Tritenzine (Tritenzin)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceAmlodipine + Valsartan + HydrochlorothiazideAmlodipine + Valsartan + Hydrochlorothiazide
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    • Dosage form: & nbspfilm-coated tablets
    Composition:

    1 tablet contains:

    active ingredients: amlodipine besylate 6.930 mg / 13.860 mg (converted to 5000 mg amlodipine / 10.000 mg), valsartan 160,000 mg / 160.000 mg, hydrochlorothiazide 12,500 mg / 12,500 mg;

    Excipients: microcrystalline cellulose (Avicel PH 101) 52.600 mg / 42.000 mg microcrystalline cellulose (Avicel PH 102) 46.770 mg / 85,000 mg corn starch pregelatinized 48,000 mg / 105.140 mg Crospovidone 17.700 mg / 22,000 mg Sodium carboxymethyl Type A 14,000 mg / 7,000 mg calcium hydrogenphosphate anhydrous 35,000 mg / 45.000 mg colloidal silica 2.500 mg / 2.500 mg magnesium stearate 4.000 mg / 5,000 mg;

    film sheath: Opadry II OY-L-28900 White 12,000 mg (lactose monohydrate 4.320 mg Hypromellose 15 cP 3,360 mg, titanium dioxide (E171) 3.120 mg Macrogol 4000 1.200 mg) / Opadry II 31F 32400 Yellow 15,000 mg (lactose monohydrate 5.400 mg hypromellose 15 mg 4,200 cP, iron oxide yellow dye (E172) 0.052 mg, titanium dioxide (E171) 3.848 mg macrogol 4000 1.500 mg).

    Description:

    Dosage of 5 mg + 160 mg + 12.5 mg: Oval tablets, film-coated white, with bevelled edges, embossed with the inscription AVH on one side, with the risk on the other side.

    Dosage of 10 mg + 160 mg + 12.5 mg: Oval tablets, film-coated light-yellow color, with bevelled edges, with Valium on one party.

    Pharmacotherapeutic group:Antihypertensive combined (blocker "slow" calcium channel + angiotensin II receptor antagonist, a diuretic +)
    ATX: & nbsp

    C.09.D.A   Angiotensin II antagonists in combination with diuretics

    Pharmacodynamics:

    Tritenzin is a combination of three antihypertensive components complement each other mechanism control blood pressure (BP): amlodipine (a dihydropyridine derivative) - blocker "slow" calcium channel valsartan - angiotensin II receptor antagonist (ARA II) and hydrochlorothiazide (HCTZ) - thiazide diuretic. The combination of these components leads to a more pronounced decrease in blood pressure compared to that of monotherapy with each drug alone.

    Amlodipine

    Amlodipine inhibits transmembrannoe intake of calcium ions (Ca++) in cardiomyocytes and smooth muscle cells of blood vessels. The mechanism of the antihypertensive action of amlodipine is associated with a direct relaxing effect on vascular smooth muscle,causing a decrease in total peripheral vascular resistance (OPSS) and a decrease in blood pressure.

    Experimental data show that amlodipine binds both to dihydropyridine and non-dihydropyridine receptors. Reduction of cardiomyocytes and myocytes of vessel walls is due to the ingress of Ca++ through calcium channels.

    After taking in therapeutic doses in patients with hypertension amlodipine causes vasodilation, leading to a decrease in blood pressure (in the patient's position "lying" and "standing"). Reduction of blood pressure is not accompanied by a significant change in the heart rate (heart rate) and the activity of catecholamines with prolonged use.

    Amlodipine concentrations in the blood plasma correlate with the therapeutic response in both young and elderly patients.

    With arterial hypertension in patients with normal renal function amlodipine in therapeutic doses leads to a decrease in the resistance of renal vessels, an increase in the glomerular filtration rate (GFR) and effective renal blood flow of the plasma without changing the filtration fraction and the expression of proteinuria.As with other slow calcium channel blockers, patients with normal left ventricular (LV) function showed a change in hemodynamic parameters of heart function at rest and under physical exertion: a slight increase in the cardiac index, without significant effect on the maximum rate of increase in pressure in the LV to the end-diastolic pressure and LV volume. Hemodynamic studies in intact animals and healthy volunteers showed that BP reduction under the influence of Amlodipine in the range of therapeutic doses is not accompanied by a negative inotropic effect, even with simultaneous use with beta-blockers. Amlodipine does not change the function of the sinoatrial node and does not affect atrioventricular conduction in intact animals and healthy volunteers. When using amlodipine in combination with beta-blockers in patients with arterial hypertension or with angina, a decrease in blood pressure is not accompanied by undesirable changes in electrocardiographic parameters.

    The clinical efficacy of amlodipine in patients with stable angina has been demonstrated,vasospastic angina and angiographically confirmed lesion of the coronary arteries.

    Valsartan

    Valsartan - an active and specific antagonist of angiotensin II receptors, intended for oral administration. It acts selectively on the AT subtype receptors1, which are responsible for the effects of angiotensin II. Increase in plasma concentration of unbound angiotensin II due to blockade AT1-receptors under the influence of valsartan can stimulate unlocked AT2-receptors that counteract the effects of stimulation AT1receptors. Valsartan does not have any expressed agonistic activity against AT1receptors. The affinity of valsartan for the receptors of the subtype AT1 approximately 20,000 times higher than to the AT subtype receptors2.

    Valsartan does not inhibit angiotensin-converting enzyme (ACE), which converts angiotensin I into angiotensin II and causes destruction of bradykinin. Because when angiotensin II antagonists are used, there is no inhibition of ACE and accumulation of bradykinin or substance P, development of a dry cough is unlikely.

