Expiration date: 06/2025

Form of production, composition and packaging

Tablets, film-coated white color, round, biconvex, bevelled on two sides, and scored on one side.

1 tablet contains:

amlodipine besylate 6.935 mg, that corresponds to the content of amlodipine 5 mg

bisoprolol fumarate 5 mg

Excipients: magnesium stearate-1 mg; excipients of substance-granules: microcrystalline cellulose-133.065 mg, sodium carboxymethyl starch-5 mg, silicon colloidal dioxide-1 mg, magnesium stearate-1 mg.

1 tablet contains:

amlodipine bezilate 13, 87 mg, that corresponds to the content of amlodipine 10 mg

bisoprolol fumarate 5 mg

Excipients: magnesium stearate-2 mg, excipients of substance-granules: microcrystalline cellulose-273.065 mg, sodium carboxymethyl starch-10 mg, silicon colloidal dioxide-2 mg, magnesium stearate-2 mg.

Pharmacological action

The drug Niperten® Combi has a pronounced antihypertensive and antianginal effect due to the complementary action of two active substances: the blocker of "slow" calcium channels (bmcc) - amlodipine and selective beta 1-blocker - bisoprolol.

Mechanism of action of amlodipine

Amlodipine blocks the" slow " calcium channels and reduces the transmembrane current of calcium ions in the cell (to a greater extent in smooth muscle cells of blood vessels than in cardiomyocytes).

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

The mechanism of antianginal action until the end of NS studied, presumably it is associated with two effects:

• expanding peripheral arterioles reduces peripheral vascular resistance (afterload). Due to the lack of reflex tachycardia, energy and oxygen consumption of the myocardium is reduced.
  
• expansion of large coronary arteries and coronary arterioles improves the delivery of oxygen in both normal and ishemizirovanne areas of the myocardium, including coronary artery spasm (prinzmetals angina or unstable angina).
  

In patients with hypertension, taking amlodipine once a day causes a clinically significant decrease in blood pressure (BP) in the "lying" and "standing" position for 24 hours. Due to the slow development of the antihypertensive effect of amlodipine does not cause a sharp decrease in blood PRESSURE. In patients with angina pectoris, taking amlodipine 1 time per day increases the total time of physical activity, the time before the onset of angina pectoris and to a significant depression of the ST segment, and also reduces the frequency of angina attacks and the need for nitroglycerin (short-acting forms).

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

Mechanism of action of bisoprolol

Bisoprolol-selective beta 1-adrenoblokatorom, which does not have its own sympathomimetic activity and membrane stabilizing effect and is characterized by only a slight affinity for beta2-adrenoreceptoram smooth muscles of the bronchi and vessels, as well as to beta2-adrenoreceptors involved in the regulation of metabolism. Therefore, bisoprolol practically does not affect the respiratory tract resistance and metabolic processes, which are mediated through the action of PA beta2-adrenergic receptors. The selective action of bisoprolol on beta1-adrenoceptors is also preserved beyond the therapeutic range. Bisoprolol NS has a pronounced negative inotropic effect. The maximum effect is achieved in 3-4 hours after oral administration. Even with the appointment of bisoprolol I once a day, its therapeutic effect is maintained for 24 hours, since its half-life (T1 / 2) of blood plasma - 10-12 hours. As a rule, the maximum antihypertensive effect is achieved after 2 weeks after the start of treatment. Bisoprolol reduces the activity of the sympathoadrenal system, blocking beta1-adrenoceptors of the heart. With a single oral administration in patients with coronary heart disease (CHD) without signs of chronic heart failure (CHF), bisoprolol reduces the heart rate (heart rate), reduces the volume of the heart and, as a result, reduces the ejection fraction and the need for myocardium in oxygen. With long-term therapy, initially increased OPSS is reduced. Reduction of renin activity in blood plasma is considered as one of the mechanisms of antihypertensive action of beta-blockers.

