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Perindopres Trio

Angiotensin-converting enzyme (ACE) inhibitors, other combinations. Perindopril, amlodipine and indapamide.

Perindopres Trio is a combination of three antihypertensive components with complementary mechanisms to control the blood pressure in patient with hypertension. Perindopril tert-butylamine is an ACE inhibitor, indapamide is a sulfonamide diuretic, amlodipine is a calcium ion influx inhibitor of the dihydropyridine group. The pharmacological properties of Perindopres Trio are derived from those of each of the components taken separately. In addition, the combination of perindopril/indapamide produces the additive synergy of the antihypertensive effects of two components.

Perindopres® Trio is indicated for treatment of hypertension in the patients that require therapy with the fixed dose combination of perindopril, indapamide and amlodipine.

The product is indicated for oral use.

One Perindopres® Trio tablet per day as a single dose, preferably to be taken in the morning and before a meal.

The fixed dose combination is not suitable for the initial therapy.

If a change of the dose of Perindopres® Trio fixed combination is required, titration should be done with the individual components.

Special populations.

Renal impairment (see sections “Contraindications” and “Special warnings for use”). In severe renal impairment (creatinine clearance below 30 ml/min), treatment is contraindicated. In patients with moderate renal impairment (creatinine clearance 30 to 60 ml/min), Perindopres® Trio at the doses of 8 mg/2.5 mg/5 mg and 8 mg/2.5 mg/10 mg is contraindicated. Usual medical follow-up should include frequent monitoring of creatinine and blood potassium.

Elderly patients (see section “Special warnings for use”). It should be considered that elimination of perindoprilat is decreased in the elderly (see subsection “Pharmacokinetics”). Elderly patients can be treated with Perindopres® Trio according to the renal function (see section “Contraindications”).

Hepatic impairment (see sections “Contraindications”, “Special warnings for use” and subsection “Pharmacokinetics”). Perindopres® Trio  is contraindicated in patients with severe hepatic impairment. In patients with mild to moderate hepatic impairment, Perindopres® Trio  should be administrated with caution, as dosage recommendations for amlodipine in these patients have not been established.

Pediatric population.

Information on the safety and efficacy of Perindopres® Trio in children is not available, therefore, it should not be used in this age group.

APPROVED
Order of the Ministry of Health of Ukraine
No. 360 of February 23, 2022
Marketing Authorisation
No. UA/19239/01/01
No. UA/19239/01/02
No. UA/19239/01/03
No. UA/19239/01/04

INSTRUCTION
for Medical Use
PERINDOPRES® TRIO

Composition:

active substances: perindopril, indapamide, amlodipine;

Perindopres® Trio, tablets, 4 mg/1.25 mg/5 mg

Each tablet contains: 4 mg perindopril tert-butylamine (corresponding to 3.338 mg of perindopril), 1.25 mg indapamide and 6.935 mg amlodipine besilate (corresponding to 5 mg amlodipine);

Perindopres® Trio, tablets, 4 mg/1.25 mg/10 mg

Each tablet contains: 4 mg perindopril tert-butylamine (corresponding to 3.338 mg of perindopril), 1.25 mg indapamide and 13.87 mg amlodipine besilate (corresponding to 10 mg amlodipine);

Perindopres® Trio, tablets, 8 mg/2.5 mg/5 mg

Each tablet contains: 8 mg perindopril tert-butylamine (corresponding to 6,676 mg of perindopril), 2.5 mg indapamide and 6.935 mg amlodipine besilate (corresponding to 5 mg amlodipine);

Perindopres® Trio, tablets, 8 mg/2.5 mg/10 mg

Each tablet contains: 8 mg perindopril tert-butylamine (corresponding to 6,676 mg of perindopril), 2.5 mg indapamide and 13.87 mg amlodipine besilate (corresponding to 10 mg amlodipine);

excipients: pregelatinised starch, cellulose microcrystalline, croscarmellose sodium, Colloidal anhydrous silica, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

Perindopres® Trio, tablets, 4 mg/1.25 mg/5 mg – white or off-white flat round bevelled edge tablets.

Perindopres® Trio, tablets, 4 mg/1.25 mg/10 mg – white or off-white flat round bevelled edge scored tablets.

Perindopres® Trio, tablets, 8 mg/2.5 mg/5 mg – white or off-white flat round bevelled edge scored tablets.

Perindopres® Trio, tablets, 8 mg/2.5 mg/10 mg – white or off-white flat round bevelled edge scored tablets.

Pharmacotherapeutic group. Angiotensin-converting enzyme (ACE) inhibitors, other combinations. Perindopril, indapamide and amlodipine. ATC code С09В Х01.

Pharmacological properties.

Perindopres Trio is a combination of three antihypertensive components with complementary mechanisms to control the blood pressure in patient with hypertension. Perindopril tert-butylamine is an ACE inhibitor, indapamide is a sulfonamide diuretic, amlodipine is a calcium ion influx inhibitor of the dihydropyridine group. The pharmacological properties of Perindopres Trio are derived from those of each of the components taken separately. In addition, the combination of perindopril/indapamide produces the additive synergy of the antihypertensive effects of two components.

