Арител® Plus 2,5 mg +6,25 mg

General characteristics. Structure:

Active agents of 2,5 mg + 6,25 mg - a bisoprolola fumarate 2,5 mg and a hydrochlorothiazide of 6,25 mg;
excipients – starch of prezhelatinizirovanny 17 mg; silicon dioxide colloid (Aerosil) of 1,5 mg; lactoses monohydrate (sugar milk) 40 mg; magnesium stearate of 0,75 mg; cellulose of microcrystallic 32 mg;
structure of a film cover – Selekoat of AQ-02140/A 3 mg [a gipromelloz (gidroksipropilmetiltsellyuloz) of 1,65 mg, a macrogoal (polyethyleneglycol 400) of 0,27 mg, a macrogoal (polyethyleneglycol 6000) of 0,42 mg, titanium dioxide of 0,63 mg, dye a sunset of yellow 0,03 mg].

Description:
Tablets, film coated yellow-orange color, round, biconvex from crosswise risky. On cross section two layers: inside layer of almost white color.

Pharmacological properties:

Арител® Plus – the combined drug which part are бисопролол and a hydrochlorothiazide.
Pharmacodynamics
Bisoprolol.
The selection β1-адреноблокатор without internal sympathomimetic activity. Has hypotensive, antiarrhytmic and anti-anginal effect. Blocks in low doses β1-адренорецепторы hearts, reduces stimulated catecholamines formation of a cyclic adenozimonofosfat (tsAMF) from adenosinetriphosphate (ATP), reduces intracellular current of calcium ions, renders negative hrono-, dromo-, batmo-and inotropic action (urezhat the heart rate (HR), oppresses cordial conductivity, reduces excitability and contractility of a myocardium). At increase in a dose blocks β2-адренорецепторы.
The general peripheric vascular resistance at the beginning of use of β-adrenoblockers, in the first 24 hours increases (as a result of reciprocal increase of activity of α-adrenoceptors and elimination of stimulation β2-адренорецепторов), in 1-3 days is returned to initial, and at long appointment decreases.
The hypotensive effect is connected with reduction of minute volume of blood, suppression of sympathetic stimulation of peripheral vessels, decrease of the activity system renin-angiotensin-aldosteronovoy by inhibition of β-adrenoceptors of the juxtaglomerular device of kidneys (that leads to reduction of secretion of a renin), recovery of sensitivity of baroreceptors of an aortic arch (there is no strengthening of their activity in response to a lowering of arterial pressure) and influence on the central nervous system. At arterial hypertension the effect develops in 2-5 days, stable action – in 1-2 months.
Hydrochlorothiazide.
Thiazide diuretic. Reduces a reabsorption of ions of sodium in a cortical segment of a Henle's loop, without influencing its site passing in a kidney medulla. Blocks a karboangidraza in proximal department of gyrose renal tubules, strengthens removal by kidneys of potassium ions, hydrocarbonates and phosphates. Practically does not influence an acid-base state. Strengthens removal by kidneys of ions of magnesium; detains in an organism calcium ions and slows down removal of urates. The diuretic effect develops in 1-2 hours, reaches a maximum in 4 hours, remains within 6-12 hours. Diuretic action decreases at reduction in the rate of glomerular filtering and stops at the size of its less than 30 ml/min.
Pharmacokinetics
Bisoprolol.
After intake absorption makes 80-90% of digestive tract. Meal does not influence extent of absorption. Time of achievement of the maximum concentration in a blood plasma makes 2-4 hours. Communication with proteins of a blood plasma makes about 30%. Badly gets through a blood-brain and placental barrier. Secretion with breast milk – insignificant. It is metabolized in a liver. The elimination half-life makes 9-12 hours. It is removed by kidneys (50% - in not changed look), less than 2% - through intestines.
Hydrochlorothiazide.
At intake it is soaked up quickly, but it is incomplete. Time of achievement of the maximum concentration in a blood plasma makes about 4 hours. Bioavailability of a hydrochlorothiazide – 60-80%. Communication with proteins of a blood plasma makes 40%. Gets through a placental barrier and it is allocated in breast milk. It is not metabolized. It is removed by kidneys generally in not changed look by means of glomerular filtering and active canalicular secretion. The elimination half-life makes about 8 hours.

