Tarka tablets p.p.o. modified release 240 mg 4 mg N28

Tarka®

Interactions due to verapamil:

In vitro studies

indicate that verapamil is metabolized by the isoenzymes CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18 of cytochrome P450.

Verapamil is an inhibitor of the CYP3A4 isoenzyme and P-glycoprotein. Clinically significant interactions were observed with simultaneous use with inhibitors of the CYP3A4 isoenzyme, and an increase in the concentration of verapamil in the blood plasma was observed, while inducers of the CYP3A4 isoenzyme decreased the concentration of verapamil in the blood plasma. Accordingly, when using such agents simultaneously, the possibility of this interaction should be taken into account.

Co-administration of trandolapril/verapamil and a drug that is primarily metabolized by CYP3A4 or is a P-gp substrate may be accompanied by an increase in the concentration of such drug. This may result in increased or prolonged duration of both therapeutic and side effects of the drug used in conjunction with trandolapril/verapamil.

The table summarizes the data on drug interactions caused by verapamil content.

Other possible interactions with verapamil

Dabigatran

When dabigatran etexilate was co-administered with verapamil administered orally, the Cmax and AUC values ​​of dabigatran increased depending on the time of use and the dosage form of verapamil. The greatest increase in dabigatran values ​​was observed when the first dose of immediate-release verapamil was taken 1 hour before dabigatran etexilate (Cmax increased by 180% and AUC increased by 150%).

When using the sustained release formulation of verapamil, this effect was progressively reduced (Cmax increased by 90% and AUC by 70%), as well as when using multiple doses of verapamil (Cmax increased by 60% and AUC by 50%), which may be explained by the induction of P-glycoprotein in the gastrointestinal tract with long-term use of verapamil.

When verapamil was administered 2 hours after taking dabigatran etexilate, no clinically significant interaction was observed (Cmax increased by 10% and AUC by 20%), since dabigatran was completely absorbed after 2 hours. In a study in patients with atrial fibrillation, dabigatran concentrations increased by no more than 21%, and no increase in the risk of bleeding was observed.

There are no data on the interaction of dabigatran etexilate with verapamil administered parenterally; no clinically significant interaction is expected.

With regard to the prolongation of blood coagulation, the use of verapamil, as a rule, did not affect the plasma concentration-effect relationship of dabigatran. No unexpected safety data were obtained when dabigatran etexilate was co-administered with verapamil.

Drugs that bind to plasma proteins

Verapamil, as a drug that is highly bound to plasma proteins, should be used with caution when taken simultaneously with other drugs that have a similar ability. It is possible to increase the concentrations in the blood plasma of drugs characterized by a high degree of protein binding (including coumarin and indanedione derivatives, non-steroidal anti-inflammatory drugs, quinine, salicylates, sulfinpyrazone).

Flecainide

A study involving healthy volunteers showed that the combined use of verapamil and flecainide may have an additive effect with a decrease in myocardial contractility, a slowdown in atrioventricular conduction and myocardial repolarization.

Disopyramide

Pending data on a possible interaction between verapamil and disopyramide, disopyramide should not be administered 48 hours before or 24 hours after use.

Ivabradin

Due to its moderate inhibitory effect on CYP3A4, verapamil (at a dose of 120 mg 2 times a day) when used simultaneously led to an increase in the AUC of ivabradine by 2-3 times.

Both verapamil and ivabradine are heart rate depressants and, therefore, co-administration may worsen the patient's heart rate. The simultaneous use of verapamil with ivabradine is contraindicated due to the development of an additional negative chronotropic effect.

Procainamide, quinidine and other drugs known to prolong the QT interval

Increased risk of developing QT prolongation.

Valproic acid

Verapamil increases the concentration of valproic acid in the blood due to suppression of metabolism involving cytochrome P450.

Nicotine

Nicotine accelerates metabolism in the liver, leads to a decrease in the concentration of verapamil in the blood, and reduces the severity of antianginal, antihypertensive and antiarrhythmic effects.

Ranitidine

Increases the level of verapamil in the blood plasma.

Calcium preparations

Reduced effectiveness of verapamil.

Sympathomimetics

Sympathomimetics reduce the antihypertensive effect of verapamil.

Estrogens

Estrogens reduce the antihypertensive effect of verapamil due to fluid retention in the body.

Antihypertensives, diuretics, vasodilators

Strengthening the antihypertensive effect.

