Pharmacy No. 84. Delivery of medicines to your home and office.

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Instructions for use of TRIPLIXAM

All warnings for each ingredient as listed below apply to Triplixam.

Lithium

Concomitant use of lithium and the combination of perindopril/indapamide is usually not recommended.

Double blockade of the RAAS

Hypotension, syncope, stroke, hyperkalemia and renal dysfunction (including acute renal impairment) have been reported in susceptible patients, especially when co-administered with drugs that act on the RAAS. Thus, dual blockade of the RAAS using an ACE inhibitor and an angiotensin II receptor antagonist or aliskiren is not recommended.

Combined use with aliskiren is contraindicated in patients with diabetes mellitus or impaired renal function (GFR <60 ml/min/1.73 m2).

Potassium-sparing medications, potassium supplements, or potassium-containing salt substitutes

The combined use of perindopril and potassium-sparing drugs, potassium supplements, or potassium-containing salt substitutes is generally not recommended.

Neutropenia/agranulocytosis/thrombocytopenia/anemia

Neutropenia, agranulocytosis, thrombocytopenia and anemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and no other complicating factors, neutropenia rarely develops. Perindopril should be used with extreme caution in patients with collagen diseases, concomitant use of immunosuppressants, allopurinol or procainamide, as well as in the presence of risk factors, especially if there is a history of impaired renal function. Some of these patients developed severe infections, in some cases untreatable with antibiotics. If such patients are taking perindopril, periodic leukocyte count analysis is recommended. Patients should report any signs of infection (eg, sore throat, fever) to their doctor.

Hypersensitivity/angioedema

Rare cases of angioedema of the face, extremities, lips, tongue, pharynx and/or larynx have been reported in patients treated with ACE inhibitors, including perindopril. These conditions can develop at any time during therapy. In such cases, you should immediately stop taking the drug and monitor the patient's condition until the symptoms disappear completely. In cases where swelling affects only the face and lips, its symptoms usually resolve without special treatment, but antihistamines may be used to relieve symptoms.

Angioedema of the larynx can be fatal. Involvement of the tongue, larynx or pharynx can lead to airway obstruction, appropriate treatment should be started immediately, administer subcutaneous epinephrine solution 1:

1000 (0.3-0.5 ml) and/or take measures to ensure airway patency.

A higher incidence of angioedema has been established in black patients receiving ACE inhibitors.

Patients with a history of angioedema not related to ACE inhibitor therapy may be at increased risk of developing angioedema when treated with ACE inhibitors.

There are rare cases of the development of angioedema of the intestine during therapy with ACE inhibitors. Patients experienced abdominal pain (sometimes with nausea or vomiting); in some cases this was not preceded by angioedema of the face, C-1 esterase activity was normal. Angioedema was diagnosed through procedures including abdominal CT or ultrasound, or during surgery. Symptoms disappeared after stopping the ACE inhibitor. These phenomena should be taken into account when carrying out differential diagnosis in patients with abdominal pain receiving ACE inhibitors.

Anaphylactoid reactions during desensitization

Separately, reports of patients who experienced long-term, life-threatening anaphylactoid reactions when taking ACE inhibitors during desensitizing treatment with hymenoptera venom (bees, wasps) were highlighted. ACE inhibitors should be prescribed with caution to patients prone to allergic reactions and undergoing desensitization. However, these reactions can be prevented by temporarily discontinuing ACE inhibitors at least 24 hours before desensitization.

Anaphylactoid reactions during LDL apheresis

Life-threatening anaphylactoid reactions have been reported rarely in patients receiving ACE inhibitors during LDL apheresis using dextran sulfate. These reactions can be avoided by temporarily suspending treatment with ACE inhibitors until apheresis is performed.

Patients on hemodialysis

Anaphylactoid reactions have been reported in patients undergoing hemodialysis using high fluid permeability membranes (eg, AN69®) and concomitantly taking an ACE inhibitor. In such patients, a different type of hemodialysis membrane or a different class of antihypertensive drug should be used.

Hepatic encephalopathy

When liver function is impaired, the use of thiazide and thiazide-like diuretics can lead to the development of hepatic encephalopathy. In this case, you should immediately stop taking the diuretic.

