Co-Parnavel, tablets 0.625 mg+2 mg 30 pcs

Co-Parnavel is a combined drug containing the ACE inhibitor perindopril and the thiazide-like diuretic indapamide. The synergistic action of perindopril and indapamide determines the pharmacological properties of the drug.

Perindopril is an ACE inhibitor whose mechanism of action is associated with inhibition of ACE activity, resulting in reduction of angiotensin II, which has a vasoconstrictor effect, and also destroys bradykinin, which has a vasodilator effect, to inactive heptapeptide.

As a result, perindopril decreases aldosterone secretion, increases plasma renin activity by the principle of feedback; with long-term use it reduces total peripheral vascular resistance (PPR), which is mainly due to the effect on the vessels in the muscles and kidneys. These effects are not accompanied by retention of salts and fluids or development of reflex tachycardia.

Perindopril has therapeutic effects due to the active metabolite, perindoprilat. Other metabolites are pharmacologically inactive.

Perindopril normalizes heart function by promoting vein dilation (decreased preload) through changes in prostaglandin metabolism and decreased RPS (decreased post-load).

In chronic heart failure (CHF), perindopril reduces filling pressures in the left and right ventricles of the heart, decreases PPS, increases cardiac output and increases cardiac index, and increases peripheral blood flow in the muscles.

Indapamide belongs to the group of sulfonamides and by its pharmacological properties is close to thiazide diuretics. Indapamide inhibits sodium reabsorption in cortical segment of renal tubules increasing renal excretion of sodium, chlorine and to a lesser extent potassium and magnesium, increasing diuresis and decreasing blood pressure (BP). Antihypertensive action

The drug Co-Parnavel has a dose-dependent antihypertensive effect on both diastolic and systolic BP in standing and lying position. The antihypertensive effect lasts for 24 hours. Therapeutic effect occurs in less than 1 month after the start of treatment and is not accompanied by tachycardia. Treatment discontinuation does not cause “withdrawal” syndrome.

The synergistic effect of perindopril and indapamide compared to monotherapy with these drugs was noted. Perindopril is effective in therapy of arterial hypertension of any severity. Antihypertensive effect is achieved maximum in 4-6 hours after a single dose and lasts for 24 hours. 24 hours after perindopril administration there is significant (about 80%) residual ACE inhibition.

Perindopril shows antihypertensive effect in patients with both low and normal plasma renin activity.

Perindopril has a vasodilator effect, helps to restore elasticity of large vessels and vascular wall structure of small arteries. It also reduces left ventricular hypertrophy.

The concomitant use of thiazide diuretics enhances the antihypertensive effect.

Indapamide in monotherapy has antihypertensive effect within 24 hours at doses that have minimal diuretic effect. Indapamide improves elasticity of large arteries, decreases PPS, reduces left ventricular hypertrophy. Increasing the dose of indapamide does not increase the antihypertensive effect, but increases the risk of adverse events.

Indapamide has no effect on lipid metabolism (total cholesterol, high (HDL) and low density lipoprotein cholesterol (LDL), triglycerides) and carbohydrate metabolism.

Pharmacokinetics

The combined use of perindopril and indapamide does not change their pharmacokinetic characteristics compared to the separate administration of these drugs. Perindopril after oral administration is rapidly absorbed in the gastrointestinal tract (GIT) and reaches maximum plasma concentration (Cmax) within 1 hour. Perindopril has no pharmacokinetic activity.

Approximately 27% of the total amount of perindopril taken orally enters the bloodstream as the active metabolite perindoprilat. In addition to perindoprilat, 5 other metabolites with no pharmacological activity are formed. Cmax of perindoprilat is reached after 3-4 hours.

Ingestion of perindopril with meals is accompanied by a decrease in conversion of perindopril to perindoprilate, accordingly its bioavailability is reduced. Therefore, perindopril should be taken once daily, before meals.

There is a linear dependence of plasma concentration of perindopril on its dose. The volume of distribution of free perindoprilat is 0.2 l/kg. Binding to plasma proteins is insignificant; binding of perindoprilat, mainly to ACE, is less than 20% and depends on its concentration.

