Perindide, 0.625 mg+2 mg 30 pcs

Pharmacotherapeutic group

hypertensive combined (diuretic + ACE inhibitor)

ATX code

C09BA04

Pharmacodynamics:

Perindide is a combination drug containing the angiotensin-converting enzyme (ACE) inhibitor perindopril and the thiazide-like diuretic indapamide. The drug has antihypertensive diuretic and vasodilatory effects.

Perindide has a pronounced dose-dependent antihypertensive effect, independent of the age and body position of the patient and not accompanied by reflex tachycardia. Does not affect the metabolism of lipids (total cholesterol low density lipoproteins (LDL) very low density lipoproteins (VLDL) high density lipoproteins (HDL) triglycerides (TG) and carbohydrates) including in diabetic patients. Reduces the risk of hypokalemia due to monotherapy with a diuretic.

The antihypertensive effect lasts for 24 hours.

A steady decrease in blood pressure (BP) is achieved within 1 month with Perindide without an increase in heart rate (HR). Discontinuation of treatment does not lead to development of “withdrawal” syndrome.

Perindopril is an ACE inhibitor whose mechanism of action is associated with inhibition of ACE activity, resulting in reduction of angiotensin II formation eliminates the vasoconstrictor effect of angiotensin II and reduces aldosterone secretion. The use of perindopril does not lead to retention of sodium and fluid does not cause reflex tachycardia during long-term treatment. The antihypertensive effect of perindopril develops in patients with low or normal plasma renin activity.

Perindopril acts through its main active metabolite, perindoprilat. Its other metabolites are inactive.

The action of the drug Perindopril results in:

– vein dilation due to changes in prostaglandin metabolism (reduction of cardiac preload);

– reduction of total peripheral resistance (TPR) (reduction of cardiac postload).

In patients with heart failure, perindopril promotes:

– decreased left and right ventricular filling pressures;

– increased cardiac output and cardiac index;

– increased regional muscle blood flow.

Perindopril is active in arterial hypertension of any severity: mild moderate to severe. Maximum antihypertensive effect develops 4-6 hours after a single oral administration and lasts for 24 hours.

Cessation of therapy does not lead to development of “withdrawal” syndrome.

It has vasodilator properties and restores elasticity of large arteries. The addition of a thiazide diuretic enhances the antihypertensive (additive) effect of perindopril.

Indapamide refers to sulfonamide derivatives is a thiazide diuretic. Indapamide inhibits sodium reabsorption in the cortical segment of the renal tubules which increases renal excretion of sodium and chlorine and leads to increased diuresis. To a lesser extent increases the excretion of potassium and magnesium. Having the ability to selectively block “slow” calcium channels indapamide increases the elasticity of arterial walls and reduces the RPS. It has a hypotensive effect in doses not having a pronounced diuretic effect. Increasing the dose of indapamide does not entail increasing the antihypertensive effect but increases the risk of adverse events.

Indapamide in patients with arterial hypertension has no effect on:

– lipid metabolism: LDL and HDL TG

– carbohydrate metabolism even in patients with diabetes mellitus and arterial hypertension.

Pharmacokinetics:

The combined use of perindopril and indapamide does not change their pharmacokinetic parameters compared to the separate administration of these drugs.

Perindopril

It is rapidly absorbed from the gastrointestinal tract (GIT) after oral administration. Bioavailability is 65-70%. Food intake reduces the conversion of perindopril to perindoprilate. The elimination half-life (T1/2) from blood plasma is 1 hour.

The maximum plasma concentration is reached 3-4 hours after oral administration. Since intake with food reduces conversion of perindopril to perindoprilate and bioavailability of the drug perindopril should be taken once a day in the morning before breakfast. By taking perindopril once daily sustained concentration is achieved within 4 days.

It is metabolized in the liver to form the active metabolite perindoprilat. In addition to the active metabolite perindoprilat, perindopril forms 5 inactive metabolites. Binding to blood plasma proteins is dose-dependent and is 20%. Perindoprilat easily passes through the histohematic barriers except the blood-brain barrier, a small amount passes through the placenta and into the breast milk. Excreted by the kidneys The T1/2 of perindoprilat is about 17 hours. It does not cumulate.

In elderly patients with renal and cardiac insufficiency, excretion of perindoprilat is delayed.

In patients with renal failure, it is recommended that the dose of perindoprilat be reduced according to the severity of renal failure (creatinine clearance (CK)).

The dialysis clearance of perindoprilat is 70 ml/min.

Perindopril kinetics is altered in patients with cirrhosis: hepatic clearance is reduced by half. However, the amount of perindoprilat produced is not reduced, requiring no dose adjustment.