Medicines for the treatment of HIV infection

Some drugs used to treat HIV infection, such as ritonavir, may inhibit the metabolism of verapamil, resulting in increased plasma concentrations of verapamil. Caution should be exercised or the dose of verapamil should be reduced.

Lithium

Increased lithium neurotoxicity has been observed during concomitant administration of verapamil and lithium, with no change or increase in serum lithium concentrations. However, additional administration of verapamil also led to a decrease in serum lithium concentrations in patients regularly taking lithium by mouth. Patients taking both drugs should be closely monitored.

β-blockers for intravenous administration

β-blockers for intravenous administration should not be used during treatment with Tarka® (see section "Contraindications"). Combined treatment with verapamil and beta-blockers can cause severe impairment of AV conduction, which, in some cases, can cause the development of severe bradycardia and cardiac depression.

Muscle relaxants

The effect of muscle relaxants may be enhanced.

Clinical data and preclinical studies suggest that verapamil may enhance the activity of muscle relaxants (such as curare and depolarizing agents).

Dantrolene

In patients susceptible to malignant hyperthermia, intravenous administration of dantrolene with simultaneous administration of calcium channel blockers led to hyperkalemia and myocardial depression.

The simultaneous use of both drugs in the treatment of malignant cardiac tachyarrhythmias caused by hyperthermia should be avoided.

The combination of dantrolene sodium and calcium channel blockers is not recommended in the treatment of malignant hyperthermia.

The combined use of the muscle relaxant dantrolene (IV) and verapamil is potentially dangerous (can cause fatal ventricular fibrillation). Concomitant use of verapamil and dantrolene is not recommended during the treatment of malignant hyperthermia.

In experimental studies in animals, coadministration of verapamil and dantrolene (IV) resulted in fatal ventricular fibrillation. This combination is potentially dangerous.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

When taken together with all antihypertensive drugs, NSAIDs (including acetylsalicylic acid, used in high doses as an anti-inflammatory drug, for example, to relieve pain) may reduce the antihypertensive effect of trandolapril. Increase blood pressure monitoring when adding or discontinuing any NSAID in a patient taking trandolapril.

In addition, NSAIDs and ACE inhibitors have been shown to further increase serum potassium, while renal function may be impaired. This effect is usually reversible and occurs more often in patients with impaired renal function.

NSAIDs, including acetylsalicylic acid, except when acetylsalicylic acid is used as an antiplatelet agent, should not be taken together with ACE inhibitors by patients with heart failure. The simultaneous use of acetylsalicylic acid and verapamil may lead to an increase in the number and severity of adverse events from taking acetylsalicylic acid (the risk of bleeding may increase).

Ethanol (alcohol)

Increased concentration of ethanol in blood plasma. Ethanol increases the risk of developing arterial hypotension.

HMG-CoA reductase inhibitors (statins)

Simvastatin/atorvastatin/lovastatin

In patients receiving verapamil, treatment with HMG-CoA reductase inhibitors (i.e. simvastatin/atorvastatin/lovastatin) should be started with the lowest possible doses and gradually increased during therapy. It has been noted that the simultaneous use of verapamil and high doses of simvastatin increases the risk of developing myopathy/rhabdomyolysis. If it is necessary to prescribe verapamil to patients already receiving HMG-CoA reductase inhibitors, then it is necessary to review and reduce their doses according to the concentration of cholesterol in the blood serum.

Fluvastatin, pravastatin and rosuvastatin are not metabolized by the CYP3A4 isoenzyme, so their interaction with verapamil is least likely.

Inhalational anesthetics

When inhaled anesthetics and calcium antagonists, such as verapamil hydrochloride, are used concomitantly, the dose should be carefully selected to avoid excessive depression of the cardiovascular system.

Interactions due to trandolapril:

Neutral endopeptidase inhibitors (NEP)

Concomitant use of ACE inhibitors and NEP inhibitors, such as sacubitril (available as a fixed-dose combination with valsartan) and racecadotril, is contraindicated as concomitant inhibition of ACE and neprilysin (neutral endopeptidase, NEP) may increase the risk of angioedema (see Contraindications sections). " and "Special instructions").

The simultaneous use of ACE inhibitors (trandolapril) and dipeptidyl peptidase type IV (DPP-IV) inhibitors (gliptins), for example, sitagliptin, saxagliptin, vildagliptin, linagliptin, may be accompanied by an increased risk of developing angioedema.

