Nebilong AM (Tablets) Instructions for Use

Marketing Authorization Holder

Micro Labs Limited (India)

ATC Code

C07FB (Selective beta-adrenergic blocking agents in combination with calcium channel blockers)

Active Substances

Amlodipine (Rec.INN registered by WHO)

Nebivolol (Rec.INN registered by WHO)

Dosage Form

Nebilong AM

Tablets 5.0 mg + 5.0 mg: 10, 15, 30, 60, 100 or 105 pcs.

Dosage Form, Packaging, and Composition

Tablets are flat-cylindrical, round, two-layer (one layer is white, the other layer is yellow) with a bevel and a score on one side.

7 pcs. – PVC/Aluminum blisters (1) – cardboard packs.
7 pcs. – PVC/Aluminum blisters (4) – cardboard packs.
7 pcs. – PVC/Aluminum blisters (7) – cardboard packs.
10 pcs. – PVC/Aluminum blisters (1) – cardboard packs.
10 pcs. – PVC/Aluminum blisters (3) – cardboard packs.
10 pcs. – PVC/Aluminum blisters (10) – cardboard packs.

Clinical-Pharmacological Group

Calcium channel blocker

Pharmacotherapeutic Group

BMCC (Bone Mineral Crystal Complex)

Pharmacological Action

A combined preparation containing Amlodipine and Nebivolol.

Amlodipine

A slow calcium channel blocker, a dihydropyridine derivative, has antianginal and antihypertensive action. It blocks calcium channels, reduces the transmembrane transition of calcium ions into the cell (more so in vascular smooth muscle cells than in cardiomyocytes).

The antianginal effect is due to the dilation of coronary and peripheral arteries and arterioles.

• In angina, it reduces the severity of myocardial ischemia; by dilating peripheral arterioles, it reduces total peripheral resistance, decreases cardiac afterload, and reduces myocardial oxygen demand.
• By dilating coronary arteries and arterioles in unchanged and ischemic areas of the myocardium, it increases oxygen supply to the myocardium (especially in vasospastic angina); prevents spasm of coronary arteries (including that caused by smoking).

In patients with stable angina, a single daily dose increases exercise tolerance, slows the development of angina and “ischemic” ST-segment depression, and reduces the frequency of angina attacks and the consumption of nitroglycerin and other nitrates.

It has a long-term, dose-dependent antihypertensive effect. The antihypertensive action is due to a direct vasodilating effect on vascular smooth muscles. In arterial hypertension, a single dose provides a clinically significant reduction in blood pressure over 24 hours (in the patient’s lying and standing positions). Orthostatic hypotension is quite rare with the use of amlodipine. It does not cause a reduction in exercise tolerance or left ventricular ejection fraction. It reduces the degree of left ventricular myocardial hypertrophy. It does not affect myocardial contractility and conduction, does not cause a reflex increase in heart rate, inhibits platelet aggregation, increases glomerular filtration rate, and has a weak natriuretic effect.

It does not have any adverse effect on metabolism and plasma lipid concentrations and can be used to treat patients with bronchial asthma, diabetes mellitus, and gout. A significant decrease in blood pressure is observed after 6-10 hours, the duration of the effect is 24 hours.

Nebivolol

Nebivolol is a lipophilic, cardioselective beta-blocker with vasodilating properties. It has antihypertensive, antianginal, and antiarrhythmic action. It reduces elevated blood pressure at rest, during physical exertion, and under stress. It competitively and selectively blocks synaptic and postsynaptic β₁-adrenergic receptors, making them inaccessible to catecholamines, and modulates the release of the endothelial vasodilating factor nitric oxide (NO).

Nebivolol is a racemate consisting of two enantiomers: SRRR-nebivolol (D-nebivolol) and RSSS-nebivolol (L-nebivolol), combining two pharmacological actions.

• D-Nebivolol is a competitive and highly selective blocker of β-adrenergic receptors (affinity for β₁-adrenergic receptors is 293 times higher than for β₂-adrenergic receptors).
• L-Nebivolol has a mild vasodilating effect by modulating the release of the relaxing factor from the vascular endothelium.

The antihypertensive effect develops on the 2nd-5th day of treatment, a stable effect is noted after 1 month. This effect persists with long-term treatment. The antihypertensive effect is also due to a reduction in the activity of the renin-angiotensin-aldosterone system (does not directly correlate with changes in plasma renin activity).