Indications to use:

Arterial hypertension of soft and moderate severity.

Route of administration and doses:

Арител® Plus is recommended to be accepted in the morning, during meal. Tablets should be swallowed entirely, without chewing, washing down with a small amount of water. The recommended initial dose makes 2,5 mg of a bisoprolol + 6,25 mg of a hydrochlorothiazide of 1 times a day.
For individual selection of a dose of Aritel® Plus is issued in the following dosages containing:
2,5 mg of a bisoprolol and 6,25 mg of a hydrochlorothiazide
5 mg of a bisoprolol and 6,25 mg of a hydrochlorothiazide
10 mg of a bisoprolol and 6,25 mg of a hydrochlorothiazide
Each subsequent increase in a dose has to be carried out not less than in two weeks.
If increase in a dose of drug is badly transferred by the patient, the dose decline is possible.
The patient with moderated by an abnormal liver function, moderate renal failures, and also dose adjustment is not required to patients of advanced age. At patients with heavy abnormal liver functions and kidneys (clearance of creatinine more than 30 ml/min.) the maximum daily dose of a bisoprolol should not exceed 10 mg.
Duration of a course is established by the doctor.

With care:
Performing the desensibilizing therapy, atrioventricular block of the I degree, psoriasis, coronary heart disease, liver failure, renal failure (KK more than 30 ml/min.), a thyrotoxicosis, a pheochromocytoma (against the background of treatment by α-adrenoblockers)))))))))), a hyperthyroidism, water and electrolytic disturbances (a hyponatremia, a hypopotassemia, a hypercalcemia), gout, a restrictive cardiomyopathy, inborn heart diseases or defect of the valve of heart with the expressed hemodynamic disturbances, a rigid diet, depressions (including in the anamnesis), a myasthenia, at patients of advanced age.

Features of use:

During therapy by the drug Aritel® Plus control of ChSS and the ABP (in an initiation of treatment – daily, then – 1 time in 3-4 months), behind the content of glucose in blood at patients with a diabetes mellitus is necessary (1 time in 4-5 months). At elderly patients therapy should be begun with the dosage form of drug containing a low dose of a bisoprolol. At the same time regular control of a condition of patients is necessary, it is also recommended to control function of kidneys (1 times in 4-5 months). It is necessary to train the patient in a technique of calculation of ChSS. During therapy by the drug Aritel® Plus it is also necessary to control indicators of an acid-base state and level of electrolytes (potassium, sodium, calcium).
It is necessary to reduce doses of the drug Aritel® Plus (due to reduction of maintenance of a bisoprolol in it) if ChSS at rest does not exceed 50-55 beats per minute.
During therapy by the drug Aritel® Plus it is also necessary to control indicators of an acid-base state and level of electrolytes (potassium, sodium, calcium).
Bisoprolol: it is necessary to stop treatment gradually, especially at the coronary heart disease (accompanying an ischemic heart disease). The dose is reduced within two weeks. If necessary carry out the corresponding therapy for prevention of attacks of stenocardia.
At bronchial asthma and the chronic obstructive pulmonary disease (COPD) treatment is begun with the minimum dose. Prepost functional respiratory tests. At development of a bronchospasm appoint β-adrenomimetik.
At the chronic heart failure (accompanying HSN) treatment is carried out under control of the doctor, in the minimum doses.
Considering negative dromotropic effect of β-adrenoblockers, patients should appoint them with care with AV blockade of the I St.
With peripheral disturbances of blood circulation (Raynaud's disease) β-adrenoblockers can cause an aggravation of a course of a disease therefore drug is contraindicated at such patients (see in patients. "Contraindications").
At a thyrotoxicosis of Aritel® Plus (due to the maintenance of a bisoprolol in it) can mask clinical signs of a disease (for example, tachycardia).
Patients with a pheochromocytoma should not appoint drug until treatment is carried out by α-adrenoblockers.......... During treatment control of the arterial pressure (AP) is necessary.
It is recommended to stop therapy by the drug Aritel® Plus at development of the depression caused by β-adrenoblocker reception ((((((((((due to the maintenance of a bisoprolol in it).
At elderly patients treatment is begun with a low dose, under control of a condition of the patient.
Patients with the accompanying diabetes mellitus have to know about possibility of a hypoglycemia and need of regular control of concentration of glucose for blood (especially in case of a hypopotassemia). Bisoprolol can mask hypoglycemia signs (tachycardia, heartbeat, perspiration).
The patients using contact lenses should be careful at use of the drug Aritel® Plus as β-adrenoblockers can reduce products of the lacrimal gland.
Therapy by β-adrenoblockers can aggravate the course of psoriasis.
At patients who in the anamnesis noted anaphylactic reactions (especially on флоктафенин or the desensibilizing drugs) treatment by β-adrenoblockers can aggravate these reactions and lead to development of resistance to Epinephrinum in usual doses.
Athletes have to be informed that this drug can yield false positive results when carrying out doping tests.
Hydrochlorothiazide: control of sodium in blood (especially at elderly is necessary and at cirrhosis). It is necessary to control potassium concentration in blood at elderly patients, at simultaneous treatment by thiazide and tiazidopodobny diuretics, at the cirrhosis which is followed by hypostases, ascites at a disease of coronary arteries or HSN, with the extended Q-T interval. The hypopotassemia increases risk of development of arrhythmias, increases toxicity of cardiac glycosides. The first definition of potassium concentration needs to be carried out to blood within the first week of treatment.
Thiazide diuretics can reduce removal of calcium with urine that leads to a temporary hypercalcemia. The temporary hypercalcemia can be connected with not diagnosed hyperparathyreosis. Before a research of function of epithelial bodies treatment of a tiazidama needs to be stopped.
At patients with a hyperuricemia the risk of development of attacks of gout is increased (the dose is selected individually under control of level of uric acid in blood serum). Before a research of function of epithelial bodies treatment by the drug Aritel® Plus needs to be stopped as against the background of its reception there can be a tranzitorny hypercalcemia.
Thiazide diuretics are effective at normal or slightly reduced (concentration of creatinine less than 25 mg/ml or 220 µmol/l) functions of kidneys.
The hypovolemia leads to decrease in glomerular filtering that leads to increase in urea and creatinine in blood at patients with normal function of kidneys. At patients with HPN strengthening of the existing disturbances is possible.
It is necessary to cancel before a research of content in blood and urine of catecholamines, a normetanefrin and vanililmindalny acid; credits of antinuclear antibodies.
The special attention is required in cases of carrying out surgical intervention under the general anesthesia at the patients accepting β-adrenoblockers.......... Such patients should cancel Aritel® Plus in 48 hours prior to an operative measure, to warn the anesthesiologist that the patient accepts the drug Aritel® Plus. As means for the general anesthesia it is necessary to choose drug with the minimum negative inotropic effect.

Influence on ability to manage vehicles, mechanisms:
During treatment it is necessary to be careful during the driving of motor transport and occupation other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Use at pregnancy and during breastfeeding:
Drug is contraindicated at pregnancy and during breastfeeding.

Side effects:

From the central and peripheral nervous system:
increased fatigue, adynamy, concern, dizziness, headache, drowsiness or sleeplessness, depression, disorder of memory/attention, syncope, вертиго, cryesthesia and numbness of extremities, spasms, paresthesia, hypesthesia, hyperesthesia, hallucinations, "dreadful" dreams.
From cardiovascular system: a sinus bradycardia, the expressed lowering of arterial pressure, disturbance of atrioventricular conductivity, ventricular premature ventricular contraction, orthostatic hypotension, an aggravation of a course of chronic heart failure, peripheral hypostases.
From respiratory system: at predisposed patients - laringo-and a bronchospasm, short wind, rhinitis, sinusitis, pharyngitis, a nose congestion.
From the alimentary system: abdominal pains, round ulcer, gastritis, dyspepsia, dryness of a mucous membrane of an oral cavity, nausea, vomiting, diarrhea, lock, hepatitis, jaundice.
From a musculoskeletal system: muscular weakness, systremmas, an arthralgia, including thorax, spin, neck pain, the alternating lameness.
From sense bodys: vision disorders, a hearing disorder, decrease in products of the lacrimal glands (it is necessary to consider to the patients using contact lenses), dryness and morbidity of eyes, conjunctivitis.