    In comparative clinical studies of valsartan with an ACE inhibitor, the incidence of dry cough was significantly lower (p <0.05) in patients who received valsartan (2.6% of patients who received valsartan, and in 7.9% - those who received the ACE inhibitor). In a clinical study involving patients who previously developed a dry cough in the treatment with an ACE inhibitor, this complication was observed in 19.5% of cases with valsartan treatment, and in 19.0% of cases with a thiazide diuretic. At the same time, in the group of patients treated with an ACE inhibitor, cough was observed in 68.5% of cases (p <0.005).

    Valsartan does not interact and does not block the receptors of other hormones or ion channels, which are important for the regulation of the functions of the cardiovascular system.

    In the treatment of valsartan in patients with hypertension, there is a decrease in blood pressure, not accompanied by a change in heart rate.

    The antihypertensive effect is manifested for 2 h in most patients after a single intake of valsartan inside. The maximum decrease in blood pressure develops after 4-6 hours. After taking valsartan, the duration of the antihypertensive effect persists for more than 24 hours. For repeated use, the maximum decrease in blood pressure, regardless of the dose taken, is usually achieved within 2-4 weeks and maintained at the achieved level during prolonged therapy.A sharp discontinuation of valsartan is not accompanied by a sharp increase in blood pressure or other undesirable clinical consequences. The use of valsartan in patients with chronic heart failure (II-IV functional class by classification NYHA) leads to a significant reduction in the number of hospitalizations for cardiovascular disease (which is particularly pronounced in patients who do not receive ACE inhibitors or beta-blockers). With the use of valsartan in patients with left ventricular failure (with stable hemodynamic parameters) or with left ventricular dysfunction after a previous myocardial infarction, cardiovascular mortality is reduced.

    HCTZ

    The point of application of the action of thiazide diuretics is distal convoluted renal tubules. When thiazide diuretics are applied to highly sensitive receptors of the distal tubules of the cortical layer of the kidneys, reabsorption of sodium ions (Na+) and chlorine (Cl-). Suppression of the co-transport system Na+ and Cl-, apparently, is due to competition for the sites of binding of ions Cl- in this system. As a result, excretion Na+ and Cl- increases approximately equally. As a result of diuretic action, a decrease in the volume of circulating blood (BCC) is observed, which increases the activity of renin, the secretion of aldosterone, the excretion of potassium by the kidneys and, consequently, the decrease in the potassium content in the serum.

    Pharmacokinetics:

    The pharmacokinetic parameters of amlodipine, valsartan and HCTZ are characterized by linearity.

    Amlodipine

    Suction. After ingestion of amlodipine in therapeutic doses, the maximum concentration (CmOh) in the blood plasma is achieved after 6-12 hours. Absolute bioavailability averages 64-80%. Eating food does not affect the bioavailability of amlodipine.

    Distribution. Volume of distribution (Vd) is approximately 21 l / kg. In studies with amlodipine in vitro It is shown that in patients with arterial hypertension, approximately 97.5% of circulating amlodipine binds to plasma proteins.

    Metabolism. Amlodipine intensively (approximately 90%) is metabolized in the liver with the formation of active metabolites.

    Excretion. Excretion from the blood plasma is biphasic in nature with a half-life (T1/2) from about 30 to 50 hours. Equilibrium concentrations (Css) in blood plasma are achieved after prolonged use for 7-8 days. 10% is excreted unchanged, 60% - in the form of metabolites.

    Valsartan

    Suction. After oral administration of valsartan CmOh in blood plasma is achieved after 2-4 hours. The average absolute bioavailability is 23%.

    When taking with food, there is a decrease in bioavailability (by the value of the area under the curve "concentration-time" (AUC)) by 40% and CmOh in blood plasma by almost 50%, although approximately 8 hours after ingestion of valsartan in the blood plasma in people who took it with food, and in the group receiving valsartan on an empty stomach, even. Decrease AUC, However, there is no clinically significant decrease in the therapeutic effect, so valsartan can be used regardless of the time of meal.

    Distribution. Vd valsartan in the equilibrium period after intravenous (iv) administration was about 17 liters, indicating a lack of extensive distribution of valsartan in the tissues. Valsartan is largely associated with serum proteins (94-97%), mainly with albumins.

    Metabolism. Valsartan is not exposed to the expressed metabolism (about 20% of the accepted dose is defined in the form of metabolites). The hydroxyl metabolite is determined in blood plasma at low concentrations (less than 10% of AUC valsartan). This metabolite is pharmacologically inactive.

    Excretion. The pharmacokinetic curve of valsartan is of a downward multiexponential character (T1/2α less than 1 hour and T1/2β about 9 hours). Valsartan is excreted mainly unchanged through the intestine (about 83% of the dose) and kidneys (about 13% of the dose). After iv introduction, the plasma clearance of valsartan is about 2 l / h and its renal clearance is 0.62 l / h (about 30% of the total clearance). T1/2 is 6 hours.

    HCTZ

    Suction. Absorption of HCTZ after oral administration is rapid (time to reach CmOh about 2 hours). The average increase AUC is linear in nature and proportional to the dose in the therapeutic range. With simultaneous intake of food, both the increase and decrease in the systemic bioavailability of HCTT were reported as compared with the administration of the drug on an empty stomach. The magnitude of this effect is small and clinically insignificant. The absolute bioavailability of HCTZ after oral administration is 70%.

    Distribution. The kinetics of distribution and elimination as a whole is described as a biexponential decreasing function with T1/2 6-15 hours. With multiple applications, the HCTZ kinetics does not change and when used once a day, cumulation is minimal. Visible Vd - 4-8 l / kg. 40-70% of circulating plasma HCTZ binds to blood plasma proteins, mainly with albumins. HCTZ also accumulates in erythrocytes in concentrations about 3 times higher than those in blood plasma.

