Zokardis® plus (Zocardis® plus)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceHydrochlorothiazide + ZofenoprilHydrochlorothiazide + Zofenopril
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  • Zokardis® plus
    pills inwards 
    BERLIN-PHARMA, CJSC     Russia
    • Dosage form: & nbspPills.
    Composition:

    Core:

    Active substances:

    Zofenopril calcium - 30,00 mg,

    Hydrochlorothiazide - 12.50 mg.

    Excipients: cellulose microcrystalline - 91.00 mg, lactose monohydrate - 56.20 mg, corn starch - 37.60 mg, hypromellose - 2.70 mg, silicon dioxide colloidal anhydrous - 3.00 mg, magnesium stearate - 2.00 mg;

    Sheath:

    Opadrai® pink 02B24436 - 3.80 mg [hypromellose - 2.31 mg, titanium dioxide - 1.16 mg, macrogol 400 0.23 mg, iron dye red oxide (E 172) 0.10 mg], macrogol 6000 - 1.20 mg.

    Description:Round biconvex tablets covered with a film membrane, pink with a weak grayish shade of color, with small inclusions, with a one-sided risk. View of the break: white color.
    Pharmacotherapeutic group:antihypertensive combination drug (diuretic + angiotensin-converting enzyme inhibitor).
    ATX: & nbsp

    C.09.B.A   ACE inhibitors in combination with diuretics

    C.09.B.A.15   Zofenopril in combination with diuretics

    Pharmacodynamics:Zokardis® Plus is a combination drug that includes an angiotensin-converting enzyme (ACE) inhibitor - zofenopril and thiazide diuretic - hydrochlorothiazide. The combination of the two active substances causes a synergistic antihypertensive effect, so that the blood pressure (BP) decreases more than with each of them individually.
    Zofenopril is an ACE inhibitor containing a sulfhydryl group. Inhibits the enzyme that catalyzes the conversion of angiotensin I to angiotensin II (a peptide with a vasoconstrictive effect), which leads to a decrease in the vasoconstrictive effect of angiotensin II on blood vessels and a decrease in aldosterone secretion, and can lead to an increase in serum potassium ions with the simultaneous elimination of sodium ions and liquid. The mechanism of reducing blood pressure with zofenopril is based on the primary suppression of the renin-angiotensin-aldosterone system (RAAS). ACE is identical to kininase II, an enzyme that catalyzes the breakdown of bradykinin, a peptide that has a potential vasodilator effect. Accumulation of bradykinin plays an additional role in the realization of the therapeutic effect of an ACE inhibitor - a decrease in blood pressure.
    Hydrochlorothiazide - Thiazide diuretic - disrupts the reabsorption of sodium, chlorine and water ions in the renal tubules.Increases the excretion of potassium, magnesium, hydrocarbonates; inhibits calcium ions in the body. Diuretic effect develops 2 hours after intake of hydrochlorothiazide inwards, reaches a maximum after 4 hours and lasts up to 12 hours. It helps to decrease elevated blood pressure. With the combined administration of zofenopril and hydrochlorothiazide, the loss of potassium ions associated with the action of the thiazide diuretic occurs. The result of combined therapy with zofenopril and hydrochlorothiazide is potentiation of the hypotensive effect, which is dose-dependent.
    Pharmacokinetics:

    Joint use of zofenopril and hydrochlorothiazide has little or no effect on the bioavailability of each of the active substances individually. Zofenopril is a prodrug. It turns into pharmacologically active metabolite zofenoprilat - free thiol compound, formed as a result of thioester hydrolysis.

    Suction. After oral administration zofenopril quickly and completely absorbed from the gastrointestinal tract (GIT). In organism zofenopril undergoes

    almost complete conversion into zofenoprilat, which has a pronounced pharmacological activity. The maximum concentration (CmOh) zofenoprilata in the blood serum is achieved after 1.5 hours after ingestion. The pharmacokinetics of a single dose is linear in the dose range of 10-80 mg of zofenopril. After taking 15-60 mg of zofenopril within 3 weeks of cumulation does not occur. Simultaneous food intake reduces speed, but not full suction. Area under the curve "concentration-time" (AUC) Zofenoprilata before and after meals are almost identical.

