Roxer® Combi (Roxera® Combi)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Dosage form: & nbspTfilm-covered abeys.
Composition:

1 tablet, film-coated, 5 mg + 10 mg contains:

Core:

Active substances:

Amlodipine besylate (amlodipine besylate) 6.93 mg (equivalent to amlodipine 5.00 mg)

Calcium rosuvastatin 10.40 mg (equivalent to rosuvastatin 10.00 mg)

Excipients: microcrystalline cellulose 123.08 mg, anhydrous anhydrous 56.00 mg, crospovidone 10.50 mg, silicon dioxide colloid 0.46 mg, magnesium stearate 2.63 mg

Film Sheath: 1Opadrai II 85F220163 yellow 6.3 mg

1 Opadrai II 85F220163 yellow consists of: polyvinyl alcohol 2,968 mg, macrogol 3350 1,766 mg, titanium dioxide (E171) 0.911 mg, talc 0.425 mg, ferric oxide yellow oxide (E172) 0.23 mg

1 tablet, film-coated, 10 mg + 10 mg contains:

Core:

Active substances:

Amlodipine besylate (amlodipine besylate) 13.87 mg (equivalent to amlodipine 10.00 mg)

Calcium rosuvastatin 10.40 mg (equivalent to rosuvastatin 10.00 mg)

Excipients: microcrystalline cellulose 256.56 mg, anhydrous lactose 112.00 mg, crospovidone 21.00 mg, silicon dioxide colloid 0.92 mg, magnesium stearate 5.26 mg

Film Sheath: 2Opadrai II 85F230120 orange 12.6 mg

2 Opadrai II 85F230120 orange consists of: polyvinyl alcohol 6.132 mg, macrogol 3350 3.649 mg, titanium dioxide (E171) 1.881 mg, talc 0.878 mg, ferric iron oxide yellow (E172) 0.025 mg, ferric iron oxide red (E172) 0.035 mg

1 tablet, film-coated, 5 mg + 15 mg contains:

Core:

Active substances:

Amlodipine besylate (amlodipine besylate) 6.93 mg (equivalent to amlodipine 5.00 mg)

Calcium rosuvastatin 15.59 mg (equivalent to rosuvastatin 15.00 mg)

Excipients: microcrystalline cellulose 188.09 mg, anhydrous lactose 84.00 mg, crospovidone 15.75 mg, silicon dioxide colloid 0.69 mg, magnesium stearate 3.95 mg

Film Sheath: 3Opadrai II 85F270036 tan 10.0 mg

3 Opadrai II 85F270036 tan consists of: polyvinyl alcohol 4.821 mg, macrogol 3350 2.869 mg, titanium dioxide (E171) 1.479 mg, talc 0.690 mg, iron oxide dye yellow (E172) 0.100 mg, iron oxide dye red oxide (E172) 0.028 mg, iron oxide dye black (E172) 0.014 mg

1 tablet, film-coated, 10 mg + 15 mg contains:

Core:

Active substances:

Amlodipine besylate (amlodipine besylate) 13.87 mg (equivalent to amlodipine 10.00 mg)

Calcium rosuvastatin 15.59 mg (equivalent to rosuvastatin 15.00 mg)

Excipients: cellulose microcrystalline 181.15 mg, anhydrous lactose 84.00 mg, crospovidone 15.75 mg, silicon dioxide colloid 0.69 mg, magnesium stearate 3.95 mg

Film Sheath: 4Opadrai II 85F265068 brown 10.00 mg

4Opadrai II 85F265068 brown consists of: polyvinyl alcohol 4,821 mg, macrogol 3350 2,869 mg, titanium dioxide (E171) 1.479 mg, talc 0.690 mg, iron oxide yellow oxide (E172) 0.100 mg, ferric iron oxide red (E172) 0.028 mg, iron oxide dye black (E172) 0.014 mg

1 tablet, film-coated, 5 mg + 20 mg contains:

Core:

Active substances:

Amlodipine besylate (amlodipine besylate) 6.93 mg, (equivalent to amlodipine 5.00 mg)

Calcium rosuvastatin 20.79 mg (equivalent to rosuvastatin 20.00 mg)

Excipients: microcrystalline cellulose 253.10 mg, anhydrous lactose 112.00 mg, crospovidone 21.00 mg, silicon dioxide colloid 0.92 mg, magnesium stearate 5.26 mg

Film Sheath: 5Opadrai II 85F220164 yellow 12.6 mg

5Opadrai II 85F220164 yellow consists of: polyvinyl alcohol 6,122 mg, macrogol 3350 3,643 mg, titanium dioxide (E171) 1,878 mg, talc 0,876 mg, ferric oxide yellow oxide (E172) 0.08 mg

1 tablet, film-coated, 10 mg + 20 mg contains:

Core:

Active substances:

Amlodipine besylate (amlodipine besylate) 13.87 mg (equivalent to amlodipine 10.00 mg)

Calcium rosuvastatin 20.79 mg (equivalent to rosuvastatin 20.00 mg)

Excipients: microcrystalline cellulose 246.16 mg, anhydrous lactose 112.00 mg, crospovidone 21.00 mg, silicon dioxide colloid 0.92 mg, magnesium stearate 5.26 mg

Film Sheath: 6Opaprai II white 85F280010 12.6 mg

6Opapray II white 85F280010 consists of: polyvinyl alcohol 6.161 mg, macrogol 3350 3.667 mg, titanium dioxide (E171) 1.890 mg, talc 0.882 mg

Description:

Tablets 5 mg + 10 mg:

round, slightly biconvex tablets, covered with a film coating of brownish-yellow color, with a facet, on one side there is an engraving "10-5", stamping.

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

Tablets 10 mg + 10 mg:

round, slightly biconvex tablets, covered with a film shell of light pink color, with a facet, on one side an engraving "10-10", put by a method of stamping.

View of the fracture: a rough mass of white or almost white with a filmy coating of light pink color.

Tablets 5 mg + 15 mg:

round, slightly biconcave tablets, covered with a film shell of light pink-brown color, with a facet, on one side an engraving "15-5", put by a method of an embossing.

View of the fracture: a rough mass of white or almost white with a filmy coating of light pink-brown color.