Pharmacokinetics

Amlodipine

Suction

After oral amlodipine is well absorbed. The maximum concentration (Cmax) in the blood plasma is observed after 6-12 hours. The meal is not affected by the PA absorption of amlodipine. Absolute bioavailability ranges from 64 to 80 %.

Distribution

The apparent volume of distribution is approximately 21 l/kg. Equilibrium concentration in plasma (5-15 ng/ml) is achieved after 7-8 days after the start of treatment. In in vitro studies, plasma protein binding is 93-98 %. Metabolism and excretion

Amlodipine is actively metabolized in the liver. About 90 % of the dose is converted into inactive pyridine derivatives. Approximately 10 % of the dose is displayed at night in an unchanged form. Approximately 60 % of inactive metabolites are excreted by the kidneys, 20-25% - through the intestine. Reducing the concentration of amlodipine in blood plasma occurs in two phases. The final T1 / 2 is about 35-50 hours, which allows you to take the drug once a day. The total clearance is 7 ml/min/kg (25 l/hour in a patient weighing 60 kg), in elderly patients - 19 l / hour.

In elderly patients and patients with renal insufficiency there were no significant changes in the pharmacokinetics of amlodipine. Due to a decrease in clearance in patients with hepatic insufficiency should use a lower initial dose.

Bisoprolol

Suction

Bisoprolol is almost completely (more than 90 %) absorbed in the gastrointestinal tract (GI). Its bioavailability due to low biotransformation in the "primary passage" through the liver (about 10 %) is about 90% after ingestion. Eating does not affect bioavailability. The pharmacokinetics of bisoprolol is linear in the range of doses of 5-20 mg. Cmax in blood plasma is achieved after 2-3 hours.

Distribution

Bisoprolol is widely distributed. The volume of distribution is 3, 5 l / kg.Connection with plasma proteins - about 30%.

Metabolism

It is metabolized by oxidative pathway without subsequent conjugation. All metabolites are polar (water-soluble) and excreted by the kidneys. The main metabolites found in blood plasma and urine do not have pharmacological activity. In vitro studies on human liver microchips have shown that bisoprolol is metabolized primarily by CYP3A4 isoenzyme (about 95 %), and CYP2D6 isoenzyme plays only a minor role.

Breeding

The clearance of bisoprolol is determined by the balance between the excretion of the kidneys in unchanged form (about 50 %) and metabolism in the liver (about 50 %) with the formation of metabolites, which are also excreted by the kidneys. The total clearance is 15 l / h.

T1 / 2 - 10-12 hours.

Side effect

ezhelatelnye adverse reactions observed in the use of active substances separately, presented in accordance with the classification of e frequency of side effects of the world health organization( who): very often > 1/10; often > 1/100 - < 1/10; infrequently > 1/1000 - < 1/100; rarely > I /10000 - < 1/1000; very rare < 1/10000; the frequency is unknown (can not be estimated based on available data).

Amlodipine

Disorders of the blood and lymphatic system: very rare: leukopenia, thrombocytopenia.

Immune system disorders: very rare: allergic reactions.

Metabolic and nutritional disorders: very rare: hyperglycemia.

Psychiatric disorders: uncommon: insomnia, lability of mood (including anxiety), depression rare: confusion.

Violations of the nervous system: common: headache, dizziness, sleepiness (especially at the beginning of treatment); uncommon: syncope, hypoesthesia, paresthesia, dysgeusia, tremor very rare: muscular hypertension, peripheral neuropathy.

Visual organ disorders: infrequent: visual impairment (including diplopia).

Hearing disorders and labyrinth disorders: infrequent: tinnitus.

Disorders of the digestive system: often: nausea, abdominal pain; infrequent: vomiting, changes in the mode of defecation (including constipation or diarrhea), dyspepsia, dryness of the oral mucosa; very rarely: gastritis, hyperplasia of the gums, pancreatitis.

Disorders of the liver and biliary tract: very rare: hepatitis*, jaundice*.

