Nebiloc CCB

Nebivolol hydrochloride, amlodipine besilate.

Each tablet contains: 5 mg/5 mg tab: Nebivolol (as hydrochloride) 5 mg and Amlodipine (as besilate), BP 5 mg.
5 mg/10 mg tab: Nebivolol (as hydrochloride) 5 mg and Amlodipine (as besilate), BP 10 mg.

Pharmacology: Pharmacodynamics: Nebivolol: Nebivolol is a racemate of two enantiomers, SRRR-nebivolol (or d-nebivolol) and RSSS-nebivolol (or l-nebivolol). It combines two pharmacological activities: It is a competitive and selective beta-receptor antagonist: this effect is attributed to the SRRR-enantiomer (d-enantiomer).
It has mild vasodilating properties due to an interaction with the L-arginine/nitric oxide pathway.
Single and repeated doses of nebivolol reduce heart rate and blood pressure at rest and during exercise, both in normotensive subjects and in hypertensive patients. The antihypertensive effect is maintained during chronic treatment.
At therapeutic doses, nebivolol is devoid of alpha-adrenergic antagonism.
In hypertensive patients, nebivolol increases the NO-mediated vascular response to acetylcholine (ACh) which is reduced in patients with endothelial dysfunction.
In vitro and in vivo experiments in animals showed that Nebivolol has no intrinsic sympathomimetic activity.
In vitro and in vivo experiments in animals showed that at pharmacological doses nebivolol has no membrane stabilising action.
In healthy volunteers, nebivolol has no significant effect on maximal exercise capacity or endurance.
Available preclinical and clinical evidence in hypertensive patients has not shown that nebivolol has a detrimental effect on erectile function.
Amlodipine: Amlodipine is a calcium ion influx inhibitor of the dihydropyridine group (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle.
The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle. The precise mechanism by which amlodipine relieves angina has not been fully determined but amlodipine reduces total ischaemic burden by the following two actions: Amlodipine dilates peripheral arterioles and thus, reduces the total peripheral resistance (afterload) against which the heart works. Since the heart rate remains stable, this unloading of the heart reduces myocardial energy consumption and oxygen requirements.
The mechanism of action of amlodipine also probably involves dilatation of the main coronary arteries and coronary arterioles, both in normal and ischaemic regions. This dilatation increases myocardial oxygen delivery in patients with coronary artery spasm (Prinzmetal's or variant angina).
In patients with hypertension, once daily dosing provides clinically significant reductions of blood pressure in both the supine and standing positions throughout the 24 hour interval. Due to the slow onset of action, acute hypotension is not a feature of amlodipine administration.
In patients with angina, once daily administration of amlodipine increases total exercise time, time to angina onset, and time to 1mm ST segment depression, and decreases both angina attack frequency and glyceryl trinitrate tablet consumption.
Amlodipine has not been associated with any adverse metabolic effects or changes in plasma lipids and is suitable for use in patients with asthma, diabetes, and gout.
Pharmacokinetics: Nebivolol: Both nebivolol enantiomers are rapidly absorbed after oral administration. The absorption of nebivolol is not affected by food; nebivolol can be given with or without meals.
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 metabolisers 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 therefore 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, plasma levels of the RSSS-enantiomer are slightly higher than for the SRRR-enantiomer. In slow metabolisers, this difference is larger. In fast metabolisers, elimination half-lives of the hydroxymetabolites of both enantiomers average 24 hours, and are about twice as long in slow metabolisers.
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.
Plasma concentrations are dose-proportional between 1 and 30 mg. The pharmacokinetics of nebivolol are not affected by age.
In plasma, both nebivolol enantiomers are predominantly bound to albumin.
Plasma protein binding is 98.1% for SRRR-nebivolol and 97.9% for RSSS-nebivolol.
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.
Amlodipine: Absorption distribution plasma protein binding: After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6-12 hours post dose. Absolute bioavailability has been estimated to be between 64 and 80%. The volume of distribution is approximately 21 l/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.
The bioavailability of amlodipine is not affected by food intake.
Biotransformation/elimination: The terminal plasma elimination half-life is about 35-50 hours and is consistent with once daily dosing. Amlodipine is extensively metabolised by the liver to inactive metabolites with 10% of the parent compound and 60% of metabolites excreted in the urine.

Nebivolol plus Amlodipine is indicated for the treatment of essential hypertension and the treatment of chronic stable angina.

