DUPLEKOR - instructions for use, doses, side effects, contraindications

Active substanceAmlodipine + AtorvastatinAmlodipine + Atorvastatin

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Dosage form: & nbspfilm coated tablets

Composition:

COMPOSITION per 1 tablet:

Tablets 5 mg + 10 mg

Core: Active substances: atorvastatin lysinate 12.628 mg (equivalent to atorvastatin 10 mg), amlodipine besylate 6.944 mg (equivalent to amlodipine 5 mg);

Excipients:

calcium carbonate 81,200 mg, cellulose microcrystalline (type 102) 87,948 mg, pregelatinized starch 52,360 mg, croscarmellose sodium 16,800 mg, calcium oxide 0,840 mg, sodium carboxymethyl starch (type A) 7,000 mg, giprolose 1,400 mg, polysorbate 80 1,120 mg, silicon colloidal dioxide 1,960 mg, magnesium stearate 1,400 mg;

Sheath: Opadrai II 85F 18422 white 8,400 mg (polyvinyl alcohol, partially hydrolyzed 3,360 mg, titanium dioxide (E171) 2,100 mg, macrogol 4000 1,697 mg, talc 1,243 mg).

Tablets 10 mg + 10 mg

Core: Active substances: atorvastatin lysinate 12.628 mg (equivalent to atorvastatin 10 mg), amlodipine besylate 13.888 mg (equivalent to amlodipine 10 mg);

Excipients:

calcium carbonate 72.256 mg, cellulose - microcrystalline (type 102) 87.948 mg, pregelatinized starch 52.360 mg, croscarmellose sodium 16.800 mg, calcium oxide 0.840 mg, sodium carboxymethyl starch (type A) 7,000 mg, giprolose 1,400 mg, polysorbate 80 1,120 mg, silicon colloidal dioxide 1,960 mg, magnesium stearate 1,400 mg;

Shell :. Opadrai II 85F 18422 white 8,400 mg (polyvinyl alcohol, partially hydrolyzed 3,360 mg, titanium dioxide (E171) 2,100 mg, macrogol 4000 1,697 mg, talc 1,243 mg).

Tablets 5 mg + 20 mg

Core: Active substances: atorvastatin lysinate 25,256, mg (equivalent to atorvastatin 20 mg), amlodipine besylate 6.944 mg (equivalent to amlodipine 5 mg);

Excipients:

calcium carbonate 169,344 mg, cellulose microcrystalline (type 102) 175,896 mg, pregelatinized starch 104,720 mg, croscarmellose sodium 33,600 mg, calcium oxide 1,680 mg, sodium carboxymethyl starch (type A) 14,000 mg, giprolose 2,800 mg, polysorbate 80 2,240 mg, silicon dioxide colloid 3,920 mg, magnesium stearate 2,800 mg;

Sheath: Opadrai II 85F 18422 white 16,800 mg (polyvinyl alcohol, partially hydrolyzed 6,720 mg, titanium dioxide (E171) 4,200 mg, macrogol 4000 3,394 mg, talc 2,486 mg).

Tablets 10 mg + 20 mg

Core: Active substances: atorvastatin lysinate - 25,256 mg (equivalent to atorvastatin 20 mg), amlodipine besylate 13.888 mg (equivalent to amlodipine 10 mg);

Excipients:

calcium carbonate 162,400 mg, microcrystalline cellulose (type 102) 175.896 mg, pregelatinized starch 104.720 mg, croscarmellose sodium 33.600 mg, calcium oxide 1.680 mg,sodium carboxymethyl starch (type A) 14,000 mg, giprolose 2,800 mg, polysorbate 80 2,240 mg, silicon dioxide colloid 3,920 mg, magnesium stearate 2,800 mg;

Sheath: Opadrai II 85F 18422 white 16,800 mg (polyvinyl alcohol, partially hydrolyzed 6,720 mg, titanium dioxide (E171) 4,200 mg, macrogol 4000 3,394 mg, talc 2,486mg).

Description:

Dosage of 5 mg + 10 mg

Round, biconvex tablets, covered with a film shell "of white color, engraved on one side of the SEZ, on a transverse section of white color.

Dosage of 10 mg + 10 mg

White, round, biconvex tablets, covered with a film sheath, engraved on one side of CE5. On a cross-section of white color.

Dosage 5 mg+ 20 mg

White, oblong, biconvex tablets, covered with a film sheath, engraved on one side of CE4. On a cross-section of white color.

Dosage of 10mg + 20mg

White, oblong, biconvex tablets, covered with a film sheath, engraved on one side of CE6. On a cross-section of white color.