Photosensitivity

Cases of photosensitivity have been reported with the use of thiazide and thiazide-like diuretics. It is recommended to discontinue treatment if a photosensitivity reaction develops during therapy. If it is necessary to restart diuretic therapy, it is recommended to protect areas exposed to sunlight or artificial UVA rays.

Kidney function

In case of severe renal impairment (creatinine clearance <30 ml/min), treatment with the drug is contraindicated.

Patients with moderate renal impairment (creatinine clearance <60 ml/min) are contraindicated in treatment with Triplixam at a dose of 10 mg perindopril/2.5 mg indapamide (i.e. Triplixam 10 mg/2.5 mg/5 mg and 10 mg/2.5 mg/ 10 mg).

Some patients with hypertension who do not have a history of kidney disease, but blood tests indicate functional renal failure, should stop treatment and, if restarted, use a lower dose or only one component of the drug.

In such patients, potassium and creatinine concentrations should be monitored frequently after 2 weeks of treatment and then every 2 months during the period of therapeutic stability.

Renal failure was mainly observed in patients with severe heart failure or underlying renal failure, including renal artery stenosis.

Typically, the drug is not recommended for use in cases of bilateral renal artery stenosis or the presence of one functioning kidney.

When using perindopril, significant stimulation of the RAAS was observed, especially with significant depletion of water and electrolyte reserves (strict sodium-restricted diet or prolonged use of diuretics) in patients with initially low blood pressure, renal artery stenosis, congestive heart failure or cirrhosis with edema and ascites. Blockade of the RAAS by an ACE inhibitor may lead, especially when taking the first dose and during the first 2 weeks of treatment, to an unexpected decrease in blood pressure and/or an increase in plasma creatinine concentrations, indicating functional renal failure. The onset may be acute, although rare; the time until symptoms appear varies. In such cases, treatment should begin with low doses and gradually increase. For patients with coronary artery disease or cerebrovascular disease, excessive hypotension can lead to myocardial infarction or cerebrovascular accident.

Thiazide and thiazide-like diuretics are fully effective only when renal function is not impaired or is mildly impaired (creatinine concentrations in an adult are approximately 25 mg/l lower, i.e. 220 µmol/l). In elderly patients, age, weight and gender should be taken into account when determining plasma creatinine concentrations.

Hypovolemia, which developed secondary to the loss of water and sodium when using a diuretic at the beginning of treatment, leads to a decrease in glomerular filtration. This may cause an increase in the concentration of urea and creatinine in the blood. Such transient functional renal failure has no adverse effects in patients with normal renal function, but may worsen pre-existing renal impairment.

Amlodipine can be used in normal doses in patients with renal failure. Changes in plasma amlodipine concentrations are not associated with the degree of renal dysfunction.

The effect of Triplixam has not been studied in patients with impaired renal function. In case of impaired renal function, the dose of Triplixam should correspond to the doses of its constituent components, used separately.

Hypotension and depletion of water and sodium reserves

There is a risk of developing hypotension in the presence of depleted sodium reserves (especially in patients with renal artery stenosis). Therefore, one should systematically check for signs of water and electrolyte depletion, which may occur with an accompanying episode of diarrhea or vomiting. Plasma electrolyte concentrations should be monitored regularly in such patients.

If hypotension is significant, IV infusion of isotonic saline may be necessary.

Transient hypotension is not a contraindication to continued therapy. After restoration of blood volume and blood pressure, treatment can be resumed using the drug at a lower dose or only one of the components as monotherapy.

The use of any diuretic may result in a decrease in sodium concentration, which can have serious consequences. Hyponatremia may initially be asymptomatic, so it is extremely important to regularly monitor sodium concentrations (more often in elderly patients and patients with cirrhosis).

Potassium concentration

The combination of indapamide with perindopril and amlodipine does not prevent the development of hypokalemia, especially in patients with diabetes mellitus or renal failure. As with any antihypertensive drug used in combination with a diuretic, plasma potassium concentrations should be regularly monitored.

Increased serum potassium concentrations have been reported in some patients receiving ACE inhibitors, including perindopril. Risk factors for the development of hyperkalemia are the following conditions:

renal failure, deterioration of renal function, age (>70 years), diabetes mellitus, concomitant conditions (in particular dehydration, acute cardiac decompensation, metabolic acidosis) and concomitant use of potassium-sparing diuretics (for example, spironolactone, eplerenone, triamterene or amiloride), potassium supplements or potassium-containing salt substitutes or other drugs that increase serum potassium concentrations (eg, heparin). The use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes, especially in patients with impaired renal function, may result in significant increases in serum potassium concentrations. Hyperkalemia can cause serious and sometimes fatal arrhythmias. If concomitant use of the above-mentioned drugs is necessary, such combinations should be used with caution and serum potassium concentrations should be regularly monitored.