Hypertension and Chronic Stable Angina: Adults: The usual dosage is one 5mg/5mg tablet, with or without food, once a day. The maximum daily dose should not exceed 5mg/10mg once daily.
Elderly: In patients over 65 years of age, the recommended starting dose is one 2.5mg/5mg tablet daily. The dose may be upward titrated to 5mg/10mg if needed.
Or as prescribed by the physician.
Patients with renal Impairment: No dosage adjustment is required in patients with mild to moderate renal impairment. In patients with severe renal impairment (ClCr < 30 mL/min) the recommended starting dose is 2.5mg/5mg once daily. If needed, upward titration should be performed cautiously.
Patients with hepatic disease: In patients with moderate hepatic impairment (Child-Pugh B), the recommended starting dose is 2.5mg/5mg once daily. If needed, the dosage should be upward titrated cautiously. Nebivolol and Amlodipine have not been studied in patients with severe hepatic impairment and therefore the fixed dose combination of Nebivolol plus Amlodipine is not recommended in patients with this condition.
Children and Adolescents: No studies have been conducted in children and adolescents. Therefore, use in children and adolescents is not recommended.
CYP2D6 Polymorphism: Dose adjustments are not necessary for patients who are CYP2D6 poor metabolizers. The clinical effect and safety profile observed in poor metabolizers were similar to those of extensive metabolizers.

Nebivolol: No data are available on overdosage with Nebivolol.
Symptoms: Symptoms of overdosage with beta-blockers are: bradycardia, hypotension, bronchospasm and acute cardiac insufficiency.
Treatment: In case of overdosage or hypersensitivity, the patient should be kept under close supervision and be treated in an intensive care ward. Blood glucose levels should be checked. Absorption of any 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. 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.
Amlodipine: In humans, experience with intentional overdose is limited.
Symptoms: Available data suggest that gross overdosage could result in excessive peripheral vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported.
Treatment: Administration of activated charcoal to healthy volunteers immediately or up to two hours after ingestion of amlodipine 10mg has been shown to significantly decrease amlodipine absorption.
Gastric lavage may be worthwhile in some cases. Clinically significant hypotension due to amlodipine overdosage calls for active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of extremities, and attention to circulating fluid volume and urine output. A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade. Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.

Nebivolol is contraindicated in patients with severe bradycardia (heart rate <60 bpm prior to start of treatment), heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pace maker is in place), or severe hepatic impairment (Child-Pugh > B), a history of bronchospasm and bronchial asthma, and in patients who are hypersensitive to Nebivolol or Amlodipine, pregnant or lactating.

Nebivolol: 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 alpha receptor 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: Nebivolol does not affect glucose levels in diabetic patients. Care should be taken in diabetic patients however, as nebivolol may mask certain symptoms of hypoglycaemia (tachycardia, palpitations).
Beta-adrenergic blocking agents may mask tachycardic symptoms in hyperthyroidism. Abrupt withdrawal may intensify symptoms.
Respiratory: In patients with chronic obstructive pulmonary disorders, beta-adrenergic antagonists should be used with caution as airway constriction may be aggravated.
Other: Patients with a history of psoriasis should take beta-adrenergic antagonists only after careful consideration.
Beta-adrenergic antagonists may increase the sensitivity to allergens and the severity of anaphylactic reactions.
Amlodipine: The safety and efficacy of amlodipine in hypertensive crisis has not been established.
Use in patients with heart failure: Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.
Use in patients with impaired hepatic function: As with all calcium antagonists, amlodipine's half-life is prolonged and AUC values are higher in patients with impaired liver function and dosage recommendations have not been established. The drug should therefore be administered with caution in these patients.
Amlodipine should therefore be initiated at the lower end of the dosing range and caution should be used, both on initial treatment and when increasing the dose. Slow dose titration and careful monitoring may be required in patients with severe hepatic impairment.
There are no data to support the use of amlodipine alone, during or within one month of a myocardial infarction.
Patients with renal impairment: Amlodipine may be used in such patients at normal doses. Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment. Amlodipine is not dialysable.
There are no data to support the use of amlodipine alone, during or within one month of a myocardial infarction.
Use in the Elderly: In the elderly, increase of the dosage should take place with care.

Nebivolol has pharmacological effects that may cause harmful effects on pregnancy and/or the foetus/newborn. In general, beta-adrenoreceptor blockers reduce placental perfusion, which has been associated with growth retardation, intrauterine death, abortion or early labour. Adverse effects (e.g. hypoglycaemia and bradycardia) may occur in the foetus and newborn infant. If treatment with beta-adrenoreceptor blockers is necessary, beta1-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 the foetal growth should be monitored. In case of harmful effects on pregnancy or the foetus alternative treatment should be considered. The newborn infant must be closely monitored. Symptoms of hypoglycaemia and bradycardia are generally to be expected within the first 3 days.
The safely of amlodipine in human pregnancy has not been established.
In animal studies, reproductive toxicity was observed at high doses.
Use in pregnancy is only recommended when there is no safer alternative and when the disease itself carries greater risk for mother and foetus.
Breast-feeding: Animal studies have shown that nebivolol is excreted in breast milk. It is not known whether this drug is excreted in human milk. Most beta-blockers, particularly lipophilic compounds like nebivolol and its active metabolites, pass into breast milk although to a variable extent. Therefore, breastfeeding is not recommended during administration of nebivolol.
Amlodipine is excreted in human milk. The proportion of the maternal dose received by the infant has been estimated with interquartile range of 3-7%, with a maximum of 15%. The effect of amlodipine on infants is unknown. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with amlodipine should be made taking into account the benefit of breast-feeding to the child and the benefit of amlodipine therapy to the mother.