The simultaneous use of ACE inhibitors (trandolapril) and racecadotril (an enkephalinase inhibitor used to treat acute diarrhea) may be accompanied by an increased risk of developing angioedema.

The simultaneous use of ACE inhibitors (trandolapril) and estramustine may be accompanied by an increased risk of developing angioedema.

Diuretics

Diuretics or other antihypertensive agents may enhance the antihypertensive effect of trandolapril. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, eplerenone) or potassium supplements may increase the risk of hyperkalemia, especially in patients with renal impairment. Trandolapril may reduce potassium loss when used concomitantly with thiazide diuretics.

Co-trimoxazole (trimethoprim/sulfamethoxazole)

Patients taking co-trimoxazole (trimethoprim/sulfamethoxazole) may have an increased risk of developing hyperkalemia (see section "Special Instructions").

Angiotensin II receptor blockers, aliskiren

Data from clinical trials have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by 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 renal function (including acute renal failure) compared with the use of a single drug acting on the RAAS (see sections “Contraindications”, “Special instructions”).

The simultaneous use of ACE inhibitors with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m2 body surface area) and is not recommended in other patients.

Concomitant use of ACE inhibitors with angiotensin II receptor antagonists is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Hypoglycemic agents

Concomitant use of trandolapril, like any ACE inhibitors, with hypoglycemic agents (insulin or oral hypoglycemic agents) may enhance the hypoglycemic effect and lead to an increased risk of hypoglycemia.

Lithium

Trandolapril may impair lithium excretion. Monitoring the concentration of lithium in the blood serum is necessary.

Gold

There have been reports of rare cases of nitrate-like reactions (symptoms include facial flushing, nausea, vomiting and hypotension) in patients receiving intravenous gold preparations (sodium aurothiomalate) and concomitant use of ACE inhibitors, including Tarka®.

Other

Anaphylactoid reactions have been described when high-flux polyacrylonitrile membranes were used during hemodialysis in patients receiving ACE inhibitors. Patients receiving ACE inhibitors should avoid the use of this type of membrane during hemodialysis.

ACE inhibitors may enhance the antihypertensive effect of some inhalational anesthetics.

Allopurinol, cytostatics, immunosuppressive agents and systemic corticosteroids or procainamide may increase the risk of leukopenia when treated with ACE inhibitors. Antacids may reduce the bioavailability of ACE inhibitors.

The antihypertensive effect of ACE inhibitors may be reduced when sympathomimetics are co-administered. In such cases, careful monitoring is necessary.

As with the use of any other antihypertensive drugs, co-administration of antipsychotics or tricyclic antidepressants increases the risk of developing orthostatic hypotension.

Concomitant use of angiotensin-converting enzyme and mTOR kinase inhibitors (for example, sirolimus, everolimus, temsirolimus) may be accompanied by an increased risk of developing angioedema.

Tarka tablets p.p.o. modified release 240 mg 4 mg N28

Action

Tarka is a combination drug that contains long-acting verapamil and trandolapril.
Trandolapril is the ethyl ester (prodrug) of the non-sulfhydryl ACE inhibitor trandolaprilat.

Verapamil hydrochloride is a slow calcium channel blocker (SCBC).

Trandolapril

Trandolapril suppresses the activity of the renin-angiotensin-aldosterone system in the blood plasma. Renin is an enzyme that is synthesized by the kidneys and enters the bloodstream, where it causes the conversion of angiotensinogen to angiotensin I (a low-active decapeptide). The latter is converted under the action of ACE (peptidyl dipeptidase) into angiotensin II, a powerful vasoconstrictor that causes constriction of the arteries and an increase in blood pressure, and also stimulates the secretion of aldosterone by the adrenal glands.

ACE inhibition leads to a decrease in the concentration of angiotensin II in the blood plasma, which is accompanied by a decrease in vasopressor activity and aldosterone secretion. Although aldosterone production is reduced slightly, a slight increase in serum potassium concentration may occur in combination with sodium and water loss.

A decrease in the concentration of angiotensin II through a feedback mechanism leads to an increase in renin activity in the blood plasma. Another function of ACE is the destruction of kinins (bradykinin), which have powerful vasodilatory properties, into inactive metabolites. In this regard, the suppression of ACE leads to an increase in circulating and tissue concentrations of the kallikrein-kinin system, which promotes vasodilation through activation of the prostaglandin system. This mechanism may partially determine the hypotensive effect of ACE inhibitors and is responsible for some side effects.

