Tarka, 2 mg+180 mg 28 pcs.

Tarka is a combination drug consisting of long-acting verapamil and trandolapril.

Trandolapril is the ethyl ester (prodrug) of the non-sulfhydric ACE inhibitor trandolaprilate.

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

Trandolapril

Trandolapril suppresses the activity of the plasma renin-angiotensin-aldosterone system. Renin is an enzyme that is synthesized by the kidneys and enters the bloodstream, where it causes the conversion of angiotensinogen into angiotensin I (a slightly active decapeptide). The latter is converted by ACE (peptidyl dipeptidase) into angiotensin II, a powerful vasoconstrictor that causes arterial constriction and increases BP and stimulates the secretion of aldosterone by the adrenals.

Inhibition of ACE leads to a decrease in plasma angiotensin II concentrations, which is accompanied by a decrease in vasopressor activity and aldosterone secretion. Although aldosterone production decreases slightly, there may nevertheless be a slight increase in serum potassium concentration combined with sodium and water loss.

The decrease in angiotensin II concentration through a feedback mechanism leads to an increase in plasma renin activity. Another function of ACE is the degradation of kinins (bradykinin), which have a powerful vasodilatory property, to inactive metabolites. In this regard, ACE suppression results in increased circulating and tissue concentrations of the kallikrein-kinin system, which contributes to vasodilation through activation of the prostaglandin system. This mechanism probably partially determines the hypotensive effect of ACE inhibitors and is the cause of some side effects.

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

The antihypertensive effect of trandolapril is apparent 1 h after oral administration and persists for at least 24 h. In some cases optimal BP control is achieved only after several weeks of treatment. With long-term therapy, the hypotensive effect is maintained. Trandolapril does not worsen circadian BP profile.

Verapamil

Verapamil inhibits the flow of calcium ions through “slow” calcium channels of membranes of vascular smooth muscle cells, conducting and contractile cardiomyocytes. Verapamil causes BP decrease both at rest and during physical activity due to peripheral arterioles dilation. As a result of decreased ROS (post-load), myocardial oxygen demand and energy consumption are reduced. Verapamil reduces myocardial contractility. Negative inotropic effect of the drug can be compensated by decrease of ROS. Cardiac index is not reduced, except in patients with left ventricular dysfunction.

Verapamil does not affect sympathetic regulation of cardiac activity because it does not block β-adrenoreceptors. bronchial asthma and bronchospastic conditions are not contraindications to the administration of veralamil.

Tarka

There was no evidence of interaction between verapamil and trandolapril at the pharmacokinetic or RAAS level in studies on healthy volunteers. Consequently, the synergism of the two drugs reflects their complementary pharmacodynamic effects. In clinical trials, Tarka reduced BP to a greater extent than both drugs alone.

Indications

Hypertension (high blood pressure)Arterial hypertension (patients whose blood pressure is not controlled with trandolapril and verapamil in monotherapy or patients who are indicated for combination therapy with trandolapril and verapamil in the same dosages).

Active ingredient

Verapamil, Trandolapril

Composition

1 tablet contains:

Active substances:

Trandolapril, 2 mg;

Verapamil hydrochloride, 180 mg.

Supplementary substances:

The verapamil hydrochloride layer is microcrystalline cellulose – 59.1 mg,

Sodium alginate – 240 mg,

povidone K30 – 36 mg,

magnesium stearate – 2.4 mg,

water – 22.5 mg;

trandolapril layer – corn starch – 74.3 mg,

lactose monohydrate – 107 mg,

povidone K25 – 10.7 mg,

Hypromellose 6 mPa*s (type 2910) – 4 mg,

sodium stearyl fumarate – 2 mg.

Composition of the film coating:

hypromellose 6 mPa*s (type 2910) – 11.608 mg, hypromellose 15 mPa*s – 1.152 mg, hyprolose 7 mPa*s – 1.152 mg, macrogol 400 – 1.8 mg, macrogol 6000 – 0.322 mg, talc – 1.878 mg, colloidal silicon dioxide – 0.03 mg, sodium docusate – 0.03 mg, titanium dioxide (E171) – 1.912 mg, iron oxide red dye (E172) – 0.112 mg, iron oxide yellow dye (E172) – 0.002 mg, iron oxide black dye (E172) – 0.002 mg.

