Atoris Combi - instructions for use, doses, side effects, contraindications

Active substanceAmlodipine + AtorvastatinAmlodipine + Atorvastatin

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Atoris® Combi

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KRKA, dd, Novo mesto, AO

DUPLEKOR®

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GEDEON RICHTER, OJSC Hungary

Caduet®

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Pfizer Manufakchuring Deutschland GmbH Germany

Dosage form: & nbsptfilm-covered laths

Composition:

For 1 tablet 5 mg + 10 mg / 5 mg + 20 mg

Core:

Active substances:

Amlodipine besylate (amlodipine besylate) 6.94 mg / 6.94 mg, equivalent to amlodipine 5.0 mg / 5.00 mg;

Atorvastatin calcium trihydrate 10.85 mg / 21.70 mg, equivalent to atorvastatin 10.0 mg / 20.00 mg.

Excipients:

Polysorbate 80 0.40 mg / 0.80 mg, calcium carbonate 33.15 mg / 80.00 mg, croscarmellose sodium 6.00 mg / 12.00 mg, giprolose 2.00 mg / 4.00 mg, microcrystalline cellulose 24 , 1 mg / 101.26 mg, corn pregelatinized starch 15.00 mg / 50.00 mg, magnesium stearate 1.00 mg / 2.00 mg, silicon dioxide colloid 0.65 mg / 1.30 mg

Film Sheath:

Opaprai 03H28758 white 5.00 mg / Opadrai II 85F280010 white 8.00 mg.

For 1 tablet of 10 mg + 10 mg / 10 mg + 20 mg

Poisonro:

Active substances:

Amlodipine besylate (amlodipine besylate) 13.88 mg / 13.88 mg, equivalent to amlodipine 10.00 mg / 10.00 mg;

Atorvastatin calcium trihydrate 10.85 mg / 21.70 mg, equivalent to atorvastatin 10.00 mg / 20.00 mg.

SupportsatFerrous substances:

Polysorbate 80 0.40 mg / 0.80 mg, calcium carbonate 33.15 mg / 80.00 mg, croscarmellose sodium 6.00 mg / 12.00 mg, giprolose 2.00 mg / 4.00 mg, microcrystalline cellulose 17 , 07 mg / 94.32 mg, corn pregelatinized corn starch 15.00 mg / 50.00 mg, magnesium stearate 1.00 mg / 2.00 mg, silicon dioxide colloid 0.65 mg / 1.30 mg

Film Sheath:

Opadry II 85F10919 blue 5.00 mg / 8.00 mg;

Opaprai 03H28758 white: hypromellose (3.6 mg / table), titanium dioxide (E171) (0.8 mg / table), propylene glycol (0.25 mg / table), talc (0.35 mg / tab. );

Opadry II 85F280010 white: polyvinyl alcohol (3.912 mg / table), titanium dioxide (E171) (1.2 mg / table), macrogol-3000 (2.328 mg / table), talc (0.56 mg / table);

Opadry II 85F10919 blue (for tablets with a dosage of 10 mg + 10 mg): polyvinyl alcohol (2.0 mg / table), titanium dioxide (E171) (1.075 mg / table), macrogol-3000 (1.01 mg / table) , talc (0.74 mg / tab), indigocarmine (E132) (0.175 mg / tab);

Opadry II 85F10919 blue (for tablets with a dosage of 10 mg + 20 mg): polyvinyl alcohol (3.2 mg / table), titanium dioxide (E171) (1.72 mg / table), macrogol-3000 (1.616 mg / table) , talc (1.184 mg / table), indigocarmine (E132) (0.28 mg / tab).

Description:

Tablets 5 mg + 10 mg:

Round, biconvex tablets, covered with a film shell from white to almost white, with a bevel.

View of the fracture: a rough mass of white or almost white with a film sheath from white to almost white.

Tablets 5 mg + 20 mg:

Round, biconvex tablets, covered with a film shell from white to almost white, with a facet and an engraving "5" on one side.

View of the fracture: a rough mass of white or almost white with a film sheath from white to almost white.

Tablets 10 mg + 10 mg:

Round, biconvex tablets, covered with a film shell of blue color, with a bevel.

View of the fracture: a rough mass of white or almost white with a film coating of blue color.

Tablets 10 mg + 20 mg:

Round, biconvex tablets, covered with a film shell of blue color, with a facet and an engraving "10" on one side.

View of the fracture: a rough mass of white or almost white with a film coating of blue color.

Pharmacotherapeutic group:Hypotensive + hypolipidemic agent

ATX: & nbsp

C.10.A.A.05 Atorvastatin

C.08.C.A.01 Amlodipine

Pharmacodynamics:

Atoris® Combi is a combination drug designed to treat cardiovascular diseases (arterial hypertension / angina and dyslipidemia).

Mechanism of action

Amlodipine is a dihydropyridine derivative, a blocker of "slow" calcium channels (BCCC), and atorvastatin - a hypolipidemic agent, an inhibitor of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase. The combination of amlodipine / atorvastatin has two mechanisms of action: amlodipine inhibits the flow of calcium ions through membranes into smooth muscle cells and cardiomyocytes, and atorvastatin selectively and competitively inhibits HMG-CoA reductase, which catalyzes the conversion of HMG-CoA to mevalonic acid (a precursor of steroids, including cholesterol [Xc]). The effect of systolic blood pressure (SBP), diastolic blood pressure (DBP) and concentration of low-density lipoprotein (LDL), the drug Atoris^® Combi does not differ significantly from monotherapy with amlodipine and atorvastatin.

