Tarka - instructions for use, dose, side effects, contraindications

Active substanceVerapamil + TrandolaprilVerapamil + Trandolapril

Similar drugsTo uncover

Tarka®

pills inwards

Abbott GmbH & Co. KG Germany

Tarka®

pills inwards

Abbott GmbH & Co. KG Germany

Tarka®

capsules inwards

Abbott GmbH & Co. KG Germany

Dosage form: & nbspCapsules of prolonged action.

Composition:

Composition per one capsule

Granules of trandolapril

Active substance: Trandolapril 2.0 mg.

Excipients: corn starch - 37.15 mg, lactose monohydrate - 54.5 mg, povidone (K25) - 5.35 mg, sodium stearyl fumarate - 1.0 mg.

The verapamil tablet coated with a film sheath

Active substance: verapamil hydrochloride - 180.0 mg.

Excipients: cellulose microcrystalline - 59.1 mg, sodium alginate - 240.0 mg, povidone (K30) - 36.0 mg, magnesium stearate - 2.4 mg, purified water - 22.5 mg.

Film coating: hypromellose 6 mRa - 9.576 mg, hypromellose 15 mPa - 0,950 mg, giprolose 7 mPa - 0.944 mg, macrogol 400 - 1.485 mg, macrogol 6000 - 0.266 mg, talc 0.677 mg, silicon dioxide colloid - 0.031 mg, sodium docusate - 0.025 mg, titanium dioxide E171 - 2.546 mg;

Hard gelatin capsule (cap): titanium dioxide (E171) - 1,2125 mg, iron dye red oxide (E172) - 0.0672 mg, gelatin - 37.8419 mg, sodium lauryl sulfate - 0.0784 mg; (housing): titanium dioxide (E171) 1.8187 mg, iron dye red oxide (E172) 0.1008 mg, gelatin 56.7629 mg, sodium lauryl sulfate 0.1176 mg.

Description:

Hard gelatinous pale pink opaque capsules (size 0).Contents of capsules: white granules (trandolapril), verapamil white tablet of oblong biconvex form with film coating.

Pharmacotherapeutic group:A combined hypotensive drug ("slow" calcium channel blocker (BCC) + angiotensin converting enzyme (ACE) inhibitor).

ATX: & nbsp

C.09.B.B.10 Verapamil and Tradolapril

C.09.B.B ACE inhibitors in combination with calcium channel blockers

Pharmacodynamics:

Tarka® - combined preparation, which includes verapamil prolonged action and trandolapril.

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

Verapamil is a blocker of slow calcium channels.

Pharmacodynamics

Trandolapril

Trandolapril inhibits the activity of the renin-angiotensin-aldosterone system (RAAS) of 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 (low-activity decapeptide). The latter is converted by ACE (peptidyl dipeptidase) into angiotensin II, a potent vasoconstrictor,causing a narrowing of the arteries and increased blood pressure (BP), as well as stimulating the secretion of aldosterone by the adrenal glands.

Inhibition of ACE leads to a decrease in angiotensin II in the blood plasma, which is accompanied by a decrease in vasopressor activity and aldosterone secretion. Although the production of aldosterone decreases insignificantly, nevertheless, a slight increase in serum potassium in combination with loss of sodium and water can be observed.

Reducing the concentration of angiotensin II by the feedback mechanism leads to an increase in renin activity in the blood plasma. Another function of ACE is the destruction of kinin (bradykinin), which has a powerful vasodilating effect, to inactive metabolites. In this regard, suppression of ACE leads to an increase in circulating and tissue concentrations of the kallikrein-kinin system, which contributes to vasodilation by activating 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 hypertension, the use of ACE inhibitors leads to a comparable decrease in blood pressure in the "lying" and "standing" positions without compensatory increase in the heart rate (HR). Total peripheral vascular resistance (OPSS) decreases, cardiac output does not change or increases, renal blood flow increases, and the glomerular filtration rate usually does not change. A sharp discontinuation of therapy was not accompanied by a rapid increase in blood pressure. The antihypertensive effect of trandolapril is manifested 1 hour after ingestion and persists for at least 24 hours. In some cases, optimal control of BP can be achieved only a few weeks after the start of treatment. With prolonged therapy, the antihypertensive effect persists. Trandolapril does not worsen the daily profile of blood pressure.

Verapamil

Verapamil inhibits the current of calcium ions through the "slow" calcium channels of membranes of smooth muscle cells of vessels carrying and contractile cardiomyocytes. Verapamil causes a decrease in blood pressure at rest, and with physical exertion due to the expansion of peripheral arterioles.As a result of the decrease in OPSS (afterload), myocardial oxygen demand and energy consumption decrease. Verapamil reduces myocardial contractility. Negative inotropic effect of the drug can be compensated by a decrease in OPSS. The cardiac index does not decrease, except for 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 states are not a contraindication to the appointment of verapamil.

Clinical efficacy and safety

The drug Tarka®

In studies on healthy volunteers, as well as animals, there was no interaction between verapamil and trandolapril at the level of pharmacokinetic parameters or RAAS. Consequently, the synergism of the two drugs reflects their complementary pharmacodynamic effects. In clinical trials, the drug Tarka® reduced blood pressure more than both drugs alone.