Pharmacotherapeutic group:hypotensive + hypolipidemic agent (blocker of "slow" calcium channels and inhibitor of HMG-CoA reductase).

ATX: & nbsp

C.10.A.A.05 Atorvastatin

C.08.C.A.01 Amlodipine

Pharmacodynamics:

Combined drug: atorvastatin, a hypolipidemic agent, an inhibitor of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase, amlodipine - dihydropyridine derivative, blocker of "slow" calcium channels (BCCI).

Combined drug therapy - leads to a dose-dependent decrease systolic and diastolic blood pressure (BP) and low density lipoprotein cholesterol (LDL cholesterol).

The effect on systolic and diastolic blood pressure or LDL cholesterol is not significantly different from that of amlodipine and atorvastatin alone. AT Within the Duplexer® development program, a bioequivalence study was conducted in which the biological equivalence of the fixed combination of amlodipine and atorvastatin (Duplexer®) and the free combination of these drugs was demonstrated.

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, but amlodipine reduces ischemia in the following two ways:

1. Amlodipine expands peripheral arterioles and thus reduces the overall peripheral resistance of blood vessels (OPSS), i.e. afterload on the heart. Since the heart rate (heart rate) does not change, reducing the load on the heart leads to a reduction in energy consumption and oxygen demand.

2. The mechanism of action of amlodipine probably also includes the enlargement of the main coronary arteries and coronary arterioles, both in unchanged and in 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).

In patients with hypertension receiving amlodipine in a single daily dose provides a clinically significant decrease in blood pressure for 24 hours, both in the "lying", and "standing". Due to the slow start of the action, amlodipine does not cause acute arterial hypotension.

In patients with angina, the use of amlodipine once a day increases the time exercise, prevents the development of an attack of angina and depression of the segment ST (by 1 mm), reduces the incidence of angina attacks and the number of short-acting nitroglycerin (sublingual) short-acting tablets taken. Amlodipine does not adversely affect the metabolism and lipids, plasma and can be used in patients with bronchial asthma, diabetes and gout.

In patients with heart failure III-IV functional class (by classification of NYHA) reception of amlodipine did not lead to a worsening of clinical state (tolerance of physical activity, fraction of left ventricular ejection, heart and clinical symptoms).

Atorvastatin

Atorvastatin selectively and competitively inhibits HMG-CoA reductase, which catalyzes the conversion of 3-hydroxy-3-methylglutarylcoenzyme A to mevalonic acid- a precursor of steroids, including cholesterol (cholesterol). Triglycerides and cholesterol in the liver are included in the composition of cholesterol, very low density lipoproteins (cholesterol-VLDL), enter the blood plasma and transport to peripheral tissues. Low-density lipoprotein cholesterol (LDL cholesterol) is formed from cholesterol-VLDL during interaction with LDL-C receptor cholesterol characterized by high affinity for these lipoproteins.

Atorvastatin reduces the concentration of cholesterol and lipoproteins in the blood plasma by inhibition of HMG-CoA reductase and the synthesis of cholesterol in the liver, and an increase in the number of "liver" LDL-C receptors on the cell surface, which leads to increased capture and catabolism of LDL-C. Atorvastatin reduces the formation of LDL cholesterol, provides a significant and persistent increase in LDL-C receptor activity, combined with a favorable change in the quality of LDL particles.

Reduces the concentration of total cholesterol (30-46%), LDL cholesterol (41 -61%), apolipoprotein B (34 - 50%) and triglycerides (14 - 33%), while leading to an increase in the concentration of high density lipoprotein cholesterol (HDL cholesterol) and apolipoprotein A1. These results are the same for patients with heterozygous hereditary hypercholesterolemia, non-hereditary forms hypercholesterolemia, as well as mixed hyperlipidemia, including patients with type 2 diabetes mellitus.

Atorvastatin is effective for reducing the concentration of LDL cholesterol in patients with homozygous hereditary hypercholesterolemia, i.e. a population usually resistant to therapy with other lipid-lowering agents.Reliably reduces risk of development of ischemic complications (including fatal outcome of myocardial infarction) in 16%, the risk of re-hospitalization for angina, accompanied by signs of myocardial ischemia - by 26%. The effect of atorvastatin on the risk of ischemic outcomes and mortality was independent of the initial concentration of LDL cholesterol and was comparable in patients with myocardial infarction (MI) without a tooth Q and unstable angina; men and women, patients younger and older than 65 years. Atorvastatin significantly reduced the development of the following complications:

	Risk reduction
Coronary complications (CHD with fatal outcome and non-fatal MI)	36 %
General cardiovascular complications and revascularization procedures	20%
Common coronary complications	29 %
Stroke (fatal and nonfatal)	26%

Pharmacokinetics:

Amlodipine

Suction:

After oral administration amlodipine well absorbed, the maximum concentration in the plasma is achieved after 6 - 12 hours. Absolute bioavailability of 64-80%. Bioavailability of amlodipine does not change when eating.

