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medicalmeds.eu Medicines The hypotensive combined means (APF+ inhibitor a blocker of "slow" calcium channels). Tarka

Tarka

Препарат Тарка. Abbott Laboratories (Эбботт Лэбораториз) Нидерланды


Producer: Abbott Laboratories (Abbott Leboratoriz) Netherlands

Code of automatic telephone exchange: C09BB10

Release form: Firm dosage forms. Capsules.

Indications to use: Arterial hypertension.


General characteristics. Structure:

Trandolaprit granules

Active agent: trandolaprit 2,0 mg

Excipients: starch corn — 37,15 mg, lactoses monohydrate — 54,5 mg, povidone (K25) — 5,35 mg, the sodium stearylfumarating — 1,0 mg.

Hydrochloride verapamil tablet, film coated

Active agent: verapamil hydrochloride of 180,0 mg

Excipients: cellulose microcrystallic — 59,1 mg, sodium alginate — 240,0 mg, povidone (K30) — 36,0 mg, magnesium stearate — 2,4 mg, the water purified — 22,5 mg.

Film covering: a gipromelloza of 6 mPa — 9,576 mg, a gipromelloz of 15 mPa — 0,950 mg, a hypro rod of 7 mPa — 0,944 mg, a macrogoal of 400 — 1,485 mg, a macrogoal of 6000 — 0,266 mg, talc — 0,677 mg, silicon dioxide colloid — 0,031 mg, sodium докусат — 0,025 mg, titanium E171 dioxide — 2,546 mg;

Solid gelatin capsule (lid): titanium E171 dioxide — 1,2125 mg, dye ferrous oxide red E172 — 0,0672 mg, gelatin — 37,8419 mg, sodium lauryl sulfate — 0,0784 mg; (case): titanium E171 dioxide — 1,8187 mg, dye ferrous oxide red E172 — 0,1008 mg, gelatin — 56,7629 mg, sodium lauryl sulfate — 0,1176 mg.

Description

Solid gelatin light pink opaque capsules (size 0). Contents of capsules: (trandolaprit) granules of white color, a tablet of verapamil of a hydrochloride of white color of an oblong biconvex shape with a film covering.




Pharmacological properties:

Tarka — the combined drug which part are verapamil of the prolonged action and trandolaprit.

Trandolapril represents ethyl ether (pro-medicine) of not sulphhydryl inhibitor of an angiotensin-converting enzyme (APF) of a trandolaprilat.

Verapamil a hydrochloride — a blocker "slow calcium channels (BMKK).

Pharmacodynamics. Trandolapril

Trandolapril suppresses activity the system renin-angiotensin-aldosteronovoy (SRAA) of a blood plasma. The renin is an enzyme which is synthesized by kidneys and comes to a blood stream where causes transformation of angiotensinogen into angiotensin I (low-active decapeptide). The last turns under the influence of APF (peptidildipeptidaza) into angiotensin II — the powerful vasoconstrictor causing narrowing of arteries and increase in the arterial pressure (AP), and also stimulating secretion of Aldosteronum with adrenal glands.

The inhibition of APF leads to decrease in concentration of angiotensin II in a blood plasma which is followed by reduction of angiotonic activity and secretion of Aldosteronum. Though development of Aldosteronum decreases slightly, nevertheless, small increase in content of potassium in blood serum in combination with loss of sodium and water can be observed.

Decrease in concentration of angiotensin II on a feedback mechanism leads to increase in activity of a renin in a blood plasma. Other APF function is destruction of the kinin (bradykinin) possessing powerful vasodilating action to inactive metabolites. In this regard suppression of APF leads to increase in the circulating and fabric concentration of kallikrein-kinin system that promotes vasodilatation due to activation of system of prostaglandins. This mechanism, perhaps, partially defines anti-hypertensive effect of APF inhibitors and is the reason of development of some side effects.