Pharmacokinetics:

The drug Tarka®

There is no information on the pharmacokinetic interaction of verapamil and trandolapril or trandolaprilate,so the pharmacokinetics of the two drugs in a joint application does not differ from that when administered separately.

Trandolapril

Trandolapril is a prodrug and is hydrolyzed to the active diacid metabolite of trandolaprilate.

Suction

Trandolapril is rapidly absorbed after oral administration. Time to reach the maximum concentration (TC_m_Oh) Trandolapril in blood plasma - about 1 hour. The absolute bioavailability of trandolapril is about 10%.

Average Vehicle_m_Oh Trandolaprilat in blood plasma is 3-8 hours. Absolute bioavailability of trandolaprilat with trandolapril is about 13%. The maximum concentration and the area under the concentration-time curve does not depend on the time of ingestion.

Distribution

The association of trandolapril with plasma proteins is about 80% and does not depend on concentration. The volume of distribution of trandolapril (V_d) is about 18 liters. The association with 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), indicating a better binding quality with increasing concentration.

Metabolism

In the blood plasma trandolapril is subjected to hydrolysis by enzymes to the formation of an active diacid metabolite of trandolaprilate.

Excretion

The half-life (T_1/2) - less than 1 hour. With repeated administration of trandolapril, the equilibrium concentration of trandolaprilat is reached after about 4 days in healthy volunteers and in young or elderly patients with hypertension. In the equilibrium state, the effective T_1/2Trandolaprilat together with a small fraction of the drug taken varies between 15 and 23 hours, which probably reflects a binding to plasma and tissue ACE. After receiving labeled trandolapril, 33% of the drug was excreted by the kidneys and 66% by the intestine. About 9-14% of the dose of trandolapril is excreted as trandolaprilate by the kidneys. In a small amount, it is excreted unchanged through the kidneys (less than 0.5%). The total plasma clearance of trandolapril and trandolaprilat after intravenous administration of approximately 2 mg of the drug is approximately 52 liters per hour and 7 liters per hour, respectively. Renal clearance of trandolaprilat varies from 0.15 to 4 liters per hour, depending on the dose.

Special patient groups

Children

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

Elderly patients and gender differences

The pharmacokinetic properties of trandolapril have been studied in elderly patients (over 65 years of age) and in both sexes. The concentration of trandolapril in blood plasma increases in elderly patients with hypertension. However, the plasma concentration of trandolaprilate and its ACE inhibitory activity in patients with hypertension of the elderly and young patients are the same. The pharmacokinetics of trandolapril and trandolaprilate, as well as ACE inhibitory activity in elderly patients of both sexes are the same.

Race

Pharmacokinetics in representatives of different races has not been studied.

Renal insufficiency

Compared with healthy volunteers in hemodialysis patients with creatinine clearance less than 30 ml per minute, plasma concentrations of trandolapril and trandolaprilate are approximately 2-fold higher, and renal clearance is reduced by approximately 85%. Patients with renal failure are recommended to correct the dose of the drug.

Liver failure

In comparison with healthy volunteers in patients with alcoholic liver cirrhosis of mild to moderate severity, the plasma concentration of trandolapril andtrandolaprilate increases 9-fold and 2-fold, respectively, but the ACE-inhibitory activity does not change. Patients with hepatic insufficiency may require the administration of smaller doses of the drug.

Verapamil

Verapamil is a racemic mixture consisting of the same amount R-enantiomer and Senantiomer. Verapamil is actively metabolized. One of the 12 metabolites found in urine is noravapamil, whose pharmacological activity is 10-20% of that of verapamil; its share is 6% of the withdrawn drug. The equilibrium concentrations of norverapamil and verapamil are similar. Equilibrium concentration with long-term use once a day is achieved after 3-4 days.

Suction

More than 90% of the intravenous dose of verapamil is rapidly absorbed into the small intestine. Bioavailability is only 22% because of the pronounced effect of "primary passage" through the liver. With repeated use, the average bioavailability can increase to 30%. TS_m_Ohis 4-15 hours. The maximum plasma concentration of noravapamil is reached approximately 5-15 hours after taking the drug.Eating does not affect the bioavailability of the drug.

Distribution

Verapamil is well distributed in the body tissues, the volume of distribution varies within 1.8-6.8 l / kg in healthy volunteers. The connection with blood plasma proteins is about 90%.

Metabolism

Verapamil is actively metabolized. In vitro metabolic studies have shown that verapamil is metabolized by isoenzymes CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18 cytochrome P450. In healthy volunteers, after active administration of verapamil, active metabolism occurred in the liver, and 12 metabolites were found, most of them in trace amounts. The main metabolites were identified as forms N- and O-dealkylated derivatives of verapamil. Of these metabolites, only noravapamil has any significant pharmacological effect (approximately 20% of the original component), which was found during the study on dogs.

Excretion

Average half-lifewhen you re-enter it is 8 hours. Approximately 50% of the drug taken is excreted through the kidneys within 24 hours, 70% - within five days. Up to 16% of the drug taken is excreted through the intestine. Approximately 3-4% of the drug is excreted through the kidneys unchanged.The total clearance of verapamil is about the same as the hepatic blood flow, i.e. about 1 l / h / kg (in the range of 0.7-1.3 l / h / kg).