Pharmacodynamics of amlodipine

Amlodipine blocks the flow of calcium ions through the membranes into the smooth muscle cells of the myocardium and vessels. The mechanism of hypotensive action of amlodipine is due to a direct relaxing effect on the smooth muscles of the vessels. The exact mechanism of action of amlodipine in angina is not definitively established, however, two ways of reducing myocardial ischemia under the influence of amlodipine are known:

1. Amlodipine dilates the peripheral arterioles and, thus, reduces the overall peripheral vascular resistance (OPSS) - postload. The heart rate (heart rate) does not change at the same time, which, consequently, leads to a decrease in heart burden, a reduction in energy consumption and oxygen demand;

2. The mechanism of action of amlodipine probably also includes expansion of the main coronary arteries and coronary arterioles both in unchanged and ischemic zones of the myocardium. Their dilatation increases the flow of oxygen into the myocardium in patients with vasospastic angina (Prinzmetal angina or variant angina) and prevents the development of coronary vasoconstriction caused by smoking.

In patients with hypertension, a single daily dose of amlodipine provides a clinically significant decrease in blood pressure (BP) for 24 hours in both the "lying" and "standing" positions. At a physiological pH level amlodipine is presented in the form of an ionized compound that is characterized by a gradual interaction with the calcium channel receptors, in connection with which,there is a gradual onset of the effect. Due to the slow start of action amlodipine does not cause acute arterial hypotension.

In patients with angina, the use of amlodipine once a day increases the time required for exercise, prevents the development of an attack of angina and segment depression ST (by 1 mm) on the electrocardiogram (ECG), reduces the frequency of angina attacks, allows reducing the consumption of nitroglycerin tablets.

Amlodipine does not adversely affect the metabolism and lipids of blood plasma and can be used in patients with bronchial asthma, diabetes and gout.

It was noted that amlodipine prevents the progressive thickening of the intima-media of the carotid arteries. In patients receiving amlodipine, there is a significant decrease in the total mortality from cardiovascular events, myocardial infarction (MI), stroke, progression of chronic heart failure (CHF), unstable angina. Also, the frequency of percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass grafting is reduced.The frequency of hospitalizations for unstable angina decreases.

Pharmacodynamics of atorvastatin

Atorvastatin reduces the concentration of Xs and lipoproteins in the blood plasma due to the inhibition of HMG-CoA reductase and the synthesis of Xc in the liver and an increase in the number of "liver" LDL receptors on the cell surface, which leads to an increase in the capture and catabolism of LDL.

Atorvastatin and some of its metabolites are pharmacologically active in humans. The primary site of atorvastatin is the liver, where the synthesis of cholesterol is carried out and the clearance of LDL. The degree of decrease in the concentration of LDL in the blood plasma correlates with the dose of the drug to a greater extent than with its systemic concentration. The dose of the drug is selected taking into account the response to the treatment (see section "Method of administration and dose").

In patients with homozygous and heterozygous familial hypercholesterolemia, non-family forms of hypercholesterolemia and mixed dyslipidemia and hypercholesterolemia (including patients with type 2 diabetes mellitus) atorvastatin in doses of 10-80 mg reduces serum concentrations of total cholesterol (OXc), Xc-LDL and apolipoprotein B (apo-B),and Xc of very low density lipoproteins (Xc-VLDL) and triglycerides (TG), and causes a variable increase in the concentration of high-density lipoproteins (HDL-C) in the blood plasma.

Atorvastatin reduces the formation of LDL and the number of LDL particles. It causes a pronounced and persistent increase in the activity of LDL receptors in combination with favorable changes in the quality of LDL particles. Atorvastatin reduces the concentration of LDL-C in patients with homozygous familial hypercholesterolemia, which usually does not respond to lipid-lowering therapy.

In patients with isolated hypertriglyceridemia atorvastatin reduces the concentrations of OXc, Xc-LDL, Xc-VLD, apo-B, TG and Xc of low-density lipoproteins (LPNEVP) and increases the concentration of HDL-C in the blood plasma.

In patients with disbetalipoproteinemia atorvastatin reduces the serum concentration of intermediate-density lipoprotein cholesterol (Xc-LLPP).

In patients with hyperlipoproteinemia IIa and IIb types according to Fredrickson classification, the median increase in serum HDL concentration in the treatment with atorvastatin (10-80 mg) is 5.1-8.7%.The change in this indicator does not depend on the dose. In the analysis, these patients also showed a dose-dependent decrease in the ratio of OXc / Xc-HDL and Xc-LDL / Xc-HDL-PA to 29-44% and 37-55%, respectively.

Treatment with atorvastatin results in a marked reduction in the risk of ischemic outcomes and mortality by 16%. The risk of re-hospitalization for angina and confirmed myocardial ischemia is reduced by 26%. The effect of atorvastatin on the risk of ischemic outcomes and mortality does not depend on the initial serum concentration of Xc-LDL and is comparable in patients with MI without a tooth Q and unstable angina, men and women, patients under the age of 65 years and younger.

Atorvastatin significantly reduces the development of the following complications:

	Risk reduction
Coronary complications (IHD with fatal outcome and nonfatal myocardial infarction)	36%
General cardiovascular complications and revascularization procedures	20%
Common coronary complications	29%
Stroke (fatal and nonfatal)	26%

There is no significant reduction in overall and cardiovascular mortality, although there is a positive trend.

In patients with type 2 diabetes, and at least one of the following risk factors atorvastatin influenced the development of cardiovascular complications as follows:

	Relative risk reduction
Major cardiovascular complications (fatal and nonfatal acute MI, latent MI, death as a result of exacerbation of IHD, unstable angina, coronary artery bypass, PTCA, revascularization, stroke)	37%
MI (fatal and nonfatal acute MI, latent MI)	42%
Stroke (fatal and nonfatal)	48%

In patients with atherosclerosis, the total volume of atheroma, serum concentrations of Xc-LDL, OXc, Tg, apo-B, C-reactive protein decreased in the presence of atorvastatin and there was an increase in serum concentration of HDL-C.

