Ko-Racilez® (Co-Rasilez®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceAliskiren + HydrochlorothiazideAliskiren + Hydrochlorothiazide
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  • Ko-Racilez®
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    Novartis Pharma AG     Switzerland
    • Dosage form: & nbspfilm coated tablets
    Composition:

    1 tablet, film-coated, contains:

    active ingredients: aliskiren hemifumarate 165.75 mg or 331.50 mg (aliskiren base 150 mg or 300 mg, respectively), hydrochlorothiazide 12.5 mg or 25.0 mg;

    auxiliary substances for the following dosages: 150 + 12.5 mg / 150 + 25 mg / 300 + 12.5 mg / 300 + 25 mg, respectively; cellulose microcrystalline 120.75 mg / 134.25 mg / 241.50 mg / 241.50 mg, crospovidone 49.70 mg / 50.20 mg / 100.40 mg / 99.40 mg, lactose monohydrate 25.00 mg / 50,00 mg / 25,00 mg / 50,00 mg, wheat starch 24.50 mg / 49.00 mg / 24.50 mg / 49.00 mg, povidone 12.00 mg / 12.00 mg / 24, 00 mg / 24.00 mg, magnesium stearate 5.35 mg / 6.70 mg / 9.35 mg / 10.70 mg, silicon dioxide colloid 5,30 mg / 8.80 mg / 7.10 mg / 10, 60 mg, talc 4.15 mg / 8.30 mg / 4.15 mg / 8.30 mg.

    Shell composition film coated tablets, 150 + 12.5 mg: white coating mixture (titanium dioxide, macrogol 4000, talc, hypromellose) -16.00 mg; film coated tablets, 150 + 25 mg: coating mixture for white (titanium dioxide, macrogol 4000, talc, hypromellose) - 17.397 mg, a mixture for applying a yellow coating (dye iron oxide yellow, macrogol 4000, talc, hypromellose) - 0.576 mg, the coating mixture is red (iron dye oxide red, macrogol 4000, talc, hypromellose) - 0.027 mg;

    film coated tablets, 300 + 12.5 mg: black coating mixture (dye iron oxide black, macrogol 4000, talc, hypromellose) - 0.078 mg, white coating mixture (titanium dioxide, macrogol 4000, talc, hypromellose) - 25,860 mg, the coating mixture is red (iron dye oxide red, macrogol 4000, talc, hypromellose) - 0.062 mg;

    film coated tablets, 300 + 25 mg: mixture for white coating (titanium dioxide, macrogol 4000, talc, hypromellose) - 23.868 mg, mixture for, application of a yellow coating (iron dye oxide yellow, macrogol 4000, talc, hypromellose) - 2,080 mg, the coating mixture is red (iron dye oxide red, macrogol 4000, talc, hypromellose) - 0.052 mg.

    Description:Film coated tablets, 150 + 12.5 mg: oblong biconvex tablets, coated with a white film coating, with a bevel. On one side of the tablet is squeezed out LCI, on the other side - NVR.

    The tablets covered with a film cover, 150 + 25 mg: oblong, biconcave tablets covered with a film membrane of pale yellow color, with a facet. On one side of the tablet, CLL is squeezed out, on the other side - NVR.

    Film-coated tablets, 300 + 12.5 mg: oblong, biconvex tablets, covered with a white film shell with a purple hue, with a bevel. On one side of the tablet is squeezed out CVI, on the other - NVR.

    The tablets covered with a film cover, 300 + 25 mg: oblong, biconcave tablets, covered with a film cover of light yellow color, with a facet. On one side of the tablet is squeezed out CW, on the other side - NVR.

    Pharmacotherapeutic group:Hypotensive combination drug (renin inhibitor + diuretic)
    ATX: & nbsp

    C.09.X.A.52   Aliskiren and hydrochlorothiazide

    Pharmacodynamics:

    The preparation of Co-Racilez® is a combination of two antihypertensive drugs with a complementary mechanism for controlling blood pressure (BP): aliskiren, direct inhibitor of renin, and hydrochlorothiazide, thiazide diuretic.

    Aliskiren

    Aliskiren is a direct inhibitor of repine of a nonpeptidic structure, which has pronounced activity when taken orally. Inhibiting renin, aliskiren thereby inhibiting renin-angiotensin-aldosterone system (RAAS) during the activation phase, blocking the conversion angiotensinogen in angiotensin I and thereby reducing concentration angiotensin I and angiotensin II (ATP). 13, while other agents that inhibit the RAAS (angiotensin-converting enzyme (ACE) inhibitors and antagonists of ATP (Arap) receptors), causing a compensatory increase in renin activity in plasma, aliskiren treatment results in plasma decrease activity of renin in hypertensive patients ( AG) by about 50-80%.

    Increased plasma renin activity is associated with an increased risk of cardiovascular disease in both patients with normal blood pressure and patients with AG.