Tablets 10 mg + 15 mg:

round, slightly biconvex tablets covered with a pink film shell, with a bevel, on one side an engraving "15-10", applied by embossing.

View of the fracture: a rough mass of white or almost white with a film shell of pink color.

Tablets 5 mg + 20 mg:

round, slightly biconvex tablets, covered with a film coating of light yellow color, with a facet, on one side an engraving "20-5", put by stamping.

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

Tablets 10 mg + 20 mg:

round, slightly biconvex tablets, coated with a white film shell, with a bevel, on one side the engraving "20-10", applied by embossing.

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

Pharmacotherapeutic group:hypotensive + hypolipidemic agent
ATX: & nbsp
  • Rosuvastatin and amlodipine
    • Pharmacodynamics:

    Roxer® Combi is a combined preparation containing amlodipine - blocker of "slow" calcium channels and rosuvastatin - a hypolipidemic agent, an inhibitor of HMG-CoA reductase (statin), intended for therapy in patients with arterial hypertension and dyslipidemia.

    Amlodipine

    Amlodipine is a dihydropyridine derivative, blocks "slow" calcium channels, reduces the transmembrane current of calcium ions into cardiomyocytes and smooth muscle cells of blood vessels.

    The mechanism of antihypertensive action of amlodipine is due to a direct relaxing effect on the smooth muscle cells of the vessels.

    The mechanism of antianginal action is not fully understood, presumably a decrease in myocardial ischemia is associated with two effects:

    1. Amlodipine dilates the peripheral arterioles and, thus, reduces the overall peripheral resistance (afterload). Since the heart rate at the same time remains unchanged, there is a decrease in the load on the heart, the need for myocardium in energy and oxygen decreases;

    2. the mechanism of action of amlodipine also probably includes expansion of the main coronary arteries and coronary arterioles both in unchanged and ischemic areas of the myocardium, which increases the oxygen supply to the myocardium in patients with spasm of the coronary arteries (Prinzmetal angina or variant angina), prevents spasm of the coronary arteries (including caused by smoking).

    In patients with arterial hypertension, amlodipine once a day provides a clinically significant reduction in blood pressure (BP) in the "lying" and "standing" for 24 hours.In connection with the slow development of antihypertensive effect amlodipine does not cause acute arterial hypotension.

    In patients with angina, receiving amlodipine 1 time per day increases the time required for exercise, the time until the onset of angina attack, and before the depression of the segment ST on 1 mm, and also reduces the frequency of angina attacks and the need for taking nitroglycerin tablets.

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

    Rosuvastatin

    Rosuvastatin is a selective, competitive inhibitor of HMG-CoA reductase, an enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A into mevalonate, the precursor of cholesterol (Xc). The main target of the action of rosuvastatin is the liver, where the synthesis of Xc and catabolism of low-density lipoproteins (LDL) is carried out.

    Rosuvastatin increases the number of "hepatic" LDL receptors on the cell surface, increasing the uptake and catabolism of LDL, which in turn leads to inhibition of the synthesis of very low density lipoproteins (VLDL), thus reducing the total amount of LDL and VLDL.

    Pharmacokinetics:

    Suction, distribution

    Amlodipine

    After oral administration at therapeutic doses amlodipine well absorbed, maximum concentration (Cmax) in the blood plasma is observed after 6-12 hours. Absolute bioavailability is from 64 to 80%. The volume of distribution is about 21 l / kg. In studies in vitro it was shown that about 97.5% of circulating amlodipine binds to plasma proteins. Simultaneous food intake does not affect the bioavailability of amlodipine.

    Rosuvastatin

    Cmax rosuvastatin in the blood plasma is reached about 5 hours after ingestion. Absolute bioavailability is about 20%. Rosuvastatin is metabolized predominantly by the liver, which is the main site for the synthesis of Xc and the metabolism of LDL-C. The volume distribution of rosuvastatin is about 134 liters. Approximately 90% of rosuvastatin binds to blood plasma proteins, mainly albumin.

    Metabolism, excretion

    Amlodipine

    The final half-life (T1/2) of amlodipine from the blood plasma is approximately 35-50 hours, which allows taking the drug 1 time per day. Amlodipine is actively metabolized in the liver with the formation of inactive metabolites, 60% of the dose is excreted by the kidneys in the form of inactive metabolites, 10% - unchanged, and 20-25% - through the intestines with bile.

    Rosuvastatin

    Rosuvastatin undergoes limited metabolism (about 10%). In studies in vitro Using human hepatocytes, it was shown that rosuvastatin is a nonspecific substrate for metabolism mediated by the cytochrome P450 system. The main isoenzyme involved in the metabolism of rosuvastatin is isoenzyme CYP2C9. Isozymes CYP2C19, CYP3A4 and CYP2D6 are less involved in metabolism. The main revealed metabolites of rosuvastatin are N-desmethyl and lactone metabolites. N-desmethyl is about 50% less active than rosuvastatin, lactone metabolites are pharmacologically inactive. More than 90% of the pharmacological activity of inhibiting circulating HMG-CoA reductase is provided by rosuvastatin, the rest - by its metabolites. About 90% of the dose of rosuvastatin is excreted unchanged through the intestine (including absorbed and unabsorbed rosuvastatin), the rest is excreted by the kidneys. About 5% of the accepted dose is excreted unchanged by the kidneys. T1/2 from the blood plasma is about 19 hours. T1/2 does not change with increasing dose of rosuvastatin.The average geometric plasma clearance is about 50 l / h (coefficient of variation 21.7%). As with other inhibitors of HMG-CoA reductase, a membrane carrier Xc is involved in the "hepatic" capture of rosuvastatin, which plays an important role in the "hepatic" elimination of rosuvastatin.

    Linearity / nonlinearity

    The systemic exposure of rosuvastatin increases in proportion to the dose. Pharmacokinetic parameters do not change with daily intake.

    Pharmacokinetics of special groups of patients

    Age and gender

    The sex and age of the patient does not have a clinically significant effect on the pharmacokinetics of rosuvastatin. The pharmacokinetics of rosuvastatin in children and adolescents with a heterozygous form of familial hypercholesterolemia was similar to that of adult volunteers. The time required to achieve CmOh Amlodipine in blood plasma, virtually independent of age. In elderly patients there is a tendency to decrease the clearance of amlodipine, which leads to an increase in the area under the concentration-time curve (AUC) and T1/2 Increase AUC and T1/2 in patients with chronic heart failure corresponds to the expected value for a given age group.