    Metabolism. HCTZ is displayed unchanged.

    Excretion. T1/2 the final phase is 6-15 hours. With repeated application, the kinetics of HCTZ does not change, with the use of 1 time per day, the accumulation of the drug is minimal. More than 95% of the absorbed dose of HCTZ is excreted unchanged in kidneys with urine.

    Amlodipine +valsartan+ HCTZ

    After ingestion of the drug Tritensin CmOh Amlodipine, valsartan and HCTZ are reached after 6-8, 3 and 2 hours, respectively. The rate and extent of absorption of tritensin are equivalent to the bioavailability of amlodipine, valsartan and HCTZ when taken in separate tablets.

    Pharmacokinetics in special clinical cases

    Patients younger than 18 years. Pharmacokinetic features of the use of the drug Tritenzin in children under 18 years of age have not been established.

    Patients over 65 years of age. Time to reach CmOh Amlodipine in blood plasma in young and elderly patients is the same. In elderly patients the clearance of amlodipine is slightly reduced, which leads to an increase AUC and T1/2-

    In elderly patients, the systemic effect of valsartan was somewhat more pronounced than in young patients, but this was not clinically significant.

    There are limited data on the reduction in systemic clearance of HCTZ in patients over 65 years of age (healthy volunteers or patients with hypertension) compared with younger patients.

    In patients with impaired renal function. In patients with impaired renal function, the pharmacokinetic parameters of amlodipine do not change significantly.

    There was no correlation between renal function (creatinine clearance (CC)) and systemic exposure of valsartan (AUC) in patients with varying degrees of impaired renal function.

    In the presence of renal failure, the mean maximum plasma concentrations and values AUC HCTZ is increased, and the rate of excretion is reduced. In patients with impaired renal function from mild to moderate T1/2 almost doubles. The renal clearance of HCTZ in patients with impaired renal function is reduced compared to normal indices (about 300 ml / min). The drug Tritensin is contraindicated in patients with severe renal failure (QC less than 30 ml / min), anuria, and should be used with caution in patients with mild and moderate renal insufficiency (CK 30-90 ml / min).

    Patients with impaired hepatic function. Patients with impaired liver function have reduced clearance of amlodipine, which leads to an increase AUC approximately 40-60%. On average, patients with liver disorders are mild (5-6 points on the Child-Pugh scale) and an average (7-9 points on the Child-Pugh scale) severity of bioavailability (by AUC) Valsartan is doubled in comparison with healthy volunteers (of the corresponding age, sex and body weight). Since the dysfunction of the liver does not have a clinically significant effect on the kinetics of HCTZ, correction of its dose in patients with impaired liver function is not required.The drug Tritensin is contraindicated in patients with severe hepatic insufficiency (more than 9 on the Child-Pugh scale), with biliary cirrhosis and cholestasis, and should be used with caution in patients with mild and moderate liver impairment.

    Indications:

    Hypertension II and III degree.

    Contraindications:

    - Hypersensitivity to amlodipine, valsartan, HCTZ, other derivatives of sulfonamide and dihydropyride series, as well as other auxiliary components of the drug;

    - hereditary angioedema, or edema in patients on the background of previous therapy with antagonists of ARA II receptors;

    - Pregnancy and pregnancy planning, the period of breastfeeding;

    - severe violations of the liver (more than 9 points on the scale Child-Pugh), biliary cirrhosis and cholestasis;

    - severe renal dysfunction (GFR <30 ml / min / 1.73 m2), anuria, patients on hemodialysis;

    - hypokalemia refractory to adequate therapy, hyponatremia, hypercalcemia, as well as hyperuricemia with clinical manifestations;

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

    - severe arterial hypotension (systolic blood pressure less than 90 mm Hg), collapse, cardiogenic shock;

    - clinically significant aortic stenosis;

    - hemodynamically unstable heart failure after acute myocardial infarction;

    - simultaneous use with aliskiren in patients with type 2 diabetes mellitus.

    Carefully:

    If you have any of the listed diseases before taking the drug, be sure to consult a doctor.

    Care should be taken when using the drug in patients with unilateral or bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney; at conditions accompanied by a decrease in BCC and water-electrolyte disorders: nephropathy, accompanied by loss of salts, prerenal (cardiogenic) impairment of kidney function; patients with hypokalemia, hypomagnesemia, hyponatremia, hypochloraemia, hypercalcemia; in patients with mitral or aortic stenosis, hypertrophic obstructive cardiomyopathy, in patients with chronic heart failure III-IV functional class by classification NYHA, with acute coronary syndrome, with violations of liver function of mild and moderate severity, especially against the background of bile duct obstruction (less than 9 on the Child-Pugh scale), with diabetes mellitus, systemic lupus erythematosus, hyperuricemia, elevated cholesterol and triglyceride levels, in patients with closed-angle glaucoma, as well as in patients after kidney transplantation. Care should be taken when using the drug in elderly patients.

    Care should be taken when using the drug Tritensin with potassium salts, potassium-sparing diuretics, potassium-containing substitutes edible salt, as well as with medicines that can cause an increase in the potassium content in the blood (eg, heparin).

    Pregnancy and lactation:

    Like any drug that affects the renin-angiotensin-aldosterone system (RAAS), the drug Tritenzin should not be used in women planning a pregnancy. When using any drug that affects RAAS, the doctor should inform the woman of childbearing age of the potential danger of these drugs during pregnancy.

    The use of the drug Tritenzin during pregnancy is contraindicated.

