Triapin® (Triapin®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceRamipril + FelodipineRamipril + Felodipine
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  • Triapin®
    pills inwards 
    Sanofi-Aventis Deutschland GmbH     Germany
    • Dosage form: & nbspExtended-release tablets coated with a film sheath
    Composition:

    Triapine 2.5 mg + 2.5 mg

    1 tablet contains:

    active substances: felodipine - 2.5 mg, ramipril - 2.5 mg;

    Excipients:

    core tablet Giprolose 10 mg, hypromellose (viscosity 5 mPa.s) 0.4 mg, hypromellose (viscosity 50 mPa. s) 70 mg, hypromellose 10,000 mPas s 30 mg, lactose 52 mg, corn pregelatinized corn starch - about 49 mg, microcrystalline cellulose - 27 mg, macrogol glyceryl hydroxy stearate - 2.5 mg, propyl gallate - 0.06 mg, sodium aluminosilicate 47 mg, sodium stearyl fumarate 4.1 mg;

    film sheath - iron dye oxid yellow (E172) 0.3 mg, iron dye reddish brown oxide (E172) 0.04 mg, hypromellose (viscosity 6 mPa ● s) - 7.4 mg, macrogol-6000 - 1.9 mg, paraffin - about 0.1 mg, titanium dioxide (E 171) -0.7 mg.

    Triapin 5 mg + 5 mg 1 tablet contains: active substances: felodipine - 5 mg, ramipril - 5 mg; excipients: tablet core - giprolose - 10 mg, hypromellose (viscosity of 5 mPa ● s) - 0,9 mg, hypromellose (viscosity of 50 mPa ● s) - 70 mg, hypromellose (viscosity of 10,000 mPa ● s ) - 30 mg, lactose 51.5 mg, corn pregelatinized corn starch - about 47 mg, microcrystalline cellulose 26.5 mg, macrogol glycerol hydroxy stearate 5 mg, propyl gallate - 0.06 mg, sodium aluminosilicate 47 mg, sodium stearate and lf mind arate 4.2 mg; film sheath - iron dye oxide yellow (E172) - 0.07 mg, iron dye reddish brown oxide (E172) - 0.5 mg, hypromellose (viscosity 6 mPa ● s) - 7.6 mg, macrogol-6000 -1.9 mg, paraffin about 0.1 mg, titanium dioxide (E 171) - 0.8 mg.

    Description:

    Triapine 2.5 mg + 2.5 mg

    Round biconvex tablets covered with a film coating of a yellowish brown color, with a bevel, with an engraved "I" on one side and

    2.5 - on the other side. The core of the tablet consists of two layers: one layer is white or almost white, the other layer is yellow.

    Triapine 5 mg + 5 mg

    Round biconvex tablets covered with a film shell of a reddish-brown color, with a facet, with an engraved "I" on one side OE and 5 - on the other side. The core of the tablet consists of two layers: one layer is white or almost white, the other layer is yellow.

    Pharmacotherapeutic group:(angiotensin-converting enzyme (ACE) inhibitor + blocker of "slow" calcium channels (BCCC)
    ATX: & nbsp

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

    C.09.B.B.05   Ramipril and felodipine

    Pharmacodynamics:

    Both drugs that make up the combination: BCCC - felodipine and an ACE inhibitor - ramipril, reduce blood pressure (BP) due to dilatation of peripheral blood vessels. BCCI dilates the arterial bed, while ACE inhibitors expand both the arterial and venous channels. Vasodilatation and, consequently, a decrease in blood pressure can activate the sympathetic nervous system and the renin-angiotensin-aldosterone system. Inhibition of ACE leads to a decrease in plasma concentrations of angiotensin II.

    The hypotensive effect of a single dose of Triapin® drug develops in 1 -2 hours. The maximum hypotensive effect is achieved within 2-4 weeks, with prolonged treatment the effect is preserved. The hypotensive effect is maintained at a 24-hour dosing interval.

    Felodipine is a blocker of "slow" calcium channels, which reduces blood pressure by decreasing the total peripheral vascular resistance as a result of a direct relaxing effect on the smooth muscles of the vessels. Due to the selective effect on smooth muscle arterioles, therapeutic doses of felodipine do not affect myocardial contractility and conductivity. Felodipine reduces vascular resistance in the kidneys.This does not affect normal glomerular filtration. In case of impaired renal function, glomerular filtration may increase. Felodipine has a weak natriuretic and diuretic effect, fluid retention does not occur in the body.

    Ramipril. The active metabolite of ramipril-ramiprilate formed under the action of "hepatic" enzymes is a long-term

    active ACE inhibitor. In the blood plasma and tissues ACE catalyzes the conversion of angiotensin I to angiotensin II (vasoconstrictor active substance) and cleavage of the active vasodilator substances - bradykinin. Therefore, when taking ramipril decreases the formation of angiotensin II and bradykinin accumulation that leads to vasodilation and reduce blood pressure, and also contributes to the cardioprotective effects of ramipril and its endotelioprotektivnoe effect due to induction of nitric oxide (NO) in endothelial cells through activation of prostaglandin synthesis system and prostaglandins increase under the influence of increasing blood and tissue activity of kallikrein-kinin system.

