Pharmacological properties

Pharmacodynamics. the diswagger contains two antihypertensive components with additional mechanisms of control hell at patients from an essential ag: amlodipin belongs to the class of antagonists of calcium, and valsartan — to a class of antagonists of angiotensin іі. the combination of these ingredients shows additive antihypertensive effect, lowering arterial blood pressure more than each of components separately.

Amlodipin. Amlodipin inhibits transmembrane penetration of calcium ions into unstriated muscles of heart and vessels. The mechanism of antihypertensive action of an amlodipin is caused by the direct relaxing impact on unstriated muscles of vessels that predetermines reduction of OPSS and leads to decrease in the ABP. Experimental data confirm what amlodipin communicates in dihydropyridinic and not hydropyridinic places of binding. Sokratitelny processes of a cardiac muscle and unstriated muscles of vessels depend on passing of extracellular calcium to these cells through specific ion channels.

After introduction in therapeutic doses to patients from essential AG amlodipin causes a vazodilatation which leads to decrease in the ABP in provisions of the patient sitting and standing. Such decrease in the ABP is not followed by significant change of speed of warm reductions or levels of catecholamines in blood plasma at long dosing.

Effect correlates with concentration in blood plasma at patients of young and advanced age.

therapeutic doses of an amlodipin lead

At patients with AG and normal function of kidneys to decrease in renal vascular resistance and increase in level of glomerular filtration and also an effective renal stream of blood plasma without changes of the filtered fraction or a proteinuria.

As well as in a case with other blockers of calcium channels, measurements of a hemodynamics of warm function at rest and at loading (or when walking) at patients with normal function of the ventricles treated amlodipiny in general showed small increase in cardiac index without significant effect on dP/dt or on left ventricular and diastolic pressure or volume. In hemodynamic researches amlodipin did not show negative inotropic effect at use in therapeutic doses for intact animals and people, even at the combined introduction with blockers of β-adrenoceptors.

Amlodipin does not change

function of a sinoatrial node and atrioventricular conductivity at healthy animals or people. At use of an amlodipin in a combination with blockers of β-adrenoceptors at patients with essential AG or stenocardia of changes of indicators of the ECG it was not noted.

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observed positive clinical effects of an amlodipin at patients with the chronic stable stenocardia, vasospastic stenocardia and an ischemic heart disease confirmed angiographically.

Valsartan. Valsartan is an active and specific antagonist of receptors of angiotensin ІІ, intended for internal use. It affects selectively receptors of the AT _{1 subtype} which are seldom widespread and are responsible for effects of angiotensin ІІ. The increased angiotensin II levels owing to blockade of AT ₁ - receptors valsartany can stimulate free AT ₂ - receptors that counterbalances effect of AT ₁ - receptors. Valsartan does not show any partial activity of agonist concerning AT ₁ - receptors and has much more bigger (approximately by 20,000 times) affinity to AT ₁ - to receptors, than to AT ₂ - to receptors.

Valsartan does not oppress APF known also under the name of a kininaza ІІ which turns angiotensin І into angiotensin ІІ and destroys bradykinin.

Knows that reception of a valsartan reduces the level of hospitalization of patients with chronic heart failure (class II-IV on NYHA). More significant effect was reached at patients who did not receive APF inhibitors or blockers of β-adrenoceptors. It is also established that reception of a valsartan reduced cardiovascular mortality at clinically stable patients with pathology of a left ventricle or left ventricular dysfunction after a myocardial infarction.

Other researches: double blockade system renin-angiotensin-aldosteronovoy (SRAA).

Knows that in two big randomized controlled studies studied use of a combination of APF inhibitor or the antagonists of receptors of angiotensin (ARA). In these researches when comparing with monotherapy considerable positive differences concerning influence on kidneys and/or a cardiovascular system and mortality are not revealed, however the increased risk of development of a hyperpotassemia, acute damage of kidneys and/or hypotensions was established. Taking into account similarity of pharmacokinetic properties these results are also relevant for other APF or ARA inhibitors. Thus, patients should not accept at the same time APF and ARA inhibitors with a diabetic nephropathy. The side effects caused by bradykinin are not revealed. Valsartan does not enter interaction and does not block receptors of other hormones or ion channels which, as we know, play an important role in regulation of functions of a cardiovascular system.

