Tarka modified-release pills 4mg + 240mg 28pcs

Composition

Film-coated verapamil tablet:

Active ingredient:

verapamil hydrochloride – 180.0 mg.

Auxiliary substances:

microcrystalline cellulose – 59.1 mg,

sodium alginate-240.0 mg,

povidone (K 30) – 36.0 mg,

magnesium stearate-2.4 mg,

purified water-22.5 mg.

Film coating:

hypromellose 6 MPa-9.576 mg, hypromellose 15 MPa-0.950 mg, hyprolose 7 MPa-0.944 mg. macrogol 400-1.485 mg, macrogol 6000-0.266 mg, talc -0.677 mg, colloidal silicon dioxide-0.031 mg, sodium docusate-0.025 mg, titanium dioxide E 171-2.546 mg;

Solid gelatin capsule (cap):

titanium dioxide E 171 – 1.2125 mg, iron oxide red dye E 172-0.0672 mg, gelatin-37.8419 mg, sodium lauryl sulfate -0.0784 mg; (capsule): titanium dioxide E 171 – 1.8187 mg, iron oxide red dye E 172-0.1008 mg, gelatin-56.7629 mg, sodium lauryl sulfate-0.1176 mg

Pharmacological action

Tarka is a combination drug that includes long-acting verapamil and trandolapril.

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

Verapamil hydrochloride is a slow calcium channel blocker.

Trandolapril

Trandolapril inhibits the activity of the renin-angiotensin-aldosterone system in 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-activity decapeptide). The latter is converted by ACE (peptidyl dipeptidase) into angiotensin II, a powerful vasoconstrictor that causes narrowing of the arteries and increases blood pressure, as well as stimulates the secretion of aldosterone by the adrenal glands.

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

A decrease in the concentration of angiotensin II by the feedback mechanism leads to an increase in the activity of renin in blood plasma. Another function of ACE is to break down kinins (bradykinin), which have a powerful vasodilating property, to inactive metabolites. In this regard, ACE inhibition leads to an increase in circulating and tissue concentrations of the kallikrein-kinin system, which contributes to vasodilation due to activation of the prostaglandin system. This mechanism may partially determine the antihypertensive 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 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 glomerular filtration rate usually does not change. Abrupt discontinuation of therapy was not accompanied by a rapid increase in blood pressure.

The antihypertensive effect of trandolapril appears 1 hour after oral use and persists for at least 24 hours. In some cases, optimal blood pressure control can be achieved only a few weeks after the start of treatment. With long-term therapy, the antihypertensive 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 OPSS (afterload), the myocardial oxygen demand and energy consumption decreases. Verapamil reduces myocardial contractility. The negative inotropic effect of the drug can be compensated by a decrease in OPSS. The cardiac index does not decrease, except in patients with left ventricular dysfunction.

Verapamil does not affect the sympathetic regulation of cardiac activity, since it does not block beta-adrenergic receptors. bronchial asthma and bronchospastic conditions are not contraindications to the use of veralamil.

Tarka

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

Indications

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

Use during pregnancy and lactation

Use during pregnancy is contraindicated. Breast-feeding period. The use of Tarka® is not recommended during breastfeeding. Preference should be given to drugs with the studied safety profile for this group of patients, especially when feeding newborns and premature babies.

Contraindications

— a history of angioedema associated with the use of ACE inhibitors;

— hereditary and idiopathic angioedema;

— cardiogenic shock;

— chronic heart failure III and IV functional class NYHA classification;

— AV-block II and III degree (except for patients with an artificial pacemaker);

— sinoatrial blockade;

acute myocardial infarction;

— SSSU (except for patients with an artificial pacemaker);

acute heart failure;

— fibrillation/atrial flutter in patients with the syndrome Wolff-Parkinson-white;

— bradycardia;

— severe arterial hypotension;

— severe impaired renal function (CC

— pregnancy;

— the period of breastfeeding;

— age under 18 years (effectiveness and safety not established);

— simultaneous use of colchicine and dantrolene;

— aortic stenosis or obstruction of the outflow tract of the left ventricle;

hypertrophic obstructive cardiomyopathy;

— simultaneous use of beta-blockers (in/in) (except patients undergoing treatment in the intensive care unit);

— lactose intolerance, lactase deficiency, a syndrome of glucose-galactose malabsorption (product contains lactose);

— hypersensitivity to any component of the preparation or to any other ACE inhibitor.