Distribution:

The distribution volume is approximately 21 l / kg. Approximately 97% of circulating amlodipine binds to plasma proteins. Equilibrium concentrations of amlodipine in blood plasma are achieved through 1 - 8 days of regular medication.

Metabolism and excretion:

Amlodipine is metabolized in the liver with the formation of inactive metabolites, 10% of unchanged amlodipine and 60% of metabolites are excreted by the kidneys. Excretion from the blood plasma is biphasic with a terminal half-life of approximately 30-50 hours.

Special populations of patients

Age, heart failure

The time required to achieve Cmah amlodipine in blood plasma, virtually independent of age. Patients in the elderly have a tendency to decrease the clearance of amlodipine, which leads to an increase AUC and half-life (T1/2).

In patients of different age groups with chronic heart failure (CHF), an increase AUC and T1/2. Such an increase AUC was noted in patients with hepatic insufficiency.

Renal impairment

The concentrations of amlodipine in plasma do not depend on the degree of renal failure. Patients with impaired renal function may take usual initial doses of the drug. Amlodipine not output during dialysis.

Dysfunction of the liver

In patients with impaired hepatic function, the half-life increases.

Atorvastatin

Suction: Atorvastatin quickly absorbed after ingestion; maximum plasma concentrations are achieved within 1-2 hours. The degree of absorption increases with the dose of atorvastatin. Absolute bioavailability Atorvastatin is approximately 12%, and systemic bioavailability inhibitory activity against HMG-CoA reductase is approximately 30%.

Low systemic bioavailability is due to presystemic metabolism (absorption) in the mucosa of the gastrointestinal tract and / or metabolism at the "primary passage" through the liver.

Distribution: The average volume of atorvastatin distribution is approximately 381 liters. Atorvastatin more than 98 % binds to blood plasma proteins.

Metabolism: Atorvastatin is metabolized by isoenzymes of the cytochrome P450 system ZA4 to ortho- and para-hydroxylated derivatives and various products of beta oxidation. In addition to other metabolic pathways, these products are further metabolized, via, conjugation with glucuronide. In vitro, inhibition of HMG-CoA reductase by ortho- and para-hydroxylated metabolites is equivalent to inhibition observed for atorvastatin. Approximately 70 % decrease in the activity of HMG-CoA reductase occurs due to the action of active circulating metabolites.

Excretion: Atorvastatin is excreted mainly with bile after hepatic and / or extrahepatic metabolism. However, the drug does not appear to undergo significant intestinal hepatic recirculation. The average half-life of atorvastatin from plasma is approximately -14 hours. Due to the action of active metabolites, the half-life of the inhibitory activity of HMG-CoA reductase is approximately 20-30 hours.

.Special populations of patients

Elderly patients

The concentrations of atorvastatin and its metabolites in blood plasma in healthy elderly volunteers are higher than in healthy young volunteers, although lipolipidemic effects are comparable to those in young adults.

Floor

The concentration of atorvastatin in blood plasma in women differs from that in men (maximum concentration (Cmah) in women is about 20% higher, and the area under the curve "concentration-time" (AUC) on 10%. below), but clinically significant differences in the effect of the drug on lipid metabolism in men and women have not been revealed.

Patients of childhood

There are no pharmacokinetic data for this patient population.

Patients with impaired renal function

Kidney disease does not affect the concentration of atorvastatin in the blood plasma, so dose adjustments in patients with impaired renal function are not required.

Patients with hepatic impairment

The concentrations of atorvastatin and its metabolites in blood plasma are significantly increased (Cmax approximately 16 times, AUC - 11 times) in patients with chronic liver disease caused by excessive drinking (class B - Child-Pugh classification).

Indications:

Duplexer® is designed to treat arterial hypertension in patients with dyslipidemia, whose condition is adequately controlled by the administration of amlodipine and atorvastatin at the same dosages that are included in Duplexor® (with or without clinically severe coronary heart disease (CHD)) and having one of the the following diseases:

- Primary hypercholesterolemia, including familial hypercholesterolemia (familial heterozygous hypercholesterolemia), or combined (mixed) hyperlipidemia (corresponding to Type IIa and IIb according to Fredrickson's classification)

homozygous familial hypercholesterolemia

- when the hypolipidemic diet and other non-pharmacological methods of treating dyslipidemia are little or ineffective.