    Angiotensin II stimulates the release of aldosterone, therefore, taking ramipril leads to a decrease in the secretion of aldosterone and an increase in the serum concentrations of potassium ions. Due to the negative feedback between angiotensin II concentration and renin secretion, a decrease in angiotensin II concentration leads to an increase in renin plasma activity.

    It is also assumed that with the increase in bradykinin activity, some undesirable reactions (dry cough) occur in part.

    Pharmacokinetics:

    Felodipine (long-acting dosage form): bioavailability is about 15% and does not depend on food intake. The maximum plasma concentration is achieved after 3 - 5 hours. The connection with plasma proteins is 99%. The volume of distribution in the equilibrium state is 10 l / kg. The half-life of felodipine is about 25 hours, the equilibrium state is reached after 5 days. With long-term treatment, there is no risk of cumulation. The clearance of felodipine averages 1200 ml / min. In elderly patients, a decrease in clearance leads to an increase in the concentration of felodipine in the blood plasma.Age is only a partial explanation of interindividual differences in the concentration of felodipine in the blood plasma. Felodipine is metabolized in the liver, and all of its known metabolites are devoid of vasodilator action. Approximately 70% of the accepted dose is excreted in the form of metabolites by the kidneys, and about 10% - through the intestine. Less than 0.5% of the dose is excreted unchanged by the kidneys. Impaired renal function does not affect plasma concentrations of felodipine.

    Ramipril: after oral administration ramipril quickly absorbed from the gastrointestinal tract (50-60%). The food slows down its absorption, but does not affect the fullness of the intake. Ramipril is subjected to intense presystemic metabolism / activation (mainly in the liver by hydrolysis), which results in its only active metabolite, ramiprilate, whose activity for inhibiting ACE is about 6 times that of ramipril. In addition, as a result of metabolism of ramipril, pharmacological activity-forming diketopiperazine is formed, which then undergoes conjugation with glucuronic acid, ramiprilate is also glucuronized and metabolized to diketopiperazic acid.

    The bioavailability of ramipril after ingestion varies from 15% (for a dose of 2.5 mg) to 28% (for a dose of 5 mg). Bioavailability of the active metabolite - ramiprilata - after ingestion of 2.5 mg and 5 mg of ramipril is approximately 45% (compared with intravenous administration of the same dose of ramipril).

    After taking ramipril inside the maximum plasma concentrations of ramipril and ramiprilata are reached after 1 and 2 - 4 hours, respectively. The decrease in plasma concentration of ramiprilata occurs in several stages: the phase of distribution and excretion with a half-life (T1 / 2) of ramiprilata, which is approximately 3 hours, then the intermediate phase with T1/2 ramiprilata, about 15 hours, and a final phase with a very low concentration of ramipril in plasma and T1/2 ramiprilata, which is about 4-5 days. This final phase is due to the slow release of ramiprilata from a strong bond with ACE receptors. Despite a prolonged final phase with a single daily ramipril intake of 2.5 mg or more, the equilibrium plasma concentration of ramiprilate is reached after approximately 4 days of treatment.With the course use of the drug "effective" T1/2 depending on the dose is 13-17 hours.

    The association with blood plasma proteins is about 73% for ramipril, and 56% for ramiprilate.

    After intravenous administration, the volume of distribution of ramipril and ramiprilate is approximately 90 liters and 500 liters, respectively.

    Approximately 80-90% of metabolites in urine and bile have been identified as ramiprilata and its metabolites. Ramipril glucuronide and ramipril diketopiperazine constitute approximately 10-20% of the total metabolites in urine, and the urinary content of unmetabolized ramipril is approximately 2%.

    In case of violations of kidney function (clearance of creatinine (CC) less than 60 ml / min.) Excretion of ramiprilate and its metabolites by the kidneys slows down. This leads to an increase in the plasma concentration of ramiprilate, which decreases more slowly than in patients with normal renal function.

    Bioequivalence of a fixed combination (felodipineramipril) and simultaneously taken individual preparations of felodipine and ramipril

    The pharmacokinetics of ramipril, ramiprilat and felodipine of the preparation Triapin® does not change significantly compared to that for individual preparations of felodipine and ramipril: felodipine tablets

    prolonged action and ramipril tablets. Felodipine does not affect the inhibition of ACE caused by ramiprilate. Thus, fixed-combination tablets felodipineramipril are bioequivalent to simultaneously taken separate components of this combination (felodipine prolonged action and ramipril).