With caution: hyperkalemia; breaking of the liver and/or renal function (QC more than 30 ml/min); in systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma) especially on the background of treatment with corticosteroids and antimetabolites; the risk of agranulocytosis and neutropenia; the oppression of bone marrow hematopoiesis, AV-block I degree; bradycardia; hypotension; state, accompanied by a decrease in BCC (including diarrhea, vomiting), bilateral renal artery stenosis, stenosis of the artery to a solitary kidney (eg, post-transplant), condition after kidney transplantation diseases associated with impaired neuromuscular transmission (myasthenia gravis syndrome of Lambert-Eaton heavy muscular dystrophy Duchenne); in patients who are on a diet with restriction of salt; before the procedure apheresis of low-density lipoprotein (LDL), the simultaneous holding of desensitizing therapy allergens (e. g. Hymenoptera venom) – the risk of anaphylactoid reactions (in some cases life-threatening); surgery (General anesthesia) – the risk of excessive reduction in blood pressure, hemodialysis using a high-flow polyacrylonitrile membrane – the risk of anaphylactoid reactions.

Side effects

The following are side effects that may or may not have been associated with taking the drug:  Tarka during clinical trials.

Nervous system disorders:  frequently (from ≥1/100 to

Disorders of the cardiovascular system:  frequently (from ≥1/100 to

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

Gastrointestinal disorders:  (≥1/100 to

Common disorders:  frequently (from ≥1/100 to

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

Infectious diseases:  bronchitis.

Disorders of the blood and lymphatic system:  leukopenia, thrombocytopenia.

Metabolic disorders:  hyperkalemia.

Mental disorders:  anxiety, insomnia.

Nervous system disorders:  disequilibrium, paresthesia, drowsiness, fainting.

Visual disturbances:  visual impairment, “shroud” in front of the eyes.

Labyrinth disorders:  dizziness.

Disorders of the cardiovascular system:  complete AV block, resting angina, bradycardia, palpitations, tachycardia.

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

Respiratory, thoracic and mediastinal disorders:  shortness of breath, nasal congestion.

Gastrointestinal disorders:  nausea, diarrhea, dryness of the oral mucosa.

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

Musculoskeletal and connective tissue disorders: arthralgia, myalgia.

Kidney and urinary tract disorders: pollakiuria, polyuria.

Genital disorders: erectile dysfunction.

Common disorders: chest pain, swelling, weakness.

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

Additional significant side effects observed with verapamil:

Immune system disorders: hypersensitivity.

Endocrine system disorders: hyperprolactinemia.

Cardiac disorders: AV block I, II, III degrees, sinus node arrest (“sinus arrest”), heart failure.

Disorders of the digestive system: gum hyperplasia, abdominal pain, abdominal discomfort.

Skin and subcutaneous tissue disorders: urticaria.

Breast disorders: gynecomastia, galactorrhea.

There are several separate reports of cases of paralysis (tetraparesis) associated with the combined use of verapamil and colchicine. This could be due to colchicine penetration through the BBB due to the suppression of the activity of the CYP 3A4 and P-glycoprotein eoenzymes under the action of verapamil. The combined use of colchicine and verapamil is not recommended.

Additional significant side effects that were observed with the use of turandolapril:

Disorders of the blood and lymphatic system: agranulocytosis.

Immune system disorders: hypersensitivity.

Gastrointestinal disorders: vomiting, abdominal pain, pancreatitis.

Skin and subcutaneous tissue disorders: alopecia.