Perindopril is excreted by the kidneys. The “effective” half-life (T1/2) of the free fraction is about 17 hours, so the equilibrium state is reached within 4 days.

The excretion of perindopril is slower in the elderly and in patients with cardiac and renal insufficiency.

The dialysis clearance of perindopril is 70 ml/min.

In patients with cirrhosis, the “hepatic” clearance of perindopril is reduced by half, while the total amount of perindoprilate produced is not reduced and no dosing adjustment is required.

Indapamide is rapidly and completely absorbed from the gastrointestinal tract. The cma of indapamide is reached in plasma after 1 hour. Binding with plasma proteins is 79%. T1/2 is 14-24 h (average 18 h). Repeated intake of indapamide does not lead to its cumulation in the body. It is eliminated mainly by the kidneys (70%) and intestine (22%) as inactive metabolites. Pharmacokinetics of indapamide does not change in patients with renal insufficiency.

Indications

Essential hypertension (patients who are indicated for combination therapy).

Active ingredient

Indapamide, Perindopril

How to take, the dosage

Overly, once a day, preferably in the morning before breakfast, without chewing, drinking plenty of fluids. The dose of the drug is adjusted individually for each patient, depending on the patient’s condition and individual response to treatment.

Doses are given for perindopril/indapamide ratio. The recommended starting dose is 1 tablet of Co-Parnavel (2 mg/0.625 mg) once daily. If adequate blood pressure control is not achieved after 1 month of therapy, the dose should be increased to 1 tablet of Co-Parnavel (4 mg/1.25 mg) once daily.

Patients in the elderly

The recommended starting dose is 1 tablet of the drug at 2 mg/0.625 mg once daily.

If the desired antihypertensive effect is not achieved after a renal function study, a 1 tablet dose of 4 mg/1.25 mg may be switched to.

Patients with impaired renal function

In severe renal impairment (creatinine clearance less than 30 ml/min), use of the drug is contraindicated.

Patients with moderate renal impairment (creatinine clearance 30-60 ml/min) are recommended to start therapy with the required doses of the drugs (in monotherapy) included in the drug Co-Parnavel.

In patients with impaired renal function (creatinine clearance of 60 ml/min or more), no dose adjustment is required.

Potassium and creatinine serum concentrations should be monitored regularly.

Patients with hepatic impairment

Dose adjustment is not required in patients with moderate hepatic impairment.

The use of the drug is contraindicated in patients with severe hepatic impairment.

Children and adolescents

The drug should not be used in children and adolescents under 18 years of age because efficacy and safety have not been established.

If you miss one or more doses at your next appointment, Co-Parnavel should be taken at the usual dose; a higher dose should not be taken.

Interaction

Unwanted drug combinations

Lithium drugs

Concomitant use of lithium drugs and ACE inhibitors may cause reversible increase in plasma lithium concentration and associated toxic effects. Additional administration of thiazide diuretics may contribute to further increase in lithium and increase the risk of manifestation of toxicity.

The concomitant use of the combination of perindopril and indapamide with lithium preparations is not recommended. Regular monitoring of plasma lithium concentrations is required if this therapy is administered (see section “Special Precautions”).

Combinations of drugs requiring special attention

Baclofen: Increased antihypertensive effect is possible. BP and renal function should be monitored; if necessary, correction of the dose of hypotensive drugs is required.

– Non-steroidal anti-inflammatory drugs (NSAIDs), including high doses of acetylsalicylic acid (more than 3 g/day): concomitant administration of ACE inhibitors and NSAIDs (acetylsalicylic acid at a dose with anti-inflammatory effects, cyclooxygenase-2 (COX-2) inhibitors and non-selective NSAIDs) may result in decreased antihypertensive effects.

The concomitant use of ACE inhibitors and NSAIDs may lead to worsening of renal function, including development of acute renal failure and increased serum potassium, especially in patients with reduced renal function. Caution should be exercised when prescribing this combination, especially in elderly patients.

Patients should compensate for fluid loss and monitor renal function regularly, both at the start of treatment and during treatment.

