Bisoprolol AML (Tablets) Instructions for Use

Marketing Authorization Holder

Severnaya Zvezda NAO (Russia)

Contact Information

SEVERNAYA ZVEZDA NAO (Russia)

ATC Code

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

Active Substances

Amlodipine (Rec.INN registered by WHO)

Bisoprolol (Rec.INN registered by WHO)

Dosage Forms

	Bisoprolol AML	Tablets 5 mg+5 mg: 10 or 30 pcs.
		Tablets 5 mg+10 mg: 10 or 30 pcs.
		Tablets 10 mg+10 mg: 10 or 30 pcs.
		Tablets 10 mg+5 mg: 10 or 30 pcs.

Dosage Form, Packaging, and Composition

Tablets white or almost white, round, flat-cylindrical, with a bevel.

Excipients: microcrystalline cellulose – 132.5 mg, sodium carboxymethyl starch – 5 mg, magnesium stearate – 1.5 mg, colloidal anhydrous silicon dioxide (anhydrous aerosil) – 1 mg.

10 pcs. – contour cell packaging (3) – cardboard packs.
10 pcs. – contour cell packaging (5) – cardboard packs.
10 pcs. – contour cell packaging (6) – cardboard packs.
30 pcs. – contour cell packaging (2) – cardboard packs.
30 pcs. – contour cell packaging (3) – cardboard packs.
30 pcs. – polymer jars – cardboard packs.
30 pcs. – polymer bottles – cardboard packs.

Tablets white or almost white, round, flat-cylindrical, with a bevel.

Excipients: microcrystalline cellulose – 174 mg, sodium carboxymethyl starch – 7 mg, magnesium stearate – 2 mg, colloidal anhydrous silicon dioxide (anhydrous aerosil) – 2 mg.

10 pcs. – contour cell packaging (3) – cardboard packs.
10 pcs. – contour cell packaging (5) – cardboard packs.
10 pcs. – contour cell packaging (6) – cardboard packs.
30 pcs. – contour cell packaging (2) – cardboard packs.
30 pcs. – contour cell packaging (3) – cardboard packs.
30 pcs. – polymer jars – cardboard packs.
30 pcs. – polymer bottles – cardboard packs.

Tablets white or almost white, round, flat-cylindrical, with a bevel and a score on one side.

Excipients: microcrystalline cellulose – 222 mg, sodium carboxymethyl starch – 8.5 mg, magnesium stearate – 2.5 mg, colloidal anhydrous silicon dioxide (anhydrous aerosil) – 2 mg.

10 pcs. – contour cell packaging (3) – cardboard packs.
10 pcs. – contour cell packaging (5) – cardboard packs.
10 pcs. – contour cell packaging (6) – cardboard packs.
30 pcs. – contour cell packaging (2) – cardboard packs.
30 pcs. – contour cell packaging (3) – cardboard packs.
30 pcs. – polymer jars – cardboard packs.
30 pcs. – polymer bottles – cardboard packs.

Tablets white or almost white, round, flat-cylindrical, with a bevel and a score on one side.

Excipients: microcrystalline cellulose – 265 mg, sodium carboxymethyl starch – 10 mg, magnesium stearate – 3 mg, colloidal anhydrous silicon dioxide (anhydrous aerosil) – 2 mg.

10 pcs. – contour cell packaging (3) – cardboard packs.
10 pcs. – contour cell packaging (5) – cardboard packs.
10 pcs. – contour cell packaging (6) – cardboard packs.
30 pcs. – contour cell packaging (2) – cardboard packs.
30 pcs. – contour cell packaging (3) – cardboard packs.
30 pcs. – polymer jars – cardboard packs.
30 pcs. – polymer bottles – cardboard packs.

Clinical-Pharmacological Group

Antihypertensive combination drug (selective beta₁-adrenergic blocker + slow calcium channel blocker)

Pharmacotherapeutic Group

Antihypertensive agent, combination (selective beta1-adrenergic blocker + slow calcium channel blocker (CCB))

Pharmacological Action

This medicinal product has pronounced antihypertensive and antianginal effects due to the complementary action of two active ingredients: the CCB amlodipine and the selective beta₁-adrenergic blocker bisoprolol.