Common disorders: fever.

Side effects that have been reported with other ACE inhibitors are listed below:

Disorders of the blood and lymphatic system: pancytopenia.

Nervous system disorders: transient cerebrovascular accident.

Cardiac disorders: myocardial infarction, cardiac arrest.

Vascular disorders: brain hemorrhage.

Disorders of the digestive system: intestinal angioedema.

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

Kidney and urinary tract disorders: acute renal failure.

Laboratory and instrumental data: reduced hemoglobin and hematocrit.

Interaction

Verapamil-related interactions

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

Verapamil is a CYP3A4 and P-glycoprotein inhibitor. A clinically significant interaction was observed when used concomitantly with CYP3A4 inhibitors, with an increase in the level of verapamil in blood plasma, while CYP3A4 inducers reduced the concentration of verapamil in blood plasma. Accordingly, with the simultaneous use of such tools, the possibility of this interaction should be taken into account.

The table summarizes data on drug interactions due to the content of verapamil.

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

The drug’s possible effect on verapamil or verapamil on another drug with simultaneous use of alpha-adrenoblockers prazosin, an increase in the Cmax of prazosin (approximately 40%), does not affect the T1/2 of prazosin. Terazosine increase in terazosin AUC (approximately 24%) and Cmax (approximately 25%).

Antiarrhythmics Flecainidminimum effect on plasma clearance of flecainide (quinidine) Decrease in oral clearance of quinidine (approximately 35%). Bronchodilating mediatheophylline decreases oral and systemic clearance (approximately 20%). For smokers-a decrease of about 11%. Anticonvulsants Carbamazepine Increased carbamazepine AUC (approximately 46%) in patients with resistant partial epilepsy. Antidepressantsimipramine An increase in the AUC of imipramine (approximately 15%), does not affect the level of the active metabolite, desipramine. Hypoglycemic agents for ingestion of glyburide increases Cmax of glyburide (approximately 28%), AUC (approximately 26%). Antimicrobial agents Clarithromycin may increase the level of verapamil. Erythromycin may increase the level of verapamil. Rifampicin increases the AUC (approximately 97%), Cmax (approximately 94%), and bioavailability (approximately 92%) of verapamil. Telithromycin may increase the level of verapamil. Anticancer agents Doxorubicin Increases the AUC (89%) and Cmax (61%) of doxorubicin when taking verapamil orally in patients with small cell lung cancer. Intravenous use of verapamil in patients with advanced neoplasms does not affect the plasma clearance of doxyrubicin.

Barbituratefenobarbital increases the oral clearance of verapamil by approximately 5 times. Benzodiazepines and other tranquilizers of buspirone increase the AUC and Cmax of buspirone by 3.4 times. Midazolam increases the AUC (approximately 3-fold) and Cmax (approximately 2-fold) of midazolam. Beta-blockers of metoprolol increase the AUC (approximately 32.5%) and Cmax (approximately 41%) of metoprolol in patients with angina pectoris.

Propranolol Increases the AUC (approximately 65%) and Cmax (approximately 94%) of propranolol in patients with angina pectoris. Cardiac glycoside digitoxin decreases total clearance (approximately 27%) and extrarenal clearance (approximately 29%) of digitoxin. Digoxin levels in healthy volunteers increased by Cmax (approximately 45-53%), Css(approximately 42%), and AUC (approximately 52%) of digoxin. Reducing the digoxin dose. Histamine H2-receptor blockers Cimetidine increases the AUC of R-and S-verapamil (approximately 25% and 40%, respectively) with a decrease in the clearance of R – and S-verapamil.

The immunosuppressant cyclosporine increases the AUC, Css, and Cmax (by approximately 45%) of cyclosporine. Sirolimusmay increase the level of sirolimus. Tacrolimusthe tacrolimus level may increase. Everolimusthe level of everolimus may increase. Hypolipidemic agents-HMG-CoA reductase inhibitors atorvastatin may increase the level of atorvastatin, increase the level of verapamil by approximately 42.8% in blood plasma.