Combinations of drugs requiring attention

– Tricyclic antidepressants, antipsychotics (neuroleptics): drugs of these classes increase antihypertensive effect and increase the risk of orthostatic hypotension (additive effect).

– Glucocorticosteroids, tetracosactide: decreased antihypertensive effect (fluid and sodium ion retention as a result of glucocorticosteroid action).

– Other hypotensive agents: may increase the antihypertensive effect.

Perindopril

Simultaneous use is contraindicated

Aliskiren: In patients with diabetes mellitus or impaired renal function (GFR less than 60 ml/min/1.73 m2) there is an increased risk of hyperkalemia, impaired renal function and increased incidence of cardiovascular morbidity and mortality.

The concomitant use is not recommended

Aliskiren: In patients without diabetes mellitus or impaired renal function, there may be an increased risk of hyperkalemia, impaired renal function, increased incidence of cardiovascular morbidity and mortality.

Averse drug combinations

Kalium-saving diuretics (amiloride, spironolactone, eplerenone, triamterene) and potassium preparations: ACE inhibitors decrease the renal potassium loss caused by the diuretic.

The simultaneous use of potassium-saving diuretics (e.g., spironolactone, eplerenone, triamterene, amiloride), potassium preparations, and potassium-containing salt substitutes can lead to a significant increase in serum potassium up to and including death.

If co-administration of ACE inhibitor and the above drugs is necessary (in case of confirmed hypokalemia), caution should be exercised and plasma potassium and ECG parameters should be monitored regularly.

Drugs causing hyperkalemia

Some drugs or drugs of other pharmacological classes can increase the risk of hyperkalemia: aliskiren and aliskiren-containing drugs, potassium salts, potassium-saving diuretics, ACE inhibitors, ARAII (angiotensin II receptor antagonists), NSAIDs, heparin, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim. The combination of these drugs increases the risk of hyperkalemia.

Combinations of agents requiring special attention

Hypoglycemic oral agents (sulfonylurea derivatives) and insulin: The following effects have been described for captopril and enalapril. ACE inhibitors may increase the hypoglycemic effect of insulin and sulfonylurea derivatives in patients with diabetes. The development of hypoglycemia is very rare (due to increased glucose tolerance and reduced insulin requirement).

Double blockade of the RAAS: There are reports that in patients with established atherosclerotic disease, heart failure, or diabetes mellitus with target organ damage, concurrent therapy with an ACE inhibitor and ARAII is associated with higher rates of arterial hypotension, syncope, hyperkalemia, and impaired renal function (including acute renal failure) compared with use of the RAAS-acting drug alone.

Double blockade (e.g., when ACE inhibitor is combined with ARAII) should be limited to individual cases with careful monitoring of renal function, potassium and BP. Estramustine: Concomitant use may increase the risk of side effects such as angioedema.

Glyptins (linagliptin, saxagliptin, sitagliptin, vitagliptin): Simultaneous use with ACE inhibitors may increase the risk of angioedema due to inhibition of dipeptidyl peptidase IV (DPP-IV) activity by glyptin.

– General anesthesia agents: simultaneous use of ACE inhibitors and general anesthesia agents may increase the antihypertensive effect.

– Diuretics (thiazide and loop diuretics): use of diuretics at high doses may lead to hypovolemia, and adding perindopril to therapy may lead to arterial hypotension.

– Gold drugs: when ACE inhibitors, including perindopril, are administered to patients receiving gold drugs (sodium aurothiomalate) by infusion, nitrate-like reactions (facial hyperemia, nausea, vomiting, arterial hypotension) have been noted.

Indapamide

Combinations of agents requiring special attention

– Drugs that can cause pirouette-type arrhythmias: Because of the risk of hypokalemia, caution should be exercised when using indapamide concomitantly with drugs that may cause pirouette arrhythmias, such as antiarrhythmic agents (quinidine, hydroquinidine, disopyramide, amiodarone, dofetilide, ibutilide, brettilia tozilate, sotalol); some neuroleptics chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine); benzamides (amisulpride, sulpiride, sultopride, thiapride); butyrophenones (droperidol, haloperidol); other neuroleptics (pimozide) other drugs such as bepridil, cisapride, difemanil methyl sulfate, IV erythromycin, halofantrine, misolastin, moxifloxacin, pentamidine, sparfloxacin, IV vincamine, methadone, astemizole, terfenadine. Hypokalemia should be avoided and, if necessary, should be corrected; QT interval should be monitored.