    Indications:

    Arterial hypertension (with insufficient effectiveness of monotherapy with felodipine or ramipril)

    Contraindications:

    • Hypersensitivity to felodipine (or other dihydropyridine derivatives), ramipril, other ACE inhibitors or to any of the excipients of the drug.
    • Angioedema in history (risk of rapid angioedema development).
    • Instability of hemodynamics: cardiogenic shock, chronic heart failure in the stage of decompensation, acute myocardial infarction, unstable angina, stroke.
    • Atrioventricular blockade of II and III degree.
    • Hemodynamically significant obstructive stenosis of heart valves, including hemodynamically significant stenosis of the aortic or mitral valve.
    • Dynamic obstruction of cardiac outgrowth, including hypertrophic obstructive cardiomyopathy (GOKMP).
    • Hemodynamically significant stenosis of the renal arteries
    • (bilateral or unilateral in the case of a single kidney).
    • The condition after a recent transplantation of the kidney.
    • Simultaneous use of drugs containing aliskiren, in patients with moderate or severe renal failure (clearance of severe renal insufficiency (creatinine clearance less than 60ml / min) and patients with diabetes mellitus.
    • Simultaneous use with angiotensin II receptor antagonists in patients with diabetic nephropathy.
    • Primary hyperaldosteronism.
    • Heavy Hepatic Insufficiency (more than 9 points on the Child-Pyo scale).
    • Heavy renal disease insufficiency (creatinine clearance less than 20 ml / min) or hemodialysis (lack of sufficient clinical experience).
    • Pregnancy.
    • The period of the breast
    • feeding.
    • Age to 18 years (effectiveness and safety not established).
    • Extracorporeal methods of treatment leading to blood contact with negatively charged surfaces, such as hemodialysis or hemofiltration with or hemofiltration with defined by high-flow membranes (polyacrylonitrile membranes) and apheresis of low-density lipoproteins with dextran sulfate (high risk of severe anaphylactoid reactions).
    • Insufficiency of lactase, galactose intolerance, glucose-galactose malabsorption syndrome (due to the content of lactose in the formulation).

    Carefully:
    • Simultaneous application of the preparation Triapish with preparations containing aliskiren, or angiotensin receptor antagonists II (with a double blockade of the renin-angiotensin-aldosterone system (RAAS), there is an increased risk of excessive reduction in blood pressure, the development of hyperkalemia and impaired renal function).
    • States in which excessive lowering blood pressure is especially dangerous (stenosing lesions of the coronary and cerebral arteries, expressed arteries expressed ventricular arrhythmias).
    • Conditions accompanied by increased activity of the RAAS in which the inhibition of ACE is a risk of sharp reduction in blood pressure with the deterioration of kidney function (expressed arterial hypertension, chronic heart failure, moderate, hemodynamically significant unilateral renal artery stenosis with two kidneys preceding diuretics, vodnoelektrolitnogo balance disturbances, diarrhea, vomiting, patients with cirrhosis and impaired liver function (less than 9 points on the scale Chayld- Pugh) with edema and / or ascites).
    • Renal dysfunction (creatinine clearance 20- 50 ml / min) (the risk of hyperkalemia and decrease in the number of leukocytes).
    • Systemic diseases connective tissue (including systemic lupus erythematosus, scleroderma).
    • Concomitant therapy glucocorticosteroids, Immunomodulators, cytostatics, antimetabolites, allopurinol, procainamide, and lithium salts, inhibition of bone marrow hematopoiesis (risk of disorders of immune reactions, neutropenia and agranulocytosis).
    • Diabetes mellitus (risk of developing hyperkalemia).
    • Elderly age (risk of more severe antihypertensive actions).
    • Hyperkalemia.
    Pregnancy and lactation:


    Dosing and Administration:

    Tablets should be swallowed whole, with enough liquid. Tablets can be taken regardless of food intake or after a light meal without much fat or carbohydrates.

    You can not chew the tablets or before meals, divide them into parts and grind them.

    Doses

    Adults, including patients old age Usually, treatment should start with taking one tablet of the drug Triapin 2.5 mg + 2.5 mg once a day. After 2-4 pedules, the dose can be increased to one tablet of Triapin 5 mg + 5 mg once a day.

    The maximum daily dose is 2 tablets of the drug Triapin 2.5 mg + 2.5 mg once a day or 1 tablet of the drug Triapin 5 mg + 5 mg once a day.

    Use of Triapin in selected patient groups

    Before switching to Triapin, a preliminary individual titration of the doses of both components of the preparation is necessary.

    Patients with prior diuretic therapy

    It is necessary, if possible, to cancel diuretics for 2-3 days (depending on the duration of the action of diuretics) before starting treatment with Triapin, or at least reduce the dose of diuretics taken. When the absence of such an opportunity should begin treatment with ramipril from a dose of 1.25 mg per day and increase the dose of ramipril to 2.5 mg per day before switching to Triapin 2.5 mg + 2.5 mg.

    Patients with incompletely adjusted water electrolyte balance, patients with severe arterial hypertension, as well as patients for whom excessive blood pressure reduction may pose a certain risk (for example, in severe atherosclerotic lesions of the coronary and cerebral arteries)

    It should begin treatment with ramipril at a dose of 1.25 mg per day and increase the dose of ramipril to 2.5 mg per day before switching to Triapin 2.5 mg + 2.5 mg.

