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NEBICIP Tablets (Nebivolol) Print PDF

Pharmacodynamics

Nebivolol is a beta-adrenergic receptor blocking agent. In extensive metabolizers (most of the population) and at doses ?10 mg, nebivolol is preferentially beta 1 selective. In poor metabolizers and at higher doses, nebivolol inhibits both beta 1 and beta 2 - adrenergic receptors. Nebivolol lacks intrinsic sympathomimetic and membrane stabilizing activity at therapeutically relevant concentrations. At clinically relevant doses, nebivolol does not demonstrate alpha 1 - adrenergic receptor blockade activity. Various metabolites, including glucuronides, contribute to beta-blocking activity.

The mechanism of action of the antihypertensive response of nebivolol has not been definitively established. Possible factors that may be involved include:

decreased heart rate,

decreased myocardial contractility,

diminution of tonic sympathetic outflow to the periphery from cerebral vasomotor centers,

suppression of renin activity and

vasodilation and decreased peripheral vascular resistance.

Pharmacokinetics

Nebivolol is metabolized by a number of routes, including glucuronidation and hydroxylation by CYP2D6. The active isomer (d-nebivolol) has an effective half-life of about 12 hours in CYP2D6 extensive metabolizers (most people), and 19 hours in poor metabolizers and exposure to d-nebivolol is substantially increased in poor metabolizers. This has less importance than usual, however, because the metabolites, including the hydroxyl metabolite and glucuronides (the predominant circulating metabolites), contribute to beta-blocking activity.

Plasma levels of d-nebivolol increase in proportion to dose in extensive metabolizers (EMs) and poor metabolizers (PMs) for doses up to 20 mg. Exposure to l-nebivolol is higher than to d-nebivolol but l-nebivolol contributes little to the drug's activity as d-nebivolol's beta receptor affinity is >1000-fold higher than l-nebivolol. For the same dose, PMs attain a 5-fold higher C max and 10-fold higher area under curve (AUC) of d-nebivolol than do EMs. d-Nebivolol accumulates about 1.5-fold with repeated once-daily dosing in EMs.

Absorption and Distribution Absorption of nebivolol is similar to an oral solution. The absolute bioavailability has not been determined.

Mean peak plasma nebivolol concentrations occur approximately 1.5 to 4 hours post-dosing in EMs and PMs.

Food does not alter the pharmacokinetics of nebivolol. Under fed conditions, nebivolol glucuronides are slightly reduced. Nebivolol may be administered without regard to meals.

The in vitro human plasma protein binding of nebivolol is approximately 98%, mostly to albumin, and is independent of nebivolol concentrations.

Metabolism and Excretion Nebivolol is predominantly metabolized via direct glucuronidation of parent and to a lesser extent via N-dealkylation and oxidation via cytochrome P450 2D6. Its stereospecific metabolites contribute to the pharmacologic activity.

After a single oral administration of 14 C-nebivolol, 38% of the dose was recovered in urine and 44% in feces for EMs and 67% in urine and 13% in feces for PMs. Essentially all nebivolol was excreted as multiple oxidative metabolites or their corresponding glucuronide conjugates.

Special Populations Renal Disease: The apparent clearance of nebivolol was unchanged following a single 5 mg dose of nebivolol in patients with mild renal impairment. and it was reduced negligibly in patients with moderate (ClCr 30 to 50 mL/min), but by 53% in patients with severe renal impairment (ClCr

Hepatic Disease: d-Nebivolol peak plasma concentration increased 3-fold, exposure (AUC) increased 10-fold, and the apparent clearance decreased by 86% in patients with moderate hepatic impairment (Child-Pugh Class B). The starting dose should be reduced in hypertensives with moderate hepatic impairment. No formal studies have been performed in patients with severe hepatic impairment and nebivolol should be contraindicated for these patients.

Hypertension

Stable mild and moderate chronic heart failure in addition to standard therapies in elderly patients ? 70 years

Hypertension

The dose of NEBICIP should be individualized to the needs of the patient. For most patients, the recommended starting dose is 5 mg once daily, with or without food, as monotherapy or in combination with other agents. For patients requiring further reduction in blood pressure, the dose can be increased at 2-week intervals up to 40 mg. A more frequent dosing regimen is unlikely to be beneficial.

Renal Impairment In patients with severe renal impairment (ClCr NEBICIP 2.5 once daily; upward titration should be performed cautiously if needed. Nebivolol has not been studied in patients receiving dialysis.