Mechanism of action of amlodipine

Amlodipine blocks calcium channels, reduces the transmembrane transition of calcium ions into the cell (more in vascular smooth muscle cells than in cardiomyocytes).

The antihypertensive effect of amlodipine is due to a direct relaxing effect on vascular smooth muscle cells, which leads to a decrease in total peripheral vascular resistance.

The mechanism of antianginal action is not fully understood, it may be related to the following two effects.

Expansion of peripheral arterioles reduces total peripheral vascular resistance, i.e., afterload. Since Amlodipine does not cause reflex tachycardia, myocardial energy and oxygen consumption is reduced.

Expansion of large coronary arteries and coronary arterioles improves oxygen supply to both normal and ischemic areas of the myocardium. Due to these effects, myocardial oxygen supply is improved, even with coronary artery spasm (Prinzmetal’s angina or unstable angina).

In patients with arterial hypertension, taking the drug once a day causes a clinically significant reduction in blood pressure in the supine and standing positions throughout the 24-hour interval between doses. Due to the slow development of the antihypertensive effect of amlodipine, it does not cause acute arterial hypotension.

In patients with angina, taking the drug once daily increases total exercise time, time to onset of angina attack, and time to significant ST-segment depression, and also reduces the frequency of angina attacks and the need for sublingual nitroglycerin.

No negative effect of amlodipine on plasma lipid metabolism, blood glucose, and serum uric acid was found.

Mechanism of action of bisoprolol

Bisoprolol is a selective beta₁-adrenergic blocker without intrinsic sympathomimetic activity and does not have membrane-stabilizing action.

It has only slight affinity for the β₂-adrenergic receptors of bronchial and vascular smooth muscle, as well as for the beta2-adrenergic receptors involved in metabolic regulation. Therefore, bisoprolol generally does not affect airway resistance and metabolic processes involving β₂-adrenergic receptors.

The selective action of the drug on β₁-adrenergic receptors is maintained even beyond the therapeutic range.

Bisoprolol does not have a pronounced negative inotropic effect.

The maximum effect of the drug is achieved 3-4 hours after oral administration. Even when bisoprolol is prescribed once a day, its therapeutic effect lasts for 24 hours due to the plasma T_1/2, which is 10-12 hours. As a rule, the maximum antihypertensive effect is achieved 2 weeks after the start of treatment.

Bisoprolol reduces the activity of the sympathoadrenal system by blocking cardiac β₁-adrenergic receptors.

With a single oral dose in patients with coronary artery disease without signs of chronic heart failure, bisoprolol reduces heart rate, reduces cardiac stroke volume and, as a result, reduces ejection fraction and myocardial oxygen demand. During long-term therapy, the initially increased total peripheral vascular resistance decreases. The reduction in plasma renin activity is considered one of the components of the hypotensive action of beta-adrenergic blockers.

Pharmacokinetics

Amlodipine

Absorption

Amlodipine is well absorbed after oral administration. C_max in plasma is observed after 6-12 hours. Taking the drug with food does not affect its absorption. Absolute bioavailability is 64-80%.

Distribution

Apparent V_d is 21 L/kg. Equilibrium plasma concentration (5-15 ng/ml) is reached after 7-8 days of starting the drug.

In vitro studies have shown that circulating Amlodipine is approximately 93-98% bound to plasma proteins.

Amlodipine penetrates the blood-brain barrier.

Metabolism and excretion

Amlodipine undergoes intensive metabolism in the liver. Approximately 90% of the ingested dose is converted to inactive pyridine derivatives. Approximately 10% of the ingested dose is excreted unchanged in the urine. Approximately 60% of the amount of inactive metabolites is excreted by the kidneys and 20-25% through the intestines. The decrease in plasma concentration is biphasic. The terminal T_1/2 is approximately 35-50 hours, which allows the drug to be administered once a day. Total clearance is 7 ml/min/kg (25 L/h in patients weighing 60 kg). In elderly patients, it is 19 L/h.

Special patient groups

No significant changes in the pharmacokinetics of amlodipine were observed in elderly patients and patients with renal failure.

Due to reduced clearance, patients with hepatic impairment should be prescribed lower initial doses.