    Patients with impaired renal function

    When creatinine is cleared from 20 to 50 ml / min, ramipril should be started at a dose of 1.25 mg per day and the dose of ramipril increased to 2.5 mg per day before switching to pa of the drug Triapin 2.5 mg + 2.5 mg.

    Do not exceed the maximum dose of ramipril 5 mg per day.

    When creatinine clearance is less than 20 ml / min and in hemodialysis patients, experience with ramipril is not available. The drug is contraindicated for use in severe disorders of kidney function (see section "Contraindications").

    Patients with hepatic impairment

    Because the felodipine and ramipril metabolized in the liver, it is recommended to begin treatment of patients with impaired liver function with low doses of felodipine or ramipril under strict medical supervision.The maximum permissible daily dose of ramipril in such cases is 2.5 mg. Experience with Triapin in patients with severe impairment of liver function (more than 9 points on the Child-Pugh scale) is absent. The drug is contraindicated for use in severe violations of liver function (see section "Contraindications")

    Children

    Experience with Triapin children are absent, so it should not be used in this category of patients.

    Side effects:

    The following undesirable effects are presented in

    According to the following gradations of the frequency of their development but classification of the World Health Organizations: very often (> 10%); often (> 1%, <10%); infrequently (> 0.1%, <1%); rarely (> 0.01%, <0.1%); rarely, including individual communications (<0.01%); the frequency is unknown (according to the available data, the frequency can not be determined).

    In connection with the reception of ramipril, the following adverse reactions may develop: Heart failure Infrequently: myocardial ischemia, including attacks of angina pectoris or myocardial infarction, tachycardia, arrhythmia, sensation palpitations, peripheral edema.

    Violations from the blood and lymphatic system

    Infrequently: eosinophilia.

    Rarely: decrease in the number leukocytes in peripheral blood, including neutropenia or agranulocytosis, decrease in the number erythrocytes in peripheral blood, reduction of hemoglobin, decrease in the number platelets in peripheral blood.

    Frequency unknown: oppression bone marrow hematopoiesis, pancytopenia, hemolytic anemia.

    Violations from the nervous systems

    Often: headache, dizziness (a feeling of "lightness" in

    head).

    Infrequently: vertigo, paresthesia,

    agevzia (loss of taste sensitivity), dysgeusia (impaired taste

    sensitivity).

    Rarely: tremor

    equilibrium.

    Frequency unknown: ischemia

    of the brain, including ischemic stroke and transient cerebral circulation, violation

    psychomotor reactions (decreased response), burning sensation of the skin, parosmia (impaired perception of odors).

    Disturbances on the part of the organ of sight

    Infrequently: visual disorders, including blurred vision.

    Rarely: conjunctivitis.

    Hearing disorders

    caustically: hearing impairment, ringing in ears.

    Disturbances from the respiratory system, chest and mediastinum

    Often: "dry cough (increasing at night and in the "lying" position), bronchitis, sinusitis, dyspnea.

    Infrequently: bronchospasm, including weighting of the course of bronchial asthma, congestion of the nose.

    Disturbance of the digestive tract

    Often: mucositis gastrointestinal tract, digestive disorders, abdominal discomfort, dyspepsia, diarrhea, nausea, vomiting.

    Infrequently: fatal pancreatitis (cases of pancreatitis with a lethal outcome with the administration of ACE inhibitors have been extremely rare) increased activity of pancreatic enzymes in the blood plasma, angioedema of the small intestine, pain in the upper abdomen, including those associated with gastritis, constipation, dryness of the oral mucosa.

    Rarely: glossitis.

    Frequency unknown: aphthous stomatitis (inflammatory reaction of the mucous membrane of the oral cavity).

    Infringements from kidneys and

    urinary tract

    Infrequently: impaired kidney function, including the development of acute renal failure, an increase in the amount of excreted urine, an increase in pre-existing proteinuria, an increase in the concentration of urea and creatinine in the blood.

    Disturbances from skin

    integuments and subcutaneous tissues

    Often: skin rash, in particular maculopapular.

    Infrequently: angioedema, including fatal outcome (laryngeal edema can cause airway obstruction leading to legal outcome) cutaneous itching, hyperhidrosis (increased sweating).

    Rarely: exfoliative dermatitis, urticaria, onycholysis.

    Very rarely: reactions photosensitization.

    Frequency unknown: toxic epidermal necrolysis, Stevens-Johnson, erythema multiforme, pemphigus, weighting the course of psoriasis, psoriasis dermatitis, pemphigoidia or lechinoid (lichen-like) exanthema or enanthema, alopecia.

    Disorders from the side of the skeletal-muscular and connective fabrics

    Often: muscle cramps, myalgia.

    Infrequently: arthralgia.

    Infringements from endocrine system

    Frequency unknown: syndrome inadequate secretion

    antidiuretic hormone (SAN ADH).

