm Hg);
- severe peripheral circulatory disorders.
Overdose
Overdose data are not available.
Symptoms: bradycardia, arterial hypotension, bronchospasm and acute heart failure.
Treatment: Continuous patient’s observation and treatment should be provided in an intensive care unit. Blood glucose monitoring is recommended. An active substance absorption in the gastrointestinal tract can be prevented by gastric lavage, charcoal and laxatives administration. Artificial ventilation of the lungs may be necessary. Atropine or Methylatropine administration is recommended to prevent bradycardia or increased vagotonia.
Hypotension and shock should be treated with plasma or plasma substitutes and, if necessary, catecholamines. The beta-blocking effect can be controlled by slow i/v/ administration of Isoprenaline hydrochloride, at initial dose of about 5 mcg/min or Dobutamine, at initial dose of 2.5 mcg/min, until the expected effect is achieved. In difficult cases Isoprenaline can be combined with Dopamine. If this measure does not lead to the desired effect, then you can add Glucagon i/v at the rate of 50-100 μg/kg. If necessary, the injection should be repeated within an hour and then, if necessary, an intravenous infusion of Glucagon should be carried out at the rate of 70 μg/kg/ h. In extreme cases with bradycardia resistant to therapy a pacemaker can be used.
Precautions
The following warnings and precautions are common for β-blockers.
Anesthesia:
Stable β-adrenergic receptor blockade reduces the risk of cardiac arrhythmias during anesthesia and intubation. In case of preparation for surgery when β-adrenergic receptors blockade should be stopped, then it should be canceled at least 24 hours before the surgery.
Caution is needed when using certain anesthetics that cause myocardial depression. Patient’s vagal reactions can be prevented with intravenous atropine infusion.
Heart and blood vessels:
In general, β-blockers should not be prescribed to patients with untreated heart failure until their condition has been stabilized.
In patients with ischemic heart disease, β-blocker therapy should be discontinued gradually, within 1-2 weeks period. If necessary – in order to prevent the exacerbation of angina pectoris - it is recommended to start the treatment simultaneously with substitute drugs.
Β-adrenergic receptor blockers can cause bradycardia. In case the pulse falls below 50-55 beats per minute at rest and/or the patient develops symptoms indicative for bradycardia, the dose should be reduced.
Β-adrenergic receptor blockers should be used with caution in:
- Patients with peripheral circulatory disorders (Raynaud's disease or Raynaud's syndrome, intermittent claudication), due to the exacerbation of these diseases may occur;
- Patients with 1st degree AV block due to the negative conduction effect of β-blockers;
- Patients with Prinzmetal angina – due to unhindered vasoconstriction of coronary arteries, mediated through α-adrenergic receptors: β-adrenergic receptor blockers can increase frequency and duration of angina attacks.
Nebivolol combination with calcium antagonists such as Verapamil and Diltiazem, group I antiarrhythmics, as well as with central-acting antihypertensive drugs is not recommended evidently.
Metabolism and endocrine system:
Nebivolol has no effect on glucose level in diabetic patients. However, care must be taken in patients with diabetes, as Nebivolol can mask certain symptoms of hypoglycemia (tachycardia, palpitations).
In case of thyroid gland hyperfunction, β-blockers can mask such a symptom as tachycardia. In a sudden therapy withdrawal these symptoms may worsen.
Respiratory tract:
In patients with a chronic obstructive pulmonary disease β-blockers should be used with caution as airway constriction may develop.
Other:
Patients with a history of psoriasis should be prescribed β-blockers only after the situation has been properly analyzed.
Β-adrenergic receptor blockers can increase sensitivity to allergens and severity of anaphylactic reactions.
Regular Patient Monitoring is required at the beginning of chronic heart failure treatment with Nebivolol. Do not stop the treatment suddenly unless it required urgently.
This drug product contains lactose. Patients with rare congenital galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this drug product.
Use in pregnancy and lactation
In pregnancy
Nebivolol possesses pharmacological effects that can have adverse effects on pregnancy and /or the fetus and newborn. In general, β-blockers are believed to decrease blood flow in placenta associated with growth retardation, intrauterine death, miscarriage and premature contractions. Adverse events such as hypoglycemia and bradycardia may occur in a fetus and a newborn baby. In case of β-blockers treatment needed, the preference should be given to β1-selective β-blockers.
Nebivolol should only be used during pregnancy when it is absolutely necessary. If Nebivolol treatment is considered necessary, uteroplacental blood flow and fetal growth monitoring should be carried out. When harmful effect on pregnancy or on the fetus has been established then it is necessary to consider treatment with alternative drugs. Newborns should be closely monitored. Symptoms such as hypoglycemia and bradycardia can be expected in most cases within the first 3 days.
In breastfeeding
Experiments in animals have shown that Nebivolol passes into breast milk. It is not known whether this process can also be observed in humans. Most β-adrenergic receptor blockers, especially lipophilic compounds such as Nebivolol and its active metabolites, pass, although to a different degree, into breast milk. Therefore, breastfeeding is not recommended during treatment with Nebivolol.
Ability to drive and work with mechanisms
No studies have been conducted on Nebivolol effect on ability to drive and work with machinery. Pharmacodynamic studies have shown that Nebivolol has no effect on psychomotor function. When driving a car or work with machinery, it should be borne in mind that dizziness and fatigue may occur.
Storage conditions and Shelf-life
Store at temperatures not above 25°C
Keep out of reach of children!
Shelf life - 3 years
Do not use after expiry date printed on the package.
Prescription status
On prescription
Package
14 tablets in a blister strip made of polyvinyl chloride and flexible aluminum foil packaging.
2 blisters placed into a cardboard box together with a patient leaflet.
Manufacturer Information
Foreign production and trade unitary enterprise “Reb-Pharma”, 223216, Republic of Belarus, Minsk region, Chervensky district, Smilovichi, Sadovaya St., 1, tel./fax: (+375) 17 240 26 35,
Comment type is not specified in the component properties.