    Distribution. Approximately 88% of zofenopril binds to plasma proteins. Volume of distribution (Vd) in the saturation stage is 96 liters.

    Metabolism. The main metabolite is zofenoprilat, metabolized in various ways: conjugation with glucuronic acid, cyclization and conjugation with glucuronic acid, conjugation with cysteine ​​and Smethylation of thiol group.

    Excretion. Zofenopril after ingestion is excreted by the kidneys (69%) and through the intestine (26%), which indicates two ways of elimination (kidney and liver). After ingestion of zofenopril, the elimination half-life (T 1/2) zofenoprilata is 5.5 hours, and its total clearance is 1300 ml / min.

    Pharmacokinetics in special cases

    In patients with impaired renal function with a creatinine clearance (CK) of more than 45 mL / min, zofenoprilat is excreted at the same rate as in patients with preserved kidney function (QC greater than 90 mL / min).

    In patients with impaired renal function with KK less than 45 ml / min the rate of excretion of zofenoprilat is reduced to approximately 50% of the normal values.

    In patients with impaired renal function at the terminal stage, which are treated with hemodialysis or peritoneal dialysis, the rate of excretion of zofenoprilat is reduced to 25% of the normal values. In patients with impaired liver function of mild and moderate severity when taking single doses of zofenopril with a radioactive label, the value of CmOh and time to reach the maximum concentration (TCmOh) for zofenoprilat coincided with those of healthy volunteers. However, the values AUC in patients with cirrhosis of the liver were twice as high as in healthy volunteers. Thus, patients with mild to moderate liver function impairment should be assigned half of the usual initial dose of zofenopril.

    In patients with severe impairment of liver function, data on the pharmacokinetics of zofenopril and zofenoprilat are not available.

    Hydrochlorothiazide.

    Suction. After oral administration hydrochlorothiazide absorbed by 65-75%. Absorption depends on the duration of passage in the intestine (it increases with a slow passage, for example, with simultaneous intake with food). TSmOh in blood plasma is 1-5 h. The concentration of hydrochlorothiazide in the blood plasma is characterized by linearity with respect to the dose, but the relationship between the concentration of hydrochlorothiazide in blood plasma and the severity of arterial hypotension is not established. T1/2 from blood plasma is from 5.6 to 14.8 hours.

    Distribution. Thiazides are characterized by a wide distribution in body fluids and in large amounts (92%) bind to blood plasma proteins, in particular albumin; which leads to low renal clearance and, thus, to a longer duration of action. Hydrochlorothiazide passes through the placentabut does not penetrate through the blood-brain barrier.

    Metabolism and excretion. Hydrochlorothiazide in the body is not metabolized and almost completely (more than 95%) is excreted by the kidneys unchanged. In elderly patients and with renal dysfunction, clearance of hydrochlorothiazide significantly decreases, which leads to a significant increase in its concentration in the blood plasma.In patients with cirrhosis of the liver, there is no change in the pharmacokinetics of hydrochlorothiazide.

    Indications:Essential hypertension I-II severity (patients who are shown combined therapy or with insufficient effectiveness of monotherapy with zofenopril calcium).
    Contraindications:
    - Hypersensitivity to zofenopril or other ACE inhibitors, hydrochlorothiazide or other derivatives of sulfonamides, or to any of the excipients that make up the formulation (see the "Composition" section);

    - lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome;

    - angioedema in the anamnesis (including associated with the use of ACE inhibitors);

    - congenital / idiopathic angioedema;

    - Patients with myocardial infarction who are on treatment by hemodialysis (efficacy and safety of the drug are not studied); expressed violations of the liver (more than 9 points on the scale Child-Pugh);