Pharmacokinetics:

Suction

After taking Atoris® Combi, two distinct peaks of maximum concentration were recorded inside (C_mOh) in the blood plasma. The concentration of atorvastatin reached a maximum after 1-2 hours, and amlodipine in 6-12 hours. The rate and degree of absorption (bioavailability) of amlodipine and atorvastatin with the combined amlodipine / atorvastatin did not differ from that with simultaneous administration of amlodipine and atorvastatin tablets: C_max Amlodipine-101%, the area under the concentration-time curve (AUC) of amlodipine -100%, C_maxatorvastatin 94%, atorvastatin AUC 105%.

Although simultaneous intake of food caused a decrease in the rate and extent of absorption of atorvastatin with the combined amlodipine / atorvastatin preparation by approximately 32% and 11%, respectively (C_mOh 68% and AUC 89%), but similar changes in bioavailability were detected when one atorvastatin was used. At the same time, eating did not affect the degree of decrease in serum LDL concentration.

Amlodipine well absorbed after oral administration at therapeutic doses, reaching C_mOh in blood plasma 6-12 hours after admission. Absolute bioavailability according to calculations is 64-80%. Research in vitro showed that circulating amlodipine approximately 97.5% is associated with plasma proteins. The intake of food does not affect the absorption of amlodipine. Bioavailability of amlodipine did not change after ingestion (C_mOh 105% and AUC 101%) compared with fasting rates.

Atorvastatin quickly absorbed after ingestion, its concentration in the blood plasma reaches a maximum after 1-2 hours.The degree of absorption and concentration of atorvastatin in the blood plasma increase in proportion to the ingested dose. The absolute bioavailability of atorvastatin is about 14%, and the systemic bioavailability of inhibitory activity against HMG-CoA reductase is about 30%. Low systemic bioavailability is due to presystemic metabolism (absorption) in the mucous membrane of the gastrointestinal tract and / or metabolism during the "primary passage" through the liver. Food intake slightly reduces the rate and degree of absorption (by 25% and 9%, respectively, as evidenced by the results of the determination of C_mOh and AUC), however, a decrease in plasma LDL is similar to that of fasting atorvastatin. Despite the fact that after taking atorvastatin in the evening its concentration in the blood plasma is lower (C_mOhand AUC approximately 30%) than after taking in the morning, a decrease in the concentration of LDL does not depend on the time of day in which the drug is taken.

Distribution

Amlodipine: the volume of distribution is approximately 21 liters.

Atorvastatin: the average volume of atorvastatin distribution is about 381 liters. The connection with plasma proteins is not less than 98%.The ratio of the content in the erythrocytes / plasma is about 0.25, that is atorvastatin poorly penetrates into red blood cells.

Metabolism and excretion

Amlodipine: half-life (T_1/2) of amlodipine from the blood plasma is about 35-50 hours, which allows prescribing the drug once a day. Equilibrium concentration in the blood plasma is achieved after 7-8 days of constant intake of the drug. Metabolized in the liver with the formation of inactive metabolites, 10% of the unchanged drug and 60% of metabolites are excreted by the kidneys.

Atorvastatin is largely metabolized with the formation of ortho- and para-hydroxylated derivatives and various beta-oxidation products. In conditions in vitro ortho- and para-hydroxylated metabolites have an inhibitory effect on HMG-CoA reductase, comparable to that of atorvastatin. Approximately 70% decrease in the activity of HMG-CoA reductase occurs due to the action of active circulating metabolites. Research results in vitro suggest that isoenzyme CYP3A4 liver plays an important role in the metabolism of atorvastatin. In favor of this fact is an increase in the concentration of atorvastatin in human blood plasma with simultaneous administration of erythromycin,which is an inhibitor of this isoenzyme. Research in vitro They also showed that atorvastatin is a weak isoenzyme inhibitor CYP3A4. There was no clinically significant effect of atorvastatin on the concentration in the blood plasma of terfenadine, which is metabolized mainly by isoenzyme CYP3A4, so it is unlikely that atorvastatin has a significant effect on the pharmacokinetics of other isoenzyme substrates CYP3A4 (see section "Interaction with other drugs").

Atorvastatin and its metabolites are excreted mainly with bile as a result of hepatic and / or extrahepatic metabolism, atorvastatin not subject to severe intestinal hepatic recirculation. T_1/2 atorvastatin is about 14 hours, with T_1/2inhibitory activity against HMG-CoA reductase, due to the presence of active metabolites, is about 20-30 hours. After oral administration, less than 2% of the dose is excreted by the kidneys.

Pharmacokinetics in selected patient groups

Impaired liver function

The concentration of atorvastatin in blood plasma is significantly increased (C_mOh - about 16 times, a AUC - approximately 11 times) in patients with alcoholic liver cirrhosis (class B according to the Child-Pugh classification) (see section "Contraindications").

Impaired renal function

Concentrations of amlodipine in blood plasma do not depend on the degree of renal failure, amlodipine not output during dialysis.

Kidney disease does not affect the concentration of atorvastatin in the blood plasma; therefore, dose adjustments in patients with renal dysfunction are not required (see section "Method of administration and dose").

Floor

The concentration of atorvastatin in blood plasma in women is different (C_mOh about 20% higher, a AUC - 10% lower) than that of men, but clinically significant differences in the effect of the drug on lipid metabolism in men and women have not been identified.

Elderly patients

The time required to achieve C_mOh (TC_mOh) of amlodipine in blood plasma, practically does not depend on age. Patients in the elderly have a tendency to decrease the clearance of amlodipine, which leads to an increase AUC and the elongation T_1/2. In patients of different age groups with CHF, there was an increase AUC and the elongation T_1/2. The tolerability of amlodipine in the same doses in elderly patients and young patients is equally good.

Concentrations of atorvastatin in blood plasma in patients aged 65 years and older are higher (C_mOh - by about 40%, AUC - approximately 30%) than in young patients, with no difference in safety, efficacy, or achievement of lipid-lowering therapy in elderly patients compared with the general population.