How to take, the dosage

Adults are prescribed 1 cap. 1 time per day. The drug should be taken orally, preferably in the morning after a meal. The capsule should be swallowed whole with water.

Interaction

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

Verapamil is an inhibitor of CYP3A4 and P-glycoprotein. A clinically significant interaction was observed when concomitant use with CYP3A4 inhibitors, with an increase in plasma verapamil levels, while CYP3A4 inducers decreased plasma verapamil concentrations. Accordingly, the possibility of this interaction should be taken into account when concomitant use of these drugs.

When antiarrhythmic drugs and beta-adrenoblockers are used concomitantly with the drug Tarka, an increase of adverse effects on the cardiovascular system (more severe AV-blockade, greater reduction of HR, development of heart failure and increased arterial hypotension) is possible.

The simultaneous use of quinidine with the drug Tarka increases the hypotensive effect. Pulmonary edema may develop in patients with hypertrophic obstructive cardiomyopathy.

The simultaneous use of antihypertensives, diuretics and vasodilators with Tarka increases the hypotensive effect.

The simultaneous use of prazosin, terazosin with Tarka increases the hypotensive effect.

Concomitant use of Tarka with some drugs for the treatment of HIV infection (ritonavir) may inhibit the metabolism of verapamil, which leads to increased plasma concentrations. Doses of verapamil should be reduced with concomitant use.

Concomitant use of carbamazepine with Tarca increases plasma levels of carbamazepine, which may be accompanied by carbamazepine-related side effects – diplopia, headache, ataxia or dizziness.

The concomitant use of lithium with the drug Tarka increases the neurotoxicity of lithium.

Concomitant use of rifampicin with the drug Tarka may reduce the hypotensive effect of verapamil.

Colchicine is a substrate for CYP3A4 isoenzyme and P-glycoprotein. Verapamil is known to inhibit the activity of CYP3A isoenzyme and P-glycoprotein. Therefore, when used concomitantly with verapamil, the concentration of colchicine in blood may increase significantly. Concomitant use of the drugs is contraindicated.

In patients with CHD, cases of hyperkalemia and suppression of myocardial function have been reported when verapamil is administered after dantrolene. Co-administration is contraindicated.

The simultaneous use of sulfinpyrazone with Tarka may decrease the hypotensive effect of verapamil.

The effect of muscle relaxants may be increased when concomitant use with the drug Tarka.

The simultaneous use of acetylsalicylic acid as an antiplatelet agent with verapamil may increase the tendency to bleeding.

Concomitant use with verapamil increases plasma ethanol levels.

Concomitant use with verapamil may increase serum levels of simvastatin/atorvastatin/lovastatin.

Patients receiving verapamil should start treatment with HMG-CoA reductase inhibitors (i.e., simvastatin/atorvastatin/lovastatin) at the lowest possible dose with gradual increase during therapy. If verapamil needs to be administered to patients already receiving HMG-CoA reductase inhibitors, then their doses should be reviewed and reduced accordingly to their serum cholesterol concentrations.

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

Trandolapril-induced interactions

Diuretics or other hypotensive drugs may increase the hypotensive effect of trandolapril.

Potassium-saving diuretics (spironolactone, amiloride, triamterene) or potassium preparations increase the risk of hyperkalemia, especially in patients with renal insufficiency. Trandolapril may reduce potassium loss when combined with thiazide diuretics.

The concomitant use of trandolapril (as well as any ACE inhibitors) with hypoglycemic agents (insulin or oral hypoglycemic agents) may increase the hypoglycemic effect and lead to an increased risk of hypoglycemia.

Trandolapril may impair lithium excretion. Serum lithium levels should be monitored.

Anaphylactoid reactions have been described in patients receiving ACE inhibitors when high-strength polyacrylonitrile membranes are used during hemodialysis. In patients receiving ACE inhibitors, this type of membrane should be avoided during hemodialysis.

Non-steroidal anti-inflammatory drugs (NSAIDs) may decrease the hypotensive effect of trandolapril, so BP should be monitored when NSAIDs are added to trandolapril therapy or when they are withdrawn.