The use of nebivolol improves systemic and intracardiac hemodynamic parameters. Nebivolol reduces heart rate and blood pressure at rest and during exercise, decreases left ventricular end-diastolic pressure, reduces total peripheral resistance, improves diastolic heart function (reduces filling pressure), and increases ejection fraction. By reducing myocardial oxygen demand (reduction in heart rate, decrease in preload and afterload), it reduces the number and severity of angina attacks and improves exercise tolerance.

Pharmacokinetics

Amlodipine

After oral administration, Amlodipine is slowly absorbed from the gastrointestinal tract. The mean absolute bioavailability is 64%, C_max in serum is observed after 6-12 hours. Steady-state concentrations are achieved after 7-8 days of therapy. Concurrent food intake does not affect the absorption of amlodipine. The mean V_d is 21 L/kg of body weight, indicating that most of the drug is in the tissues, and a smaller part is in the blood. It is 97.5% bound to plasma proteins. Amlodipine crosses the blood-brain barrier.

Amlodipine undergoes slow but active metabolism in the liver in the absence of a significant first-pass effect. Metabolites do not have significant pharmacological activity.

After a single oral dose, T_1/2 ranges from 35 to 50 hours; with repeated administration, T_1/2 is approximately 45 hours. About 60% of the orally administered dose is excreted by the kidneys, mainly as metabolites, 10% unchanged, and 20-25% through the intestine with bile. The total clearance of amlodipine is 0.116 ml/s/kg (7 ml/min/kg, 0.42 L/h/kg).

It is not removed by hemodialysis.

Pharmacokinetics in special patient groups

In elderly patients (over 65 years), the elimination of amlodipine is slowed (T_1/2 is 65 hours) compared to young patients, but this difference is not clinically significant. Prolongation of T_1/2 in patients with hepatic impairment suggests that with long-term administration, accumulation of the drug in the body will be higher (T_1/2 – up to 60 hours). Renal impairment does not significantly affect the kinetics of amlodipine.

Nebivolol

After oral administration, both enantiomers of nebivolol are rapidly absorbed from the gastrointestinal tract. Concurrent food intake does not affect absorption. Bioavailability averages 12% in patients with “rapid” metabolism (first-pass effect) and is almost complete in patients with “slow” metabolism. Plasma clearance in most patients (with “rapid” metabolism) is achieved within 24 hours, and for hydroxymetabolites – after several days. Plasma concentrations of 1-30 µg/L are dose-proportional. Binding to plasma proteins (mainly albumin) is 98.1% for D-nebivolol and 97.9% for L-nebivolol.

Nebivolol is actively metabolized, partially forming active hydroxymetabolites. The metabolism of nebivolol occurs via acyclic and aromatic hydroxylation, partial N-dealkylation, and glucuronidation; in addition, glucuronides of hydroxymetabolites are formed. The rate of nebivolol metabolism via aromatic hydroxylation is genetically determined by oxidative polymorphism and depends on the CYP2D6 isoenzyme. The metabolic rate does not affect the efficacy of nebivolol.

One week after oral administration, 38% (the amount of unchanged active substance is less than 0.5%) of the dose is excreted by the kidneys and 48% through the intestine. In patients with “rapid” metabolism, the T_1/2 values of nebivolol enantiomers from plasma average 10 hours. In patients with “slow” metabolism, these values increase by 3-5 times. In patients with “rapid” metabolism, the T_1/2 values of hydroxymetabolites of both enantiomers from plasma average 24 hours; in patients with “slow” metabolism, these values approximately double.

Pharmacokinetics in special patient groups

Pharmacokinetic parameters show no age or gender differences.

Considering the differences in metabolic rate, the dose of the drug should always be selected individually: patients with “slow” metabolism require a lower dose.

Indications

• Arterial hypertension (for patients who require combination therapy).

ICD codes

Dosage Regimen

Take the drug orally, once daily. Swallow the tablet whole with a sufficient amount of liquid; do not chew or crush.

Initiate therapy with one tablet (5 mg + 5 mg) per day. Administer the dose at the same time each day, with or without food.

If the therapeutic effect is insufficient after a minimum of two weeks, the dose may be increased to two tablets (10 mg + 10 mg) once daily.

