Nebil

Nebil

nebivolol

Manufacturer:

Getz Pharma

Distributor:

Getz Pharma
Full Prescribing Info
Contents
Nebivolol HCl.
Description
Nebivolol (Nebil) is chemically described as (1RS, 1'RS)-1, 1'-[(2RS, 2'SR)-bis(6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-yl)]-2, 2'-iminodiethanol hydrochloride. Its molecular formula is C22H25F2NO4.
Action
Beta-blocker.
Pharmacology:
Mechanism of Action: Nebivolol is a racemic mixture of SRRR and RSSS in a β1- selective adrenoceptor antagonist whose hemodynamic effects differ from those of classical β-adrenoceptor antagonist as a result of a vasodilating action. It has mild vasodilating properties attributed to its interaction with the L-arginine/nitric oxide pathway, a property not shared by other β-blockers. Nebivolol lacks intrinsic sympathomimetic and membrane stabilizing activity at therapeutically relevant concentrations. At clinically relevant doses, nebivolol does not demonstrate α1-adrenergic receptor blockade activity.
Pharmacokinetics: Nebivolol is rapidly absorbed following oral administration. The absorption of nebivolol is not affected by food. It is extensively metabolized in the liver by alicyclic and aromatic hydroxylation, N-dealkylation and glucuronidation; the hydroxy metabolites are reported to be active. The rate of aromatic hydroxylation by cytochrome P450 isoenzyme CYP206 is subject to genetic polymorphism and bioavailability, and half-life (t½) vary widely. In fast metabolizers, the elimination t½ of nebivolol is about 10 hrs and all the hydroxy metabolites is about 24 hrs. Peak plasma concentration of unchanged drug plus active metabolites are 1.3-1.4 times higher in slow metabolizers and the half-lives of nebivolol and its hydroxy metabolites are prolonged. Nebivolol is about 98% bound to plasma  proteins. It is excreted in the urine and feces, almost entirely as metabolites. The pharmacokinetics of nebivolol are not affected by age. One week after administration, 38% of the dose is excreted in the urine and 48% in the feces. Urinary excretion of unchanged nebivolol is <0.5% of the dose.
Special Populations: Renal Insufficiency: The apparent clearance of nebivolol is unchanged following a single dose of nebivolol 5 mg in patients with mild renal insufficiency (CrCl 50-80 mL/min) and it is reduced negligibly in patients with moderate renal insufficiency (CrCl 30-50 mL/min). However, it is reduced by 53% in patients with severe renal insufficiency (CrCl <30 mL/min). The dose of nebivolol should be adjusted in patients with severe renal insufficiency.
Hepatic Insufficiency: Nebivolol peak plasma concentration increased 3-fold, exposure (AUC) increased 10-fold, and the apparent clearance decreased by 86% in patients with moderate hepatic insufficiency (Child-Pugh Class B). The starting dose should be reduced in patients with moderate hepatic insufficiency.
Indications/Uses
Treatment of essential hypertension, stable, mild and moderate chronic heart failure in addition to standard therapies in elderly patients ≥70 years and may be used alone or in combination with other antihypertensive agents.
Dosage/Direction for Use
Hypertension: Adult: 1 tablet (5 mg) daily, preferably at the same time of the day. Tablets may be taken with or without meals. The initial up titration should be done at 1-2 weekly intervals based on patient tolerability. The maximum recommended dose is 10 mg once daily. The blood pressure-lowering effect becomes evident after 1-2 weeks of treatment. Occasionally, the optimal effect is reached only after 4 weeks.
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 edema, cardiogenic shock, symptomatic bradycardia or AV block).
Patients with Renal Insufficiency: The recommended starting dose is 2.5 mg daily, if needed, the daily dose may be increased to 5 mg. The upward titration should be performed cautiously.
Patients with Hepatic Insufficiency: In patients with moderate hepatic insufficiency, the recommended initial dose is 2.5 mg once daily. Upward titration should be performed cautiously if needed.
Elderly >65 years: The recommended starting dose is 2.5 mg daily. If needed, the daily dose may be increased to 5 mg.
Chronic Heart Failure: The treatment of stable chronic heart failure has to be initiated with a gradual up titration of dosage until the optimal individual maintenance dose is reached.
Patients should have stable chronic heart failure without acute failure during the past 6 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 stabilized during the past 2 weeks prior to initiation of nebivolol treatment.
Overdosage
The most common signs and symptoms associated with nebivolol overdosage are tachycardia and hypotension. Other important adverse events reported with nebivolol overdosage include cardiac failure, dizziness, hypoglycemia, fatigue and vomiting. Other adverse events associated with β-blocker overdose include bronchospasm and heart block. If overdose occurs, nebivolol should be stopped and general supportive and specific symptomatic treatment should be provided.
Contraindications
Hypersensitivity to nebivolol HCl or to any of the components of Nebil. Severe hepatic insufficiency; acute heart failure, cardiogenic shock or episodes of heart failure decompensation requiring IV inotropic therapy. Sick sinus syndrome including sino-atrial block; 2nd- and 3rd- 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 <90 mmHg); severe peripheral circulatory disturbances.