– Drugs that may cause hypokalemia: amphotericin B (intravenous), gluco- and mineralocorticosteroids (when administered systemically), tetracosactide, laxatives that stimulate gastrointestinal motility (GI): increased risk of hypokalemia (additive effect). Control of plasma potassium content is necessary, and its correction, if necessary. Particular attention should be paid to patients concomitantly receiving cardiac glycosides. Laxatives that do not stimulate gastrointestinal motility should be used.

– Cardiac glycosides: hypokalemia increases the toxic effects of cardiac glycosides. When concomitant use of indapamide and cardiac glycosides, plasma potassium and ECG parameters should be monitored and, if necessary, therapy should be adjusted.

Combinations of agents requiring attention

Metformin: functional renal insufficiency, which may occur with diuretics, especially loop diuretics, when concomitant administration of metformin increases the risk of lactic acid lactoacidosis. Metformin should not be used if plasma creatinine concentration exceeds 15 mg/L (135 µmol/L) in men and 12 mg/L (110 µmol/L) in women.

Iodine-containing contrast agents: dehydration of the body against the background of taking diuretics increases the risk of acute renal failure, especially when using high doses of iodine-containing contrast agents. Before using iodine-containing contrast agents, patients should compensate the volume of circulating blood.

– Calcium salts: concomitant use can lead to hypercalcemia due to reduced renal calcium excretion.

Cyclosporine: increase of creatinine concentration in plasma is possible without change in circulating cyclosporine, even if liquid and sodium ion levels are normal.

Special Instructions

Lithium preparations

The concomitant use of perindopril and indapamide with lithium preparations is not recommended.

Parenavel therapy is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 ml/min). Some patients with arterial hypertension without previous renal impairment may show signs of acute renal failure during Co-Parnavel therapy. In this case, treatment with the drug should be discontinued.

Thereafter, combination therapy may be resumed with low-dose Co-Parnavel or perindopril and indapamide may be used in monotherapy. Such patients should have their serum potassium and creatinine monitored regularly every 2 weeks after initiation of therapy and every 2 months thereafter with Co-Parnavel.

Acute renal failure is more common in patients with severe chronic heart failure or underlying renal impairment, including bilateral renal artery stenosis or artery stenosis of the only functioning kidney. The drug is not recommended for patients with bilateral stenosis of the renal arteries or stenosis of the artery of the only functioning kidney. Arterial hypotension and electrolyte balance disorders

Hyponatremia is associated with a risk of sudden development of arterial hypotension (especially in patients with bilateral renal artery stenosis or artery stenosis of the only functioning kidney).

Hence, in the dynamic monitoring of patients, attention should be paid to possible symptoms of dehydration and decreased plasma electrolytes, e.g., after prolonged diarrhea or vomiting. Such patients require regular monitoring of plasma electrolytes. Intravenous administration of 0.9% sodium chloride solution may be required if there is a marked decrease in blood pressure.

Transient arterial hypotension is not a contraindication for further continuation of therapy. After recovery of circulating blood volume and blood pressure, therapy with Co-Parnavel may be resumed using low doses of the drug, or using perindopril and indapamide in monotherapy.

Potassium content

The simultaneous use of perindopril and indapamide does not prevent hypokalemia, especially in patients with diabetes or renal insufficiency. As with other hypotensive agents in combination with a diuretic, regular monitoring of plasma potassium is necessary.

Auxiliary substances

Please note that the excipients of the drug contain lactose monohydrate; therefore the drug is contraindicated in patients with hereditary lactose intolerance or lactase deficiency or glucose-galactose malabsorption.