The maximum recommended daily dose is two tablets. Do not exceed this maximum dose.

Dosage adjustment is not typically required for patients with mild to moderate renal impairment. The drug is contraindicated in patients with severe renal impairment (creatinine clearance less than 20 mL/min).

Use with caution in patients with mild to moderate hepatic impairment. The drug is contraindicated in patients with severe hepatic impairment.

For elderly patients (over 65 years), exercise caution; initiate therapy at the standard starting dose and monitor renal function periodically.

Regularly monitor blood pressure and heart rate during therapy. Abrupt discontinuation of beta-blocker therapy is not recommended; taper the dose gradually over 10 to 14 days.

Adverse Reactions

According to WHO, adverse effects are classified according to their frequency of occurrence as follows: very common (≥10% of prescriptions); common (≥1% and <10%); uncommon (≥0.1% and <1%); rare (≥0.01% and <0.1%); very rare (<0.01%); frequency unknown (insufficient data to estimate frequency).

Amlodipine

Nervous system disorders common – headache, dizziness, increased fatigue, drowsiness; uncommon – general malaise, asthenia, hypoesthesia, paresthesia, peripheral neuropathy, tremor, insomnia, mood lability, unusual dreams, increased excitability, depression, anxiety, taste perversion; very rare – migraine, apathy, agitation, ataxia, amnesia, asthenia, increased sweating; frequency unknown – extrapyramidal disorders.

Digestive system disorders common – nausea, abdominal pain; uncommon – vomiting, constipation or diarrhea, flatulence, dyspepsia, anorexia, dry oral mucosa, thirst; rare – gingival hyperplasia, increased appetite; very rare – pancreatitis, gastritis, jaundice (due to cholestasis), hyperbilirubinemia, increased activity of hepatic transaminases, hepatitis.

Cardiovascular system disorders common – palpitations, flushing; uncommon – excessive decrease in blood pressure; very rare – syncope, dyspnea, vasculitis, orthostatic hypotension, development or worsening of chronic heart failure, cardiac arrhythmias (including bradycardia, ventricular tachycardia, and atrial fibrillation), myocardial infarction, chest pain, pulmonary edema.

Respiratory system disorders uncommon – dyspnea, rhinitis, epistaxis; very rare – cough.

Blood and lymphatic system disorders very rare – thrombocytopenic purpura, leukopenia, thrombocytopenia.

Urinary system disorders uncommon – frequent urination, painful urination, nocturia; very rare – dysuria, polyuria.

Reproductive system and breast disorders uncommon – gynecomastia, erectile dysfunction.

Musculoskeletal and connective tissue disorders uncommon – muscle cramps, myalgia, arthralgia, back pain, arthrosis; rare – myasthenia.

Skin and subcutaneous tissue disorders rare – dermatitis; very rare – alopecia, xeroderma, cold sweat, skin pigmentation disorder.

Allergic reactions uncommon – skin itching, skin rash (including erythematous, maculopapular rash, urticaria); very rare – angioedema, erythema multiforme.

Special senses disorders uncommon – tinnitus, diplopia, accommodation disorder, xerophthalmia, conjunctivitis, eye pain, visual disturbances; very rare – parosmia.

Metabolism and nutrition disorders very rare – hyperglycemia.

General disorders and administration site conditions uncommon – chills, pain of unspecified location, increase/decrease in body weight.

Nebivolol

Nervous system disorders common – headache, dizziness, increased fatigue, weakness, paresthesia; uncommon – nightmares, depression, decreased ability to concentrate, drowsiness, insomnia; very rare – syncope.

Eye disorders uncommon – visual impairment (dry eyes).

Digestive system disorders common – nausea, constipation, diarrhea, dry oral mucosa; uncommon – dyspepsia, flatulence, vomiting.

Cardiovascular system disorders common – peripheral edema; uncommon – bradycardia, acute heart failure, worsening of chronic heart failure, slowing of AV conduction/AV block, marked decrease in blood pressure, orthostatic hypotension, cardiac arrhythmias, cardialgia, exacerbation of intermittent claudication.

Respiratory system disorders common – dyspnea; uncommon – bronchospasm (including in the absence of a history of obstructive pulmonary disease), rhinitis.

Reproductive system disorders uncommon – erectile dysfunction.

