What is this medicine used for?
NicarlolÒ is indicated for:
Treatment of idiopathic hypertension.
Treatment of stable mild and moderate heart failure in addition to standard therapies in elderly patients aged 70 years and older.
How to take this medicine and how much to take?
Administration:
NicarlolÒ tablets may be taken with meals, preferably at the same time of the day.
Dosage:
Hypertension:
The usual dose is 5mg daily, preferably taken at the same time of the day.
In elderly patients and patients with renal failure, a lower starting dose may be required.
Dosage is individualized to patient tolerance.
The therapeutic effect on blood pressure becomes evident after 1-2 weeks of treatment. Occasionally, the optimal effect is reached only after 4 weeks.
Treatment of chronic heart failure:
Your treatment will be started and closely supervised by an experienced physician.
The usual initial dose is 1.25mg (half a tablet 2.5mg) daily. This may be increased after 1-2 weeks to 1 tablet of 2.5mg daily and then to 1 tablet of 5mg daily (1 tablet of 5mg daily and 2 tablets of 2.5mg daily) until the treatment dose is reached.
The maximum recommended dose is 10mg nebivolol once daily.
Appropriate dose should be prescribed individually and you must follow the doctor’s instructions.
You will need to be under the close supervision for at least 2 hours by an experienced physician when you start treatment and every time your dose is increased.
Your doctor may reduce the dose if necessary.
You should not stop the treatment abruptly as this can make your heart failure worse.
When should you not take this medicine?
NicarlolÒ tablets are contraindicated if:
You are hypersensitivity to nebivolol or any excipients of the product.
You have liver insufficiency or liver function impairment.
You have acute heart failure, cardiogenic shock or episodes of heart failure decompensation requiring I.V. inotropic therapy.
You are suffering from sick sinus syndrome, including sino-atrial block.
You have second and third degree heart block (without a pacemaker).
You have history of bronchospasm and bronchial asthma.
You are suffering from untreated phaeochromocytoma.
You have metabolic acidosis.
You have bradycardia (heart rate < 60bpm prior to start of therapy).
You have hypotension (systolic blood pressure < 90mmHg).
You have severe peripheral circulatory disturbances.
Adverse drug reactions (ADR):
Like all medicines, this medicine can cause side effects although not everybody experiences them.
Common (1/100 ≤ ADR <1/10):
Nervous system disorders: Headache, dizziness, paresthesia.
Respiratory, thoracic and mediastinal disorders: Dyspnea.
Digestive disorders: Constipation, nausea, diarrhea.
General disorder: Fatigue, edema.
If you experience any side effects including those not listed above, inform your doctor immediately to get in time treatment (see Undesirable effects in the Medication guide for healthcare professionals in this package insert).
What other medicines or foods should be avoided while taking this medicine?
Before taking this medicine, tell your doctor all the other medicines you are taking or have recently taken, including prescription and non-prescription, herbal medicines or functional foods, especially the following medicines:
Medicines used for the treatment of high blood pressure or cardiovascular disease (amiodarone, amlodipine, cibenzolin, clonidine, digoxin, diltiazem, disopyramid, felodipine, flecainide, guanfacin, hydroquinidine, lacidipine, lidocaine, methyldopa, mexiletin, moxonidine, nicardipine, nifedipine, nimodipine, nitrendipin, propafenone, quinidine, rilmenidine, verapamil).
Sedatives: Barbiturate, phenothiazine and thioridazine.
Antidepressant drugs: Amitriptyline, paroxetine, fluoxetine.
Anaesthesia drugs during surgery.
Medicines used to treat asthma, blocked nose or certain eye disorders such as glaucoma (increased pressure in the eye) or dilation (widening) of the pupil.
Baclofen (used for the treatment of spastic movement), amifostine (used to treat cancer): These medications when given with nebivolol can affect blood pressure and/or cardiac function.
Medicines used for the treatment of excessive stomach acid or peptic ulcers (antacid drug), e.g. cimitedine: you should take NicarlolÒ during a meal and antacid drugs between meals.
This list is not complete and other drugs may interact with nebivolol. Tell your doctor about all the medicines you are using. Do not use a new medication without telling your doctor.
What should you do if you miss a dose?
Take the missed dose as soon as you remember. If the dose is close to the next dose, skip the missed dose and go back to your regular dosing schedule. Do not take a double dose at once. Do not change the dose or discontinue the medication without your doctor’s advice.