Heart disorders: often: a feeling of heartbeat; very rare: myocardial infarction, arrhythmia (bradycardia, ventricular tachycardia, atrial fibrillation).

Vascular disorders: often: a feeling of" tides " of blood to the skin; infrequent: a marked decrease in blood PRESSURE; very rare: vasculitis.

Disorders of the respiratory system, chest and mediastinum: infrequent: shortness of breath, rhinitis; very rare: cough.

Disorders of the kidneys and urinary tract: infrequent: pollakiuriya, painful urge to urinate, nicturia.

Disorders of the genital organs and breast: infrequent: impotence, gynecomastia.

General disorders and disorders at the site of administration: often: peripheral edema, increased fatigue; infrequent: chest pain, asthenia, pain, unspecified localization, General malaise.

Disorders of the musculoskeletal and connective tissue: often: swelling of the ankles; infrequent: arthralgia, myalgia, muscle cramps, back pain.

Disorders of the skin and subcutaneous tissues: infrequent: alopecia, purpura, skin discoloration, increased sweating, itching, skin rash, exanthema; very rare: angioedema, multiforme exudative erythema, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, photosensitivity.

Laboratory and instrumental data: infrequent: weight gain, weight loss; very rare: increased activity of "liver" enzymes* in blood plasma.

* In most cases it is associated with cholestasis

Bisoprolol

Metabolic and nutritional disorders: rare: increased triglyceride concentration in blood plasma.

Psychiatric disorders: uncommon: depression rare: hallucinations, nightmares.

Violations of the nervous system: common: headache** dizziness**; uncommon: insomnia; rare: syncope.

Disorders on the part of the organ of vision: rarely: reduced tear (should be considered when wearing contact lenses); very rarely: conjunctivitis.

Hearing impairment and labyrinth disorders: rare: hearing impairment.

Heart disorders: infrequent: violation of AV conduction, bradycardia, exacerbation of symptoms of CHF.

Vascular disorders: often: a feeling of cold or numbness in the limbs, a marked decrease in blood PRESSURE; infrequently: orthostatic hypotension.

Disorders of the respiratory system, chest and mediastinal organs: infrequent: bronchospasm in patients with BA or respiratory obstruction in history; rare: allergic rhinitis.

Disorders of the gastrointestinal tract: often: nausea, vomiting, diarrhea, constipation.

Disorders of the liver and biliary tract: rare: hepatitis.

Disorders of the skin and subcutaneous tissues: rare: hypersensitivity reactions, such as itching, skin rash, hyperemia of the skin; very rare: alopecia. Beta-blockers can exacerbate psoriasis or cause a psoriasis-like rash.

Disorders of the musculoskeletal and connective tissue: infrequent: muscle weakness, muscle cramps.

Violations of the genital organs and breast cancer: rare: impotence.

General disorders injection site: frequent: fatigue**; uncommon: exhaustion**.

Laboratory and instrumental data: rarely: increased activity of "hepatic" transaminases (aspartate aminotransferase (ACT), alanine aminotransferase (ALT)) in blood plasma.

** Especially often these symptoms appear at the beginning of treatment. They are usually mild in nature and usually take place 1-2 weeks after the start of treatment.

Special conditions

Amlodipine

In patients with CHF (III and IV functional class according to NYHA classification), treatment is carried out with caution, due to the possibility of pulmonary edema, which is not associated with worsening symptoms of CHF.

Bisoprolol

Discontinuation of bisoprolol therapy should not be sudden, especially in patients with IVS, except for the presence of clear indications for drug withdrawal. Sudden cancellation of bisoprolol may lead to a temporary deterioration of cardiovascular disease. Bisoprolol should be used with extreme caution in patients with hypertension or angina in combination with CHF. Like other beta-blockers, bisoprolol may increase sensitivity to allergens and enhance anaphylactic reactions, so caution should be exercised while conducting desensitizing therapy. The use of epinephrine (adrenaline) does not always give the expected therapeutic effect.