Prescribing of medicament to patients with AG leads

to decrease in the ABP, without affecting at the same time pulse rate.

beginning of antihypertensive activity is noted by

At most of patients after appointment in a single dose of medicament within 2 h, and the maximum decrease in the ABP is reached within 4–6 h

Antihypertensive effect remains more than 24 h after reception of a single dose. On condition of regular use of medicament the maximum therapeutic effect is usually reached during 2–4 weeks and remains at the reached level during long therapy. Sudden cancellation of a valsartan does not lead to restoration to AG or other collateral clinical phenomena.

Valsartan/amlodipin. The combination of an amlodipin besilat/valsartan with AG causes antihypertensive effect during about 24 h in patients. Sudden medicament withdrawal does not lead to fast increase in the ABP.

combination therapy can provide to

At patients at whom the ABP is adequately controlled amlodipiny in unacceptable hypostases similar control of the ABP at reduction of hypostases.

Pharmacokinetics

Linearity. Valsartan and amlodipin show linearity of pharmacokinetics.

Amlodipin

Absorption. After internal use in therapeutic doses of an amlodipin separately the C _max in blood plasma is reached during 6–12 h. The calculated absolute bioavailability is 64–80%. Food significantly affects bioavailability of an amlodipin.

Distribution. The volume of distribution is about 21 l/kg. It is known that in researches of an amlodipin in vitro it is proved that at patients from essential AG about 97.5% of the circulating medicament contact proteins of blood plasma.

Biotransformation. Amlodipin intensively (about 90%) is metabolized in a liver to inactive metabolites.

Removal. Removal of an amlodipin from blood plasma two-phase, with T _½ about 30-50 h. Equilibrium levels in blood plasma are reached after constant removal within 7–8 days. 10% of an initial amlodipin and 60% of metabolites of an amlodipin are removed with urine.

Valsartan

Absorption. After administration of medicament in the C _max valsartana in blood plasma is reached during 2–4 h. The average size of absolute bioavailability of medicament is 23%. Food reduces exposure of a valsartan as shows AUC (concentration in blood plasma — time), approximately by 40%, and the C _max in blood plasma — by 50% though in 8 h after use the concentration of a valsartan in blood plasma is identical to the group taking the medicament on an empty stomach and group of the patients taking the medicament after a meal. Decrease in AUC is not followed by clinically significant decrease in therapeutic effect therefore valsartan it is possible to accept irrespective of meal.

Distribution. The equilibrium volume of distribution of a valsartan in/in introductions is later about 17 l that indicates what valsartan is distributed in fabrics not intensively. Valsartan strongly contacts proteins of blood plasma (94–97%), mainly z seralbumin.

Biotransformation. Valsartan is not transformed substantially as only 20% of a dose pass into metabolites. In blood plasma in low concentration (10% of AUC of a valsartan) the hydroxymetabolite which pharmacological is inactive is identified.

Removal. The multiexponential kinetics of removal (T _½ is characteristic _{a valsartan α} 1 h and T _{½ β} about 9 h). Valsartan is brought, mainly, in not changed state with a stake (about 83% of a dose) and urine (about 13% of a dose). Later in/in introductions the clearance of a valsartan in blood plasma is about 2 l/h, and its renal clearance — about 0.62 l/h (about 30% of the general clearance). T _½ a valsartana — 6 h

Valsartan/amlodipin. After oral administration of the medicament Difors C _max in blood plasma of a valsartan and amlodipin it is reached for 3 and 6–8 h respectively. Speed and extent of absorption of the medicament Difors are equivalent to bioavailability of a valsartan and an amlodipin when assigning separately.