At patients with arterial hypertension use of APF inhibitors leads to comparable decrease in the ABP in situation "lying" and "standing" without compensatory increase in the heart rate (HR). The General Peripheric Vascular Resistance (GPVR) decreases, cordial emission does not change or increases, the renal blood stream increases, and the glomerular filtration rate usually does not change. The sharp termination of therapy was not followed by bystry increase in the ABP. The anti-hypertensive effect of a trandolapril is shown in 1 h after intake and remains within, at least, 24 hours. In certain cases optimum control of the ABP manages to achieve only in several weeks after an initiation of treatment. At long therapy the anti-hypertensive effect remains. Trandolapril does not worsen the ABP daily profile.

Verapamil

Verapamil inhibits current of calcium ions through "slow" calcium channels of membranes of smooth muscle cells of the vessels which are carrying out and sokratitelny cardiomyocytes. Verapamil causes decrease in the ABP, both at rest, and at an exercise stress due to expansion of peripheral arterioles. As a result of decrease in OPSS (afterload) the need of a myocardium for oxygen and energy consumption decreases. Verapamil reduces contractility of a myocardium. The negative inotropic effect of drug can be compensated by reduction of OPSS. Cardiac index does not decrease, except for patients with dysfunction of a left ventricle.

Verapamil does not influence sympathetic regulation of cordial activity as does not block beta adrenoceptors. Bronchial asthma and bronkhospastichesky states are not a contraindication to purpose of verapamil.

Tarka

In researches on healthy volunteers interaction between verapamil and trandolaprily at the level of pharmacokinetic parameters or RAAS was not revealed. Therefore, a synergism of two medicines reflects their complementary pharmakodinamichesky effects. In clinical trials drug Tarka reduced the ABP more than both drugs separately.

Pharmacokinetics. Trandolapril

Trandolapril is quickly soaked up after intake. Absolute bioavailability about 10%. Time of achievement of the maximum concentration (TCmax) in a blood plasma about 1 h.

Communication trandolaprit with proteins of a blood plasma — about 80% and does not depend on concentration. The volume of distribution of a trandolapril (Vd) makes about 18 l. Elimination half-life (T1/2) less than 1 h. At repeated use the equilibrium condition of concentration of a trandolaprilat is reached approximately in 4 days, both at healthy volunteers, and at patients of young and advanced age with arterial hypertension.

In a blood plasma trandaloprit is exposed to hydrolysis before formation of an active metabolite of a trandolaprilat. TCmax of a trandolaprilat in a blood plasma makes 3-8 h Cmax and AUC (the area under a curve "concentration time") do not depend on meal. Absolute bioavailability of a trandolaprilat at reception of a trandolapril makes about 13%. Communication with blood proteins depends on concentration and varies from 65% (at concentration of 1000 ng/ml) to 94% (at concentration of 0,1 ng/ml). In an equilibrium state concentration of effective T1/2 of a trandolaprilat together with small fraction of the accepted drug varies between 15 h and 23 h that probably reflects linkng with plasma and fabric APF. Trandolaprilat has high affinity to APF. 9-14% of a dose of a trandolapril are removed in the form of a trandolaprilat by kidneys. After reception of a marked trandolapril in 33% of drug also 66% through intestines were removed by kidneys. In insignificant quantity it is removed in not changed look through kidneys (less than 0,5%).

The renal clearance of a trandolaprilat varies from 0,15 to 4 l/h depending on a dose.

Special groups of patients

Children

The pharmacokinetics of a trandolapril was not studied at children up to 18 years.

Elderly patients

Concentration of a trandolapril in a blood plasma increases at elderly patients with arterial hypertension (65 years are more senior). However, plasma concentration of a trandolaprilat and it APF-ingibiruyushchaya activity at patients with arterial hypertension of advanced age and young patients identical.

The pharmacokinetics trandolaprit also a trandolaprilat, and also APF-ingibiruyushchaya activity at elderly patients of both floors identical.

Renal failure

In comparison with healthy volunteers at the patients who are on a hemodialysis and with the clearance of creatinine (CC) less than 30 ml/min., plasma concentration of a trandolaprilat is approximately twice higher, and the renal clearance is reduced approximately by 85%. Drug dose adjustment is recommended to patients with a renal failure.

Liver failure

In comparison with healthy volunteers at patients with alcoholic cirrhosis of easy and moderate severity plasma concentration trandolaprit and the trandolaprilata increases by 9 times and twice respectively, but APF-ingibiruyushchaya activity does not change. At patients with a liver failure purpose of smaller doses of drug can be required.