In patients with arterial hypertension, the use of ACE inhibitors leads to a comparable decrease in blood pressure in the “lying” and “standing” positions without a compensatory increase in heart rate. OPSS decreases, cardiac output does not change or increases, renal blood flow increases, and the glomerular filtration rate usually does not change. Abrupt cessation of therapy was not accompanied by a rapid increase in blood pressure.

The antihypertensive effect of trandolapril appears within 1 hour after oral administration and persists for at least 24 hours. In some cases, optimal blood pressure control can only be achieved several weeks after the start of treatment. With long-term therapy, the hypotensive effect persists. Trandolapril does not worsen the circadian blood pressure profile.

Verapamil

Verapamil inhibits the flow of calcium ions through the “slow” calcium channels of the membranes of vascular smooth muscle cells, conducting and contractile cardiomyocytes. Verapamil causes a decrease in blood pressure, both at rest and during exercise, due to the expansion of peripheral arterioles. As a result of a decrease in peripheral vascular resistance (afterload), the myocardial oxygen demand and energy consumption are reduced. Verapamil reduces myocardial contractility. The negative inotropic effect of the drug can be compensated by a decrease in peripheral vascular resistance. The cardiac index does not decrease, except for patients with left ventricular dysfunction.

Verapamil does not affect the sympathetic regulation of cardiac activity because it does not block β-adrenergic receptors. bronchial asthma and bronchospastic conditions are not a contraindication to the use of veralamil.

Tarka

In studies in healthy volunteers, there was no evidence of interaction between verapamil and trandolapril at the level of pharmacokinetic parameters or the RAAS. Therefore, the synergism of two drugs reflects their complementary pharmacodynamic effects. In clinical studies, Tarka lowered blood pressure to a greater extent than both drugs alone.

Pharmacokinetics

Trandolapril

Suction

After oral administration, trandolapril is rapidly absorbed. Absolute bioavailability is about 10%. TCmax in blood plasma is about 1 hour.

Distribution

The binding of trandolapril to plasma proteins is about 80% and is independent of concentration. Vd of trandolapril is about 18 l. T1/2 <1 hour. With repeated use, Css is achieved in approximately 4 days, both in healthy volunteers and in young and elderly patients with arterial hypertension.

Metabolism

In blood plasma, trandolapril undergoes hydrolysis to form the active metabolite trandolaprilat. TCmax of trandolaprilat in blood plasma is 3-8 hours. Cmax and AUC do not depend on food intake. The absolute bioavailability of trandolaprilat when taking trandolapril is about 13%. The binding to blood proteins depends on the concentration and varies from 65% (at a concentration of 1000 ng/ml) to 94% (at a concentration of 0.1 ng/ml). At steady state, the concentration of effective T1/2 of trandolaprilat, together with a small fraction of the drug taken, varies between 15 hours and 23 hours, which probably reflects binding to plasma and tissue ACE.

Removal

Trandolaprilat has a high affinity for ACE. 9-14% of the trandolapril dose is excreted as trandolaprilat by the kidneys. After taking labeled trandolapril orally, 33% of the drug was excreted by the kidneys and 66% through the intestines. A small amount is excreted unchanged through the kidneys (less than 0.5%).

The renal clearance of trandolaprilat varies from 0.15 to 4 l/h depending on the dose.

Pharmacokinetics in special clinical situations

Children. The pharmacokinetics of trandolapril have not been studied in children under 18 years of age.

Elderly patients. Plasma concentrations of trandolapril increase in elderly patients with arterial hypertension (over 65 years of age). However, the plasma concentration of trandolaprilat and its ACE-inhibitory activity in elderly and young patients with arterial hypertension are the same. The pharmacokinetics of trandolapril and trandolaprilat, as well as ACE-inhibiting activity in elderly patients of both sexes are the same.

Kidney failure. Compared with healthy volunteers, in patients on hemodialysis and with CC <30 ml/min, the plasma concentration of trandolaprilat is approximately 2 times higher, and renal clearance is reduced by approximately 85%. For patients with renal failure, dose adjustment of the drug is recommended.

Liver failure. Compared with healthy volunteers, in patients with alcoholic cirrhosis, the plasma concentrations of trandolapril and trandolaprilat increase by 9 and 2 times, respectively, but the ACE inhibitory activity does not change. In patients with liver failure, lower doses of the drug may be required.