Special populations of patients

Children. Data on medicament pharmacokinetics at children are absent.

Patients of advanced age (of 65 years). Time of achievement of the C _max an amlodipina in blood plasma approximately identical at patients of young and advanced age. At patients of advanced age the clearance of an amlodipin tends to decrease that leads to increase in AUC and lengthening of T _½ . Srednya system AUC of a valsartan at elderly people is 70% higher, than at patients of young age therefore it is necessary to be careful at increase in a dose.

Renal failure. Renal failures significantly do not influence pharmacokinetics of an amlodipin. As expected concerning connection which renal clearance is only 30% of the general plasma clearance the correlations between a condition of function of kidneys and system exposure of a valsartan did not note. Therefore patients with weak and moderate renal failures accept a usual initial dose.

Abnormal liver function. At patients with a liver failure the clearance of an amlodipin decreases that leads to increase in AUC approximately for 40–60%. On average at patients with slight and moderate chronic diseases of a liver the exposure (it is determined by AUC values) a valsartana twice exceeds that at healthy volunteers (are selected on age, sex and body weight). Patients have to be careful with diseases of a liver at medicament use.

Indication

Essentsialnaya ag at patients whose hell is not regulated by means of monotherapy amlodipiny or valsartany.

Use

Patients at whom hell is not regulated by monomedicaments of an amlodipin or valsartan can be transferred to

to combination therapy by medicament a diswagger. the recommended dose — 1 tablet a day. the diswagger is accepted regardless of meal, washing down with a small amount of water.

Patients, accepting valsartan and amlodipin separately, it is possible to transfer to Difors containing the same doses of components. Before transition to a combination of the fixed doses the individual selection of a dose of separate components is recommended (that is an amlodipina and a valsartana). In case of clinical need it is possible to consider the possibility of direct replacement of monotherapy by a combination with the fixed doses.

Maximum daily dose — 1 tablet of medicament Difors 80 or 1 a tablet of medicament Difors 160, or 1 tablet Diforsa XL (the maximum allowed doses of components of medicament — 10 mg on the maintenance of an amlodipin, 320 mg on the maintenance of a valsartan).

Dosing in separate groups of patients

Renal failure. The medicament Difors is contraindicated to patients with a heavy renal failure. For patients with slight and moderate renal failures there is no need for medicament Difors dose adjustment. At patients with renal failures of moderate severity it is recommended to control levels of potassium and creatinine in blood.

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Simultaneous use of the medicament Difors with aliskireny is contraindicated to patients with a renal failure (SKF of 60 mg/min. / 1.73 m ² ).

Diabetes. Simultaneous use of the medicament Difors with aliskireny is contraindicated to patients with diabetes.

Abnormal liver function. With care it is necessary to apply Difors at patients with abnormal liver functions or obstructive diseases of bilious ways. The maximum recommended dose for patients with slight or moderate abnormal liver functions without cholestasia makes 80 mg of a valsartan. Recommendations about dosing of an amlodipin for patients with a slight or moderate abnormal liver function are not developed.

Patients of advanced age (65 years are more senior). For patients of advanced age usual dose schemes are recommended, however it is necessary to be careful at increase in a dose of drug.

Pediatric populations. Safety and efficiency of use of the medicament Difors for children (aged up to 18 years) did not investigate. Data are absent.

Children. Treatment researches were not conducted by this medicament of children (age up to 18 years). Therefore before obtaining fuller information the medicament Difors is not recommended to be used for treatment of children.

Contraindication

Hypersensitivity to active substance, derivatives of dihydropyridine or any of medicament components.

Heavy abnormal liver functions, biliary cirrhosis or cholestasia.

Heavy renal failures (speed of glomerular filtration (SGF) of 30 ml/min. / 1.73 m ² ).

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It is contraindicated to patients who are on dialysis.

