Instruction for use: Niperten Combi

Active substance Amlodipine + Bisoprolol

ATX Code C07FB selective beta-blockers in combination with other antihypertensive agents

Pharmacotherapeutic group:

Antihypertensive drugs combined (.beta.1-blocker + selective blocker of the "slow" calcium channels (BCCI) [Beta-blockers in combination]

Antihypertensive drugs combined (β1-selective blocker blocker + "slow" calcium channels (BCCI) [Calcium channel blockers in combination]

The nosological classification (ICD-10)

I10 Essential (primary) hypertension

Hypertension, Arterial hypertension, Arterial hypertension crisis course, Essential Hypertension

Primary hypertension, Arterial hypertension, complications of diabetes, hypertension, The sudden increase in blood pressure, Hypertensive disorders of blood circulation, hypertensive condition, hypertensive crises, hypertension, arterial Hypertension, malignant Hypertension, Hypertonic disease, Hypertensive crisis, Hypertension, accelerated hypertension, malignant hypertension, The aggravation of hypertensive disease, Transient hypertension, Isolated systolic hypertension

I15 Secondary hypertension

Arterial hypertension, complications of diabetes, hypertension, The sudden rise in blood pressure, Hypertensive disorders of blood circulation, hypertensive condition, hypertensive crises, hypertension, arterial hypertension, malignant hypertension, Hypertensive crisis, Hypertension, accelerated hypertension, malignant hypertension, hypertensive crisis, The aggravation of hypertensive disease, Transient hypertension, hypertension, Arterial hypertension, Arterial hypertension crisis course, renovascular hypertension, symptomatic hypertension, renal hypertension, Renovascular hypertension, Symptomatic hypertension

Structure and Composition

Tablets 1 tab.

Active substance-substance granules:

amlodipine besylate (amlodipine besylate) 6,935 mg

(Amlodipine equivalent - 5 mg)

bisoprolol fumarate 5 mg

Excipients substance granules: MCC - 133.065 mg; Sodium carboxymethyl - 5 mg; colloidal silicon dioxide - 1 mg; Magnesium stearate - 1 mg

Excipients: magnesium stearate - 1 mg

Tablets 1 tab.

Active substance-substance granules:

amlodipine besylate (amlodipine besylate) 6,935 mg

(Amlodipine equivalent - 5 mg)

bisoprolol fumarate 10 mg

Other ingredients: MCC - 273.065 mg; Sodium carboxymethyl starch - 10 mg; colloidal silicon dioxide - 2 mg; magnesium stearate - 2 mg

Excipients: magnesium stearate - 2 mg

Tablets 1 tab.

Active substance-substance granules:

amlodipine besylate (amlodipine besylate) 13.87 mg

(Amlodipine equivalent - 10 mg)

bisoprolol fumarate 5 mg

Excipients substance granules: MCC - 271.13 mg; Sodium carboxymethyl starch - 10 mg; colloidal silicon dioxide - 2 mg; magnesium stearate - 2 mg

Excipients: magnesium stearate - 2 mg

Tablets 1 tab.

Active substance-substance granules:

amlodipine besylate (amlodipine besylate) 13.87 mg

(Amlodipine equivalent - 10 mg)

bisoprolol fumarate 10 mg

Excipients substance granules: MCC - 266.13 mg; Sodium carboxymethyl starch - 10 mg; colloidal silicon dioxide - 2 mg; magnesium stearate - 2 mg

Excipients: magnesium stearate - 2 mg

The drug forms

Tablets, 5 mg + 5 mg: Round, biconvex, white, with bevel on both sides and mark on one side.

Tablets, 5 mg + 10 mg: Oval, biconvex, white color, with Valium on one party.

Tablets, 10 mg + 5 mg: round, slightly biconvex, white, with a facet and Valium on one party and chasing «CS» on the other side.