Special patient groups

Children

The available data on the pharmacokinetic properties of the drug in children are limited. After intravenous administration, the average half-life of verapamil is 9.17 hours, and the average clearance is 30 liters / h, while it is approximately 70 liters per hour in an adult weighing 70 kilograms. The equilibrium concentration in the blood plasma is slightly lower in children after taking the drug inward than in adults.

Elderly patients

Age can affect the pharmacokinetic properties of verapamil when it is taken by patients with hypertension. The half-life can be increased in elderly patients. There was no correlation between the antihypertensive effect of verapamil and age.

Renal insufficiency

Impaired renal function does not affect the pharmacokinetic properties of verapamil, which was found in comparative studies involving patients with terminal renal failure and patients with normal renal function. Verapamil and norverapamil are not excreted in significant amounts by hemodialysis.

Liver failure

Bioavailability and the half-life of verapamil increased in patients with cirrhosis of the liver. However, the kinetic characteristics of verapamil remain unchanged in patients with compensated liver dysfunction.

Indications:

Arterial hypertension (for patients who are not controlled by arterial pressure with trandolapril and verapamil in monotherapy or patients who are shown combined therapy with trandolapril and verapamil in the same dosages).

Contraindications:

- hypersensitivity to any component of the drug or to any other ACE inhibitor;

- angioedema in history, associated with the administration of ACE inhibitors;

- hereditary and idiopathic angioedema;

- cardiogenic shock;

- atrioventricular blockade of II or III degree (except for patients with an artificial pacemaker);

- syndrome of weakness of the sinus node (except for patients with an artificial pacemaker);

- heart failure with a reduced ejection fraction (EF) of less than 35% and / or pulmonary artery wedge pressure of more than 20 mm Hg;

- atrial fibrillation / flutter in the presence of additional pathways (including patients with Wolff-Parkinson-White syndrome, Launa-Ganong-Levin syndrome). These patients are at risk of developing ventricular tachyarrhythmias, including ventricular fibrillation in the case of verapamil;

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

- simultaneous use with β-blockers (intravenously) (except for patients undergoing intensive care unit treatment);

- severe violations of kidney function (QC less than 30 ml / min), including hemodialysis;

- cirrhosis of the liver with ascites;

- simultaneous use with aliskiren and aliskirenoderzhaschimi drugs in patients with diabetes mellitus and / or renal dysfunction (GFR less than 60 ml / min / 1.73 m²);

- pregnancy;

- the period of breastfeeding;

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

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

Carefully:

Hyperkalemia; with systemic diseases of connective tissue (including systemic lupus erythematosus, scleroderma),especially against the background of corticosteroids and antimetabolites - the risk of agranulocytosis and neutropenia; oppression of bone marrow hematopoiesis; acute myocardial infarction; atrioventricular blockade of the 1st degree; bradycardia; asystole; symptomatic arterial hypotension; conditions, accompanied by a decrease in the volume of circulating blood (BCC) (including diarrhea, vomiting); bilateral stenosis of the renal arteries; stenosis of the artery of a single kidney (for example, after kidney transplantation); use in representatives of the Negroid race (see section "Special instructions"); impaired liver function; hypertrophic obstructive cardiomyopathy; diseases accompanied by a violation of neuromuscular transmission (myasthenia gravis gravis, Lambert-Eaton syndrome, muscular dystrophy Duchesne); in patients who observe a diet with restriction of table salt; before the procedure for the apheresis of low density lipoproteins (LDL), simultaneous conduct of desensitizing therapy with allergens (for example, Hymenoptera venom) - the risk of developing anaphylactoid reactions (in some cases - life-threatening); surgical intervention (general anesthesia) - the risk of excessive LD reduction,hemodialysis using high-flow polyacrylonitrile membranes - the risk of anaphylactoid reactions; heart failure with PV more than 35%; simultaneous use with digoxin.

Pregnancy and lactation:

Safety of Tarka® in pregnant women is not established. Use during pregnancy is contraindicated. There are separate observations on the development of lung hypoplasia in newborns, intrauterine growth retardation of the fetus, open arterial duct and hypoplasia of the bones of the skull after the use of ACE inhibitors during pregnancy.

There is no information on teratogenic or embryo / fetotoxic effects of ACE inhibitors in the 1st trimester of pregnancy, but this possibility can not be completely ruled out. Patients planning a pregnancy should be prescribed antihypertensive drugs for which safety of use during pregnancy has been proven, except when the use of ACE inhibitors is necessary. If pregnancy occurs during the administration of an ACE inhibitor, it must be immediately discontinued and hypotensive therapy approved for use during pregnancy should be prescribed.It is known that with the use of ACE inhibitors in the 2 nd and 3 rd trimester of pregnancy, fetotoxic effects of drugs on the fetus (renal dysfunction, low blood pressure, slowing ossification of the skull bones) and toxic effects on the newborn (renal failure, arterial hypotension, hyperkalemia) are possible. In the case of trandolapril, starting with the second trimester of pregnancy, an ultrasound evaluation of the function of the kidneys of the fetus and the state of the bones of the skull is recommended. Newborns whose mothers took ACE inhibitors during pregnancy should be under the supervision of a physician to exclude arterial hypotension.