    - severe renal dysfunction (CC less than 45 ml / min);

    - bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney (risk of developing renal failure);

    - a condition after a recent kidney transplantation (no experience with the drug);

    - Pregnancy;

    - lactation period;

    - age to 18 years (efficacy and safety of the drug are not established).
    Carefully:
    - bronchial asthma;

    - violation of water-electrolyte balance, dehydration;

    - Ischemic heart disease (CHD);

    - chronic cardiac insufficiency of III-IV functional class according to NYHA classification;

    - severe cerebrovascular disease;

    - Stenosis of the aortic aorta with a violation of the parameters of hemodynamics or other obstacles to outflow of blood from the left ventricle;

    - impaired liver function of moderate severity (risk of hepatic coma) (less than 9 on the Child-Pugh scale);

    - chronic renal failure (CRF) (US more than 45 ml / min);

    -Patients who follow a diet with restriction of table salt or who are on hemodialysis;

    - primary aldosteronism;

    - diabetes mellitus, gout;

    - psoriasis, systemic lupus erythematosus, scleroderma;
    Pregnancy and lactation:
    Zokardis ® Plus during pregnancy is not recommended. In the case of planning or diagnosing pregnancy during treatment with Zokardis® Plus, the drug should be immediately discontinued. Zofenopril and thiazides are absorbed into breast milk, so Zokardis® plus is contraindicated in lactation. Also, the relationship between the use of thiazides during lactation and the reduction or even suppression of lactation, hypokalemia, as well as the appearance of hypersensitivity to derivatives of sulfonamides.

    If you need to use the drug Zokardis ® Plus during lactation, breastfeeding should be discontinued.
    Dosing and Administration:

    Zokardis® Plus tablets are taken orally once a day, regardless of food intake.

    Adults the usual maintenance dose is 1 tablet of Zokardis® plus once a day.

    Elderly patients (over 65 years of age) with a normal kidney function (KC more than 90 ml / min) and in patients with mild renal dysfunction (CC greater than 45 ml / min), dose adjustment is not required.

    With severe renal dysfunction (CC less than 45 ml / min), the use of the drug is contraindicated (see section Contraindications).

    Patents with impaired liver function

    In patients with impaired liver function of mild and moderate severity (less than 9 on the Child-Pugh scale), dose adjustment is not required.

    Side effects:

    Possible side effects when using Zokardis ® plus, as well as with monotherapy with active substances alone, are shown below in the descending frequency of occurrence: often (> 1/100, <1/10), infrequently (> 1/1000, <1/100), rarely (> 1/10000, <1/1000), very rarely (<1/10000), including individual messages.

    Zokardis® plus

    Disturbances from the nervous system

    Often: dizziness, headache.

    Infrequently: drowsiness or insomnia, fainting, increased muscle tone.

    Heart Disease

    In some cases: stenocardia, atrial fibrillation, myocardial infarction, palpitations, "hot flushes" of blood to the skin of the face, marked decrease in blood pressure or increased blood pressure.

    Disturbances from the respiratory system, chest and mediastinal organs

    Often: cough (disappears after drug discontinuation). Infrequently: shortness of breath, bronchitis, pharyngitis.

    Disorders from the gastrointestinal tract

    Infrequently: dryness of the oral mucosa, nausea, abdominal pain,

    dyspepsia, gastritis, gingivitis.

    Disturbances from the skin and subcutaneous tissues

    Infrequently: angioedema, psoriasis, acne, dry skin, skin itching, urticaria rash.

    Disturbances from musculoskeletal and connective tissue

    Infrequently: backache.

    Disorders from the kidneys and urinary tract

    Infrequently: polyuria.

    Violations of the genitals and mammary gland

    Infrequently: violation of potency.

    Laboratory and instrumental data

    Infrequently: hypercholesterolemia, hyperglycemia, hyperlipidemia, hypokalemia, hyperkalemia, hyperuricemia, increased creatinine concentration in the blood plasma and activity of "liver" enzymes.