The drug is recommended to be used in those cases when combination therapy with amlodipine and low doses of atorvastatin is needed.

It is possible to use the drug with other antihypertensive and antianginal drugs.

Contraindications:

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

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

Shock (including cardiogenic shock);

Hemodynamically unstable heart failure after acute myocardial infarction myocardium;

Active liver disease or persistent increase in the activity of "hepatic" enzymes more than 3 times higher than the norm of unclear etiology (see section Specials instructions);

Pregnancy and lactation;

The use of reproductive age in women who do not use adequate methods of contraception;

Combined use with itraconazole, ketoconazole and telithromycin (see p. section Interactions with other drugs).

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

Carefully:

Arterial hypotension, acute myocardial infarction (and within 1 month after it), CHF of non-ischemic etiology III-IV functional class by classification NYHA, syndrome of weakness of the sinus node (SSSU), hypertrophic obstructive cardiomyopathy, impaired liver function, patients abusing alcohol and / or liver disease in the anamnesis, patients with risk factors for rhabdomyolysis (renal failure of moderate severity (CC less than 60 ml / min, heavy disturbances of water-electrolyte balance, endocrine and metabolic disorders, severe acute infections (sepsis), uncontrolled epilepsy, extensive surgical interventions, trauma), hypothyroidism, own or seminal ny muscle disease history,myotoxicity when taking other HMG-CoA reductase inhibitors or fibrates, conditions accompanied by an increase in the concentration of atorvastatin in the systemic bloodstream), age over 65, as the concentration of atorvastatin increases with age.

Pregnancy and lactation:

Women of childbearing age should use reliable and adequate contraception. The drug 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

Pregnancy

Duplexor® is contraindicated during pregnancy. Security the use of amlodipine and atorvastatin in pregnancy is not established.

When establishing pregnancy, Duplexor® should be treated immediately stop, if necessary start alternative therapy.

Lactation period

Data on whether the amlodipine, atorvastatin and their metabolites into the breast milk is absent. Duplexor® is contraindicated in the period lactation.

Dosing and Administration:

Inside, 1 tablet once a day at any time of the day, regardless of the time of ingestion.

Duplexor® is not recommended as starting monotherapy, as the dose Duplexor® should be determined by titrating the dose of individual components drug taking into account the data on the doses and methods of using amlodipine and atorvastatin.

In accordance with the results of dose titration, the recommended dose is one Doplexer® 5 mg + 10 mg tablet (amlodipine + atorvastatin, respectively), one tablet of Duplekor® 10 mg + 10 mg (amlodipine + atorvastatin), one tablet of Duplekor® 5 mg + 20 mg (amlodipine + atorvastatin, respectively), or one tablet of Duplexer® 10 mg + 20 mg (amlodipine + atorvastatin, respectively) once a day. The maximum daily dose is one tablet of Duplexor ® 10 mg + 20 mg (amlodipine + atorvastatin, respectively) once a day.

The drug is used in combination with non-medicated treatments, including diet, exercise, weight loss in obese patients, rejection of smoking.When used in patients with arterial hypertension in a dose of 5 mg + 10 mg (at the beginning of therapy), blood pressure monitoring is necessary every 2-4 weeks and, if necessary, an increase in the dose to 10 mg + 10 mg / day is possible. With IHD, the recommended dose (for amlodipine) is 5-10 mg / day.

Elderly patients

Duplexor® dosage adjustment is not required.

Children and teenagers under 18 years of age

The efficacy and safety of Duplexor® in children and adolescents (under 18 years of age) has not been adequately studied, therefore, the appointment of a drug in this category of patients is not recommended.

Patients with impaired hepatic function

Duplexer® is contraindicated in patients with liver disease in the active phase or with a persistent increase in the activity of "hepatic" enzymes in the serum, exceeding the upper limit of the norm (VGN) 3 times (see section Contraindications and Special instructions).

Patients with impaired renal function

Correction of the dose is not required.

Side effects:

The undesirable effects that can occur when taking atorvastatin or amlodipine separately, can be considered as potential side effects when taking Duplexer®.

The frequency of adverse reactions is given separately for atorvastatin and amlodipine.The data are classified according to the system-organ classes according to the classification MedDRA and with the following frequency: very often (> 1/10), often (> 1/100 to <1/10), infrequently (> 1/1 000 to <1/100), rarely (> 1/10 000 to < 1/1 000), very rarely (<1/10 000).