    It is known that the use of ACE inhibitors that affect RAAS, pregnant in the II and III trimesters, leads to damage or death of the developing fetus. Given the mechanism of action of ARA II, the risk to the fetus can not be ruled out. According to the retrospective analysis, the use of ACE inhibitors in the first trimester of pregnancy was accompanied by the development of the pathology of the fetus and the newborn. HCTZ penetrates the placental barrier. With the use of thiazide diuretics, including HCTZ, embryonic or neonatal thrombocytopenia, as well as other unwanted reactions observed in adult patients, is possible during pregnancy. In case of unintended admission of valsartan in pregnant women, cases of spontaneous abortion, malignancy and renal dysfunction in newborns are described. Data on the use of amlodipine in pregnant women is not enough to judge its effect on the fetus.

    If pregnancy is diagnosed with the drug Tritenzin, the drug should be discontinued as soon as possible.

    It is not known whether valsartan and / or amlodipine with breast milk in women.In experimental studies, valsartan was isolated from breast milk. HCTZ is also excreted in breast milk.

    The drug Tritensin should not be used during breastfeeding.

    Dosing and Administration:

    The drug should be taken orally, washed down with a small amount of water, regardless of food intake.

    The recommended daily dose is 1 tablet containing amlodipine + valsartan + HCTZ in a dose 5 mg + 160 mg + 12.5 mg, 10 mg + 160 mg + 12.5 mg. The drug is taken once a day.

    For convenience, patients receiving amlodipine, valsartan and HCTZ in separate tablets can be transferred to therapy with Tritensin, containing the same doses of active ingredients; with insufficient control of blood pressure in the background double combination therapy (valsartan + HCTZ, amlodipine + valsartan and amlodipine + HCTZ), patients can be transferred to triple combined treatment with Tritensin in appropriate doses.

    You can increase the dose 2 weeks after the start of therapy.

    The maximum antihypertensive effect of the drug is noted 2 weeks after the dose is increased. The maximum dose of the drug is 10 mg + 320 mg + 25 mg per day.

    Use in patients over 65 years of age

    Correction of the dose is not required.In patients in this category, if necessary, a reduction in the initial dose to the lowest-dose amlodipine, i.e., is possible. one tablet containing amlodipine + valsartan + HCTZ in a dose of 5 mg + 160 mg + 12.5 mg.

    Use in children and adolescents under the age of 18 years

    Since the safety and efficacy of the drug in children and adolescents (under 18 years) are not established, the drug is not recommended for use in patients in this category.

    Patients with impaired renal function

    For patients with impaired renal function of mild to moderate severity (GFR ≥ 30 mL / min / 1.73 m2, but ≤ 90 ml / min / 1.73 m2) correction of the initial dose is not required. The drug should not be used in patients with impaired renal function of a serious degree (GFR <30 ml / min / 1.73 m2) due to the presence of HCTZ in the formulation. The use of thiazide diuretics in monotherapy in patients with disorders of severe function (GFR <30 ml / min / 1.73 m2) is ineffective, but simultaneous use with "loop" diuretics in patients of this category is possible.

    Patients with impaired hepatic function

    Due to the presence in the composition of valsartan, HCTZ and amlodipine, the drug Tritensin is contraindicated in patients with severe hepatic dysfunction (more than 9 on the Child-Pugh scale),and it should be used with caution in patients with impaired liver function of mild to moderate severity (5-9 on the Child-Pugh scale) and obstructive liver disease. In patients in this category, if necessary, a reduction in the initial dose of the drug Tritenzin to the lowest-dose amlodipine is possible. those. one tablet containing amlodipine + valsartan + HCTZ in a dose of 5 mg + 160 mg + 12.5 mg.

    Side effects:

    Below are all the undesirable phenomena observed with the simultaneous use of amlodipine, valsartan and HCTZ, as well as amlodipine, valsartan and HCTT monotherapy.

    Amlodipine +valsartan+ HCTZ

    The safety of the use of amlodipine + valsartan + HCTZ at a maximum dose of 10 mg + 320 mg + 25 mg was studied in a study involving 2271 patients, 582 of whom received valsartan in combination with HCTZ and amlodipine.

    When using the combination of amlodipine + valsartan + HCTZ, no new adverse events (AEs) were detected compared to single-agent monotherapy. Good tolerability of the drug amlodipine + valsartan + HCTZ was observed even after prolonged use.

    The frequency of AE was not related to gender, age or race. When using amlodipine + valsartan + HCTZ, the changes in laboratory parameters were minimal and did not differ from those on monotherapy with separate components. With concurrent administration of HCTT together with valsartan (double combination therapy), a decrease in the hypokalemic effect of HCTZ is noted.

    Amlodipine

    The following criteria were used to estimate the frequency (according to the classification of the World Health Organization (WHO)): very often (≥1 / 10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10,000, <1/1000); very rarely (<1/10 000), the frequency is unknown (insufficient data to estimate the frequency of development). Within each group allocated according to frequency of occurrence, the undesirable reactions are distributed in order of decreasing importance.

    Violations of the blood and lymphatic system: very rarely - leukopenia, thrombocytopenia.

    Immune system disorders: very rarely - allergic reactions.

    Disorders from the metabolism and nutrition: very rarely - hyperglycemia.

    Disorders of the psyche: infrequently - insomnia, lability of mood, anxiety.

    Disturbances from the nervous system: often - headache, drowsiness, dizziness; infrequently - tremor, hypoesthesia, taste disorders, paresthesia, fainting; very rarely - muscle hypertonia, neuropathy.

    Disturbances on the part of the organ of sight: infrequent - visual disturbances, diplopia.

    Hearing disorders and labyrinthine disorders: infrequent - noise in the ears.

    Heart Disease: often - a feeling of palpitations; very rarely - arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation), myocardial infarction.