Indapamide

It is rapidly and almost completely absorbed in the gastrointestinal tract. Food intake slightly slows down absorption but does not significantly affect the amount of indapamide adsorbed. Maximum plasma concentration is reached 1 hour after a single oral dose. Binds to plasma proteins by 79%. T1/2 is 14 to 24 hours (average 18 hours). (18 hours on average). It does not cumulate.

Metabolized in the liver. It is excreted by the kidneys (70%) mainly as metabolites (the fraction of unchanged drug is about 5%) and in the intestine with the bile as inactive metabolites (22%). In patients with renal insufficiency pharmacokinetic parameters of the drug do not change significantly.

Indications

Active ingredient

Composition

1 film-coated tablet contains:

active ingredients: indapamide 0.625 mg and perindopril erbumin 2 mg;

excipients: microcrystalline cellulose 44.1125 mg, lactose monohydrate 86.8 mg, colloidal silicon dioxide 0.45 mg, magnesium stearate 0.75 mg;

film coating composition: color Vincoat WT-01985 brown 5.00 mg.

(Composition of Vincoat WT-01985 brown per tablet: hypromellose 2.80 mg, macrogoal – 400 0.45 mg, titanium dioxide 0.77 mg, talc 0.23 mg, macrogoal – 6000 0.27 mg, iron oxide red dye 0.50 mg.).

How to take, the dosage

Once daily by mouth, preferably in the morning hours before breakfast with plenty of fluid.

The initial dose is 1 tablet of Perindid (0625 mg + 2 mg) once daily. If after 1 month of taking the drug it is not possible to achieve adequate BP control, the drug dose should be increased to 1 tablet of Perindid (125 mg + 4 mg) once daily.

Elderly patients

The starting dose is 1 tablet of Perindid (0625 mg + 2 mg) once daily.

Patients with impaired renal function

Patients with renal impairment (CK of 60 ml/min or more) do not require dose adjustment. Regular monitoring of plasma creatinine and potassium concentrations is required during therapy.

In patients with a CKR of 30-60 ml/min, the maximum dose of Perindid is 0625 mg + 2 mg once daily.

In severe renal dysfunction (CKD less than 30 ml/min), therapy with Perindide is contraindicated (see section “Contraindications”).

Patients with impaired liver function

In patients with moderate impairment of liver function, no dose adjustment is required.

Children and adolescents

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

Interaction

Perindide

Indesirable drug combinations

Lithium preparations

The simultaneous use of lithium preparations and ACE inhibitors may cause a reversible increase in plasma lithium concentration and associated toxic effects. Additional administration of thiazide diuretics may contribute to further increase in lithium concentration and increase the risk of manifestation of toxicity. Concomitant use of the combination of perindopril and indapamide with lithium preparations is not recommended. In case of such therapy, regular monitoring of plasma lithium concentration is required (see section “Special Precautions”).

Combinations of drugs requiring special attention

Baclofen

The antihypertensive effect may increase. BP and renal function should be monitored and dosage adjustment of hypotensive agents is required if necessary.

Non-steroidal anti-inflammatory drugs (NSAIDs) including high doses of acetylsalicylic acid (>3 g/day)

The administration of NSAIDs may decrease diuretic natriuretic and antihypertensive effects. With significant fluid loss and in elderly patients acute renal failure may develop (due to decreased glomerular filtration rate). Patients should compensate fluid loss and regularly monitor renal function at the beginning of treatment.

Combinations of agents requiring attention

Tricyclic antidepressants antipsychotics (neuroleptics)

The drugs of these classes enhance the antihypertensive effect and increase the risk of orthostatic hypotension (additive effect).

Glucocorticosteroids tetracosactide

Decreased antihypertensive effect (fluid and sodium ion retention due to glucocorticosteroid action).

Other hypotensive agents: may increase the antihypertensive effect.

Perindopril

Undesirable drug combinations

Potassium-saving diuretics (amiloride spironolactone triamterene both in monotherapy and in combination) and potassium preparations

The ACE inhibitors reduce renal potassium loss caused by the diuretic. Concomitant use of potassium-saving diuretics (e.g., spironolactone triamterene amiloride) potassium preparations and potassium-containing salt substitutes can lead to a significant increase in serum potassium content up to and including death. If concomitant use of ACE inhibitor and the above mentioned drugs is necessary (in case of confirmed hypokalemia), caution should be exercised and plasma potassium and ECG parameters should be monitored regularly.

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).

Combinations of agents requiring attention

Allopurinol cytostatics and immunosuppressive agents glucocorticosteroids (when used systemically) and procainamide

Simultaneous use with ACE inhibitors may be accompanied by an increased risk of leukopenia.

General anesthesia agents

The co-administration of ACE inhibitors and general anesthesia agents may increase the antihypertensive effect.

Diuretics (thiazide and loop diuretics)

The use of diuretics at high doses may lead to hypovolemia and addition of perindopril to therapy may cause arterial hypotension.