The use of bisoprolol can "mask" the symptoms of hyperthyroidism.

In patients with pheochromocytoma, bisoprolol can be used only against the background of the use of alpha-blockers.

Before General anesthesia, the anesthesiologist should be informed that the patient is taking beta-blockers. If it is necessary to stop the therapy with beta-blockers before surgery, the withdrawal of the drug should be carried out gradually and completed 48 hours before General anesthesia.

Patients with asthma or COPD showed the simultaneous application of bronchodilatory funds. Patients with BA may increase respiratory resistance, which requires an increase in the dose of beta2-adrenomimetikov.

Impact on the ability to drive vehicles and machinery: 

During drug therapy Unipertan® Combi must be careful when driving and working with other technical devices, require high concentration and psychomotor speed reactions.

Method of application

Inside, preferably in the morning, regardless of the time of meal. Not to chew. The recommended daily dose is 1 tablet of a certain dosage. The selection and titration of dose is done by the attending physician individually for each patient when used in monotherapy of drugs included in the drug Unipertan® Combi. Duration of therapy Therapy drug Unipertan® Kombi is lengthy. In patients with impaired liver function, the excretion of amlodipine may be delayed. A special dosage regimen in such patients is not defined, but the drug in this case should be used with caution. For patients with severe liver dysfunction, the maximum daily dose of bisoprolol is 10 mg. renal dysfunction in patients with impaired renal function of mild to moderate severity dose adjustment is generally not required. Amlodipine is not excreted in hemodialysis. In patients on hemodialysis, amlodipine should be used with extreme caution. In patients with severe dysfunction of nights (creatinine clearance (CC) less than 20 ml/min) the maximum daily dose of bisoprolol is 10 mg. Patients elderly patients elderly recommended the drug Unipertan® Kombi in normal doses. When increasing the dose requires caution. Kids Drug Unipertan® Combi is not recommended for use in children under the age of 18, the data on safety and efficacy of the drug. With the abolition of the drug, a gradual reduction in the dose is recommended, a sharp discontinuation of therapy can lead to a temporary deterioration in the clinical condition, especially in patients with ischemic heart disease.

Overdose: 

Amlodipine

Symptoms: a marked decrease in blood pressure WITH the possible development of reflex tachycardia and excessive peripheral vasodilation (risk of severe and persistent hypotension, including the development of shock and death).

Treatment: gastric lavage, application of activated carbon, the maintenance functions of the cardiovascular system, monitoring of indicators of function of heart and lungs, exalted position of the lower extremities, monitoring of circulating blood volume and urine output. Intensive symptomatic therapy. To restore vascular tone, vasoconstrictor drugs are used (in the absence of contraindications to their use), in order to eliminate the blockade of calcium channels - intravenous administration of calcium gluconate. Hemodialysis is effective NS.

Bisoprolol

Symptoms: AV blockade, severe bradycardia, marked decrease in blood PRESSURE, bronchospasm, acute heart failure and hypoglycemia.

Sensitivity to single high dose bisoprolol varies greatly among individual patients, and probably patients with CHF are highly sensitive.

Treatment: in case of overdose, it is necessary to stop taking bisoprolol and start supporting symptomatic therapy.

In severe bradycardia: intravenous administration of atropine. The effect of singing is insufficient, with caution, you can enter a drug that has a positive chronotropic effect. Sometimes it may be necessary to temporarily set the artificial rhythm driver.

With a marked decrease in blood PRESSURE: intravenous plasma-substituting solutions and vasopressors. Intravenous glucagon may also be indicated. In AV blockade: the patient should be under constant supervision and receive treatment with beta-adrenomimetics, such as epinephrine (adrenaline). If necessary, the production of an artificial rhythm driver.

In case of exacerbation of the course of CHF: intravenous diuretics, drugs with a positive inotropic effect, as well as vasodilators.

In bronchospasm: the use of bronchodilators, including beta2-adrenomimetics and / or aminophylline.