Hepatic Impairment In patients with moderate hepatic impairment, the recommended initial dose is NEBICIP 2.5 once daily; upward titration should be performed cautiously if needed. Nebivolol has not been studied in patients with severe hepatic impairment and therefore NEBICIP is not recommended in that population.

Elderly No dose adjustment is required.

Children and Adolescents The safety and efficacy of nebivolol in children aged less than 18 years have not been established. Therefore, use in children and adolescents is not recommended.

Chronic Heart Failure in Elderly

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. For those patients receiving cardiovascular drug therapy including diuretics and/or digoxin and/or angiotensin converting enzyme (ACE) inhibitors and/or angiotensin II antagonists, dosing of these drugs should be stabilised during the past two weeks prior to initiation of NEBICIP treatment.

The initial uptitration should be done according to the following steps at 1-2 weekly intervals based on patient tolerability: Half-tablet of NEBICIP 2.5 . to be increased to one tablet of NEBICIP 2.5 once daily, then to NEBICIP 5 once daily and then to 2 tablets of NEBICIP 5 once daily.

The maximum recommended dose is 10 mg NEBICIP 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 .

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.

Renal Impairment 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 ? 250 mol/L). Therefore, the use of NEBICIP in these patients is not recommended.

Hepatic Impairment Data in patients with hepatic insufficiency are limited. Therefore the use of NEBICIP in these patients is contraindicated.

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

Children and Adolescents The safety and efficacy of nebivolol in children aged less than 18 years have not been established. Therefore, use in children and adolescents is not recommended.

CYP2D6 Polymorphism No dose adjustments are necessary for patients who are CYP2D6 poor metabolizers. The clinical effect and safety profiles observed in poor metabolizers were similar to those of extensive metabolizers.

Severe bradycardia

Heart block greater than first degree

Cardiogenic shock

Decompensated cardiac failure

Sick sinus syndrome (unless a permanent pacemaker is in place)

Hypertensives with severe hepatic impairment (Child-Pugh >B)

Heart failure patients with hepatic impairment

Heart failure patients with severe renal insufficiency (serum creatinine ?250?mol/L)

Hypersensitivity to any component of this product

Drug Interactions

Myocardial Depressants or Inhibitors of AV Conduction NEBICIP should be used with care when myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the phenylalkylamine and benzothiazepine classes), or antiarrhythmic agents, such as disopyramide, are used concurrently. Both digitalis glycosides and beta-blockers slow AV conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. NEBICIP should not be combined with other beta-blockers.

Catecholamine-Depleting Drugs Patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, should be closely monitored, because the added beta-blocking action of NEBICIP may produce excessive reduction of sympathetic activity.

Clonidine In patients who are receiving NEBICIP and clonidine, NEBICIP should be discontinued for several days before the gradual tapering of clonidine.

CYP2D6 Inhibitors Drugs that inhibit CYP2D6 can be expected to increase plasma levels of nebivolol. Use caution when NEBICIP is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc.)

Non-dihydropyridine Calcium Channel Blockers Because of significant negative inotropic and chronotropic effects in patients treated with beta-blockers and calcium channel blockers of the verapamil and diltiazem type, caution should be used in patients treated concomitantly with these agents and ECG and blood pressure should be monitored.

Histamine-2 Receptor Antagonists Cimetidine (400 mg twice daily) causes a 23% increase in the plasma levels of d-nebivolol.

Sildenafil The co-administration of nebivolol and sildenafil decreased AUC and C max of sildenafil by 21 and 23% respectively. The effect on the C max and AUC for d-nebivolol was also small (<20%). The effect on vital signs (e. g. pulse and blood pressure) was approximately the sum of the effects of sildenafil and nebivolol.

Hypotensive Agents Do not use NEBICIP with other beta-blockers. Closely monitor patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, because the added beta-blocking action of NEBICIP may produce excessive reduction of sympathetic activity. In patients who are receiving NEBICIP and clonidine, discontinue NEBICIP for several days before the gradual tapering of clonidine.

Digitalis Glycosides Both digitalis glycosides and beta-blockers slow AV conduction and decrease the heart rate. Concomitant use can increase the risk of bradycardia.