Verapamil may inhibit uterine contractions when applied at the end of pregnancy. In addition, based on the pharmacological properties, we can not exclude the possibility of developing bradycardia and arterial hypotension of the fetus.

Breastfeeding period

Verapamil is excreted in breast milk in small amounts. Data on the use of trandolapril in the period of breastfeeding are absent.

Application of the drug Tarka® is not recommended during breastfeeding.Preference should be given to drugs with a studied safety profile for this group of patients, especially when feeding newborns and premature babies.

Dosing and Administration:

Inside. Capsule swallowed whole and washed down with water. The drug is best taken in the morning after eating.

Adults

The recommended dose is one capsule per day. With prolonged treatment, the maximum daily dose of the drug for verapamil should not exceed 480 mg.

Special patient groups

Children and teenagers under 18 years of age

Application of the drug Tarka® is not recommended in children and adolescents under the age of 18 due to the fact that the efficacy and safety of the drug are not established (see the section "Contraindications").

Elderly age

Influence of the drug Tarka® has been studied in a limited number of elderly patients with hypertension. Pharmacokinetic data show that the systemic availability of Tarka® in elderly patients is higher compared with younger patients with hypertension. In some elderly patients, there may be a more pronounced decrease in blood pressure compared with younger patients.

Side effects:

Below are the side effects that were recorded during clinical trials and post-marketing use of the drug.

According to the WHO classification, all reactions are distributed according to organ systems and the frequency of development: very often (> 1/10); often (> 1/100, <1/10); infrequently (> 1/1000, <1/100); rarely (> 1/10000, <1/1000); very rarely (<1/10000); frequency is unknown (can not be determined from available data).

Often			Infrequently		Rarely	Rarely	Frequency unknown
Infectious and parasitic diseases
					plain herpes	bronchitis	upper respiratory tract infection, pharyngitis, sinusitis , rhinitis , glossitis *, urinary tract infection
Violations of the blood and lymphatic system
						pancytopenia, leukopenia, thrombocytopenia	agranulocytosis, decline hemoglobin, decline hematocrit, hemolytic anemia*
Immune system disorders
			hypersensitivity
Disorders from the metabolism and nutrition
			hyperlipidemia		anorexia		rise appetite, hyperkalemia, hypercholesterolemia, hyperglycemia, hyponatremia, hyperuricemia, gout, fermentopathy
Disorders of the psyche
						depression, increased excitability, anxiety, aggressiveness	insomnia, sleep disorders , hallucinations, decreased libido, confusion
Disturbances from the nervous system
head pain, giddiness		tremor, drowsiness		fainting		hemorrhage in the brain, loss of consciousness, violation of balance, hyperesthesia, paresthesia, dysgeusia	transient ischemic attack*, transitory violation of cerebral blood circulation, myoclonus, migraine, extrapyramidal disorder. paralysis (tetraparesis)
Disturbance of vision
						violation of view, "shroud" before the eyes	blepharitis, edema conjunctiva, disorder view
Hearing disorders and labyrinthine disorders
giddiness							noise in ears
Heart Disease
atrioventricular block of degree I		sensation palpitation				angina pectoris, bradycardia. tachycardia, fibrillation auricles, cardiac failure, stop hearts	myocardial infarction, atrioventricular blockade of II, III degree, sinus bradycardia, arrest of sinus node ("sinus arrest"), asystole, arrhythmia, ventricular tachycardia,myocardial ischemia, pathological changes on an electrocardiogram
Vascular disorders
expressed decline HELL, orthostatic hypotension, shock, hyperemia dermal integuments,						lability arterial pressures	arterial hypertension, angiopathy, disease peripheral vessels, varicose veins
"tides" of blood to the skin of the face
Disturbances from the respiratory system, chest organs and the mediastinum
cough						bronchial asthma, dyspnea, obstruction nose	bronchospasm, inflammation mucous upper shells respiratory paths, obstruction upper respiratory paths, productive cough, pharyngitis, pain in the oropharynx, nasal bleeding, disorder activities respiratory system
disorders of the digestive tract
constipation		nausea, diarrhea, abdominal pain, breaches of hand gastrointestinal tract				vomiting, dryness in the throat, dryness mucous shells oral cavity, pancreatitis	abdominal discomfort, dyspepsia, gastritis, flatulence, gingival hyperplasia, bloody vomiting, ileus, intestinal angioedema *
disorders of the liver and biliary tract
		abnormalities functional liver tests		hyperbilirubinemia		hepatitis, jaundice. cholestasis	cholestatic jaundice*
disorders of the skin and subcutaneous tissue
		rash, skin itch, face swelling, increased sweating		alopecia, diseases leather		angioedema, exudative erythema, psoriasis, dermatitis, urticaria	Stevens-jonson syndrome, toxic epidermal necrolysis, purpura, eczema, acne, dry skin
disorders of the musculoskeletal and connective tissue
						arthralgia, myalgia,	pain in the back, pain in the
						muscular weakness	limbs, bone pain, osteoarthritis, muscle spasm
disorders of the kidneys and urinary tract ways
	polyuria			azotemia		acute renal insufficiency *	pollakiuria
disorders of the genitals and breast
						erectile dysfunction, gynecomastia	galactorrhea
General disorders and disorders at the site of administration
	chest pain					edema, peripheral edema, asthenia, weakness	fever, worsening state of health, malaise
laboratory and instrumental data
						increased activity of transaminases, activity of alkaline phosphatase, lactate dehydrogenase activity, lipase activity, potassium content in blood, immunoglobulin concentration, activity gamma- glutamyl transferase	rise concentrations creatinine, concentrations urea, concentrations prolactin

* - undesirable side effect is characteristic for the whole class of inhibitors apf.