    Vascular disorders: often - "tides" of blood to the face; infrequent - marked decrease in blood pressure; very rarely - vasculitis.

    Disturbances from the respiratory system, chest and mediastinal organs: infrequently - shortness of breath, rhinitis; very rarely - cough.

    Disorders from the digestive system: often - pain in the upper abdomen, nausea; infrequent - vomiting, indigestion, dryness of the oral mucosa, constipation, diarrhea; very rarely - pancreatitis, gastritis, gingival hyperplasia.

    Disorders from the liver and bile ducts: very rarely - hepatitis, jaundice.

    Disturbances from the skin and subcutaneous tissues: infrequently - alopecia, increased sweating, itching, skin rash, purpura, discoloration, photosensitivity; very rarely - angioedema, urticaria, erythema multiforme, Stevens-Johnson syndrome.

    Disturbances from the musculoskeletal and connective tissue: infrequently - back pain, muscle spasm, myalgia, arthralgia.

    Disorders from the kidneys and urinary tract: infrequently - violations of urination, nocturia, pollakiuria.

    Violations of the genitals and breast: infrequently gynecomastia, erectile dysfunction.

    General disorders and disorders at the site of administration: often - peripheral edema, increased fatigue; infrequent asthenia, discomfort, general weakness, pain in the chest, pain of unspecified localization.

    Laboratory and instrumental data: infrequently - increase or decrease in body weight; very rarely - an increase in the activity of "liver" transaminases.

    Valsartan

    Below are the AEs detected in patients with arterial hypertension during clinical trials, as well as in clinical practice and laboratory studies.For AEs detected in clinical practice and laboratory studies, it is not possible to establish frequency of occurrence, therefore for these AEs it is indicated: "frequency is unknown".

    To assess the frequency of occurrence, the following criteria were used (according to WHO classification): 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 (insufficient data to estimate the frequency of development). Within each group allocated according to frequency of occurrence, the undesirable reactions are distributed in order of decreasing importance.

    Violations of the blood and lymphatic system: the frequency is unknown - a decrease in hemoglobin and hematocrit, neutropenia, thrombocytopenia.

    Immune system disorders: frequency unknown - hypersensitivity reactions, including serum sickness.

    Disorders from the metabolism and nutrition: the frequency is unknown - an increase in the potassium content in the serum.

    Hearing disorders and labyrinthine disorders: infrequently - vertigo.

    Vascular disorders: the frequency is unknown - vasculitis.

    Disturbances from the respiratory system, chest and mediastinal organs: infrequently - cough.

    Disorders from the digestive system: infrequently - pain in the abdomen.

    Disturbances from the liver and bile ducts: frequency unknown - increased activity of "liver" enzymes, increased bilirubin concentration in blood plasma.

    Disturbances from the skin and subcutaneous tissues: frequency unknown - angioedema, skin itching, rash, bullous dermatitis.

    Disturbances from musculoskeletal and connective tissue: the frequency is unknown - myalgia.

    Disorders from the kidneys and urinary tract: frequency unknown - increased creatinine concentration in blood plasma, impaired renal function, including acute renal failure.

    General disorders and disorders at the site of administration: infrequently - increased fatigue.

    In clinical trials with valsartan in patients with hypertension, the following AEs were noted (regardless of their causal relationship with the study drug): viral infections, upper respiratory tract infections, pharyngitis, rhinitis, sinusitis, insomnia, decreased libido.

    HCTZ

    The following AEs were detected with the use of thiazide diuretics (including GTC) in monotherapy.

    To assess the frequency of occurrence, the following criteria were used (according to WHO classification): very often (≥1 / 10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10000, <1/1000); very rarely (<1/10000), the frequency is unknown (insufficient data to estimate the frequency of development). Within each group allocated according to frequency of occurrence, the undesirable reactions are distributed in order of decreasing importance.

    Disorders from the metabolism and nutrition: very often - (especially against the background of high doses of HCTZ) hypokalemia, an increase in the concentration of lipids in the blood plasma; often hyponatremia, hypomagnesemia and hyperuricemia; rarely - hypercalcemia, hyperglycemia, glucosuria and worsening of the course of diabetes mellitus; very rarely - hypochloraemic alkalosis.

    Disturbances from the skin and subcutaneous tissues: often - hives and other skin rashes; rarely - photosensitivity; very rarely - necrotizing vasculitis and toxic epidermal necrolysis, lupus-like reactions, exacerbation of cutaneous manifestations of systemic lupus erythematosus; frequency is unknown - erythema multiforme.

    Disorders from the digestive system: often - decreased appetite, mild nausea, vomiting; rarely - discomfort in the abdomen, constipation, diarrhea; very rarely - pancreatitis.

    Disorders from the liver and bile ducts: rarely intrahepatic cholestasis or jaundice.

    Vascular disorders: often - orthostatic hypotension (may increase with alcohol, sedatives or pain medications).

    Heart Disease: rarely - arrhythmia.

    Disturbances from the nervous system: rarely - headache, paresthesia, dizziness.

    Disorders of the psyche: rarely - sleep disorders, depression.

    Disorders from the side of the organ of vision: rarely - visual impairment (especially in the first few weeks of treatment); frequency unknown - acute development of closed-angle glaucoma.

    Violations from the blood and lymphatic system: rarely - thrombocytopenia, sometimes in combination with purpura; very rarely - agranulocytosis, oppression of bone marrow hematopoiesis, hemolytic anemia, leukopenia, frequency unknown - aplastic anemia.

    Violations of the genitals and breast: often - impotence.

    Immune system disorders: very rarely - hypersensitivity reactions.

