Dosage Availability (per box of 30’s):
5mg / 5mg Tablet
5mg / 10mg Tablet
BETA1 BLOCKER / CALCIUM CHANNEL BLOCKER / ANTI-HYPERTENSIVE
Each tablet contains:
Nebivolol (as hydrochloride) 5mg
Amlodipine (as besilate) 5mg
Nebivolol (as hydrochloride) 5mg
Amlodipine (as besilate) 10mg
Nebivolol plus Amlodipine is indicated for the treatment of essential hypertension and the treatment of chronic stable angina.
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.
Hypertension and Chronic Stable Angina
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.
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 does 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.
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.
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 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 propertied 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 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.
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.
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 I- 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.
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 (CICr 50 to 80 mL/min), and it was reduced negligibly in patients with moderate (CICr 30 to 50 mL/min). The apparent clearance of Nebivolol in patients with severe renal impairment (CICr <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
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.
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.
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.
Abrupt Cessation of Therapy
Patients with coronary artery disease treated with Nebivolol should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported in patients with coronary artery disease following the abrupt discontinuation of therapy with β-blockers. Myocardial infarction 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 β-blockers, when discontinuation of Nebivolol is planned, patients should be carefully observed and advised to minimize physical activity. Nebivolol should be tapered over 1 to 2 weeks when possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that Nebivolol be promptly reinstituted, at least temporarily.
Sympathetic stimulation is a vital component supporting circulatory function in the setting of congestive heart failure, and β-blockade may result in further depression of myocardial contractility and precipitate more severe failure. In patients who have compensated congestive heart failure, Nebivolol should be administered cautiously. If heart failure worsens, discontinuation of Nebivolol should be considered.
In general, patients with bronchospastic diseases should not receive β-blockers.
Anesthesia and Major Surgery
If Nebivolol is to be continued perioperatively, patients should be closely monitored when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used. If β-blocking therapy is withdrawn prior to major surgery, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. The β-blocking effects of Nebivolol can be reversed by (β-agonists, e.g., dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Additionally, difficulty in restarting and maintaining the heartbeat has been reported with β-blockers.
Diabetes and Hypoglycemia
Nebivolol does not affect glucose levels in patients with diabetes. β-blockers however may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be advised about these possibilities and Nebivolol should be used with caution.
β-blockers may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of β-blockers may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate a thyroid storm.
Peripheral Vascular Disease
Non-dihydropyridine Calcium Channel Blockers
Because of significant negative inotropic and chronotropic effects in patients treated with β -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.
Class I antiarrhythmics (quinidine, hydroquinidine, cibenzoline, flecainide, disopyramide, lidocaine, mexiletine, propafenone)
The effect on atrio-ventricular conduction time may be potentiated and negative inotropic effect increased.
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”.
Class III antiarrhythmic drugs (Amiodarone)
The effect on atrio-ventricular conduction time may be potentiated.
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.
Dihydropyridine calcium antagonists (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).
Concomitant use may counteract the effect of beta-adrenergic antagonists. Beta-adrenergic agents may lead to unopposed alpha-adrenergic activity of sympathicomimetic agents with both alpha- and beta-adrenergic effects (risk of hypertension, severe bradycardia and heart block).
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.
Increased Angina and/or Myocardial Infarction
Rarely, patients, particularly those with severe obstructive coronary artery disease, have developed documented increased frequency, duration and/or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been elucidated.
Since the vasodilation induced by Amlodipine is gradual in onset, acute hypotension has rarely been reported after oral administration. Nonetheless, caution, as with any other peripheral vasodilator, should be exercised when administering Amlodipine, particularly in patients with severe aortic stenosis.
In vitro studies have demonstrated that at therapeutically relevant concentrations, d- and l-nebivolol do not inhibit any cytochrome P450 pathways. Drugs that inhibit CYP2D6 (i.e., paroxetine, fluoxetine, thioridazine and quinidine) can be expected to increase plasma levels of Nebivolol. When Nebivolol is co-administered with an inhibitor or an inducer of this enzyme, patients should be closely monitored and the Nebivolol dose adjusted according to blood pressure response.
Concomitant administration of Nebivolol (10 mg once daily) and digoxin (0.25 mg once daily) for 10 days in 14 healthy adult individuals resulted in no significant changes in the pharmacokinetics of digoxin or Nebivolol.
Administration of Nebivolol (10 mg once daily for 10 days) led to no significant changes in the pharmacokinetics of Nebivolol or R- or S-warfarin following a single 10 mg dose of warfarin. Similarly, Nebivolol has no significant effects on the anticoagulant activity of warfarin, as assessed by prothrombin time and INR profiles from 0 to 144 hours after a single 10 mg warfarin dose in 12 healthy adult volunteers.
No pharmacokinetic interactions were observed in healthy adults between Nebivolol (10 mg daily for 10 days) and furosemide (40 mg single dose), hydrochlorothiazide (25 mg once daily for 10 days), or spironolactone (25 mg once daily for 10 days).