Overdose:

In clinical trials, the maximum dose of trandolapril was 16 mg. At the same time, there were no signs of his intolerance.

Symptoms of an overdose of the drug Tarka®, due to verapamil: marked decrease in blood pressure, atrioventricular block, bradycardia and asystole and negative inotropic effect.

Cases of death from an overdose have been recorded.

Symptoms of an overdose of the drug Tarka®, due to trandolapril: marked decrease in blood pressure, shock, stupor, bradycardia, water-electrolyte disorders, renal failure, hyperventilation, tachycardia, palpitations, dizziness, anxiety and cough.

Treatment

In case of an overdose, the stomach and intestines are washed.Further absorption of verapamil, located in the gastrointestinal tract, must be prevented by gastric lavage, sorbent administration (Activated carbon) and laxative.

In addition to common measures (maintenance of an adequate volume of circulating blood by transfusion of plasma and plasma substitutes) aimed at the treatment of significant decrease in blood pressure (e.g., shock), can also be carried inotropic support via dopamine, dobutamine or isoprenaline.

Treatment of overdoses of verapamil includes parenteral administration of calcium preparations, the use of beta-agonists and gastric lavage. Considering the slow absorption of the drug of prolonged action, patients are observed up to 48 h; during this period, hospitalization may be required.

Verapamil is not removed during hemodialysis.

In case of an overdose of trandolapril, an intravenous infusion of 0.9% sodium chloride solution is recommended. If there is a marked decrease in blood pressure, the patient should be moved to Trendelenburg position. If possible, intravenous catecholamines can also be administered. If the drug has been taken recently, measures should be taken,directed to the removal of trandolapril from the body (for example, induce vomiting, carry out gastric lavage, prescribe sorbents and sodium sulfate). It is not established whether trandolapril (or its active metabolite trandolaprilat) to be excreted during hemodialysis. With the development of bradycardia, resistant to treatment, the use of a pacemaker is indicated. It is often necessary to monitor the main indicators of vital functions and the content of electrolytes and creatinine in the blood serum.

Interaction:

Interactions due to verapamil

Research in vitro evidence that verapamil metabolized by isozymes CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18 cytochrome P450.

Verapamil is an inhibitor of the isoenzyme CYP3A4 and P-glycoprotein. A clinically significant interaction was observed with simultaneous application with isoenzyme inhibitors CYP3A4, while there was an increase in the concentration of verapamil in the blood plasma, while inductors of the isoenzyme CYP3A4 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 the data on drug interaction, due to the content of verapamil.