    Disorders from the respiratory system, the thoracic and mediastinal organs: very rarely - respiratory distress syndrome, including non-cardiogenic pulmonary edema and pneumonitis.

    Disorders from the nochek and urinary tract: frequency unknown - acute renal failure, impaired renal function.

    General disorders and disorders at the site of administration: frequency is unknown - hyperthermia, asthenia.

    Disturbances from the musculoskeletal and connective tissue: frequency unknown - muscle spasm.

    If any of the unwanted reactions listed in the manual is aggravated, or if you notice any other undesirable reactions not listed in the instructions, tell your doctor.

    Overdose:

    Data on cases of drug overdose are currently not available.

    Valsartan

    With an overdose of valsartan, you can expect the development of a marked decrease in blood pressure and dizziness.

    Amlodipine

    An overdose of amlodipine can lead to excessive peripheral vasodilation and possible reflex tachycardia. There was also reported the occurrence of a pronounced and prolonged decline in blood pressure until the development of shock with a lethal outcome.

    In the event of a marked decrease in blood pressure, the patient should be laid, raising his legs, and take active measures to support the activity of the cardiovascular system, including regular monitoring of the heart and respiratory system, circulating blood volume (BCC) and the amount of urine released.

    To maintain normal vascular tone in the absence of contraindications, it is possible to use vasopressor drugs. If the drug has been taken recently, vomiting or gastric lavage can be effective. The use of activated carbon in healthy volunteers was accompanied by a decrease in the absorption of amlodipine. Valsartan and amlodipine with hemodialysis not removed, whereas for the removal of HCTZ hemodialysis can be effective.

    Interaction:

    General drug interactions for valsartan and HCTZ

    Lithium preparations

    With simultaneous use of lithium drugs with ACE inhibitors, angiotensin II receptor antagonists or thiazide diuretics, a reversible increase in lithium serum levels and associated increased toxic effects were noted.The risk of toxic manifestations associated with the use of lithium drugs may be further increased with simultaneous use with the drug Tritensin. since the renal clearance of lithium preparations is slowed by exposure to thiazide diuretics. In this regard, it is recommended that careful monitoring of lithium content in serum is recommended.

    Amlodipine

    In monotherapy with amlodipine, no clinically significant interaction with thiazide diuretics, beta-blockers, ACE inhibitors, long-acting nitrates, nitroglycerin for sublingual use, digoxin, warfarin, atorvastatin, sildenafil, aluminum and magnesium hydroxide, simethicone, cimetidine, nonsteroidal anti-inflammatory drugs, antibiotics and hypoglycemic drugs for oral administration. Simultaneous reception of amlodipine and ethanol does not affect the pharmacokinetics of the latter.

    Inhibitor inhibitors CYP3A4

    With the simultaneous use of amlodipine in a dose of 5 mg / day with diltiazem at a dose of 180 mg / day, in elderly patients with arterial hypertension, an increase in system exposure of amlodipine by 1.6 times was noted.When using amlodipine with potent inhibitors of isoenzyme CYP3A4 (e.g., ketoconazole, itraconazole and ritonavir), an even more pronounced increase in the systemic exposure of amlodipine is possible. It is necessary to use caution amlodipine with inhibitors of isoenzyme CYP3A4.

    In connection with inhibition of the isoenzyme CYP3A4 with simultaneous administration with grapefruit juice, the bioavailability of amlodipine may increase. In a clinical study in healthy volunteers, however, there were no significant changes in pharmacokinetics when taking amlodipine at a dose of 10 mg with 240 ml of grapefruit juice.

    Inductors of isoenzyme CYP3A4

    Since the use of amlodipine with isoenzyme inducers CYP3A4 (e.g., carbamazepine, phenobarbital, phenytoin, phosphenytoin, primidon, rifampicin, herbal preparations containing St. John's wort pierced) can lead to a marked decrease in its concentration in the blood plasma, caution should be exercised when using amlodipine with isoenzyme inducers CYP3A4.

    Simvastatin

    Multiple simultaneous use of simvastatin 80 mg / day and amlodipine at a dose of 10 mg / day leads to an increase in the exposure of simvastatin by 77%.It is recommended to reduce the dose of simvastatin to 20 mg / day in patients taking amlodipine.

    Valsartan

    It was found that with valsartan monotherapy there is no clinically significant interaction with the following drugs: cimetidine, warfarin, furosemide, digoxin, atenolol, indometacin, HCTZ, amlodipine, glibenclamide.

    Double blockade of RAAS with the use of angiotensin II receptor antagonists, ACE inhibitors or aliskiren

    Simultaneous use of angiotensin II receptor antagonists with other drugs that affect RAAS leads to an increase in the incidence of arterial hypotension, hyperkalemia, and renal dysfunction. It is necessary to monitor blood pressure, kidney function, and the content of plasma electrolytes when using the drug Tritenzin with other drugs that affect RAAS.

    Drugs and substances that affect the potassium content in blood serum

    When used simultaneously with biologically active additives containing potassium, potassium-sparing diuretics, eplerenone, potassium-containing salt substitutes or with other drugs,which can cause an increase in the potassium content in the blood (for example, with heparin), care should be taken and regular monitoring of potassium in the blood.

    Non-steroidal anti-inflammatory drugs (NSAIDs), including selective inhibitors of cyclooxygenase-2 (COX-2)

    It is possible to reduce the diuretic and antihypertensive action of valsartan when used simultaneously with NSAIDs, including selective inhibitors of COX-2, for example, with salicylic acid derivatives, indomethacin. Moreover, in elderly patients with concomitant hypovolemia (including due to diuretics) or with impaired renal function, the simultaneous use of ARA II and NSAIDs, including selective inhibitors of COX-2, can lead to impaired renal function. In patients in this group, renal function testing is recommended.