Tablets, 10 mg + 10 mg: round, slightly biconvex, white, with a facet and Valium on one party.

pharmachologic effect

hypotensive.

pharmacodynamics

The drug Niperten® Combi has antianginal and antihypertensive effect due to synergistic effect of the two active substances: BCCI - amlodipine - and selective beta1-blockers - bisoprolol.

The mechanism of action of amlodipine. Amlodipine slow calcium channel blocking and reduces current transmembrane calcium ions into the cell (mainly in vascular smooth muscle cells than cardiac myocytes).

The antihypertensive effect is due to direct amlodipine relaxing effect on vascular smooth muscle cells, which results in lower systemic vascular resistance.

The mechanism of anti-anginal action is not fully understood, it is associated with supposedly two effects.

1. Expansion of peripheral arterioles reduces peripheral vascular resistance (afterload). Due to the absence of reflex tachycardia and the energy consumption of oxygen by the myocardium is reduced.

2. Extension of the major coronary arteries and coronary arterioles improves the delivery of oxygen in normal and in ischemic areas of the myocardium, including with coronary artery spasm (Prinzmetal angina or unstable angina).

In patients with hypertension receiving amlodipine 1 time per day causes a clinically significant reduction in blood pressure in the supine position and standing 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 reception amlodipine 1 time per day increases the total time of exercise, the time to development of angina attack until significant ST segment depression, and also reduces the frequency of angina attacks and the need for reception of nitroglycerin (short-form).

Not observed negative influence on the concentration of amlodipine of lipids, glucose, and uric acid in the blood plasma.

The mechanism of action of bisoprolol. Bisoprolol - selective beta1-blocker that does not have its own sympathomimetic activity and membrane-stabilizing effect and characterized by a negligible affinity for the beta2-adrenoceptor bronchial smooth muscle and blood vessels, as well as to the beta2-adrenergic receptors involved in the regulation of metabolism. Therefore, bisoprolol virtually no effect on airway resistance and metabolic processes that are mediated through the effect on beta2-adrenergic receptors. The selective effect of bisoprolol on beta1-adrenergic receptors is preserved outside the therapeutic range. Bisoprolol does not have a pronounced negative inotropic effect. The maximum effect is achieved after 3-4 h after intake. Even when assigning 1 bisoprolol once daily its therapeutic effect is maintained for 24 hours as its T1 / 2 of plasma -. 10-12 hours As a rule, the maximum antihypertensive effect is achieved within 2 weeks after initiation of treatment. Bisoprolol reduces the activity simpatoadrenalovoj system by blocking the beta1-adrenergic receptors of the heart. For a single ingestion in patients with coronary artery disease with no evidence of heart failure bisoprolol slows heart rate, reduce heart stroke volume and, as a consequence, reduces the ejection fraction and myocardial oxygen demand. When long-term therapy initially elevated peripheral vascular resistance is reduced. Reducing the activity of renin in blood plasma is considered as one of the mechanisms of antihypertensive action of beta-blockers.

Pharmacokinetics

Amlodipine

Suction. After oral administration of amlodipine is well absorbed. Cmax plasma levels observed after 6-12 hours. Ingestion of amlodipine does not affect the absorption. The absolute bioavailability of 64 to 80%.

Distribution. Visible Vd is about 21 L / kg. Css plasma (5-15 ng / ml) were achieved after 7-8 days after initiation of treatment. In studies in vitro binding to plasma proteins is 93-98%.

Metabolism and excretion. Amlodipine is extensively metabolised in the liver. About 90% of the dose is converted to inactive pyridine derivatives. Approximately 10% of the dose is excreted by the kidneys unchanged. Approximately 60% of inactive metabolites excreted by the kidneys, 20-25% - through the intestines. Reduced amlodipine plasma concentration occurs in two phases. The final T1 / 2 is about 35-50 hours, allowing you to take the drug 1 time per day. Total clearance of 7 ml / min / kg (25 liters / hour for a patient with body weight of 60 kg), in elderly patients - 19 l / h.