Bisoprolol

Absorption

Bisoprolol is almost completely (more than 90%) absorbed from the gastrointestinal tract. The bioavailability of bisoprolol due to insignificant first-pass metabolism in the liver (at a level of approximately 10%) is about 90% after oral administration. Food intake does not affect bioavailability. Bisoprolol exhibits linear kinetics, with plasma concentrations proportional to the dose taken in the range from 5 to 20 mg. C_max in plasma is reached after 2-3 hours.

Distribution

Bisoprolol is distributed quite widely. V_d is 3.5 L/kg. Binding to plasma proteins reaches approximately 30%.

Metabolism

It is metabolized via the oxidative pathway without subsequent conjugation. All metabolites are polar (water-soluble) and are excreted by the kidneys. The main metabolites found in plasma and urine do not exhibit pharmacological activity. Data from in vitro experiments with human liver microsomes show that bisoprolol is metabolized primarily by the CYP3A4 isoenzyme (about 95%), and the CYP2D6 isoenzyme plays only a minor role.

Excretion

The clearance of bisoprolol is determined by the balance between renal excretion unchanged (about 50%) and hepatic metabolism (about 50%) to metabolites, which are also excreted by the kidneys. Total clearance is 15 L/h. T_1/2 – 10-12 hours.

Indications

• Arterial hypertension: replacement therapy with single-component preparations of amlodipine and bisoprolol in the same doses.

ICD codes

Dosage Regimen

The drug is taken orally.

The tablets should be taken in the morning, regardless of food intake, without chewing.

The recommended daily dose is 1 tablet per day of a specific dosage.

Selection and titration of the dose individually for each patient is carried out by the doctor during the prescription of single-component preparations containing the active substances included in the drug Bisoprolol AML.

Duration of treatment

Treatment with Bisoprolol AML is usually long-term therapy.

Impaired liver function

In patients with impaired liver function, the elimination of amlodipine may be slowed. A special dosage regimen for this group of patients has not been established, however, the drug in this case should be prescribed with caution. For patients with severe liver dysfunction, the maximum daily dose of bisoprolol is 10 mg.

Impaired renal function

Patients with mild or moderate renal impairment generally do not require dosage adjustment. Amlodipine is not removed by dialysis. Amlodipine should be prescribed with particular caution to patients undergoing dialysis.

For patients with severe renal impairment (creatinine clearance less than 20 ml/min), the maximum daily dose of bisoprolol is 10 mg.

Elderly patients

The drug can be prescribed to elderly patients in usual doses. Caution is required only when increasing the dose.

Children

The drug is not recommended for use in children under 18 years of age due to the lack of data on efficacy and safety.

Treatment should not be stopped abruptly, as this may lead to a temporary deterioration in clinical condition. Especially, treatment should not be abruptly discontinued in patients with coronary artery disease. A gradual dose reduction is recommended.

Adverse Reactions

Undesirable side reactions observed when using the active ingredients separately are presented in accordance with the following frequency grouping criteria: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000), unknown (cannot be estimated from the available data).

Amlodipine

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

Immune system disorders very rare – allergic reactions.

Metabolism and nutrition disorders very rare – hyperglycemia.

Psychiatric disorders uncommon – insomnia, mood changes (including anxiety), depression; rare – confusion.

Nervous system disorders common – headache, dizziness, drowsiness (especially at the beginning of treatment); uncommon – syncope, hypoesthesia, paresthesia, dysgeusia, tremor; very rare – muscle hypertonia, peripheral neuropathy.

Eye disorders uncommon – visual impairment (including diplopia).

Ear and labyrinth disorders uncommon – tinnitus.

Gastrointestinal disorders common – nausea, abdominal pain; uncommon – vomiting, change in bowel habits (including constipation or diarrhea); dyspepsia, dry oral mucosa; very rare – gastritis, gingival hyperplasia, pancreatitis.

Hepatobiliary disorders: very rare – hepatitis*, jaundice*.

Cardiac disorders common – palpitations; very rare – myocardial infarction, arrhythmia (bradycardia, ventricular tachycardia, atrial fibrillation).