    Common Disorders,

    Infrequently: weakness, flu-like syndrome, peripheral edema, infectious diseases.

    Zofenopril (monotherapy):

    Violations of blood and lymphatic system

    Infrequently: reduction of hemoglobin, hematocrit, platelet count and leukocyte count, agranulocytosis and pancytopenia.

    There are individual messages about hemolytic anemia in patients with deficiency of glucose-6-phosphate dehydrogenase.

    Disturbances from the nervous system

    Infrequently: headache, dizziness.

    Rarely: depression, psychoemotional lability, sleep disturbance, paresthesia.

    Impaired sensory organs

    Infrequently: confusion, noise in the ears, disruption of accommodation and taste perception.

    Violations from the side of serdia

    Often: after initiating therapy or increasing the dose - a marked decrease in blood pressure, in particular, in certain risk groups.

    Rarely: peripheral edema, orthostatic hypotension, chest pain.

    In some cases: tachycardia, palpitations, arrhythmias, angina pectoris, myocardial infarction (usually associated with a marked decrease in blood pressure), transient ischemic cerebral circulation and cerebral hemorrhage.

    Disturbances from the respiratory system, chest and mediastinal organs

    Often: cough (disappears after drug discontinuation).

    Rarely: shortness of breath, sinusitis, rhinitis, bronchitis, bronchospasm.

    In isolated cases the upper respiratory tract was involved in angioedema, leading to their obstruction.

    Disorders from the gastrointestinal tract

    Often: nausea, vomiting.

    Infrequently: dryness of the oral mucosa, abdominal pain, nausea, vomiting, diarrhea, constipation.

    Rarely: glossitis.

    In some cases: Cholestatic jaundice, hepatitis, pancreatitis, intestinal obstruction, angioedema, intestinal edema.

    Disturbances from the skin and subcutaneous tissues

    Infrequently: allergic reactions and hypersensitivity reactions (skin rash, itching, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, psoriasis-like changes and alopecia). These phenomena can be accompanied by fever, myalgia and arthralgia, eosinophilia and / or an increase in the titer of antinuclear antibodies (ANA).

    Rarely: angioedema, sweating.

    In some cases the relationship between the administration of ACE inhibitors and the development of angioedema has been established, involving the larynx and facial tissues in the process.

    Disturbances from musculoskeletal and connective tissue

    Infrequently: myalgia, muscle cramps.

    Disorders from the kidneys and urinary tract

    Rarely: violation of urination. Possible development or aggravation of renal failure.

    Violations of the genitals and mammary gland

    Rarely: violation of potency.

    Common Disorders

    Often: increased fatigue, weakness.

    Laboratory and instrumental data

    Infrequently: a transient increase in the concentration of urea in the blood and creatinine in the blood plasma, in particular,with existing renal failure, severe chronic heart failure and renovascular hypertension, increased activity of "liver" enzymes and serum bilirubin concentration.

    Hydrochlorothiazide (monotherapy):

    Violations of blood and lymphatic system

    Rarely: leukopenia, neutropenia, agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic anemia, oppression of bone marrow hematopoiesis.

    Disturbances from the nervous system

    Often: dizziness.

    Rarely: anxiety, sleep disturbance, depression, obnubilation, paresthesia.

    Disturbances on the part of the organ of sight

    Rarely: xanthopsia, transient disruption of accommodation.

    Violations from the side of serdia

    Infrequently: orthostatic hypotension.

    Rarely: arrhythmias.

    Disturbances from the respiratory system, chest and mediastinal organs

    Rarely: dyspnea (including pneumonitis and pulmonary edema).

    Disorders from the gastrointestinal tract

    Infrequently: anorexia, pain in the epigastric region, diarrhea, constipation, inflammation of the salivary glands, pancreatitis.

    Rarely: intrahepatic cholestatic jaundice.