Elderly patients and patients with renal insufficiency was not observed significant changes in the pharmacokinetics of amlodipine. Due to the reduced clearance in patients with hepatic failure should apply a lower initial dose.

bisoprolol

Suction. Bisoprolol is almost completely (90%) absorbed from the gastrointestinal tract. Due to its low bioavailability biotransformation during the initial passage through the liver (approximately 10%) is approximately 90% after oral administration. Food does not affect the bioavailability. The pharmacokinetics of bisoprolol are linear in the dose range 5-20 mg. Cmax plasma levels achieved in 2-3 hours.

Distribution. Bisoprolol is distributed widely enough. Vd is 3.5 L / kg. Communication with plasma proteins - about 30%.

Metabolism. It is metabolized by oxidative way without subsequent conjugation. All metabolites are polar (water soluble) and the kidneys. Major metabolites detected in plasma and urine do not possess pharmacological activity. in vitro studies in human liver microsomes showed that bisoprolol is metabolized mainly via isoenzyme CYP3A4 (about 95%) and CYP2D6 isozyme plays only a minor role.

Withdrawal. The clearance of bisoprolol is determined by the equilibrium between the renal excretion as unchanged (about 50%) and metabolism in the liver (approximately 50%) with the formation of metabolites that are also excreted by the kidneys. The total clearance is 15 l / h. T1 / 2 - 10-12 h.

Indications

Arterial hypertension (for the replacement of amlodipine and bisoprolol in the same doses when used in monotherapy).

Contraindications

Amlodipine

unstable angina (except Prinzmetal's angina);

hemodynamically unstable heart failure after myocardial infarction;

clinically significant aortic stenosis.

bisoprolol

congestive heart failure or chronic heart failure decompensation requiring of inotropic therapy;

AV blockade II and III level without pacemaker;

syndrome sick sinus;

sinoatrial block;

bradycardia (heart rate less than 60 beats / min.);

severe bronchial asthma (BA) or chronic obstructive pulmonary disease;

severe peripheral arterial circulatory disorders, or Raynaud's syndrome;

pheochromocytoma (without the simultaneous use of alpha-blockers);

metabolic acidosis.

The combination of amlodipine / bisoprolol

Hypersensitivity to amlodipine to other dihydropyridine derivatives, bisoprolol and / or any of the excipients;

severe hypotension (Sad less than 100 mm Hg..);

shock (including cardiogenic);

Children up to age 18 years (effectiveness and safety have been established).

Precautions: chronic heart failure (including non-ischemic etiology III-IV functional class NYHA classification), hepatic failure, renal failure, hyperthyroidism, diabetes mellitus, with considerable fluctuations in the concentration of plasma glucose, AV block I degree, Prinzmetal angina , peripheral arterial occlusive disease, psoriasis (including history), fasting (strict diet), pheochromocytoma (while the use of alpha-blockers), asthma and chronic obstructive pulmonary disease, while conducting desensitizing therapy, general anesthesia, patients elderly, hypotension, diabetes mellitus type 1, aortic stenosis, mitral stenosis, acute myocardial infarction (after 28 days).

Pregnancy and breast-feeding

Use of the drug during pregnancy Niperten® Combi possible if the benefit to the mother outweighs the risk of side effects in the fetus and newborn.

If necessary, use Niperten® Combi during lactation should stop breastfeeding.

Amlodipine

In experimental studies, embryotoxic and foetotoxic effects of the drug have not been established. However, the use of amlodipine in pregnancy is possible if the potential benefit to the mother outweighs the potential risk to the fetus.

Data on amlodipine excretion in breast milk is not. However, it is known that other BCCI - dihydropyridine derivatives - appear in breast milk. If necessary, treatment with amlodipine during lactation should stop breastfeeding.

bisoprolol

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

Beta-blockers reduce blood flow to the placenta and can affect fetal development. It is necessary to monitor blood flow in the placenta and uterus, as well as fetal growth and development. In case of occurrence of adverse events in respect of pregnancy and / or fetal alternative therapy should be assigned. Examine carefully the newborn, the symptoms of hypoglycemia and bradycardia may occur during the first 3 days of life.