Verapamil

About 90% of the verapamil dose accepted inside quickly are soaked up in a small intestine. Bioavailability makes only 22% because of the expressed effect of "primary passing" through a liver. At repeated use average bioavailability can increase up to 30%. Meal does not exert impact on bioavailability of drug. TCmax makes 4-15 h. The maximum plasma concentration of a norverapamil is reached approximately in 5-15 hours after administration of drug. Equilibrium concentration at repeated use is reached in 3-4 days once a day. Communication with proteins of a blood plasma about 90%.

T1/2 at repeated use is equal on average 8 h; 3 — 4% of a dose are removed by kidneys in not changed look. Metabolites are removed by kidneys (70%) and through intestines (16%). One of 12 metabolites found in urine is norverapamit which pharmacological activity makes 10-20% of that of verapamil; its share makes 6% of the removed drug. Equilibrium concentration norverapamit also verapamil similar. The pharmacokinetics of verapamil does not change at a renal failure. Bioavailability and T1/2 of verapamil increase at patients with cirrhosis. However the pharmacokinetics of verapamil does not change at patients with the compensated abnormal liver function. The renal failure does not exert impact on verapamil removal.

Tarka

There are no data on pharmacokinetic interaction of verapamil and a trandolapril or trandolaprilat therefore the pharmacokinetics of two drugs at combined use does not differ from that, at their appointment separately.


Indications to use:

Essential arterial hypertension (patients to whom the combination therapy is shown).


Route of administration and doses:

Inside. The capsule is swallowed entirely and washed down with water. It is the best of all to accept drug in the morning after food.

Adults

The recommended dose — one capsule a day.


Features of use:

Abnormal liver function

As trandolaprit it is metabolized in a liver with formation of an active metabolite, patients with an abnormal liver function should appoint drug with care and at careful observation of the doctor.

Arterial hypotension

At patients with uncomplicated arterial hypertension after reception of the first dose of a trandolapril or increase in a dose of drug, and also after its increase noted development of the arterial hypotension which was followed by clinical symptoms. Risk of arterial hypotension higher at the patients who lost a lot of water and salts as a result of long therapy by diuretics, restrictions of consumption of table salt, dialysis, diarrhea or vomiting. At such patients before therapy trandolaprily it is necessary to stop therapy by diuretics and to fill the volume of the circulating blood (VCB) and/or content of sodium.

Agranulocytosis/oppression of a marrowy hemopoiesis

At treatment APF inhibitors described cases of an agranulocytosis and oppression of function of marrow. These phenomena meet at patients with a renal failure, especially with general diseases of connecting fabric more often. At such patients (for example, with a system lupus erythematosus or a scleroderma) reasonablly regularly to control number of leukocytes in blood and urine protein content, especially at a renal failure, treatment by corticosteroids and antimetabolites.

Quincke's disease

Trandolapril can cause a Quincke's disease of the person, language, a throat and/or throat. There are data that APF inhibitors cause a Quincke's disease in patients of negroid race more often.

Against the background of treatment APF inhibitors also noted cases of a Quincke's disease of intestines. Such opportunity should be considered at development of the abdominal pains (which are followed by nausea or vomiting or without these symptoms) against the background of reception of a trandolapril.

Heart failure

Verapamil therefore use of the combined drug should be avoided at patients with heavy dysfunction of a left ventricle (for example, with fraction of emission of a ventricle less than 30%, increase in pressure of jamming of pulmonary capillaries more than 20 mm of mercury is a part of drug Tarka. or the expressed symptoms of chronic heart failure) and patients with any degree have dysfunctions of a left ventricle if they receive beta adrenoblockers.

Special groups of patients

Drug Tarka was not studied at children up to 18 years therefore its use in this age group is not recommended.

General measures of precaution

At some patients receiving diuretics (especially in the first days of treatment), after purpose of a trandolapril or increase in its dose, sharp decrease in the ABP is observed.