Concomitant administration of Nebivolol (10 mg once daily) and ramipril (5 mg once daily) for 10 days in 15 healthy adult volunteers produced no pharmacokinetic interactions.
Concomitant administration of Nebivolol (10 mg single dose) and losartan (50 mg single dose) in 20 healthy adult volunteers did not result in pharmacokinetic interactions.
The pharmacokinetics of Nebivolol (5 mg single dose) was not affected by the co-administration of ranitidine (150 mg twice daily). Cimetidine (400 mg twice daily) causes a 23% increase in the plasma levels of d-nebivolol.
The pharmacokinetics of Nebivolol (10 mg single dose) was not affected by repeated co-administration (4, 8, 12, 16, 22, 28, 36, and 48 hours after Nebivolol administration) of activated charcoal.
The co-administration of Nebivolol and 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%). The effect on vital signs (e.g., pulse and blood pressure) was approximately the sum of the effects of sildenafil and Nebivolol.
Utilizing population pharmacokinetic analyses, derived from hypertensive patients, the following drugs were observed not to have an effect on the pharmacokinetics of Nebivolol: acetaminophen, acetylsalicylic acid, atorvastatin, esomeprazole, ibuprofen, levothyroxine sodium, metformin, sildenafil, simvastatin, or tocopherol.
No meaningful changes in the extent of in vitro binding of Nebivolol to human plasma proteins were noted in the presence of high concentrations of diazepam, digoxin, diphenylhydantoin, enalapril, hydrochlorothiazide, imipramine, indomethacin, propranolol, sulfamethazine, tolbutamide, or warfarin. Additionally, Nebivolol did not significantly alter the protein binding of the following drugs: diazepam, digoxin, diphenylhydantoin, hydrochlorothiazide, imipramine, or warfarin at their therapeutic concentrations.
In vitro data indicate that Amlodipine has no effect on the human plasma protein binding of digoxin, phenytoin, warfarin, and indomethacin.
Co-administration of Amlodipine with cimetidine does not alter the pharmacokinetics of amlodipine.
Co-administration of 240 mL of grapefruit juice with a single oral dose of Amlodipine 10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of Amlodipine.
Co-administration of the antacid Maalox with a single dose of Amlodipine had no significant effect on the pharmacokinetics of Amlodipine.
A single 100 mg dose of sildenafil in subjects with essential hypertension had no effect on the pharmacokinetic parameters of Amlodipine. When Amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.
Co-administration of multiple 10 mg doses of Amlodipine with 80 mg of atorvastatin resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin.
Co-administration of Amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.
Single and multiple 10 mg doses of Amlodipine had no significant effect on the pharmacokinetics of ethanol.
Co-administration of Amlodipine with warfarin did not change the warfarin prothrombin response time.
In clinical trials, Amlodipine has been safely administered with thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, non-steroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs.
Worldwide, 6,545 patients, including 5038 patients treated for hypertension and the remaining 1507 subjects treated for other cardiovascular diseases, have been exposed to Nebivolol in clinical trials. Doses ranged from 0.5 mg to 40 mg and the duration of treatment lasted up to 24 months, with over 1900 patients treated for at least 6 months, and approximately 1300 patients for more than one year. In placebo-controlled clinical trials comparing nebivolol with placebo, discontinuation of treatment due to adverse events was reported in 2.8% of patients treated with Nebivolol and 2.2% of patients given placebo. The most common adverse events that led to discontinuation of Nebivolol were headache (0.4%), nausea (0.2%) and bradycardia (0.2%). In three 12-week, placebo-controlled monotherapy trials involving 920 hypertensive patients treated with either Nebivolol 5 mg (N5) or Nebivolol 10 mg (N10) of Nebivolol and 205 patients given placebo (P) and for which the rate of occurrence was at least 1% of patients treated with Nebivolol and greater than the rate for those treated with placebo in at least one dose group, the following treatment emergent adverse events were observed; Headache: P (6%), N5 (9%), N10 (6%). Fatigue: P (1%), N5 (2%), N10 (2%). Dizziness: P (2%), N5 (2%), N10 (3%). Diarrhea: P (2%), N5 (2%), N10 (2%). Nausea: P (0%), N5 (1%), N10 (3%). Insomnia: P (0%), N5 (1%), N10 (1%). Chest pain: P (0%), N5 (0%), N10 (1%). Bradycardia: P (0%), N5 (0%), N10 (0%). Dyspnea: P (0%), N5 (0%), N10 (1%). Rash: P (0%), N5 (0%), N10 (1%). Peripheral edema: P (0%), N5 (1%), N10 (1%). Other reported adverse events with an incidence of at least 1% in the more than 5,300 patients treated with Nebivolol in controlled or open-label trials, whether or not attributed to treatment, include;
Body as a whole: asthenia.