Perindopril

Neutropenia/agranulocytosis

In patients taking ACE inhibitors there may be cases of neutropenia/agranulocytosis, thrombocytopenia and anemia. In patients with normal renal function, in the absence of other complications, neutropenia is rare and resolves on its own after withdrawal of ACE inhibitors.

Perindopril should be used with great caution in patients with connective tissue disease concomitantly receiving immunosuppressive therapy, allopurinol or procainamide, especially in existing renal impairment.

These patients may develop severe infections that do not respond to intensive antibiotic therapy. If perindopril is prescribed, periodic monitoring of blood leukocyte counts is recommended. The patient should be warned that in case of any signs of infectious disease (sore throat, fever) it is necessary to immediately consult a physician.

Angioneurotic edema (Quincke’s edema)

In rare cases, angioedema of the face, lips, tongue, uvula and/or larynx may develop when taking ACE inhibitors, including perindopril. If these symptoms occur, the drug should be stopped immediately, and the patient should be observed until the signs of edema disappear completely.

If only the face and lips are affected, angioedema usually resolves on its own or antihistamines may be used to treat its symptoms. Angioedema accompanied by swelling of the tongue and larynx may result in airway obstruction and death. If these symptoms occur, epinephrine (adrenaline) (1:1000 dilution (0.3 or 0.5 ml) should be administered immediately by subcutaneous injection and/or airway patency should be ensured.

In patients with a history of Quincke’s edema not associated with ACE inhibitors, there may be an increased risk of it when taking this group of drugs (see section “Contraindications”).

In rare cases, angioedema of the intestine develops during therapy with ACE inhibitors. Patients have abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without preceding angioedema of the face and with normal C-1 esterase enzyme activity.

The diagnosis is established by abdominal computed tomography, ultrasound or at the time of surgery. Symptoms disappear after discontinuation of ACE inhibitors. In patients with abdominal pain receiving ACE inhibitors, the possibility of angioedema of the bowel must be considered in the differential diagnosis.

Anaphylactoid reactions during desensitization procedures

There have been isolated reports of long-term, life-threatening anaphylactoid reactions in patients receiving ACE inhibitors during desensitization therapy with venom from hymenopteran insects (bees, wasps).

ACE inhibitors should be used with caution in patients with a history of severe allergic reactions or susceptibility to allergic reactions undergoing desensitization procedures. Administration of ACE inhibitor should be avoided in patients receiving immunotherapy with venom of hymenopterous insects. The development of anaphylactoid reactions can be avoided by temporarily withdrawing the ACE inhibitor at least 24 hours before the desensitization procedure.

Anaphylactoid reactions during LDL apheresis

In rare cases, life-threatening anaphylactoid reactions may develop in patients receiving ACE inhibitors during LDL apheresis with dextran sulfate. To prevent anaphylactoid reactions, therapy with an ACE inhibitor should be discontinued before each LDL apheresis procedure using high-flow membranes.

Hemodialysis

In patients receiving ACE inhibitors, anaphylactoid reactions have been reported when performing hemodialysis using high-flow membranes (e.g., AN69®). Therefore, it is advisable to use a different type of membrane or to use a hypotensive drug from a different pharmacotherapeutic group.

Cough

Dry cough may occur against the background of ACE inhibitor therapy, which disappears after discontinuation of the drugs of this group. If you have a dry cough, be aware of the possible association between this symptom and ACE inhibitor therapy. If the physician considers that therapy with an ACE inhibitor is necessary for the patient, therapy with Co-Parnavel may be continued.

The risk of arterial hypotension and/or renal failure (in patients with chronic heart failure, water-electrolyte balance disorders, etc.).Significant activation of the renin-angiotensin-aldosterone system (RAAS) may be observed in some pathological states, especially with severe hypovolemia and reduced plasma electrolyte content (against the background of a diet with restriction of table salt or long-term use of diuretics), in patients with baseline low blood pressure, renal artery stenosis (including bilateral), chronic heart failure or cirrhosis with edema and ascites.