Indications:

- The drug Atoris® Combi is indicated for patients with hypertension with three or more risk factors for cardiovascular events (fatal and nonfatal CHD, need for revascularization procedures, fatal and nonfatal MI, stroke and transient ischemic attack), with normal or moderately elevated serum concentration of Xs without clinically expressed CHD.

- The drug Atoris® Combi is used in cases when combined therapy with amlodipine and low doses of atorvastatin is recommended.

Possible simultaneous use of the drug Atoris® Combi with other antihypertensive and / or antianginal agents.

- The drug Atoris® Combi is used in cases when the lipid-lowering diet and other non-pharmacological methods of treating dyslipidemia turn out to be little or ineffective.

Contraindications:

- Hypersensitivity to amlodipine and other derivatives of dihydropyridine, atorvastatin or any component of the drug;

- active liver disease or persistent increase in activity of "liver" enzymes more than 3 times higher than the upper limit of the norm (VGN) of unclear etiology;

- pregnancy, the period of breastfeeding, use in women of reproductive age who do not use adequate methods of contraception;

- in children under the age of 18 (efficacy and safety not established);

- severe arterial hypotension (SBP less than 90 mm Hg);

- severe or clinically significant aortic stenosis;

- hemodynamically unstable heart failure after acute myocardial infarction (by amlodipine).

Carefully:

Hepatic failure or liver disease in history, CHF of non-ischemic etiology III-IV functional class according to NYHA classification, unstable angina, aortic stenosis, acute myocardial infarction (and within 1 month after it), age over 70 years, renal dysfunction, hypothyroidism.

As with the application of other BCCI, caution should be exercised when receiving amlodipine in patients with sinus syndromenode (SSSU), mitral stenosis, hypertrophic obstructive cardiomyopathy (GOKMP), arterial hypotension.

Also, the drug Atoris® Combi should be used with caution in patients who abuse alcohol.

Pregnancy and lactation:

The drug Atoris® Combi is contraindicated in pregnancy, as the composition of the drug is atorvastatin. Women of reproductive age during treatment should use adequate methods of contraception. The drug Atoris® Combi can be prescribed to women of reproductive age only if the probability of pregnancy is low and the patients are informed of the possible risk to the fetus.

The drug Atoris® Combi is contraindicated in the period of breastfeeding, since it includes atorvastatin. There is no information on the induction of atorvastatin with breast milk. Given the possibility of developing unwanted reactions in infants, women who receive the drug Atoris® Combi should stop breastfeeding.

In animal studies amlodipine had no effect on reproductive function, but had reproductive toxicity when administered at very high doses (50 times the maximum recommended dose for a person).

It is not recommended to use amlodipine during pregnancy or during breastfeeding.

Dosing and Administration:

The drug Atoris® Combi is taken orally one tablet once a day at any time, regardless of the time of ingestion.

One tablet of the drug Atoris® Combi contains 5 mg + 10 mg, 5 mg + 20 mg, 10 mg + 10 mg or 10 mg + 20 mg (amlodipine and atorvastatin, respectively).

The initial and maintenance doses are selected individually taking into account the efficacy and tolerability of both components in the treatment of arterial hypertension / angina and dyslipidemia.

The drug Atoris® Combi can be administered to patients who already take one of the components of the drug in monotherapy.

The drug Atoris® Combi is used in combination with non-medicated treatments, including diet, exercise, weight loss in obese patients, quitting.

When starting treatment with a dose of 5 mg + 10 mg in patients with hypertension, it is necessary to control blood pressure and lipid concentration in the blood plasma every 2-4 weeks and, if necessary, transfer to a dose of 10 mg + 10 mg.

IHD (amlodipine): the recommended dose is 5-10 mg once a day.

Primary hypercholesterolemia and combined (mixed) dyslipidemia (atorvastatin): for the majority of patients - 10 mg once a day. The therapeutic effect manifests itself within 2 weeks and usually reaches a maximum within 4 weeks, with prolonged treatment the effect is preserved.

Use in patients with impaired liver function: see the sections "Contraindications" and "Special instructions".

Use in patients with impaired renal function: correction of the dose is not required.

Use in elderly patients: correction of the dose is not required.

The maximum daily dose of atorvastatin is 80 mg, amlodipine - 10 mg.

Use in combination with other medicines

If a simultaneous use with cyclosporine, telaprevir, boceprevir, tipranavir / ritonavir is required, the dose of atorvastatin should not exceed 10 mg / day, with clarithromycin not more than 20 mg / day.

Caution should be exercised and the lowest effective dose of atorvastatin should be used when combined with HIV protease inhibitors, hepatitis C virus protease inhibitors, clarithromycin and itraconazole.

Side effects:

In general, the tolerability of the combination amlodipine / atorvastatin was good.There were no unexpected undesirable effects in combination therapy with amlodipine / atorvastatin.

Undesirable effects were consistent with those previously identified with amlodipine and / or atorvastatin (see below). Most of the undesirable effects were easily or moderately expressed. Because of adverse effects or laboratory abnormalities, treatment with amlodipine / atorvastatin was discontinued in 5.1% of patients, and placebo at 4.0%.

Amlodipine

Further, the frequency of adverse reactions is understood to be: very often ≥ 10%, often from ≥ 1% to <10%, infrequently from ≥ 0.1% to <1%, rarely from 0.01% to <0.1 %, very rarely - <0.01%).

Violations of the blood and lymphatic system: infrequently: leukopenia, thrombocytopenia; very rarely: thrombocytopenic purpura.

Disorders from the metabolism and nutrition: infrequently: hyperglycemia.

Disturbances from the nervous system: often: dizziness, headache, drowsiness; infrequent: fainting, hypoesthesia, paresthesia, hypertension, peripheral neuropathy, tremor, unusual dreams, nervousness, depression, anxiety, taste change, extrapyramidal disorders; rarely: convulsions, apathy, agitation; very rarely: ataxia, amnesia.

Disorders of the psyche: infrequently: insomnia, frequent mood swings.