Lovastatin may increase the level of lovastatin. Simvastatin increases the AUC (approximately 2.6-fold) and Cmax (approximately 4.6-fold) of simvastatin. Serotonin receptor antagonists Almotriptan increases the AUC (approximately 20%) and Cmax (approximately 24%) of almotriptan.

Uricosuric agentsulfine pyrazoneincrease in the oral clearance of verapamil (approximately 3 times), decrease in its bioavailability (approximately 60%). Other grapefruit juice increases in AUC of R-and S-verapamil (approximately 49% and 37%, respectively) and Cmax of R – and S-verapamil (approximately 75% and 51%, respectively). T1 / 2 and renal clearance did not change. Hypericum perforatum decreases the AUC of R-and S-verapamil (approximately 78% and 80%, respectively) with a decrease in Cmax.

Other possible interactions of verapamil

Concomitant use of antiarrhythmic drugs and beta-blockers with Tarka may increase the adverse effect on the cardiovascular system (more pronounced AV block, a more significant decrease in heart rate, the development of heart failure and increased arterial hypotension).

Concomitant use of quinidine with Tarka increases the hypotensive effect. Patients with hypertrophic obstructive cardiomyopathy may develop pulmonary edema.

Concomitant use of antihypertensive agents, diuretics and vasodilators with Tarka increases the hypotensive effect.

When used simultaneously with the drug Tarka prazosin, terazosin increases the hypotensive effect.

When used concomitantly with Tarka, some drugs for the treatment of HIV infection (ritonavir) may inhibit the metabolism of verapamil, which leads to an increase in its concentration in blood plasma. When using verapamil concomitantly, the dose should be reduced.

Concomitant use of carbamazepine with Tarka increases the level of carbamazepine in the blood plasma, which may be accompanied by carbamazepine-related side effects-diplopia, headache, ataxia or dizziness.

Concomitant use of lithium with Tarka increases the neurotoxicity of lithium.

When rifampicin is co-administered with Tarka, the hypotensive effect of verapamil may be reduced.

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

Hyperkalemia and suppression of myocardial function have been reported in patients with CHD who received verapamil after taking dantrolene. Concomitant use of drugs is contraindicated.

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

When used concomitantly with Tarka, the effect of muscle relaxants may increase.

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

When used concomitantly with verapamil, the level of ethanol in the blood plasma increases.

Concomitant use with verapamil may lead to an increase in 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 increases during therapy. If it is necessary to prescribe verapamil to patients who are already receiving HMG-CoA reductase inhibitors, then their doses should be reviewed and reduced accordingly 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.

Trandolapril-related interactions

Diuretics or other antihypertensive medications may increase the antihypertensive effect of trandolapril.

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

Concomitant use of trandolapril (as with 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 the elimination of lithium. It is necessary to monitor the level of lithium in the blood serum.

Other interactions

When using high-flow polyacrylonitrile membranes during hemodialysis in patients treated with ACE inhibitors, anaphylactoid reactions have been described. In patients receiving ACE inhibitors, the use of this type of membrane during hemodialysis should be avoided.

Nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce the hypotensive effect of trandolapril, so when NSAIDs are added to trandolapril therapy or they are discontinued, blood pressure control is necessary.

ACE inhibitors may enhance the antihypertensive effect of certain drugs for inhalation anesthesia.

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

Aitacids may reduce the bioavailability of ACE inhibitors.

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

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

How to take, course of use and dosage

Adults are prescribed 1 capsule 1 time/day.

The drug should be taken orally, preferably in the morning after a meal. The capsule is swallowed whole, washed down with water.