    Violations from the exchange substances and nutrition

    Often: increase of content potassium in the blood.

    Infrequently: anorexia, decrease appetite.

    Frequency unknown: decline content of sodium ions in blood.

    Vascular disorders

    Often: excessive decrease in blood pressure, violation of orthostatic regulation of vascular tonus (orthostatic hypotension), syncopal conditions.

    Infrequently: "tides" of blood to the skin of the face.

    Rarely: the occurrence or intensification of circulatory disorders against the background of vascular lesions, vasculitis.

    Frequency unknown: Raynaud's syndrome.

    General disorders and disorders

    at the site of administration

    Often: pain in the chest, increased fatigue.

    Infrequently: fever.

    Rarely: asthenia (weakness).

    Disorders from the immune system

    systems

    Frequency unknown: anaphylactic or anaphylactoid reactions (with the inhibition of ACE, the amount of anaphylactoid reactions to insect venoms increases), an increase in the concentration of antinuclear antibodies.

    Disturbances from the liver and bile ducts

    Infrequently: increased activity of "hepatic" enzymes and / or concentration of conjugated bilirubin in blood plasma.

    Rarely: Cholestatic jaundice, hepatocellular lesions.

    Frequency unknown: acute liver failure,Cholestatic or cytolytic hepatitis (lethal outcome was observed extremely rarely).

    Violations of the genitals and mammary gland Infrequently: erectile disfunction with transient dysfunction, decreased libido.

    The frequency is unknown: gynecomastia.

    Disorders of the psyche Infrequent: depressed mood, anxiety, nervousness, motor anxiety, sleep disturbances, including drowsiness.

    Rarely: confusion.

    The frequency is unknown: attention violation.

    Adverse effects on the fetus

    Disturbance of fetal kidney development, decrease in fetal and newborn infants, impaired renal function, hyperkalaemia, skull bones hypoplasia, oligohydramnion, limb contracture,

    deformation of the bones of the skull, hypoplasia of the lungs.

    In connection with the reception of felodipa, the following adverse reactions may develop: Heart failure

    Often: peripheral

    edema.

    Infrequently: tachycardia, sensation

    palpitation.

    Rarely are syncopal states.

    Disturbances from the nervous system

    Often - a headache.

    Infrequent - dizziness, paresthesia.

    Disorders from the gastrointestinal tract

    Infrequent - nausea, pain in the abdomen.

    Rarely, vomiting.

    Very rarely - gingival hyperplasia, gingivitis.

    Disorders from the kidneys and urinary tract

    Very rarely - frequent urination.

    Disturbances from the skin and subcutaneous tissues

    Infrequently: skin rash, itching.

    Rarely: hives.

    Rarely: reactions

    photosensitization, leukocytoclastic vasculitis (allergic skin vasculitis).

    Disturbances from the musculoskeletal and connective

    muscular and connective tissue

    Rarely - arthralgia, myalgia.

    Violation of the vessels

    Often - "tides" of blood to the skin of the face.

    General disorders and disorders at the site of administration

    Infrequent - a feeling of fatigue.

    Immune system disorders

    Very rarely - reactions of increased sensitivity,for example, angioedema, an increase in body temperature. Disturbances from the liver and bile ducts Rarely: rise activity "hepatic" enzymes.

    Violations of the genitals and mammary gland Rarely: impotence, sexual disorder.


    Overdose:

    Overdose can cause excessive peripheral vasodilation with pronounced lowering of blood pressure, bradycardia (sometimes tachycardia), atrioventricular blockade I-III degree, hypokalemia, ventricular extrasystole, ventricular fibrillation, shock, electrolyte imbalance, and renal insufficiency.

    Primary detoxification with, for example, gastric lavage, the appointment of adsorbents and (or) laxatives (if possible in the first 30 minutes). With a pronounced decrease in blood pressure: in addition to replenishing the volume of circulating blood and salts, it may be necessary to administer agrarian adrenergic sympathomimetics and angiotensin II. With bradycardia, atrioventricular blockade or excessive excitation of the vagus nerve, enter atropine. A specific antidote for felodipine is calcium preparations (an overdose shows a slow intravenous injection of 10% calcium chloride or calcium gluconate, followed by a switch to a long infusion).

    Experiments with regard to the efficacy of forced diuresis, changes in urinary pH, hemofiltration or dialysis for the purpose of accelerated elimination of ramipril or ramiprilate are not available.

    Interaction:

    Contraindicated combinations - Use of some high-flow membranes with a negatively charged surface (for example,polyacrylonitrile membranes) during hemodialysis or hemofiltration; use of dextran sulfate in the apheresis of low density lipoproteins Risk of development of severe

    anaphylactoid reactions.

    - Simultaneous use of the preparation of Triapin and preparations containing aliskiren

    The simultaneous use of Triapin and preparations containing aliskiren, in patients with diabetes mellitus or moderate or severe renal failure with creatinine clearance less than 60 ml / min is contraindicated and not

    is recommended in other patients (see the sections "Contraindications", "With caution", "Special instructions").

