NEBILOC CCB Nebivolol Hydrochloride / Amlodipine Besilate 5mg / 10mg Tablet 1's

In clinical trials and worldwide post marketing experience there were reports of Nebivolol overdose. The most common signs and symptoms associated with Nebivolol over dosage 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 β-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 β-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 p2-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.
Single oral doses of Amlodipine maleate equivalent to 40 mg Amlodipine/kg and 100 mg Amlodipine/kg in mice and rats, respectively, caused death. Single oral Amlodipine maleate doses equivalent to 4 or more mg Amlodipine/kg or higher in dogs (11 or more times the maximum recommended human dose on a mg/m² basis) caused a marked peripheral vasodilation and hypotension. Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of Amlodipine is limited. Reports of intentional overdosage include a patient who ingested 250 mg and was asymptomatic and was not hospitalized; another (120 mg) was hospitalized, underwent gastric lavage and remained normotensive; the third (105 mg) was hospitalized and had hypotension (90/50 mmHg) which normalized following plasma expansion.
A case of accidental drug overdose has been documented in a 19-month-old male who ingested 30 mg Amlodipine (about 2 mg/kg). During the emergency room presentation, vital signs were stable with no evidence of hypotension, but a heart rate of 180 bpm. Ipecac was administered 3.5 hours after ingestion and on subsequent observation (overnight) no sequelae were noted.
If massive overdose should occur, active cardiac and respiratory monitoring should be instituted. Frequent blood pressure measurements are essential. Should hypotension occur, cardiovascular support including elevation of the extremities and the judicious administration of fluids should be initiated. If hypotension remains unresponsive to these conservative measures, administration of vasopressors (such as phenylephrine) should be considered with attention to circulating volume and urine output. Intravenous calcium gluconate may help to reverse the effects of calcium entry blockade. As Amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.

 

 

Nebivolol has pharmacological effects that may cause harmful effects on pregnancy and/or the fetus/newborn. In general, beta-adrenoceptor blockers reduce placental perfusion, which has been associated with growth retardation, intrauterine death, abortion or early labor. Adverse effects (e.g. hypoglycemia and bradycardia) may occur in the fetus and newborn infant. No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with Amlodipine maleate at doses up to 10 mg Amlodipine/kg/day (respectively 8 times* and 23 times* the maximum recommended human dose of 10 mg on a mg/m2 basis) during their respective periods of major organogenesis. However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) in rats receiving Amlodipine maleate at a dose equivalent to 10 mg Amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose. There are no adequate and well-controlled studies in pregnant women. The fixed dose combination of Nebivolol and Amlodipine therefore should not be used during pregnancy.
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. It is not known whether Amlodipine is excreted in human milk. Therefore, breastfeeding is not recommended during administration of Nebivolol.

 

Store at temperatures not exceeding 30°C.

 

