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Drug Details

NEBILET 5 mg tablets

• Drug Class Description
  Cardioselective b-blockers (beta- blockers).
• Generic Name
  Nebivolol
• Presentation
  Tablet. White, round, cross-scored tablet. The tablet can be divided in equal quarters.
• Description
  Each Nebilet 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: each tablet contains 141.75 mg of lactose monohydrate. Excipients: amongst others lactose monohydrate
• Indications
  

  Hypertension

  Treatment of essential hypertension. Chronic heart failure (CHF) Treatment of stable mild and moderate chronic heart failure in addition to standard therapies in elderly patients > 70 years.

• Adult Dosage
  

  Hypertension

  Adults

  The dose is one tablet (5 mg) daily, preferably at the same time of the day. Tablets may be taken with meals.

  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 Nebilet 5 mg is combined with hydrochlorothiazide 12.5-25 mg.

  Patients with renal insufficiency

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

  Patients with hepatic insufficiency

  Data in patients with hepatic insufficiency or impaired liver function are limited. Therefore the use of Nebilet in these patients is contra-indicated.

  Elderly

  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.

  Children and adolescents

  No studies have been conducted in children and adolescents. Therefore, use in children and adolescents is not recommended.

  Chronic heart failure (CHF)

  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 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 stabilised during the past two weeks prior to initiation of Nebilet 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.

  Tablets may be taken with meals.

  Patients with renal insufficiency

  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 250μmol/L). Therefore, the use of nebivolol in these patients is not recommended.

  Patients with hepatic insufficiency

  Data in patients with hepatic insufficiency are limited. Therefore the use of Nebilet in these patients is contra-indicated.

  Elderly

  No dose adjustment is required since uptitration to the maximum tolerated dose is individually adjusted.

  Children and adolescents

  No studies have been conducted in children and adolescents. Therefore, use in children and adolescents is not recommended.

• Child Dosage
  Not recommended.
• Elderly Dosage
  Initially 2.5mg daily, increase if necessary to 5mg daily.
• Contra Indications
  

  - Hypersensitivity to the active substance or to any of the excipients.

  - 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-blocking agents, Nebilet is contra-indicated in:

  • sick sinus syndrome, including sino-atrial block.

  • second and third degree heart block (without a pacemaker).

  • history of bronchospasm and bronchial asthma.

  • untreated phaeochromocytoma.

  • metabolic acidosis.

  • bradycardia (heart rate < 60 bpm prior to start therapy).

  • hypotension (systolic blood pressure < 90 mmHg).

  • severe peripheral circulatory disturbances.

• Special Precautions
  

  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 (CHF), unless their condition has been stabilised.

  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 drugs is generally not recommended.

  Metabolic/Endocrinological

  Nebilet 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.

  Beta-adrenergic antagonists may increase the sensitivity to allergens and the severity of anaphylactic reactions.

  The initiation of Chronic Heart Failure treatment with nebivolol necessitates regular monitoring.

  This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp-lactase deficiency or glucose-galactose malapsorption should not take this medicinal product.

• Interactions
  

  Pharmacodynamic interactions:

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

   

  Combinations 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 “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 Nebilet.

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

  Baclofen (antispastic 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, and 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 Nebilet 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 drugs, 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.

• Adverse Drug Reactions
  

  Adverse events are listed separately for hypertension and CHF because of differences in the background diseases.

  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:

  SYSTEM ORGAN CLASS	Common (1/100 to < 1/10)	Uncommon (1/1,000 to 1/100)	Very Rare (1/10,000)	Not Known
  Immune system disorders				angioneurotic oedema, hypersensitivity
  Psychiatric disorders		nightmares; depression
  Nervous system disorders	headache, dizziness, paraesthesia		syncope
  Eye disorders		impaired vision
  Cardiac disorders		bradycardia, heart failure, slowed AV conduction/AV-block
  Vascular disorders		hypotension, (increase of) intermittent claudication
  Respiratory, thoracic and mediastinal disorders	dyspnoea	bronchospasm
  Gastrointestinal disorders	constipation, nausea, diarrhoea	dyspepsia, flatulence, vomiting
  Skin and subcutaneous tissue disorders		pruritus, rash erythematous	psoriasis aggravated
  Reproductive system and breast disorders		impotence
  General disorders and administration site conditions	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 involving 1067 patients taking nebivolol and 1061 patients taking placebo. In this study, a total of 449 nebivolol patients (42.1%) reported at least possibly causally related adverse reactions compared to 334 placebo patients (31.5%). The most commonly reported adverse reactions in nebivolol patients were bradycardia and dizziness, both occurring in approximately 11% of patients. The corresponding frequencies among placebo patients were approximately 2% and 7%, respectively.

  The following incidences were reported for adverse reactions (at least possibly drug-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.

  - Drug intolerance 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.