    The simultaneous use of Triapin preparations and receptor antagonists for angiotensin II The simultaneous use of the preparation of Triapin and antagonists of receptors for angiotensin 11 in patients with diabetic nephropathy is contraindicated and not recommended in other patients (see the sections "Contraindications", "With caution", "Special instructions").

    Combinations not recommended

    With potassium salts, potassium-sparing diuretics (nfor example, amiloride, triamterene, spironolactone and its derivative eplerenone) and other drugs capable of increasing the serum potassium content

    Possible to increase the content of potassium in the serum, sometimes significantly expressed (while the application requires careful control of potassium in blood serum).

    With drugs inducing or inhibiting isoenzyme CYP3A4 Felodipine is a substrate of isoenzyme CYP3A4.

    Medicines, inducing or inhibiting isoenzyme CYP3A4, have a significant effect on the plasma concentration of felodipine.

    To drugs that enhance metabolism felodipine due to induction of isoenzyme CYP3A4, relate carbamazepine; phenytoin; barbiturates, including phenobarbital; rifampicin, as well as St. John's wort (Hypericum perforatum). When appointing felodipine concomitantly with carbamazepine, phenytoin, phenobarbital AUC (area under the concentration-time curve) decreases by 93%, and the maximum plasma concentration (Cmax) - by 82%. A similar effect is possible with Deerslayer perforated. Combinations with isoenzyme inducers should be avoided CYP3A4.

    To strong inhibitors of isoenzyme CYP3A4 include azole antifungal drugs, including itraconazole, ketoconazole; macrolide antibiotics, including erythromycin; cimetidine; telithromycin and HIV-progease inhibitors. With the simultaneous use of felodipine with itraconazole Cmax increases 8 times, a AUC - 6 times. During the application of felodipine Simultaneously with erythromycin, the Cmax and AUC increased almost 2.5 times. Combinations with strong inhibitors of isoenzyme CYP3A4.

    Some flavonoids grapefruit juice suppress isoenzyme CYP3A4.

    Simultaneous reception of felodipine with grapefruit juice increases Cmax and AUC felodipine, approximately, 2 times. The combined use of this combination should be avoided. Combinations that require compliance with watchfulness - FROM antihypertensive drugs drugs (especially diuretics) and other drugs that reduce blood pressure (nitrates, tricyclic antidepressants, funds for general and local anesthesia) Potentiation of antihypertensive effect.

    • With sleeping pills, narcotic and non-narcotic analgesics Perhaps a more pronounced decrease in blood pressure.

    • With vasopressor adrenomimetics (epinephrine [adrenaline])

    Weakened action of ramipril, requires careful monitoring of blood pressure.

    • With allopurinol, procainamide, cytostat Icicle / and,

    immunosuppressants, systemic glucocorticosteroids and other drugs that can affect hematological parameters Joint application increases the risk of developing leukopenia (see section "Special instructions").

    • With lithium salts

    Increase serum the concentration of lithium and the enhancement of the cardio- and neurooxic effects of lithium, so it is necessary to control the lithium content in the blood serum.

    • FROM hypoglycemic agents for oral administration (derivatives of sulfonylureas, biguanides), insulins

    In connection with the decrease in insulin resistance under the influence of ACE inhibitors, it is possible to increase the hypoglycemic effect of these drugs, up to the development of hypoglycemia. It is recommended that blood glucose concentration be carefully monitored at the beginning of the combined use of hypoglycemic agents and ACE inhibitors.

    • With vildagliptin and other glyptins

    In patients taking both ACE inhibitors and vildagliptin and other glyptins, there was an increase in the incidence of angioedema.

    • With estramustine In patients taking both ACE inhibitors and estramustine, there was an increase in the incidence of angioedema.

      • With inhibitors mTOR (mammalian Target of Rapamycin - target of rapamycin in mammalian cells)

      In patients taking both ACE inhibitors and inhibitors mTOR, there was an increase in the incidence of angioedema. Combinations that should be taken into account

      With non-steroidal anti-inflammatory drugs (indomethacin, acetylsalicylic acid) It is possible to weaken the action of ramipril, increase the risk of renal dysfunction and increase the content of potassium ions in the blood serum.

      • With heparin

      It is possible to increase the content of potassium ions in the blood serum.

      • With sodium chloride

        • Weakening of the antihypertensive effect of the preparation Triapin®.

        • FROM ethanol

        Increased symptoms of vasodilation.

        • With estrogens Weakening of the antihypertensive effect of the drug Triapin * (fluid retention).

          • With theophylline

          Simultaneous use of felodipine and theophylline for oral administration reduces the absorption of theophylline by approximately 20%. This phenomenon probably has little clinical significance.

          • With tacrolimus

          Felodipine can increase the concentration of tacrolimus.With simultaneous application it is necessary to monitor the concentration of tacrolimus in the serum, a dose correction of tacrolimus may be required.