    Ethnic groups

    Pharmacokinetic studies showed approximately a twofold increase in the median AUC and Cmax rosuvastatin in patients of the Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese and Koreans), compared with similar indicators in patients of the European race. The Indians had an increase in the median AUC and Cmax approximately in 1,3 times. Population pharmacokinetic analysis did not reveal clinically significant differences in pharmacokinetics among patients of the Caucasian and Negroid race.

    Impaired renal function

    Disturbance of renal function does not significantly affect the kinetics of amlodipine. Amlodipine not excreted by hemodialysis.

    In patients with mild to moderate severity of renal dysfunction, the plasma concentration of rosuvastatin or NThe metabolite does not change significantly. In patients with severe renal dysfunction (creatinine clearance less than 30 ml / min), the concentration of rosuvastatin in blood plasma is 3 times higher, and the concentration N-detemethyl metabolite is 9 times higher than in healthy volunteers. The concentration of rosuvastatin in blood plasma in patients on hemodialysis was approximately 50% higher than in healthy volunteers.

    Impaired liver function

    Data on the use of amlodipine in patients with impaired liver function are limited. In patients with impaired hepatic function, amlodipine clearance decreases, which leads to an elongation of T1/2 and AUC by about 40-60%. In patients with a liver function disorder of 7 and lower on the Child-Pugh scale, the lengthening T1/2 rosuvastatin was not noted. In two patients with impaired liver function on grade 8 and 9 on the Child-Pugh scale, the T1/2, at least in 2 times. Experience with rosuvastatin in patients with impaired liver function more than 9 points on the Child-Pugh scale is not available.

    Genetic polymorphism

    Inhibitors of HMG-CoA reductase, including, rosuvastatin bind to transport proteins OATP1B1 (a polypeptide transporting organic anions involved in the capture of statins by hepatocytes) and BCRP (efflux conveyor). In carriers of genotypes SLC01B1 (OATP1B1) p.521NC and ABCG2 (BCRP) p.421AA there was an increase in exposure (AUC) rosuvastatin 1.6 and 2.4 times, respectively, compared with carriers of genotypes SLCOIBI p.52ITT and ABCG2 p.421S.

    Indications:

    The preparation of Roxer® Combi is indicated for therapy in patients with arterial hypertension and dyslipidemia; in patients with arterial hypertension,(for preventing the development of major cardiovascular events), the condition of which is adequately controlled by simultaneous administration of rosuvastatin and amlodipine at the same doses as in the formulation of the drug Roxer® Combi.

    Contraindications:

    Amlodipine

    - Severe arterial hypotension (systolic blood pressure less than 90 mm Hg).

    - Hemodynamically unstable heart failure after acute myocardial infarction.

    - Obstruction of the outflow tract of the left ventricle (including severe aortic stenosis).

    Rosuvastatin

    - Diseases of the liver in the active phase (including a persistent increase in the activity of "liver" transaminases and any increase in the activity of "liver" transaminases in the serum more than 3 times compared with the upper limit of the norm).

    - Severe violations of kidney function (QC less than 30 ml / min).

    - Myopathy.

    - Use in patients predisposed to the development of myotoxic complications.

    - Simultaneous administration of cyclosporine.

    - Pregnancy, the period of breastfeeding, use in women of childbearing age, who do not use adequate methods of contraception.

    Combination of amlodipine / rosuvastatin

    - Hypersensitivity to amlodipine, other derivatives of dihydropyridine, rosuvastatin or any component of the drug.

    - Age to 18 years (effectiveness and safety not established).

    - Lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.

    Carefully:

    Hepatic failure, liver disease in history, chronic heart failure (CHF) of non-ischemic etiology III-IV functional class by classification NYHA, unstable angina, aortic stenosis, mitral stenosis, hypertrophic obstructive cardiomyopathy (GOKMP), acute myocardial infarction (and within 1 month after it), sinus node weakness syndrome (severe tachycardia, bradycardia), arterial hypotension, concomitant use with inhibitors or inducers isoenzyme CYP3A4, myopathy / rhabdomyolysis risk-renal failure, hypothyroidism, hereditary muscle diseases in history (including family history) and previous history of muscle toxicity with other HMG-CoA reductase inhibitors or fibrates, excessive alcohol use, age 65 or older years,conditions in which increased plasma concentrations of rosuvastatin, race (Mongoloid race), simultaneous use with fibrates, sepsis, extensive surgical interventions, trauma, severe metabolic, endocrine or electrolyte disorders or uncontrolled convulsions are noted.

    Pregnancy and lactation:

    The drug Roxer® Combi is contraindicated in pregnancy and during breastfeeding.

    Pregnancy

    Women of reproductive age should apply adequate methods of contraception.

    Since Xc and other Xc biosynthesis products are important for fetal development, the potential risk of inhibiting HMG-CoA reductase exceeds the benefit of using the drug during pregnancy. Data on reproductive toxicity of rosuvastatin, obtained from animal studies, are limited.

    In case of pregnancy during therapy, taking the drug should be immediately canceled.

    The safety of amlodipine during pregnancy is not established. In animal studies, reproductive toxicity was noted with amlodipine in high doses.Use during pregnancy is only possible if the potential benefit to the mother exceeds the possible risk to the fetus.

    Breastfeeding period

    There is no data on the allocation of amlodipine to breast milk. However, it is known that other "slow" calcium channel blockers (BCCs) - dihydropyridine derivatives are secreted into breast milk.

    Data on the allocation of rosuvastatin in human milk are not available, it is known that rosuvastatin is excreted in the milk of rats.

    Fertility

    In some patients with the use of calcium channel blockers, reversible biochemical changes in the sperm head were noted. There was no evidence of the effect of amlodipine on fertility in rats.

    Dosing and Administration:

    Inside, 1 time per day at any time, regardless of the time of ingestion.

    The tablet should be swallowed whole, do not chew and do not grind, squeezed with water. Before starting therapy with the drug Roxer® Combi, the patient should begin to observe the standard hypocholesterolemic diet and continue to observe it during therapy.

    The recommended dose of the drug Roxer® Combi is 1 tablet per day.