The system-organ class MedDRA

Frequency of occurrence

For atorvastatin

For amlodipine

On the part of the blood and lymphatic system

Infrequently

Rarely

Thrombocytopenia

Thrombocytopenia, leukopenia

Allergic reactions

Often

Rarely

Hypersensitivity

Anaphylactic reactions, angioedema, bullous rash (including erythema multiforme, Stephen-Johnson syndrome and toxic epidermal necrolysis)

Hypersensitivity, urticaria, angioedema, erythema multiforme, exfoliative dermatitis, Stephen-Johnson syndrome, Quincke's edema, photosensitivity

Disorders from the metabolism and nutrition

Often

Infrequently

Rarely

Hyperglycaemia

Hypoglycaemia

Hyperglycaemia

Mental disorders

Infrequently

Rarely

Insomnia, nightmares

Insomnia, mood lability (including anxiety), depression

Confusion of consciousness

From the nervous system

Often

Infrequently

Rarely

Headache

Dizziness, hypoesthesia, dysgeusia, amnesia, paresthesia

Peripheral neuropathy (without further clarification)

Drowsiness, dizziness, headache (especially at the beginning of treatment)

Fainting, tremor, dysgeusia, hypoesthesia, paresthesia

Muscle tone, peripheral neuropathy

From the side of the organ of vision

Infrequently

Visual impairment (including diplopia)

From the side of the hearing and labyrinth organs

Infrequently

Noise in ears

From the side of the cardiovascular system

Often

Infrequently

Rarely

"Tides" of blood to the skin of the face, peripheral edema of the ankles and feet

Heart palpitations, marked decrease in blood pressure

Myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation), vasculitis

On the part of the respiratory system, the organs of the thorax and the mediastinum

Often

Infrequently

Rarely

Pain in the chest, pain in the nasopharynx, nosebleeds

Shortness of breath, rhinitis

Cough

From the side of the digestive tract

Often

Infrequently

Rarely

Diarrhea, constipation, flatulence, nausea, dyspepsia, abdominal pain

Vomiting

Abdominal pain, nausea

Vomiting, indigestion, bowel dysfunction (including diarrhea and constipation), dryness of the oral mucosa

Pancreatitis, gastritis, hypertrophic gingivitis

From the hepatobiliary system

Rarely

Hepatitis, cholestatic jaundice, pancreatitis

Liver failure

Hepatitis, cholestatic jaundice

From the skin and subcutaneous fat

Often

Infrequently

Skin rash, itching

Alopecia

Alopecia, purpura, skin pigmentation, hyperhidrosis, itching, rash, exanthema

From the musculoskeletal system and connective tissue

Often

Infrequently

Rarely

Myalgia, arthralgia, back pain

Myopathy

Myositis, rhabdomyolysis, muscle spasms

Swelling of ankle joints

Arthralgia, myalgia, muscle spasms, back pain

From the side of the kidneys and urinary tract

Infrequently

Violation of urination, nocturia, pollakiuria

From the reproductive system and breast

Infrequently

Rarely

erectile disfunction

Gynecomastia

Erectile dysfunction, gynecomastia

General disorders and disorders at the site of administration

Often

Infrequently

Rarely

Increased fatigue, asthenia, chest pain

General weakness

Peripheral edema

Edema, increased fatigue

Pain in the chest, asthenia, pain, general malaise

Laboratory research

Often

Infrequently

Rarely

Increase of activity of "liver" enzymes, increase of activity of creatine phosphokinase in blood serum

Weight gain

Weight gain, weight loss

Increased activity of "liver" enzymes

Overdose:

There is no information about an overdose of the drug.

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, and a pronounced and persistent decrease in blood pressure, incl. 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.The pronounced decrease in blood pressure caused by an overdose of amlodipine requires active measures aimed at maintaining the function of the cardiovascular system, including control. heart and lung function, elevated limb position and control of the volume of circulating blood and diuresis. To restore the tone of blood vessels and blood pressure, it may be useful to use a vasoconstrictor, if there is no contraindication to its purpose, to eliminate the effects of calcium channel blockade - iv calcium gluconate.
Treatment of an overdose of atorvastatin - There are no specific agents for the treatment of atorvastatin overdose. In case of an overdose, symptomatic and supportive treatment should be provided as needed. An evaluation of liver function and activity of creatine phosphokinase (CK) in serum should be performed.