    In patients with AH when using aliskiren in a dose of 150 and 300 mg 1 once a day, there is a dose-dependent long-term reduction in both systolic and diastolic blood pressure within 24 hours, including the early morning hours. When receiving aliskiren at a dose of 300 mg / day the ratio of the residual antihypertensive action of the drug to the maximum effect for diastolic blood pressure is 98%.

    After 2 weeks of taking the drug, a decrease in blood pressure is observed in 85-90% of the maximum antihypertensive effect. which is maintained at the achieved level during a long (up to 1 year) application.

    The severity of the antihypertensive effect does not depend on age, sex, race and body mass index.

    When using aliskiren in controlled studies, there was no effect of taking the "first dose" (a pronounced decrease in blood pressure) and the effect of the drug on the heart rate (heart rate). After the cessation of aliskiren therapy, a slow return of blood pressure to the baseline within a few weeks is noted, without the development of a withdrawal syndrome and an increase in renin plasma activity.

    Combined therapy with aliskiren with thiazide diuretic (hydrochlorothiazide), ACE inhibitor (ramipril), slow calcium channel blocker (amlodipine), LTP receptor antagonist (valsartan), and beta-blocker (atenolol) is well tolerated by patients and allows an additional reduction in blood pressure.

    Hydrochlorothiazide

    The point of application of the action of thiazide diuretics is distal convoluted renal tubules. When thiazide diuretics are exposed to highly sensitive receptors in the distal tubules of the cortical layer of the kidneys, reabsorption of the ions sodium (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, the excretion of sodium and chlorine ions increases approximately to the same extent. As a result of diuretic action, a decrease in the volume of circulating blood is observed, which increases the activity of renin, the secretion of aldosterone, the excretion of potassium ions by the kidneys. consequently, a decrease in the content of potassium ions in the blood serum.

    A: Tskiren / Hydrochlorothiazide

    In patients with AH in the use of the drug Ko-Racilez® Once-a-day, there is a dose-dependent long-term reduction in both systolic and diastolic blood pressure within 24 hours. When application of the decrease in blood pressure largely occurs during the first week of use and reaches a maximum effect within 4 weeks. Severity of antihypertensive effect Co-Racilez® does not depend on age, sex, race, or body mass index. After discontinuing treatment with Co-Racialysis® gradual return of blood pressure to baseline values ​​within 3-4 weeks, without development withdrawal syndrome and increased plasma renin activity.

    Co-Racialysis® in doses of 150 / 12.5 mg and 300 / 12.5 mg in patients with baseline diastolic blood pressure (DBP)> 95 mm Hg. Art. and less than 110 mm Hg. Art. caused a dose-dependent decrease in blood pressure (systolic / diastolic) from 17.6 / 11.9 mm Hg. Art. up to 21.2 / 14.3 mm Hg. , respectively, but compared with 7.5 / 6.9 mm Hg. Art. in the placebo group. The greatest decrease in blood pressure when using the drug Ko-Racileus® was significantly greater than the decrease in blood pressure on a background of monotherapy with aliskiren or hydrochlorothiazide at appropriate doses. The use of Ko-Racilez ® neutralized the increase in plasma renin activity caused by hydrochlorothiazide.

    There was also a trend towards a greater decrease in blood pressure and a higher degree of BP control with the use of Ko-Racilez® in comparison with the monotherapy of each of the drugs individually in patients with additional risk factors for complications from the cardiovascular system (diabetes mellitus, renal dysfunction, or history of cardiovascular disease).

    The safety of the combination therapy was similar to that of the monotherapy regimens regardless of the severity of the AH,as well as from the absence or presence of additional risk factors for the development of complications from the cardiovascular system.

    The incidence of severe BP reduction and related adverse events in patients treated with Co-Racilez®, including patients over the age of 65, was from 1/1000 to 1/100 (frequency gradation was infrequent).

    Pharmacokinetics:

    Aliskiren

    After oral administration, the time to reach the maximum concentration (TmOh) was about 1-3 hours. Absolute bioavailability - 2.6%. Eating lowers the maximum concentration in the blood plasma (CmOh) and the area under the curve "concentration-time" (AUC), but this does not have a significant effect on the pharmacodynamics of the drug, so it can be taken regardless of food intake. The equilibrium concentration is reached within 5-7 days after ingestion (once a day) and the plasma concentration in the equilibrium state is approximately 2 times higher than that at the beginning of the treatment.

    Aliskiren is evenly distributed in systemic blood flow after ingestion. After intravenous administration, the average volume of distribution in the equilibrium state is about 135 liters, indicating that aliskiren is significantly distributed in the extravascular space.The connection with blood plasma proteins is moderate (47-51%) and does not depend on the concentration of aliskiren in blood plasma. The average half-life of plasma is about 40 hours (in the interval 34-41 h). Aliskiren is excreted mainly unchanged through the intestine. About 1.4% of the total dose taken internally is metabolized. Metabolism of aliskiren occurs with the participation of isoenzyme CYP3A4. After ingestion, about 0.6% of the dose is found in the urine. After intravenous administration, the average plasma clearance is about 9 l / h. FROMmOh and AUC aliskirenum increase linearly with increasing doses in the range of 75-600 mg.