Verapamil

Suction

About 90% of an oral dose of verapamil is rapidly absorbed in the small intestine. Bioavailability is only 22% due to the pronounced “first pass” effect through the liver. With repeated use, the average bioavailability can increase up to 30%. Food intake does not affect the bioavailability of the drug. TCmax is 4-15 hours. The maximum plasma concentration of norverapamil is achieved approximately 5-15 hours after taking the drug.

Distribution

Css with repeated use 1 time/day is achieved in 3-4 days. The binding to plasma proteins is about 90%.

Metabolism

One of the 12 metabolites found in urine is norverapamil, the pharmacological activity of which is 10-20% of that of verapamil; its share is 6% of the excreted drug. Cssnorverapamil and verapamil are similar.

Removal

T1/2 with repeated use is on average 8 hours. 3-4% of the dose is excreted unchanged by the kidneys. Metabolites are excreted by the kidneys (70%) and through the intestines (16%).

Pharmacokinetics in special clinical situations

The pharmacokinetics of verapamil does not change with impaired renal function. Impaired renal function does not affect the elimination of verapamil.

The bioavailability and T1/2 of verapamil are increased in patients with liver cirrhosis. However, the pharmacokinetics of verapamil remains unchanged in patients with compensated liver dysfunction.

Tarka

There is no information on the pharmacokinetic interaction between verapamil and trandolapril/trandolaprilat, therefore the pharmacokinetics of both drugs when used in combination do not differ from that when they are prescribed separately.

Instructions for use TARKA® (TARKA®)

Interactions due to verapamil

In vitro studies indicate that verapamil is metabolized with the participation of the isoenzymes CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18.

Verapamil is an inhibitor of CYP3A4 and P-glycoprotein (P-gp). Clinically significant interactions were observed with concomitant use with CYP3A4 inhibitors, with an increase in verapamil plasma concentrations observed, while CYP3A4 inducers decreased verapamil plasma concentrations. With such combinations, the possibility of interaction must be taken into account.

Combinations not recommended

When used concomitantly with potassium-sparing diuretics or potassium supplements

there is a risk of developing hyperkalemia.

Colchicine

- substrate of CYP3A and transport P-glycoprotein. Verapamil is known to be an inhibitor of CYP3A and P-gp. When verapamil and colchicine are administered concomitantly, inhibition of P-gp and/or CYP3A by verapamil may result in increased colchicine exposure. Combined use is not recommended.

Dantrolene:

In a patient with coronary artery disease who was taking verapamil, hyperkalemia and depression of myocardial function developed after administration of dantrolene. The combined use of these drugs is not recommended.

Combinations to use with caution

Antihypertensive drugs

enhance the hypotensive effect of Tarka.

Diuretics:

in patients receiving diuretics, especially with water-salt imbalance, blood pressure may decrease excessively at the beginning of treatment with ACE inhibitors.

Lithium:

simultaneous use of ACE inhibitors with lithium can cause lithium retention in the body. In such cases, lithium concentrations should be monitored frequently.

Anesthetics:

Tarka® may enhance the hypotensive effect of some anesthetics.

Opioid analgesics/psychotropics:

Postural hypotension may occur.

Allopurinol, cytostatics or immunosuppressants, systemic corticosteroids, or procainamide:

the risk of developing leukopenia increases.

Concomitant use of verapamil with drugs that may have a depressant effect on the heart

(beta-blockers, antiarrhythmic drugs, inhalational anesthetics) may lead to an undesirable additive effect.

Quinidine:

simultaneous oral administration of verapamil and quinidine in some cases caused arterial hypotension and pulmonary edema in patients with hypertrophic (obstructive) cardiomyopathy.

Digoxin:

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

Muscle relaxants:

enhancing the effects of muscle relaxants (such as neuromuscular blockers).

Tranquilizers, neuroleptics, antidepressants:

As with all antihypertensive drugs, there is an increased risk of developing orthostatic hypotension when Tarka is combined with tranquilizers, antipsychotics or antidepressants containing imipramine.

Clarithromycin, erythromycin, telithromycin:

it is possible to increase the concentration of verapamil in plasma.

Rifampicin:

a decrease in verapamil AUC (approximately 97%), Cmax (approximately 94%), bioavailability after oral administration (approximately 92%) may reduce the antihypertensive effect.