Data for the withdrawal of bisoprolol in breast milk does not. If necessary, treatment with bisoprolol during lactation should stop breastfeeding.

Side effects

Undesirable side reactions seen with the active ingredients alone are presented in accordance with the classification of the frequency of side effects WHO: very often ≥1 / 10; often ≥1 / 100- <1/10; uncommon ≥1 / 1000- <1/100; rare ≥1 / 10000- <1/1000; very rare <1/10000; Frequency not known (can not be estimated from available data).

Amlodipine

From the blood and lymphatic system: very rarely - leukopenia, thrombocytopenia.

Immune system: very rarely - allergic reactions.

On the part of metabolism and nutrition: very rarely - hyperglycemia.

Mental disorders: rarely - insomnia, mood lability (including anxiety), depression; rare - confusion.

From the nervous system: often - headache, dizziness, sleepiness (especially at the beginning of treatment); infrequently - syncope, hypoesthesia, paraesthesia, dysgeusia, tremor; rarely - muscle hypertonicity, peripheral neuropathy.

On the part of the organ of vision: rarely - visual disturbances (including diplopia).

On the part of the ear and labyrinth disorders: rarely - ringing in the ears.

From the digestive system: often - nausea, stomach pain; rarely - vomiting, changes in bowel movements (including constipation or diarrhea), indigestion, dryness of the oral mucosa; very rarely - gastritis, gingival hyperplasia, pancreatitis.

On the part of the liver and biliary tract: very rarely - hepatitis , jaundice .

From the heart: Often - palpitations; very rarely - myocardial infarction, arrhythmia (bradycardia, ventricular tachycardia, atrial fibrillation).

On the part of the vessels: often - a feeling of rush of blood to the skin of the face; infrequently - marked reduction of blood pressure; very rarely - vasculitis.

The respiratory system, organs, thoracic and mediastinal disorders: rarely - dyspnea, rhinitis; very rarely - cough.

On the part of the kidney and urinary tract: rare - pollakiuria, tenesmus, nocturia.

From the genitals and breast: rarely - impotence, gynecomastia.

General disorders and administration in place: often - peripheral edema, increased fatigue; infrequently - chest pain, asthenia, pain, unspecified, general malaise.

On the part of the musculoskeletal and connective tissue disorders: often - swelling of the ankles; Infrequent - arthralgia, myalgia, muscle cramps, back pain.

Skin and subcutaneous tissue disorders: rare - alopecia, purpura, skin discoloration, excessive sweating, itching, skin rash, rash; very rarely - angioneurotic edema, exudative erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, photosensitivity.

Laboratory and instrumental data: rarely - weight gain, weight loss; very rare - increase in liver enzymes in the blood plasma .

bisoprolol

On the part of metabolism and nutrition: rarely - increased plasma concentrations of triglycerides.

Mental disorders: uncommon: depression; rarely - hallucinations, nightmares.

From the nervous system: often - headache dizziness; rarely - insomnia; rarely - a faint.

From a sight organ: seldom - a decrease lacrimation (to consider when wearing contact lenses); very rarely - conjunctivitis.

On the part of the ear and labyrinth disorders: rarely - a violation hearing.

From the heart: rarely - a violation of AV conduction, bradycardia, exacerbation of heart failure symptoms.

On the part of the vessels: often - cooling sensation or numbness in the extremities, marked reduction in blood pressure; Uncommon: orthostatic hypotension.

The respiratory system, organs, thoracic and mediastinal disorders: rarely - bronchospasm in patients with asthma or airway obstruction in history; rarely - allergic rhinitis.

On the part of the digestive tract: often - nausea, vomiting, diarrhea, constipation.

On the part of the liver and biliary tract: rarely - hepatitis.

Skin and subcutaneous tissue disorders: rarely - hypersensitivity reactions, such as itching, skin rash, redness of the skin; very rare - alopecia. Beta-blockers may exacerbate psoriasis or induce psoriasis-like rash.