    Disturbances from the skin and subcutaneous tissues

    Infrequently: photosensitivity, skin hyperemia.

    Rarely: development of lupus-like syndrome, exacerbation of the cutaneous form

    systemic lupus erythematosus, necrotizing angiitis, anaphylactic

    reaction, toxic epidermal necrolysis.

    Disturbances from musculoskeletal and connective tissue

    Rarely: muscle cramps, weakness.

    Disorders from the kidneys and urinary tract

    Rarely: renal dysfunction, interstitial nephritis.

    Common Disorders

    Rarely: fever.

    Laboratory and instrumental data

    Often: hyperglycemia, glycosuria, hyperuricemia, disorders of water and electrolyte imbalance (including hyponatraemia and hypokalaemia), increasing the concentration of cholesterol and triglycerides in the blood.

    Overdose:
    Symptoms: marked decrease in blood pressure, shock, bradycardia, disturbances of water-electrolyte balance and renal failure.

    Zofenopril symptoms of overdose may be: marked reduction of blood pressure until the development of collapse, myocardial infarction, acute stroke or thromboembolic complications, convulsions, stupor.The most frequent symptoms of an overdose of hydrochlorothiazide are nausea and drowsiness. Overdosage of hydrochlorothiazide is associated with loss of electrolytes (hypokalemia, hypochloraemia) and dehydration (increased diuresis). Hypokalemia can lead to muscle cramps and / or severe arrhythmias with simultaneous administration of cardiac glycosides or antiarrhythmics.

    Treatment: is symptomatic and supportive. Strict medical supervision is required, preferably in a separation / intensive care unit. Regular monitoring of the electrolytes and creatinine content in the blood plasma is necessary. If the drug is taken recently, then you can take measures to prevent absorption from the gastrointestinal tract (gastric lavage, the appointment of adsorbents and sodium sulfate). With a sharp decrease in blood pressure, the patient should be given a "lying" position with raised legs; to decide on the use of drugs that increase the volume of circulating blood (BCC) and / or treatment with angiotensin II. Bradycardia or severe vagal reactions should be eliminated with atropine; it is possible to install an artificial pacemaker.ACE inhibitors are excreted by dialysis, but the use of high-permeability membranes from polyacrylonitrile should be avoided.
    Interaction:

    Zofenopril

    It is not recommended to use together with potassium-sparing diuretics (spironolactone, triamterene, amiloride), potassium preparations because of the risk of hyperkalemia.

    If, as a result of diagnosed hypokalemia, the simultaneous use of these drugs is indicated, they should be used with caution, with regular monitoring of potassium in the blood serum and electrocardiogram (ECG). Caution is required when combined with "loop "diuretics. Prior treatment with diuretics in high doses may at the beginning of therapy with Zokardis® plus lead to a decrease in BCC and promote the development of arterial hypotension.

    ACE inhibitors can enhance the antihypertensive effect of some general anesthetics.

    When combined with narcotic analgesics, tricyclic antidepressants, neuroleptics and barbiturates there may be a development of orthostatic hypotension.

    When used simultaneously with other antihypertensive agents (alpha and beta adrenoblockers, blockers of "slow" calcium channels) the hypotensive effect can be potentiated. Caution is required when using simultaneously with nitrates or other vasodilators. Simultaneous reception cyclosporine with ACE inhibitors increases the risk of developing renal dysfunction.

    When combined allopurinol, procainamide, cytostatics or immunosuppressants with ACE inhibitors, the risk of developing hypersensitivity reactions, leukopenia increases.

    In rare cases, ACE inhibitors can increase the hypoglycemic action of insulin and hypoglycemic agents for oral administration (eg, sulfonylureas) in patients with diabetes mellitus. In these cases, simultaneous use of ACE inhibitors may require a reduction in the dose of hypoglycemic agent for ingestion and insulin.

    Sympathomimetics can reduce the hypotensive effect of ACE inhibitors. When used simultaneously with antacids a decrease in the bioavailability of ACE inhibitors is possible.