ACE inhibitors may increase the hypotensive effect of some agents for inhalation anesthesia.

Allopuripol, cytostatics, immunosuppressive drugs and systemic corticosteroids or procainamide may increase the risk of leukopenia when treated with ACE inhibitors.

Aitacids may decrease the bioavailability of ACE inhibitors.

The antihypertensive effect of ACE inhibitors may be reduced if sympathomimetics are coadministered. In such cases careful monitoring is necessary.

As with any other hypotensive drug, co-administration of neuroleptics or tricyclic antidepressants increases the risk of orthostatic hypotension.

Special Instructions

Hepatic impairment

As trandolapril is metabolized in the liver to form an active metabolite, the drug should be administered with caution in patients with hepatic impairment and with close medical supervision.

Arterial hypotension

In patients with uncomplicated arterial hypertension, the development of arterial hypotension accompanied by clinical symptoms has been noted after the first dose of trandolapril or increasing the dose of the drug. The risk of arterial hypotension is higher when water-electrolyte balance is impaired as a result of long-term therapy with diuretics, salt restriction, dialysis, diarrhea, or vomiting. In such patients, before initiating therapy with trandolapril, therapy with diuretics should be discontinued and the BOD and/or sodium content should be replenished.

Agranulocytosis/oppression of bone marrow hematopoiesis

In treatment with ACE inhibitors, cases of agranulocytosis and suppression of bone marrow function have been described. These phenomena are more common in patients with impaired renal function, especially with systemic connective tissue diseases. In these patients (e.g., systemic lupus erythematosus or scleroderma) it is advisable to monitor regularly the number of leukocytes in blood and protein content in urine, especially in patients with impaired renal function, treatment with corticosteroids and antimetabolites.

Trandolapril may cause angioedema of the face, tongue, pharynx and/or larynx. There is evidence that ACE inhibitors are more likely to cause angioedema in non-Hispanic patients.

In the background of treatment with ACE inhibitors there have also been cases of angioedema of the intestine. This possibility should be considered if abdominal pain (with or without nausea or vomiting) develops with trandolapril.

Heart failure

The combination drug contains verapamil, so use of Tarka should be avoided in patients with severe left ventricular dysfunction (e.g., with a ventricular ejection fraction less than 30%, elevated pulmonary capillary wedging pressure greater than 20 mm Hg, or severe symptoms of pulmonary edema).Hg, or significant symptoms of chronic heart failure) and in patients with any degree of left ventricular dysfunction if they are receiving beta-adrenoblockers.

Particular patient groups

Tarka has not been studied in children less than 18 years of age, so its use in this age group is not recommended.

General precautions

In some patients receiving diuretics (especially in the first days of treatment), there is a sharp decrease in BP after prescribing trandolapril or increasing its dose.

Kidney function impairment

When examining patients with arterial hypertension, renal function should always be evaluated. In patients with CKD less than 30 ml/min, lower doses of trandolapril should be prescribed.

Patients with impaired renal function, chronic heart failure, bilateral renal artery stenosis, or artery stenosis of a single kidney (e.g., after renal transplantation) have an increased risk of impaired renal function. In some patients with arterial hypertension without impaired renal function, increased blood urea nitrogen and serum creatinine may be observed when trandolapril is prescribed in combination with a diuretic.

Hyperkalemia

In patients with arterial hypertension, especially with impaired renal function, Tarka may cause hyperkalemia.

Surgery/general anesthesia

In surgical procedures or general anesthesia with drugs causing arterial hypotension, trandolapril may block angiotensin II formation associated with compensatory renin release.

Desensitization

In patients receiving ACE inhibitors during desensitization treatment (e.g., by hymenopteran venom), life-threatening anaphylactic reactions may occur in rare cases.

L LDL-apheresis

When LDL-apheresis is performed, life-threatening anaphylactic reactions have been observed in patients receiving ACE inhibitors.

Impact on driving and operating machinery

Cautiousness is required when driving vehicles and engaging in other potentially dangerous activities requiring increased concentration and rapid psychomotor reactions, especially at the beginning of treatment. The drug Tarca may contribute to an increase in the blood alcohol content and slow down its excretion. In this regard, the effects of alcohol may be enhanced.