    Protein-carriers

    The simultaneous use of valsartan with inhibitors of the carrier protein OATP1B1 (rifampicin, ciclosporin) and with an inhibitor of carrier protein MRP2 (ritonavir) may lead to an increase in systemic bioavailability of valsartan.

    HCTZ

    Other antihypertensive drugs

    Thiazide diuretics increase the antihypertensive effect of other antihypertensive drugs (including guanethidine, methyldopa, beta adrenoblockers, vasodilating agents, slow calcium channel blockers, ACE inhibitors, ARA II, direct renin inhibitors).

    Curare like muscle relaxants

    Thiazide diuretics, including HCTT, potentiate the action of curare-like muscle relaxants (eg, tubocurarine chloride).

    NSAIDs

    It is possible to reduce the diuretic and antihypertensive effect of the thiazide component of the drug Tritensin when used simultaneously with NSAIDs, for example, with acetylsalicylic acid, indomethacin. Concomitant hypovolemia can lead to the development of acute renal failure.

    Drugs affecting the content of potassium in the blood

    The risk of hypokalemia increases with simultaneous use of other diuretics, glucocorticosteroids, adrenocorticotropic hormone, amphotericin B, carbenoxolone and acetylsalicylic acid (at a dose of more than 3 g).

    Drugs affecting the sodium content in the blood

    Hyponatremic effect caused by diuretics,can be intensified with simultaneous use with antidepressants, antipsychotic, anticonvulsants, etc. Caution should be exercised in the long-term simultaneous use of the drug Tritensin with the above preparations.

    Hypoglycemic agents

    When using HCTZ, there is a change in glucose tolerance, and therefore patients with diabetes mellitus may require a correction of insulin doses and hypoglycemic agents for oral ingestion. Since the use of HCTT with metformin may develop lactic acidosis (due to a violation of the function of the night on the background of therapy with HCTZ), caution should be exercised when using the drug Tritensin in patients receiving metformin treatment.

    Cardiac glycosides

    Hypokalemia and hypomagnesemia (undesirable effects of thiazide diuretics) can contribute to the development of cardiac rhythm disturbances in patients receiving cardiac glycosides.

    H- and m-holinoblokatory

    H- and m-holinoblokatory (incl. atropine, biperidene) can increase the bioavailability of HCTZ. which is associated with a decrease in peristalsis of the gastrointestinal tract and the rate of gastric emptying.Accordingly, stimulators of motility of the gastrointestinal tract (cisapride) can reduce the bioavailability of HCTZ.

    Anion exchange resins

    Absorption of HCTT decreases in the presence of colestyramine and colestipol. HCTZ should be taken within 4 hours or 4-6 hours after taking these compounds.

    Vitamin D and calcium salts

    Simultaneous reception of HCTT with vitamin D or calcium preparations can lead to an increase in the calcium content in the blood.

    Cyclosporin

    With the simultaneous use of HCTT and cyclosporine, the risk of developing hyperuricemia and the appearance of symptoms resembling gout are increased.

    Methyldopa

    Hemolytic anemia cases have been reported with simultaneous use of HCTT and methyldopa.

    Other types of interaction

    The simultaneous use of thiazide diuretics, including HCTZ, can lead to: an increase in the frequency of hypersensitivity reactions to allopurinol; increase the risk of developing unwanted reactions of amantadine; intensifying the hyperglycemic effect of diazoxide; a reduction in the excretion of drugs with cytotoxic action (eg, cyclophosphamide, methotrexate) to the potentiation of their myelosuppressive effects.Also, HCTZ can reduce the body's response to the introduction of pressor amines (noradrenaline), but this effect is clinically insignificant and can not interfere with the simultaneous use of drugs.

    Ethanol, barbiturates and narcotic drugs

    Simultaneous use with HCTZ may contribute to the development of orthostatic hypotension.

    Special instructions:

    Deficiency in the body of sodium and / or decreased BCC

    In controlled studies, the combination amlodipine + valsartan + HCTZ in a maximum daily dose (10 mg + 320 mg + 25 mg) in patients with arterial hypertension II and III degree of severity in 1.7% of cases there was a marked decrease in blood pressure, including orthostatic hypotension (compared to 1.8%, 0, 4% and 0.2% on the background of combination therapy valsartan + HCTZ in a dose of 320 mg + 25 mg, amlodipine + valsartan in a dose of 10 mg + 320 mg and amlodipine + HCTZ in a dose of 10 mg + 25 mg, respectively).

    In patients with severe BCC deficiency and / or hyponatremia, for example, in patients receiving high doses of diuretics, ARA II, in rare cases, symptomatic arterial hypotension may develop. Before starting treatment with Tritensin, you should adjust the sodium content in the body and / or BCC, or start therapy under close medical supervision.

    In case of development of arterial hypotension, the patient should be laid with raised legs, if necessary, an intravenous infusion of 0.9% sodium chloride solution. After stabilization of blood pressure, treatment with Tritenzin can be continued.

    Renal impairment

    The drug Tritensin should not be used in patients with severe impaired renal function (GFR <30 ml / min) due to the presence of HCTZ. In patients with chronic kidney disease, thiazide diuretics can cause azotemia. The use of thiazide diuretics in monotherapy in patients with severely impaired renal function (GFR <30 ml / min) is ineffective, however, concurrent use with the "loop" diuretics in this category of possible patients. For patients with impaired renal function of mild and moderate (GFR ≥ 30 mL / min / 1.73 m2, but ≤ 90 ml / min / 1.73 m2) correction of the initial dose is not required.