From urinogenital system: disturbance potentiality/libido, cystitis, renal colic, polyuria, intersticial nephrite.
From endocrine system: a hyperglycemia (at patients with a non-insulin-dependent diabetes mellitus), a hypoglycemia (at the patients receiving insulin).
Allergic reactions: skin rash, small tortoiseshell, purpura, photosensitization, anaphylaxis.
From integuments: rashes, acne, skin itch, sweating strengthening, dermahemia, exfoliative dermatitis, aggravation of symptoms of psoriasis, alopecia.
Laboratory indicators: increase in activity of "hepatic" transaminases, a gipertriglitseridemiya, a hypercholesterolemia, a hyperglycemia, a glucosuria, a hyperuricemia, reversible increase in concentration of creatinine and urea in a blood plasma, disturbances of water and electrolytic balance, a metabolic alkalosis, thrombocytopenia, a leukopenia, an agranulocytosis.
Influence on a fruit: pre-natal growth inhibition, hypoglycemia, bradycardia.
Others: gout, syndrome of "cancellation" (arterial hypertension), increase in body weight.

Interaction with other medicines:

At simultaneous use of the drug Aritel® Plus with Phenytoinum (at intravenous administration) and medicines for inhalation general anesthesia (derivatives of hydrocarbons) expressiveness of cardiodepressive action and probability of excessive decrease in the ABP can amplify (due to maintenance as a part of drug of a bisoprolol).
The clearance of lidocaine and xanthines can decrease in connection with possible increase in their concentration in a blood plasma, especially at patients with initially increased clearance of theophylline (due to maintenance as a part of drug of a bisoprolol).
At simultaneous use of drugs of calcium and/or vitamin D in high doses the hypercalcemia can develop and the risk of emergence of a metabolic acidosis increases (due to maintenance as a part of hydrochlorothiazide drug).
Арител® Plus is contraindicated to use in a combination with floktafeniny, sultopridy, MAO inhibitors (except for MAO inhibitors of V type). Strengthening of hypotensive effect of the drug Aritel® Plus at simultaneous use with antidepressants, neuroleptics, blockers of "slow" calcium channels (BMKK) (amlodipiny, felodipiny, nifedipine, nikardipiny, nimodipiny, nitrendipiny), angiotensin-converting enzyme inhibitors (including captopril, enalapril), irbesartany, diuretics, a clonidine, sympatholytics, gidralaziny and other antihypertensives is possible.
Weakening of hypotensive effect of the drug Aritel® Plus at co-administration with glucocorticosteroids (for system use), estrogen, non-steroidal anti-inflammatory drugs (indometacin, piroxicam, Naproxenum, phenylbutazone) and tetrakozaktidy is possible.
At simultaneous use with the drug Aritel® Plus action of not depolarizing muscle relaxants and anticoagulating effect of coumarinic derivatives can amplify. Cardiac glycosides, Methyldopum, Reserpinum, гуанфацин, BMKK (verapamil, diltiazem, амлодипин, фелодипин, nifedipine, никардипин, нимодипин, нитрендипин), antiarrhytmic means, and also means which can initiate arrhythmias like "pirouette" (астемизол, bepridit, erythromycin, галофантрин, pentamidine, спарфлоксацин, терфенадин), increase risk of development and/or strengthening of bradycardia, an atrioventricular block and chronic heart failure. At simultaneous use with sotaloly the hypopotassemia and development of ventricular arrhythmia like "pirouette" is possible. At simultaneous use of the drug Aritel® Plus with salts of lithium increase in concentration of the last in blood to toxic level is possible.
Efficiency of insulin and hypoglycemic means for intake can decrease. Not hydrogenated alkaloids of an ergot increase risk of development of disturbances of peripheric circulation.
At simultaneous use of the drug Aritel® Plus with the allergens used for an immunotherapy or with extracts of allergens for skin tests, and also with Allopyrinolum or with yodosoderzhashchy X-ray contrast diagnostic intravenous agents, the risk of development of allergic reactions increases.
At co-administration of the drug Aritel® Plus with meflokhiny development of bradycardia is possible; with carbamazepine – hyponatremias; with cyclosporine – increase in content of creatinine in blood serum is possible.
Sulfasalazinum increases concentration of a bisoprolol in a blood plasma; rifampicin – shortens an elimination half-life of a bisoprolol.
Bisoprolol and a hydrochlorothiazide it is not necessary to combine with other drugs from group of β-adrenoblockers..........