On the part of the musculoskeletal and connective tissue disorders: rarely - muscle weakness, muscle cramps.

From the genitals and breast: rarely - impotence.

General disorders and administration in place: often - fatigue **; infrequently - ** exhaustion.

Laboratory and instrumental data: rarely - increased activity of hepatic transaminases (AST, ALT) in blood plasma.

Interaction

Amlodipine

Concomitant use of amlodipine with thiazide diuretics, beta-blockers, long-acting nitrates, nitroglycerin (short-form), NSAIDs, antibiotics and hypoglycemic agents for oral use is deemed safe.

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

It should be used with caution in conjunction with amlodipine isoenzyme inhibitors SYR3A4, although adverse events related to the above interaction, have been reported.

The simultaneous use of amlodipine SYR3A4 isoenzyme inducers (including rifampin, St. John's wort) may reduce amlodipine plasma concentration. Caution must be exercised with concomitant use of amlodipine with isoenzyme inducers SYR3A4.

Simultaneous use of multiple amlodipine 10 mg of simvastatin and 80 mg of simvastatin leads to increased exposure to 77%. In such cases it is necessary to limit the dose of simvastatin 20 mg / day.

Grapefruit juice, cimetidine, aluminum hydroxide / magnesium hydroxide (consisting of antacids) and sildenafil did not affect the pharmacokinetics of amlodipine.

Amlodipine may enhance the antihypertensive effect of other antihypertensive agents. Amlodipine has no effect on the pharmacokinetics of atorvastatin, digoxin, ethanol (including beverages containing alcohol), warfarin or cyclosporin.

Amlodipine has no effect on laboratory parameters.

bisoprolol

Not recommended combinations of drugs. BCCI (verapamil and to a lesser extent diltiazem) while the use of bisoprolol may lead to a decrease in myocardial contractility, marked reduction in blood pressure and AV conduction disorders. In particular, in / with the introduction of verapamil to patients taking beta-blockers, may lead to severe hypotension and AV blockade.

Antihypertensive drugs central action (clonidine, methyldopa, moxonidine, rilmenidine) while the use of bisoprolol may lead to a slowing of the heart rate, reduction in cardiac output and vasodilation due to the reduction of the central sympathetic tone. Abrupt withdrawal of these drugs, especially before discontinuation of beta-blockers, may increase risk of "rebound" hypertension.

Combinations of drugs that require caution. BCCI, dihydropyridine derivatives (eg, nifedipine), while the use of bisoprolol may increase the risk of hypotension. In patients with heart failure can not eliminate the risk of further deterioration of the contractile function of the heart.

Class I antiarrhythmics (eg quinidine, disopyramide, lidocaine, phenytoin, flecainide, propafenone), while the use of bisoprolol may reduce AV conduction and myocardial contractility. Class III antiarrhythmics (eg amiodarone) while the use of bisoprolol may increase the violation of AV conduction.

Parasympathomimetic agent in an application with bisoprolol may increase the violation of AV conduction and increase the risk of bradycardia.

The simultaneous use of beta-blockers for topical application (eg eye drops for glaucoma treatment) may enhance the systemic effects of bisoprolol (lowering blood pressure, slowing of the heart rate). Concomitant use with insulin and hypoglycemic agents for the reception inside can strengthen their hypoglycemic effect. Symptoms of hypoglycemia, particularly tachycardia, may be masked. Such interactions are more likely when using non-selective beta-blockers.

Funds for general anesthesia may attenuate reflex tachycardia and increase the risk of hypotension (see. "Special Instructions"). Cardiac glycosides while the use of bisoprolol may lead to an increase of the pulse of time and the development of bradycardia. NSAIDs may reduce the antihypertensive effect of bisoprolol.

The simultaneous use of bisoprolol with beta-adrenergic agonists (such as isoprenaline, dobutamine) may reduce the effect of each drug. The simultaneous use of bisoprolol with agonists affecting the beta- and alpha-adrenergic receptors (such as norepinephrine, epinephrine), may enhance the effects of these vasoconstrictive agents arising with alpha-adrenoceptors, leading to increased blood pressure.