Contraindicated simultaneous use of MACAW, including valsartan, or APF inhibitors with aliskireny to patients with diabetes or a renal failure (ml/min. SGF60 / 1.73 m ² ).

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It is contraindicated to the pregnant women and women planning pregnancy (see Use during pregnancy and feeding by a breast).

Heavy hypotension.

Shock (including cardiogenic).

Obstruction of the removing path of a left ventricle (for example a hypertrophic subaortic stenosis and a stenosis of an aorta of heavy degree).

Hemodynamically unstable heart failure after an acute myocardial infarction.

Side effects

Side reactions which were observed most often or were considerable or heavy: nasopharyngites, flu, hypersensitivity, a headache, a faint, orthostatic hypotension, hypostases, hypostases of soft tissues, face edemas, peripheral hypostases, the increased fatigue, face reddening, an asthenia and inflows.

side Below-mentioned reactions are classified by

by the systems of bodies and frequency of emergence. Frequency of emergence of side reactions was estimated by such criteria: very often (≥1/10); often (1/100– ≤ 1/10); infrequently (1/1000– ≤ 1/100); seldom (1/10 000– ≤ 1/1000); very seldom (1/10,000); frequency is unknown (it is impossible to estimate on the available data).

side reactions are given by

For each frequency in group in decreasing order of the importance.

Infection: often — a nasopharyngitis, flu.

from the immune system: seldom — hypersensitivity.

Disturbance of food and metabolism: often — a hypopotassemia; infrequently — anorexia, a hypercalcemia, a lipidemia, a hyperuricemia, a hyponatremia.

from an organ of sight: seldom — a disorder of vision; infrequently — deterioration in sight.

from mentality: seldom — excitement.

from nervous system: often — a headache; infrequently — an incoordination, dizziness, drowsiness, postural dizziness, paresthesia.

from an organ of hearing and a labyrinth: infrequently — a golokruzheniye; seldom — sonitus.

from heart: infrequently — tachycardia, heart consciousness; seldom — a syncope.

from vessels: infrequently — orthostatic hypotension; seldom — arterial hypotension.

from a respiratory system: infrequently — cough, a sore throat and throats.

from digestive system: infrequently — abdominal discomfort and upper abdomens pain, a constipation, diarrhea, nausea, dryness in a mouth.

from skin and hypodermic fabrics: infrequently — skin rash, an erythema; seldom — the increased sweating, urticaria, a dieback, an itching.

from a musculoskeletal system: infrequently — a swelling of joints, a dorsodynia, an arthralgia; seldom — muscular spasms, heavy feeling in muscles.

from kidneys and an urinary system: seldom — the speeded-up urination, a polyuria, increase in level of urea nitrogen in blood.

Disturbance of a reproductive system: seldom — disturbance of erectile function.

General disturbances: often — hypostases, hypostasis of soft tissues, a face edema, peripheral hypostasis, increased fatigue, inflows, an asthenia, hyperaemia.

Additional information concerning a combination. Peripheral hypostasis, the known side effect of an amlodipin, at patients who applied a combination amlodipin/valsartan in general was noted with a smaller frequency (5.1%), than against the background of use of an amlodipin separately.

Additional information concerning medicament components. Undesirable reactions which were noted at use of one of medicament components earlier (an amlodipina or a valsartana) can also arise at medicament Difors use even if they were not noted during the conducted clinical trials or during the post-marketing period.