In hypoglycemia: intravenous solution of dextrose (glucose).

Bisoprolol is practically not excreted by hemodialysis.

Indications

Arterial hypertension (to replace amlodipine and bisoprolol in the same doses when used in monotherapy).

Contraindications

amlodipin

• Unstable angina (except for princmetal 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.
  
• Atrioventricular block (AV) II and III degree, without pacemaker.
  

 Syndrome of weakness of sinus node.

• Sinoatrial blockade.
  
• Severe bradycardia (heart rate less than 60 beats/min).
  
• Severe forms of bronchial asthma (BA) or chronic obstructive pulmonary disease (COPD).
  
• Severe peripheral arterial blood circulation disorders or Raynaud's syndrome.
  
• Pheochromocytoma (without simultaneous use of alpha-blockers).
  
• Metabolic acidosis.
  

Amlodipine/bisoprolol combination

• Hypersensitivity to amlodipine, other dihydropyridine derivatives, bisoprolol and/or any auxiliary substances.
  
• Severe hypotension (systolic blood PRESSURE less than 100 mm Hg. V.).
  
• Shock (including cardiogenic).
  
• Children under 18 years of age (efficacy and safety of the national Assembly are established).
  

With caution: 

CHF (including non-ischemic etiology III-IV functional class NYHA classification), hepatic failure, renal failure, hyperthyroidism, diabetes mellitus, with considerable fluctuations of glucose concentration in blood plasma, AV blockade of I degree, Prinzmetal's angina, occlusive peripheral arterial disease, psoriasis (including in history), fasting (strict diet), pheochromocytoma (with simultaneous use of alpha-blockers), asthma and COPD, while desensitizing therapy, General anesthesia, use in elderly patients, arterial hypotension, type 1 diabetes mellitus, aortic stenosis, mitral stenosis, acute myocardial infarction (after the first 28 days).

Pregnancy and lactation: 

The use of the drug Unipertan® Kombi in pregnancy is possible if the benefit to the mother outweighs the risk of side effects in the fetus and newborn.

If necessary, use of the drug Unipertan® Kombi lactation breastfeeding should be discontinued.

Amlodipine

In experimental studies, the embryotoxic and fetotoxic effect of the drug is not established. However, the use of amlodipine during pregnancy is possible if the potential benefit to the mother exceeds the possible risk to the fetus. There is no data on the excretion of amlodipine with breast milk. However, it is known that other bmcc - dihydropyridine derivatives are excreted in breast milk. If necessary, amlodipine treatment during lactation is recommended to stop breastfeeding.

Bisoprolol

The use of bisoprolol during pregnancy is possible if the potential benefit to the mother exceeds the possible risk to the fetus.

Beta-blockers reduce the blood supply to the placenta and can affect the development of the fetus. It is necessary to monitor blood flow in the placenta and uterus, as well as the growth and development of the fetus. In the case of adverse events in relation to pregnancy and/or the fetus, an alternative therapy should be prescribed. It is necessary to carefully examine the newborn, in the first 3 days of life, symptoms of hypoglycemia and bradycardia may appear.

There is no data on the excretion of bisoprolol with breast milk. If necessary, treatment with bisoprolol during lactation is recommended to stop breastfeeding.

Drug interaction

Amlodipine

Simultaneous use of amlodipine with thiazide diuretics, beta-blockers, nitrates of prolonged action, nitroglycerin (short-acting forms), nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics and hypoglycemic agents for oral administration is considered safe.

Concomitant use with strong or moderate inhibitors of CYP3A4 isoenzyme (protease inhibitors, verapamil or diltiazem, antifungal drugs from the azole group, macrolides, such as erythromycin or clarithromycin) can lead to a significant increase in the systemic exposure of amlodipine.

It should be used with caution amlodipine simultaneously with CYP3A4 isoenzyme inhibitors, although adverse events associated with the above interaction have not been reported.