Abrupt Cessation of Therapy

Patients with coronary artery disease treated with NEBICIP should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction (MI) and ventricular arrhythmias have been reported in patients with coronary artery disease following the abrupt discontinuation of therapy with beta-blockers. MI and ventricular arrhythmias may occur with or without preceding exacerbation of the angina pectoris. Even patients without overt coronary artery disease should be cautioned against interruption or abrupt discontinuation of therapy. As with other beta-blockers, when discontinuation of NEBICIP is planned, patients should be carefully observed and advised to minimize physical activity. NEBICIP should be tapered over 1 to 2 weeks when possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that NEBICIP be promptly reinstituted, at least temporarily.

Cardiac Failure

In general, beta-adrenergic antagonists should not be used in patients with untreated congestive heart failure, unless their condition has been stabilized.

Angina and Acute Myocardial Infarction

Listed below are other reported adverse reactions with an incidence of at least 1% in more than 4300 patients treated with nebivolol in controlled or open-label trials except for those already appearing in Table 1, terms too general to be informative, minor symptoms or adverse reactions unlikely to be attributable to drug because they are common in the population. These adverse reactions were in most cases observed at a similar frequency in placebo-treated patients in the controlled studies.

Body as a Whole: asthenia

Gastrointestinal System Disorders: abdominal pain

Metabolic and Nutritional Disorders: hypercholesterolemia

Nervous System Disorders: paresthesia

Laboratory abnormalities: In controlled monotherapy trials of hypertensive patients, nebivolol was associated with an increase in BUN, uric acid, triglycerides and decrease in HDL cholesterol and platelet count.

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 AV block occurred in 1.4% of nebivolol patients compared to 0.9% of placebo patients.

Edema of the lower limb were reported by 1.0% of nebivolol patients compared to 0.2% of placebo patients.

Post-marketing Experience

The following reactions have been identified from spontaneous reports of nebivolol received worldwide and have not been listed elsewhere. These adverse reactions have been chosen for inclusion due to a combination of seriousness, frequency of reporting or potential causal connection to nebivolol. Adverse reactions common in the population have generally been omitted. Because these adverse reactions were reported voluntarily from a population of uncertain size, it is not possible to estimate their frequency or establish a causal relationship to nebivolol exposure: abnormal hepatic function (including increased AST, ALT and bilirubin), acute pulmonary edema, acute renal failure, AV block (both second - and third-degree), bronchospasm, erectile dysfunction, hypersensitivity (including urticaria, allergic vasculitis and rare reports of angioedema), MI, pruritis, posriasis, Raynaud's phenomenon, peripheral ischemia/claudication, somnolence, syncope, thrombocytopenia, various rashes and skin disorders, vertigo and vomiting.

The most common signs and symptoms associated with nebivolol overdosage are bradycardia and hypotension. Other important adverse events reported with nebivolol overdose include cardiac failure, dizziness, hypoglycemia, fatigue and vomiting. Other adverse events associated with beta-blocker overdose include bronchospasm and heart block.

Due to extensive drug binding to plasma proteins, hemodialysis is not expected to enhance nebivolol clearance.

If overdose occurs, nebivolol should be stopped and general supportive and specific symptomatic treatment should be provided. Based on expected pharmacologic actions and recommendations for other beta-blockers, the following general measures should be considered when clinically warranted:

Bradycardia: Administer IV atropine. If the response is inadequate, isoproterenol or another agent with positive chronotropic properties may be given cautiously. Under some circumstances, transthoracic or transvenous pacemaker placement may be necessary.

Hypotension: Administer IV fluids and vasopressors. Intravenous glucagon may be useful.

Heart Block (second or third degree): Patients should be carefully monitored and treated with isoproterenol infusion. Under some circumstances, transthoracic or transvenous pacemaker placement may be necessary.

Congestive Heart Failure: Initiate therapy with digitalis glycoside and diuretics. In certain cases, consideration should be given to the use of inotropic and vasodilating agents.

Bronchospasm: Administer bronchodilator therapy such as a short acting inhaled beta 2 - agonist and/or aminophylline.

Hypoglycemia: Administer IV glucose. Repeated doses of IV glucose or possibly glucagon may be required.

In the event of intoxication where there are symptoms of shock, treatment must be continued for a sufficiently long period consistent with the 12-19 hour effective half-life of nebivolol. Supportive measures should continue until clinical stability is achieved.

NEBICIP 2.5 . Strip of 10 tablets NEBICIP 5 . Strip of 10 tablets