Renal failure

At inspection of patients with arterial hypertension it is necessary to estimate function of kidneys always. With clearance of creatinine less than 30 ml/min. are required from patients purpose of smaller doses of a trandolapril.

At patients with a renal failure, chronic heart failure, a bilateral stenosis of renal arteries or a stenosis of an artery of the only kidney (for example, after its transplantation) the risk of deterioration in renal function is increased. At some patients with arterial hypertension, without renal failure, at purpose of a trandolapril in a combination with diuretic increase in an urea nitrogen in blood and serumal creatinine can be observed.

Hyperpotassemia

At patients with arterial hypertension, especially with a renal failure, drug Tarka can cause a hyperpotassemia.

Surgical intervention / general anesthesia

At surgeries or carrying out the general anesthesia using the drugs causing arterial hypotension trandolaprit can block the formation of angiotensin II connected with compensatory emission of a renin.

Desensitization

At the patients receiving APF inhibitors during a desensitization course (for example, poison of Hymenoptera), development of life-threatening anaphylactic reactions is in rare instances possible.

LPNP-aferez

When carrying out LPNP-aferez's at the patients receiving APF inhibitors development of zhizneugrozhayushchy anaphylactic reactions was observed.

INFLUENCE ON ABILITY TO MANAGE MOTOR TRANSPORT AND TO WORK WITH MECHANISMS

It is necessary to be careful at control of vehicles and occupation other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions, especially in an initiation of treatment. Tark's drug can promote increase in blood alcohol content and slow down its removal. In this regard effects of alcohol can be strengthened.


Side effects:

Side effects which had possible or probable communication with administration of drug Tarka during clinical trials are included below.

Disturbances from a nervous system: often (from ≥1/100 to <1/10): headache, dizziness.

Disturbances from cardiovascular system: often (from ≥1/100 to <1/10): atrioventricular block of the I degree.

Disturbances from respiratory system, bodies of a thorax and a mediastinum: often (from ≥1/100 to <1/10): cough.

Disturbances from digestive tract: often (from ≥1/100 to <1/10): lock.

General frustration: often (from ≥1/100 to <1/10): adynamy.

Except the reactions revealed during clinical trials in the course of post-registration use the following side effects were revealed: Infectious diseases: bronchitis.

Disturbances from blood and lymphatic system: leukopenia, thrombocytopenia.

Disturbances from a metabolism: hyperpotassemia.

Disturbances of mentality: alarm, sleeplessness.

Disturbances from a nervous system: disturbance of balance, paresthesia, drowsiness, syncope.

Disturbances from an organ of sight: a vision disorder, "veil" before eyes.

Labyrinth disturbances: dizziness.

Disturbances from cardiovascular system: total atrioventricular block, rest stenocardia, bradycardia, heart consciousness, tachycardia.

Disturbances from vessels: arterial hypotension, a hyperemia of integuments, rushes of blood to face skin.

Disturbances from respiratory system, bodies of a thorax and a mediastinum: asthma, nose congestion.

Disturbances from digestive tract: nausea, diarrhea, dryness of a mucous membrane of an oral cavity.

Disturbances from skin and hypodermic fabrics: Stephens-Johnson's syndrome, Quincke's disease, skin itch, rash.

Disturbances from skeletal and muscular and connecting fabric: arthralgia, mialgiya.

Disturbances from kidneys and urinary tract: pollakiuria, polyuria.

Disturbances from generative organs: erectile dysfunction.

General frustration: stethalgia, hypostases, weakness.

Laboratory and tool data: increase in activity of a lactate dehydrogenase, activity of an alkaline phosphatase, concentration of creatinine, concentration of urea, activity of aspartate aminotransferase, activity of alaninaminotranspherase of blood.

Additional significant side effects which were observed at verapamil use:

Disturbances from immune system: hypersensitivity.

Disturbances from endocrine system: giperprolaktinemiya.

Disturbances from heart: atrioventricular block of I, II, III degrees, stop of a sinus node ("sine arrest"), heart failure.

Disturbances from the alimentary system: a hyperplasia of gums, an abdominal pain, discomfort in a stomach.

Disturbances from skin and hypodermic fabrics: small tortoiseshell.