          • Desensitizing therapy with

          increased sensitivity to poison of insects ACE inhibitors increase the likelihood of developing severe anaphylactic or anaphylactoid reactions to insect venoms. It is assumed that this effect can occur when other allergens are used.

          - With table salt Increased consumption of table salt with food can weaken the antihypertensive effect of the drug Triapin.

    Special instructions:

    Double blockade of RAAS with simultaneous application of the preparation of Triapin with preparations containing aliskiren, or antagonists of angiotensin II receptors is not recommended, due to the risk of excessive reduction in blood pressure, the development of hyperkalemia and impaired renal function.

    The simultaneous use of the preparation Triapin® with preparations containing aliskiren, in patients with diabetes mellitus and / or moderate or severe renal failure with creatinine clearance less than 60 ml / min is contraindicated (see section "Contraindications").

    Simultaneous use with angiotensin II receptor antagonists in patients with diabetic nephropathy is contraindicated (see section "Contraindications").

    When an angioedema develops, for example, a person (lips, eyelids) or tongue, or a swallowing or breathing disorder, the patient should immediately stop taking the drug. Angioedema of the tongue, pharynx or larynx (possible symptoms: a violation of swallowing or breathing) can be life threatening and requires emergency care (immediate subcutaneous injection of epinephrine (adrenaline) 1: 1000 (0.3-0.5 ml) solution or slow intravenous administration of 1 mg / ml epinephrine (note the breeding instructions) under ECG and AD control. hospitalization and observation for at least 12-24 hours until the symptoms are completely resolved.

    If there is an indication in the medical history of an angioneurotic edema that is not associated with the administration of ACE inhibitors, then such patients have a risk of developing it with Triapin®.

    The intestinal form of angioedema was recorded in patients treated with ACE inhibitors.These patients had abdominal pain (with or without nausea and vomiting); in some cases without prior edema of the face and with normal activity C1- esterases. This condition was diagnosed during CT or ultrasound examinations abdominal cavity or during surgery; symptoms were resolved after the withdrawal of the ACE inhibitor. In patients taking an ACE inhibitor and having abdominal pain, an differential diagnosis should

    The intestinal form of angioedema is included. In the treatment of ACE inhibitors, angioedema is more often reported in patients of the Negroid race, compared with patients of the Caucasoid race. It is necessary to observe the function of the kidneys, especially during the first weeks of treatment, and especially careful monitoring is recommended in patients with concomitant circulatory failure, renovascular vascular kidney disease (for example, with stenosis of the renal arteries, even clinically insignificant, or with unilateral hemodynamically significant stenosis of the renal artery, since in this case even a slight increase serum concentration creatinine may indicate a unilateral reduction in kidney function), in patients with impaired renal function, in patients after kidney transplantation.

    In some patients who received treatment with ACE inhibitors, including ramipril, observed an increase in the content of potassium ions in the blood serum. The risk group for hyperkalemia includes patients with renal insufficiency, diabetes mellitus, or patients who simultaneously take potassium-sparing diuretics, potassium supplements or potassium-containing salts, as well as patients receiving treatment with other drugs, the use of which is accompanied by an increase in serum potassium (for example, heparin). If the simultaneous use of the listed drugs it is necessary to regularly monitor the potassium content in the blood serum.

    Because of the possibility of developing hyponatremia, regular monitoring of the content of sodium ions in the blood serum is required. The likelihood of developing proteinuria is higher in patients with deficiency of renal function or at relatively high doses of ACE inhibitors.

    There is an increased risk of severe arterial hypotension and renal disease deficiency if patients with reno- vascular hypertension and established bilateral stenosis of the renal arteries, or stenosis of the artery of a single kidney, take ACE inhibitors. In patients with unilateral renal artery stenosis (in the presence of two kidneys), the reduction in renal function can occur only with small changes in serum creatinine concentration.

    Experience with Triapin in patients with newly transplanted kidney is absent.

    In rare cases, the use of ACE inhibitors is accompanied by a syndrome that begins with cholestatic jaundice, then progresses to fulminant necrosis of the liver (sometimes with a fatal outcome). The mechanism of this syndrome is unknown. With the development of jaundice, or a marked increase in the activity of "hepatic" transaminase, it is necessary to abolish the ACE inhibitor and provide the appropriate medical control.

    During major surgeries or in the treatment of pain medication that can reduce blood pressure, there may be an excessive decrease in blood pressure, which can be corrected by increasing the volume of circulating blood.

    In some patients, mainly in patients with chronic heart failure (as well as with renal insufficiency or without it) taking high doses of loop diuretics, in the case of hyponatremia or with a decrease in renal function after taking the first dose of the drug, it is possible the development of an excessive decrease in blood pressure that occurs with clinical symptoms. Therefore, the appointment such patients of the drug Triapin should Perform only after additional analysis of the condition and proper titration of the doses of individual components. Triapin can be administered only with stable hemodynamic parameters.In patients with hypertension without cardiac or renal insufficiency, it is possible to develop arterial hypotension, mainly in the case of a reduced volume of circulating blood due to diuretic therapy, restricted salt content in the diet, diarrhea or vomiting.