Interaction:

It has been shown that the pharmacokinetics of amlodipine 10 mg in combination with atorvastatin 80 mg in healthy volunteers does not change. Amlodipine did not influence Cmatorvastatin, but caused an increase AUC on 18%.The interaction of Duplexor® with other drugs has not been specifically studied, but each component has been studied separately.

Possible interactions with amlodipine

The use of the following combinations of drugs is not recommended

Infusion solution of dantrolene: In animals that were injected intravenously simultaneously verapamil and dantrolene, ventricular fibrillation was usually noted. Given this circumstance, simultaneous use of amlodipine and dantrolene should be avoided.

The use of the following combinations should be carried out with extreme caution

Baclofen: The hypotensive effect intensifies. In this case, it may be necessary to monitor blood pressure and reduce the dose of an antihypertensive drug.

Inhibitors - isoenzyme CYP3A4: With the simultaneous use of an inhibitor of isoenzyme CYP3A4 erythromycin by healthy young volunteers and an isoenzyme inhibitor CYP3A4 diltiazem elderly patients noted an increase in the concentration of amlodipine in blood plasma, by 22% and 50%, respectively. However, the clinical significance of these data is unknown.It can not be ruled out that powerful inhibitors of isoenzyme CYP3 A4 (e.g., ketoconazole, itraconazole, ritonavir) can increase the concentration of amlodipine in the blood plasma to a greater extent than diltiazem.

Inductors of isoenzyme CYP3A4: antiepileptic agents (for example, carbamazepine, phenobarbital, phenytoin, phosphenytoin, primidon), rifampicin: due to the induction of amlodipine metabolism we can expect a decrease in the concentration of blockers of "slow" calcium channels (in particular amlodipine) in the blood plasma. AT case of taking the above isoenzyme inducers CYP3A4 recommended clinical observation and, if necessary, dose adjustment of amlodipine, otherwise - simultaneous reception of an isoenzyme inducer CYP3 A4 should be discontinued.

The use of the following combinations is acceptable

Blockers of a1-adrenergic receptors (prazozin, alfuzosin, doxazosin, tamsulosin, terazosin): one can expect an increase in the hypotensive effect with a risk of pronounced orthostatic hypotension.

Amifostin: increased hypotensive effect due to manifestations of undesirable amifostine.

Tricyclic antidepressants / Neuroleptics: increased risk of developing arterial hypotension or orthostatic hypotension (additive effect).

Beta-blockers (bisoprolol, carvedilol, metoprolol): risk of development arterial hypotension or heart failure in the case of latent or uncontrolled heart failure (the negative inotropic effect of beta-blockers may be amplified). In the case of simultaneous use of amlodipine and beta-blockers, sympathetic reflex reactions, manifested as a result of excessive hemodynamic effect, may weaken.

Corticosteroids, tetracosactide: the hypotensive effect may be weakened by a decrease in the absorption of sodium and water caused by glucocorticosteroids.

Other antihypertensives: concomitant administration of antihypertensive agents (beta-blockers, angiotensin II receptor antagonists, diuretics, angiotensin-converting enzyme (ACE) inhibitors) may enhance the antihypertensive effect of amlodipine.

Simultaneous use with nitrates or other vasodilating agents may lead to an additional reduction HELL.

Sildenafil: with primary arterial hypertension, a single dose100 mg of sildenafil had no effect on the pharmacokinetic parameters of amlodipine. When taking amlodipine in combination with sildenafil, each drugthe drug reduces blood pressure independently of the other.

Cimetidine, atorvastatin, aluminum- or magnesium-containing antacids, grapefruit juice do not affect the pharmacokinetics of amlodipine.

Studies of drug interactions have shown that amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin; ethyl, alcohol (alcohol), warfarin and cyclosporine.

With the joint application of slow calcium channel blockers with lithium preparations, an increase in the manifestation of their neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, and tinnitus) is possible.

Calcium preparations can reduce the effect of blockers of slow calcium channels. Although in the study of amlodipine, a negative inotropic effect is usually not observed, nevertheless, some slow calcium channel blockers can increase the severity of the negative inotropic effect of antiarrhythmic agents that cause lengthening of the interval QT (eg, amiodarone and quinidine).

Possible interactions with atorvastatin

The use of the following combinations is contraindicated

Itraconazole, ketoconazole: the risk of dose-dependent adverse events, for example, rhabdomyolysis increases (the metabolism of atorvastatin in the liver decreases).

Telithromipin: the risk of dose-dependent adverse events, such as rhabdomyolysis, increases (atorvastatin metabolism in the liver decreases).

The use of the following combinations of drugs is not recommended Gemfibrozil and other derivatives of fibroic acid: the risk of dose-dependent adverse events, for example, rhabdomyolysis increases (the metabolism of atorvastatin in the liver decreases).