Disturbances from a mammary gland: gynecomastia, galactorrhoea.

There are several separate messages on cases of development of paralysis (tetraparesis) connected with combined use of verapamil and colchicine. It could be connected with penetration of colchicine through a blood-brain barrier in connection with suppression of activity of an isoenzyme of CYP3A4 and P-glycoprotein under the influence of verapamil. Combined use of colchicine and verapamil is not recommended.

Additional significant side effects which were observed at use of a trandolapril:

Disturbances from blood and lymphatic system: agranulocytosis.

Disturbances from immune system: hypersensitivity.

Disturbances from digestive tract: vomiting, abdominal pain, pancreatitis.

Disturbances from skin and hypodermic fabrics: alopecia.

General frustration: fever.

Side effects which were registered at use of other APF inhibitors are listed below:

Disturbances from blood and lymphatic system: pancytopenia.

Disturbances from a nervous system: passing disturbance of cerebral circulation.

Disturbances from heart: myocardial infarction, cardiac standstill.

Disturbances from vessels: hematencephalon.

Disturbances from the alimentary system: intestinal Quincke's disease.

Disturbances from skin and hypodermic fabrics: mnogoformny erythema, toxic epidermal necrolysis.

Disturbances from kidneys and urinary tract: acute renal failure.

Laboratory and tool data: decrease in hemoglobin and hematocrit.


Interaction with other medicines:

The interactions caused by verapamil:

The researches in vitro demonstrate that verapamil is metabolized under the influence of isoenzymes of CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18 of P450 cytochrome.

Verapamil is inhibitor of an isoenzyme CYP3A4 and R-glycoprotein. Clinically significant interaction was noted at simultaneous use with CYP3A4 isoenzyme inhibitors, at the same time increase in concentration of verapamil in a blood plasma while inductors of an isoenzyme CYP3A4 reduced concentration of verapamil in a blood plasma was observed. Respectively, at simultaneous use of similar means, it is necessary to consider a possibility of this interaction.

In the table the data on medicinal interaction caused by the content of verapamil are generalized.

 
Drug                                       Possible action on verapamil or verapamil
                                                     on other drug at simultaneous use
Alpha adrenoblockers
Prazozinum                                  Increase in Cmax of Prazozinum (~ 40%), does not influence Prazozinum T1/2.
Terazozin                                 Increase in AUC of a terazozin (~ 24%) and Cmax (~ 25%).
Antiarrhytmic means
Flekainid                                the Minimum action on plasma clearance
                                                  flekainida (<~ 10%); does not influence plasma clearance of verapamil.
Quinidine                                    Decrease in peroral clearance of quinidine (~ 35%).
Bronkhodilatiruyushchy means
Theophylline                                Reduction of peroral and system clearance (~ 20%).
                                                  The smoking patients have a decrease on ~ 11%.
Anticonvulsants
Carbamazepine                           Increase in AUC carbamazepine (~ 46%) at patients with
                                                  resistant partial epilepsy.
Antidepressants
Imipraminum                               Increase in AUC of Imipraminum (~ 15%)