Pharmacology: Pharmacodynamics: The fixed dose combination of Nebivolol plus Amlodipine combines two antihypertensive/antianginal agents with complimentary mechanisms of action to improve blood pressure control in patients with hypertension and angina in patients with coronary artery disease; Nebivolol, a member of the β adrenoceptor antagonist class, and Amlodipine, a member of the dihydropyridine calcium antagonist class.
Nebivolol: Nebivolol is a racemate of two enantiomers, SRRR-nebivolol (d-nebivolol) and RSSS-nebivolol (l-nebivolol). It combines two pharmacological activities; it is a competitive and highly selective beta 1 receptor antagonist (d-nebivolol), and it has vasodilating properties due to an interaction with the L arginine/nitric oxide pathway (l-nebivolol). 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. During acute and chronic treatment with Nebivolol in hypertensive patients systemic vascular resistance is decreased. Despite heart rate reduction, cardiac output is either maintained or improved due to an increase in stroke volume. The clinical relevance of the hemodynamic differences as compared with other beta₁ receptor blockers has not been full elucidated. In hypertensive patients, nebivolol increases the NO-mediated vascular response to acetylcholine which is reduced in patients with endothelial dysfunction. In vitro and in vivo experiments in animals have found that Nebivolol has no intrinsic sympathomimetic activity or membrane stabilizing action. In healthy volunteers, nebivolol has no significant effect on maximal exercise capacity or endurance.
Amlodipine: Amlodipine inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that Amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Serum calcium concentration is not affected by Amlodipine. Within the physiologic pH range, Amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure. 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 ischemic burden by the following two actions: 1. 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. 2. The mechanism of action of Amlodipine also probably involves dilatation of the main coronary arteries and coronary arterioles, both in normal and ischemic regions. This dilatation increases myocardial oxygen supply. 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 administration of Amlodipine. 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. Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving Amlodipine and concomitant beta-blockers. In clinical studies in which Amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed. In clinical trials with angina patients alone, Amlodipine therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks.
Pharmacokinetics: Nebivolol: Absorption: After oral administration, nebivolol is rapidly absorbed with peak plasma drug levels reached within 0.5 to 2 hrs. Food has no effect on absorption. The oral bioavailability averages 12% in fast metabolizers and 96% in slow metabolizers. At steady state and at the same dose level, the peak plasma concentration of unchanged Nebivolol is about 23 times higher in poor metabolizers than in extensive metabolizers.
Distribution: In plasma, both Nebivolol enantiomers are predominantly bound to albumin. Plasma protein binding is 98.1% for SRRR-nebivolol and 79.9% for RSSS-nebivolol.
Metabolism and Elimination: 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. Exposure to d-nebivolol is substantially increased in poor metabolizers but this has less importance than usual because the metabolites, including the hydroxyl metabolite and glucuronides (the predominant circulating metabolites), contribute to β-blocking activity. Plasma levels of d-nebivolol increase in proportion to dose in extensive and poor metabolizers for doses up to 20mg. 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, poor metabolizers attain a 5 fold higher Cmax and 10 fold higher AUC of d-nebivolol than do extensive metabolizers. D-nebivolol accumulates about 1.5-fold with repeated once-daily dosing in extensive metabolizers. Steady-state plasma levels in most subjects (fast metabolizers) are reached within 24 hours for Nebivolol and within a few days for the hydroxy-metabolites. Plasma concentrations are dose-proportional between 1 and 30mg. The pharmacokinetics of Nebivolol is not affected by age. After a single oral administration of 14C-nebivolol, 38% of the dose was recovered in urine and 44% in feces for extensive metabolizers and 67% in urine and 13% in feces for poor metabolizers. Essentially all Nebivolol was excreted as multiple oxidative metabolites or their corresponding glucuronide conjugates.
Elderly: The pharmacokinetics of Nebivolol is not affected by age.
Patients with renal impairment: The apparent clearance of Nebivolol was unchanged following a single 5 mg dose of Nebivolol in patients with mild renal impairment (ClCr 50 to 80 mL/min), and it was reduced negligibly in patients with moderate (ClCr 30 to 50 mL/min). The apparent clearance of Nebivolol in patients with severe renal impairment (ClCr <30 mL/min) was reduced by 53%. The dose of Nebivolol should be adjusted in patients with severe renal impairment. Nebivolol should be used with caution in patients receiving dialysis, since no formal studies have been conducted in this population.
Patients with hepatic impairment: D-Nebivolol peak plasma concentration increased 3-fold, 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 patients with moderate hepatic impairment. No formal studies have been performed in patients with severe hepatic impairment and Nebivolol should be contraindicated for these patients.
Amlodipine: Absorption: After oral administration of therapeutic doses, Amlodipine is well absorbed with peak plasma drug levels reached 6-12 hours post dose. Absolute bioavailability has been estimated to be between 64 and 90%. The bioavailability of Amlodipine is not altered by the intake of food. Steady state plasma levels of Amlodipine are reached after 7-8 days of consecutive dosing.
Distribution: The volume of distribution is approximately 21 L/kg. Approximately 97.5% of circulating Amlodipine is bound to plasma proteins.
Metabolism and Elimination: Amlodipine is extensively metabolized (approximately 90%) by the liver to inactive metabolites with 10% of the parent compound and 60% of the metabolites excreted in the urine. The terminal plasma elimination half life is about 35-50 hours and is consistent with once daily dosing.
Elderly: The time to reach peak plasma concentrations of Amlodipine is similar in elderly and younger subjects. Amlodipine clearance tends to be decreased with resulting increases in AUC and elimination half life in elderly patients.
Patients with renal impairment: The pharmacokinetics of Amlodipine is not significantly influenced by renal impairment. Amlodipine is not dialyzable.
Patients with hepatic impairment: The half life of Amlodipine is prolonged (56 hours) in patients with hepatic impairment and dosage recommendations have not been established.