The use of the following combinations should be carried out with extreme caution

Inhibitors of isoenzymes or cytochrome P450 systems 4: atorvastatin is metabolized by the system's isozymes, cytochrome P450, CYP AP4.

Erythromycin, an inhibitor CYP ZA4, increased the concentration of atorvastatin in blood plasma by 40%. Simultaneous administration of atorvastatin and inhibitors CYP 4, some macrolide antibiotics (eg, erythromycin, clarithromycin), immunosuppressants (cyclosporine),antifungal agents related to azoles (eg, itraconazole, ketoconazole), amiodarone, protease inhibitors or antidepressants, nefazodone, can lead to interaction, which will lead to an increase in the concentration of atorvastatin in the blood plasma. Therefore, simultaneous use with these drugs should be done with caution.

Inductors of cytochrome P450 isoenzymes ZA4: simultaneous use of atorvastatin and inducers of cytochrome P450 ZA4 isoenzymes (for example, phenytoin, rifampicin) can lead to a significant decrease in the concentration atorvastatin in the blood plasma. Due to the presence of a double mechanism of interaction of rifampicin (induction of enzymes of the cytochrome P4503A4 system and inhibition of the hepatocyte capture vector of OATP1B1), a joint application atorvastatin and rifampicin resulted in an average increase in the parameters of Cmax and AUC atorvastatin by 12 and 90%, respectively. On the contrary, taking atorvastatin after a while after taking rifampicin was accompanied by a significant decrease (approximately 80%) concentrations of atorvastatin in blood plasma.

Warfarin: taking atorvastatin together with warfarin may lead to increased anticoagulant effect with a risk of bleeding. Patients receiving warfarinshould be under the supervision of a physician, as it may be necessary Correction of the dose of anticoagulant.

A nicotinic acid: lipid-lowering doses of nicotinic acid (more than 1 g / day) may increase the risk of myopathy with simultaneous administration with HMG-CoA reductase inhibitors. Rarely, as a consequence of rhabdomyolysis and myoglobinuria, a kidney can developfailure. Therefore, it is necessary to consider relation "benefit-risk" of simultaneous use of atorvastatin and nicotinic acid in lipid-lowering doses.

The use of the following combinations is acceptable

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 content of LDL cholesterol remained unchanged. Grapefruit juice: Grapefruit juice contains one or more components that inhibit CYP3A4 and, therefore, can lead to an increase in concentrations in the plasma of the drug, the metabolism of which proceeds with the isozymes of the cytochrome system CYP3A4. Consumption, one glass (240 ml) of grapefruit juice resulted in an increase AUC atorvastatin by 37% and to a decrease AUC of the active orthohydroxy metabolite of atorvastatin by 20.4%. However, large amounts of grapefruit juice (more than 1.2 liters per day for 5 days) increase AUC atorvastatin 2.5 times and AUC active inhibitors of HMG-CoA reductase (atorvastatin and metabolites) in 1,3 times.

Simultaneous intake of large quantities of grapefruit juice and atorvastatin is not recommended.

Oral contraceptives: application of atorvastatin. together with an oral contraceptive containing norethisterone and ethinyl estradiol, led to an increase in the concentrations of norethisterone and ethinyl estradiol in blood plasma. This effect should be taken into account when choosing an oral contraceptive for a woman receivingatorvastatin.

Colestipol: the lipid-lowering effect of the combination with colestipol exceeds that for each drug alone, despite a decrease in the concentration of atorvastatin by 25% when it is used concomitantly with colestipol.

Other interactions

Antipyrine (phenazone): simultaneous administration of multiple doses of atorvastatin and phenazone revealed a slight effect on the clearance of phenazone, or the absence of this effect.

For atorvastatin no interaction with non-steroidal anti-inflammatory drugs, antibiotics, hypoglycemic drugs, cimetidine, antihypertensive agents.

With prolonged use of digoxin simultaneously with 10 mg of atorvastatin, a small increase in the equilibrium concentrations of digoxin was observed.

Assessment of the effects of amiodarone or verapamil on atorvastatin not carried out. It is known that both drugs - amiodarone and verapamil - Suppress the activity of cytochrome enzymes, CYP3A4, and their simultaneous use with atorvastatin may lead to an increase in the concentration of atorvastatin.

With the simultaneous use of atorvastatin and fusidic acid, rhabdomyolysis may develop.

Special instructions:

Chronic heart failure

In patients with CHF (III-IV functional class by classification NYHA) non-ischemic-etiology in the use of amlodipine, there is a likelihood of pulmonary edema. Therefore, such patients should be administered with caution.