                                                   Does not influence concentration of an active metabolite, desipramine.
Hypoglycemic means for intake
Glyburidum                                     Increases Glyburidum Cmax (~ 28%), AUC (~ 26%).
Antimicrobic means
Klaritromitsin                            Vozmozhno increase in concentration of verapamil.
Erythromycin                               increase in concentration of verapamil is possible.
Rifampicin                              Decreases AUC (~ 97%), Cmax (~ 94%), bioavailability
                                                  (~ 92%) verapamil.
Telitromitsin                           Vozmozhno increase in concentration of verapamil.
Antineoplastic means
Doxorubicine                            Increases AUC (89%) and Cmax (61%) of doxorubicine
                                                 at verapamil reception inside at patients with small-celled lung cancer
                                                   Administration of verapamil intravenously at patients with progressing
                                                  new growths does not influence plasma clearance of a doksirubitsin.
Barbiturates
Phenobarbital                            Increases peroral clearance of verapamil ~ by 5 times.
Benzodiazepines and other tranquilizers
Buspiron                                   Uvelichivayetsya AUC and Cmax of a buspiron ~ by 3,4 times.
Midazolam                                Increases AUC (~ by 3 times) and Cmax (~ twice) midazolam.
Beta adrenoblockers
Metoprolol                              Uvelichivayetsya AUC (~ 32,5%) and Cmax (~ 41%) metoprolola
                                                  at patients with stenocardia.
Propranolol                            Increases AUC (~ 65%) and Cmax (~ 94%) propranolol
                                                     at patients with stenocardia.
Cardiac glycosides
Digitoxin                                 Decreases the general clearance (~ 27%) and extrarenal clearance
                                                    (~ 29%) digitoxin.
Digoxin                                    At healthy volunteers Cmax increase (on ~ 45-53%),
                                                    Css (equilibrium concentration) (on ~ 42%) and AUC (on ~ 52%) digoxin.
                                                    Digoxin dose decline.
Antagonists of H2 of receptors
Cimetidinum                                    Increases AUC R-(~ 25%) and S-(~ 40%) verapamil with
                                                      corresponding reduction of clearance of R-and S-verapamil.
Immunodepressants
Cyclosporine                               Increases AUC, Css, Cmax (on ~ 45%) cyclosporine.
Sirolimus                                   Vozmozhno increase in concentration of a sirolimus.
Takrolimus                                  Vozmozhno increase in concentration of a takrolimus.
Everolimus                                   Vozmozhno increase in concentration of an everolimus.
Hypolipidemic means inhibitors of HMG-CoA reductase
Atorvastatin                                 Vozmozhno increase in concentration of an atorvastatin,
                                                      increase in concentration of verapamil on ~ 42,8% in a blood plasma.
Lovastatin                                   Vozmozhno increase in concentration of a lovastatin.
Simvastatin                                Uvelichivayetsya AUC (~ by 2,6 times) and Cmax (~ by 4,6 times) a simvastatina.
Antagonists of receptors of serotonin
Almotriptan                                Uvelichivayetsya AUC (~ 20%) and Cmax (~ 24%) almotriptana.
Uricosuric means
Sulfinpyrazonum                               Increase in peroral clearance of verapamil (~ by 3 times),
                                                      decrease in its bioavailability (~ 60%).
Others
Grapefruit juice                       Increase in AUC R-(~ 49%) and S-(~ 37%) verapamil and Cmax R-
                                                        (~ 75%) and S-(~ 51%) verapamil. T 1/2 and renal clearance
                                                       did not change.
The St. John's Wort which is made a hole                Decreases AUC R-(~ 78%) and S-(~ 80%) verapamil with
                                                            corresponding decrease in Cmax.

Other possible types of interaction of verapamil

Antiarrhytmic means, beta adrenoblockers

Strengthening of adverse influence on cardiovascular system (more expressed atrioventricular block, more considerable urezheniye of ChSS, development of symptoms of heart failure and strengthening of arterial hypotension) is possible.

Quinidine

Strengthening of hypotensive action.

At patients with a hypertrophic subaortic stenosis the fluid lungs can develop.

Hypotensive, diuretics, vazodilatator

Strengthening of anti-hypertensive action.

Prazozinum, теразозин

Strengthening of hypotensive action.

Means for treatment of HIV infection

Some drugs for treatment of HIV - infections, such as ритонавир, can inhibit verapamil metabolism that leads to increase in its concentration in a blood plasma. At simultaneous use the dose of verapamil has to be lowered.

Carbamazepine

Increase in concentration of carbamazepine in a blood plasma that can be followed by side effect inherent to carbamazepine — a diplopia, a headache, an ataxy or dizziness.

Lithium

Increase in a neurotoxicity of lithium. Control of concentration of lithium in blood serum is necessary.

Rifampicin

Can reduce hypotensive effect of verapamil.

Colchicine

Colchicine is substrate for an isoenzyme of CYP3A4 and a P-glycoprotein. It is known that verapamil suppresses activity of an isoenzyme of CYP3A and P-glycoprotein. Therefore at simultaneous use with verapamil concentration of colchicine in blood can increase considerably. Combined use of drugs is contraindicated.

