Tarka retard pills 4mg + 240mg №28

Instructions for medical use

medicinal product

ТАРКА®

Tarka

Not

Tablets with modified release, film coated 2 mg / 180 mg, 4 mg / 240 mg

Composition

One pill with modified release, film coated contains

active substances:

Trandolapril 2 mg and Verapamil hydrochloride 180 mg;

Trandolapril 4 mg and Verapamil Hydrochloride 240 mg;

Excipientsin trandolapril layer: corn starch, lactose monohydrate, povidone (Mr 29000, K value 25), hypromellose (type 2910, viscosity 6 mPa · s), sodium stearyl fumarate

excipients in the verapamil layer: microcrystalline cellulose, sodium alginate, povidone (Mr 45000, K value 30), Magnesium stearate, purified water

film coating tablets: hypromellose (type 2910, viscosity 6 mPa • s), hypromellose (type 2910, viscosity 15 mPa • s), hydroxypropylcellulose (viscosity 7 mPa • s), macrogol 400, macrogol 6000, talc, silicon dioxide anhydrous colloidal dioxide, sodium dokuzat, titanium dioxide (E 171), iron oxide red (E 172), iron oxide yellow (E 172), iron oxide black (E 172).

2 mg / 180 mg: Oval-shaped tablets, film-coated pink color, with an engraving of the Knoll trademark "182" on one side;

4 mg / 240 mg: Red-brown film-coated oval-shaped pills with an engraving of the Knoll “244” trademark on one side.

Means affecting the system of renin-angiotensin. ACF inhibitors in combination with other drugs. ACF inhibitors in combination with Calcium channel blockers. Trandolapril + verapamil.

ATC code C09BB10

Pharmacology

Tarka pills are two-layer: one layer is designed for the slow release of verapamil hydrochloride, the other for the immediate release of trandolapril.

Since the kinetic interaction between verapamil and trandolapril or trandolaprilat has not been established, the individual kinetic parameters of these two drugs are generally applied to this combination drug.

Trandolapril

After oral administration, trandolapril is very rapidly absorbed. Maximum concentrations of trandolapril in plasma are reached approximately one hour after taking the drug. Absolute bioavailability of trandolapril is approximately 10%.

The average values ​​of the maximum concentration of trandolaprilat in the blood plasma are reached after about 3-8 hours. Absolute bioavailability of trandolaprilat after taking Trandolapril is approximately 13%. Meal does not affect the maximum concentration (Cmax) or the area under the curve (AUC) of trandolaprilat.

The time to reach peak plasma concentration is about 30 minutes. Trandolapril is very rapidly excreted from blood plasma, its half-life is less than 1 hour. Trandolapril is hydrolyzed in plasma to trandolaprilat, a specific inhibitor of the angiotensin-converting enzyme (ACE).
Absolute bioavailability of trandolaprilat is 13%. The amount of trandolaprilat formed does not depend on food intake. The time to reach the average peak plasma concentration of trandolaprilat is 3-8 hours. The binding of trandolaprilat to plasma proteins is approximately 80% and does not depend on the concentration. The distribution of trandolapril is approximately 18 liters. Binding to trandolaprilat proteins depends on its concentration and varies in the range from 65% at a concentration of 1000 ng / ml to 94% at a concentration of 0.1 ng / ml, which indicates saturation of the binding with increasing concentration of trandolaprilat. Trandolapril undergoes hydrolysis with the participation of esterases to form the active dibasic metabolite of trandolaprilat.

In healthy volunteers, trandolapril is rapidly excreted from plasma, while the average half-life does not exceed one hour. With repeated administration of trandolapril, the equilibrium concentration of trandolaprilat is reached after about 4 days in both healthy volunteers and in young patients and elderly patients suffering from arterial hypertension.The effective half-life of trandolaprilat in equilibrium is in the range from 15 to 23 hours, given the small fraction of the drug taken, probably associated with plasma and tissue ACE.

In humans, after ingestion of a drug with a radioactive label, 33% of the radioactivity was detected in the urine and 66% in the feces. Approximately 9-14% of the accepted dose of trandolapril is excreted in the urine in the form of trandolaprilat. A minor amount of trandolapril is excreted unchanged in the urine (<0.5%). The total plasma clearance of trandolapril and trandolaprilat after intravenous administration of 2 mg is approximately 52 l / h and 7 l / h, respectively. The kidney clearance of trandolaprilata varies from 0.15 to 4 liters per hour, depending on the dose.