    Before using the drug Roxer® Combi, it is necessary to achieve BP control by simultaneous administration of two active components of the drug in stable doses. The dose is selected after previous titration of the doses of individual components of the drug.

    If a change in the dose of one of the active substances in a fixed combination preparation is required (for example, due to a newly diagnosed disease, a change in the patient's condition or drug interaction), individual doses of individual components need to be individually selected.

    Elderly patients

    Correction of the dose is not required.

    Impaired renal function

    In patients with mild or moderate severity of renal dysfunction, dose adjustment is not required. Application of the drug Roxer® Combi is contraindicated in patients with severe renal dysfunction (KC less than 30 ml / min).

    Impaired liver function

    Despite the extension of T1/2 in patients with impaired hepatic function when using BCCC, including amlodipine, dose adjustment is usually not required.

    The use of the drug Roxer® Combi in patients with liver disease in the active phase is contraindicated (see.section "Contraindications").

    Ethnic groups

    When studying the pharmacokinetic parameters of rosuvastatin in patients belonging to different ethnic groups, there was an increase in the systemic concentration of rosuvastatin among Japanese and Chinese. This fact should be taken into account when using the drug Roxer® Combi in these patient groups. The recommended initial dose of rosuvastatin for patients of the Mongoloid race is 5 mg / day. Patients of the Mongoloid race use rosuvastatin in a dose of 40 mg is contraindicated.

    Genetic polymorphism

    In carriers of genotypes SLCO1B1 (OATP1B1) p.521NC and ABCG2 (BCRP) p.421AA there was an increase in exposure (AUC) to rosuvastatin in comparison with carriers of genotypes SLCO1B1 p.521TT and ABCG2 p.421S. For patients carrying genotypes с.521СС or с.421АА the recommended maximum dose of rosuvastatin is 20 mg once a day.

    Concomitant therapy

    Rosuvastatin binds to various transport proteins (in particular, to OATP1B1 and BCRP). With the simultaneous use of the drug Roxer® Combi with medicines (such as ciclosporin, some human immunodeficiency virus (HIV) protease inhibitors, including a combination of ritonavir with atazanavir, lopinavir and / or tipranavir),increasing the concentration of rosuvastatin in blood plasma due to interaction with transport proteins, may increase the risk of myopathy (including rhabdomyolysis). In such cases, the possibility of prescribing alternative therapy or temporary discontinuation of the drug Roxer® Combi should be evaluated. If you need to use the above drugs, you should evaluate the benefit-risk ratio of concomitant therapy with the drug Roxer® Combi and consider the possibility of dose adjustment for rosuvastatin.

    Children

    Safety of the use of the drug Roxer® Combi in children and adolescents under the age of 18 years is not established. It is not recommended to use the drug Roxer® Combi in patients younger than 18 years.

    Side effects:

    Classification of the frequency of development of side effects of the World Health Organization (WHO):

    Often

    ≥ 1/10

    often

    from ≥ 1/100 to <1/10

    infrequently

    from ≥ 1/1000 to <1/100

    rarely

    from ≥ 1/10000 to <1/1000

    rarely

    < 1/10000

    frequency unknown

    can not be estimated from the available data.

    Classification MedDRA

    Undesirable effects

    Frequency

    Amlodipine

    Rosuvastatin

    Violations of the blood and lymphatic system

    Leukopenia

    Rarely

    -

    Thrombocytopenia

    Rarely

    Frequency unknown

    Immune system disorders

    Hypersensitivity reactions, including angioedema

    -

    Rarely

    Allergic reactions

    Rarely

    -

    Disorders from the metabolism and nutrition

    Hyperglycaemia

    Rarely

    -

    Disorders from the endocrine system

    Diabetes mellitus type 21

    -

    Often

    Disorders of the psyche

    Insomnia

    Infrequently

    -

    Lability of mood (including anxiety)

    Infrequently

    -

    Increased excitability, unusual dreams

    Infrequently

    -

    Confusion of consciousness

    Rarely

    -

    Apathy, agitation, ataxia

    Rarely

    -

    Depression

    Infrequently

    Frequency unknown

    Disturbances from the nervous system

    Dizziness, headache

    Often

    Often

    Drowsiness

    Often

    -

    Tremor, dysgeusia, hypoesthesia, paresthesia

    Infrequently

    -

    Migraine

    Rarely

    -

    Memory loss

    Rarely

    Rarely

    Peripheral Neuropathy

    Infrequently

    Rarely

    Parosmia

    Rarely

    -

    Disturbances on the part of the organ of sight

    Visual impairment (including diplopia), a violation of accommodation, xerophthalmia, conjunctivitis, pain in the eyes

    Infrequently

    -

    Violations from the organ of hearing and

    labyrinthine violations

    Noise ("ringing") in the ears

    Infrequently

    -

    Heart Disease

    Heart palpitations

    Often

    -

    Myocardial infarction

    Rarely

    -

    Fainting

    Rarely

    -

    Development or aggravation of CHF flow

    Rarely

    -

    Heart rhythm disturbances (including bradycardia, ventricular tachycardia and atrial fibrillation)

    Rarely

    -

    Vascular disorders

    Feeling of "tides" of blood to the skin of the face

    Often

    -

    Marked decrease in blood pressure

    Infrequently

    -

    Orthostatic hypotension

    Rarely

    -

    Vasculitis

    Rarely

    -

    Disturbances from the respiratory system, chest and mediastinal organs

    Dyspnea

    Infrequently

    Frequency unknown

    Rhinitis

    Infrequently

    -

    Nose bleed

    Infrequently

    -

    Cough

    Rarely

    Frequency unknown

    Infringements from

    digestive

    systems

    Abdominal pain, nausea

    Often

    Often

    Constipation

    Infrequently

    Often

    Anorexia

    Infrequently

    -

    Vomiting

    Infrequently

    -

    Dyspepsia, flatulence, dryness of the oral mucosa, thirst

    Infrequently

    -

    Increased appetite

    Rarely

    -

    Hyperplasia of gums

    Rarely

    -

    Gastritis

    Rarely

    -

    Pancreatitis

    Rarely

    Rarely

    Diarrhea

    Infrequently

    Frequency unknown

    Disorders from the liver and

    bile ducts

    Hepatitis

    Rarely

    Rarely

    Jaundice

    Rarely

    Rarely

    Hyperbilirubinemia

    Rarely

    -

    Increased activity of "liver" transaminases

    Rarely

    Rarely

    Disturbances from the skin and subcutaneous tissues

    Alopecia

    Rarely

    -

    Purpura, discoloration, increased sweating, exanthema

    Infrequently

    -

    Angioedema, multiforme exudative erythema, exfoliative dermatitis, Quincke's edema, xeroderma, cold sweat, photosensitivity