Disturbances on the part of the organ of sight: infrequently: visual impairment, diplopia, accommodation disorder, xerophthalmia, conjunctivitis, pain in the eyes.

Hearing disorders and labyrinthine disorders: infrequently: "ringing" in the ears.

Heart Disease: often: peripheral edema (ankle and foot), palpitations, orthostatic hypotension; infrequently: excessive decrease in blood pressure; rarely: development or exacerbation of heart failure; very rarely: heart rhythm disturbances (including bradycardia, ventricular tachycardia and atrial fibrillation), MI, chest pain, migraine.

Vascular disorders: often: a feeling of heat ("hot flashes" of blood to the skin of the face); infrequently: marked decrease in blood pressure, vasculitis.

Disturbances from the respiratory system, chest and mediastinal organs: infrequently: shortness of breath, rhinitis, cough.

Disorders from the digestive system: often: abdominal pain, nausea; infrequently: changes in the bowel movement (including constipation, flatulence), dyspepsia, diarrhea, anorexia, dryness of the oral mucosa, thirst, gingival hyperplasia, increased appetite, gastritis, pancreatitis, vomiting.

Disturbances from the liver and bile ducts: very rarely: hyperbilirubinemia, jaundice (usually cholestatic), increased activity of "hepatic" transaminases in blood plasma, hepatitis.

Disturbances from the skin and subcutaneous tissues: infrequently: alopecia, increased sweating, purpura, impaired skin pigmentation, urticaria; rarely: skin itching, skin rash, angioedema, erythema multiforme, dermatitis.

Disturbances from musculoskeletal system and connective tissue: infrequently: arthralgia, muscle cramps, myalgia, back pain, arthrosis; rarely: myasthenia gravis.

Disorders from the kidneys and urinary tract: infrequently: pollakiuria, frequent urination, painful urination, nocturia; very rarely: dysuria, polyuria.

Violations of the genitals and mammary glands: infrequently: gynecomastia, impotence.

General disorders and disorders at the site of administration: often: peripheral edema, fatigue; infrequently: general weakness, malaise, pain of unspecified localization, taste distortion, chills, nosebleeds; very rarely: parosmia, xeroderma, "cold" sweat.

Laboratory and instrumental data: infrequently: increase or decrease in body weight.

Atorvastatin

The most frequent adverse reactions (≥ 1%):

Infectious and parasitic diseases: nasopharyngitis.

Disorders from the metabolism and nutrition: hyperglycemia.

Disturbances from the nervous system: insomnia, headache, asthenic syndrome.

Disturbances from the respiratory system, chest and mediastinal organs: sore throat, nosebleed.

Disorders from the gastrointestinal tract: nausea, diarrhea, abdominal pain, indigestion, constipation, flatulence.

Disturbances from musculoskeletal and connective tissue: arthralgia, pain in the extremities, musculoskeletal pain, muscle cramps, myalgia, swelling of the joints.

Laboratory and instrumental data: deviation from the norm of the results of "liver" tests, increased activity of serum creatine phosphokinase (CK).

Less frequent adverse reactions (≤1%):

Violations of the blood and lymphatic system: thrombocytopenia.

Immune system disorders: allergic reactions (including anaphylaxis).

Disorders from the metabolism and nutrition: weight gain, hypoglycemia.

Disorders of the psyche: unusual dreams.

Disturbances from the nervous system: dizziness, amnesia, paresthesia, peripheral neuropathy, hypesthesia, a violation of taste perception.

Disturbances on the part of the organ of sight: the appearance of "shroud" before the eyes.

Hearing disorders and labyrinthine disorders: noise in ears.

Disorders from the digestive system: vomiting, anorexia, hepatitis, discomfort in the abdomen, belching, pancreatitis.

Disturbances from the liver and bile ducts: hepatitis, cholestatic jaundice.

Disturbances from the skin and subcutaneous tissues: urticaria, skin itch, skin rash, bullous rash, polymorphic exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome).

Disturbances from the musculoskeletal and connective tissue: back pain, myositis, immuno-mediated necrotizing myopathy, muscle weakness, neck pain, rhabdomyolysis.

General disorders and disorders at the site of administration: malaise, impotence, peripheral edema, chest pain, secondary renal failure, increased fatigue, fever.

Laboratory and instrumental data: leukocyturia.

Injuries, intoxication and complications of manipulation: tendonopathy (in some cases with a rupture of the tendon).

In post-marketing application Some inhibitors of HMG-CoA reductase (statins), including atorvastatin, reported the following undesirable effects: memory loss, depression, sexual dysfunction, gynecomastia, single cases of development of interstitial lung disease (especially with prolonged use), there have also been cases of increased levels of glycosylated hemoglobin in blood plasma.

The causal relationship with the use of the amlodipine / atorvastatin combination was not established for all of the above reactions.

Overdose:

There is no information about an overdose. how amlodipine, and atorvastatin actively bind to blood plasma proteins, so a significant increase in clearance of the combined drug in hemodialysis is unlikely.

Symptoms of an overdose of amlodipine:

- excessive peripheral vasodilation leading to reflex tachycardia;

- a pronounced and persistent decrease in blood pressure, including with the development of shock and death.

Symptoms of an overdose of atorvastatin: not described.

Treatment of an overdose of amlodipine:

- reception of activated carbon immediately or within 2 hours after taking amlodipine at a dose of 10 mg leads to a significant delay in absorption of the drug. In some cases, gastric lavage may be effective;

- a pronounced decrease in blood pressure caused by an overdose of amlodipine requires active measures aimed at maintaining the function of the cardiovascular system, including monitoring the performance of the heart and lungs, the elevated position of the limbs, monitoring the volume of circulating blood and diuresis;

- to restore blood pressure and vascular tone, it may be useful to use a vasoconstrictive drug, if there is no contraindication to its purpose;

- to eliminate the effects of calcium channel blockade - intravenous calcium gluconate.

Specific means for treatment of atorvastatin overdose no. In case of an overdose, symptomatic and supportive treatment should be provided as needed.