Gastrointestinal System Disorders: abdominal pain.
Metabolic and Nutritional Disorders: hypercholesterolemia and hyperuricemia.
Nervous System Disorders: paraesthesia. The following adverse events have been identified from spontaneous reports of Nebivolol received worldwide and have not been listed elsewhere. These adverse events have been chosen for inclusion due to a combination of seriousness, frequency of reporting or potential causal connection to Nebivolol. Because these events 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, atrioventricular block (both second and third degree), bronchospasm, erectile dysfunction, hypersensitivity (including urticaria, allergic vasculitis and rare reports of angioedema), myocardial infarction, pruritus, psoriasis, Raynaud’s phenomenon, peripheral ischemia/claudication, somnolence, syncope, thrombocytopenia, various rashes and skin disorders, vertigo, and vomiting.
Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. In general, treatment with Amlodipine is well-tolerated at doses up to 10 mg daily. Most adverse reactions reported during therapy with Amlodipine were of mild or moderate severity. In controlled clinical trials directly comparing Amlodipine (N=1730) in doses up to 10 mg to placebo (N=1250), discontinuation of Amlodipine due to adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo (about 1%). The most common side effects are headache and edema. The incidence of side effects which occurred in a dose related manner is as follows; Edema: P (0.6%), A5 (3.0%), A10 (10.8%). Dizziness: P (1.5%), A5 (3.4%), A10 (3.4%). Flushing: P (0.0%), A5 (1.4%), A10 (2.6%). Palpitation: P (0.6%), A5 (1.4%), A10 (4.5%). Other adverse experiences which were not clearly dose related but which were reported with an incidence greater than 1.0% in placebo-controlled clinical trials include the following; Headache: P (7.8%), A (7.3%). Fatigue: P (2.8%), A (4.5%). Nausea: P (1.9%), A (1.9%). Abdominal Pain: P (0.3%), A (1.6%). Somnolence: P (0.6%), A (1.4%). For several adverse experiences (edema and flushing) that appears to be drug and dose related there was a greater incidence in women than men. The following events occurred in <1% but >0.1% of patients in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship:
Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, hypotension, peripheral ischemia, syncope, tachycardia, postural dizziness, postural hypotension, vasculitis.
Central and Peripheral Nervous System: hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo.
Gastrointestinal: anorexia, constipation, dyspepsia,** dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia.
General: allergic reaction, asthenia, ** back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease.
Musculoskeletal System: arthralgia, arthrosis, muscle cramps, ** myalgia.
Psychiatric: sexual dysfunction (male** and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization.
Respiratory System: dyspnea,** epistaxis.
Skin and Appendages: angioedema, erythema multiforme, pruritus, ** rash, ** rash erythematous, rash maculopapular. **These events occurred in less than 1% in placebo-controlled trials, but the incidence of these side effects was between 1% and 2% in all multiple dose studies.
Special Senses: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus.
Urinary System: micturition frequency, micturition disorder, nocturia.
Autonomic Nervous System: dry mouth, sweating increased.
Metabolic and Nutritional: hyperglycemia, thirst.
Hemopoietic: leukopenia, purpura, thrombocytopenia.
The following events occurred in <0.1% of patients: cardiac failure, pulse irregularity, extrasystoles, skin discoloration, urticaria, skin dryness, alopecia, dermatitis, muscle weakness, twitching, ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, coughing, rhinitis, dysuria, polyuria, parosmia, taste perversion, abnormal visual accommodation, and xerophthalmia. Amlodipine therapy has not been associated with clinically significant changes in routine laboratory tests. No clinically relevant changes were noted in serum potassium, serum glucose, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine.
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.
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.
Foods, Drugs, Devices and Cosmetics Act prohibits dispensing without a prescription.
STORE AT TEMPERATURES NOT EXCEEDING 30OC
NEBILOC CCB® is a registered trademark of Ajanta Pharma Philippines, Inc.
Nebivolol HCl + Amlodipine besilate (Nebiloc CCB®) 2.5mg/5mg Tablet X 30 tablets / box in alu-alu blister pack
Nebivolol HCl + Amlodipine besilate (Nebiloc CCB®) 2.5mg/10mg Tablet X 30 tablets / box in alu-alu blister pack
Nebivolol HCl + Amlodipine besilate (Nebiloc CCB®) 5mg/5mg Tablet X 30 tablets / box in alu-alu blister pack
Nebivolol HCl + Amlodipine besilate (Nebiloc CCB®) 5mg/10mg Tablet X 30 tablets / box in alu-alu blister pack
Nebivolol HCl + Amlodipine besilate (Nebiloc CCB®) 10mg/5mg Tablet X 30 tablets / box in alu-alu blister pack
Nebivolol HCl + Amlodipine besilate (Nebiloc CCB®) 10mg/10mg Tablet X 30 tablets / box in alu-alu blister pack