    Rarely

    -

    Itchy skin

    Infrequently

    Infrequently

    Skin rash

    Infrequently

    Infrequently

    Hives

    Rarely

    Infrequently

    Stevens-Johnson Syndrome

    -

    Frequency unknown

    Disturbances from the musculoskeletal

    systems and

    connective tissue

    Swelling of the ankles

    Often

    -

    Backache

    Infrequently

    -

    Muscle cramps

    Infrequently

    -

    Myalgia

    Infrequently

    Often

    Osteoarthritis

    Infrequently

    -

    Myopathy (including myositis)

    -

    Rarely

    Rhabdomyolysis

    -

    Rarely

    Arthralgia

    Infrequently

    Rarely

    Myasthenia gravis

    Rarely

    -

    Immuno-mediated necrotizing myopathy

    -

    Frequency unknown

    Disorders from the nochek and urinary tract

    Painful urination, nocturia, frequent urination

    Infrequently

    -

    Dysuria, polyuria

    Rarely

    -

    Hematuria

    -

    Rarely

    Violations of the genitals and mammary gland

    Disturbance of erectile function

    Infrequently

    -

    Gynecomastia

    Infrequently

    Frequency unknown

    General disorders and disorders at the site of administration

    Asthenia

    Infrequently

    Often

    Increased fatigue

    Often

    -

    Chest pain

    Rarely

    -

    Peripheral edema

    Often

    Frequency unknown

    General malaise

    Infrequently

    -

    Laboratory and instrumental data

    Weight gain, weight loss

    Infrequently

    -
    1 The frequency depends on the presence or absence of risk factors (fasting blood glucose concentration ≥ 5.6 mmol / l, body mass index (BMI)> 30 kg / m2, increased concentration of triglycerides in blood plasma, arterial hypertension in history).

    When using amlodipine, there were isolated cases of development of extrapyramidal syndrome.

    As with other HMG-CoA reductase inhibitors, the incidence of adverse reactions with rosuvastatin is dose dependent.

    Some of the HMG-CoA reductase inhibitors reported the following side effects: depression, sleep disorders, including insomnia and nightmares, sexual dysfunction. Single cases of interstitial lung disease have been reported, especially with prolonged use of drugs (seesection "Special instructions").

    Description of individual adverse reactions with rosuvastatin

    Disorders from the kidneys and urinary tract

    With the use of rosuvastatin, proteinuria can be detected. Changes in the amount of protein in the urine (from absence or trace amounts to ++ or more) are observed in less than 1% of patients receiving a dose of 10-20 mg / day, and about 3% of patients receiving a dose of 40 mg / day. In most cases, proteinuria decreases or disappears during therapy and does not indicate the occurrence of acute or progressive concomitant renal disease.

    Disturbances from musculoskeletal system and connective tissue

    When using rosuvastatin in all dosages and, especially when taking doses exceeding 20 mg / day, the following effects on the musculoskeletal system were reported: myalgia, myopathy (including myositis), in rare cases, rhabdomyolysis with or without acute renal failure .

    A dose-related increase in activity of creatine phosphokinase (CK) is observed in a small number of patients taking rosuvastatin. In most cases, it was insignificant, asymptomatic and temporary.In case of increased activity of CK (more than 5 times higher than the upper limit of the norm (VGN)) therapy should be suspended.

    Disturbances from the liver and bile ducts

    As with the use of other inhibitors of HMG-CoA reductase, the use of rosuvastatin shows a dose-dependent increase in the activity of "hepatic" transaminases in a small number of patients. In most cases, it is insignificant, asymptomatic and temporary.

    Laboratory data

    With the use of rosuvastatin, an increase in the activity of CKK, glucose concentration, glycosylated hemoglobin, bilirubin in blood plasma, activity of gamma-glutamyltranspeptidase, alkaline phosphatase, and changes in plasma concentrations of thyroid hormones were also observed.

    Overdose:

    Symptoms

    The available data suggest that a significant overdose of amlodipine may lead to excessive peripheral vasodilation and the development of reflex tachycardia (the risk of development of severe and persistent arterial hypotension, including the development of shock and death).

    Treatment

    In case of an overdose, stop taking the drug Roxer® Combi and provide symptomatic therapy.

    In some cases, it may be effective to wash the stomach, taking activated charcoal immediately or within 2 hours after using amlodipine at a dose of 10 mg leads to a decrease in the rate of absorption of the drug. To eliminate the effects of calcium channel blockade - intravenous calcium gluconate. It is necessary to monitor liver function and activity of CKK, there is no specific antidote, hemodialysis is ineffective.

    Interaction:

    Amlodipine

    Inhibitor inhibitors CYP3A4

    With simultaneous application diltiazem in a dose of 180 mg and amlodipine at a dose of 5 mg in patients with hypertension of advanced age (from 69 to 87 years), an increase in the systemic exposure of amlodipine by 57%.

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

    Powerful inhibitors of isoenzyme CYP3A4 (e.g., ketoconazole, itraconazole) 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: isoenzyme inhibitor CYP3A4. Patients taking concomitantly clarithromycin and amlodipine, increased risk of lowering blood pressure. Patients who take this combination are recommended to be under close medical supervision.

    Inductors of isoenzyme CYP3A4

    Data on the effect of inducers of the isoenzyme CYP3A4 on the pharmacokinetics of amlodipine are not available. Simultaneous application of inducers of the isoenzyme CYP3A4 (for example, rifampicin, St. John's Wort) can reduce the concentration of amlodipine in the blood plasma. Care must be taken when using amlodipine with CYP3A4 isoenzyme inductors at the same time.