Special patient groups

Children: Trandolapril pharmacokinetics has not been studied in patients under the age of 18 years.

Elderly patients and gender: Trandolapril pharmacokinetics has been studied in elderly patients (over 65 years old) of both sexes. In elderly patients with arterial hypertension, the concentration of trandolapril in the blood plasma increases, but the concentration of trandolaprilat in the blood plasma and the degree of suppression of ACE activity do not differ in elderly patients and young patients with arterial hypertension. The pharmacokinetics of trandolapril and trandolaprilat and the degree of suppression of ACE activity are comparable in men and women of older age suffering from arterial hypertension.

Race: Pharmacokinetic differences in members of different races have not been studied.

Renal failure: Compared with healthy individuals in patients with renal insufficiency, the concentration of trandolapril and plasma trandolaprilat is about two times higher. In patients with creatinine clearance less than 30 ml / min and in patients on hemodialysis, renal clearance is reduced by about 85%. Dose adjustment is recommended in patients with impaired renal function.

Hepatic insufficiency: Patients with mild and moderate alcoholic liver cirrhosis had tradolapril and trandolaprilat concentrations in the blood plasma after ingestion were 9 and 2 times higher than in healthy individuals, but the degree of suppression of ACE activity did not change. Patients with hepatic impairment should use lower doses.

Verapamil

More than 90% of orally administered verapamil is absorbed. The average bioavailability is 22%, after repeated administration may increase up to 30%.

Eating does not affect the bioavailability of verapamil.

The average time to reach peak plasma concentration is 4–15 hours. The peak concentration of norverapamil in the blood plasma is reached approximately 5–15 hours after dosing.

Binding of verapamil to plasma proteins is approximately 90%.

The half-life after repeated administration is 8 hours. 3-4% of the administered dose is excreted by the kidneys in an unchanged condition.The metabolite is excreted in the urine (70%) and feces (16%).

Special patient groups

Children: information on pharmacokinetics in children is limited. After intravenous administration, the average half-life of verapamil was 9.17 hours, and the average clearance was 30 l / h, whereas in an adult patient with a body weight of 70 kg it was 70 l / h. Concentration in the blood plasma in a state of equilibrium is somewhat lower after the drug is taken orally in children as compared with adults.

The elderly: with aging, the pharmacokinetics of verapamil changes in patients suffering from arterial hypertension. The elimination half-life may increase in elderly people. It is established that the effect of verapamil does not depend on the age of the patient.

Renal failure: In comparative studies in patients with end-stage renal failure and in healthy individuals, the effect of renal dysfunction on verapamil pharmacokinetics has not been established. Verapamil and norverapamil are slightly excreted by hemodialysis.

Hepatic insufficiency: the bioavailability and half-life of verapamil is increased in patients with cirrhosis of the liver. However, the kinetics of verapamil does not change in patients with compensated liver dysfunction.

Tarka is a fixed combination of an ACE inhibitor, trandolapril and a calcium antagonist, verapamil.

Trandolapril

Trandolapril blocks the plasma renin-angiotensin-aldosterone system (RAS), which causes a decrease in plasma angiotensin II levels and leads to a decrease in vasopressor activity and a decrease in aldosterone secretion. Although the latter decrease is not significant, a slight increase in serum potassium concentration may occur along with loss of sodium and fluid. Trandolapril also contributes to peripheral vasodilation by activating the prostaglandin system. In patients with arterial hypertension, the use of ACE inhibitors leads to a decrease in blood pressure both in the prone position and in the standing position, about the same, without a compensatory increase in heart rate. Peripheral arterial resistance decreases without change or with an increase in cardiac output.

An increase in renal blood flow is observed, but the glomerular filtration rate remains unchanged. Achieving optimal reduction in blood pressure may require several weeks of therapy in some patients. Antihypertensive effects persist during long-term therapy. Abrupt cancellation of therapy is not accompanied by a rapid increase in blood pressure.

The antihypertensive effect of trandolapril is established 1 hour after the dose has been taken and lasts for 24 hours, without affecting the circadian rhythm of the arterial pressure.

Verapamil

The pharmacological action of verapamil is due to the inhibition of calcium ion current through the slow calcium channels of the cell membrane of vascular smooth muscle and myocardial cells.

The mechanism of action of verapamil provides the following effects.

1. Arterial vasodilation.

Verapamil lowers blood pressure, both at rest and during physical activity due to the expansion of peripheral arterioles.