Mechanism of action.

Perindopril is an inhibitor of the angiotensin converting enzyme (ACE inhibitor) which converts angiotensin I to angiotensin II (a vasoconstricting substance); in addition, the enzyme stimulates the secretion of aldosterone by the adrenal cortex and stimulates the degradation of bradykinin (a vasodilatory substance) into inactive heptapeptides. This results in a reduction in aldosterone secretion; an increase in plasma renin activity, since aldosterone no longer exercises negative feedback; a reduction in total peripheral resistance with a preferential action on the vascular bed in muscle and the kidney, with no accompanying salt and water retention or reflex tachycardia, with chronic treatment.

The antihypertensive action of perindopril also occurs in patients with normal or low renin concentrations.

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

Perindopril reduces the work of the heart: by a vasodilatory effect on veins (probably caused by changes in the metabolism of prostaglandins), by reduction in pre-load and the total peripheral resistance thus reducing afterload.

Studies carried out on patients with cardiac insufficiency have shown a reduction in left and right ventricular filling pressures; a reduction in total peripheral vascular resistance; an increase in cardiac output and an improvement in the cardiac index; an increase in regional blood flow in muscle.

In addition, exercise test results also showed improvement.

Indapamide is a sulphonamide derivative with an indole ring, pharmacologically related to the thiazide group of diuretics. Indapamide inhibits the reabsorption of sodium in the cortical dilution segment. It increases the urinary excretion of sodium and chlorides and, to a lesser extent, the excretion of potassium and magnesium, thereby increasing urine output and having an antihypertensive action.

Amlodipine is a calcium ion influx inhibitor of the dihydropyridine group (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle.

Pharmacodynamic effects.

Perindopril/indapamide: In hypertensive patients regardless of age, the perindopril/indapamide combination exerts a dose-dependent antihypertensive effect on diastolic and systolic arterial pressure in the lying and standing position. The antihypertensive effect of the product is dose-dependent. During clinical trials, the concomitant administration of perindopril and indapamide produced antihypertensive effects of a synergic nature in relation to each of the products administered alone.

Perindopril: Perindopril is active in all grades of hypertension: mild to moderate or severe. A reduction in systolic and diastolic arterial pressure is observed in the lying and standing position. The antihypertensive activity after a single dose is maximal at between 4 and 6 hours and is maintained over 24 hours. There is a high degree of residual ACE blocking (approximately 80%) at 24 hours post-administration).

In patients who respond, normalised blood pressure is reached after one month and is maintained without tachyphylaxis.

Withdrawal of treatment has no rebound effect on hypertension.

Perindopril has vasodilatory properties and restores elasticity of the main arterial trunks, corrects histomorphometric changes in resistance arteries and produces a reduction in left ventricular hypertrophy. If necessary, the addition of a thiazide diuretic leads to an additive synergy.

The combination of an ACE inhibitor with a thiazide diuretic decreases the hypokalaemia risk associated with the diuretic alone.

Indapamide: Indapamide, as monotherapy, has an antihypertensive effect which lasts for 24 hours. This effect occurs at doses at which the diuretic properties are minimal.

Its antihypertensive action is proportional to an improvement in arterial compliance and a reduction in total and arteriolar peripheral vascular resistance.

Indapamide reduces left ventricular hypertrophy.

When a dose of thiazide diuretic and thiazide-related diuretics is exceeded, the antihypertensive effect reaches a plateau, whereas the adverse effects continue to increase. If the treatment is ineffective, the dose should not be increased.

Furthermore, the studies of different duration (short-term, mid-term and long-term) in hypertensive patients have shown that indapamide has no effect on lipid metabolism (triglycerides, LDL-cholesterol and HDL-cholesterol) and has no effect on carbohydrate metabolism, even in diabetic hypertensive patients.

Amlodipine. The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle. The precise mechanism by which amlodipine relieves angina has not been fully determined but amlodipine reduces total ischemic burden by the following two actions:

  • Amlodipine dilates peripheral arterioles and thus, reduces the total peripheral resistance (afterload) against which the heart works. Since the heart rate remains stable, this unloading of the heart reduces myocardial energy consumption and oxygen requirements.
  • The mechanism of action of amlodipine also probably involves dilatation of the main coronary arteries and coronary arterioles, both in normal and ischemic regions. This dilatation increases myocardial oxygen delivery in patients with coronary artery spasm (Prinzmetal’s or variant angina).

In patients with hypertension, once daily dosing provides clinically significant reductions of blood pressure in both the supine and standing positions throughout the 24-hour interval. Due to the slow onset of action, acute hypotension is not a feature of amlodipine administration.

Amlodipine has not been associated with any adverse metabolic effects or changes in plasma lipids and is suitable for use in patients with asthma, diabetes, and gout.

Clinical efficacy and safety.

Perindopril/ indapamide.