Combinations to Consider

NSAIDs:

the use of NSAIDs may lead to a weakening of the hypotensive effect of ACE inhibitors. In addition, NSAIDs and ACE inhibitors have been described to have an additive effect on increasing serum potassium and decreasing renal function. Usually these effects are reversible and are observed, as a rule, in patients with impaired renal function.

Acetylsalicylic acid:

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

Antacids:

reduce the bioavailability of ACE inhibitors.

Sympathomimetics:

may reduce the antihypertensive effects of ACE inhibitors. The patient should be closely monitored to ensure the desired clinical effect is achieved.

Ethanol:

enhances the hypotensive effect.

Verapamil may increase concentrations of carbamazepine, cyclosporine

and
theophylline
in blood plasma, thereby increasing the risk of toxicity of these drugs.

Everolimus, sirolimus, tacrolimus:

it is possible to increase the level of these drugs in the blood plasma.

Rifampicin, phenytoin

and
phenobarbital
reduce the plasma concentration of verapamil, and
cimetidine
may increase the plasma concentration of verapamil.

Verapamil may increase prazosin

in blood plasma.

HMG-CoA reductase inhibitors:

Increased serum levels of simvastatin (metabolized by CYP3A4) have been reported when administered concomitantly with verapamil. Concomitant use of verapamil and high doses of simvastatin has been reported to increase the risk of myopathy/rhabdomyolysis. Treatment with HMG-CoA reductase inhibitors (such as simvastatin, atorvastatin or lovastatin) in patients taking verapamil should be started at the lowest possible dose and titrated upward. If treatment with verapamil is to be prescribed to patients already taking an HMG-CoA reductase inhibitor (simvastatin, atorvastatin or lovastatin), the dose of the statin should be reduced and serum cholesterol concentrations adjusted accordingly.

Atorvastatin:

possible increase in atorvastatin levels. Atorvastatin increases the AUC of verapamil by approximately 42.8%.

Lovastatin:

possible increase in lovastatin levels.

Simvastatin:

increases the AUC of simvastatin by approximately 2.6 times, the Cmax of simvastatin by 4.6 times.

Fluvastatin, pravastatin and rosuvastatin

are not metabolized by cytochrome CYP3A4 and do not interact with verapamil.

Hypoglycemic agents:

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

Grapefruit juice:
Grapefruit juice increases verapamil plasma concentrations. You should not consume grapefruit juice along with Tarka.

Tarka tab p/plen obol 180mg+2mg N28 (Abbott)