How should you keep this medicine?
Store the medicine below 300C, protect from light and humidity.
Signs and symptoms of over dosage:
Symptoms of overdose of nebivolol are similar to beta-blockers, such as bradycardia, hypotension, bronchospasm, acute cardiac insufficiency.
What to do when you have taken more than the recommended dosage?
Call your doctor or immediately go to the nearest health care facility.
Care that should be taken when taking this medicine?
Conditions where caution should be taken.
Before taking this medicine, tell your doctor if you have any of the following conditions:
You are pregnant, plan to become pregnant, or are breastfeeding.
You have any liver, kidney, respiratory and cardiovascular problems.
You are taking other medicines that may result in hypotension.
You have skin diseases such as psoriasis.
You have asthma, blocked nose.
You have epilepsy.
You have diabetes.
You have stomach pain.
You are taking a muscle relaxant or receiving cancer treatment.
This medicine contains lactose. If you have rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, you should not take this medicine.
Recommendation during pregnancy and lactation:
Pregnancy:
Nebivolol has pharmacological effects that may cause harmful effects on pregnancy and/or the foetus/newborn. Nebivolol should not be used during pregnancy unless clearly necessary. If treatment with nebivolol is considered necessary, the uteroplacental blood flow and foetal growth should be monitored.
Lactation:
It is not known whether this drug is excreted into human milk. Therefore, breast feeding in not recommended during administration of nebivolol.
Effects on ability to drive and use machines:
Nebivolol may cause tiredness and/or dizziness and if you are affected you should not drive or use any machines.
When should you consult your doctor?
You are using other drugs, including prescription and non-prescription, herbal medicines or functional foods.
You are pregnant, plan to become pregnant or breastfeeding.
You have had an allergic reaction to the drug.
You have a history of respiratory, heart, liver, kidney disease.
You are taking other medicines that may result in hypotension.
If you want or need to stop taking this medicine.
For further information, please consult your doctor or pharmacist.
Shelf-life: 36 months from the date of manufacture.
MEDICATION GUIDE FOR HEALTHCARE PROFESSIONALS
Pharmacological properties:
Pharmacodynamic properties:
Nebivolol is a racemate of two enantiomers, SRRR-nebivolol (or d-nebivolol) and RSSS-nebivolol (or l-nebivolol). The drug combines both pharmacological effects: The effect of nebivolol is the combination of two pharmacological effects:
Nebivolol is a competitive and selective beta-receptor antagonist, due to the SRRR-enatiomer (d-enantiomer).
Nebivolol has mild vasodilating properties due to an interaction with the L-arginine/nitric oxide pathway.
Pharmacokinetic properties:
Absorption:
Both nebivolol enantiomers are rapidly absorbed after oral administration. The absorption of nebivolol is not affected by food; therefore, it can be given with or without meals.
The oral bioavailability of nebivolol averages 12% in fast metabolizing patients and is virtually complete in slow metabolisers. At steady state and at the same dose level, the peak plasma concentration of unchanged nebivolol is about 23 times higher in poor metabolisers than in extensive metabolisers. When unchanged drug plus active metabolites are considered, the difference in peak plasma concentrations is 1.3 to 1.4 fold. Because of the variation in rates of metabolism, the dose of nebivolol should always be adjusted to the individual requirements of the patient: Poor metabolisers may require lower doses.
Plasma concentrations are dose-proportional between 1 and 30 mg. The pharmacokinetics of nebivolol are not affected by age.
Distribution:
Steady-state plasma levels in most subjects (fast metabolisers) are reached within 24 hours for nebivolol and within a few days for the hydroxy-metabolites. In plasma, both enantiomers of nebivolol are mostly combined with albumin. Plasma protein binding is 98.1% for SRRR-nebivolol and 97.9% for RSSS-nebivolol.
Metabolism:
Nebivolol is extensively metabolised, partly to active hydroxy-metabolites. Nebivolol is metabolised via alicyclic and aromatic hydroxylation, N-dealkylation and glucuronidation. In addition, glucuronides of the hydroxy-metabolites are formed. The metabolism of nebivolol by aromatic hydroxylation is subject to the CYP2D6 dependent genetic oxidative polymorphism.