Skin and subcutaneous tissue disorders uncommon – skin itching, erythematous rash; very rare – exacerbation of psoriasis, photodermatosis, increased sweating; frequency unknown – alopecia.

Allergic reactions frequency unknown – angioedema, urticaria, hypersensitivity.

The following adverse reactions have also been described with the use of some beta-adrenergic receptor antagonists: hallucinations, psychosis, confusion, coldness/cyanosis of the extremities, Raynaud’s syndrome.

Contraindications

Severe liver dysfunction; severe renal failure (creatinine clearance less than 20 ml/min) (no experience of use); acute heart failure; shock (including cardiogenic); decompensated chronic heart failure (requiring inotropic therapy); sick sinus syndrome, including sinoatrial block; second- and third-degree AV block (without a pacemaker); bradycardia (heart rate less than 60 beats/min); severe arterial hypotension (systolic blood pressure less than 90 mm Hg); unstable angina (except for Prinzmetal’s angina); left ventricular outflow tract obstruction (including severe aortic stenosis); hemodynamically unstable heart failure after myocardial infarction; broncho-obstructive syndrome in COPD and bronchial asthma; severe forms of bronchial asthma and COPD in history; pheochromocytoma (without simultaneous use of alpha-blockers); depression; metabolic acidosis; severe peripheral circulatory disorders (intermittent claudication, Raynaud’s syndrome); age under 18 years (efficacy and safety not established); lactose intolerance, lactase deficiency or glucose-galactose malabsorption (the preparation contains lactose); simultaneous use with floctafenine, sultopride; hypersensitivity to nebivolol and other beta-blockers, amlodipine and other dihydropyridine derivatives, as well as to other components of the preparation.

With caution renal dysfunction (creatinine clearance more than 20 ml/min), mild or moderate liver dysfunction, diabetes mellitus, thyroid dysfunction, history of bronchospasm episodes, burdened allergic history (possible increased sensitivity to allergens, worsening of allergic reactions and reduced therapeutic response to epinephrine), psoriasis, first-degree AV block, Prinzmetal’s angina, COPD, peripheral atherosclerosis, pheochromocytoma (during therapy with alpha-blockers), arterial hypotension, aortic stenosis, mitral stenosis, non-ischemic chronic heart failure NYHA class III-IV, acute myocardial infarction (after the first 28 days), unstable angina, hypertrophic obstructive cardiomyopathy, with simultaneous use with inhibitors and inducers of the CYP3A4 isoenzyme; in elderly patients (over 65 years).

Use in Pregnancy and Lactation

The use of the drug during pregnancy and breastfeeding is contraindicated.

Amlodipine

In experimental studies, fetotoxic and embryotoxic effects of amlodipine have not been established; use during pregnancy is possible only if the benefit to the mother outweighs the potential risk to the fetus.

There are no data indicating the excretion of amlodipine in breast milk. However, it is known that other slow calcium channel blockers – dihydropyridine derivatives – are excreted in breast milk. Therefore, if it is necessary to use the drug during lactation, the issue of discontinuing breastfeeding should be considered.

Nebivolol

During pregnancy, the drug is used only for strict indications if the intended benefit to the mother outweighs the potential risk to the fetus (due to the possibility of fetal growth retardation, intrauterine fetal death, premature birth, as well as the development of bradycardia, arterial hypotension, hypoglycemia, and respiratory paralysis in the newborn).

If the use of beta-blockers during pregnancy is necessary, selective beta₁-blockers are preferred. Treatment should be discontinued 48-72 hours before delivery. In cases where this is not possible, it is necessary to monitor uteroplacental blood flow and fetal growth, and ensure strict monitoring of the newborn for the first 3 days after delivery.

Animal studies have shown that Nebivolol is excreted in the milk of lactating animals. There are no data on the excretion of nebivolol into breast milk. However, most beta-blockers, especially lipophilic compounds (e.g., Nebivolol and its metabolites), penetrate into breast milk to some extent. Therefore, the use of the drug is not recommended for women during breastfeeding. If taking the drug during lactation is necessary, breastfeeding should be discontinued.

Use in Hepatic Impairment

The use of the drug is contraindicated in severe hepatic impairment.

The drug should be used with caution in mild or moderate hepatic impairment.