The ADVANCE study was a multicentre, international, randomised, 2×2 factorial designed trial aimed at determining the benefits of blood pressure lowering with the fixed combination perindopril/ indapamide vs placebo on top of current standard therapy [double blind comparison (prospective randomised open study with blinded evaluation)] on major macrovascular and microvascular events in type 2 diabetic patients. The primary end-point was a composite of major macrovascular (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) and microvascular (new or worsening nephropathy and eye disease) events. Overall, 11,140 type 2 diabetic patients were involved in the trial. Among them, 83% were hypertensive, 32% and 10% presented a history of macro- or micro-vascular disease respectively and 27% had microalbuminuria. Concomitant therapies included blood pressure lowering agents (75%), lipid lowering agents (35% mainly statins 28%), aspirin or other antiplatelets (47%).

After a mean duration of follow-up of 4.3 years, the treatment with perindopril/ indapamide resulted in a significant relative risk reduction of 9 % in the primary endpoint (95 % CI [0.828;0.996], p=0.041). The benefit was driven by a significant relative risk reduction of 14 % in total mortality (95 % CI [0.75;0.98], p=0.025), of 18 % in cardiovascular deaths (95 % CI [0.68;0.98], p=0.027) and of 21 % in total renal events (95 % CI [0.74;0.86], p<0.001) in the perindopril / indapamide group compared to the placebo group.

In the sub-group of interest of hypertensive patients, there was a relative risk reduction of 9 % in the combined major macrovascular and microvascular events in the perindopril/ indapamide group compared to the placebo group (95 % CI [0.82;1.00], p=0.052). There was also a significant relative risk reduction of 16 % in total mortality (95 % CI [0.73;0.97], p=0.019), of 20 % in cardiovascular deaths (95 % CI [0.66;0.97], p=0.023) and of 20 % in total renal events (95 % CI [0.73;0.87], p<0.001) in the perindopril / indapamide group compared to the placebo group.

Pharmacokinetic properties.

The co-administration of perindopril/indapamide and amlodipine does not change their pharmacokinetic properties by comparison to separate administration.

Perindopril

Absorption and bioavailability. After oral administration, the absorption of perindopril is rapid and the peak concentration is achieved within 1 hour (perindopril is a prodrug and perindoprilat the active metabolite). The plasma half-life of perindopril is equal to 1 hour.

As ingestion of food decreases conversion of perindopril to perindoprilat, hence bioavailability, perindopril tert-butylamine should be administered orally in a single daily dose in the morning before a meal. There is a linear relationship between perindopril dose and plasma concentrations.

Distribution: The volume of distribution is approximately 0.2 L/kg for unbound perindoprilat. Protein binding of perindoprilat to plasma proteins is 20%, principally to angiotensin converting enzyme, but is concentration-dependent.

Biotransformation: Twenty-seven percent of the administered perindopril dose reaches the bloodstream as the active metabolite perindoprilat. In addition to active perindoprilat, perindopril yields five metabolites, all inactive. The peak plasma concentration of perindoprilat is achieved within 3 to 4 hours.

Elimination: Perindoprilat is eliminated in the urine and the terminal half-life of the unbound fraction is approximately 17 hours, resulting in steady-state within 4 days.

Special Populations

Elderly. Elimination of perindoprilat is decreased in the elderly, and also in patients with heart or renal failure.

Renal impairment. Dosage adjustment in renal insufficiency is desirable depending on the degree of impairment (creatinine clearance).

In case of dialysis: Dialysis clearance of perindoprilat is equal to 70 mL/min.

Hepatic cirrhosis: Perindopril pharmacokinetics is modified; hepatic clearance of the parent molecule is reduced by half. However, the quantity of perindoprilat formed is not reduced (see the sections “Posology and method of administration”, “Special warnings and precautions for use”).

Indapamide

Absorption. Indapamide is rapidly and completely absorbed from the digestive tract. The peak plasma level is reached in humans approximately one hour after oral administration of the product.

Distribution. Plasma protein binding is 79%.

Metabolism and elimination. The elimination half-life is between 14 and 24 hours (average 18 hours). Repeated administration does not produce accumulation.

Elimination is mainly in the urine (70% of the dose) and faeces (22%) in the form of inactive metabolites. The pharmacokinetics is unchanged in patients with renal insufficiency.

Amlodipine

Absorption and bioavailability. After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6-12 hours post dose. Absolute bioavailability has been estimated to be between 64 and 80%. The bioavailability of amlodipine is not affected by food intake.

Distribution: The volume of distribution is approximately 21 L/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.

Elimination: The terminal plasma elimination half-life is about 35-50 hours and is consistent with once daily dosing. Amlodipine is predominantly metabolized in the liver to form inactive metabolites, 60% of the metabolites are excreted in the urine and 10% unchanged.

Special populations

Elderly. The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger subjects. Amlodipine clearance tends to be decreased with resulting increases in AUC and elimination half-life in elderly patients. Increases in AUC and elimination half-life in patients with congestive heart failure were as expected for the patient age group studied.