Interaction:

It has been shown that the pharmacokinetics of amlodipine at a dose of 10 mg with combined therapy with atorvastatin 80 mg in healthy volunteers does not change.The use of amlodipine did not affect C_mOh atorvastatin, but caused an increase AUC on 18% in a blood plasma.

The interaction of the amlodipine / atorvastatin combination with other drugs has not been specifically studied. Below is the information for each component individually.

Amlodipine

Amlodipine can safely be used concomitantly with antibiotics and hypoglycemic agents for oral administration.

Inhibitor inhibitors CYP3A4: with the simultaneous use of diltiazem 180 mg and amlodipine at a dose of 5 mg in elderly patients (aged 69 to 87 years) with arterial hypertension, increased systemic exposure (AUC) of amlodipine by 57%.

The simultaneous use of amlodipine and erythromycin in healthy volunteers (18 to 43 years old) does not lead to significant changes in the exposure of amlodipine (an AUC increase of 22%). Despite the fact that the clinical significance of these effects is not fully understood, they can be more pronounced in elderly patients.

Strong inhibitors of isoenzyme CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) can lead to an increase in the concentration of amlodipine in the blood plasma to a greater extent than diltiazem. It should be used with caution amlodipine and isoenzyme inhibitors CYP3A4.

Clarithromycin: clarithromycin is an inhibitor of the isoenzyme CYP3A4. There is an increased risk of developing arterial hypotension in patients receiving clarithromycin simultaneously with amlodipine. With simultaneous use of amlodipine with clarithromycin, it is recommended to carefully monitor the condition of patients.

Inductors of isoenzyme CYP3A4: data on the effect of inducers of the isoenzyme CYP3A4 on the pharmacokinetics of amlodipia. Simultaneous application of inducers of the isoenzyme CYP3A4 (for example, rifampicin, St. John's wort perforated) and amlodipine can lead to a decrease in the concentration of amlodipine in the blood plasma. It should be used with caution amlodipine and inductors of the isoenzyme CYP3A4.

Cimetidine: with the simultaneous use of amlodipine with cimetidine, the pharmacokinetics of amlodipine does not change.

Grapefruit juice: simultaneous single intake of 240 ml of grapefruit juice and 10 mg of amlodipine inwards is not accompanied by a significant change in the pharmacokinetics of amlodipine, however, the possibility of genetic polymorphism of the isoenzyme CYP3A4 should be considered. In this regard, the simultaneous use of the drugAtoris® Combi and grapefruit or grapefruit juice is not recommended because of the possible increase in the bioavailability of amlodipine in some patients, which can lead to an increase in the antihypertensive effect of amlodipine.

In contrast to other BCCC, clinically significant interaction of amlodipine was not detected with concomitant use with non-steroidal anti-inflammatory drugs (NSAIDs), special indomethacin.

It is possible to increase the anti-anginal and antihypertensive action of BCCC when used simultaneously with thiazide and loop diuretics, verapamil, angiotensin-converting enzyme (ACE) inhibitors, beta-blockers and nitrates, as well as an increase in their antihypertensive effect when used simultaneously with alpha1-adrenoblockers, neuroleptics. Although no negative inotropic effect was usually observed in the study of amlodipine, nevertheless, some BCCI can enhance the severity of negative inotropic action antiarrhythmic drugs that cause lengthening of the interval QT (eg, amiodarone and quinidine). With simultaneous application of BCCC with lithium preparations may enhance the neurotoxicity of lithium (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus).

Amlodipine does not affect the conditions in vitro on the degree of binding to blood plasma proteins digoxin, phenytoin, warfarin and indomethacin.

Aluminum / magnesium-containing antacids: they do not have a single dose significant influence on the pharmacokinetics of amlodipine.

Sildenafil: a single dose of 100 mg of sildenafil in patients with essential hypertension does not affect the pharmacokinetics of amlodipine. With simultaneous use, each drug independently reduces blood pressure.

Digoxin: with the simultaneous use of amlodipine with digoxin in healthy volunteers, the serum concentration and renal clearance of digoxin do not change.

Ethanol (alcoholic beverages): with a single and repeated application in a dose of 10 mg amlodipine has no significant effect on the pharmacokinetics of ethanol.

Warfarin: amlodipine does not affect the changes in prothrombin time caused by warfarin.

Cyclosporine: Studies of the interaction of amlodipine and cyclosporine were carried out only in patients undergoing kidney transplantation.These studies demonstrated either no effect of amlodipine on the minimum concentration of cyclosporine in the blood plasma, or a possible increase of up to 40%. Consideration should be given to monitoring the plasma cyclosporin concentration in patients after kidney transplantation with this combination of drugs.

Tacrolimus: there is a risk of increasing the concentration of tacrolimus in the blood plasma when used simultaneously with amlodipine. To avoid the development of tacrolimus toxicity with amlodipine in patients receiving tacrolimus treatment, it is necessary to monitor its concentration in the blood plasma and dose adjustment if necessary.

Dantrolene: cases of lethal atrial fibrillation and cardiovascular insufficiency were observed intravenously in experiments with animals with simultaneous use of verapamil and dantrolene in connection with the development of hyperkalemia. In view of the risk of developing hyperkalemia, it is recommended to avoid the use of BCCC, such as amlodipine, in patients with suspected or confirmed malignant hyperthermia, as well as during treatment of this condition.

Simvastatin: repeated simultaneous use of amlodipine in a dose of 10 mg and simvastatin at a dose of 80 mg leads to an increase in the concentration of simvastatin in blood plasma by 77% compared with simvastatin monotherapy. Limit the dose of simvastatin to 20 mg per day.

Impact on laboratory test results: is unknown.

Atorvastatin

Because the atorvastatin is metabolized by isoenzyme CYP3A4, simultaneous use of atorvastatin with isoenzyme inhibitors CYP3A4 can lead to an increase in the concentration of atorvastatin in the blood plasma. The degree of interaction and the effect of potentiation is determined by the variability of the effect on the isoenzyme CYP3A4.