Use in Renal Impairment

The use of the drug is contraindicated in severe renal failure (creatinine clearance less than 20 ml/min) (no experience with use).

The drug should be used with caution in renal impairment (creatinine clearance more than 20 ml/min).

Pediatric Use

The use of the drug is contraindicated in children under 18 years of age (efficacy and safety have not been established).

Geriatric Use

The drug should be used with caution in elderly patients (over 65 years of age).

Special Precautions

During therapy with the drug, it is necessary to monitor body weight and salt intake; an appropriate diet is indicated (the drug contains Amlodipine).

Maintenance of oral hygiene and dental supervision are necessary (to prevent soreness, bleeding, and gingival hyperplasia).

Blood pressure and heart rate control at the beginning of drug use should be daily.

In elderly patients, monitoring of renal function is necessary (once every 4-5 months).

Beta-blockers should not be used in patients with untreated chronic heart failure until the condition has stabilized.

The drug should not be prescribed to patients with pheochromocytoma until treatment with alpha-blockers has been initiated. Blood pressure must be monitored in this case.

It is recommended to discontinue therapy with the drug if depression develops caused by taking the beta-blocker (due to the nebivolol content).

Abrupt discontinuation of beta-blockers is unacceptable. Discontinuation of beta-blockers should be gradual, over 10 days (up to 2 weeks in patients with coronary artery disease).

The effectiveness of beta-blockers is lower in smokers than in non-smoking patients.

In exertional angina, the drug dose should provide a resting heart rate within 60-80 beats/min, and during exercise – no more than 110 beats/min.

Beta-blockers can cause bradycardia: the dose should be reduced or the drug discontinued if the heart rate is less than 60 beats/min.

Beta-blockers must be used with caution in the following groups of patients

• With peripheral circulatory disorders, as these symptoms may worsen;
• With first-degree AV block, as beta-blockers negatively affect impulse conduction time;
• With Prinzmetal’s angina due to unopposed α-receptor-mediated coronary artery vasoconstriction (beta-adrenergic antagonists may increase the number and duration of angina attacks).

Patients using contact lenses should take into account that beta-blocker use may reduce tear fluid production.

During surgical interventions, the anesthesiologist should be informed that the patient is taking the drug. Continuation of beta-blockade reduces the risk of arrhythmia during general anesthesia and intubation. If preparation for surgery involves interruption of beta-blockade, beta-adrenergic antagonists should be discontinued at least 24 hours before surgery.

Anesthetics that cause myocardial depression should be used with caution. Vagal reactions in the patient can be prevented by intravenous administration of atropine.

Nebivolol does not affect plasma glucose concentration in patients with diabetes mellitus. Nevertheless, caution should be exercised when treating these patients, as Nebivolol may mask certain symptoms of hypoglycemia (e.g., tachycardia, palpitations) caused by the use of hypoglycemic agents. Abrupt withdrawal of the drug may cause exacerbation of disease symptoms and the development of a thyrotoxic crisis.

Plasma glucose concentration should be monitored once every 4-5 months (in patients with diabetes mellitus).

Beta-blockers may increase sensitivity to allergens and the severity of anaphylactic reactions. Nebivolol may be the cause of a severe reaction to a number of allergens when prescribed to patients with a history of a severe anaphylactic reaction to these allergens. Such patients may not respond to the usual doses of epinephrine (adrenaline) used to treat anaphylactic shock.

Beta-blockers should be used with caution in patients with COPD, as bronchospasm may worsen.

When deciding on the use of the drug in patients with psoriasis, the expected benefit and the possible risk of exacerbation of psoriasis should be carefully weighed.

Effect on the ability to drive vehicles and operate machinery

During therapy, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Drug Interactions

Amlodipine

Amlodipine can be safely used for the treatment of arterial hypertension together with thiazide diuretics, alpha- and beta-blockers, or ACE inhibitors .

In patients with stable angina, Amlodipine can be used with other antianginal agents, for example, with long-acting or short-acting nitrates, beta-blockers .

Unlike other slow calcium channel blockers, no clinically significant interaction of amlodipine was found when used concomitantly with NSAIDs, including indomethacin .

Enhancement of the antianginal and antihypertensive effects of slow calcium channel blockers is possible when used concomitantly with thiazide and “loop” diuretics, ACE inhibitors and nitrates , as well as enhancement of their antihypertensive effect when used concomitantly with alpha₁-blockers, antipsychotics .