Impaired hepatic function: Very limited clinical data are available regarding amlodipine administration in patients with hepatic impairment. Patients with hepatic insufficiency have decreased clearance of amlodipine resulting in a longer half-life and an increase in AUC of approximately 40-60%.

Clinical particulars.

Indication.

Perindopres® Trio is indicated for treatment of hypertension in the patients that require therapy with the fixed dose combination of perindopril, indapamide and amlodipine.

Contraindications.

  • Dialysis patients.
  • Patients with untreated decompensated heart failure.
  • Severe renal impairment (creatinine clearance below 30 mL/min) for dosages 4 mg/1.25 mg/5 mg and 4 mg/1.25 mg/10 mg.
  • Moderate renal impairment (creatinine clearance below 60 mL/min) for dosages of 8 mg/2.5 mg/5 mg or 8 mg/2.5 mg/10 mg;
  • Hypersensitivity to the active substances, to other sulphonamides, to dihydropyridine derivatives, any other ACE-inhibitor or to any of the excipients listed in the section “Composition”.
  • Pregnancy or pregnancy planning (see the section “Fertility, pregnancy and lactation”).
  • Lactation (see the section “Fertility, pregnancy and lactation”).
  • History of angioedema (Quincke’s oedema) associated with previous ACE inhibitor therapy (see the section “Special warnings and precautions for use”).
  • Hereditary/idiopathic angioedema.
  • Hepatic encephalopathy.
  • Severe hepatic impairment.
  • Hypokalaemia.
  • Severe hypotension.
  • Shock, including cardiogenic shock.
  • Obstruction of the outflow-tract of the left ventricle (e.g. high-grade aortic stenosis).
  • Hemodynamically unstable heart failure after acute myocardial infarction.
  • Concomitant use with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73m2) (see the sections “Special warnings and precautions for use” and “Interaction with other medicinal products and other forms of interaction”).
  • Concomitant use with sacubitril/valsartan (see the sections “Special warnings and precautions for use” and “Interaction with other medicinal products and other forms of interaction”).
  • Extracorporeal treatments leading to contact of blood with negatively charged surfaces (see the section “Interaction with other medicinal products and other forms of interaction”).
  • Significant bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney (see the section “Special warnings and precautions for use”).

Interaction with other medicinal products and other forms of interaction.

Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see the sections “Contraindications” and “Special warnings and precautions for use”).

Drugs inducing hyperkalaemia.

Some drugs or therapeutic classes may increase the occurrence of hyperkalaemia: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin-II receptors antagonists, NSAIDs, heparins, immunosuppressant agents such as ciclosporin or tacrolimus, trimethoprim. The combination of these drugs increases the risk of hyperkalaemia.

Concomitant use contraindicated (see the section “Contraindications”).

Aliskiren: In diabetic or impaired renal patients, risk of hyperkalaemia, worsening of renal function and cardiovascular morbidity and mortality increase.

Extracorporeal treatments: Treatments with dialysis or haemofiltration with certain high-flux membranes (e.g. polyacrylonitril membranes) and low density lipoprotein (LDP) apheresis with dextran sulphate due to increased risk of severe anaphylactoid reactions (see the section “Contraindications”). If such treatment is required, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Sacubitril/valsartan: The concomitant use of perindopril with sacubitril/valsartan is contraindicated as the concomitant inhibition of neprilysin and ACE may increase the risk of angioedema. Sacubitril/valsartan must not be started until 36 hours after taking the last dose of perindopril therapy. Perindopril therapy must not be started until 36 hours after the last dose of sacubitril/valsartan (see the sections “Contraindications” and “Special warnings and precautions for use”).

Concomitant use not recommended.

Perindopril/ indapamide.

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Use of perindopril combined with indapamide with lithium is not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels should be performed (see the section “Special warnings and precautions for use”).

Perindopril.

Aliskiren: In patients other than diabetic or impaired renal patients, risk of hyperkalaemia, worsening of renal function and cardiovascular morbidity and mortality increase (see the section “Special warnings and precautions for use”).

Angiotensinreceptor blocker: It has been reported in the literature that in patients with established atherosclerotic disease, heart failure, or with diabetes with end organ damage, concomitant therapy is associated with a higher frequency of hypotension, syncope, hyperkalaemia, and worsening renal function (including acute renal failure) as compared to use of a single renin-angiotensin-aldosterone system agent. Dual blockade (e.g., by combining an ACE inhibitor with an angiotensin II receptor antagonist) should be limited to individually defined cases with close monitoring of renal function, potassium levels, and blood pressure (see the section “Special warnings and precautions for use”).

Estramustine: Risk of increased adverse effects such as angioneurotic oedema (angioedema).

Potassium-sparing drugs (e.g. triamterene, amiloride, etc.), potassium salts: Hyperkalaemia (potentially lethal), especially in conjunction with renal impairment (additive hyperkalaemic effects). The combination of perindopril with the previously-mentioned drugs is not recommended (see the section “Special warnings and precautions for use”). If concomitant use is nonetheless indicated, they should be used with caution and with frequent monitoring of serum potassium. For use of spironolactone in heart failure, see “Concomitant use which requires special care” as follows.