Vascular disorders common – flushing; uncommon – marked decrease in blood pressure; very rare – vasculitis.

Respiratory, thoracic and mediastinal disorders uncommon – dyspnea, rhinitis; very rare – cough.

Renal and urinary disorders uncommon – pollakiuria, painful urination, nocturia.

Reproductive system and breast disorders uncommon – impotence, gynecomastia.

Musculoskeletal and connective tissue disorders: common – ankle edema; uncommon – arthralgia, myalgia, muscle cramps, back pain.

Skin and subcutaneous tissue disorders uncommon – alopecia, purpura, skin discoloration, hyperhidrosis, pruritus, rash, exanthema; very rare – angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke’s edema, photosensitivity.

General disorders and administration site conditions common – peripheral edema, increased fatigue; uncommon – chest pain, asthenia, pain, general malaise.

Investigations: uncommon – weight increase, weight decrease; very rare – increased liver enzyme activity*.

*In most cases with cholestasis

Bisoprolol

Metabolism and nutrition disorders rare – increased triglyceride concentration.

Psychiatric disorders uncommon – depression; rare – hallucinations, nightmares.

Nervous system disorders common – headache**, dizziness; uncommon – insomnia; rare – syncope.

Eye disorders rare – decreased lacrimation (should be considered when wearing contact lenses); very rare – conjunctivitis.

Ear and labyrinth disorders rare – hearing impairment.

Cardiac disorders uncommon – AV conduction disturbance, bradycardia, worsening of chronic heart failure symptoms.

Vascular disorders common – feeling of cold or numbness in the extremities, marked decrease in blood pressure; uncommon – orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders uncommon – bronchospasm in patients with a history of bronchial asthma or airway obstruction; rare – allergic rhinitis.

Gastrointestinal disorders common – nausea, vomiting, diarrhea, constipation.

Hepatobiliary disorders rare – hepatitis.

Skin and subcutaneous tissue disorders rare – hypersensitivity reactions such as skin itching, rash, skin hyperemia; very rare – alopecia. Beta-adrenergic blockers may exacerbate the symptoms of psoriasis or cause psoriasis-like rash.

Musculoskeletal and connective tissue disorders uncommon – muscle weakness, muscle cramps.

Reproductive system and breast disorders rare – impotence.

General disorders and administration site conditions common – increased fatigue; uncommon – exhaustion.

Investigations rare – increased activity of liver transaminases in the blood (AST, ALT).

** These symptoms occur especially frequently at the beginning of the course of treatment. Usually these phenomena are mild and disappear, as a rule, within 1-2 weeks after the start of treatment.

Contraindications

For amlodipine

• Unstable angina (except for Prinzmetal’s angina);
• Hemodynamically unstable heart failure after myocardial infarction;
• Clinically significant aortic stenosis.

For bisoprolol

• Acute heart failure or chronic heart failure in the decompensation stage requiring inotropic therapy;
• Second- and third-degree AV block, without a pacemaker;
• Sick sinus syndrome;
• Sinoatrial block;
• Severe bradycardia (heart rate less than 60 beats/min);
• Severe forms of bronchial asthma or chronic obstructive pulmonary disease (COPD);
• Severe peripheral arterial circulatory disorders or Raynaud’s syndrome;
• Pheochromocytoma (without simultaneous use of alpha-blockers);
• Metabolic acidosis.

For the Amlodipine/bisoprolol combination

• Hypersensitivity to amlodipine, other dihydropyridine derivatives, bisoprolol and/or any of the excipients;
• Severe arterial hypotension (systolic BP less than 100 mm Hg);
• Shock (including cardiogenic);
• Children under 18 years of age (efficacy and safety have not been established).

With caution

CHF (including non-ischemic etiology NYHA functional class III-IV), hepatic insufficiency, renal insufficiency, hyperthyroidism, diabetes mellitus with significant fluctuations in blood glucose concentration, first-degree AV block, Prinzmetal’s angina, occlusive peripheral arterial diseases, psoriasis (including history), fasting (strict diet), pheochromocytoma (with simultaneous use of alpha-blockers), bronchial asthma and COPD, concurrent desensitizing therapy, general anesthesia, elderly age, arterial hypotension, type 1 diabetes mellitus, aortic stenosis, mitral stenosis, acute myocardial infarction (after the first 28 days).