Such interactions are more likely when using non-selective beta-blockers. Antihypertensives, and other agents with possible antihypertensive effect (for example, tricyclic antidepressants, barbiturates, phenothiazines), may enhance the antihypertensive effect of bisoprolol.

Combinations of drugs that should be considered. Mefloquine while the use of bisoprolol may increase the risk of bradycardia.

MAO inhibitors (except MAO inhibitors) may increase the antihypertensive effect of beta-blockers. Concomitant use may also lead to hypertonic kriza.Rifampitsin causes a slight shortening of the T1 / 2 bisoprolol. Typically, a dose adjustment is required.

Ergotamine derivatives while the use of bisoprolol increase the risk of peripheral circulatory disorders.

Dosing and Administration

Inside, preferably in the morning, regardless of mealtime. Do not chew.

The recommended daily dose - 1 tab. specific dosage.

Selection and dose titration carried out by the attending physician individually for each patient when used in monotherapy drugs included in the drug Niperten® Combi.

The duration of therapy. Combination therapy with Niperten® is prolonged.

Abnormal liver function. Patients with impaired hepatic function Amlodipine elimination may be delayed. Special dosing regimen in such patients is not defined, but in this case, the drug should be used with caution. For patients with severe hepatic impairment, the maximum daily dose is 10 mg bisoprolol.

Impaired renal function. Patients with impaired light or moderate renal function dose adjustment is usually not required. Amlodipine does not appear in hemodialysis. In patients on hemodialysis, amlodipine should be used with extreme caution.

In patients with severe renal impairment (Cl creatinine less than 20 mL / min). The maximum daily dose is 10 mg bisoprolol.

Elderly patients. Elderly patients taking the drug recommended Niperten® Combi in normal doses. By increasing the dose needed to be careful.

Children. The drug Niperten® Combination not recommended for use in children under 18 years of safety data and efficacy of the drug is not.

When the drug is recommended cancellation of a gradual reduction in dose, abrupt cessation of therapy may result in a temporary worsening of the clinical condition, especially in patients with CAD.

Overdose

Amlodipine

Symptoms: marked reduction of blood pressure with 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, activated carbon, maintenance of cardiovascular function, the control performance of the heart and lungs, the exalted position of the lower extremities, control of BCC and diuresis. Intensive symptomatic therapy. To restore vascular tone used vasoconstrictor drugs (in the absence of contraindications to their use), in order to eliminate the blockade of calcium channels - in / in the introduction of calcium gluconate. Hemodialysis is ineffective.

bisoprolol

Symptoms: AV block, bradycardia, marked reduction in blood pressure, bronchospasm, acute cardiac insufficiency and hypoglycaemia.

Sensitivity to single receiving high doses of bisoprolol varies greatly among individual patients, and probably with CHF patients have a high sensitivity.

Treatment: an overdose need to stop taking bisoprolol and initiate supportive symptomatic therapy.

In severe bradycardia: in / atropine. If the effect is insufficient, you can enter with caution drugs having a positive chronotropic effect. Sometimes it may require temporary staging an artificial pacemaker.

In marked decrease in blood pressure: in / in a plasma-solutions and vasopressor agents. It can also be shown in / glucagon.

When AV blockade: the patient must be under constant supervision and be treated with agonists such as epinephrine (adrenaline). If necessary - setting an artificial pacemaker.

When exacerbation of chronic heart failure: in / with the introduction of diuretics, drugs with positive inotropic effect and vasodilators.

When bronchospasm: the use of bronchodilators, including beta2-agonists and / or aminophylline.

When hypoglycemia: / in the introduction of dextrose (glucose). Bisoprolol virtually displayed by hemodialysis.

special instructions

Amlodipine

In patients with chronic heart failure (III and IV functional class NYHA classification) treatment is carried out with caution, due to the possibility of pulmonary edema that is not associated with worsening of the symptoms of heart failure flow.