    Hydrochlorothiazide

    Absorption after oral administration is rapid (TmOh about 2 hours). The kinetics of distribution and elimination as a whole is described as a bi-exponential decreasing function, with a finite half-life of 6-15 hours.

    The average increase AUC is linear in nature and proportional to the dose in the therapeutic range. When repeated application of the kinetics of hydrochlorothiazide does not change, when used once a day, cumulation is minimal. The apparent volume of distribution is 4-8 l / kg. 40-70% of the hydrochlorothiazide circulating in the blood plasma binds to blood plasma proteins, mainly with albumin. Hydrochlorothiazide also accumulates in red blood cells in concentrations approximately 3 times higher such in the blood plasma. Absolute bioavailability after oral administration - 70%; More than 95% of the absorbed dose is excreted unchanged by the kidneys.

    With simultaneous intake of food, both the increase and decrease in the systemic bioavailability of hydrochlorothiazide were reported compared with fasting. The magnitude of this effect is small and does not have significant clinical significance.

    Aliskiren / Hydrochlorothiazide

    After applying the drug Co-Racialysis® TmOh is within 1 h for aliskiren and 2.5 h for hydrochlorothiazide.

    The rate and extent of absorption of the drug Co-Racialysis® is equivalent to the bioavailability of aliskiren and hydrochlorothiazide in the case of their use in monotherapy. Food intake has the same effect on the bioavailability of the drug Co-Racialysis®, as well as with monotherapy with aliskiren and hydrochlorothiazide.

    Pharmacokinetics in specific patient groups

    Sex, body mass index and race do not influence the pharmacokinetics of the drug Ko-Racilez®.

    Patients with impaired hepatic function

    PSince the pharmacokinetics of aliskiren and hydrochlorothiazide does not change significantly in patients with impaired liver function of the lung (5-6 points by the scale Child-Pugh) and medium (7-9 points for the scale Child-Pugh) severity, correction of the initial dose of the drug Ko-Racialysis® in this category patients not required.

    Pharmacokinetic features of the use of the drug Ko-Racilez in patients with hepatic dysfunction (more than 9 points for the scale Child-Pugh) not studied. Since the composition of the preparation Ko-Racileus® is included hydrochlorothiazide, the drug is not recommended for patients with hepatic dysfunction (more than 9 points for the scale Child-Pugh).

    Patients with impaired function of night

    The pharmacokinetics of aliskiren was studied in patients with impaired renal function of varying severity. Indicators AUC and TmOh aliskiren in patients with impaired renal function after a single application and after reaching the equilibrium state increased by 0.8-2 times compared with healthy volunteers. However, no correlation was found between the above changes and the severity of renal impairment.

    It is not necessary to change the initial dose of the drug in patients with impaired renal function of mild to moderate severity (creatinine clearance more than 30 ml / min.).

    When studying the pharmacokinetics of aliskiren in patients with terminal a stage of a chronic illness of the nights which are on a hemodialysis or undergoing a procedure of hemodialysis, it was found that with a single admission of 300 mg of aliskiren, the pharmacokinetics of the drug varied insignificantly. The duration of hemodialysis did not affect the pharmacokinetics of aliskiren in this category patients. Consequently, dose adjustment is not required in patients with terminal stage chronic kidney disease.

    When hydrochlorothiazide is used patients with impaired renal function AUC and CmOh hydrochlorothiazide increase, while the speed of excretion drug is reduced. In patients with impaired renal function of moderate severity period half-life of hydrochlorothiazide almost 2-fold increase, renal the clearance of hydrochlorothiazide decreases in significant compared to normal values ​​of about 300 ml / min.

    Patients over the age of 65 years

    When using the drug Ko-Racialysis® the patients older than 65 years of dose adjustment no drug is required.

    Patients under the age of 18 years

    Pharmacokinetic features application of Ko-Racilez® patients under the age of 18 years were not studied.

    Indications:Arterial hypertension (patients who are shown combined therapy). The drug can be used with insufficient control of BP against a background of monotherapy with aliskiren or hydrochlorothiazide, for convenience of appointment in patients who have already received aliskiren together with hydrochlorothiazide in separate tablets in the same doses, as well as to initiate treatment in patients with moderate and severe arterial hypertension (systolic BP> 160 mm Hg and / or diastolic blood pressure> 100 mm Hg).