The use of ACE inhibitors causes RAAS blockade, due to this a sharp decrease in blood pressure and/or increase in plasma creatinine concentration indicating the development of acute renal failure may occur, which is often observed with the first dose of the drug or during the first 2 weeks of therapy. Sometimes these conditions develop acutely. In such cases, when resuming therapy it is recommended to use a combination of perindopril and indapamide at a lower dose and then gradually increase the dose.

Patients of advanced age

Before starting Co-Parnavel, renal function and plasma potassium should be evaluated. The initial dose should be adjusted according to the degree of blood pressure decrease, especially in case of decreased circulating blood volume and chronic heart failure (functional class IV according to NYHA classification). Such measures help to avoid a sharp decrease in blood pressure.

Atherosclerosis

The risk of arterial hypotension exists in all patients, but special caution should be exercised when using the drug in patients with coronary heart disease and insufficiency of cerebral circulation. In such patients, treatment should be started with a dose of 2 mg/0.625 mg (initial dose).

Patients with renovascular hypertension

Patients with diagnosed or suspected renal artery stenosis should be started with a 2 mg/0.625 mg drug dose in the hospital setting, monitoring renal function and plasma potassium content. Some patients may develop acute renal failure, which is reversible after drug withdrawal.

In patients with chronic heart failure (NYHA functional class IV) and in patients with type 1 diabetes mellitus (risk of spontaneous increase of potassium), treatment should be initiated with starting dose of 2 mg/0.625 mg of Co-Parnavel and under medical supervision.

Patients with Diabetes Mellitus

When prescribing the drug to patients with diabetes mellitus who are receiving oral hypoglycemic agents or insulin, blood glucose concentrations should be monitored regularly during the first month of therapy.

Surgery/general anesthesia

The use of ACE inhibitors in patients undergoing surgery with general anesthesia may cause significant decreases in blood pressure, especially with the use of general anesthesia drugs with antihypertensive effect.

The use of ACE inhibitors, including perindopril, should be discontinued 12 hours before the surgical intervention and the anesthesiologist should be informed about the use of ACE inhibitors.

Ethnic differences

Perindopril, like other ACE inhibitors, appears to have less pronounced antihypertensive effects in non-Hispanic patients compared with other races. It is possible that this difference is due to the fact that non-Hispanic patients with arterial hypertension are more likely to have low renin activity.

Aortic stenosis/ Mitral stenosis/Hypertrophic obstructive cardiomyopathy

ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction and with aortic and/or mitral stenosis.

Hepatic failure

In rare cases cholestatic jaundice occurs against the background of ACE inhibitors administration, with progression of which fulminant hepatic necrosis develops, sometimes with fatal outcome. If jaundice or significant increase in liver transaminase activity occurs with ACE inhibitors, Co-Parnavel should be discontinued.

Anemia may occur in patients after renal transplantation or in patients on hemodialysis. The greater the decrease in hemoglobin, the greater the initial hemoglobin decrease. This effect does not seem to be dose-dependent, but may be related to the mechanism of action of ACE inhibitors.

Hyperkalemia

Hyperkalemia may develop during treatment with ACE inhibitors, including perindopril. The risk factors of hyperkalemia are renal insufficiency, elderly age, diabetes mellitus, some associated conditions (decreased volume of circulating blood, decompensated chronic heart failure, metabolic acidosis), concomitant use of potassium-saving diuretics (such as spironolactone, eplerenone, triamterene, amiloride) as well as potassium preparations or potassium-containing salt substitutes and use of other drugs that increase plasma potassium content (e.g., heparin).

Hyperkalemia can lead to serious disturbances of the heart rhythm, sometimes with fatal consequences. Simultaneous use of the above drugs should be done with caution.

Indapamide

The use of thiazide and thiazide-like diuretics may lead to hepatic encephalopathy if liver function is impaired. In this case the use of Co-Parnavel should be stopped immediately.

Photosensitivity

There have been reports of photosensitivity reactions when taking thiazide and thiazide-like diuretics. If hypersensitivity reactions occur with the drug, treatment should be discontinued. If it is necessary to resume the use of Co-Parnavel, the exposed skin should be protected from direct sunlight and artificial ultraviolet rays.

Water-electrolyte balance.

The plasma sodium content.