Depletion of potassium reserves with the development of hypokalemia is the main risk when using thiazide and thiazide-like diuretics. Decreased potassium levels (<3.4 mmol/L) should be prevented in high-risk groups such as elderly and/or malnourished patients (regardless of how many medications they are taking), patients with liver cirrhosis and edema and ascites, coronary artery disease and cardiac insufficiency. In such cases, hypokalemia increases the toxicity of cardiac glycosides and the risk of developing arrhythmias.

The high-risk group also includes patients with an increased QT interval on the ECG, regardless of the etiology of the disease. Hypokalemia, as well as bradycardia, is a predisposing factor in the development of serious cardiac arrhythmias (especially torsades de pointes), which can be fatal.

In all cases, potassium concentrations should be regularly monitored. The first analysis of plasma potassium should be performed within the first week after starting treatment. If potassium concentration decreases, correction is required.

Calcium concentration

Thiazide and thiazide-like diuretics may reduce urinary excretion of calcium and lead to a slight and temporary increase in plasma calcium. Significant increases in calcium concentrations may be associated with undiagnosed hyperparathyroidism. In such cases, treatment should be stopped until the results of a study of parathyroid function are obtained.

Renovascular hypertension

Treatment of renovascular hypertension consists of revascularization. However, ACE inhibitors may have a beneficial effect in patients with renovascular hypertension awaiting reconstructive surgery or when such surgery is not possible.

If Triplixam is prescribed to patients with confirmed or suspected renal artery stenosis, treatment should begin in the hospital using the drug in low doses and regular monitoring of renal function and potassium concentrations, because Some patients experienced functional renal failure, which resolved when treatment was discontinued.

Cough

When using ACE inhibitors, a dry cough was observed, which was persistent and disappeared when treatment was discontinued. If this symptom occurs, an iatrogenic etiology should be considered. If the prescription of an ACE inhibitor is necessary, treatment can be continued.

Atherosclerosis

All patients are at risk of hypotension, but special attention should be paid to patients with coronary artery disease or cerebrovascular insufficiency. In such patients, therapy should be started at a low dose.

Hypertensive crisis

The safety and effectiveness of amlodipine in hypertensive crisis have not been established.

Heart failure/severe heart failure

Patients with heart failure should be treated with caution. In a long-term placebo-controlled study in patients with severe heart failure (NYHA class III and IV), the incidence of pulmonary edema was higher in the amlodipine group than in the placebo group. Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure. the risk of cardiovascular complications and mortality may increase.

In patients with severe heart failure (grade IV), treatment should be started under medical supervision with a low dose. Therapy with beta-blockers in patients with arterial hypertension and coronary insufficiency should not be interrupted; ACE inhibitors are added to beta-blockers.

Aortic or mitral valve stenosis/hypertrophic cardiomyopathy

ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction.

Diabetes

In patients with insulin-dependent diabetes mellitus (tendency to hyperkalemia), treatment should be started under medical supervision with a low dose. Glycemic levels should be monitored in patients with diabetes mellitus who have previously received oral hypoglycemic drugs or insulin, namely during the first month of treatment with an ACE inhibitor.

In patients with diabetes mellitus, especially those with low potassium concentrations, it is necessary to monitor the concentration of glucose in the blood.

Ethnic differences

Like other ACE inhibitors, perindopril is less effective in lowering blood pressure in blacks than in other races, possibly due to low renin levels in blacks with high blood pressure.

Surgery/anesthesia

The use of ACE inhibitors may lead to hypotension during anesthesia, especially if the anesthetic used is a drug with hypotensive potential. It is therefore recommended to discontinue treatment with long-acting ACE inhibitors such as perindopril the day before surgery.

Liver dysfunction

In rare cases, the use of ACE inhibitors has been associated with a syndrome that begins with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is unknown. In patients taking ACE inhibitors who experience jaundice or significant increases in liver enzymes, ACE inhibitor therapy should be discontinued and closely monitored.