    Contraindications:- Hypersensitivity to aliskiren (including angioedema due to aliskiren in history), hydrochlorothiazide, sulfonamides, or any component of the drug

    - Pregnancy and the period of breastfeeding

    - Severe violations of the liver (more than 9 points on the scale Child-Pugh)

    - Anuria, severe renal dysfunction (KK less than 30 ml / min)

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

    - Age to 18 years (efficiency and safety not established)

    - Simultaneous drug administration Ko-Racilez® with ACE inhibitors (ACE inhibitors) and aangiotensin II receptor antagonists (ARA II) in patients with type 2 diabetes mellitus

    - Simultaneous reception with a strong inhibitor of P-glycoprotein cyclosporine, itraconazole

    - Lactose intolerance or glucose-galactose malabsorption, lactase deficiency (lactose formulation comprises a)

    Carefully:

    Caution must be exercised when using the drug in patients with bilateral or unilateral renal artery stenosis or stenosis renal artery only (no experience clinical application) reduced circulating blood volume (CBV), hyponatremia, hyperkalemia with diabetes mellitus (due to the risk of hyperkalemia), patients receiving drugs that can raise blood potassium content (including including NSAIDs, ACE inhibitors, ARA II), patients with hypokalemia and hypomagnesemia (including background nephropathies accompanied by loss of salts), patients with severe heart failure (III-IV class NYHA classification)patients with mitral or aortic stenosis, and hypertrophic obstructive cardiomyopathy, patients with a history of allergic history, systemic lupus erythematosus, patients with closed-angle glaucoma, hyperuricemia, elevated cholesterol and triglycerides, while using moderate inhibitors of P-glycoproteinketoconazole, verapamil).

    Pregnancy and lactation:

    Pregnancy

    Sufficient data on the use of aliskiren in pregnant women do not. In experimental studies aliskiren did not have a teratogenic effect. The use of drugs that directly affect RAAS during pregnancy can cause the development of fetal and newborn pathologies, and also lead to their death. Aliskiren, as well as other agents having a direct effect on RAAS, should not be used in pregnancy and in patients planning pregnancy. Before using drugs that affect RAAS, the doctor should inform patients of reproductive age about the potential for fetal risk when using these medicines during pregnancy.At the onset of pregnancy during the treatment with aliskiren, the drug should be stopped immediately.

    Hydrochlorothiazide penetrates the placenta. With the use of thiazide diuretics, including hydrochlorothiazide, pregnancy may develop embryonic or neonatal thrombocytopenia, as well as other unwanted reactions observed in adults.

    Since the safety of the use of the drug Ko-Racilez ® in pregnancy has not been studied, the drug is contraindicated in pregnant women or patients planning pregnancy. When pregnancy occurs during treatment with Co-Racilez®, the drug should be discontinued as soon as possible.

    Breastfeeding period

    It is not known whether the aliskiren in breast milk. Hydrochlorothiazide excreted in breast milk.

    If taking Co-Racilez ® is necessary during lactation, then breastfeeding should be discontinued.

    Fertility

    In studies of reproductive toxicity in rats, there was no undesirable effect of aliskiren on fertility. There is no data on the effects of aliskiren on fertility in rights.

    Dosing and Administration:

    The drug is taken orally, with a small amount of water, once a day, regardless of food intake. In case the patient takes Co-Racilez® together with food, the amount of food should be small. Recommended daily dose - 1 tablet preparation of Co-Racilez®, containing aliskiren / hydrochlorothiazide at a dose of 150 / 12.5 mg, 150/25 mg, 300 / 12.5 mg or maximum 300/25 mg.

    When appointing preparation of Co-Racilez® the decrease in blood pressure largely occurs already during the first week of use and reaches a maximum value within 4 weeks.

    Patients with moderate or severe hypertension (systolic BP> 160 mm Hg and / or diastolic blood pressure> 100 mm Hg) should be treated at a dose of 150 / 12.5 mg once a day. With insufficient control of blood pressure after 2-4 weeks of therapy, the dose of the drug can be gradually (titration dose) increased to a maximum daily dose of 300/25 mg once a day. The dose of the drug is selected individually depending on the clinical effect.

    With insufficient control of BP against a background of monotherapy with aliskiren or hydrochlorothiazide, patients can be transferred to combination therapy with Co-Racilez ® at appropriate doses.

    For convenience, patients receiving therapy aliskirenom and hydrochlorothiazide in individual tablets, can be switched to therapy Co-Racilez®, containing the same dose of components. The preparation of Co-Racilez® should not be used in combination with ACE inhibitors or APA-II in patients with type 2 diabetes mellitus.

    Use in patients with impaired renal or hepatic function

    In patients with impaired renal function (QC more than 30 ml / min) and liver light (5-6 points on the scale Child-Pugh) and moderate (7-9 points on the scale Child-Pugh) the degree of correction of the dose of the drug is not required.

    Use in patients over 65 years of age

    Patients over 65 years of age are not required to adjust the dose.

    Use in children and adolescents under the age of 18 years

    Because safety and efficiency preparation of Co-Racilez® children and adolescents (under the age of 18) do not are installed, the drug is not recommended apply in this category of patients.

    Side effects:

    Co-Racialus® (aliskiren + hydrochlorothiazide)

    The safety of Co-Racilez® was evaluated in more than 3900 patients.