    Hydrochlorothiazide

    Caution is required when combined with colistiramine and colestipol. Simultaneous reception of anion-exchange resins reduces the absorption of hydrochlorothiazide. Kolestyramine or colestipol in their single admission are associated hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by 85 and 43%, respectively.

    Diuretics, which are derivatives of sulfonamides, should be taken at least 1 hour before or 4-6 hours after taking these drugs. Glucocorticosteroids, corticotropin, amphotericin B (parenteral): when they are taken together with hydrochlorothiazide, disturbances in the water-electrolyte balance of the blood, especially the development of hypokalemia, can occur. With the simultaneous use of hydrochlorothiazide with calcium salts or with preparations containing calcium, it is possible to increase the content of calcium in the blood serum, due to the reduction of its excretion.

    With the simultaneous use of hydrochlorothiazide with cardiac glycosides there is a risk of arrhythmia.

    Medicines that can cause piruet-type arrhythmia (a special form of polymorphic ventricular tachycardia with wave, screw or spindle configuration of ventricular complexes in combination with an increase or decrease in the amplitude of the teeth of the complex QRS, which can lead to ventricular fibrillation or asystole): because of the risk of hypokalemia, caution is required when hydrochlorothiazide is used together with some antiarrhythmics, antipsychotics and other drugs that can lengthen the interval QT and cause arrhythmia of the "pirouette" type.

    When combined hydrochlorothiazide with Nondepolarizing muscle relaxants - strengthening the action of nondepolarizing muscle relaxants. Thiazides may increase the risk of side effects amantadine. Antifungal agents (probenecid, sulfinpyrazone, allopurinol): it may be necessary to correct the dose of the hypo-uricemic agent (increasing the dose of probenecid or sulfinpyrazone), since hydrochlorothiazide can increase the concentration of uric acid in the serum. Simultaneous use with thiazide diuretics can increase the frequency of development of hypersensitivity reactions to allopurinol.

    The drug Zokardis® plus

    Simultaneous use of drugs lithium and the drug Zokardis® plus is not recommended because of the risk of increased intoxication with lithium.If simultaneous reception is still necessary, then regular monitoring of lithium content in serum is also necessary.

    Nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid at a dose of more than 3 g / day, reduce the antihypertensive effect of ACE inhibitors and diuretics. In addition, there are reports that the effects of NSAIDs and ACE inhibitors that increase potassium levels in the blood serum can be summarized, while renal function may be compromised. The corresponding effects are reversible and they develop in patients with existing renal dysfunction. In rare cases, acute renal failure may develop, primarily in patients with impaired renal function.

    Ethanol enhances the hypotensive effect of ACE inhibitors and hydrochlorothiazide.

    Simultaneous use of drugs containing trimethoprim (eg, biseptol) with ACE inhibitors and thiazides increases the risk of hypercalcemia.

    Special instructions:

    Zofenopril

    During the period of Zokardis® Plus therapy, the patient's condition should be monitored regularly, especially at the beginning of treatment.As with other ACE inhibitors, one should keep in mind the possibility of developing symptomatic arterial hypotension (even a few hours after taking the first dose of the drug) in patients with severe chronic heart failure, impaired renal function, as well as in patients with impaired water-electrolyte balance, conditioned by previous therapy with diuretics, salt-free diet, diarrhea, vomiting, or on hemodialysis. In patients with IHD, expressed by cerebrovascular disease, with stenosis of the aortic aorta with violations of hemodynamics or other obstacles to the outflow of blood from the left ventricle, a significant reduction in blood pressure can lead to myocardial infarction and / or stroke.

    Arterial hypotension with severe consequences is rare and transient. Transient arterial hypotension is not a contraindication to further continuation of therapy with the drug. Rarely with the treatment with ACE inhibitors, the syndrome begins with cholestatic jaundice, which progresses to acute hepatic necrosis. The mechanism of this syndrome is unclear.Patients who have jaundice or marked increase in the activity of "hepatic" enzymes in the treatment of ACE inhibitors should abolish ACE inhibitors and provide medical supervision.