Violations function liver

Before starting treatment with atorvastatin and periodically during treatment, control function of the liver. AT the case of increased activity of the "hepatic". Enzymes exceeding the upper limit of normal (VGN) 3 times, it is recommended reduce the dose of the drug or stop taking it.

In patients with impaired hepatic function, the half-life of amlodipine increases, so Duplexor® should be given to such patients with caution.

Caution should be given to Duplexor® patients who have abused alcohol and / or have a history of liver disease.

Muscle Effects

In patients who received atorvastatin, myalgia was observed. Myopathy should be diagnosed in patients taking HMG-CoA reductase inhibitors that exhibit unexplained symptoms, such as pain or muscle soreness, muscle weakness, or muscle cramps. In such cases, it is necessary to monitor the activity of CK. The activity of CK should not be measured after intensive physical exertion or if there is a likely alternative cause of increased activity of CK. If the activity of CK is significantly higher than the norm (more than 5 times higher than ULN), the activity of CK should be determined regularly for 5-7 days to confirm the results.

Before the beginning of the drugDuplexor® When taking atorvastatin in monotherapy, patients with risk factors for rhabdomyolysis should take the drug with caution. The activity of CK should be determined before starting treatment with atorvastatin in the following situations:

Impaired renal function

Hypothyroidism

Own or family anamnesis of muscular diseases

The presence in the anamnesis of myotoxicity on the background of taking other inhibitors of HMG-Co A-reductase or fibrates

Liver disease in history and / or alcohol abuse

In elderly patients (> 65 years) in case of presence of risk factors for development rhabdomyolysis

The expected benefit and risk of treatment should be carefully weighed and patients monitored regularly. If the activity of CK is increased by more than 5 times compared with VGN, treatment should not be started.

During treatment

It is recommended that patients be informed of the need to report promptly to the doctor about cases of unexpected muscle pain, muscle weakness, or spasms, especially in combination with malaise or fever. If muscle pain, weakness, or convulsions occurs during treatment with Duplexor®, CPC activity should be monitored.If it is determined that the activity of CKK is more than 5 times higher than the VGN, treatment should be discontinued.

If the muscle symptoms are severe and cause daily discomfort throughout the day, even if the activity of the CK is increased by less than 5 times compared with the VGN, treatment should be discontinued.

In the event of the disappearance of symptoms and return to the norm of the activity of CKK, consideration should be given to the re-administration of Duplexer® with a lower dose of atorvastatin and careful monitoring of the patient.

The increase in the activity of CK should be taken into account in the differential diagnosis of pain in the chest in assessing the likelihood of developing myocardial infarction.

When Atorvastatin, as well as other drugs of this class, rare cases of rhabdomyolysis with acute renal failure due to myoglobinuria have been described.

Joint administration of Duplexer® and dantrolene (solution for infusions), gemfibrozil or other fibrates is not recommended.

When combined use of cyclosporine, nicotinic acid in lipid-lowering I doses (more than 1 g per day), derivatives of fibroic acid, macrolide antibiotics, including erythromycin, clarithromycin, antifungal drugs related to azoles (itraconazole, ketoconazole), nefazodone, as well as HIV protease inhibitors, the risk of myopathy increases during treatment with HMG-CoA reductase inhibitors (see Interactions with Other Drugs).

Effect on the ability to drive transp. cf. and fur:Studies on the effect of the drug on the ability to drive vehicles and the use of mechanisms were not carried out. Caution should be exercised when driving vehicles and controlling machinery when taking Duplexor®, taking into account the possible development of excessive depression of blood pressure, dizziness and fainting.

Form release / dosage:

Tablets coated with an evaluation coat, 5 mg + 10 mg, 10 mg + 10 mg, 5 mg + 20 mg, 10mg + 20mg.

Packaging:10 tablets in blister from PA / Al/ PVC-foil and aluminum foil. 3 blisters in a cardboard box with instructions for use.

Storage conditions:Keep in dry the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children!

Shelf life:2 years. Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-001323

Date of registration:02.12.2011

The owner of the registration certificate:GEDEON RICHTER, OJSC GEDEON RICHTER, OJSC Hungary

Manufacturer: & nbsp

GEDEON RICHTER ROMANIA, S.A. Romania

Representation: & nbspGEDEON RICHTER OJSC GEDEON RICHTER OJSC Hungary

Information update date: & nbsp02.12.2011

Illustrated instructions

Instructions

DUPLEKOR® (Duplecor® )