Beta-blockers when used concomitantly with amlodipine may exacerbate the course of chronic heart failure.

Amlodipine can be safely used with antibiotics and oral hypoglycemic agents .

Although a negative inotropic effect is usually not observed in studies of amlodipine, nevertheless, some slow calcium channel blockers may enhance the severity of the negative inotropic effect of antiarrhythmic agents that cause QT interval prolongation (for example, amiodarone and quinidine ).

A single dose of sildenafil 100 mg in patients with arterial hypertension does not affect the pharmacokinetic parameters of amlodipine. When used concomitantly with sildenafil, blood pressure control is necessary (risk of arterial hypotension).

Repeated use of amlodipine 10 mg and atorvastatin 80 mg is not accompanied by significant changes in the pharmacokinetic parameters of atorvastatin.

Concomitant long-term use of simvastatin 80 mg/day and amlodipine 10 mg/day leads to a 77% increase in simvastatin exposure. It is recommended to reduce the simvastatin dose in patients taking Amlodipine to 20 mg/day.

Ethanol (beverages containing alcohol) Amlodipine, when used as a single dose and repeatedly at a dose of 10 mg, does not affect the pharmacokinetics of ethanol.

Antiviral agents (ritonavir) increase plasma concentrations of slow calcium channel blockers, including amlodipine.

Antipsychotics and isoflurane – enhancement of the antihypertensive effect of dihydropyridine derivatives.

Calcium preparations may reduce the effect of slow calcium channel blockers.

When slow calcium channel blockers are used concomitantly with lithium preparations (no data for amlodipine), an increase in the manifestation of their neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus) is possible.

Studies of the simultaneous use of amlodipine and cyclosporine in healthy volunteers and all patient groups, except for patients after kidney transplantation, have not been conducted. Various studies of amlodipine with cyclosporine in patients after kidney transplantation show that the use of this combination may not lead to any effect, or may increase the C_min of cyclosporine to varying degrees up to 40%. These data should be taken into account and cyclosporine concentration should be monitored in this group of patients when cyclosporine and amlodipine are used concomitantly.

When used concomitantly, Amlodipine may increase the systemic exposure of tasonermin in plasma. In such cases, regular monitoring of tasonermin in the blood and dose adjustment if necessary is required.

Does not affect the serum concentration of digoxin and its renal clearance.

Does not significantly affect the effect of warfarin (prothrombin time).

Cimetidine does not affect the pharmacokinetics of amlodipine.

In in vitro studies, Amlodipine does not affect the plasma protein binding of digoxin, phenytoin, warfarin and indomethacin .

Grapefruit juice simultaneous single intake of 240 mg of grapefruit juice and 10 mg of amlodipine orally is not accompanied by a significant change in the pharmacokinetics of amlodipine. Nevertheless, it is not recommended to use grapefruit juice and Amlodipine simultaneously, because with genetic polymorphism of the CYP3A4 isoenzyme, an increase in the bioavailability of amlodipine and, consequently, an enhancement of the antihypertensive effect is possible.

Aluminum- or magnesium-containing antacids single administration does not significantly affect the pharmacokinetics of amlodipine.

Inhibitors of the CYP3A4 isoenzyme when diltiazem 180 mg and amlodipine 5 mg were used concomitantly in patients aged 69 to 87 years with arterial hypertension, an increase in the systemic exposure of amlodipine by 57% was noted. Concomitant use of amlodipine and erythromycin in healthy volunteers (aged 18 to 43 years) did not lead to significant changes in amlodipine exposure (increase in AUC by 22%). Although the clinical significance of these effects is not entirely clear, they may be more pronounced in elderly patients.

Potent inhibitors of the CYP3A4 isoenzyme (e.g., ketoconazole, itraconazole) may lead to an increase in amlodipine plasma concentration to a greater extent than diltiazem. Amlodipine and inhibitors of the CYP3A4 isoenzyme should be used with caution.

Clarithromycin is an inhibitor of the CYP3A4 isoenzyme. In patients taking clarithromycin and Amlodipine concomitantly, there is an increased risk of decreased blood pressure. Patients taking such a combination are recommended to be under close medical supervision.