Inhibitors of transport protein OATP1B1: atorvastatin and its metabolites are substrates of the transport protein OATP1B1. Inhibitors of OATP1B1 (for example, ciclosporin) may increase the bioavailability of atorvastatin. Thus, simultaneous use of atorvastatin 10 mg and cyclosporine at a dose of 5.2 mg / kg / day leads to an increase in the concentration of atorvastatin in blood plasma by 7.7 times (see the section "Method of administration and dose").

The risk of developing myopathy during treatment with other drugs of this class is increased with simultaneous application cyclosporine, fibrin acid derivatives, erythromycin, antifungal preparations of azoles, and nicotinic acid in lipid-lowering doses (more than 1 g / day) (see section "Special instructions", subsection "Action on skeletal muscles").

Antacids: simultaneous ingestion of a suspension containing magnesium and aluminum hydroxides, reduced the concentration of atorvastatin in the blood plasma by approximately 35%, but the degree of decrease in the concentration of LDL-C was not changed.

Phenazone: atorvastatin does not affect the pharmacokinetics of phenazone, therefore interaction with other drugs metabolized by the same isoenzymes of the cytochrome P450 system is not expected.

Itraconazole: simultaneous use of atorvastatin in doses of 20 mg to 40 mg and itraconazole at a dose of 200 mg resulted in an increase in the value AUC atorvastatin in the blood plasma.

Grapefruit juice: since the grapefruit juice contains one or more components that inhibit the isoenzyme CYP3A4, its excessive intake (more than 1.2 liters per day) can cause an increase in the concentration of atorvastatin in the blood plasma.

Inductors of isoenzyme CYP3A4: simultaneous use of atorvastatin with inducers of the isoenzyme CYP3A4 (for example,efavirenz or rifampicin) can lead to a decrease in the concentration of atorvastatin in the blood plasma. Because of the dual mechanisms of interaction with rifampicin (isoenzyme CYP3A4 inducer and an inhibitor of the transport protein OATR1V1 hepatocytes), the simultaneous application of atorvastatin and rifampicin as atorvastatin delayed after receiving rifampicin significantly reduces the concentration of atorvastatin in plasma.

Colestipol: with the simultaneous use of colestipol, the concentration of atorvastatin in blood plasma decreased by about 25%, but the hypolipidemic effect of the combination of atorvastatin and colestipol exceeded that of each drug alone.

Digoxin: with repeated administration of digoxin and atorvastatin at a dose of 10 mg, the equilibrium concentrations of digoxin in the blood plasma did not change. However, when using digoxin in combination with atorvastatin at a dose of 80 mg / day, the concentration of digoxin in the blood plasma increased by approximately 20%. Patients receiving digoxin simultaneously with atorvastatin, require appropriate monitoring.

Erythromycin / clarithromycin: with the simultaneous use of atorvastatin and erythromycin (500 mg 4 times daily) or clarithromycin (500 mg twice daily) that inhibit the isoenzyme CYP3A4, an increase in the concentration of atorvastatin in the blood plasma was observed (see section "Special instructions", subsection "Action on skeletal muscles ").

Azithromycin: with the simultaneous use of atorvastatin (10 mg once a day) and azithromycin (500 mg once a day), the concentration of atorvastatin in the blood plasma did not change.

Terfenadine: with the simultaneous use of atorvastatin and terfenadine, no clinically significant changes in the pharmacokinetics of terfenadine have been identified.

Contraceptives for oral administration: with simultaneous use of atorvastatin and a contraceptive for oral administration containing norethindrone and ethinyl estradiol, there was a significant increase in AUC of norethindrone and ethinyl estradiol by approximately 30% and 20%, respectively. This effect should be considered when choosing a contraceptive for oral administration for a woman receiving atorvastatin.

Warfarin: no signs of a clinically significant interaction of atorvastatin with warfarin were found.

Diltiazem: simultaneous use of atorvastatin in a dose of 40 mg with diltiazem in a dose of 240 mg, leads to an increase in the concentration of atorvastatin in blood plasma.

Cimetidine: signs of clinically significant interaction of atorvastatin with cimetidine was not detected.

Amlodipine: with the simultaneous use of atorvastatin 80 mg and amlodipine 10 mg, the pharmacokinetics of atorvastatin did not change in the equilibrium state.

Inhibitors of proteases: simultaneous use of atorvastatin with protease inhibitors, known as isoenzyme inhibitors CYP3A4, was accompanied by an increase in the concentration of atorvastatin in blood plasma. In addition, there was an increase in the concentration of atorvastatin when used simultaneously with HIV protease inhibitors (combinations of lopinavir and ritonavir, saquinavir and ritonavir, darunavir and ritonavir, fosamprenavir, fosamprenavir with ritonavir and nelfinavir), hepatitis C virus protease inhibitors (boceprevir), clarithromycin and itraconazole. Caution should be exercised when these drugs are used concomitantly, and the lowest effective dose of atorvastatin should be used.

Fusidic acid: during postmarketing studies, there have been cases of rhabdomyolysis in patients taking both fusidic acid and atorvastatin. Patients should be carefully monitored and accounted for that the temporary cancellation of atorvastatin may be appropriate.

Colchicine: in spite of the fact that no simultaneous application of colchicine and atorvastatin has been carried out, there are reports of the development of myopathy with this combination. Care should be taken when using atorvastatin and colchicine concomitantly.

Other concomitant therapy: in clinical trials atorvastatin used in combination with antihypertensive agents and estrogens, who appointed with a substitute purpose. There were no signs of clinically significant undesirable interaction. Studies of interaction with specific drugs have not been conducted.

Phenazone (antipyrine): as atorvastatin does not affect the pharmacokinetics of phenazone, it is not expected to interact with other drugs that are metabolized by the same isoenzyme.