Possible types of interactions associated with the enzyme system CYP-450
A drug	Possible action on verapamil or verapamil for another drug with simultaneous application				A comment
Alpha-blockers
Prazozin	Increase in maximum concentration (C_max) prazosin (~ 40%), does not affect the half-life prazosin.				Additional antihypertensive action.
Terazozin	The increase in the area under the "concentration-time" curve (AUC) terazosin (~ 24%) and C_max (~25 %).
Antiarrhythmics
Flecainide			Minimum effect on plasma clearance of flecainide (<~ 10%); does not affect the plasma clearance of verapamil.
Quinidine			Decreased oral clearance of quinidine (~35 %).		Gain antihypertensive actions. There may be pulmonary edema in patients with hypertrophic obstructive cardiomyopathy.
Bronchodilator funds
Theophylline			Reduction of oral and systemic clearance (~20 %).		Reduced clearance in smokers (~11 %).
Anticonvulsants / antiepileptics
Carbamazepine			Increase AUC carbamazepine (~46%) in patients with resistant partial epilepsy.		An increase in the concentration of carbamazepine, which can cause the development of side effects of carbamazepine, such as diplopia, headache, ataxia or dizziness.
Phenytoin			Reduction of the concentration of verapamil in the blood plasma.
Antidepressants
Imipramine			Increase AUC imipramine (~15%).		Does not affect the concentration of the active metabolite, desipramine.
Hypoglycemic agents
Glyburide			C increases_m_Oh glyburide (~28 %), AUC (~26 %).
Anti-gouty agents
Colchicine			Increase AUC colchicine (~ 2.0 times) and C_m_Oh (~ 1.3 times).		Reduce the dose of colchicine (see the instructions for using colchicine).
Antimicrobial agents
Clarithromycin			It is possible to increase the concentration of verapamil in the blood plasma.
Erythromycin			It is possible to increase the concentration of verapamil in the blood plasma.
Rifampicin			Decreased AUC (~97%), C_m_Oh(~94%), bioavailability (~92%) of verapamil.		Antihypertensive effect may decrease.
Telithromycin			It is possible to increase the concentration of verapamil in the blood plasma.
Antineoplastic agents
Doxorubicin		Increases AUC (104%) and C_m_Oh (61%) of doxorubicin.			In patients with small cell lung cancer.
Barbiturates
Phenobarbital		The oral clearance of verapamil is increased 5-fold.
Benzodiazepines and other tranquilizers
Buspirone		Increases AUC and C_maxbuspirone ~ 3.4 times.
Midazolam		Increases AUC (~ 3 times) and Cmax (~ 2-fold) of midazolam.
Beta-blockers
Metoprolol		Increases AUC (~32.5%) and C_m_Oh (~41%) metoprolol in patients with angina pectoris.			See section "Special instructions".
Propranolol		Increases AUC (~ 65%) and C_m_Oh (~ 94%) propranolol in patients with angina pectoris.
Cardiac glycosides
Digitoxin		The overall clearance decreases (~27%) and extrarenal clearance (~29%) digitoxin.
Digoxin		In healthy volunteers, C increases_m_Oh (on ~44%), C_12h (on ~53 %), C_ss (on ~44%) and AUC (on ~50%) of digoxin.			Reduce the dose of digoxin. See section "Special instructions".
Antagonists H2 receptors
Cimetidine		Increases AUC R- (~25%) and S-(~40 %) verapamil with a corresponding decrease in clearance R- and S-verapamila.
Immunological / immunosuppressive agents
Cyclosporin		Increases AUC, C_ss, FROM_m_Oh (on ~45%) of cyclosporine.
Everolimus		Everolimus: increases AUC (~ 3.5 times) and C_m_Oh (~ 2.3 times). Verapamil: increases C_t_rough (the concentration of the drug in the blood plasma immediately before taking its next dose) (~ 2.3 times).			It may be necessary to determine the concentration and titration of the dose of everolimus.
Sirolimus		AUC increases sirolimus (~ 2.2 times); increases AUC of S-verapamil (~ 1.5 times).			It may be necessary to determine the concentration and titration of the dose of sirolimus.
Tacrolimus		It is possible to increase the concentration of tacrolimus in the blood plasma.
Hypolipidemic agents (inhibitors of HMG-CoA reductase)
Atorvastatin		It is possible to increase the concentration of atorvastatin, increase the concentration of verapamil on ~43% in plasma blood.
Lovastatin				It is possible to increase the concentration of lovastatin in the blood plasma and AUC verapamil (~ 63%) and FROM_m_Oh (~32 %).
Simvastatin				Increases AUC (~ 2.6 times) and C_m_Oh (~ 4.6-fold) of simvastatin.
Serotonin Receptor Agonists
Almotriptan				Increases AUC (~20%) and FROM_m_Oh (~24 %) of almotriptan.
Urikozuric means
Sulfinpyrazone				Increase in oral clearance of verapamil (~ 3 times), a decrease in its bioavailability (~60 %).		Antihypertensive effect may decrease.
Other
Grapefruit juice				Increase AUC R- (~49%) and S- (~37%) of verapamil and C_m_Oh R- (~75%) and S-(~51 %) verapamil.		Absence of influence on T1 / 2 and renal clearance. Grapefruit juice should not be taken with verapamil.
St. John's Wort perforated				Decreased AUC R- (~78%) and S- (~80%) of verapamil with a corresponding decrease FROM_m_Oh.

Other Possible Interactions of Verapamil

Hypotensive drugs, diuretics, vasodilators

Increased antihypertensive action.

Means for the treatment of HIV infection

Some drugs to treat HIV infection, such as ritonavir, can inhibit the metabolism of verapamil, which leads to an increase in its concentration in the blood plasma. Care should be taken to reduce the dose of verapamil.

Lithium

Increased neurotoxicity of lithium was observed during simultaneous reception of verapamil and lithium in the absence of changes or an increase in the concentration of lithium in the serum. However, an additional dose of verapamil also led to a decrease in serum lithium concentration in patients who regularly take lithium inside. Care should be taken to monitor the condition of patients taking both drugs.

β -adrenoceptor for intravenous administration

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

Muscle relaxants

The effect of muscle relaxants can increase.

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

Nonsteroidal anti-inflammatory drugs (NSAIDs)

When combined with all antihypertensive drugs, NSAIDs (including acetylsalicylic acid, used in a high dose as an anti-inflammatory drug, for example to relieve pain) can reduce the antihypertensive effect of trandolapril. It is necessary to strengthen the control of arterial pressure with additional reception or the termination of reception of any NSAIDs by the patient accepting trandolapril. In addition, it was found that NSAIDs and ACE inhibitors lead to an additional increase in potassium in the blood serum, while kidney function may be impaired.Such an effect, as a rule, is 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 in patients with heart failure. Simultaneous intake of acetylsalicylic acid and verapamil can lead to an increase in the number and severity of adverse events from taking acetylsalicylic acid (the risk of bleeding may increase).

Ethanol (alcohol)

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

Inhibitors of HMG-CoA reductase (statins)

Simvastatin / atorvastatin / lovastatin

Patients receiving verapamil, treatment with inhibitors HMG-CoA reductase (ie simvastatin / atorvastatin / lovastatin) should be started with as low a dose as possible with a gradual increase during therapy. It was noted that simultaneous use of verapamil and high doses of simvastatin increases the risk of myopathy / rhabdomyolysis.If it is necessary to appoint verapamil patients already receiving inhibitors of HMG-CoA reductase, it is necessary to review and reduce their dose according to the concentration of cholesterol in the blood serum.