    Tacrolimus: with simultaneous use with amlodipine there is a risk of increasing tacrolimus concentration in the blood plasma. In order to avoid the toxicity of tacrolimus when used simultaneously with amlodipine, tacrolimus concentration in the blood plasma of the patients should be monitored and the dose of tacrolimus adjusted if necessary.

    The simultaneous use of amlodipine for the therapy of hypertension from thiazide diuretics, alpha, beta-adrenoblockers, nitrates or angiotensin-converting enzyme (ACE) inhibitors, is considered safe. In patients with stable angina pectoris amlodipine can be used simultaneously with other antianginal agents, for example, with nitrates of prolonged or short-acting, beta-blockers.

    In contrast to other BCCC, clinically significant interaction of amlodipine was not detected with simultaneous application from nonsteroidal anti-inflammatory drugs (NSAIDs), including with indomethacin.

    It is possible to increase the anti-anginal and antihypertensive effect of BCC with simultaneous application from thiazide and "loop" diuretics, ACE inhibitors, beta-blockers and nitrates, as well as increased antihypertensive action when used simultaneously with alpha1-adrenoblockers, neuroleptics.

    Although no negative inotropic effects were usually observed in the study of amlodipine, nevertheless some BCCCs can increase the negative inotropic effect of antiarrhythmic agents that cause prolongation of the QT interval (for example, amiodarone and quinidine).

    The simultaneous use of amlodipine from antibiotics and hypoglycemic agents for oral intake is considered safe.

    A single dose of 100 mg sildenafil in patients with essential hypertension does not affect the pharmacokinetics parameters of amlodipine.

    Repeated use of amlodipine in a dose of 10 mg and atorvastatin in a dose of 80 mg is not accompanied by significant changes in the pharmacokinetics of atorvastatin.

    Simvastatin

    Simultaneous repeated use of amlodipine in a dose of 10 mg and simvastatin at a dose of 80 mg leads to an increase in the exposure of simvastatin by 77%. In such patients, the dose of simvastatin should be limited to 20 mg / day.

    Ethanol (drinks, containing alcohol)

    Amlodipine with a single and repeated application in a dose of 10 mg does not affect the pharmacokinetics of ethanol.

    Antiviral drugs (ritonavir) increase plasma concentrations of BCCC, including amlodipine.

    Neuroleptics and isoflurane increase the antihypertensive effect of dihydropyridine derivatives.

    Preparations of calciumI can reduce the effect of BCCI.

    Lithium

    With the simultaneous use of BCCC with lithium preparations (there is no data for amlodipine), amplificationmanifestations of neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus).

    Cyclosporin

    Studies of simultaneous use of amlodipine and cyclosporine were carried out only on a group of patients after kidney transplantation. The use of this combination can either not influence, or increase the minimum concentration of cyclosporine in varying degrees up to 40%. It is necessary to monitor the concentration of cyclosporine in the blood plasma in this group of patients with the simultaneous use of amlodipine and cyclosporine.

    Digoxin

    With simultaneous application amlodipine has no effect on serum concentration and renal clearance of digoxin.

    Warfarin

    Amlodipine does not significantly affect the effects of warfarin.

    Cimetidine does not affect the pharmacokinetics of amlodipine.

    In studies in vitro Amlodipine does not affect the binding to plasma proteins digoxin, phenytoin, warfarin and indomethacin.

    Grapefruit juice

    Simultaneous single intake of 240 mg of grapefruit juice and 10 mg of amlodipine by mouth is not accompanied by a significant change in the pharmacokinetics of amlodipine. Nevertheless, it is not recommended to use grapefruit juice and amlodipine At the same time, as in the genetic polymorphism of the isoenzyme CYP3A4, it is possible to increase the bioavailability of amlodipine and, as a result, enhance the antihypertensive effect.

    Aluminum, magnesium-containing antacids at a single admission do not have a significant effect on the pharmacokinetics of amlodipine.

    Rosuvastatin

    Effect of other drugs on rosuvastatin

    Inhibitors of transport proteins

    Rosuvastatin is a substrate for some transport proteins, in particular, OATP1B1 and BCRP. Simultaneous use of drugs that are inhibitors of these transport proteins may be accompanied by an increase in the concentration of rosuvastatin in the blood plasma and an increased risk of myopathy (see Table 1, sections "Dosing and Administration", "Special instructions").

    Cyclosporin

    With simultaneous application of rosuvastatin and cyclosporine AUC rosuvastatin is an average of 7 times higher than that seen in healthy volunteers (see Table 1). Simultaneous use with rosuvastatin does not affect the concentration of cyclosporine in the blood plasma. The use of rosuvastatin is contraindicated in patients taking ciclosporin (cm.section "Contraindications").

    HIV protease inhibitors

    Simultaneous use of HIV protease inhibitors can significantly increase the exposure of rosuvastatin (see Table 1). Simultaneous application of 20 mg rosuvastatin and a combination of two HIV protease inhibitors (400 mg lopinavir / 100 mg ritonavir) is accompanied by an increase in equilibrium AUC0-24h) and CmOh rosuvastatin 2 and 5 times, respectively. Therefore, simultaneous administration of rosuvastatin and HIV protease inhibitors is not recommended (see Table 1, section "Method of administration and dose").

    Gemfibrozil and other lipid-lowering agents

    The simultaneous use of rosuvastatin and gemfibrozil leads to an increase in CmOh and AUC rosuvastatin in blood plasma in 2 times (see the section "Special instructions.") Based on the data on the specific interaction, pharmacokinetically significant interaction with fenofibrate is not expected, possibly pharmacodynamic interaction.Gemfibrozil, fenofibrate, other fibrates and lipid-lowering doses of nicotinic acid (doses more than 1 g / day) increased the risk of myopathy with simultaneous use with HMG-CoA reductase inhibitors, possibly due to the fact that they can cause myopathy when used in monotherapy (see section "Special instructions").In such patients, therapy should begin at a dose of 5 mg / day (see the sections "Contraindications", "Method of administration and dose", "Special instructions"). Simultaneous application of fibrates and rosuvastatin in a daily dose of 40 mg is contraindicated.

    Ezetimibe

    The simultaneous use of rosuvastatin 10 mg and ezetimibe at a dose of 10 mg was accompanied by an increase AUC rosuvastatin in patients with hypercholesterolemia (see Table 1). It is impossible to exclude the pharmacodynamic interaction between rosuvastatin and ezetimibe, which is manifested by an increased risk of developing unwanted reactions.