Contraindications:

- hypersensitivity to a bisoprolol and other components of drug;
- hypersensitivity to a hydrochlorothiazide and other sulfonamides;
- bronchial asthma;
- chronic obstructive pulmonary disease;
- dekompensirovanny chronic heart failure (CHF);
- cardiogenic shock;
- sick sinus syndrome (including sinuatrial blockade);
- an atrioventricular block of II and III degrees without artificial pacemaker;
- the expressed bradycardia (ChSS less than 50 beats/min);
- alternative stenocardia (Printsmetal's stenocardia);
- a pheochromocytoma (without simultaneous use of α-adrenoblockers))))))))));
- unmanageable diabetes mellitus;
- the expressed disturbances of peripheric circulation (including Reynaud's syndrome);
- heavy arterial hypotension (systolic arterial pressure is less than 100 mm of mercury.);
- refractory hypopotassemia, hyponatremia, hypercalcemia;
- metabolic acidosis;
- hypovolemia;
- acute renal failure;
- chronic renal failure (clearance of creatinine (CC) less than 30 ml/min.);
- simultaneous use with floktafeniny, sultopridy;
- concomitant use of antiarrhytmic medicines;
- concomitant use of drugs of lithium;
- a concomitant use of inhibitors of a monoaminooxidase (MAO) (except for MAO inhibitors of B type);
- age up to 18 years (efficiency and safety are not established);
- lactose intolerance, deficit of lactase or glyukozo-galaktozny malabsorption;
- pregnancy;
- lactation period.

Overdose:

Symptoms: the expressed decrease in the ABP, bradycardia, an acute heart failure, ventricular premature ventricular contraction, an atrioventricular block, spasms, a bronchospasm.
Treatment: a gastric lavage, purpose of the adsorbing means, symptomatic therapy. In case of the expressed decrease in the ABP it is necessary to give to the patient horizontal position with the raised legs, to make completion of volume of the circulating blood. At bradycardia atropine in a dose of 1-2 mg, a glucagon in a dose of 12 mg (slowly bolyusno), if necessary – in the form of infusion in a dose of 1-10 mg/hour is intravenously entered. In the subsequent Epinephrinum (adrenaline) in a dose of 15-85 mkg (which introduction can be repeated, but its total quantity should not exceed 300 mkg) or a dopamine in a dose of 2,5 - 10 mkg/kg/min. is appointed. At an acute heart failure cardiac glycosides, diuretics, a glucagon are shown. If there are no fluid lungs signs, then plasma substituting solutions are intravenously appointed, at their inefficiency – Epinephrinum, a dopamine, Dobutaminum. At ventricular premature ventricular contraction lidocaine is applied. At the developed atrioventricular block it is necessary to enter intravenously 1-2 mg of atropine, Epinephrinum or to establish a temporary pacemaker. At spasms diazepam intravenously is recommended. At a bronchospasm it is inhalation are entered β2-адреномиметики.

Storage conditions:

In the dry, protected from light place at a temperature not above 25 °C. To store in the place, unavailable to children. Period of validity 2 years. Not to apply after a period of validity.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 2,5 mg + 6,25 mg.
On 7, 10 or 30 tablets in a blister strip packaging from a film of the polyvinyl chloride and printing aluminum foil varnished.
On 1, 2, 4 blister strip packagings on 7 tablets or on 1, 2, 3, 5, 10 blister strip packagings on 10 tablets or on 1, 3 blister strip packagings on 30 tablets together with the application instruction place in a pack from a cardboard.