Co-trimoxazole (trimethoprim/sulfamethoxazole): Patients taking concomitant co-trimoxazole may be at increased risk for hyperkalaemia (see the section “Special warnings and precautions for use”).

Amlodipine.

Dantrolene (infusion): In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalaemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalaemia, it is recommended that the co-administration of calcium channel blockers such as amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.

Grapefruit or grapefruit juice: The bioavailability may be increased in some patients resulting in increased blood pressure lowering effects

Concomitant use which requires special care.

Perindopril/ indapamide.

Baclofen: Increased antihypertensive effect. Monitor blood pressure and adapt antihypertensive dosage if necessary.

Perindopril/ indapamide.

Non-steroidal anti-inflammatory medicinal products including acetylsalicylic acid at high doses: When ACE inhibitors are administered simultaneously with non-steroidal anti-inflammatory drugs, i.e. acetylsalicylic acid at anti-inflammatory dosage regimens, COX-2 inhibitors and non-selective NSAIDs, attenuation of the antihypertensive effect may occur. Concomitant use of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.

Perindopril.

Antidiabetic agents (insulin, oral hypoglycaemic agents): Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicines may cause an increased blood-glucose lowering effect with risk of hypoglycaemia. This phenomenon appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment.

Diuretics: Patients, especially those who are volume and/or salt depleted, may experience excessive reduction in blood pressure after initiation of therapy with an ACE inhibitor. The possibility of hypotensive effects can be reduced by discontinuation of the diuretic, by increasing volume or salt intake prior to initiating therapy with low and progressive doses of perindopril. In arterial hypertension, when prior diuretic therapy can have caused salt/volume depletion, either the diuretic must be discontinued before initiating the ACE inhibitor (in which case a non-potassium-sparing diuretic can be thereafter reintroduced) or the ACE inhibitor must be initiated with a low dosage and progressively increased. In diuretic-treated congestive heart failure, the ACE inhibitor should be initiated at a very low dosage, possibly after reducing the dosage of the associated non-potassium-sparing diuretic. In all cases, renal function (creatinine levels) must be monitored during the first few weeks of ACE inhibitor therapy.

Potassium-sparing diuretics (eplerenone, spironolactone): With eplerenone or spironolactone at doses between 12.5 mg to 50 mg by day and with low doses of ACE inhibitors in the treatment of class II-ІV heart failure (NYHA) with an ejection fraction < 40 %, and previously treated with ACE inhibitors and loop diuretics, risk of hyperkalaemia, potentially lethal, especially in case of non-observance of the prescription recommendations on this combination. Before initiating the combination, check the absence of hyperkalaemia and renal impairment. A close monitoring of the kalaemia and creatininaemia is recommended in the first month of the treatment once a week at the beginning and, monthly thereafter.

Racecadotril: ACE inhibitors (e.g. perindopril) are known to cause angioedema. This risk may be elevated when used concomitantly with racecadotril (a drug used against acute diarrhoea).

mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus): Patients taking concomitant mTOR inhibitors therapy may be at increased risk for angioedema (see the section “Special warnings and precautions for use”).

Indapamide.

Due to the risk of hypokalaemia, indapamide should be administered with caution when associated with medicinal products that induced torsades de pointes such as:

  • class IA antiarrhythmic agents (quinidine, hydroquinidine, disopyramide);
  • class III antiarrhythmic agents (amiodarone, dofetilide, ibutilide, bretylium, sotalol);
  • some neuroleptics (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (amisulpride, sulpiride, sultopride, tiapride), butyrophenones (droperidol, haloperidol), other neuroleptics (pimozide);
  • other substances such as bepridil, cisapride, diphemanil, IV erythromycin, halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, IV vincamine, methadone, astemizole, terfenadine.

Prevention of low potassium levels and correction if necessary: monitoring of the QT interval.

Amphotericin В (IV route), glucocorticoids and mineralocorticoids(systemic route), tetracosactide, stimulant laxatives: Increased risk of low potassium levels (additive effect). Monitoring of potassium levels, and correction if necessary; particular consideration required in cases of treatment with cardiac glycosides. Non stimulant laxatives should be used.

Digitalis products. Low potassium and magnesium levels favour the toxic effects of cardiac glycosides. Potassium and magnesium levels and ECG should be monitored and treatment reconsidered if necessary.

Allopurinol: Concomitant treatment with indapamide may increase the incidence of hypersensitivity reactions to allopurinol.

Amlodipine.

CYP3A4 inducers: Upon co-administration of known inducers of the CYP3A4, the plasma concentration of amlodipine may vary. Therefore, blood pressure should be monitored and dose regulation considered both during and after concomitant medication particularly with strong CYP3A4 inducers (e.g. rifampicin, Hypericum perforatum).

Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise to significant increase in amlodipine exposure. The clinical translation of these PK variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus be required.

There is an increased risk of hypotension in patients receiving clarithromycin with amlodipine. Close observation is recommended in these patients.