Amlodipin: often — vomiting, drowsiness, dizziness, feeling of heartbeat, abdominal pain, nausea, a swelling of ankles; infrequently — insomnia, change of mood (including alarm), a depression, a tremor, a dysgeusia, a faint, a giposteziya, a disorder of vision (including a diplopia), sonitus, hypotension, dispnoe, rhinitis, vomiting, dyspepsia, an alopecia, a purpura, discolorations of skin, a hyperhidrosis, an itching, a dieback, myalgia, muscular spasms, pain, urination disturbances, increase in frequency of a mocheispukaniye, impotence, a gynecomastia, thorax pain, a general malaise, increase or degrowth of a body; seldom — confusion of consciousness; very seldom — the leykotsitopeniya, thrombocytopenia, allergic reactions, a hyperglycemia, hypertensia, peripheral neuropathy, sometimes at patients, especially with a heavy obstructive aterokslerotichesky heart trouble, raised the frequency, duration and weight of stenocardia or acute myocardial infarction at the beginning of use of blockers of calcium channels or at increase in their dose; arrhythmia (including bradycardia, ventrikulyarny tachycardia and fibrillation of auricles), a vasculitis, pancreatitis, gastritis, a hyperplasia of gums, hepatitis, jaundice, increase in level of enzymes of a liver, a Quincke's disease, a multiformny erythema, a small tortoiseshell, exfoliative dermatitis, Stephens's syndrome — Johnson, a Quincke's edema, photosensitivity, are usually connected with a cholestasia. Separate cases of an extrapyramidal syndrome were noted.

Valsartan. Following additional by-effects decided during tests at monotherapy valsartany irrespective of relationship of cause and effect on medicament which is studied.

Frequency is unknown to

— decrease in level of hemoglobin, decrease in level of a hematocrit, a neutropenia, thrombocytopenia, increase in level of potassium in blood plasma, increase in level of hepatic tests, including concentration of bilirubin in blood plasma, a renal failure and disturbance of renal functions, increase in level of creatinine in blood plasma, a Quincke's disease, myalgia, a vasculitis, reactions of hypersensitivity, including a serum disease.

Special instructions Safety and efficiency of an amlodipin at treatment of hypertensive crisis are not established to

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.

Patients with deficit in an organism of sodium and/or OCK. At patients from uncomplicated AG (0.4%) the excess hypotension is noted. The patients from the activated RAAS (with the reduced content of sodium and/or OCK, which receive high doses of diuretics) accepting blockers of angiotenzinovy receptors can have a symptomatic hypotension. Are recommended correction of this state before Difors's use or careful medical observation at the beginning of therapy.

When developing arterial hypotension at use of the Difors praparat of the patient should be put on a back and if it is necessary, to carry out in to infusion of physiological solution. To continue treatment before stabilization of the ABP.

Hyperpotassemia. It is necessary to carry out with care simultaneous treatment by the potassium additives, kaliysberegayushchy diuretics, salt substitutes containing potassium or other medicaments which can increase potassium level (heparin, etc.). If use of the medicine influencing potassium level is considered necessary in combination with valsartany, control of level of potassium in blood plasma is recommended.

Renal artery stenosis. There are no data on use of the medicament Difors for patients about one - or a bilateral renal artery stenosis or a stenosis of the only kidney as levels of urea and creatinine in blood plasma can increase.

Transplantation of a kidney. There is no experience of safe use of the medicament Difors for patients from the kidney which is recently postponed transplantation.

Abnormal liver function. Valsartan is brought mainly in not changed view with bile. T _½ an amlodipina increases also AUC indicator (concentration in blood plasma — time) the highest at patients with defeats of function of a liver; recommendations concerning dosing are not established. The extra care is necessary at use of the medicament Difors for patients with an abnormal liver function of light and moderate severity or obstructive diseases of a gall bladder. The maximum recommended dose for patients with a slight or moderate abnormal liver function without cholestasia makes 80 mg of a valsartan.

Renal failure. Concerning use of the medicament Difors for patients with a renal failure see CONTRAINDICATIONS and USE. To patients with renal failures of easy or moderate degree (SKF of 30 ml/min. / 1.73 m ² ) dose adjustment is not required. At moderate disturbances of renal functions it is recommended to control levels of potassium and creatinine in blood. Simultaneous use of antagonists of receptors of angiotensin, including valsartan, or APF inhibitors with aliskireny is contraindicated to patients with renal failures (SKF of 60 mg/min. / 1.73 m ² ).