    Patients for whom a pronounced reduction in blood pressure is particularly dangerous (eg, in patients with coronary or cerebrovascular insufficiency), the drug should be taken and the appropriate doses of this combination should be selected by titration of the doses of individual preparations of felodipine and ramipril.If it is possible to achieve the necessary antihypertensive effect with the help of doses of ramipril and felodipine, equal to the doses contained in the preparation of Triapin, the patient can be transferred to the combination with fixed doses of the drug Triapin. In some cases felodipine may cause excessive decrease in blood pressure with tachycardia, which can provoke an exacerbation of the course of angina pectoris.

    Triapin can cause agranulocytosis and neutropenia. These undesirable reactions have been demonstrated with other ACE inhibitors: less common in patients without complications, and more often in patients with renal deficiency, especially when the latter is accompanied by systemic disease connective tissue (for example, systemic lupus erythematosus or scleroderma) on the background of treatment with immunosuppressive drugs. It is necessary to control the number of leukocytes in peripheral blood in patients with systemic diseases connective tissue, especially if the disease is accompanied by a violation of kidney function. After withdrawal of the ACE inhibitor

    neutropenia and agranulocytosis are reversible.If during treatment with the drug Triapin "develop symptoms such as fever, lymphadenopathy and (or) tonsillitis, you should see a doctor (you need control of the number of leukocytes in

    peripheral blood).

    During treatment with an ACE inhibitor, a "dry" cough may appear, which disappears after the drug is withdrawn.

    Simultaneous treatment ACE inhibitors and hypoglycemic drugs (insulin and hypoglycemic drugs for oral administration) can lead to an increase in hypoglycemic action with a risk of hypoglycemia. This effect is most pronounced at the beginning of treatment and in patients with impaired renal function.

    Metabolism of felodipine

    is carried out by means of isoenzyme CYP3A4.

    Therefore, combinations with drugs-strong inhibitors or isoenzyme inducers-should be avoided CYP3A4. For the same reason, simultaneous reception should be avoided.

    grapefruit juice (see section "Interaction with other drugs").

    It is not recommended to combine lithium preparations with an ACE inhibitor.

    In patients during hemodialysis using certain high-flow membranes (for example,

    polyacrylonitrile membranes) on the background of the administration of ACE inhibitors (see also the instructions of membrane manufacturers), life-threatening, rapidly developing, allergic-like (anaphylactoid) reactions have been described, sometimes up to the development of shock. It is necessary to avoid the combined use of Triapin and this type of membrane, for example, for urgent hemodialysis or hemofiltration. In this case, it is preferable to use other types of membranes or to exclude the use of ACE inhibitors. Similar reactions were observed in the apheresis of low-density lipoproteins using dextran sulfate. Therefore, this method should not be used in patients taking ACE inhibitors. Like other ACE inhibitors, the likelihood and severity of anaphylactic and

    anaphylactoid reactions to insect venom during desensitization (for example, bees and wasps).

    When felodipine was used, there was a development of moderate gingival hyperplasia in patients with severe

    gynovitis / periodontitis. This hyperplasia can be avoided or cause its reverse development with careful hygiene of the oral cavity during the administration of the preparation Triopin


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

    Impact on the ability to drive vehicles and engage in other potentially hazardous activities

    Some side effects (for example, such symptoms associated with lowering blood pressure, like dizziness) can lead to impaired concentration and slow psychomotor reactions, which can increase the risk in situations where it is of particular importance, for example, when driving or working with mechanisms.


    Form release / dosage:

    Tablets of prolonged action, covered with a film membrane (2.5 mg + 2.5 mg).

    Tablets of prolonged action, film-coated (5 mg + 5 mg).

    For 10 or 14 tablets in a blister of PVC / aluminum foil. For 2 or 3 blisters together with instructions for use in a cardboard box.

    Packaging:


    For 10 or 14 tablets in a blister of PVC / aluminum foil. For 2 or 3 blisters together with instructions for use in a cardboard box.

    Storage conditions:

    For the dosage of 2.5 mg + 2.5 mg: at a temperature of no higher than 30 ° C.

    For the dosage of 5 mg + 5 mg: at a temperature of no higher than 25 ° C.

    Keep out of the reach of children.

    Shelf life:

    For tablets 2.5 mg + 2.5 mg -2 years

    For tablets 5 mg + 5 mg - 2.5 years

    Do not use after the expiration date stated on the package

    Terms of leave from pharmacies:On prescription
    Registration number:LP-000160
    Date of registration:13.01.2011
    The owner of the registration certificate:Sanofi-Aventis Deutschland GmbHSanofi-Aventis Deutschland GmbH Germany
    Manufacturer: & nbsp
    Information update date: & nbsp13/01/2011
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