Concomitant use to be taken into consideration.

Perindopril/ indapamide/ amlodipine.

Imipramine-like antidepressants (tricyclics), neuroleptics: Increased antihypertensive effect and increased risk of orthostatic hypotension (additive effect).

Other antihypertensive agents: could result in additional blood pressure lowering effect.

Corticosteroids, tetracosactide: Reduction in antihypertensive effect (salt and water retention due to corticosteroids).

Perindopril.

Antihypertensive agents and vasodilators: Concomitant use with nitroglycerin and other nitrates, or other vasodilators, may further reduce blood pressure.

Allopurinol, cytostatic or immunosuppressive agents, systemic corticosteroids or procainamide: Concomitant administration with ACE inhibitors may lead to an increased risk for leukopenia.

ACE inhibitors may enhance the hypotensive effects of certain anaesthetic drugs.

Diuretics (thiazide or loop diuretics): Prior treatment with high dose diuretics may result in volume depletion and in a risk of hypotension when initiating therapy with perindopril.

Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin): Increased risk of angio-oedema, due to dipeptidyl peptidase IV (DPP-IV) decreased activity by the gliptin, in patients co-treated with an ACE inhibitor.

Sympathomimetics: may reduce the antihypertensive effects of ACE inhibitors.

Gold preparations: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including perindopril.

Indapamide.

Metformin: Lactic acidosis due to metformin caused by possible functional renal insufficiency linked to diuretics and in particular to loop diuretics. Do not use metformin when plasma creatinine levels exceed 15 mg/l (135 micromol/L) in men and 12 mg/l (110 micromol/L) in women.

In cases of dehydration caused by diuretics, there is an increased risk of acute renal insufficiency, particularly when high doses of iodinated contrast media are used. Rehydration should be carried out before the iodinated compound is administered.

Calcium salts: Risk of increased levels of calcium due to reduced elimination of calcium in the urine.

Ciclosporine: Risk of increased creatinine levels with no change in circulating levels of ciclosporine, even when there is no salt and water depletion.

Amlodipine.

Atorvastatin, digoxin or warfarin: In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin or warfarin.

Tacrolimus: There is a risk of increased tacrolimus blood levels when co-administered with amlodipine. In order to avoid toxicity of tacrolimus, administration of amlodipine in a patient treated with tacrolimus requires monitoring of tacrolimus blood levels and dose adjustment of tacrolimus when appropriate.

Mechanistic Target of Rapamycin (mTOR) Inhibitors: mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. With concomitant use of mTOR inhibitors, amlodipine may increase exposure of mTOR inhibitors.

Ciclosporine: No drug interaction studies have been conducted with ciclosporine and amlodipine in healthy volunteers or other populations with the exception of renal transplant patients, where variable trough concentration increases (average 0 % to 40 %) of ciclosporine were observed. Consideration should be given to monitoring ciclosporine levels in renal transplant patients on amlodipine, and ciclosporine dose reductions should be made as necessary.

Simvastatin: Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77 % increase in exposure to simvastatin compared to simvastatin alone. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily.

Special warnings and precautions for use.

All warnings related to each component, listed as follows, should apply also to the fixed combination of Perindopres® Trio.

Lithium. The combination of lithium and the combination of perindopril/indapamide is usually not recommended (see the section “Interaction with other medicinal products and other forms of interaction”).

RAAS dual blockade. There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see the section “Interaction with other medicinal products and other forms of interaction”). If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Potassium-sparing drugs, potassium supplements or potassium-containing salt substitutes.

The combination of perindopril and potassium-sparing drugs, potassium supplements or potassium-containing salt substitutes is usually not recommended (see the section “Interaction with other medicinal products and other forms of interaction”).

Neutropenia/ agranulocytosis/ thrombocytopenia/ anaemia. Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and no other complicating factors, neutropenia occurs rarely. Perindopril should be used with extreme caution in patients with collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if there is pre-existing impaired renal function. Some of these patients developed serious infections which in a few instances did not respond to intensive antibiotic therapy. If perindopril is used in such patients, periodical monitoring of white blood cell counts is advised and patients should be instructed to report any sign of infection (e.g. sore throat, fever) (see the section “Undesirable effects”).

Renovascular hypertension. There is an increased risk of hypotension and renal insufficiency when patient with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with ACE inhibitors (see the section “Contraindications”). Treatment with diuretics may be a contributory factor. Loss of renal function may occur with only minor changes in serum creatinine even in patients with unilateral renal artery stenosis.

The treatment for renovascular hypertension is revascularisation. Nonetheless, angiotensin converting enzyme inhibitors can be beneficial in patients presenting with renovascular hypertension who are awaiting corrective surgery or when such a surgery is not possible.

If Perindopres® Trio 4 mg/1.25 mg/5 mg and 4 mg/1.25 mg/10 mg is prescribed to patients with known or suspected renal artery stenosis, treatment should be started in a hospital setting at a low dose and renal function and potassium levels should be monitored, since some patients have developed a functional renal insufficiency which was reversed when treatment was stopped.