Dantrolen

At patients with coronary heart disease at purpose of verapamil after reception of a dantrolen cases of a hyperpotassemia and suppression of function of a myocardium were noted. Combined use of drugs is contraindicated.

Sulfinpyrazonum

Can reduce hypotensive effect of verapamil.

Muscle relaxants

The effect of muscle relaxants can amplify.

Acetylsalicylic acid (Aspirin) as antiagregantny means

Tendency to bleedings can increase.

Ethanol (alcohol)

Increase in concentration of ethanol in a blood plasma.

Inhibitors of HMG-CoA reductase (statines)

Simvastatin/atorvastatin/lovastatin

The patients receiving verapamil, treatment by HMG-CoA reductase inhibitors (i.e. simvastatinom/atovastatinom/lovastatiny) should begin with perhaps lower doses with their gradual increase in the course of therapy. If the patients who are already receiving HMG-CoA reductase inhibitors need to appoint verapamil, then it is necessary to reconsider and lower their doses according to concentration of cholesterol in blood serum.

Fluvastatin, правастатин and розувастатин are not metabolized under the influence of CYP3A4 isoenzymes therefore their interaction with verapamil is least probable.

The interactions caused trandolaprily:

Diuretics

Diuretics or other antihypertensives can strengthen hypotensive action of a trandolapril. Kaliysberegayushchy diuretics (Spironolactonum, amiloride, Triamterenum) or drugs of potassium increase risk of a hyperpotassemia, especially at patients with a renal failure. Trandolapril can reduce loss of potassium at combined use with thiazide diuretics.

Hypoglycemic means

Simultaneous use of a trandolapril, as well as any APF inhibitors, with hypoglycemic means (insulin or hypoglycemic means for intake) can strengthen hypoglycemic effect and lead to increase in risk of a hypoglycemia.

Lithium

Trandolapril can worsen lithium removal. Control of concentration of lithium in blood serum is necessary.

Others

At use during a hemodialysis of high-flowing membranes from polyacrylonitrile at the patients receiving APF inhibitors anaphylactoid reactions were described. At the patients receiving APF inhibitors it is necessary to avoid use of membranes of this kind during a hemodialysis.

Non-steroidal anti-inflammatory drugs (NPVP) can reduce hypotensive action of a trandolapril therefore at accession of NPVP to therapy trandolaprily or their cancellation control of the ABP is necessary.

APF inhibitors can strengthen hypotensive action of some means for an inhalation anesthesia.

Allopyrinolum, cytostatics, immunosuppressive means and system corticosteroids or procaineamide can increase risk of development of a leukopenia at treatment by APF inhibitors.

Antacids can reduce bioavailability of APF inhibitors.

Anti-hypertensive effect of APF inhibitors can be reduced at joint purpose of sympathomimetics. In such cases careful monitoring is necessary.

As well as in case of use of any other antihypertensives, joint purpose of neuroleptics or tricyclic antidepressants increases risk of development of orthostatic hypotension.


Contraindications:

Hypersensitivity to any component of drug or to the APF any other inhibitor; the Quincke's disease in the anamnesis connected with reception of APF inhibitors; hereditary and idiopathic Quincke's edema; cardiogenic shock; chronic heart failure of III and IV functional classes on NYHA classification; an atrioventricular block of II or III degrees (except for patients with an artificial pacemaker); sinuatrial blockade; acute myocardial infarction; a sick sinus syndrome (except for patients with an artificial pacemaker); acute heart failure; a fibrillation/atrial flutter at patients with a WPW-syndrome; the expressed bradycardia; heavy arterial hypotension; heavy renal failure (KK less than 30 ml/min.); pregnancy; feeding period breast; age up to 18 years (efficiency and safety are not established); concomitant use with colchicine and dantroleny; an aortal stenosis or obstruction of the taking-out path of a left ventricle; hypertrophic subaortic stenosis; simultaneous use with beta adrenoblockers (intravenously) (except for the patients undergoing treatment in intensive care unit); a lactose intolerance, deficit of lactase, a syndrome of glyukozo-galaktozny malabsorption (drug contains lactose).

