Niperten^® Combi (Tablets) Instructions for Use

ATC Code

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

Active Substances

Bisoprolol (Rec.INN registered by WHO)

Amlodipine (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Beta₁-adrenoblocker

Pharmacotherapeutic Group

Beta-adrenergic blockers; beta-adrenergic blockers, other combinations; beta-adrenergic blockers and calcium channel blockers

Pharmacological Action

A combined antihypertensive drug. It has pronounced antihypertensive and antianginal effects due to the complementary action of two active substances: a slow calcium channel blocker – amlodipine and a selective beta₁-adrenergic blocker – bisoprolol.

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 associated with the following two effects.

• Dilation of peripheral arterioles reduces total peripheral vascular resistance, i.e., afterload. Since amlodipine does not cause reflex tachycardia, myocardial energy and oxygen consumption decreases;
• Dilation of large coronary arteries and coronary arterioles improves oxygen supply to both normal and ischemic areas of the myocardium. This improves myocardial oxygen supply, even during 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 for 24 hours. Due to the slow development of the antihypertensive effect, amlodipine does not cause a sharp decrease in blood pressure.

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

No negative effect of amlodipine on the concentration of lipids, glucose and uric acid in the blood serum was found.

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

The selective action of the drug on beta₁-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, since its T_1/2 from blood plasma 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 beta₁-adrenergic receptors of the heart.

With a single oral dose in patients with coronary artery disease without signs of chronic heart failure, bisoprolol reduces heart rate, decreases 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 decrease in plasma renin activity is considered one of the components of the hypotensive action of beta-adrenergic blockers.

Pharmacokinetics

Amlodipine

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

Apparent V_d is 21 L/kg. C_ss in blood plasma (5-15 ng/ml) is achieved after 7-8 days from the start of drug administration. In vitro studies have shown that binding to plasma proteins is 93-98%.

Amlodipine undergoes intensive metabolism in the liver. Approximately 90% of the administered dose is converted into inactive pyridine derivatives. Approximately 10% of the administered 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 a patient weighing 60 kg), in elderly patients – 19 L/h.

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

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

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

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 obtained from experiments with human liver microsomes in vitro show that bisoprolol is metabolized primarily by the CYP3A4 isoenzyme (about 95%), and the CYP2D6 isoenzyme plays only a minor role.

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 in the urine. Total clearance is 15 L/h. T_1/2 is 10-12 hours.

Indications

Treatment of arterial hypertension (for replacement therapy with single-component preparations of amlodipine and bisoprolol in the same doses).

ICD codes

Dosage Regimen

Tablets

Take orally.

The recommended daily dose is 1 tablet of a certain dosage. Therapy is long-term.

The selection and titration of the dose is carried out by the doctor individually for each patient during the prescription of single-component preparations containing the active substances that are part of the combined preparation.

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, 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.

Patients with mild or moderate renal impairment usually do not require adjustment of the dosage regimen. Amlodipine is not removed by dialysis. Patients on hemodialysis should be prescribed amlodipine 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.

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

When discontinuing the drug, a gradual dose reduction is recommended, since abrupt cessation of therapy may lead to a temporary deterioration in clinical condition, especially in patients with coronary artery disease.

Adverse Reactions

Amlodipine

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

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; frequency unknown – extrapyramidal disorders.

Eye disorders uncommon – visual impairment (including diplopia).

Ear and labyrinth disorders: uncommon – tinnitus.

Cardiac disorders common – palpitations, flushing; uncommon – marked decrease in blood pressure, arrhythmia (bradycardia, ventricular tachycardia, atrial fibrillation); very rare – myocardial infarction, vasculitis.

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

Gastrointestinal disorders common – nausea, abdominal pain, change in bowel habits (including constipation or diarrhea), dyspepsia; uncommon – dry mouth, vomiting; very rare – gastritis, gingival hyperplasia, pancreatitis, hepatitis (mostly with cholestasis), jaundice (mostly with cholestasis), increased activity of liver enzymes (mostly with cholestasis).

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

Reproductive system and breast disorders: uncommon – impotence, gynecomastia.