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

Interactions caused by trandolapril:

Diuretics

Diuretics or other antihypertensives may increase the antihypertensive effect of trandolapril. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, eplerenone) or potassium preparations may increase the risk of hyperkalemia, especially in patients with renal insufficiency. Trandolapril can reduce potassium loss when combined with thiazide diuretics.

Angiotensin II receptor blockers, aliskiren

Clinical studies have shown that the double blockade of the renin-angiotensin-aldosterone system (RAAS) by 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) compared with the use of a single drug that affects RAAS (see "Contraindications", "Special instructions").

Hypoglycemic agents

The simultaneous use of trandolapril, as well as any ACE inhibitors, with hypoglycemic agents (insulin or hypoglycemic agents for oral administration) can increase hypoglycemic effect and lead to an increased risk of hypoglycemia.

Lithium

Trandolapril may worsen the excretion of lithium. It is necessary to control the concentration of lithium in the blood serum.

Gold

There have been reports of rare cases of nitrate-like reactions (their symptoms include facial flushing, nausea, vomiting and arterial hypotension) in patients with intravenous administration of drugs of gold (sodium aurotyomalata) and simultaneous administration of ACE inhibitors, including the drug Tarka®.

Other

When using high-flux polyacrylonitrile membranes during hemodialysis in patients receiving ACE inhibitors, anaphylactoid reactions were described.Patients receiving ACE inhibitors should avoid the use of membranes of this type during hemodialysis.

ACE inhibitors can enhance the antihypertensive effect of some agents for inhalation anesthesia.

Allopurinol, cytotoxic drugs, immunosuppressive agents and systemic corticosteroids or procainamide may increase the risk of developing leukopenia in the treatment of ACE inhibitors.

Antacids can reduce the bioavailability of ACE inhibitors.

The antihypertensive effect of ACE inhibitors can be reduced by the joint appointment of sympathomimetics. In such cases careful monitoring is necessary.

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

Special instructions:

The following specific instructions apply to the preparation of Tarka® because of the presence of trandolapril:

Angioedema

Trandolapril can cause angioedema, swelling of the face, lower extremities, tongue, vocal cords and / or larynx. There is evidence that,that ACE inhibitors often cause angioedema in patients of the Negroid race.

Against the background of treatment with ACE inhibitors, cases of angioedema of the intestine were also noted. This possibility should be considered when developing abdominal pain (accompanied by nausea or vomiting, or without these symptoms) against the background of trandolapril.

Patients with angioneurotic edema should immediately stop treatment with ACE inhibitors and monitor before the edema is eliminated. Angioedema in the face is usually resolved spontaneously. Edema that spreads not only to the facial area, but also the vocal folds, can be life-threatening because of the risk of airway obstruction. With angioneurotic edema of the tongue, vocal folds or larynx, immediate subcutaneous injection of 0.3-0.5 ml of epinephrine (adrenaline) solution (1: 1000) is required, as well as other therapeutic measures, if necessary.

Patients with vasorenal hypertension

ACE inhibitors can be used before the onset of operative therapy of vasorenal hypertension or in cases when surgical treatment will not be performed.In patients with unilateral or bilateral stenosis of the renal arteries, the risk of development of severe arterial hypotension and renal failure in the treatment of ACE inhibitors is increased. Taking diuretics can increase the risk. Impaired renal function may result in minor changes in serum creatinine concentration even in patients with unilateral renal artery stenosis. In such patients treatment should be started in a hospital with small doses of the drug followed by careful selection of a dose under close medical supervision. Diuretics should be discontinued; kidney function and potassium content in serum should be monitored in the first weeks of treatment.

Impaired renal function

When examining patients with hypertension, kidney function should always be evaluated.

In patients with impaired renal function, chronic heart failure, bilateral stenosis of the renal arteries, or stenosis of the artery of a single kidney (for example, after its transplantation), the risk of impaired renal function is increased. In some patients with hypertension,not having previous expressed renal diseases, with the appointment of trandolapril in combination with a diuretic, there may be an increase in urea nitrogen in the blood and serum creatinine.

Proteinuria

Proteinuria may develop, especially in patients with existing renal dysfunction or when taking relatively high doses of ACE inhibitors.

Double blockade of the renin-angiotensin-aldosterone system (RAAS)

There is evidence that concomitant use of ACE inhibitors and angiotensin II or aliskiren receptor blockers increases the risk of hypotension, hyperkalemia and decreased renal function (including acute renal failure).

For this reason, the double blockade of RAAS by the combined use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see "Contraindications", "Interaction with other medicinal products").

If double blockade therapy is considered absolutely necessary, it should be performed only under the supervision of a specialist and with careful monitoring of kidney function, blood pressure and electrolyte concentration.

ACE inhibitors and angiotensin II receptor blockers should not be used simultaneously in patients with diabetic nephropathy.

Hyperkalemia

In patients with arterial hypertension, especially with impaired renal function, the drug Tarka® can cause hyperkalemia. The risk factors for hyperkalemia include renal failure, the intake of potassium-sparing diuretics, the simultaneous use of drugs for the treatment of hypokalemia, diabetes mellitus and / or left ventricular dysfunction after a previous myocardial infarction.

Cough

With the use of ACE inhibitors, dry non-productive cough may occur, disappearing after the withdrawal of therapy.