In impaired renal function

The use of the drug is contraindicated in severe renal impairment (CKD

. The drug should be used with caution in bilateral renal artery stenosis, artery stenosis of the sole renal artery, the condition after renal transplantation.

In patients with liver dysfunction

Patients with liver dysfunction should use the drug with caution.

Pediatric use

It is contraindicated in children and adolescents under 18 years of age.

Synopsis

Pink, oval, film-coated, modified-release tablets with “Δ182” engraved on one side.

Contraindications

– history of angioedema associated with the use of ACE inhibitors;

– hereditary and idiopathic Quincke’s edema;

– cardiogenic shock;

– Chronic heart failure of III and IV functional class according to NYHA classification;

– AV-blockade of II and III degree (except for patients with artificial pacemaker);

– sinoatrial block;

– acute myocardial infarction;

– CAD (except for patients with artificial pacemaker);

– acute heart failure; <

– atrial fibrillation/tripping in patients with Wolff-Parkinson-White syndrome;

– severe bradycardia;

– severe arterial hypotension;

– severe renal impairment;

– pregnancy;

– breastfeeding period;

– under 18 years of age (efficacy and safety not established);

– concomitant use with colchicine and dantrolene;

– aortic stenosis or left ventricular outflow tract obstruction;

– hypertrophic obstructive cardiomyopathy;

– concomitant use with beta-adrenoblockers (IV) (except for patients being treated in the intensive care unit);

– lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome (the drug contains lactose);

– hypersensitivity to any component of the drug or any other ACE inhibitor.

With caution: hyperkalemia; impaired liver function and/or renal function (CKR greater than 30 ml/min); in systemic connective tissue diseases (including systemic lupus erythematosus). systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma) especially during treatment with corticosteroids and antimetabolites; risk of agranulocytosis and neutropenia; bone marrow suppression, grade I AV blockade; bradycardia; hypotension; conditions accompanied with decrease of the blood circulation (including diarrhea, vomiting), bilateral stenosis of the renal arteries, stenosis of the artery of a single kidney (for example, after transplantation), conditions after kidney transplantation, diseases accompanied by impaired neuromuscular transmission (myasthenia gravis, Lambert-Eaton syndrome, severe Duchenne muscular dystrophy); in patients on a diet with restriction of table salt; Before low-density lipoprotein (LDL) apheresis procedure, simultaneous desensitization therapy with allergens (e.g., venom of hymenoptera) – risk of anaphylactoid reactions (in some cases – life-threatening); surgical intervention (general anesthesia) – risk of excessive BP decrease, hemodialysis with high-flow polyacrylonitrile membranes – risk of anaphylactoid reactions.

Side effects

The following are the side effects that have had a possible or probable association with the administration of Tarka during clinical trials.

Nervous system disorders: frequently (≥1/100 to

Cardiovascular system disorders: frequently (≥1/100 to

Respiratory, thoracic and mediastinal system disorders: (≥1/100 to

Gastrointestinal disorders: (≥1/100 to

General disorders: often (≥1/100 to

In addition to reactions identified during clinical studies, the following side effects were identified during post-registration use:

Infectious diseases: bronchitis.

Blood and lymphatic system disorders: leukopenia, thrombocytopenia.

Metabolic disorders: hyperkalemia.

Mental disorders: anxiety, insomnia.

Nervous system disorders: balance disorders, paresthesias, somnolence, fainting.

Visual organ disorders: visual disturbances, “shadows” in front of the eyes.

Labyrinth disorders: dizziness.

Cardiovascular system disorders: complete AV-blockade, resting angina pectoris, bradycardia, palpitations, tachycardia.

Vascular disorders: arterial hypotension, skin hyperemia, flushes to the skin of the face.

Respiratory system, chest and mediastinum disorders: shortness of breath, nasal congestion.

Gastrointestinal disorders: nausea, diarrhea, dry mouth.

Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, angioedema, skin itching, rash.

Muscular and connective tissue disorders: arthralgia, myalgia.

Renal and urinary tract disorders: pollakiuria, polyuria.