    The incidence of adverse events (AEs) was not related to gender, age, body mass index, or race.When using the drug in a dose up to 300/25 mg total frequency of AE was similar to that in the placebo group. AEs as a whole were moderately expressed, were temporary and rarely required discontinuation of therapy with the drug. Most often with the use of the drug Ko-Racialysis® patients had diarrhea.

    Diarrhea is a dose-dependent AE associated with the use of aliskiren. In controlled clinical trials, the incidence of diarrhea in patients receiving Co-Racilez® was low and similar to that in the aliskiren or hydrochlorothiazide monotherapy group.

    The content of potassium in blood plasma

    In a large placebo-controlled clinical study, the mutually opposite effects of aliskiren (in doses of 150 mg or 300 mg per day) and hydrochlorothiazide (in doses of 12.5 mg or 25 mg per day) on the content of potassium ions in blood plasma practically balanced each other in many patients. In other cases, patients either had hypo- or hyperkalemia. HA, arising against the background of the application of each of the components separately AEs, noted against the background of the application of each of the components separately, can occur when taking the drug Ko-Racileus®, even if the AE data are not were noted in clinical studies preparation.

    Aliskiren

    With the use of the drug in a dose of up to 300 mg, the overall frequency of AE was similar to that in the placebo trial. AEs as a whole were moderately expressed, were temporary and rarely required discontinuation of therapy with the drug. The most frequent use of aliskiren in patients was observed diarrhea. Other AEs, observed during treatment with aliskiren, included a skin rash and angioedema. In controlled clinical trials angioedema during treatment with aliskiren was observed rarely, with a frequency comparable to those in the placebo group or hydrochlorothiazide. The incidence of coughing with placebo and aliskiren was almost the same.

    To estimate the frequency of development of AE, the following criteria were used (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 / 10000, <1/1000); very rarely (<1/10000), including individual messages: the frequency is unknown (can not be calculated but available data). Within each group, the frequency adverse reactions are presented in order of decreasing significance of AEs observed with aliskiren during clinical trials

    Disorders from the digestive system: often diarrhea.

    Disturbance from the skin and subcutaneous tissues: infrequently - a skin rash.

    Laboratory data: often hyperkalemia.

    Hemoglobin and hematocrit: against a background of monotherapy with aliskiren, there was a slight decrease in hemoglobin and hematocrit (an average of 0.05 mmol / L and 0.16% vol., respectively), not requiring withdrawal of the drug. Reduction of hemoglobin and hematocrit are also observed when using other agents that affect RAAS, in particular ACE inhibitors and angiotensin receptor antagonists II.

    The content of potassium in the blood plasma: On a background of monotherapy with aliskirenom in patients with hypertension, in rare cases there was a slight increase in the serum potassium content. In patients with diabetes mellitus, the serum potassium content increased more often (5.5%) with the use of aliskiren simultaneously with ACE inhibitors.

    AEs observed with aliskiren in clinical practice, including spontaneous reports and cases described in the literature

    Since spontaneous reports of AEs come in a voluntary order from a population of undetermined size, it is not possible to estimate the frequency of these AEs (the frequency is unknown).

    Disturbance from the skin and subcutaneous tissues: severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, skin itching, reddening of the skin.

    Immune system disorders: hypersensitivity reactions, anaphylactic reactions, urticaria.

    Impaired nervous system: dizziness.

    Disorders from the urinary system: violations of kidney function of any severity.

    Vascular disorders: marked decrease in blood pressure, peripheral edema.

    Disorders from the digestive system: nausea, vomiting.

    Disorders from the liver and bile ducts: abnormal liver function.

    Laboratory data: increased serum creatinine concentration, increased activity of "hepatic" enzymes.

    Hydrochlorothiazide

    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.

    Immune system disorders: very rarely - hypersensitivity reactions.

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

    Impaired nervous system: rarely - headache, paresthesia, dizziness.

    Vascular disorders: often - orthostatic hypotension (may worsen with alcohol, sedatives or pain medication); very rarely - necrotic vasculitis.

    Heart Disease: rarely - arrhythmia.

    Disturbances from the respiratory system. organs of the thorax and mediastinum: very rarely - respiratory disorders (distress), including pulmonary edema and pneumonitis.

    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.

    Disturbances from the skin and subcutaneous tissues: often - hives and other skin rashes; rarely photosensitization reactions; very rarely - toxic epidermal necrolysis, lupus-like reactions, exacerbation of cutaneous manifestations of systemic lupus erythematosus.

    Laboratory and instrumental data: very often - hypokalemia, increased concentration of blood lipids; often - hyponatremia, hypomagnesemia, hyperuricemia; rarely - hypercalcemia, hyperglycemia, glucosuria: very rarely - hypochloremic alkalosis.

    Disorders from the endocrine system: rarely - worsening of the course of diabetes.

    Disorders from the side of the organ of vision: rarely - visual impairment.

    Violations of the genitals and breast: often - erectile disfunction.