Quincke's disease. A Quincke's edema, including edema of laryngeal and glottis which can lead to obstruction of airways and/or edema of face, lips, drinks and/or language noted at patients who applied valsartan. Some of these patients had in the anamnesis a Quincke's edema at intake of other drugs, including APF inhibitors. Use of the medicament Difors should be stopped immediately when developing a Quincke's edema, repeated use is not recommended.

Primary hyper aldosteronism. Patients with primary hyper aldosteronism should not accept the antagonist of angiotensin ІІ valsartan as their RAAS is broken in connection with basic diseases.

Heart failure / after the postponed myocardial infarction. As a result of oppression of RAAS at sensitive patients renal failures are possible. With heavy heart failure at whom function of kidneys can depend on activity of RAAS the use of APF and MACAW inhibitors caused development of an oliguria and/or the progressing azotemia and also (in rare instances) OPN and/or death in patients. Similar results were noted at use of a valsartan. Patients with heart failure or after the postponed myocardial infarction should estimate function of kidneys. It is known that in long-term placebo - a controlled research of an amlodipin at patients with heart failure of not ischemic origin of class III and IV on classification of NYHA at use of an amlodipin the frequency of cases of edematization of lungs was higher in comparison with that at placebo use, however the considerable difference in emergence or deterioration in heart failure is not revealed. Patients with stagnant heart failure have blockers of calcium channels, including amlodipin, it is necessary to apply with care as they increase risk of cardiovascular events, a fluid lungs and lethal cases.

Stenosis of an aorta and mitral valve. As well as at treatment by other vazodilatator, especially careful patients at whom the profound stenosis of an aorta of low degree or a stenosis of the mitral valve is revealed have to be.

Double blockade of RAAS. There are data that simultaneous use of APF, MACAW inhibitors or an aliskiren increases risk of developing hypotension, a hyperpotassemia and depression of function of kidneys (including OPN). Therefore it is not recommended to carry out double blockade of RAAS by the combined use of APF, MACAW inhibitors or an aliskiren. If double blockade is absolutely necessary, it should be seen off only under supervision of the expert, with implementation of frequent careful monitoring of function of kidneys, concentration of electrolytes and the ABP. It is not necessary to apply at the same time APF and MACAW inhibitors at patients with a diabetic nephropathy. Use of the medicament Difors was not studied at patients with other diseases, except AG.

Use during pregnancy or feeding by a breast

Pregnancy. It is contraindicated to the pregnant women and women planning pregnancy to apply a diswagger. Doctors should warn the women planning pregnancy about potential risk for future child at administration of medicament and to appoint to such patients alternative antihypertensive therapy with the established safety profile concerning use during pregnancy. If pregnancy is established in the course of therapy, Difors's reception should be stopped immediately and if necessary to replace with other medicine with the established safety profile concerning use for pregnant women.

Given epidemiological researches of risk of teratogenecity after influence of APF inhibitors in the I trimester of pregnancy were not

convincing; however some increase in risk cannot be excluded. It is known that use of MACAW II in II and III trimester pregnancies induces at a fruit of the person a fetotoksichnost (depression of function of kidneys, oligogidramnion, a delay of ossification of bones of a skull) and neonatal toxicity (renal failure, arterial hypotension, a hyperpotassemia).

If with ІІ a trimester of pregnancy were applied by MACAWS of II, ultrasonography of function of kidneys and a condition of bones of a skull of a fruit is recommended.

Babies whose mothers accepted the MACAW of II have to be under careful observation in case of development of arterial hypotension.

feeding Period breast. It is unknown whether gets valsartan or amlodipin into breast milk therefore it is not recommended to use medicament during feeding by a breast; it is desirable to use alternative medicaments with the studied safety profile, especially in case of feeding by a breast of newborn or premature children. If therapy by medicament is necessary for mother, feeding by a breast should be stopped.

Fertility. Clinical trials of influence on fertility were not conducted.