Inducers of the CYP3A4 isoenzyme there are no data on the effect of inducers of the CYP3A4 isoenzyme on the pharmacokinetics of amlodipine. Blood pressure should be carefully monitored when amlodipine and inducers of the CYP3A4 isoenzyme are used concomitantly.

Tacrolimus when used concomitantly with amlodipine, there is a risk of increased tacrolimus plasma concentration. To avoid tacrolimus toxicity when used concomitantly with amlodipine, tacrolimus plasma concentration should be monitored and the tacrolimus dose should be adjusted if necessary.

Nebivolol

Pharmacodynamic interaction

Concomitant use of nebivolol with floctafenine is contraindicated, as there is a threat of developing severe arterial hypotension or shock.

Concomitant use of nebivolol and sultopride is contraindicated, as it increases the risk of ventricular arrhythmia, especially torsades de pointes ventricular tachycardia.

Not recommended combinations

When used concomitantly with class I antiarrhythmic drugs (quinidine, hydroquinidine, cibenzoline, flecainide, disopyramide, lidocaine, mexiletine, propafenone) , an enhancement of the negative inotropic effect and prolongation of AV node conduction time is possible.

When beta-blockers are used concomitantly with slow calcium channel blockers (verapamil and diltiazem) , the negative effect on myocardial contractility and AV conduction is enhanced. Intravenous administration of verapamil against the background of nebivolol intake is contraindicated.

When used concomitantly with centrally acting antihypertensive agents (clonidine, guanfacine, moxonidine, methyldopa, rilmenidine) , the course of heart failure may worsen due to a decrease in sympathetic tone (decreased heart rate and cardiac output, symptoms of vasodilation). In case of abrupt withdrawal of these drugs, especially before withdrawal of nebivolol, “rebound” arterial hypertension may develop.

Combinations that should be used with caution

When used concomitantly with class III antiarrhythmic agents (amiodarone) , the effect on AV node conduction time may be enhanced.

Concomitant use of nebivolol and agents for general anesthesia may cause suppression of reflex tachycardia and increase the risk of arterial hypotension.

Concomitant use of nebivolol with insulin and oral hypoglycemic agents may mask the symptoms of hypoglycemia (palpitations, tachycardia).

Concomitant intake of nebivolol with baclofen, amifostine leads to enhanced arterial hypotension.

Combinations that should be taken into account

When nebivolol is used concomitantly with cardiac glycosides , slowing of AV conduction is possible. Nebivolol does not affect the pharmacokinetic parameters of digoxin .

Concomitant use of nebivolol and dihydropyridine slow calcium channel blockers (Amlodipine, felodipine, lercanidipine, nifedipine, nicardipine, nimodipine, nitrendipine) may increase the risk of arterial hypotension. An increase in the risk of further reduction in myocardial contractility in patients with heart failure cannot be ruled out.

When combined with antihypertensive agents, nitroglycerin , pronounced arterial hypotension may develop (particular caution is necessary when combined with prazosin).

Concomitant use of tricyclic antidepressants, barbiturates and phenothiazine derivatives may enhance the antihypertensive effect of nebivolol.

No clinically significant interaction between nebivolol and NSAIDs has been established.

Acetylsalicylic acid as an antiplatelet agent can be used concomitantly with nebivolol.

When used concomitantly, sympathomimetic agents suppress the pharmacological activity of nebivolol.

Pharmacokinetic interaction

When used concomitantly with drugs that inhibit serotonin reuptake, or other agents that are biotransformed with the participation of the CYP2D6 isoenzyme (for example, paroxetine, fluoxetine, thioridazine, quinidine), the metabolism of nebivolol slows down, its plasma concentration increases, which may lead to an increased risk of pronounced bradycardia and adverse events.

When used concomitantly with cimetidine , the plasma concentration of nebivolol increases (no data on the effect on the pharmacological effects of the drug are available).

Concomitant use of ranitidine did not affect the pharmacokinetic parameters of nebivolol.

When nebivolol is used concomitantly with nicardipine , the plasma concentrations of the active substances increase somewhat, but this has no clinical significance.

Concomitant intake of ethanol, furosemide or hydrochlorothiazide does not affect the pharmacokinetics of nebivolol.

No clinically significant interaction between nebivolol and warfarin has been established.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.