Special instructions:

Action on skeletal muscles

In patients who received atorvastatin, myalgia was observed (see section "Side effect"). The diagnosis of myopathy should be assumed in patients with common myalgia, tenderness or weakness of the muscles and / or a marked increase in the activity of CK (more than 10 times compared to HGV) in blood plasma.

Patients should immediately consult a doctor if unexplained pain, tension or weakness occurs in the muscles, especially if they are accompanied by malaise or fever. Therapy with Atoris® Combi should be discontinued if there is a marked increase in the activity of CK in the blood plasma or in the presence of confirmed or suspected myopathy.

The risk of developing myopathy when treated with other drugs of this class increases with the simultaneous use of cyclosporine, fibrin acid derivatives, erythromycin, nicotinic acid in lipid-lowering doses (more than 1 g / day) or antifungals of the azole, colchicine, telprevir, boceprevir or ritonavir / tipranavir combination . Many of these drugs inhibit isoenzyme mediated metabolism CYP3A4, and / or transport of medicinal products.

It is known that isoenzyme CYP3A4 - the main isoenzyme of the liver involved in the biotransformation of atorvastatin. Assigning atorvastatin in combination with fibrin acid derivatives, erythromycin, immunosuppressants, antifungal agents (azole derivatives) or nicotinic acid in lipid-lowering doses (more than 1 g / day), the physician should carefully weigh the expected benefit and risk of treatment and regularly observe patients for pain, or weakness in the muscles, especially during the first months of treatment and during the period of increasing the dose of any drug. If combination therapy is required, consideration should be given to the possibility of using lower initial and supporting aforementioned means. Temporary cancellation of atorvastatin may be appropriate during treatment with fusidic acid. In such situations, it may be recommended to periodically determine the activity of CK in the blood plasma, although such control does not prevent the development of severe myopathy (see section "Interaction with other drugs"). The drug Atoris® Combi can cause an increase in activity of CK (see section "Side effect").

When using atorvastatin, as well as other drugs of this class, rare cases of rhabdomyolysis with acute renal failure due to myoglobinuria are described. The risk factor for rhabdomyolysis may be a previous impairment of kidney function. Such patients should provide more thorough monitoring of the condition of the musculoskeletal system. Therapy with Atoris® Combi should be temporarily discontinued or completely eliminated if there is evidence of possible myopathy or the presence of a risk factor for renal failure against rhabdomyolysis (eg, severe acute infection, arterial hypotension, surgical intervention, trauma, metabolic, endocrine and water electrolyte disorders and uncontrolled convulsions ). Treatment with amlodipine in an adequate dose for the purpose of controlling hypertension can be continued.

As with the application of other hypolipidemic drugs of this class, after treatment with atorvastatitis, a moderate (more than 3 times as compared with the VGN) increased activity of "hepatic" transaminases: aspartate aminotransferase (ACT) and alanine aminotransferase (ALT).A persistent increase in the serum activity of "liver" transaminases (more than 3-fold compared with IGN) was observed in 0.7% of patients who received atorvastatin. The incidence of such changes with atorvastatin at doses of 10 mg, 20 mg, 40 mg, and 80 mg was 0.2%, 0.2%, 0.6%, and 2.3%, respectively. An increase in the activity of "hepatic" transaminases was usually not accompanied by jaundice or other clinical manifestations. With a decrease in the dose of atorvastatin, its temporary or complete abolition, the activity of "hepatic" transaminases returned to the baseline level. Most patients continued to take atorvastatin at a reduced dose without any clinical consequences.

Before the start of therapy, after 6 weeks and 12 weeks after the start of the use of the drug Atoris® Combi, or after increasing its dose, it is necessary to monitor the indicators of liver function. The liver function should also be monitored when there are clinical signs of liver damage. In the case of increased activity of "liver" transaminases, their activity should be monitored until it is normalized. If the increase in activity ACT or ALT more than 3 times higher than IGN is preserved, it is recommended to reduce the dose of atorvastatin or to cancel the drug Atoris® Combi (see section "Side effect").

Atorvastatin should be used with caution in patients who consume significant amounts of alcohol and / or have a history of liver disease. Active liver disease or constantly increased activity of "hepatic" transaminases of blood plasma of unknown origin is a contraindication to the use of the drug Atoris® Combi (see the section "Contraindications").

In patients with CHF (III-IV functional class by classification NYHA) of non-ischemic etiology with the use of amlodipine, there is a possibility of developing pulmonary edema.

When using inhibitors of HMG-CoA reductase, including atorvastatin, there were cases of increased glycosylated hemoglobin (HbA1) and fasting plasma glucose concentrations. Nevertheless, the risk of developing hyperglycemia is lower than the degree of reduction in the risk of vascular complications when taking statins.

It is necessary to maintain dental hygiene and supervision at the dentist (to prevent soreness, bleeding and gingival hyperplasia).

Effect on the ability to drive transp. cf. and fur:

During the treatment period, care must be taken when driving vehicles and engaging in potentially hazardous activities,requiring increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Tablets, film-coated, 5 mg + 10 mg, 5 mg + 20 mg, 10 mg + 10 mg, 10 mg + 20 mg.

Packaging:

For 10 tablets in a blister of the combined material OPA / Al / PVC and aluminum foil.

3, 6, 9 or 10 blisters together with instructions for use are placed in a cardboard pack.

Storage conditions:

At a temperature of no higher than 25 ° C, in the original packaging.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003954

Date of registration:09.11.2016

Expiration Date:09.11.2021

Date of cancellation:2018-04-12

The owner of the registration certificate:KRKA, dd, Novo mesto, AOKRKA, dd, Novo mesto, AO

Manufacturer: & nbsp

KRKA, d.d. Slovenia

Representation: & nbspKRKA, dd, Novo mesto, AOKRKA, dd, Novo mesto, AO

Information update date: & nbsp12.04.2018

Illustrated instructions

Instructions

Atoris® Combi (Atoris® Combi)