Use in Pregnancy and Lactation

Amlodipine

Experimental studies have not established fetotoxic or embryotoxic effects of the drug, but 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 dihydropyridine-derived CCBs are excreted in breast milk. Therefore, if it is necessary to prescribe amlodipine during lactation, the issue of discontinuing breastfeeding should be considered.

Bisoprolol

The use of bisoprolol during pregnancy is possible only if the intended benefit to the mother outweighs the potential risk to the fetus. Beta-blockers reduce blood flow in the placenta and may affect fetal development.

Placental and uterine blood flow should be monitored, and the growth and development of the unborn child should be observed, and if adverse events occur regarding the pregnancy and/or fetus, alternative therapy methods should be used. The newborn should be carefully examined after delivery. Symptoms of bradycardia and hypoglycemia may occur during the first three days of life.

There are no data on the excretion of bisoprolol into breast milk. Therefore, its use is not recommended for women during breastfeeding. If bisoprolol use during lactation is necessary, breastfeeding should be discontinued.

Use in Hepatic Impairment

In patients with impaired liver function, the elimination of amlodipine may be slowed. A specific dosage regimen for this group of patients has not been established, but the drug should be prescribed with caution in this case. For patients with severe hepatic impairment, the maximum daily dose of bisoprolol is 10 mg.

Use in Renal Impairment

For patients with mild or moderate renal impairment, dosage adjustment is generally not required. Amlodipine is not removed by dialysis. Amlodipine should be prescribed to patients undergoing dialysis with particular caution.

For patients with severe renal impairment (creatinine clearance less than 20 ml/min), the maximum daily dose of bisoprolol is 10 mg.

Geriatric Use

The drug can be prescribed to elderly patients at usual doses. Caution is required only when increasing the dose.

Special Precautions

Amlodipine

In patients with impaired liver function, the T_1/2 of amlodipine increases.

When prescribing the drug to such patients, caution should be exercised and liver enzyme activity should be regularly monitored.

Caution should be exercised when prescribing amlodipine to patients with CHF.

In patients with CHF (including non-ischemic etiology NYHA functional class III-IV), Amlodipine increases the risk of pulmonary edema, which is not associated with worsening of CHF symptoms.

During therapy with amlodipine, it is necessary to monitor body weight and salt intake, and an appropriate diet is indicated.

Maintenance of oral hygiene and observation by a dentist is necessary (to prevent soreness, bleeding, and gingival hyperplasia).

In vitro fertilization (IVF): in isolated cases during IVF while using CCBs, reversible biochemical changes in the sperm head were noted, leading to impaired sperm function.
In case of unsuccessful IVF attempts and after excluding other causes of infertility, the possibility of the effect of CCBs on sperm should be taken into account, provided they are used.

Bisoprolol

Monitoring of patients taking bisoprolol should include measurement of heart rate and BP, ECG, determination of blood glucose concentration in patients with diabetes mellitus (once every 4-5 months). In elderly patients, it is recommended to monitor renal function (once every 4-5 months).

The patient should be taught the method of counting heart rate and instructed on the need for medical consultation if the heart rate is less than 60 beats/min.

Before starting treatment, it is recommended to examine the function of external respiration in patients with a burdened bronchopulmonary history.

Patients using contact lenses should be aware that during treatment with the drug, a decrease in tear fluid production is possible.

When using bisoprolol in patients with pheochromocytoma, there is a risk of developing paradoxical arterial hypertension (if effective blockade of α-adrenergic receptors has not been previously achieved).

In hyperthyroidism, bisoprolol may mask certain clinical signs of hyperthyroidism (e.g., tachycardia). Abrupt withdrawal of the drug should be avoided in patients with hyperthyroidism to avoid exacerbation of symptoms.

In diabetes mellitus, it may mask tachycardia caused by hypoglycemia. Unlike non-selective beta-blockers, it practically does not enhance insulin-induced hypoglycemia and does not delay the restoration of blood glucose concentration to normal levels.