Gender organ disorders: erectile dysfunction.

General disorders: chest pain, swelling, weakness.

Laboratory and instrumental findings: increased LDH activity, alkaline phosphatase activity, creatinine concentration, urea concentration, blood ALT, AST activity.

Additional significant side effects that have been observed with verapamil:

Immune system disorders: hypersensitivity.

Endocrine system disorders: hyperprolactinemia.

Heart disorders: AV-blockade of I, II, III degree, sinus node arrest, heart failure.

Digestive system disorders: gum hyperplasia, abdominal pain, abdominal discomfort.

Skin and subcutaneous tissue disorders: urticaria.

Mammary gland disorders: gynecomastia, galactorrhea.

There are several isolated, reported cases of development of paralysis (tetraparesis) associated with co-administration of verapamil and colchicine. This could be due to the penetration of colchicine through the BBB due to inhibition of CYP 3A4 and P-glycoprotein activity by verapamil. Concomitant use of colchicine and verapamil is not recommended.

Additional significant side effects that have been observed with trandolapril:

Blood and lymphatic system disorders: agranulocytosis.

Immune system disorders: hypersensitivity.

Gastrointestinal disorders: vomiting, abdominal pain, pancreatitis.

Skin and subcutaneous tissue disorders: alopecia.

General disorders: fever.

The following are side effects that have been reported with other ACE inhibitors:

Blood and lymphatic system disorders: pancytopenia.

Nervous system disorders: transient cerebral circulation disorder.

Cardiac disorders: myocardial infarction, cardiac arrest.

Vascular disorders: cerebral hemorrhage.

Digestive system disorders: intestinal angioedema.

Skin and subcutaneous tissue disorders: erythema multiforme, toxic epidermal necrolysis.

Renal and urinary tract disorders: acute renal failure.

Laboratory and instrumental data: decrease in hemoglobin and hematocrit.

Overdose

In clinical trials, the maximum dose of trandolapril was 16 mg. There were no signs of intolerance.

In case of overdose of Tarka, the following symptoms caused by overdose may occur: marked BP decrease, AV-blockade, bradycardia, asystole. There have been recorded cases of death from overdose.

In case of overdose of Tarka the following symptoms caused by trandolapril may occur: marked BP decrease, shock, stupor, bradycardia, electrolyte disturbances, renal failure.

Treatment: symptomatic. Treatment of verapamil overdose includes parenteral administration of calcium preparations, use of beta-adrenomimetics and gastric lavage. Given the delayed absorption of the prolonged-acting drug, the patient’s condition should be monitored for 48 h; hospitalization may be required during this period. Verapamil is not eliminated by hemodialysis.

Pregnancy use

Pregnancy Safety of the drug Tarka in pregnant women has not been established. It is contraindicated for use during pregnancy. There are some observations of development of pulmonary hypoplasia in newborns, delayed fetal growth, patent ductus arteriosus and hypoplasia of cranial bones after use of ACE inhibitors during pregnancy.

No data on teratogenic or embryo/fetotoxic effects of ACE inhibitors during first trimester of pregnancy, but such possibility cannot be excluded completely. In patients planning pregnancy, hypotensive drugs for which the safety of use during pregnancy has been proven should be prescribed, unless ACE inhibitor use is necessary.

If pregnancy occurs while taking an ACE inhibitor, it should be immediately discontinued and a more appropriate treatment should be prescribed. It is known that ACE inhibitors administration in the second and third trimesters of pregnancy may cause fetotoxic effects of the drugs (impaired renal function, scarcity of water, delayed ossification of the skull bones) and toxic effects on the newborn (renal failure, hypotension, hyperkalemia).

In case of trandolapril administration starting from the second trimester of pregnancy, ultrasound assessment of fetal renal function and skull condition is recommended. Newborns whose mothers took ACE inhibitors during pregnancy should be under medical supervision to exclude arterial hypotension.

Breast-feeding period The use of Tarka during breast-feeding is contraindicated. Verapamil is excreted into the breast milk. There are no data on the use of trandolapril during breastfeeding. Preference should be given to drugs with a studied safety profile for this group of patients, especially when feeding newborns and premature infants.