Musculoskeletal and connective tissue disorders common – muscle cramps; uncommon – arthralgia, myalgia.

Immune system disorders uncommon – urticaria; very rare – angioedema.

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

General disorders and administration site conditions very common – edema; common – ankle edema, increased fatigue, asthenia; uncommon – chest pain, back pain, pain of unspecified localization, general malaise, weight increased, weight decreased.

Bisoprolol

Metabolism and nutrition disorders rare – increased concentration of triglycerides in blood plasma.

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

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

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

Ear and labyrinth disorders: rare – hearing disorders.

Cardiac disorders common – feeling of cold or numbness in the extremities, marked decrease in blood pressure; uncommon – AV conduction disturbance, bradycardia, worsening of chronic heart failure symptoms, orthostatic hypotension.

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

Gastrointestinal disorders common – nausea, vomiting, diarrhea, constipation; rare – hepatitis, increased activity of liver transaminases in the blood (AST and ALT).

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*.

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

Contraindications

Amlodipine

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

Bisoprolol

Acute heart failure or chronic heart failure in the stage of decompensation, requiring inotropic therapy; AV block II and III degree without a pacemaker; sick sinus syndrome; sinoatrial block; severe bradycardia (heart rate less than 60 beats/min); severe forms of bronchial asthma or COPD; severe peripheral arterial circulation disorders or Raynaud’s syndrome; pheochromocytoma (without simultaneous use of alpha-adrenergic blockers); metabolic acidosis.

Amlodipine/bisoprolol combination

Severe arterial hypotension (systolic blood pressure less than 100 mm Hg); shock (including cardiogenic); age under 18 years (efficacy and safety not established); hypersensitivity to amlodipine, other dihydropyridine derivatives, bisoprolol.

With caution

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

Use in Pregnancy and Lactation

Use during pregnancy is possible only if the intended benefit to the mother outweighs the potential risk to the fetus.

If it is necessary to use the drug during lactation, breastfeeding should be discontinued.

Amlodipine

In experimental studies, fetotoxic and embryotoxic effects of the drug were not established, but use during pregnancy is possible only if the benefit to the mother outweighs the possible 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 amlodipine during lactation, the issue of discontinuing breastfeeding should be decided.

Bisoprolol

Use of bisoprolol during pregnancy is possible only if the intended benefit to the mother outweighs the potential risk to the fetus.

Beta-adrenergic blockers reduce blood flow in the placenta and may affect fetal development. Blood flow in the placenta and uterus should be monitored, and the growth and development of the unborn child should be observed. If adverse events occur in relation to pregnancy and/or the fetus, alternative therapy should be prescribed. The newborn should be carefully examined after birth. Symptoms of bradycardia and hypoglycemia may occur in the first three days of life.

There are no data on the excretion of bisoprolol in breast milk. If treatment with bisoprolol is necessary during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

The drug should be prescribed with caution in hepatic insufficiency.

Use in Renal Impairment

The drug should be prescribed with caution in renal insufficiency.

Pediatric Use

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

Geriatric Use

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

Special Precautions

Patients with heart failure should take amlodipine with caution. In patients with heart failure III-IV FC according to NYHA classification, amlodipine increases the risk of pulmonary edema, which is not associated with worsening symptoms of chronic heart failure.

Discontinuation of bisoprolol treatment should not be sudden, especially in patients with coronary artery disease, unless there are clear indications for drug withdrawal. Sudden withdrawal of bisoprolol may lead to temporary worsening of cardiovascular pathology.

Bisoprolol should be used with particular caution in patients with arterial hypertension or angina in combination with heart failure.

As with other beta-adrenergic blockers, bisoprolol may cause increased sensitivity to allergens and enhanced anaphylactic reactions, so caution should be exercised during simultaneous desensitizing therapy. The use of epinephrine may not always give the expected therapeutic effect.

When using bisoprolol, symptoms of hyperthyroidism may be masked.

In patients with pheochromocytoma, bisoprolol should be prescribed only against the background of the use of alpha-adrenergic blockers.

Before general anesthesia, the anesthesiologist must be informed about the patient’s intake of beta-adrenergic blockers. If it is necessary to cancel the beta-adrenergic blocker before surgery, this should be done gradually and completed approximately 48 hours before anesthesia.