With simultaneous use of clonidine, its administration can be discontinued only several days after discontinuation of bisoprolol. Increased severity of hypersensitivity reactions and lack of effect from usual doses of epinephrine (adrenaline) may occur in patients with a burdened allergic history.

If planned surgical treatment is necessary, bisoprolol should be discontinued 48 hours before general anesthesia. If the patient has taken bisoprolol before surgery, an agent for general anesthesia with minimal negative inotropic effect should be selected for him.

Reciprocal vagus nerve activation can be eliminated by intravenous administration of atropine (1-2 mg).

Drugs that deplete catecholamine stores (including reserpine) may enhance the effect of beta-blockers, so patients taking such combinations of drugs should be under constant medical supervision for detection of marked decrease in BP or bradycardia.

Patients with bronchospastic diseases can be prescribed cardioselective beta-blockers with caution in case of intolerance and/or ineffectiveness of other antihypertensive agents while simultaneously using bronchodilators. During treatment with beta-blockers, airway resistance may increase in patients with concomitant bronchial asthma. If the dose of bisoprolol is exceeded in such patients, there is a danger of developing bronchospasm.

If increasing bradycardia (heart rate less than 60 beats/min.), marked decrease in BP (systolic BP less than 100 mm Hg), AV block is detected in patients, it is necessary to reduce the dose or discontinue treatment.

It is recommended to discontinue bisoprolol therapy if depression develops.

Treatment should not be abruptly interrupted due to the risk of developing severe arrhythmias and myocardial infarction. The drug should be withdrawn gradually, reducing the dose over 2 weeks or more (reduce the dose by 25% every 3-4 days).

The drug should be discontinued before testing the concentration of catecholamines, normetanephrine, vanillylmandelic acid in blood and urine, and antinuclear antibody titers.

In smokers, the effectiveness of beta-blockers is lower.

Effect on ability to drive vehicles and operate machinery

During treatment with the drug, caution must be exercised when driving vehicles and working with complex machinery.

Overdose

Amlodipine

Symptoms marked decrease in BP with possible development of reflex tachycardia and excessive peripheral vasodilation (risk of developing marked and persistent arterial hypotension, including with the development of shock and fatal outcome).

Treatment gastric lavage, administration of activated charcoal, maintenance of cardiovascular function, monitoring of heart and lung function parameters, elevated position of the limbs, control of circulating blood volume and diuresis. Intensive symptomatic therapy. To restore vascular tone – use of vasoconstrictor drugs (in the absence of contraindications to their use); to eliminate the effects of calcium channel blockade – intravenous administration of calcium gluconate. Hemodialysis is not effective.

Bisoprolol

Symptoms AV block, marked bradycardia; marked decrease in BP, bronchospasm, acute heart failure and hypoglycemia. Sensitivity to a single high dose of bisoprolol varies greatly among individual patients and patients with CHF are likely to be highly sensitive.

Treatment in case of overdose, first of all, it is necessary to stop taking the drug and begin supportive symptomatic therapy.

For marked bradycardia: intravenous administration of atropine. If the effect is insufficient, an agent with a positive chronotropic effect can be administered with caution. Sometimes temporary placement of a pacemaker may be required.

For marked decrease in BP: intravenous administration of plasma-substituting solutions and vasopressor drugs. Intravenous administration of glucagon may also be indicated.

For AV block: patients should be under constant observation and receive treatment with beta-adrenergic agonists such as epinephrine. If necessary, placement of a pacemaker.

For exacerbation of CHF: intravenous administration of diuretics, drugs with a positive inotropic effect, and vasodilators.

For bronchospasm: administration of bronchodilators, including beta₂-adrenergic agonists and/or aminophylline.

For hypoglycemia: intravenous administration of dextrose (glucose).

Bisoprolol is practically not dialyzable.

Drug Interactions

Amlodipine

Simultaneous use of amlodipine with thiazide diuretics, beta-blockers, long-acting nitrates, sublingual nitroglycerin preparations, NSAIDs, antibiotics and oral hypoglycemic agents is considered safe.

CYP3A4 inhibitors: Amlodipine should be used with caution simultaneously with CYP3A4 inhibitors.

Strong and moderate CYP3A4 inhibitors (e.g., protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) may increase the plasma concentration of amlodipine to clinically significant levels.