T1/2 of amlodipine is prolonged and AUC values are higher in patients with impaired liver function; there are no recommendations on dosing of the drug. Therefore, the use of amlodipine should be started with a low dose and with caution both at the beginning of treatment and when increasing the dose. Slow dose titration and close monitoring are necessary in patients with severe hepatic impairment.

The pharmacokinetics of Triplixam in patients with liver dysfunction have not been studied. Taking into account the effects of each individual component of this combination, Triplixam is contraindicated in patients with severe hepatic impairment and should be used with caution in patients with mild to moderate hepatic impairment.

Uric acid

Patients with high levels of uric acid may have an increased risk of gout attacks.

Elderly patients

Before initiating therapy, renal function and potassium concentrations should be assessed. The initial dose is adjusted depending on changes in blood pressure, especially in the case of depletion of water and electrolyte reserves, to avoid the development of hypotension. In elderly patients, the dose of amlodipine should be increased with caution.

Impact on the ability to drive vehicles and operate machinery

The effect of Triplixam on the ability to drive a car and operate machinery has not been studied.

Perindopril and indapamide do not affect the ability to drive a car or use machinery, but some patients may experience individual reactions with a decrease in blood pressure. Amlodipine may have minor to moderate effects on the ability to drive and operate machines.

If patients suffer from dizziness, headache, fatigue, tiredness or nausea, the speed of psychomotor reactions may be reduced, as a result of which the ability to operate a car or operate machinery may be impaired. Patients are advised to exercise caution, especially at the beginning of treatment.

Preclinical safety data

Perindopril.

In chronic oral toxicity studies (rats and monkeys), the target organ was the kidney, which caused reversible damage. Mutagenicity was not observed in in vitro or in vivo studies.

Reproductive toxicity studies (rats, mice, rabbits and monkeys) showed no evidence of embryotoxicity or teratogenicity. However, ACE inhibitors as a class commonly induce adverse effects on late fetal development, leading to fetal death or birth defects in rodents and rabbits:

kidney damage and increased peri- and postnatal mortality. There was no effect on fertility in female or male rats. No carcinogenicity was observed in long-term studies in rats and mice.

Indapamide.

Use in high doses (40-8000 times higher than the therapeutic dose) in various animal species has shown a deterioration in the diuretic properties of indapamide. Serious symptoms of poisoning during acute toxicity studies of indapamide administered intravenously or intraperitoneally were associated with the pharmacological effects of indapamide, such as bradypnea and peripheral vasodilation.

Indapamide did not exhibit mutagenic or carcinogenic properties.

Reproductive toxicity studies revealed no embryotoxicity or teratogenicity in rats, mice or rabbits. No negative effects on fertility were observed in female or male rats.

Perindopril/indapamide.

With the combination of perindopril/indapamide, toxicity increased slightly compared with the administration of the drugs separately. No increased renal reactions were observed in rats. However, gastrointestinal toxicity was observed with this combination in dogs and increased maternal toxicity in rats (compared to perindopril). However, these adverse effects were detected at dose levels that exceeded the safe limit compared to the therapeutic doses used.

Preclinical studies conducted separately for perindopril and indapamide did not reveal genotoxic, carcinogenic or teratogenic potential.

Amlodipine.

Reproductive studies in rats and mice have demonstrated delayed birth, prolonged duration of labor, and decreased neonatal survival at doses approximately 50 times the maximum recommended human dose on a mg/kg basis.

Effect on fertility of rats when administered amlodipine (males - for 64 days, females - for 14 days before mating) at a dose of up to 10 mg/kg/day (8 times* higher than the maximum recommended dose for humans of 10 mg based on mg/m2 ) was missing. In another study, male rats were administered amlodipine besylate for 30 days at a dose comparable to that used in humans at mg/kg; a decrease in plasma FSH and testosterone concentrations was noted, as well as a decrease in the specific gravity of sperm and the number of mature spermatids and Sertoli cells.

In rats and mice receiving amlodipine with food for 2 years at concentrations based on doses of 0.5, 1.25 and 2.5 mg/kg/day, no carcinogenicity was shown. The high dose (similar in mice and twice* in rats higher than the maximum recommended clinical dose of 10 mg mg/m2) was close to the maximum tolerated dose in mice but not in rats.

Mutagenicity studies did not reveal any drug-related effects at the gene or chromosome level.

*Based on the patient’s body weight of 50 kg.