Perindopres® Trio 8 mg/2.5 mg/5 mg or 8 mg/2.5 mg/10 mg should not be used in patients suffering from, or suspected of having renal artery stenosis. In this case, treatment should be started in a hospital with a lower dose than the recommended dose.

Hypersensitivity/ angioedema. Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported rarely in patients treated with angiotensin converting enzyme inhibitors, including perindopril. This may occur at any time during treatment.

In such cases perindopril should be discontinued promptly and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient. In those instances where swelling has been confined to the face and lips the condition generally resolved without treatment, although antihistamines have been useful in relieving symptoms.

Angioedema associated with laryngeal oedema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, which may include subcutaneous epinephrine solution 1:1 000 (0.3 mL to 0.5 mL) and/or measures to ensure a patent airway, should be administered promptly.

Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-blacks.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see the section “Contraindications”).

Intestinal angioedema has been reported rarely in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases, there was no prior facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan, or ultrasound or at surgery and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

The combination of perindopril with sacubitril/valsartan is contraindicated due to the increased risk of angioedema (see the section “Contraindications”).

Sacubitril/valsartan must not be initiated until 36 hours after taking the last dose of perindopril therapy. If treatment with sacubitril/valsartan is stopped, perindopril therapy must not be initiated until 36 hours after the last dose of sacubitril/valsartan (see the sections “Contraindications” and “Interaction with other medicinal products and other forms of interaction”). Concomitant use of other NEP inhibitors (e.g. racecadotril) and ACE inhibitors may also increase the risk of angioedema (see the section “Interaction with other medicinal products and other forms of interaction”). Hence, a careful benefit-risk assessment is needed before initiating treatment with NEP inhibitors (e.g. racecadotril) in patients on perindopril.

Concomitant use of mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus): Patients taking concomitant mTOR inhibitors therapy may be at increased risk for angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) (see the section “Interaction with other medicinal products and other forms of interaction”).

Anaphylactoid reactions during desensitization: There have been isolated reports of patients experiencing sustained, life-threatening anaphylactoid reactions while receiving ACE inhibitors during desensitisation treatment with hymenoptera (bees, wasps) venom. ACE inhibitors should be used with caution in allergic patients treated with desensitisation, and avoided in those undergoing venom immunotherapy.

However, these reactions could be prevented by temporary withdrawal of ACE inhibitor for at least 24 hours before treatment in patients who require both ACE inhibitors and desensitisation.

Anaphylactoid reactions during LDL apheresis: Rarely, patients receiving ACE inhibitors during low density lipoprotein (LDL)-apheresis with dextran sulphate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE-inhibitor therapy prior to each apheresis.

Haemodialysis patients: Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes (e.g., AN 69®) and treated concomitantly with an ACE inhibitor. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Primary aldosteronism: Patients with primary hyperaldosteronism generally will not respond to anti-hypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of this medicinal product is not recommended.

Hepatic encephalopathy: When liver function is impaired, thiazide diuretics and thiazide-related diuretics may cause hepatic encephalopathy. Hepatic encephalopathy is a contraindication to the use of this medicinal product.

Photosensitivity: Cases of photosensitivity reactions have been reported with thiazides and related thiazides diuretics (see the section “Undesirable effects”). If photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re-administration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the sun or to artificial UVA.

Renal function: In cases of severe renal impairment (creatinine clearance < 30 mL/min), treatment is contraindicated. For patients with a moderate renal impairment (creatinine clearance < 60 mL/min), treatment is contraindicated with Perindopres® Trio doses containing 8 mg/2.5 mg of perindopril/indapamide combination (i.e., Perindopres® Trio 8 mg/2.5 mg/5 mg and 8 mg/2.5 mg/10 mg). In certain hypertensive patients without pre-existing apparent renal lesions and for whom renal blood tests show functional renal insufficiency, treatment should be stopped and possibly restarted either at a low dose or with one constituent only. In these patients, usual medical follow-up will include frequent monitoring of potassium and creatinine, after two weeks of treatment and then every two months during therapeutic stability period. Renal failure has been reported mainly in patients with severe heart failure or underlying renal failure including renal artery stenosis.

This combination is usually not recommended in case of bilateral renal artery stenosis or a single functioning kidney.

Risk of arterial hypotension and/or renal insufficiency (in cases of cardiac insufficiency, water and electrolyte depletion, etc.): Marked stimulation of the renin-angiotensin-aldosterone system has been observed with perindopril particularly during marked water and electrolyte depletions (strict sodium restricted diet or prolonged diuretic treatment), in patients whose blood pressure was initially low, in cases of renal artery stenosis, congestive heart failure or cirrhosis with oedema and ascites. The blocking of this system with an angiotensin converting enzyme inhibitor may therefore cause, particularly at the time of the first administration and during the first two weeks of treatment, a sudden drop in blood pressure and/or an increase in plasma levels of creatinine, showing a functional renal insufficiency. Occasionally this can be acute in onset, although rare, and with a variable time to onset. In such cases, the treatment should then be initiated at a lower dose and increased progressively.