Symptomatic arterial hypotension

In patients with uncomplicated arterial hypertension after 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 prolonged therapy with diuretics, limiting intake of table salt, dialysis, diarrhea or vomiting.In such patients, before starting therapy with trandolapril, diuretic therapy should be discontinued and the bcc and / or sodium content should be replenished.

Agranulocytosis and oppression of bone marrow hematopoiesis

In the treatment of ACE inhibitors, cases of agranulocytosis and suppression of bone marrow function have been described. The risk of developing neutropenia depends on the dose, the 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 if there is a violation of kidney function, treatment with corticosteroids and antimetabolites. These changes are reversible after the withdrawal of the ACE inhibitor.

Impaired liver function

Because the trandolapril metabolized in the liver with the formation of an active metabolite, patients with impaired liver function, the drug should be administered with caution and with careful monitoring by a physician.

Surgery / general anesthesia

When surgical interventions or general anesthesia with the use of drugs that cause arterial hypotension, trandolapril can block the secondary formation of angiotensin II associated with compensatory release of renin.

A doctor should be warned that the patient is taking an ACE inhibitor.

Desensitization

In patients receiving ACE inhibitors during the course of desensitization (for example, by the venom of Hymenoptera), in rare cases development of life-threatening anaphylactic reactions is possible.

LDL-apheresis

When LDL-apheresis was performed in patients receiving ACE inhibitors, life-threatening anaphylactic reactions were observed.

The following specific instructions apply to the preparation of Tarka® because of the presence of verapamil

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, pronounced arterial hypotension or left ventricular dysfunction.

Blockade of the heart / Atrioventricular block I degree / bradycardia / asystole

Verapamil affects atrioventricular (AV) and sinoatrial (CA) nodes and increases the time AV-conductivity. The drug should be used with caution, since development AV-blocks II or III degree (see the section "Contraindication") or single-beam, two-beam or three-beam blockade of the bundle of His need to significantly reduce the dose or complete discontinuation of verapamil and initiate the necessary treatment.

Verapamil affects AV- and CA-nodes and in rare cases can cause development AV-blocks II or III degree, bradycardia and, in some cases, asystole. These phenomena occur more often in patients with sinus node weakness syndrome.

Asystole in other patients, in addition to patients with sinus node weakness syndrome, usually takes a short time (a few seconds or less) with spontaneous restoration of atrioventricular or normal sinus rhythm. If it does not pass quickly, then immediately begin the appropriate treatment.

Beta-blockers

Mutual strengthening of cardiovascular disorders (AV-blockade II-III degree, a significant decrease in heart rate, the development of heart failure with potential arterial hypotension).Asymptomatic bradycardia (36 per minute) with atrial rhythm migration was observed in the patient simultaneously receiving timolol (beta-blocker) in the form of eye drops and verapamil inside.

Digoxin

In the case of simultaneous administration of verapamil with digoxin, the dose of digoxin should be reduced. See section "Interaction with other medicinal products".

Heart failure

Because of the presence of verapamil, patients with heart failure and an ejection fraction of more than 35% should undergo compensatory therapy before starting Tarka® and appropriate treatment further.

Arterial hypotension

In some patients receiving diuretics (especially in the first days of treatment), after the appointment of trandolapril, there may be a sharp drop in blood pressure.

Inhibitors of HMG-CoA reductase (Statins)

See section "Interaction with other medicinal products".

Neuromuscular transmission disorders

Diseases in which neuromuscular transmission is disturbed (myasthenia gravis gravis, Lambert-Eaton syndrome, Duchenne muscular dystrophy).

Other

Special patient groups

The drug Tarka® has not been studied in children and adolescents under 18 years of age, so its use in this age group is not recommended (see the section "Contraindications").

Impaired renal function

Despite the fact that during the comparative studies there was no evidence of an effect of renal dysfunction on the pharmacokinetic characteristics of verapamil in patients with terminal stage of renal failure, some reports suggest that in this case verapamil should be used with caution and with careful monitoring of patients with impaired renal function.

Verapamil can not be excreted by hemodialysis.

Impaired liver function

It should be taken with caution in severe violations of the liver.

Sodium

The drug Tarka® 180 mg + 2 mg contains 1.12 mmol (or 25.71 mg) of sodium per dose. Ego should be considered for patients who follow a diet with control of sodium intake.

Effect on the ability to drive transp. cf. and fur:

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. The drug Tarka® can contribute to increasing the alcohol content in the blood and slowing its excretion. In this regard, the effects of alcohol can be strengthened.

Form release / dosage:

Capsules of prolonged action 2 mg + 180 mg.

Packaging:

For 5, 7, 10 or 14 capsules in a PVC / Al foil blister. 1, 2, 3 or 4 blisters together with instructions for use in a cardboard box.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:П N014228 / 01

Date of registration:17.03.2008

The owner of the registration certificate:Abbott GmbH & Co. KGAbbott GmbH & Co. KG Germany

Manufacturer: & nbsp

ABBOTT, GmbH & Co. KG. KG Germany

Representation: & nbspABBOTT LABORATORIES LLC ABBOTT LABORATORIES LLC Russia

Information update date: & nbsp10.03.2015

Illustrated instructions

Instructions

Tarka® (Tarka®)