Before starting treatment with the drug, the plasma sodium content should be determined, and plasma electrolytes should be monitored regularly while taking the drug. All diuretics can cause hyponatremia, which leads to serious complications.

Hyponatremia initially may not be accompanied by clinical symptoms, so regular laboratory monitoring is necessary. More frequent monitoring of sodium is indicated in patients with cirrhosis and elderly patients.

Plasma potassium content

The therapy with thiazide and thiazide-like diuretics is associated with the risk of hypokalemia (less than 3.4 mmol/l) in the following patients The elderly, emaciated patients, patients with cirrhosis of the liver, patients with peripheral edema, ascites, coronary heart disease, and chronic heart failure. Hypokalemia in these patients increases the toxic effects of cardiac glycosides and increases the risk of arrhythmias.

Patients with an increased QT interval on ECG are at increased risk, regardless of whether the increase is due to congenital causes or to medication.

Hypokalemia, like bradycardia, contributes to severe cardiac arrhythmias, especially pirouette arrhythmias, which may be fatal. In all the described cases, regular monitoring of plasma potassium content is necessary. The first plasma potassium determination should be performed within the first week of starting therapy with Co-Parnavel.

If hypokalemia is detected, appropriate treatment should be prescribed.

Plasma calcium content

Thiazide and thiazide-like diuretics decrease renal calcium excretion, resulting in a slight and temporary increase in plasma calcium content. Severe hypercalcemia may result from occult hyperparathyroidism. Co-Parnavel should be discontinued before parathyroid function is investigated.

Plasma glucose concentrations

Monitor glucose concentrations in patients with diabetes mellitus, especially if hypokalemia is present.

Uracilic acid

Patients with elevated plasma uric acid concentrations with drug therapy may have an increased incidence of gout flare-ups.

Diuretics and renal function

The thiazide and thiazide-like diuretics are only fully effective in patients with normal or mildly impaired renal function (plasma creatinine concentration in adult patients is less than 25 mg/l or 220 µmol/L). In elderly patients the CK is calculated taking into account age, body weight and sex.

At the beginning of diuretic treatment, patients may experience a temporary decrease in glomerular filtration rate and an increase in plasma urea and creatinine concentrations due to hypovolemia and hyponatremia. This transient functional renal failure is not dangerous in patients with unchanged renal function, but in patients with renal insufficiency, its severity may increase.

Athletes Co-Parnavel may give false positive reactions in doping controls.

Influence on the ability to drive and other complex machinery

Cautious attention must be paid when driving motor vehicles and operating technical devices that require increased attention and rapid psychomotor reactions.

Contraindications

Perindopril

– Hypersensitivity to perindopril and other ACE inhibitors.

– Concomitant use with aliskiren and aliskiren-containing drugs in patients with diabetes mellitus or impaired renal function (glomerular filtration rate (GFR) less than 60 ml/min/1.73 m2).

– A history of angioedema (Quincke’s edema) associated with taking an ACE inhibitor.

– Hereditary/idiopathic angioedema.

– Pregnancy.

– Breastfeeding period.

– Age less than 18 years (effectiveness and safety not established). Indapamide

– Hypersensitivity to indapamide, other sulfonamide derivatives, severe renal insufficiency (creatinine clearance (CK) less than 30 ml/min), severe hepatic impairment or hepatic encephalopathy, hypokalemia, pregnancy, breast-feeding, age under 18 years (insufficient data on safety and efficacy). Concomitant use with drugs that can cause pirouette-type arrhythmias.

Co-Parnavel

– Hypersensitivity to the excipients in the drug.

– Concurrent use with potassium-saving diuretics, potassium and lithium preparations, and in patients with elevated plasma potassium levels;

– Lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.

– Concurrent use of drugs that prolong the QT interval.

– Bilateral renal artery stenosis or artery stenosis of the only functioning kidney.

– Because of insufficient clinical experience, Co-Parnavel should not be used in patients on hemodialysis or in patients with untreated decompensated heart failure.

– Age less than 18 years (efficacy and safety not established).