Reducing the total resistance of peripheral vessels (afterload) leads to a decrease in myocardial oxygen demand and energy.

2. Reduction of myocardial contractility.

The negative inotropic effect of verapamil is compensated by a decrease in total peripheral resistance. Cardiac index does not decrease, except for patients with left ventricular dysfunction.

Verapamil does not affect the sympathetic regulation of the heart, because it does not block beta-adrenergic receptors. Therefore, bronchospasm and similar conditions are not a contraindication for the use of verapamil.

Tarka®

Not detected pharmacokinetic or RAS interactions between verapamil and trandolapril. Therefore, the observed synergistic activity of these two active ingredients is due to their complementary pharmacological actions.

In clinical studies, Tarka® was more effective in reducing high blood pressure than each of its active ingredients separately.

The use of a combination of an ACE inhibitor and an angiotensin-II receptor blocker has been studied in two large randomized controlled trials of ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial - an ongoing study of the effects of telmisartan in monotherapy and in combination with ramipril on global endpoints) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes - perennial issues of nephropathy in diabetes). The ONTARGET study was conducted among patients with a history of cardiovascular and cerebrovascular diseases or type 2 diabetes mellitus, accompanied by symptoms of target organ damage. The VA NEPHRON-D study was conducted among patients with type 2 diabetes mellitus and diabetic nephropathy. No significant beneficial change in mortality and outcomes related to the kidneys and cardiovascular system was shown in these studies. However, compared with monotherapy, there was an increased risk of hyperkalemia, acute kidney damage and / or hypotension. Given the similar pharmacodynamic properties, these results are also applicable to other ACE inhibitors and angiotensin II receptor blockers. For this reason, ACE inhibitors and angiotensin-II receptor blockers should not be used simultaneously in patients with diabetic nephropathy.

The ALTITUDE study (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) - a study of aliskiren in type 2 diabetes mellitus using cardiovascular and renal lesions as the end pointswas developed to explore the benefits of adding aliskiren to standard therapy from an ACE inhibitor or angiotensin-II receptor blocker in patients with type 2 diabetes with chronic kidney disease or cardiovascular disease, or both. This study was prematurely completed due to an increased risk of undesirable outcomes. The frequency and deaths caused by cardiovascular diseases and stroke in numerical terms were higher in the aliskiren group than in the placebo group; serious adverse events (hyperkalemia, hypotension, and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.

- Essential arterial hypertension in patients in whom blood pressure is normalized with trandolapril and verapamil separately in the same doses, or with inadequate control of blood pressure when using only one of the active components of the drug.

For oral administration

Dosage

Adults are recommended to use 1 pill 1 time per day.

Special patient groups

Children: the safety and efficacy of the drug Tarkak in children and adolescents has not been established. Therefore, the use in this age group is not recommended.

Elderly people: some elderly patients may have a more pronounced effect of lowering blood pressure due to higher systemic bioavailability compared with younger patients suffering from arterial hypertension.

Mode of application

The pill should be swallowed whole with water, preferably after breakfast.

These adverse reactions have been reported in clinical studies and in post-marketing practice. Adverse reactions are classified by message frequency: frequent> 1/100 and <1/10, infrequent> 1/1000 and <1/100, rare> 1/10 000 and <1/1000, very rare <1/10 000 , including isolated cases.

Often

- dizziness, headache

- vestibular vertigo

- AV block I degree

- cough

- constipation

- hypotension

- orthostatic hypotension

- shock

- flushing

- hot flashes

Infrequently

- hypersensitivity

- hyperlipidemia

- tremor, drowsiness

- cardiopalmus

- nausea, diarrhea, abdominal pain, gastrointestinal upset

- abnormal liver function tests

- rash, itching, swelling of the face, hyperhidrosis

- polyuria

- chest pain

Seldom

- herpes simplex

- anorexia

- fainting

- hyperbilirubinemia

- alopecia, skin disease

- azotemia

Very rarely

- bronchitis

- pancytopenia, leukopenia, thrombocytopenia

- depression, anxiety, anxiety, aggressive behavior

- intracerebral hemorrhage, loss of consciousness, insomnia, imbalance, hyperesthesia, paresthesia, dysgeusia

- visual impairment, blurred vision

- angina pectoris, bradycardia, tachycardia, atrial fibrillation, heart failure , cardiac arrest

- fluctuations in blood pressure

- bronchial asthma, shortness of breath, swelling of the mucous membrane of the paranasal sinuses