    Limacids

    The simultaneous use of rosuvastatin and antacids containing aluminum and magnesium hydroxide leads to a decrease in the plasma concentration of rosuvastatin by approximately 50%. This effect is less pronounced if antacids are administered 2 hours after rosuvastatin administration. The clinical significance of this interaction has not been studied.

    Erythromycin

    The simultaneous use of rosuvastatin and erythromycin leads to a decrease AUFROM0-24 h) rosuvastatin by 20% and its CmOh by 30%. Such interaction can arise as a result of increased intestinal motility caused by the use of erythromycin.

    Isozymes of the cytochrome P450 system

    Research results in vivo and in vitro showed that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. Besides, rosuvastatin is a weak substrate for this isoenzyme system. Therefore, interaction of rosuvastatin with other drugs (LS) at the metabolic level with the participation of cytochrome P450 isoenzymes is not expected.

    Clinically significant interactions between rosuvastatin and fluconazole (inhibitor of isoenzymes CYP2C9 and CYP3A4) and ketoconazole (inhibitor of isoenzymes CYP2A6 and CYP3A4) was not observed.

    Fusidic acid

    Studies on the interaction of rosuvastatin and fusidic acid have not been conducted. As with the reception of other statins, post-marketing reports were received on cases of rhabdomyolysis in the joint administration of rosuvastatin and fusidic acid. Patients should be closely monitored. If necessary, a temporary discontinuation of rosuvastatin is possible.

    Interaction with drugs, which requires dose adjustment for rosuvastatin (see table 1)

    The dose of rosuvastatin should be adjusted if it is necessary to simultaneously use it with drugs that increase the exposure of rosuvastatin. If the exposure is expected to be 2 times or more, the initial dose of rosuvastatin should be 5 mg once a day. Also, the maximum daily dose of rosuvastatin should be adjusted so that the expected exposure of rosuvastatin does not exceed that for a dose of 40 mg taken without simultaneous administration of drugs interacting with rosuvastatin. For example, the maximum daily dose of rosuvastatin with simultaneous use with gemfibrozil is 20 mg (1.9 times increase in exposure), with ritonavir / atazanavir 10 mg (increase in exposure 3.1 times).

    Table 1. The effect of concomitant therapy on the exposure of rosuvastatin (AUC, data are listed in descending order) - the results of published clinical studies)

    Complementary therapy regimen

    Mode of taking rosuvastatin

    Change AUC rosuvastatin

    Cyclosporine 75-200 mg 2 times a day, 6 months

    10 mg once a day, 10 days

    An increase of 7.1 times

    Atazanavir 300 mg / ritonavir 100 mg once a day, 8 days

    10 mg once

    Increase 3.1-fold

    Lopinavir 400 mg / ritonavir 100 mg twice daily, 17 days

    20 mg once a day, 7 days

    An increase of 2.1 times

    Gemfibrozil 600 mg 2 times a day, 7 days

    80 mg once

    Increase 1.9 times

    Eltrombopag 75 mg once a day, 10 days

    10 mg once

    Increase 1.6 times

    Darunavir 600 mg / ritonavir 100 mg twice daily, 7 days

    10 mg once a day, 7 days

    Increase by 1.5 times

    Tipranavir 500 mg / ritonavir 200 mg twice daily, 11 days

    10 mg once

    Increase by 1.4 times

    Dronedarone 400 mg twice daily

    No data

    Increase by 1.4 times

    Itraconazole 200 mg once a day, 5 days

    10 mg or 80 mg once

    Increase by 1.4 times

    Ezetimibe 10 mg once a day, 14 days

    10 mg once a day, 14 days

    Increase by 1.2 times

    Fosaprenavir 700 mg / ritonavir 100 mg 2 times a day, 8 days

    10 mg once

    Without changes

    Aleglitazar 0.3 mg, 7 days

    40 mg, 7 days

    Without changes

    Silymarin 140 mg 3 times a day, 5 days

    10 mg once

    Without changes

    Fenofibrate 67 mg 3 times a day, 7 days

    10 mg, 7 days

    Without changes

    Rifampicin 450 mg once a day, 7 days

    20 mg once

    Without changes

    Ketoconazole 200 mg 2 times a day, 7 days

    80 mg once

    Without changes

    Fluconazole 200 mg once a day, 11 days

    80 mg once

    Without changes

    Erythromycin 500 mg 4 times a day, 7 days

    80 mg once

    Decrease by 28%

    Baikalin 50 mg 3 times a day, 14 days

    20 mg once

    Decrease by 47%

    Effect of rosuvastatin on other drugs

    Antagonists of vitamin K

    As with other HMG-CoA reductase inhibitors, initiation of rosuvastatin therapy or an increase in its dose in patients taking concomitant vitamin K antagonists (for example, warfarin), can lead to an increase in the International Normalized Ratio (INR). The cancellation of rosuvastatin or a decrease in its dose may result in a decrease in INR. In such cases monitoring of INR is recommended.

    Contraceptives for oral administration / hormone replacement therapy (HRT)

    The simultaneous use of rosuvastatin and oral contraceptives increases AUC ethinylestradiol and norgestrel by 26% and 34%, respectively. Such an increase in plasma concentration should be taken into account when selecting a dose of hormonal contraceptives.

    Pharmacokinetic data on the simultaneous use of rosuvastatin and HRT are absent, therefore, it is impossible to exclude a similar effect when using this combination. However, this combination was widely used during clinical trials and was well tolerated by patients.

    Other medicines

    Clinically significant interaction between rosuvastatin and digoxin is not expected.

    Special instructions:

    Before starting therapy

    Depending on the daily dose, the preparation of Roxer® Combi should be administered with caution to patients with existing risk factors for myopathy / rhabdomyolysis or the use of the drug is contraindicated (see the sections "Contraindications" and "With caution").

    During the period of drug therapy

    The patient should be informed of the need to report immediately to the doctor in the event of an unexpected occurrence of muscle pain, muscle weakness or spasms, especially in combination with malaise and fever. In such patients, the activity of CK should be determined. Therapy should be discontinued if the activity of CK is significantly increased (more than 5 times as high as the upper limit of the norm) or if the symptoms from the muscles are pronounced and cause daily discomfort (even if the CKK activity is not more than 5 times higher than the VGN) . If symptoms disappear and CPK activity returns to normal, consideration should be given to resuming the use of the Roxer® Combi drug or other HMG-CoA reductase inhibitors in smaller doses with careful medical supervision.Control of the activity of CKK in the absence of symptoms is inexpedient.