CYP3A4 inducers: simultaneous use with CYP3A4 inducers (including rifampicin, St. John’s wort) may lead to a decrease in the plasma concentration of amlodipine. Amlodipine should be used with caution simultaneously with CYP3A4 inducers.

Simvastatin: Simultaneous use with amlodipine may lead to an increase in the plasma concentration of simvastatin. Patients taking Amlodipine are not recommended to use simvastatin at a dose exceeding 20 mg/day.

Grapefruit juice, cimetidine, aluminum/magnesium (in antacids) and sildenafil do not affect the pharmacokinetics of amlodipine.

Amlodipine may enhance the antihypertensive effect of other antihypertensive agents.

Amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, ethanol (alcoholic beverages), warfarin or cyclosporine.

Amlodipine does not affect laboratory parameters.

Bisoprolol

Not recommended combinations

Calcium channel blockers (CCBs) of the verapamil type and, to a lesser extent, diltiazem, when used simultaneously with bisoprolol, can lead to a decrease in myocardial contractility, marked decrease in BP and impaired AV conduction. In particular, intravenous administration of verapamil to patients taking beta-blockers can lead to marked arterial hypotension and AV block.

Centrally acting antihypertensive agents (such as clonidine, methyldopa, moxonidine, rilmenidine) when used simultaneously with bisoprolol can lead to a decrease in heart rate and cardiac output, as well as vasodilation due to a decrease in central sympathetic tone. Abrupt withdrawal, especially before discontinuation of beta-blockers, may increase the risk of “rebound” arterial hypertension.

Combinations requiring caution

Dihydropyridine-derived CCBs (e.g., nifedipine) when used simultaneously with bisoprolol may increase the risk of arterial hypotension. In patients with CHF, the risk of subsequent deterioration of cardiac contractile function cannot be excluded.

Class I antiarrhythmic agents (e.g., quinidine, disopyramide, lidocaine, phenytoin, flecainide, propafenone) when used simultaneously with bisoprolol may reduce AV conduction and myocardial contractility.

Class III antiarrhythmic agents (e.g., amiodarone) may enhance the impairment of AV conduction.

Parasympathomimetics when used simultaneously with bisoprolol may enhance the impairment of AV conduction and increase the risk of bradycardia.

The action of topical beta-blockers (e.g., eye drops for glaucoma treatment) may enhance the systemic effects of bisoprolol (decrease in BP, decrease in heart rate).

The hypoglycemic effect of insulin or oral hypoglycemic agents may be enhanced. Signs of hypoglycemia – in particular tachycardia – may be masked. Such interaction is more likely with the use of non-selective beta-blockers.

Agents for general anesthesia may attenuate reflex tachycardia and increase the risk of arterial hypotension.

Cardiac glycosides when used simultaneously with bisoprolol may lead to an increase in impulse conduction time and the development of bradycardia.

NSAIDs may reduce the antihypertensive effect of bisoprolol.

Simultaneous use of bisoprolol with beta-adrenergic agonists (e.g., isoprenaline, dobutamine) may lead to a reduction in the effect of both drugs.

The combination of bisoprolol with adrenergic agonists affecting β- and α-adrenergic receptors (e.g., norepinephrine, epinephrine) may enhance the vasoconstrictor effects of these agents mediated by α-adrenergic receptors, leading to an increase in BP. Such interaction is more likely with the use of non-selective beta-blockers.

Antihypertensive agents, as well as other agents with possible antihypertensive effect (e.g., tricyclic antidepressants, barbiturates, phenothiazines) may enhance the antihypertensive effect of bisoprolol.

Combinations to be considered

Mefloquine when used simultaneously with bisoprolol may increase the risk of bradycardia.

MAO inhibitors (except for MAO B inhibitors) may enhance the antihypertensive effect of beta-blockers. Simultaneous use may also lead to the development of a hypertensive crisis.

Rifampicin slightly shortens the T_1/2 of bisoprolol. As a rule, dose adjustment is not required.

Ergotamine derivatives when used simultaneously with bisoprolol increase the risk of peripheral circulatory disorders.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years.

Dispensing Status

The drug is dispensed by prescription.

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.