The oral bioavailability of nebivolol averages 12% in fast metabolizing patients and is virtually complete in slow metabolisers.
Elimination:
Because of the variation in rates of metabolism, the dose of nebivolol should always be adjusted to the individual requirements of the patient: Poor metabolisers may require lower doses. In fast metabolisers, elimination half-lives of the nebivolol enantiomers average 10 hours. In slow metabolisers, they are 3-5 times longer. In fast metabolisers, elimination half-lives of the hydroxymetabolites of both enantiomers average 24 hours, and are about twice as long in slow metabolisers.
One week after administration, 38% of the dose is excreted in the urine and 48% in the faeces. Urinary excretion of unchanged nebivolol is less than 0.5% of the dose.
Indications, dosage, administration, contraindications:
Indications:
NicarlolÒ is indicated for:
Treatment of idiopathic hypertension.
Treatment of stable mild and moderate heart failure in addition to standard therapies in elderly patients aged 70 years and older.
Dosage:
Hypertension:
Adults:
The usual dose is 5mg daily, preferably taken at the same time of the day.
The therapeutic effect on blood pressure becomes evident after 1-2 weeks of treatment. Occasionally, the optimal effect is reached only after 4 weeks.
Combination with other antihypertensive drugs:
Beta-blockers can be used alone or concomitantly with other antihypertensive agents. To date, an additional antihypertensive effect has been observed only when NicarlolÒ tablets are combined with hydrochlorothiazide 12.5mg-25mg.
Patients with renal insufficiency:
The recommended starting dose for patients with renal insufficiency is 2.5mg daily. If needed, the daily dose may be increased to 5mg.
Patients with hepatic insufficiency:
Data in patients with hepatic insufficiency or impaired liver function are limited. Therefore, the use of nebivolol in these patients is contraindicated.
Elderly:
In patients over 65 years, the recommended starting dose is 2.5mg daily. If needed, the daily dose may be increased to 5mg. However, in view of the limited experience in patients above 75 years, caution must be exercised and these patients should be monitored closely.
Children:
The safety and efficacy of nebivolol in children and adolescents under 18 years of age has not been established. Therefore, nebivolol is not recommended for use in children under the age of 18 years due to a lack of data on safety and efficacy.
Chronic heart failure (CHF):
The use of nebivolol for treatment of stable chronic heart failure should involve a gradual increase 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 ACE inhibitors and/or angiotensin II antagonists, these drugs should be maintained at a stable dose for the two weeks leading up to initiation of nebivolol treatment.
The dose should be increased from the initial dose of 1.25mg daily to 2.5mg and then to 5mg daily and then 10mg daily at intervals of 1-2 weeks based on patient tolerability.
The maximum recommended dose is 10mg nebivolol once daily.
The initiation of therapy and all increases in dose should be carried out under the supervision of an experienced physician over a period of at least 2 hours to ensure that the clinical status (especially blood pressure, heart rate, conduction disturbances, signs of worsening heart failure) remains stable.
The occurrence of adverse events may prevent 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 initial dose increasing 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 worsening of heart failure. If discontinuation is necessary, the dose should be decreased step-wise weekly.
Patients with renal insufficiency:
No dose adjustment is required in mild to moderate renal insufficiency since up-titration 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 or impaired hepatic function are limited. Therefore, the use of nebivolol in these patients is contraindicated.
Elderly
No dose adjustment is required since up-titration to the maximum tolerated dose is individually adjusted.
Children and adolescents:
Nebivolol is not recommended for use in children under the age of 18 years due to a lack of data on safety and efficacy.
Administration: NicarlolÒ tablets should be taken preferably at the same time of the day with or without food.
Contraindications:
Hypersensitivity to nebivolol or any excipients of the product.
Liver insufficiency or liver function impairment.
Acute heart failure, cardiogenic shock or episodes of heart failure decompensation requiring I.V. inotropic therapy.
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 of therapy).
Hypotension (systolic blood pressure < 90mmHg).
Severe peripheral circulatory disturbances.
Special warnings and precautions for use:
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 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 suggestive of bradycardia, the dosage should be reduced.
Beta-adrenergic antagonists should be used with caution in the following conditions:
– Peripheral circulatory disorders (Raynaud’s disease or syndrome, intermittent claudication), as aggravation of these disorders may occur upon use of beta blockers.
– First degree heart block, because of the negative effect of beta-blockers on conduction time.