    If a patient with hypertension was treated with diuretics, then, if possible, they should be canceled 2-3 days before the start of treatment with Zokardis® Plus (because of the risk of developing arterial hypotension).

    Before the beginning of treatment and during therapy, it is necessary to monitor the kidney function (determine the protein content in the urine with the help of test strips in the first portion of morning urine), tk. proteinuria can occur both in patients with an existing renal dysfunction and in patients taking relatively high doses of ACE inhibitors.

    In patients with diabetes mellitus receiving treatment with hypoglycemic agents for ingestion or insulin, the first month of treatment with ACE inhibitors should regularly monitor the concentration of glucose in the blood. During the period of treatment with Zokardis ® Plus, it is possible to increase the potassium content in blood serum, especially in patients with CRF, diabetes mellitus,with the simultaneous use of potassium-sparing diuretics, potassium or potassium-containing salt substitutes, or in patients taking other medications that lead to an increase in serum potassium (for example, heparin); this effect is usually weakened by thiazide diuretics because of increased excretion of potassium. If the simultaneous use of the above mentioned drugs is necessary, then it is recommended that the content of potassium in the blood serum be checked regularly.

    There are reports of the development of neutropenia, agranulocytosis, thrombocytopenia and anemia in patients receiving treatment with ACE inhibitors. The risk of neutropenia is likely to depend on the dose and clinical state of the patient. Neutropenia is more likely to occur in patients with impaired renal function, especially if there are concomitant connective tissue diseases (including systemic lupus erythematosus, scleroderma) or in the treatment of immunosuppressants, allopurinol or procainamide, and a combination of these risk factors. Some of these patients developed severe infectious diseases, in which in some cases there was no response to intensive antibiotic therapy.

    When used in such patients, the drug Zokardis® Plus is desirable before treatment and every 2 weeks. in the first three months of treatment, and then regularly monitor the leukocyte blood count and a detailed blood test. It should be strongly recommended that the patient be informed of any symptom of an infectious disease (sore throat, fever); In this case, an analysis of the leukocyte blood formula should be made. If suspected or the detection of neutropenia, which is reversible, it is necessary to cancel the drug Zokardis® Plus and other concurrently taken medications. Before conducting a planned surgical procedure, an anesthesiologist should be advised that the patient is receiving Zokardis® plus, since there is a risk of developing arterial hypotension or even vascular collapse in case of surgery or general anesthesia, BCC should be closely monitored. It should be borne in mind that in the treatment of Zokardis® plus in patients who are shown to carry out hemodialysis or other types of blood filtration,it is possible to develop anaphylactoid reactions (edema and hyperemia of the face, marked decrease in blood pressure, dyspnea) due to the use of high-throughput filter membranes consisting of polyacrylonitrile (high-flow membranes). It is recommended to use other types of filter membranes for dialysis or alternative antihypertensive therapy using a drug from another pharmacotherapeutic group. During the period of desensitizing therapy with the use of venom (wasps, bees) of insects in patients receiving Zokardis ® Plus, it is possible to develop reactions of hypersensitivity, posing a threat to life. To avoid the corresponding reactions, prior to each session of desensitizing therapy, the therapy with ACE inhibitors should be temporarily discontinued.

    If the angioedema develops in the lips, face, neck (usually in the first weeks of treatment with ACE inhibitors), the Zokardis® Plus preparation should be immediately withdrawn and continued with an antihypertensive drug from another pharmacotherapeutic group. However, in rare cases, heavy

    angioedema with involvement of tongue, glottis or larynx can also develop after long-term use of ACE inhibitors and lead to death. In this case, emergency measures should be taken, including at least (but not necessarily this limited) immediate administration of 0.1% epinephrine (adrenaline) solution subcutaneously (0.3-0.5 ml) or slow intravenous injection of epinephrine (epinephrine) 1 ml (diluted according to the instructions!) Under the close supervision of the ECG and blood pressure. The patient should be hospitalized and observed for at least 12-24 hours (until the symptoms disappear completely).