- vomiting, dry throat, dry mouth, pancreatitis

- hepatitis, jaundice, cholestasis

- angioedema, erythema multiforme, psoriasis, dermatitis, urticaria

- arthralgia, myalgia, muscular weakness

- acute renal failure *

- erectile dysfunction, gynecomastia

- edema, peripheral edema, asthenia, fatigue

- increased activity of transaminases, increased activity of alkaline phosphatase, increased activity of lactate dehydrogenase, increased activity of lipase, increased concentration of potassium in the blood, increased concentration of immunoglobulin, increased activity of gamma-glutamyltransferase

Unknown (cannot be determined based on available data)

- upper respiratory tract infection, pharyngitis, sinusitis *, rhinitis *, glossitis *, urinary tract infections

- agranulocytosis, decrease in hemoglobin level, decrease in hematocrit, hemolytic anemia *

- increased appetite, hyperkalemia, hypercholesterolemia, hyperglycemia,

hyponatremia, hyperuricemia, gout, fermentopathy

- insomnia, sleep disorder *, hallucinations, decreased libido, confusion *

- transient ischemic attack *, acute cerebrovascular accident, myoclonus, migraine, extrapyramidal disorder,

paralysis (tetraparesis)

- blepharitis, conjunctival edema, visual impairment

- myocardial infarction, atrioventricular block (2, 3 degree), sinus bradycardia, stop of the sinus node, asystole, arrhythmias, ventricular tachycardia, myocardial ischemia, pathological changes on the electrocardiogram

- arterial hypertension, angiopathy, peripheral artery disease, varicose veins

- bronchospasm, inflammation of the upper respiratory tract, edema of the mucous membrane of the upper respiratory tract, productive cough, pharyngitis, oropharyngeal pain, nose bleeding, respiratory disease

- discomfort in the abdomen, dyspepsia , gastritis, flatulence, hypertrophic gingivitis, vomiting of blood, intestinal obstruction ,

angioedema of the intestines *

- cholestatic jaundice *

- Stevens-Johnson syndrome, toxic epidermal necrosis, purpura,

Eczema, acne, dry skin

- back pain, pain in the limbs, osteoarthritis, muscle cramps

- pollakiuria

- hyperthermia, poor health, malaise

- increased concentration of creatinine in the blood, increased concentration of urea in the blood, increased concentration of prolactin in the blood.

* Specified adverse reactions of drugs class ACE.

- hypersensitivity to tradolapril or any other ACE inhibitor and / or verapamil or any of the excipients

- use in children and adolescents (under 18)

- use in patients simultaneously receiving β-blockers for intravenous administration (with the exception of the intensive care unit)

- angioedema associated with treatment with ACE inhibitors in history

- hereditary / idiopathic angioedema

- cardiogenic shock

- atrioventricular block of the second or third degree without a functioning artificial pacemaker

- sick sinus syndrome in patients without a functioning artificial pacemaker

- heart failure with a reduced ejection fraction of less than 35% and / or pulmonary wedging pressure above 20 mm Hg.

- Atrial fibrillation / flutter in the presence of additional pathways (for example, Wolff – Parkinson – White syndrome, Laun-Gannga – Lewin syndrome). These patients are at risk of developing ventricular tachyarrhythmias, including ventricular fibrillation when taking verapamil hydrochloride.

- simultaneous use with drugs containing aliskiren in patients with diabetes mellitus or impaired renal function (glomerular filtration rate <60 ml / min / 1.73 m2)

- second and third trimester of pregnancy and lactation

- severe renal impairment (creatinine clearance <30 ml / min)

- dialysis

- cirrhosis with ascites

In vitro metabolism studies of verapamil hydrochloride have shown that it is metabolized by cytochrome P450, CYP3A4 , CYP1A2, CYP2C8, CYP2C9 and CYP2C18. Verapamil manifests itself as an inhibitor of CYP3A4 enzymes and P-glycoprotein (P-gp). Clinically important interactions have been reported with CYP3A4 inhibitors, which caused an increase in plasma levels of verapamil, while CYP3A4 inducers caused a decrease in plasma levels of verapamil, therefore monitoring for interaction with other drugs is necessary.

Colchicine is a substrate of CYP3A and transport P-glycoprotein (P-gp).Verapamil is known to be a CYP3A and P-gp inhibitor. With simultaneous use of verapamil and colchicine, inhibition of P-gp and / or CYP3A with verapamil may cause an increase in the exposure of colchicine. Combined use is not recommended.