The following special instructions apply to Tarka® due to the presence of trandolapril in the composition: Angioedema Trandolapril may cause angioedema of the face, lower extremities, tongue, vocal folds and/or larynx. There is evidence that ACE inhibitors are more likely to cause angioedema in black patients. During treatment with ACE inhibitors, cases of angioedema of the intestine have also been reported. This possibility should be considered if abdominal pain develops (with or without nausea or vomiting) while taking trandolapril. In patients with angioedema, treatment with ACE inhibitors should be discontinued immediately and observation until the edema resolves. Angioedema of the face usually resolves spontaneously. Swelling that extends not only to the facial area, but also to the vocal folds, can be life-threatening due to the risk of airway obstruction. In case of angioedema of the tongue, vocal folds or larynx, immediate subcutaneous administration of 0.3-0.5 ml of epinephrine (adrenaline) solution (1:1000) is required, as well as other therapeutic measures if necessary. Patients with renovascular hypertension ACE inhibitors can be used before the start of surgical therapy for renovascular hypertension or in cases where surgical therapy will not be performed. In patients with unilateral or bilateral renal artery stenosis, the risk of developing severe arterial hypotension and renal failure increases when treated with ACE inhibitors. Taking diuretics may increase the risk. Impaired renal function may manifest as subtle changes in serum creatinine concentrations, even in patients with unilateral renal artery stenosis. In such patients, treatment should be started in a hospital setting with small doses of the drug, followed by careful dose selection under close medical supervision. Diuretics should be discontinued; Renal function and serum potassium levels should be monitored in the first weeks of treatment. Renal dysfunction When evaluating patients with hypertension, renal function should always be assessed. Patients with impaired renal function, chronic heart failure, bilateral renal artery stenosis, or arterial stenosis of a solitary kidney (for example, after kidney transplantation) are at increased risk of worsening renal function. In some patients with arterial hypertension who do not have previous severe kidney disease, when trandolapril is prescribed in combination with a diuretic, an increase in blood urea nitrogen and serum creatinine may be observed. Proteinuria Proteinuria may develop, especially in patients with existing renal impairment or when receiving relatively high doses of ACE inhibitors. Dual blockade of the renin-angiotensin-aldosterone system (RAAS) There is evidence that the simultaneous use of ACE inhibitors and angiotensin II receptor blockers or aliskiren increases the risk of arterial hypotension, hyperkalemia and decreased renal function (including acute renal failure). For this reason, double blockade of the RAAS by combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is not recommended (see sections “Contraindications”, “Interaction with other drugs”). If therapy by double blockade is considered absolutely necessary, it should only be carried out under specialist supervision and with careful monitoring of renal function, blood pressure and electrolyte concentrations. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy. Hyperkalemia In patients with arterial hypertension, especially those with impaired renal function, Tarka® may cause hyperkalemia. Risk factors for the development of hyperkalemia include renal failure, use of potassium-sparing diuretics, concomitant use of drugs to treat hypokalemia, diabetes mellitus and/or left ventricular dysfunction after myocardial infarction. Cough When using ACE inhibitors, a dry, non-productive cough may occur, which disappears after discontinuation of therapy. Symptomatic arterial hypotension In patients with uncomplicated arterial hypertension, after taking the first dose of trandolapril, as well as after its increase, the development of symptomatic arterial hypotension was noted. The risk of arterial hypotension is higher in patients who have lost a lot of fluid and salt as a result of long-term diuretic therapy, restriction of table salt intake, dialysis, diarrhea or vomiting. In such patients, before initiating trandolapril therapy, diuretic therapy should be discontinued and blood volume and/or sodium levels should be replaced. Agranulocytosis and suppression of bone marrow hematopoiesis During treatment with ACE inhibitors, cases of agranulocytosis and suppression of bone marrow function have been described. The risk of developing neutropenia depends on the dose, type of drug and the clinical condition of the patient. These phenomena are more common in patients with impaired renal function, especially with systemic connective tissue diseases. In such patients (for example, with systemic lupus erythematosus or scleroderma), it is advisable to regularly monitor the number of leukocytes in the blood and the protein content in the urine, especially with impaired renal function, treatment with corticosteroids and antimetabolites. These changes are reversible after discontinuation of the ACE inhibitor. Impaired liver function Since trandolapril is metabolized in the liver to form an active metabolite, the drug should be prescribed to patients with impaired liver function with caution and with careful medical supervision. Surgery/general anesthesia During surgery or general anesthesia with drugs that cause hypotension, trandolapril may block the secondary formation of angiotensin II associated with compensatory renin release. The doctor should be warned that the patient is taking an ACE inhibitor. Desensitization In patients receiving ACE inhibitors during a course of desensitization (for example, hymenoptera venom), in rare cases life-threatening anaphylactic reactions may develop. LDL apheresis When performing LDL apheresis in patients receiving ACE inhibitors, the development of life-threatening anaphylactic reactions was observed. The following special instructions apply to the drug Tarka® due to the presence of verapamil in the composition: Acute myocardial infarction Due to the presence of verapamil, the drug should be used with caution in patients with acute myocardial infarction complicated by bradycardia, severe arterial hypotension or left ventricular dysfunction. Heart block/First degree atrioventricular block/Bradycardia/Asystole Verapamil affects the atrioventricular (AV) and sinoatrial (SA) nodes and increases AV conduction time. The drug should be used with caution, since the development of 2nd or 3rd degree AV block (see section “Contraindications”) or single-bundle, double-bundle or triple-bundle blockade of the His bundle require a significant dose reduction or complete cessation of taking verapamil and initiation of the necessary treatment. Verapamil affects the AV and SA nodes and in rare cases can cause the development of 2nd or 3rd degree AV block, bradycardia and, in some cases, asystole. These phenomena occur more often in patients with sick sinus syndrome. Asystole in patients other than those with sick sinus syndrome is usually of short duration (a few seconds or less) with spontaneous restoration of atrioventricular or normal sinus rhythm. If it does not go away quickly, appropriate treatment should be started immediately. Beta-blockers Mutual strengthening of disorders of the cardiovascular system (2nd-3rd degree AV blockade, significant decrease in heart rate, development of heart failure with potential arterial hypotension). Asymptomatic bradycardia (36 per minute) with migration of the rhythm through the atrium was observed in a patient simultaneously taking timolol (a beta-blocker) in the form of eye drops and verapamil orally. Digoxin If verapamil is taken concomitantly with digoxin, the dose of digoxin should be reduced. See section "Interaction with other drugs". Heart failure Due to the presence of verapamil, patients with heart failure and an ejection fraction greater than 35% should undergo compensation therapy before starting Tarka® and appropriate treatment thereafter. Arterial hypotension Some patients receiving diuretics (especially in the first days of treatment) may experience a sharp decrease in blood pressure after trandolapril administration. HMG-CoA reductase inhibitors (“Statins”) See section “Interactions with other drugs”. Neuromuscular transmission disorders Diseases in which neuromuscular transmission is disrupted (myasthenia gravis, Lambert-Eaton syndrome, Duchenne muscular dystrophy). Other Special groups of patients Tarka® has not been studied in children and adolescents under 18 years of age, therefore its use in this age group is not recommended (see section “Contraindications”), Impaired renal function Although comparative studies have not revealed effect of renal impairment on the pharmacokinetics of verapamil in patients with end-stage renal disease, some reports suggest that verapamil should be used with caution and with close monitoring in patients with renal impairment. Verapamil cannot be removed from the body by hemodialysis. Liver impairment: Use with caution in severe liver impairment. Sodium Tarka® 180 mg + 2 mg contains 1.12 mmol (or 25.71 mg) sodium per dose. This should be taken into account in patients on a sodium-controlled diet. Impact on the ability to drive vehicles and operate machinery Care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions, especially at the beginning of treatment. Tarka® may increase the level of alcohol in the blood and slow down its elimination. Due to this, the effects of alcohol may be enhanced.