Overdose

In clinical trials, the maximum dose of trandolapril was 16 mg. At the same time, there were no signs of its intolerance. Symptoms of Tarka overdose due to verapamil: marked decrease in blood pressure, atrioventricular block, bradycardia and asystole, and negative inotropic effect. Overdose deaths have been reported. Symptoms of Tarka overdose due to trandolapril: marked decrease in blood pressure, shock, stupor, bradycardia, water and electrolyte disturbances, renal failure, hyperventilation, tachycardia, rapid heartbeat, dizziness, anxiety and cough. Treatment: in case of overdose, gastric and intestinal lavage is indicated. Further absorption of verapamil in the gastrointestinal tract should be prevented by gastric lavage, use of a sorbent (activated charcoal) and a laxative.

Description

Modified release tablets, film-coated red-brown, oval, with the inscription “Δ244” on one side; cross-sectional view: from white with a yellowish or grayish tint to brownish verapamil core, white trandolapril layer.

Special instructions

Impaired liver function

Since trandolapril is metabolized in the liver to form an active metabolite, patients with impaired liver function should be prescribed the drug with caution and under close medical supervision.

Arterial hypotension

In patients with uncomplicated arterial hypertension after taking the first dose of trandolapril or increasing the dose of the drug, hypotension was observed, accompanied by clinical symptoms. The risk of hypotension is higher if the water-electrolyte balance is disturbed as a result of prolonged diuretic therapy, salt restriction, dialysis, diarrhea, or vomiting. In such patients, diuretic therapy should be discontinued before starting trandolapril therapy and BCC and/or sodium content should be replenished.

Agranulocytosis/suppression of bone marrow hematopoiesis

Cases of agranulocytosis and suppression of bone marrow function have been reported during treatment with ACE inhibitors. These phenomena are often found 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 white blood cells in the blood and the protein content in the urine, especially with impaired renal function, treatment with corticosteroids and antimetabolites.

Angioedema

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 black patients.

Cases of intestinal angioedema have also been reported during treatment with ACE inhibitors. This possibility should be considered if abdominal pain develops (with or without nausea or vomiting) while taking trandolapril.

Heart failure

Tarka contains verapamil, so the use of the combined drug should be avoided in patients with severe left ventricular dysfunction (for example, with a ventricular ejection fraction of less than 30%, increased pulmonary capillary jamming pressure of more than 20 mm Hg, or severe symptoms of chronic heart failure) and in patients with any degree of left ventricular dysfunction, if they receive beta-blockers.

Special patient groups

Tarka has not been studied in children under 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), after prescribing trandolapril or increasing its dose, a sharp decrease in blood pressure is observed.

Impaired renal function

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

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

Hyperkalemia

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

Surgical intervention/General anesthesia

During surgical procedures or general anesthesia with drugs that cause hypotension, trandolapril can block the formation of angiotensin II associated with compensatory renin release.

Desensitization

Patients receiving ACE inhibitors during a course of desensitization (for example, with hymenopteran venom) may develop life-threatening anaphylactic reactions in rare cases.

LDL apheresis

Life-threatening anaphylactic reactions were observed during LDL apheresis in patients receiving ACE inhibitors.

Influence on the ability to drive vehicles and work with mechanisms

Caution should be exercised when driving vehicles and engaging in other potentially dangerous activities that require increased concentration and speed of psychomotor reactions, especially at the beginning of treatment. Tarka may increase the blood alcohol content and slow down its elimination. In this regard, the effects of alcohol can be enhanced.

 With impaired renal function:The drug is contraindicated in patients with severe renal impairment (CC).

With caution, the drug should be used for bilateral renal artery stenosis, stenosis of the artery of a single kidney, the condition after kidney transplantation.

With impaired liver function:

Caution should be exercised when prescribing the drug to patients with impaired liver function.

Use in children:

Contraindicated in children and adolescents under 18 years of age.

Storage conditions

At a temperature not exceeding 25°C. Keep out of reach of children.

Shelf

life is 1 year.

Active ingredient

Verapamil, Trandolapril

Conditions of release from pharmacies

By prescription

Dosage form

long-acting tablets

Purpose

For adults as directed by your doctor

Indications

Hypertension