Hemodialysis: Anaphylactoid reactions have been reported on high-density polyacrylonitrile membranes used for hemodialysis in patients using ACE inhibitors. As with other antihypertensive drugs of this chemical class, the use of ACE inhibitors should be avoided in patients on renal dialysis.

Antihypertensive drugs: enhance the hypotensive effect of the drug.

Lithium: The simultaneous use of ACE inhibitors with lithium can cause a lithium delay in the body. In such cases, lithium concentration should be monitored frequently.

Narcotic / psychotropic drugs: postural hypotension may occur.

Allopurinol, cytostatics or immunosuppressants, systemic corticosteroids, or procainamide: the risk of leukopenia increases.

Cardiodepressants: simultaneous use of verapamil with cardiodepressants (beta-blockers, antiarrhythmic drugs, inhalation anesthetics) can lead to an undesirable additive effect.

Antiarrhythmic drugs, beta-blockers (including Timolol in the form of eye drops): mutual potentiation of cardiovascular effects (increased degree of atrioventricular block, increased bradycardia, induction of heart failure and potentiated hypotension).

Metoprolol: an increase in AUC (~ 32.5%) and Cmax (~ 41%) of Metoprolol in patients with angina pectoris.

Propranolol: an increase in AUC (~ 65%) and Cmax (~ 94%) of propranolol in patients with angina.

Antiviral (HIV) drugs: due to the ability of some antiviral (HIV) drugs, such as ritonavir, to inhibit metabolism, plasma concentrations of verapamil may increase. Care must be taken or the dose of verapamil reduced.

Flecainide: minimal effect on plasma clearance of flecainide (<~ 10%); no effect on plasma clearance of verapamil.

Quinidine: reduced clearance of quinidine when administered orally (~ 35%). The simultaneous use of quinidine and oral verapamil in some cases caused arterial hypotension and pulmonary edema in patients with hypertrophic (obstructive) cardiomyopathy. The electrophysiological effects of quinidine and verapamil on atrioventricular conductivity were studied with the participation of 8 patients. Verapamil significantly interfered with the effect of quinidine on atrioventricular conductivity. There was a message about an increase in quinidine levels during therapy with verapamil.

Carbamazepine: an increase in the AUC of Carbamazepine (~ 46%) in patients with partial epilepsy who are not amenable to treatment. Increased levels of carbamazepine, which can cause side effects of carbamazepine, such as diplopia, headache, ataxia, or dizziness.

Phenobarbital: an increase in the clearance of verapamil after oral administration (approximately 5 times).

Theophylline: a decrease in clearance in oral and systemic use by about 20%, in smokers - by 11%.

Digoxin: the simultaneous use of Digoxin and verapamil led to an increase in the concentration of digoxin in the blood plasma by 50-75%, which required a reduction in the dose of digoxin.

Neuromuscular blockers: may increase the effects of muscle relaxants (such as neuromuscular blockers).

Tranquilizers, antipsychotics, antidepressants: as is the case with all antihypertensive drugs, there is an increased risk of orthostatic hypotension when the drug is combined with tranquilizers, antipsychotics or antidepressants containing imipramine.

Imipramine: an increase in imucramine AUC (~ 15%) without affecting the level of its active metabolite, desipramine.

Buspirone: an increase in AUC and Smah Buspirone approximately 3.4 times.

Midazolam: an increase in the AUC of midazolam by about 3 times and Cmax - by about 2 times.

Almotriptan: increase in AUC (~ 20%) and Cmax (~ 24%) of almotriptan.

Antimicrobial agents:

Clarithromycin, Erythromycin , telithromycin: possible increase in the level of verapamil.

Rifampicin: decrease in AUC of verapamil (~ 97%), Cmax (~ 94%), bioavailability after oral administration (~ 92%), may reduce the hypotensive effect.

Doxorubicin: with simultaneous use of doxorubicin and verapamil (orally), AUC (89%) and Cmax (61%) of doxorubicin in plasma are increased in patients with small cell lung cancer. In patients with a progressive tumor stage, there are no significant changes in the pharmacokinetics of doxorubicin with simultaneous intravenous administration of verapamil.

Nonsteroidal anti-inflammatory drugs (NSAIDs): the use of NSAIDs can lead to a weakening of the hypotensive effect of ACE inhibitors. When adding or canceling NSAIDs, it is necessary to strengthen blood pressure control in patients taking Trandolapril. In addition, it is described that NSAIDs and ACE inhibitors exhibit an additive effect on the increase in serum potassium and a decrease in renal function. Usually these effects are reversible and are observed, as a rule, in patients with impaired renal function.