    Adverse events by data postmarketing research

    The following undesirable phenomena were identified according to post-marketing research: frequency unknown - acute renal failure, renal dysfunction, aplastic anemia, exudative erythema multiforme, fever, muscular spasm, asthenia, development of secondary closed-angle glaucoma.

    If any of the side effects listed in the manual are aggravated, or if you notice any other side effects not listed in the instructions, tell your doctor.

    Overdose:

    Data on cases of overdose of Ko-Racilez ® are absent.

    The most likely clinical manifestation of an overdose is a marked decrease in blood pressure due to the hypotensive effect of aliskiren and hydrochlorothiazide. When the appearance of clinical manifestations of a marked decrease in blood pressure, symptomatic treatment should be prescribed. If the drug has been taken recently, it is effective to induce vomiting and gastric lavage.

    The main clinical overdose symptoms hydrochlorothiazide are symptoms associated with loss of electrolytes (hypokalemia, hypochloraemia) and dehydration due to diuresis stimulation. The most frequent symptoms overdose - nausea and drowsiness. Hypokalemia can be accompanied by muscle spasms. When concomitant use of cardiac glycosides (or other antiarrhythmic drugs) hypokalemia may enhance cardiac arrhythmia.

    In a study of the use of aliskiren in patients with terminal chronic renal failure, hemodialysis dialysis clearance aliskiren was low (<2% oral dose). Thus, hemodialysis is ineffective for removing excess aliskiren from the body.

    Interaction:

    The simultaneous administration of aliskiren and hydrochlorothiazide did not lead to significant changes in the indices AUC in the equilibrium state and CmOh both components in healthy volunteers.

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

    In elderly patients, patients with reduced BCC (including patients on diuretic therapy), patients with impaired renal function, concurrent use of NSAIDs with thiazide diuretics and agents that affect RAAS can lead to impaired renal function. up to the development of acute renal failure, in most cases reversible. The antihypertensive and diuretic effects of hydrochlorothiazide may decrease with taking NSAIDs

    Aliskiren

    Simultaneous use of aliskiren with ACE inhibitors and angiotensin II receptor antagonists (APA II) in patients with type 2 diabetes and severe renal failure is contraindicated.

    The likelihood of interaction of aliskiren with other drugs is low. Since with simultaneous application aliskiren has no significant effect on the pharmacokinetics of acenocoumarol, atenolol, celecoxib, fenofibrate. pioglitazone, allopurinol, isosorbide 5-mononitrate, irbesartan, digoxin, ramipril, valsartan, metformin, amlodipine, atorvastatin, cimetidine and hydrochlorothiazide, while applying a dose adjustment of aliskiren or the above drugs is not required.

    Interaction at the level of the cytochrome P450 system

    Aliskiren does not inhibit isoenzymes of the cytochrome P450 system (CYPIA2. 2C8, 2C9, 2CI9, 2D6, 2EI and CYP3A) and does not induce isoenzyme CYP3A4. Because the aliskiren is slightly metabolized by isoenzymes of the cytochrome P450 system. the clinically significant effect of aliskiren on the bioavailability of drugs that are inducers or inhibitors of the cytochrome P450 system or metabolized with its participation is unlikely.

    Interaction at the P-glycoprotein level encoded by genes MDR1

    Since in studies in vitro It has been established that the P-glycoprotein (membrane transporter of molecules) plays an important role in regulating the absorption and distribution of aliskiren, it is possible to change the pharmacokinetics of the latter when used simultaneously with drugs inhibiting P-glycoprotein (depending on the degree of inhibition).

    Substrates and weak inhibitors of P-glycoprotein

    There is no significant interaction of aliskiren with weak P-glycoprotein inhibitors, such as atenolol, digoxin, amlodipine and cimetidine. When simultaneous application with atorvastatin (at a dose of 80 mg) in the equilibrium state there is an increase AUC and CmOh aliskiren (a dose of 300 mg) by 50%.

    Moderate inhibitors of P-glycoprotein

    With the simultaneous administration of a moderate inhibitor P-glycoproteina ketoconazole (200 mg) and aliskiren (300 mg), an increase in the plasma concentration of the latter (AUC and CmOh) by 80%. In experimental studies, simultaneous administration of aliskiren with ketoconazole led to an increase in the absorption of aliskiren in the gastrointestinal tract and a decrease in its excretion through the intestine with bile. With a single application of verapamil (at a dose of 240 mg), together with aliskirenom (at a dose of 300 mg), there was an increase AUC and CmOh aliskiren in 2 times.

    Changes in the plasma concentration of aliskiren with simultaneous use with ketoconazole or verapamil are expected in the range of concentrations determined with an increase in the aliskiren dose by a factor of 2.In controlled clinical trials, the safety of the drug at a dose of 600 mg was demonstrated, that is, with an increase in the maximum recommended therapeutic dose of 2 times. Therefore, when aliskiren is used together with ketoconazole or verapamil, dose adjustment of aliskiren is not required.