    Very rare cases of immuno-mediated necrotizing myopathy with clinical manifestations in the form of persistent weakness of proximal muscles and increased activity of CKK in blood serum during therapy or when the use of inhibitors of HMG-CoA reductase, including rosuvastatin, are stopped. It may be necessary to conduct additional studies of the muscular and nervous system, serological studies, as well as therapy with immunosuppressive drugs.

    Signs of increased effects on skeletal muscle with rosuvastatin and concomitant therapy were not noted. However, there have been reports of an increase in the incidence of myositis and myopathy in patients taking other HMG-CoA reductase inhibitors in combination with fibrolic acid derivatives (eg, gemfibrozil), cyclosporine, nicotinic acid in lipid-lowering doses (more than 1 g / day), antifungal agents - derivatives of azole, HIV protease inhibitors and macrolide antibiotics.

    When used simultaneously with certain HMG-CoA reductase inhibitors, gemfibrozil increases the risk of myopathy.Thus, simultaneous use of the drug Roxer® Combi and gemfibrozil is not recommended. The benefits of further changes in plasma lipid concentration when combined with the use of the drug Roxer® Combi with fibrates or nicotinic acid in lipid-lowering doses should be carefully weighed against the possible risks.

    Due to the increased risk of rhabdomyolysis, the Roxer® Combi drug should not be used in patients with acute conditions that can lead to myopathy or conditions predisposing to the development of renal failure (eg, sepsis, arterial hypotension, extensive surgical interventions, trauma, severe metabolic, endocrine and electrolyte disorders or uncontrolled convulsions).

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

    Influence on the musculoskeletal system

    When using rosuvastatin in all doses, but in particular at doses exceeding 20 mg / day, the following effects on the musculoskeletal system were reported: myalgia, myopathy, in rare cases rhabdomyolysis.Very rare cases of rhabdomyolysis with simultaneous application of HMG-CoA reductase inhibitors and ezetimibe have been noted. This combination should be used with caution, since pharmacodynamic interaction can not be ruled out.

    Determination of CKK activity

    The activity of CK can not be determined after intensive physical exertion and if there are other possible reasons for increasing its activity, this can lead to incorrect interpretation of the results. In the event that the initial activity of CK is significantly exceeded (5 times higher than ULN), a second analysis should be carried out after 5-7 days. You can not start therapy if the results of the repeated analysis confirm the initial high activity of CK (more than 5-fold excess of UGN).

    Chronic heart failure

    Against the background of amlodipine in patients with CHF III-IV functional class by classification NYHA non-ischemic origin, there was an increase in the incidence of pulmonary edema, despite the absence of signs of worsening heart failure. Caution should be exercised when performing therapy in patients with CHF (III-IV functional class by classification NYHA).

    Impaired renal function

    In patients with impaired renal function, dosage adjustment of amlodipine is not required. Changes in the concentration of amlodipine in the blood plasma are not related to the degree of impaired renal function.

    In patients receiving high doses of rosuvastatin (in particular 40 mg / day), tubular proteinuria was observed, which was observed using a test strip and in most cases has a periodic or transient. Such proteinuria does not indicate an acute or progressive comorbid kidney disease.

    Impaired liver function

    As with other preparations containing the HMG-CoA reductase inhibitor, caution should be exercised when using the drug Roxer® Combination in patients with excessive alcohol consumption and / or with a history of liver disease or its use is contraindicated (see. The sections "Contra" and "Precautions").

    It is recommended to carry out the determination of functional liver samples before the start of therapy and 3 months after the beginning of therapy. Use of the drug Roxer® Combi should stop or reduce the dose of the drug if the activity of "hepatic" transaminases in the serum is 3 times higher than VGN.

    In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome, prior to initiation of treatment with the Roxer® Combi drug, therapy of the underlying diseases should be performed.

    Ethnic Features

    In the course of pharmacokinetic studies, an increase in the plasma concentration of rosuvastatin was noted in representatives of the Mongoloid race in comparison with representatives of the European race (see the sections "With caution", "Dosage and administration", subsection "Pharmacokinetics").

    HIV protease inhibitors

    It is not recommended simultaneous use of the drug Roxer® Combi with HIV protease inhibitors (see section "Interaction with other drugs").

    Interstitial lung disease

    Some inhibitors of HMG-CoA reductase, especially for a long time, reported single cases of interstitial lung disease. Manifestations of the disease can be shortness of breath, unproductive cough and deterioration in overall health (weakness, weight loss and fever).

    If suspicion of interstitial lung disease should be discontinued therapy with HMG-CoA reductase inhibitors.

    Diabetes mellitus type 2

    In patients with a glucose concentration of 5.6 to 6.9 mmol / L, rosuvastatin therapy was associated with an increased risk of developing type 2 diabetes mellitus.

    Hypertensive crisis

    The safety and efficacy of amlodipine in hypertensive crisis have not been established.

    Special information on excipients

    The preparation of Roxer® Combi contains lactose, therefore it should not be used in the following conditions: lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.

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

    During therapy with Roxer® Combi needs to be careful when driving vehicles and working with other technical devices that require a high concentration of attention and speed of psychomotor reactions, taking into account the risk of a pronounced decrease in blood pressure, dizziness, drowsiness and other adverse reactions, especially at the beginning of treatment and with increasing doses.

    Form release / dosage:

    Tablets, film-coated, 5 mg + 10 mg, 10 mg + 10 mg, 5 mg + 15 mg, 10 mg + 15 mg, 5 mg + 20 mg, 10 mg + 20 mg.

    Packaging:

    For 7 or 10 tablets in a blister of the combined material OPA / Al / PVC-aluminum foil.

    4 or 12 blisters (the blister to 7 tablets) or 3, 6, 9 blisters (the blister 10 tablets), together with instructions for use placed into 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-003956
    Date of registration:10.11.2016
    Expiration Date:10.11.2021
    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: & nbsp11.12.2016
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