Sulfinpyrazon: an increase in the clearance of verapamil after oral administration of approximately 3 times, a decrease in bioavailability of approximately 60%. A decrease in the hypotensive effect may be observed.

Acetylsalicylic acid: the simultaneous use of Acetylsalicylic acid may increase the risk of side effects of acetylsalicylic acid (the risk of bleeding).

Antacids: reduce the bioavailability of ACE inhibitors.

Sympathomimetics: can reduce the antihypertensive effects of ACE inhibitors. You should carefully monitor the patient's condition to ensure that the desired clinical effect is achieved.

Alcohol: enhances the hypotensive effect. Alcohol increases the risk of hypotension.

Verapamil can increase the concentration of carbamazepine, cyclosporine and theophylline in the blood plasma, thereby increasing the risk of toxicity of these funds.

Everolimus, sirolimus, tacrolimus: possible increase in the level of these drugs in the blood plasma.

Rifampicin, phenytoin and phenobarbital: reduce the concentration of verapamil in the blood plasma.

Cimetidine: increase in AUC of R-verapamil (~ 25%) and S-verapamil (~ 40%) with a corresponding decrease in clearance of R- and S-verapamil.

Prazosin: increase Smakh prazosin (~ 40%) without changing the half-life. Additive hypotensive effect.

Terazosin: an increase in AUC (~ 24%) and Smah (~ 25%) terazosin. Additive hypotensive effect.

Disopyramide phosphate: there is no data on a possible interaction between verapamil and disopyramide phosphate. Therefore, disopyramide should not be used 48 hours before or within 24 hours after the use of verapamil.

HMG-CoA reductase inhibitors: an increased level of Simvastatin (metabolized by CYP3A4) has been reported in the serum when used simultaneously with verapamil. The simultaneous use of verapamil and high doses of simvastatin reportedly increased the risk of myopathy / rhabdomyolysis. Treatment with HMG-CoA reductase inhibitors (such as simvastatin, Atorvastatin or lovastatin) in patients who take verapamil should be started with the lowest possible dose and titrated in the direction of its increase. If verapamil treatment should be prescribed to patients who are already taking an HMG-CoA reductase inhibitor (simvastatin, atorvastatin or lovastatin), the dose of statin should be reduced and set accordingly to the concentration of cholesterol in the blood serum.

Atorvastatin: may increase atorvastatin levels.Atorvastatin increases the AUC of verapamil by approximately 42.8%.

Lovastatin: Lovastatin may increase.

Simvastatin: increases the AUC of simvastatin approximately 2.6 times, Smah of simvastatin 4.6 times.

Fluvastatin, pravastatin and rozuvastatin are not metabolized by cytochrome CYP3A4 and do not interact with verapamil.

Hypericum grass: Reduced AUC R- (~ 78%) and S-verapamil (~ 80%) with a corresponding decrease in Cmax.

Diuretic Therapy: Combination with diuretics or other antihypertensive drugs may enhance the antihypertensive effect of trandolapril. In patients who receive diuretics, especially in violation of water-salt balance, blood pressure may be excessively lowered at the beginning of treatment with ACE inhibitors (see the section "Special Instructions"). The likelihood of an increase in antihypertensive effects with Tarka® can be minimized by stopping diuretic administration before starting treatment with Tarka®. If discontinuation of diuretic therapy is not possible, the initial dose of Tarka® should be reduced.

Potassium-sparing diuretics (spironolactone, amiloride, triamterene) or dietary supplements with potassium may increase the risk of hyperkalemia, especially in renal failure. Trandolapril can reduce potassium loss caused by thiazide diuretics.

Antiotensin-II receptor blockers, aliskiren: data from clinical studies have shownthat the double blockade of the renin-angiotensin-aldosterone system (RAAS) through the combined use of ACE inhibitors, angiotensin-II receptor blockers or aliskiren is associated with a higher incidence of side effects such as hypotension, hyperkalemia and decreased kidney function (including acute renal failure) than the use of a single agent that affects the RAAS (see sections "Pharmacodynamics", "Contraindications", "Special Instructions").

Antidiabetic agents: in some cases, especially at the beginning of treatment, patients with diabetes mellitus may need to select a dose of antidiabetic agents or Tarka® due to increased utilization of glucose in the blood.

Gold medications: rarely reported nitritic reactions (symptoms including flushing, nausea, vomiting, and hypotension) in patients treated with injections