    Hydrochlorothiazide

    In patients with kidney disease, thiazides can aggravate azotemia. In patients with kidney function restriction hydrochlorothiazide can emulate. With the progression of renal failure, characterized by an increase in the concentration in the blood of total nitrogen, it is necessary to resolve the issue of the withdrawal of Zokardis ® plus.

    Each patient when taking diuretics requires a systematic control of the content of electrolytes in blood plasma.

    Thiazides can cause the development of violations of water-electrolyte balance (hypokalemia, hyponatremia and hypochloraemic alkalosis).Symptoms-precursors are: dryness of the oral mucosa, thirst, weakness, stupor, drowsiness, anxiety, muscle pain or cramps, muscle weakness, lowering blood pressure, oliguria, tachycardia, nausea, or vomiting.

    When taking thiazide diuretics, there may be signs of potassium deficiency, but the use of Zokardis® plus helps reduce hypokalemia caused by diuretics. The highest degree of risk of hypokalemia exists in patients with cirrhosis of the liver, increased diuresis, as well as inadequate intake of table salt inward, simultaneous use of glucocorticosteroids or corticotropin.

    In hot weather, hyponatremia of dilution may occur in patients prone to edema. Chloride deficiency usually is not expressed and does not require treatment.

    Thiazides can reduce the excretion of calcium by the kidneys and cause a slight transient increase in serum calcium without apparent disturbances in its metabolism. Expressed hypercalcemia may be a sign of latent hyperparathyroidism. Because of the effect on calcium metabolism, thiazides can distort the results of the study of parathyroid functionglands. Thiazides should be discontinued before examining the function of the parathyroid glands. Thiazides can reduce the concentration of iodine bound to the protein without causing symptoms of thyroid dysfunction. Thiazides increase the excretion of magnesium by the kidneys (risk of hypomagnesemia). In the treatment of thiazides, the development of a violation of glucose tolerance is possible. You may need to adjust the dose of insulin or hypoglycemic agent for oral administration. In the treatment of thiazides, latent-flowing diabetes mellitus can manifest.

    The relationship between increased cholesterol and triglyceride concentrations and the use of thiazide diuretics has been established. Treatment with thiazides can cause hyperuricemia or exacerbation of gout.

    Hydrochlorothiazide can cause a positive result in doping control.

    Zofenopril / Hydrochlorothiazide in combination

    The combination of ACE inhibitors with thiazide diuretics does not exclude the risk of hypokalemia, therefore, the content of potassium in the blood should be monitored regularly.

    Effect on the ability to drive transp.cf. and fur:The effect of Zokardis® plus on the ability to drive vehicles and control mechanisms has not been specifically studied, therefore, during the treatment with Zokardis® Plus, caution should be exercised when driving vehicles and engaging in potentially dangerous activities requiring increased attention and speed of psychomotor reactions.
    Form release / dosage:
    Film-coated tablets, 12.5 mg +30 mg.


    Packaging:
    For 14 tablets in a planar cell package (blister) [opaque PVC / PVDC / aluminum foil].
    By 1, 2, 4, or 7 blisters together with instructions for use in a cardboard bundle.
    Storage conditions:At a temperature of no higher than 30 ° C. Keep out of the reach of children!
    Shelf life:
    3 years. Do not use after the expiry date printed on the package.
    Terms of leave from pharmacies:On prescription
    Registration number:LP-000152
    Date of registration:13.01.2011
    Date of cancellation:2016-01-13
    The owner of the registration certificate:BERLIN-PHARMA, CJSC BERLIN-PHARMA, CJSC Russia
    Manufacturer: & nbsp
    Information update date: & nbsp30.12.2015
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