– Prinzmetal’s angina due to unopposed alpha-receptor mediated coronary artery vasoconstriction, beta-adrenergic antagonists may increase the number and duration of anginal attacks.
Metabolic/endocrinological:
Nebivolol does not affect glucose levels in diabetic patients. However, care should be taken in diabetic patients, as nebivolol may mask certain symptoms of hypoglycaemia (tachycardia, palpitations). Beta-adrenergic blocking agents may mask tachycardic symptoms in hyperthyroidism. Abrupt withdrawal may aggravate symptoms.
Other:
This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Caution should be exercised when treating patients with a history of psoriasis with beta-adrenergic antagonists as they may increase the sensitivity to allergens and the severity of anaphylactic reactions.
The initiation of CHF treatment with nebivolol necessitates regular monitoring. Treatment discontinuation should not be done abruptly unless clearly indicated.
Recommendation during pregnancy and lactation:
Pregnancy:
Nebivolol has pharmacological effects that may cause harmful effects on pregnancy and/or the foetus/newborn. In general, beta-blockers reduce placental profusion, 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-adrenoreceptor blockers is necessary, beta-1 selective adrenoreceptor 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 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 in the first 3 days.
Lactation:
Animal studies have shown that nebivolol is excreted in breast milk. It is not known whether this drug is excreted into human milk. Most beta-blockers, particularly lipophilic compounds like nebivolol and its active metabolites, pass into breast milk although to a variable extent. Breast feeding in not recommended during administration of nebivolol.
Effects on ability to drive and use machines:
Headache, dizziness may occasionally occur during the treatment with nebivolol. Therefore, caution should be taken when driving vehicles or operating machines.
Interaction with other medicinal products and other forms of interactions:
Pharmacodynamic interactions:
The following interactions are common to the beta blockade group:
Combinations that are not recommended:
Class I anti-arrhythmics (quinidine, hydroquinidine, cibenzoline, flecainide, disopyramide, lidocaine, mexiletine, propafenone): Effect on atrio-ventricular conduction time may be potentiated and the 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 used with caution:
Class III anti-arrhythmic drugs (amiodarone): Effect on atrio-ventricular conduction time may be potentiated.
Volatile halogenated anaesthetics: Concomitant use of beta-adrenergic antagonists and anaesthetics may attenuate reflex tachycardia and increase the risk of hypotension. For a general rule, sudden withdrawal of beta-blocker treatment should be avoided. The anaesthesiologist should be informed when the patient is receiving Nicarlol tablets.
Insulin and oral anti-diabetic drugs: Although nebivolol does not affect glucose levels, concomitant use may mask symptoms of hypoglycaemia (palpitations, tachycardia).
Baclofen (antispastic agent), amifostine (antineoplastic adjunt): 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 used only after careful consideration:
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 pharmacokinetics 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 and antidepressants (tricyclics, barbiturates and phenotiazines): Concomitant use may enhance the hypotensive effect of the beta-blockers (additive effect).
Nonsteroidal anti-inflammatory drugs (NSAIDs) have no effect on the blood pressure lowering effect of nebivolol.
Sympathomimetic agents: Concomitant use may counteract the effect of beta-adrenergic antagonists. Beta-adrenergic agents may lead to unopposed alpha-adrenergic activity of sympathomimetic 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 other adverse events.
Co-administration of nebivolol with cimetidine increased the plasma levels of nebivolol, without changing the clinical effect.
Co-administration of nebivolol with 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 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.
Undesirable effects:
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.
| 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 | 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 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 compares to 5.2% of the placebo patients.
Orthostatic hypotension was reported in 2.1% of nebivolol patients compared to 1.0% of placebo patients.
Drug intolerance occurred in 1.6% of the nebivolol patients compared to 0.8% of the 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 in 1.0% of nebivolol patients compared to 0.2% of placebo patients.
Inform your doctor or pharmacist about adverse reactions encountered while using this medication.
Overdose and management:
Symptoms: Symptoms of overdose with beta-adrenergic antagonists include bradycardia, hypotension, bronchospasm and acute cardiac insufficiency.
Treatment
In case of overdose or hypersensitivity to nebivolol, the patient should be transfered to healthcare facility for special care and treatment. Blood glucose levels should be checked. Absorption of any drug 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 should be used. 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.