Gold preparations

In the administration of ACE inhibitors including perindopril to patients receiving gold preparations (sodium aurothiomalate) by infusion, nitrate-like reactions (facial hyperemia, nausea, vomiting, hypotension) have been noted.

Indapamide

Combinations of agents requiring special attention

Drugs that may cause pirouette-type arrhythmias

Because of the risk of hypokalemia, caution should be exercised when using indapamide with agents that can 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 disapride diphemanil methyl sulfate erythromycin IV halofantrine misolastine moxifloxacin pentamidine sparfloxacin vincamine IV methadone astemizole terfenadine. Hypokalemia should be avoided and corrected if necessary; monitor the QT interval.

Drugs that may cause hypokalemia

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

Cardiac glycosides

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

Combinations of agents requiring attention

Metformin

Functional renal failure that may occur with diuretics, especially loop diuretics, when metformin is used concomitantly increases the risk of lactic acidosis. 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 from diuretics increases the risk of acute renal failure especially when using high doses of iodine-containing contrast agents. Patients should compensate the circulating blood volume before using iodine-containing contrast agents.

Calcium salts

The concomitant use can lead to hypercalcemia due to reduced renal excretion of calcium ions.

Cyclosporine

Possible increase of creatinine concentration in plasma without change in circulating cyclosporine even when fluid and sodium ion levels are normal.

Special Instructions

Lithium drugs

The concomitant use of Perindid with lithium preparations is not recommended.

Perindide therapy is contraindicated in patients with severe renal impairment (CKD less than 30 ml/min). In some patients with arterial hypertension without previous renal dysfunction during therapy with Perindid, signs of acute renal failure may appear. In this case, treatment with Perindid should be discontinued. Thereafter, combined therapy may be resumed using low doses of Perindid, or perindopril and indapamide may be used in monotherapy.

Such patients require regular monitoring of serum potassium and creatinine every 2 weeks after therapy start and every 2 months after therapy with Perindide.

Acute renal failure is more common in patients with severe CHF or underlying renal impairment, including bilateral renal artery stenosis or artery stenosis of the only functioning kidney.

Perindid is not recommended for patients with bilateral renal artery stenosis or artery stenosis of the only functioning kidney.

Arterial hypotension and electrolyte balance disorders

Hyponatremia is associated with the risk of sudden development of arterial hypotension (especially in patients with bilateral renal artery stenosis or artery stenosis of the only functioning kidney). Therefore, during the dynamic monitoring of patients, attention should be paid to possible symptoms of dehydration and decreased plasma electrolyte content, e.g. after prolonged diarrhea or vomiting. These patients require regular monitoring of plasma electrolytes.

In severe arterial hypotension, intravenous injection of 09% sodium chloride solution may be required.

Transient arterial hypotension is not a contraindication for further continuation of therapy. Once the RBC and BP have been restored, therapy with Perindide may be resumed using low doses of the drug or the drugs perindopril and indapamide may be used in monotherapy.

Contraindications

Perindopril

– Hypersensitivity to perindopril and other ACE inhibitors;

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

– Hereditary/idiopathic angioedema;

– Pregnancy (see

– pregnancy (see section “Pregnancy and breastfeeding”);

– breastfeeding period (see section “Pregnancy and breastfeeding period”);

– age less than 18 years (effectiveness and safety are not established).

Indapamide

– Hypersensitivity to indapamide and other sulfonamides;

– severe hepatic insufficiency (including with encephalopathy);

– hypokalemia;

– concomitant use with drugs that can cause pirouette-type arrhythmias (see Interaction with other medicinal products);

– pregnancy and breastfeeding (see section “Pregnancy and breastfeeding”);

– age less than 18 years (effectiveness and safety are not established).

Perindide

– Hypersensitivity to excipients included in the preparation;

– severe renal insufficiency (creatinine clearance (CK) less than 30 ml/min);

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

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

– concomitant use of QT interval prolonging agents (see “Interaction with other drugs”).

– concomitant use of drugs prolonging the QT interval (see section “Interaction with other medicinal products”).

– hemodialysis (no experience of use);

– chronic heart failure (decompensation stage);

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

. Systemic connective tissue diseases (including systemic lupus erythematosus scleroderma) immunosuppressant therapy (risk of neutropenia agranulocytosis) inhibition of medullary hematopoiesis reduced circulating blood volume (taking diuretics salt-free diet vomiting diarrhea) ischemic heart disease cerebrovascular diseases renovascular hypertension diabetes mellitus chronic heart failure (functional class IV according to NYHA classification) hyperuricemia (especially accompanied by gout and urate nephrolithiasis) labile BP elderly age hemodialysis with high-flow membranes (e.g., AN69®) or desensitization low-density lipoprotein (LDL) apheresis renal artery stenosis (including bilateral) condition after renal transplantation; aortic valve stenosis/hypertrophic obstructive cardiomyopathy.