In bronchial asthma or COPD, simultaneous use of bronchodilators is indicated. In patients with bronchial asthma, an increase in airway resistance is possible, which requires a higher dose of beta₂-adrenergic agonists.

Although beta₁-adrenergic blockers have less effect on lung function than non-selective beta-adrenergic blockers, the use of any beta-adrenergic blockers in patients with COPD should be avoided unless there are compelling clinical reasons for their use. If clinically necessary, bisoprolol should be used with caution. In patients with COPD, bisoprolol therapy should be started with the lowest possible dose. The appearance of new symptoms (e.g., shortness of breath, exercise intolerance, cough) should be carefully monitored.

Effect on the Ability to Drive Vehicles and Operate Machinery

During treatment with the drug, caution should be exercised when driving vehicles and working with technically complex machinery requiring increased concentration and speed of psychomotor reactions.

Drug Interactions

Amlodipine

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

Amlodipine should be used with caution concomitantly with CYP3A4 inhibitors.

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

Concomitant use with CYP3A4 inducers (including rifampicin, Hypericum perforatum) may lead to a decrease in the plasma concentration of amlodipine. Amlodipine should be used with caution concomitantly with CYP3A4 inducers.

Concomitant multiple administration of amlodipine 10 mg and simvastatin 80 mg leads to a 77% increase in simvastatin exposure. Patients taking amlodipine are not recommended to use simvastatin at doses 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.

Amlodipine has no effect on laboratory parameters.

When used concomitantly with amlodipine, there is a risk of increased serum concentration of tacrolimus, but the pharmacokinetic mechanism of this interaction is not fully understood. To prevent the toxic effect of tacrolimus when used concomitantly with amlodipine, the plasma concentration of tacrolimus should be monitored and the dose of tacrolimus adjusted if necessary.

Clarithromycin is an inhibitor of the CYP3A4 isoenzyme. When amlodipine and clarithromycin are used concomitantly, there is an increased risk of arterial hypotension. Careful medical supervision of patients receiving amlodipine concomitantly with clarithromycin is recommended.

When amlodipine and cyclosporine are used concomitantly in patients who have undergone kidney transplantation, serum cyclosporine concentration should be monitored and its dose reduced if necessary.

Bisoprolol

Slow calcium channel blockers of the verapamil type and, to a lesser extent, diltiazem, when used concomitantly with bisoprolol, may lead to decreased myocardial contractility, pronounced decrease in BP, and impaired AV conduction. In particular, intravenous administration of verapamil to patients taking beta-blockers may lead to severe arterial hypotension and AV block.

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

Slow calcium channel blockers – dihydropyridine derivatives (e.g., nifedipine) when used concomitantly with bisoprolol may increase the risk of arterial hypotension. In patients with chronic heart failure, the risk of subsequent worsening of cardiac contractile function cannot be excluded.

Class I antiarrhythmic agents (e.g., quinidine, disopyramide, lidocaine, phenytoin, flecainide, propafenone) when used concomitantly 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 concomitantly with bisoprolol may enhance the impairment of AV conduction and increase the risk of bradycardia.

The action of topically applied beta-blockers (e.g., eye drops for glaucoma treatment) may enhance the systemic effects of bisoprolol (decreased BP, decreased 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.

General anesthetics may attenuate reflex tachycardia and increase the risk of arterial hypotension.

Cardiac glycosides when used concomitantly with bisoprolol may lead to increased conduction time and the development of bradycardia.

NSAIDs may reduce the antihypertensive effect of bisoprolol.

Concomitant 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 α- and β-adrenergic receptors (e.g., norepinephrine, epinephrine) may enhance the vasoconstrictor effects of these agents mediated by α-adrenergic receptors, leading to increased BP. Such interaction is more likely with the use of non-selective beta-blockers.

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

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

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

Rifampicin causes some shortening of the T_1/2 of bisoprolol. As a rule, dose adjustment is not required.

Ergotamine derivatives when used concomitantly with bisoprolol increase the risk of impaired peripheral circulation.

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.