Simultaneous use of amlodipine with inducers of CYP3A4 isoenzyme (including rifampicin, St. John's Wort perforated) can lead to a decrease in the concentration of amlodipine in blood plasma. Caution should be exercised with simultaneous use of amlodipine with CYP3A4 inducers. Simultaneous repeated use of amlodipine at a dose of 10 mg and simvastatin at a dose of 80 mg leads to an increase in the exposure of simvastatin by 77 %. In such cases, the dose of simvastatin should be limited to 20 mg per day.

Grapefruit juice, cimetidine, aluminum hydroxide/magnesium hydroxide (as part of 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 (alcohol-containing beverages), warfarin or cyclosporine.

Amlodipine has no effect on laboratory parameters.

Bisoprolol

Not recommended drug combinations

Bmcc (verapamil and to a lesser extent diltiazem), while the use of bisoprolol may lead to a decrease in myocardial contractility, a marked decrease in blood PRESSURE and a violation of AV conduction. In particular, intravenous administration of verapamil to patients taking beta-blockers may lead to the development of severe hypotension and AV blockade.

Hypotensive agents of Central action (clonidine, methyldopa, moxonidine, rylmenidine), while the use of bisoprolol can lead to a decrease in heart rate, a decrease in cardiac output and vasodilation due to a decrease in the Central sympathetic tone. Abrupt withdrawal of these drugs, especially before discontinuation of beta-blockers, may increase the risk of" ricochet " hypertension.

Drug combinations that require caution

Bmcc, derivatives of dihydropyridine (eg, nifedipine) while the use of bisoprolol may increase the risk of hypotension. In patients with CHF, the risk of further deterioration of the contractile function of the heart cannot be excluded.

Antiarrhythmic agents of class I (e.g., quinidine, disopyramide, lidocaine, phenytoin, flecainid, propafenon) while the use of bisoprololum can reduce AV conduction and myocardial contractility. Antiarrhythmic agents of class III (eg, amiodarone), while the use of bisoprolol may increase violation of AV conductivity. Parasympathomimetic agents, while the use of bisoprolol may increase the violation of AV conductivity and increase the risk of bradycardia. Concomitant use with beta-blockers for topical use (e.g., eye drops for glaucoma treatment) may enhance the systemic effects of bisoprolol (lowering blood PRESSURE, heart rate reduction).

Simultaneous use with insulin and hypoglycemic agents for oral administration may increase their hypoglycemic effect. The symptoms of hypoglycemia, particularly tachycardia, may be masked. Such interactions are more likely when using non-selective beta-blockers.

General anaesthetic products may reduce reflex tachycardia and increase the risk of hypotension (see Special instructions). Cardiac glycosides with simultaneous use with bisoprolol can lead to an increase in the time of the pulse and to the development of bradycardia.

NSAIDs can reduce the antihypertensive effect of bisoprolol.

The simultaneous use of bisoprolol e beta-adrenomimetics (eg, isoprenaline, dobutamine) can reduce the effect of each drug. The simultaneous use of bisoprolol with agonists affecting beta - and alpha-adrenoceptors (e.g. paraponera, epinephrine) may potentiate vasoconstrictor effects of these means that occur with the participation of alpha-adrenergic receptors, leading to increased blood pressure. Such interactions are more likely when using non-selective beta-blockers. Hypotensive agents, as well as other means with a possible antihypertensive effect (for example, tricyclic antidepressants, barbiturates, phenothiazines), can enhance the antihypertensive effect of bisoprolol.

Combinations of drugs that should be taken into account

Mefloquine while the use of bisoprololum can increase the risk of bradycardia.

Monoamine oxidase inhibitors (MAO) (with the exception of MAO b inhibitors) may increase the antihypertensive effect of beta-blockers. Simultaneous use can also lead to the development of hypertensive crisis.

Rifampicin causes a slight shortening of T1 / 2 bisoprolol. As a rule, dose adjustment is not required.

Derivatives of ergotamine, while the use of bisoprolol increase the risk of peripheral blood circulation disorders.