    Strong P-glycoprotein inhibitors

    When used with such a highly active inhibitor P-glycoprotein, as ciclosporin (200 and 600 mg), in healthy volunteers there was an increase in Cmzx and AUC aliskiren (75 mg) in 2.5 and 5 times, respectively. In healthy volunteers, when aliskiren was used (at a dose of 150 mg), together with intra -conazole (at a dose of 100 mg), an increase AUC and CmOh aliskiren in 6.5 and 5.8 times, respectively.

    In this regard, it is not recommended to use the drug simultaneously with strong inhibitors of P-glycoprotein (cyclosporine, itraconazole).

    Double blockade of RAAS

    Simultaneous use of aliskiren with other drugs that affect RAAS, including those with ACE inhibitors and ARA II. leads to an increase in the incidence of severe depression of blood pressure, hyperkalemia, renal dysfunction (including acute renal failure).It is necessary to monitor the indices of blood pressure, kidney function, and also the content of plasma electrolytes at use of the preparation of Co-Racilez ® with other drugs that affect RAAS.

    Furosemide

    With the simultaneous use of aliskiren (300 mg / day) with furosemide (20 mg / day) in healthy volunteers, there was a decrease AUC and CmOh furosemide by 28% and 49%, respectively.

    In patients with heart failure, simultaneous use of aliskiren (300 mg / day) with furosemide (60 mg / day) resulted in a decrease AUC and CmOh furosemide by 17% and 27%, respectively, and by a decrease in furosemide excretion by the kidneys by 29% within 24 hours after administration. In addition, the excretion of sodium by the kidneys and the volume of urine were reduced during the first 4 hours after admission by 31% and 24%, respectively, compared with the use of furosemide in monotherapy. Given the possible decrease in systemic bioavailability of furosemide, and to prevent possible fluid retention when using aliskiren simultaneously with furosemide, the dose of furosemide must be adjusted at the beginning and during treatment, depending on the clinical response.

    Potassium and potassium-sparing diuretics

    Taking into account the experience of using other means that affect RAAS, use caution aliskiren together with preparations containing potassium, potassium-sparing diuretics, potassium-containing substitutes for edible salt or any other medicines capable of increasing the content of potassium ions in the blood.

    Grapefruit juice

    Since there is no data on the possible interaction of aliskiren with grapefruit juice, the preparation Ko-Racilez® Do not take with grapefruit juice at the same time.


    Hydrochlorothiazide

    Lithium

    With simultaneous use with ACE inhibitors and diuretics, cases of a reversible increase in the plasma concentration of lithium and its toxic effect were reported. Therefore, with the simultaneous use of hydrochlorothiazide and preparations containing lithium, it is recommended to monitor the concentration of lithium in the blood. The experience of simultaneous application of aliskiren and lithium preparations is absent.

    Other antihypertensive drugs

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

    Curare like muscle relaxants

    Thiazide diuretics, including hydrochlorothiazide, potentiate the action of curare-like muscle relaxants (for example, tubocurarine chloride).

    Drugs affecting the content of potassium in the blood

    The hypokalemic effect caused by diuretics can be intensified with simultaneous use with potassium-diuretics, glucocorticosteroids (GCS), adrenocorticotropic hormone (ACTH), amphotericin, carbenoxolane, penicillin, acetylsalicylic acid or its derivatives and antiarrhythmic drugs.

    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 Ko-Racilez together with the above preparations.

    Hypoglycemic agents

    When hydrochlorothiazide is used, there is a change in glucose tolerance, and therefore, patients with diabetes may require a correction of insulin doses and hypoglycemic agents for oral administration.

    FROMcardiac glycosides

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

    H and m-holinoblokatory

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

    Anion exchange resins

    The absorption of hydrochlorothiazide decreases in the presence of colestyramine and colestipol. Hydrochlorothiazide should be taken either within 4 hours, or 4-6 hours after taking these compounds.

    Vitamin D and calcium salts

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

    Cyclosporin

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

    Methyldopa

    Hemolytic anemia has been reported with the simultaneous use of hydrochlorothiazide and methyldopa.

    Other types of interaction

    The simultaneous use of thiazide diuretics, including hydrochlorothiazide, may lead to an increase in the frequency of hypersensitivity reactions to allopurinol; increased risk of side effects of amantadine; increase the hyperglycemic effect of diazoxide, reduce the excretion of drugs that have a cytotoxic effect (eg, cyclophosphamide, methotrexate), and potentiate their mielosuppressive effects. Also hydrochlorothiazide can reduce the body's response to the introduction of pressor amines (norepinephrine (norepinephrine)), but this effect is clinically insignificant and can not prevent simultaneous use of drugs.

    Ethanol, barbiturates and narcotics facilities: their simultaneous use with hydrochlorothiazide can potentiate development of orthostatic hypotension.

    Special instructions:

    Aliskiren can increase the content of potassium, creatinine and urea in the blood plasma. An increase in the potassium content in the blood plasma can be enhanced by the simultaneous administration of other agents that affect RAAS or the intake of an NSAID.The risk of developing hyperkalemia in patients with diabetes mellitus is increased with aliskiren therapy.