There is no data available on undesirable effects of this combination. However, side effects have been reported with individual molecules.
Nebivolol: The adverse reactions reported, which are in most of the cases of mild to moderate intensity, are tabulated as follows, classified by system organ class and ordered by frequency: see Table 1.

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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.
Amlodipine: The most commonly reported adverse reactions during treatment are somnolence, dizziness, headache, palpitations, flushing, abdominal pain, nausea, ankle swelling, oedema and fatigue.
Tabulated list of adverse reactions: The following adverse reactions have been observed and reported during treatment with amlodipine with the following frequencies: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).
Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness: see Table 2.

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Nebivolol: 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 atria-ventricular conduction. Intravenous administration of verapamil in patients with β-blocker treatment may lead to profound hypotension and atria-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 Nebivolol.
Insulin and oral antidiabetic drugs: Although nebivolol does not affect glucose level, concomitant use may mask certain symptoms of hypoglycaemia (palpitations, tachycardia).
Baclofen (antispastic 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 hypotensive effect of the beta-blockers (additive effect).
Non-steroidal anti-inflammatory drugs (NSAID): 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 adverse events.
Co-administration of cimetidine increased the plasma levels of nebivolol, without changing the clinical effect. Co-administration of ranitidine did not affect the pharmacokinetics of nebivolol. Provided Nebivolol is taken with the meal, and an antacid between meals, the two treatments can be co-prescribed.
Combining nebivolol with nicardipine slightly increased the plasma levels of both 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.
Amlodipine: In vitro data from studies with human plasma, indicate that amlodipine has no effect on protein binding of digoxin, phenytoin, warfarin or indomethacin.
Consumption of grapefruit/grapefruit juice should be avoided while taking amlodipine. The intake of grapefruit juice may result in increased plasma amlodipine concentrations, which may enhance the blood pressure lowering effects of amlodipine. This interaction has been observed with other dihydropyridine calcium antagonists and represents a class effect.
Effects of other medicinal products on amlodipine: CYP3A4 inhibitors: Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise to significant increase in amlodipine exposure resulting in an increased risk of hypotension. The clinical translation of these PK variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus be required.
CYP3A4 inducers: Upon co-administration of known inducers of the CYP3A4, the plasma concentration of amlodipine may vary. Therefore, blood pressure should be monitored and dose regulation considered both during and after concomitant medication particularly with strong CYP3A4 inducers (e.g. rifampicin, Hypericum perforatum).
Administration of amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients resulting in increased blood pressure lowering effects.
Dantrolene (infusion): In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalemia, it is recommended that the co-administration of calcium channel blockers such as amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.
Effects of amlodipine on other medicinal products: The blood pressure lowering effects of amlodipine adds to the blood pressure - lowering effects of other medicinal products with antihypertensive properties.
Tacrolimus: There is a risk of increased tacrolimus blood levels when co-administered with amlodipine but the pharmacokinetic mechanism of this interaction is not fully understood. In order to avoid toxicity of tacrolimus, administration of amlodipine in a patient treated with tacrolimus requires monitoring of tacrolimus blood levels and dose adjustment of tacrolimus when appropriate.
Cyclosporine: No drug interaction studies have been conducted with cyclosporine and amlodipine in healthy volunteers or other populations with the exception of renal transplant patients, where variable trough concentration increases (average: 0%-40%) of cyclosporine were observed. Consideration should be given for monitoring cyclosporine levels in renal transplant patients on amlodipine, and cyclosporine dose reductions should be made as necessary.
Simvastatin: Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily.
Cimetidine: Co-administration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine.
Sildenafil: When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.
Special Studies: Effect of amlodipine on other agents: Atorvastatin: Co-administration of multiple 10 mg doses of amlodipine with 80mg of atorvastatin resulted in no significant change in the steady state pharmacokinetic parameters of atorvastatin.
Digoxin: Co-administration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.
Warfarin: In healthy male volunteers, the co-administration of amlodipine does not significantly alter the effect of warfarin on prothrombin response lime. Co-administration of amlodipine with warfarin did not change the warfarin prothrombin response time.
In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin or warfarin.

Store at temperatures not exceeding 30°C. Protect from light and moisture.

Beta-Blockers / Calcium Antagonists / Anti-Anginal Drugs

C07FB12 - nebivolol and amlodipine ; Belongs to the class of selective beta-blocking agents in combination with other antihypertensives. Used in the treatment of cardiovascular diseases.

Rx