    Stenosis of the renal artery

    In patients with unilateral or bilateral renal artery stenosis or stenosis of the artery to a solitary kidney Tritenzin receiving the drug may be associated with an increase in serum urea and creatinine concentrations, so Tritenzin drug should be used with caution.

    Edema Quincke

    The emergence of hypersensitivity reactions against the background of the use of HCTZ was most often observed in patients with allergic reactions and bronchial asthma in the anamnesis.

    Quincke's edema, including swelling of the larynx and vocal cords, leading to airway obstruction, and / or edema of the face, lips, pharynx, and / or tongue edema, developed in patients who received valsartan; some of these patients had previously Edema Quincke on the background of taking other drugs, including ACE inhibitors. Admission of the drug Tritenzin in the case of the development of edema Quincke should be immediately canceled, the resumption of the drug Tritenzin in this case is prohibited.

    Insufficiency of blood circulation III-IV functional class (according to the classification NYNA), including after a previous myocardial infarction

    It is recommended to use with caution the blockers of "slow" calcium channels (including, amlodipine) in patients with heart failure III-IV functional class (according to the classification NYNA). In patients whose renal function depends on RAAS activity (eg, patients with circulatory failure III-IV functional class), ACE and ARA II therapy may be accompanied by oliguria and / or progressive azotemia and in rare cases can lead to acute renal failure and death. The examination of patients with circulatory failure and patients who underwent myocardial infarction should include a study of kidney function.

    Acute myocardial infarction

    In patients with severe ischemic heart disease, after the onset of (or increasing the dose) of amlodipine, an attack of angina or myocardial infarction may develop.

    Change in the concentration of electrolytes in blood plasma

    The simultaneous use of the drug Tritensin with potassium salts, potassium-sparing diuretics, potassium-substituting food salt substitutes, as well as with drugs that can cause an increase in the potassium content in the blood (eg, heparin), can lead to hyperkalemia.

    Therapy with thiazide diuretics can lead to the development of hypocalcemia or aggravate existing hypokalemia.

    Thiazide diuretics should be taken with caution, in the presence of conditions accompanied by loss of potassium (eg, nephropathy, cardiogenic impairment of kidney function).If hypokalemia is accompanied by clinical symptoms (eg, muscle weakness, paresthesias, changes in the ECG), therapy with Tritenzin should be discontinued. Before the beginning of therapy of HCTZ correction of existing water-electrolyte disturbances is recommended. In order to timely identify possible violations of the water-electrolyte balance during therapy, it is necessary to monitor the electrolyte content in the plasma (especially potassium).

    Therapy with thiazide diuretics can lead to the development of hyponatremia, hypochloraemia or aggravate the existing hyponatraemia. Individual cases of development of neurological symptoms in patients with hyponatremia (nausea, asthenia, disorientation, apathy). In patients with a marked decrease in the sodium level in the blood plasma or a reduced BCC, the initiation of therapy with Tritensin may be accompanied by a pronounced decrease in blood pressure. When using the drug Tritensin it is necessary to conduct regular monitoring of the electrolyte content in the blood plasma.

    Systemic lupus erythematosus

    With the use of thiazide diuretics, including HCTT, there was reported a worsening of the course or development of systemic lupus erythematosus.

    Other metabolic disorders

    Thiazide diuretics, including HCTT, can cause a change in glucose tolerance, as well as an increase in plasma concentrations of cholesterol, triglycerides and uric acid. Decreased uric acid clearance may lead to hyperuricemia and the appearance of gout symptoms in predisposed patients.

    Thiazide diuretics cause a decrease in calcium excretion and, accordingly, a moderate increase in the calcium content in the blood. Therefore, HCTT should be used with caution in patients with hypercalcemia. The development of severe hypercalcemia that does not occur after the abolition of HCTT (more than 12 mg / ml) may indicate an independent pathology. Several patients who received long-lasting thiazide diuretics had pathological changes in parathyroid glands accompanied by hypercalcemia and hypophosphatemia. In the case of hypercalcemia, an additional examination is required to clarify the diagnosis.

    Acute attack of angle-closure glaucoma

    Against the backdrop of the use of HCTT, as well as other sulfonamides, there have been cases of development of transient myopia and an acute attack of closed-angle glaucoma.The risk factor for the development of an acute attack of angle-closure glaucoma may be anamnestic data on allergic reactions to sulfonamides and penicillin. Symptoms, including a sharp drop in vision or pain in the eye, usually occur between a few hours to a week after initiation of therapy. The closed-angle form of glaucoma without therapy can lead to persistent loss of vision. Primary treatment should consist in the fastest possible withdrawal of the drug containing HCTZ. If the increased intraocular pressure is maintained, additional medical or surgical intervention may be required.

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

    Some unwanted reactions of the drug, incl. dizziness or visual disturbances, can adversely affect the ability to drive vehicles and carry out potentially dangerous activities that require increased concentration and speed of psychomotor reactions. Patients taking the drug Tritensin should be careful when driving vehicles and working with mechanisms.

    Form release / dosage:Tablets, film-coated, 5 mg + 160 mg + 12.5 mg and 10 mg + 160 mg + 12.5 mg.
    Packaging:

    For 10 tablets in PVC / ACLAR / PVC blisters // aluminum foil. 3 blisters together with instructions for use in a cardboard box.

    Storage conditions:

    Store at a temperature not exceeding 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:LP-004461
    Date of registration:15.09.2017
    Expiration Date:15.09.2022
    The owner of the registration certificate:Teva Pharmaceutical Enterprises Co., Ltd.Teva Pharmaceutical Enterprises Co., Ltd. Israel
    Manufacturer: & nbsp
    Representation: & nbspTeva Teva Israel
    Information update date: & nbsp18.10.2017
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