Special Precautions
Anesthesia: Continuation of β-blockade reduces the risk of arrhythmia during induction and intubation. If β-blockade is interrupted in preparation for surgery, the β-adrenergic antagonist should be discontinued at least 24 hrs beforehand.
Caution should be observed with certain anesthetics that cause myocardial depression. The patient can be protected against vagal reactions by intravenous administration of atropine.
Cardiac Failure: In patients who have compensated CHF, nebivolol should be administered cautiously. If heart failure worsens, discontinuation of nebivolol should be considered.
Metabolic/Endocrinological: Care should be taken in diabetic patients, however, as nebivolol may mask certain symptoms of hypoglycemia (tachycardia, palpitations). Beta-adrenergic blocking agents may mask tachycardia symptoms in hyperthyroidism. Abrupt withdrawal may intensify symptoms.
Abrupt Cessation of Therapy: 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. If the angina worsens or acute coronary insufficiency develops, it is recommended that nebivolol be promptly reinstituted, at least temporarily.
Peripheral Vascular Diseases: β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular diseases. Caution should be exercised in these patients.
Renal Insufficiency: Nebivolol should be used with caution in patients on dialysis.
Geriatric Patients: In patients >75 years, caution must be exercised and these patients should be monitored closely.
Others: Patients with a history of psoriasis should take β-adrenergic antagonists only after careful consideration. β-adrenergic antagonists may increase the sensitivity to allergens and the severity of anaphylactic reactions.
Patients with rare hereditary problems of galactose intolerance, Lapp-lactase deficiency or glucose-galactose malabsorption should not take Nebil.
Use in pregnancy: Nebivolol should be used during pregnancy (Category C) only if the potential benefit justifies the potential risk to the fetus. If treatment with nebivolol is considered necessary, the uteroplacental blood flow and the fetal growth should be monitored. In case of harmful effects on pregnancy or the fetus, alternative treatment should be considered. The newborn must be closely monitored. Symptoms of hypoglycemia and bradycardia are generally to be expected within the first 3 days.
Use in lactation: It is not known whether the drug is excreted in human milk. Because of the potential for β-blockers to produce serious adverse reactions in nursing infants, especially bradycardia, nebivolol is not recommended during nursing.
Use In Pregnancy & Lactation
Use in pregnancy: Nebivolol should be used during pregnancy (Category C) only if the potential benefit justifies the potential risk to the fetus. If treatment with nebivolol is considered necessary, the uteroplacental blood flow and the fetal growth should be monitored. In case of harmful effects on pregnancy or the fetus, alternative treatment should be considered. The newborn must be closely monitored. Symptoms of hypoglycemia and bradycardia are generally to be expected within the first 3 days.
Use in lactation: It is not known whether the drug is excreted in human milk. Because of the potential for β-blockers to produce serious adverse reactions in nursing infants, especially bradycardia, nebivolol is not recommended during nursing.
Adverse Reactions
The following adverse reactions occurred:
Hypertension: Common:
Headache, dizziness, paresthesia, dyspnea, constipation, nausea, diarrhea, tiredness, edema. Uncommon: Nightmares, depression, impaired vision, bradycardia, heart failure, slowed AV conduction/AV-block, hypotension, increased intermittent claudication, bronchospasm, dyspepsia, flatulence, vomiting, pruritus, rash, erythematous, impotence. Rare: Syncope, aggravated psoriasis.
Chronic Heart Failure: The most commonly reported adverse reactions are bradycardia and dizziness.
The other adverse reactions that occurred are cardiac failure aggravation, postural hypotension, drug intolerance, 1st degree atrio-ventricular block, edema of the lower limb.
Drug Interactions
Nebivolol should be used with care when myocardial depressants or inhibitors of AV conduction, eg, certain calcium antagonists (particularly of the phenylalkylamine [verapamil] and benzothiazepine [diltiazem] classes) or anti-arrhythmic agents eg, disopyramide are used concurrently.
Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.
Patients receiving catecholamine-depleting drugs eg, reserpine or guanethidine should be closely monitored.
In patients who are receiving nebivolol and clonidine, nebivolol should be discontinued for several days before the gradual tapering of clonidine.
CYP2D6 Inhibitors: Caution should be used when nebivolol is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc).
Cimetidine: Cimetidine causes a 23% increase in the plasma levels of d-nebivolol.
Sildenafil: The co-administration of nebivolol and a sildenafil decreased AUC and Cmax of sildenafil by 21% and 23% respectively. The effect on the Cmax and AUC for d-nebivolol was also small (<20%).
Storage
Store at temperatures not exceeding 30°C.
Protect from light and moisture.
MIMS Class
ATC Classification
C07AB12 - nebivolol ; Belongs to the class of selective beta-blocking agents. Used in the treatment of cardiovascular diseases.
Presentation/Packing
Tab 2.5 mg x 14's. 5 mg x 14's.
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