    When using the drug Ko-Racialysis® should monitor content electrolytes of blood and kidney function before the start of therapy and periodically on the background of treatment. Impairment of renal function may occur in patients receiving aliskiren and other drugs that affect RAAS, concomitantly with NSAIDs in the presence of a history of kidney disease, hypovolemia, heart failure, or liver pathology.

    Therapy with thiazide diuretics can lead to the development of hypokalemia 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, paresthesia, ECG changes), therapy with Co-Racilez ® should be discontinued. Before the beginning of hydrochlorothiazide therapy, correction of existing water-electrolyte disturbances is recommended. With the purpose of timely detection of possible violations of the water-electrolyte balance during the therapy, it is necessary to monitor the content of potassium and magnesium in the blood plasma.With the simultaneous use of hydrochlorothiazide and aliskiren, the hypokalemic effect of hydrochlorothiazide is less pronounced than with monotherapy.

    Thiazide diuretics can lead to the development of hyponatremia, hypochloremia, or aggravate existing hyponatraemia. Some cases of development of neurologic symptoms in patients with hyponatremia (nausea, asthenia, disorientation, apathy) were noted.

    In patients with a marked decrease in sodium in the blood plasma or a reduced BCC, as well as with the use of the drug Ko-Racilez® in combination with other drugs that affect RAAS, initiation of therapy with Co-Racilez® may be accompanied by a marked decrease in blood pressure. Before applying the drug, correction of the disturbances of the water electrolyte balance should be carried out. On the background of therapy it is recommended to monitor the sodium content in blood plasma. Thiazide diuretics, including hydrochlorothiazide, can cause a change in glucose tolerance, as well as an increase in the concentration of cholesterol, triglycerides and uric acid in the serum. Decreased uric acid clearance may lead to hyperuricemia and the appearance of gout in predisposed patients.

    Thiazide diuretics cause a decrease in calcium excretion, and, respectively, a moderate increase in the calcium content in the blood. Consequently hydrochlorothiazide should be used with caution in patients with hypercalcemia. The development of severe hypercalcemia that does not occur after the abolition of hydrochlorothiazide (> 12 mg / dl) may indicate an independent pathology. Several patients who received long-lasting thiazide diuretics were found to have pathological changes in the parathyroid glands, accompanied by hypercalcemia and hypophosphatemia. In the case of hypercalcemia, additional tests are needed to clarify the diagnosis.

    In patients with systemic lupus erythematosus, the use of thiazide diuretics, including hydrochlorothiazide, may exacerbate the disease.

    Development of acute angle-closure glaucoma

    Against the background of the use of hydrochlorothiazide there have been cases of development of transient myopia and acute development of closed-angle glaucoma. A risk factor for the development of acute angle-closure glaucoma may be anamnestic data on allergic reactions to sulfonamide derivatives and penicillin.

    Symptoms, including a sharp decrease 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 a persistent decrease in visual acuity. Treatment should consist in rapid withdrawal of the drug containing hydrochlorothiazide. If the increased intraocular pressure is maintained, additional medical or surgical intervention may be required.

    Anaphylactic reactions and angioedema

    There have been reports of cases of anaphylactic reactions and angioedema in the background of therapy with drugs containing aliskiren. In controlled clinical trials, angioneurotic edema on the background of aliskiren therapy developed rarely with a frequency comparable to placebo or hydrochlorothiazide. Anaphylactic reactions have been identified with the use of the drug in clinical practice, the frequency of their occurrence is unknown. It is necessary to apply with special care aliskiren in patients with a predisposition to hypersensitivity reactions.

    The drug should be taken immediately stop with signs of allergies reactions (for example, with difficulty breathing or swallowing, swelling of the face, lips, tongue, extremities) and take the necessary therapeutic measures.

    It is necessary to warn patients about the need to inform the doctor about any manifestations of allergic reactions.

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

    The effect of Ko-Racilez® on the ability to drive vehicles and work with mechanisms has not been studied, but care should be taken (risk of dizziness). When these undesirable phenomena appear, one should refrain from these activities.

    Form release / dosage:Tablets, film-coated, 150 + 12.5 mg, 150 + 25 mg, 300 + 12.5 mg, 300 + 25 mg.
    Packaging:7 tablets in a blister pack. For 1, 2, 4, 8 or 14 blisters together with instructions for medical use in a cardboard pack.

    Storage conditions:At a temperature of no higher than 30 ° C.

    Keep out of the reach of children.

    Shelf life:2.5 years.

    The drug should not be used after the expiration date.

    Terms of leave from pharmacies:On prescription
    Registration number:LSR-007456/10
    Date of registration:30.07.2010
    The owner of the registration certificate:Novartis Pharma AGNovartis Pharma AG Switzerland
    Manufacturer: & nbsp
    Representation: & nbspNOVARTIS PHARMA LLCNOVARTIS PHARMA LLC
    Information update date: & nbsp21.09.2015
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