Side effects

The frequency of adverse reactions that may occur during therapy is listed as follows: Very common >1/10 common from >1/100 to <1/10 infrequent from >1/1000 to <1/100 rare from >1/10000 to <1/1000 very rare from <1/10000 including individual reports of unspecified frequency (frequency cannot be calculated from available data).

Cardiovascular system disorders

Infrequent: marked decrease in BP including orthostatic hypotension.

very rarely: 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 (see section “Special Precautions”).

Respiratory system of the chest and mediastinum

Often: dry cough with ACE inhibitors may occur with prolonged duration of use and may disappear after discontinuation of the medications; dyspnea.

Infrequent: bronchospasm.

Very rare: eosinophilic pneumonia rhinitis.

Hematopoietic system 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 (see section “Special Precautions”).

Central and peripheral nervous system disorders

Often: paresthesia headache dizziness asthenia.

Infrequent: sleep disturbance mood lability increased sweating.

Very rare: confusion.

Digestive system disorders

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

Rarely: angioedema of the intestine cholestatic jaundice.

Very rare: pancreatitis

Unspecified frequency: hepatic encephalopathy in patients with hepatic insufficiency (see “Contraindications” and “Special Precautions”).

Skin and subcutaneous fat disorders

Often: skin rash pruritus maculopapular rash.

Infrequent: angioedema of face, lips, limbs, mucous membrane of the tongue and/or larynx; urticaria (see section “Indications”); hypersensitivity reactions in patients with predisposition to asthma and allergic reactions; hemorrhagic vasculitis.

In patients with acute 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”).

Muscular system disorders

Often: muscle cramps.

Urinary system disorders

Infrequent: renal failure.

very rarely: acute renal failure.

Reproductive system and breast disorders

Infrequent: impotence.

Sensory organs

Often: visual disturbances tinnitus.

Laboratory findings

Hypokalemia; hyponatremia with hypovolemia leading to decreased BOD and orthostatic hypotension; increased concentration of uric acid and serum glucose; slight increase in plasma concentration of creatinine and urea, reversible after discontinuation of therapy, which often develops against the background of renal artery stenosis or stenosis of the artery of the only kidney arterial hypertension against therapy with diuretics in renal failure; transient increase in plasma sodium content; hypochloremia proteinuria.

Rarely: hypercalcemia.

Overdose

Symptoms

The most likely symptom of overdose is a marked decrease in BP, sometimes combined with nausea, vomiting cramps dizziness drowsiness confusion and oliguria which may turn into anuria (as a result of hypovolemia). Electrolyte disorders may also occur (hyponatremia hypokalemia).

Treatment

The emergency measures are limited to the elimination of the drug from the body: gastric lavage and/or administration of activated charcoal, followed by restoration of the water-electrolyte balance.

In case of a pronounced BP decrease the patient should be transferred to the “lying” position on his back with his legs elevated, and if necessary correction of hypovolemia should be carried out (for example, intravenous infusion of 09% sodium chloride solution). Perindoprilat the active metabolite of perindopril can be removed from the body by dialysis.

Pregnancy use

The use of Perindid is contraindicated in pregnancy. If pregnancy is planned or diagnosed during the drug administration, the drug should be immediately discontinued and other hypotensive therapy should be prescribed. Appropriate controlled studies of ACE inhibitors in pregnant women have not been conducted. The available limited data on the effects of the drug in the first trimester of pregnancy indicate that the drug did not lead to malformations associated with fetotoxicity. It is known that long-term exposure of fetus to ACE inhibitors in II and III trimesters of pregnancy may lead to fetal malformations (decreased renal function, oligohydramnios delayed ossification of cranial bones) and development of complications in a newborn (such as renal failure, arterial hypotension, hyperkalemia). Prolonged use of thiazide diuretics in III trimester of pregnancy may cause hypovolemia in mother and decrease of uterine-placental blood flow, which leads to fetoplacental ischemia and delayed fetal development. In rare cases hypoglycemia and thrombocytopenia develop in newborns against the background of taking diuretics shortly before delivery.

If the patient received Perindid during the second or third trimesters of pregnancy it is recommended to perform fetal ultrasound examination to evaluate the condition of the skull bones and kidney function.

The use of Perindid is contraindicated during breastfeeding. It is unknown whether perindopril is excreted into the breast milk.

Indapamide is excreted in breast milk. Thiazide diuretics cause a decrease in breast milk or suppression of lactation. The newborn may develop hypersensitivity to sulfonamide derivatives hypokalemia and “nuclear” jaundice.

Because the use of perindopril and indapamide during lactation can cause severe complications in the breastfed infant, the significance of therapy to the mother should be assessed and a decision should be made to discontinue breastfeeding or to stop taking these drugs.

Similarities