Valsartan. It is known that valsartan did not cause undesirable reactions from a reproductive system in males and females of rats at oral administration in doses of 200 mg/kg/days. This dose by 6 times exceeds the maximum recommended dose for the person in terms of mg/m ² (in calculations the dose of 320 mg/days for oral administration by the patient with the body weight of 60 kg was used).

Amlodipin. At some patients who underwent treatment by blockers of calcium channels, it was reported about cases of reversible biochemical changes in heads of spermatozoa. Clinical data on an occasion of influence of an amlodipin on fertility insufficiently. It is known that in one of researches on rats undesirable reactions from fertility of males are revealed.

Ability to influence speed of response at control of vehicles or other mechanisms. Patients who accept Difors can have a dizziness or feeling of weakness after administration of medicament therefore they have to consider it during control of vehicles and work with potentially unsafe mechanisms.

Amlodipin can poorly or moderately affect ability to run vehicles or to work with other mechanisms. If patients during use of an amlodipin feel giddy, a headache, fatigue or nausea, their reaction can be broken.

Interaction

Medicamentous interactions. researches of intermedicinal interactions of medicament a diswagger with other medicines were not conducted.

Medicines at which simultaneous use it is necessary to be attentive

Other hypotensive drugs. Often used hypotensive medicaments (for example blockers of α-adrenoceptors, diuretics) and other medicines which can cause emergence of the hypotensive undesirable phenomena (for example tricyclic antidepressants, blockers of α-adrenoceptors which are applied to treatment of a benign hyperplasia of a prostate), can strengthen hypotensive action of a combination.

Simultaneous use is not recommended to

Interaction which are connected with amlodipiny

Grapefruit or grapefruit juice. Use of an amlodipin with grapefruit juice or with grapefruit as at some patients the bioavailability can be increased that will lead to strengthening of hypotensive effect of medicament is not recommended.

Medicines at which simultaneous use it is necessary to be attentive

CYP Inhibitors 3A4. Simultaneous use of an amlodipin with more or less powerful CYP inhibitors 3A4 (protease inhibitors, azolovy antifungal means, macroleads, such as erythromycin or klaritromitsin, verapamil or diltiazem) can lead to considerable strengthening of system influence of an amlodipin. Clinical manifestations of such pharmacokinetic changes can be strengthened at patients of advanced age. Clinical monitoring and correction of doses can be required.

Inductors CYP 3A4 (anticonvulsant medicaments (for example carbamazepine, phenobarbital, Phenytoinum, Primidonum), rifampicin, St. John's wort usual (Hypericum perforatum)). There are no researches concerning effects of inductors CYP 3A4 on amlodipin.

Accompanying use of inductors CYP 3A4 (for example rifampicin, a St. John's wort of usual (Hypericum perforatum)) can lead

to decrease in concentration of an amlodipin in blood plasma. It is recommended to apply with care amlodipin with inductors CYP 3A4.

Simvastatin. Reusable use of doses up to 10 mg of an amlodipin from 80 mg of a simvastatin leads to increase in exposure of a simvastatin by 77% in comparison with use of one simvastatin. It is recommended to reduce a dose of a simvastatin to 20 mg for patients who apply amlodipin.

Dantrolen (infusions). It is known that at animals lethal cases of ventrikulyarny fibrillations and cardiovascular collapses in connection with a hyperpotassemia after use of verapamil and a dantrolen in / noted century. Because of risk of development of a hyperpotassemia it is recommended to avoid simultaneous use of blockers of calcium channels, such as amlodipin, at the patients inclined to development of a malignant hyperthermia, and at treatment of malignant hyper thermies.

Medicines at which simultaneous use it is necessary to be attentive

Others. During clinical trials amlodipin did not influence pharmacokinetics of an atorvastatin, dioxine, warfarin or cyclosporine.

Interaction, connected with valsartany

Simultaneous use is not recommended to

Lities. At simultaneous use of lithium with APF or MACAW inhibitors II, including valsartan, reversible increase in plasma concentration of lithium was noted and it it is toxic