Side effects

The frequency of adverse reactions was determined in accordance with the World Health Organization recommendations: Very common (>1/10); common (>1/100, <1/10); infrequent (>1/1000, <1/100); rare (>1/10000, <1/1000); very rare (<1/10000), including individual reports; unspecified frequency (frequency cannot be calculated from available data).

Blood and lymphatic system disorders

Very rare: thrombocytopenia, leukopenia/neutropenia, agranulocytosis, aplastic anemia, hemolytic anemia.

In certain clinical situations (patients after kidney transplantation, patients on hemodialysis) ACE inhibitors may cause anemia.

Central nervous system disorders

Often: paresthesias, headache, dizziness, vertigo. Infrequent: sleep disturbance and mood swings. Very rare: confusion. Unspecified frequency: fainting.

Visual organ disorders

Often: visual disturbances.

Hearing organ disorders

Often: tinnitus.

Cardiovascular system disorders

Infrequent: marked decrease in BP, including orthostatic hypotension. Very rare: cardiac rhythm disorders, including bradycardia, ventricular tachycardia, atrial fibrillation, as well as angina and myocardial infarction, possibly due to excessive BP reduction in high-risk patients. Unspecified frequency: pirouette-type arrhythmias (possibly fatal).

Respiratory system, thorax and mediastinum disorders

Often: dry cough may occur while using ACE inhibitors, which persists for a long time while taking this group of drugs and disappears after their withdrawal. Dyspnea. Infrequent: bronchospasm. Very rare: eosinophilic pneumonia, rhinitis.

Gastrointestinal system disorders

Often: dry mouth, nausea, vomiting, abdominal pain, epigastric pain, impaired sense of taste, decreased appetite, dyspepsia, constipation, diarrhea.

Very rare: pancreatitis, angioneurotic edema of the intestine, cholestatic jaundice. Unspecified frequency: hepatic encephalopathy in patients with hepatic insufficiency.

Skin and subcutaneous fat disorders

Often: skin rash, itching, maculopapular rash.

Infrequent: angioedema of face, lips, mucous membrane of tongue, vocal folds and/or larynx; urticaria; hypersensitivity reactions in patients with predisposition to asthma and allergic reactions; hemorrhagic vasculitis. In patients with acute forms of systemic lupus erythematosus, exacerbation of the disease is possible.

very rarely: erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome.

There have been cases of photosensitivity reactions (see section “Special Precautions”).

Musculoskeletal and connective tissue disorders

Often: muscle cramps.

Urinary system disorders

Infrequent: renal failure. Very rare: acute renal failure.

Reproductive system disorders

Infrequent: impotence.

General disorders and symptoms

Infrequent: increased sweating.

Laboratory findings

Rarely: hypercalcemia.

Unspecified frequency:

– Increased QT interval on ECG.

– Increased uric acid and blood glucose concentrations during
administration of the drug.

– Increase in the activity of “hepatic” transaminases.

– Slight increase in creatinine concentration in urine and plasma, which disappears after discontinuation of therapy, more often in patients with renal artery stenosis, when treating arterial hypertension with diuretics and in cases of renal failure.

– Hypokalemia, especially significant in patients at risk.

– Hyperkalemia, more often transient.

– Hyponatremia and hypovolemia leading to dehydration and orthostatic hypotension.

Overdose

Symptoms: marked decrease in blood pressure, nausea, vomiting, muscle cramps, dizziness, drowsiness, confusion, oliguria up to anuria (due to decreased volume of circulating blood); disorders of water-electrolyte balance (low plasma sodium and potassium) are possible.

Treatment: gastric lavage and/or administration of activated charcoal, restoration of water-electrolyte balance in hospital. With a marked decrease in blood pressure the patient should be transferred to the “lying” position on his back with elevated legs; then there should be measures to increase the volume of circulating blood (intravenous injection of 0.9% sodium chloride solution). Perindoprilat, the active metabolite of perindopril, can be eliminated from the body by dialysis.

Similarities

Co-Perineva, Noliprel A Bi-forte, Noliprel A, Noliprel A forte, Perindopril-Indapamide , Perindopril, Indapamide / Perindopril-Teva