Tarka

The risk of a pronounced decrease in blood pressure increases with increased activity of the renin-angiotensin-aldosterone system (dehydration while taking diuretics, low-salt diet, hemodialysis, diarrhea and vomiting; LV failure, renovascular hypertension). In such patients, it is first necessary to adjust the indicators of water and electrolyte metabolism and it is advisable to begin treatment in a hospital.

In patients with moderate renal failure, renal function should be monitored. Acute renal failure can be observed primarily in patients with initially impaired renal function or with CHF.

There is no sufficient experience in treating the drug in cases of secondary hypertension (especially renovascular hypertension).

If angioedema develops, treatment with the drug should be discontinued immediately. Angioedema that extends only to the face usually resolves spontaneously. Swelling of the tongue, vocal cords, and pharynx can pose a threat to the patient’s life, since there is a possibility of airway obstruction. A dry and unproductive cough, which may occur while taking the drug, goes away after stopping treatment.

Pharmacokinetic data indicate that the systemic bioavailability (efficacy) of the drug in the elderly is higher than in young people suffering from arterial hypertension. Some elderly patients may experience a more pronounced decrease in blood pressure than other patients. It is recommended to assess renal function before starting treatment.

During treatment (especially if combination with potassium-sparing diuretics and K+ drugs is necessary), it is necessary to regularly monitor the concentration of K+ in the blood serum.

In patients who require extensive surgery under general anesthesia, ACE inhibitors can cause a marked decrease in blood pressure, which can be corrected by administering plasma replacement solutions.

The risk of developing neutropenia probably depends on the dose of the drug and the clinical condition of the patient. It is more often observed in patients with renal failure, especially when it is associated with systemic connective tissue diseases (SLE scleroderma), as well as during treatment with immunosuppressants. This condition is reversible after discontinuation of the ACE inhibitor.

In patients taking ACE inhibitors, anaphylactoid reactions (in some cases life-threatening) may develop during desensitization to insect venoms.

In patients who underwent LDL plasmapheresis during treatment with ACE inhibitors, anaphylactoid reactions were observed, which were life-threatening.

In patients treated with ACE inhibitors and undergoing hemodialysis with high-flow polyacrylonitrile metall sulfonate membranes (including Ap69), anaphylactoid reactions were observed. Therefore, these membranes should not be used in such patients.

Before starting and during treatment, it is necessary to monitor kidney function.

Blood pressure measurements to assess the therapeutic effect of the drug should always be carried out before taking the next dose.

No effect on the ability to drive vehicles or engage in other potentially hazardous activities that require increased concentration of attention and speed of psychomotor reactions has been established (however, taking the drug can cause dizziness and increased fatigue).