With care

Hyperpotassemia; abnormal liver functions and/or functions of kidneys (clearance of creatinine more than 30 ml/min.); at general diseases of connecting fabric (including a system lupus erythematosus, a scleroderma) especially against the background of treatment by corticosteroids and antimetabolites — risk of development of an agranulocytosis and neutropenia; oppression of a marrowy hemopoiesis; atrioventricular block of the I degree; bradycardia; arterial hypotension; the states which are followed by decrease in the volume of the circulating blood (VCB) (including diarrhea, vomiting); bilateral stenosis of renal arteries; a stenosis of an artery of the only kidney (for example, after transplantation); a state after transplantation of a kidney; the diseases which are followed by neuromuscular transmission disturbance (a myasthenia гравис, Lambert-Eaton's syndrome, heavy muscular dystrophy of Dyushen); at the patients keeping to a diet with restriction of table salt; before the procedure of an aferez of lipoproteins of the low density (LPNP), simultaneous performing the desensibilizing therapy by allergens (for example, poison of Hymenoptera) — risk of development of anaphylactoid reactions (in certain cases — zhizneugrozhayushchy); surgical intervention (the general anesthesia) — risk of development of excessive decrease in the ABP, a hemodialysis with use of high-flowing poliakrilnitrilovy membranes — risk of development of anaphylactoid reactions.

USE AT PREGNANCY AND DURING BREASTFEEDING

Pregnancy

Safety of use of drug Tarka for pregnant women is not established. Use at pregnancy is contraindicated. There are separate observations about development of a hypoplasia of lungs in newborns, a delay of pre-natal fetation, an open arterial channel and hypoplasia of bones of a skull after use of APF inhibitors during pregnancy.

There are no data on teratogenic or embrio/fetotoksichny effects of APF inhibitors in the I trimester of pregnancy, however completely it is impossible to exclude such opportunity. At the patients planning pregnancy it is necessary to appoint hypotensive drugs for which safety of use during pregnancy was proved unless use of APF inhibitors is necessary. If pregnancy occurs in the course of APF inhibitor reception, it is necessary to cancel and appoint it immediately more suitable treatment.

It is known that at use of APF inhibitors in the second and third trimester of pregnancy perhaps fetotoksichesky effect of drugs (a renal failure, an oligoamnios, delay of ossification of bones of a skull) and toxic impact on the newborn (a renal failure, arterial hypotension, a hyperpotassemia). In case of use of a trandolapril, since the second trimester of pregnancy, ultrasonic assessment of function of kidneys of a fruit and a condition of a skull is recommended. Newborns, whose mothers during pregnancy accepted APF inhibitors, have to be under observation of the doctor for an exception of arterial hypotension.

Breastfeeding period

Use of drug of Tark during breastfeeding is contraindicated. Verapamil is emitted in breast milk. Data on use of a trandolapril during breastfeeding are absent. It is necessary to give preference to drugs with the studied safety profile for this group of patients, especially when feeding newborn and premature children.


Overdose:

In clinical trials the maximum dose of a trandolapril made 16 mg. At the same time signs of its intolerance were not noted.

The symptoms of overdose of drug of Tark caused by verapamil: the expressed decrease in the ABP, an atrioventricular block, bradycardia and an asystolia.

Death cases from overdose are registered.

The symptoms of overdose of drug of Tark caused trandolaprily: the expressed decrease in the ABP, shock, a stupor, bradycardia, electrolytic disturbances and a renal failure.

Treatment: symptomatic

Treatment of overdose of verapamil includes parenteral administration of drugs of calcium, use of beta-adrenergic agonists and a gastric lavage. Considering the slowed-down absorption of drug of the prolonged action, patients are observed during to 48 h; during this period hospitalization can be required.

Verapamil is not removed at a hemodialysis.


Storage conditions:

At a temperature not above 25 °C. To store in the place, unavailable to children. Period of validity 3 years. Not to apply after a period of validity.


Issue conditions:

According to the recipe


Packaging:

Capsules of the prolonged action of 2 mg + 180 mg.

On 5, 7, 10 or 14 capsules in the blister from foil PVH/A1-. 1, 2, 3 or 4 blisters together with the application instruction in a cardboard box.



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