In patients with ischaemic heart or cerebrovascular disease an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.

Thiazide diuretics and thiazide-related diuretics are only fully effective when renal function is normal or only slightly impaired (creatinine levels lower than approximately 25 mg/L, i.e. 220 µmol/L for an adult). In the elderly the value of plasma creatinine levels should be adjusted in relation to age, weight and gender.

In elderly patients, plasma creatinine levels should be appropriate for age, body weight and sex. Hypovolaemia, secondary to the loss of water and sodium caused by the diuretic at the start of treatment, causes a reduction in glomerular filtration. It may result in an increase in blood urea and creatinine levels. This transitory functional renal insufficiency is of no adverse consequence in patients with normal renal function but may however worsen a pre-existing renal impairment.

Amlodipine may be used at normal doses in patients with renal failure. Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment.

The effect of the combination Perindopres® Trio has not been tested in renal dysfunction. In renal impairment, Perindopres® Trio doses should respect those of the individual components taken separately.

Hypotension and water and sodium depletion. There is a risk of sudden hypotension in the presence of pre-existing sodium depletion (in particular in individuals with renal artery stenosis). Therefore, systematic testing should be carried out for clinical signs of water and electrolyte depletion, which may occur with an intercurrent episode of diarrhoea or vomiting. Regular monitoring of plasma electrolytes should be carried out in such patients.

Marked hypotension may require the implementation of an intravenous infusion of isotonic saline. Transient hypotension is not a contraindication to continuation of treatment. After re-establishment of a satisfactory blood volume and blood pressure, treatment can be started again either at a reduced dose or with only one of the constituents.

Reduction in sodium levels can be initially asymptomatic and regular testing is therefore essential. Testing should be more frequent in elderly and cirrhotic patients (see the sections “Undesirable effects” and “Overdose”).

Any diuretic treatment may cause hyponatraemia, sometimes with very serious consequences. Hyponatraemia with hypovolaemia may be responsible of dehydration and orthostatic hypotension. Concomitant loss of chloride ions may lead to secondary compensatory metabolic alkalosis: the incidence and degree of this effect are slight.

Potassium levels. The combination of indapamide with perindopril and amlodipine does not prevent the onset of hypokalaemia particularly in diabetic patients or in patients with renal failure. As with any antihypertensive agent in combination with a diuretic, regular monitoring of plasma potassium levels should be carried out.

Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including perindopril. Risk factors for the development of hyperkalaemia include those with renal insufficiency, worsening of renal function, age 70 years and above, diabetes mellitus, intercurrent events, in particular dehydration, acute cardiac decompensation, metabolic acidosis and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium supplements or potassium-containing salt substitutes; or those patients taking other drugs associated with increases in serum potassium (e.g. heparin, co-trimoxazole also known as trimethoprim/sulfamethoxazole). The use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes particularly in patients with impaired renal function may lead to a significant increase in serum potassium. Hyperkalaemia can cause serious, sometimes fatal arrhythmias. If concomitant use of the previously-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium (see the section “Interaction with other medicinal products and other forms of interaction”).

Potassium depletion with hypokalaemia is a major risk with thiazide diuretics and thiazide-related diuretics. The risk of onset of lowered potassium levels (< 3.4 mmol/l) should be prevented in some high-risk populations such as elderly and/or malnourished subjects, whether or not they are taking multiple medications, cirrhotic patients with oedema and ascites, coronary patients and patients with heart failure. In such cases hypokalaemia increases the cardiac toxicity of cardiac glycosides and the risk of rhythm disorders. Subjects presenting with a long QT interval are also at risk, whether the origin is congenital or iatrogenic. Hypokalaemia, as with bradycardia, acts as a factor which favours the onset of severe rhythm disorders, in particular torsades de pointes, which may be fatal.

In all cases more frequent testing of potassium levels is necessary. The first measurement of plasma potassium levels should be carried out during the first week following the start of treatment.

If low potassium levels are detected, correction is required. Hypokalaemia found in association with low serum magnesium concentration can be refractory to treatment unless serum magnesium is corrected.

Plasma magnesium. Thiazides and related diuretics including indapamide have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia (see the sections “Interaction with other medicinal products and other forms of interaction” and “Undesirable effects”).

Calcium levels. Thiazide diuretics and thiazide-related diuretics may reduce urinary excretion of calcium and cause a mild and transient increase in plasma calcium levels. Markedly raised levels of calcium may be related to undiagnosed hyperparathyroidism. The treatment should be stopped before investigating the parathyroid function (see the section “Undesirable effects”).

Cough. A dry cough has been reported with the use of ACE inhibitors. It is characterised by its persistence and by its disappearance when treatment is withdrawn. An iatrogenic aetiology should be considered in the event of this symptom. If the prescription of an angiotensin converting enzyme inhibitor is still preferred, continuation of treatment may be considered.

Atherosclerosis. The risk of hypotension exists in all patients but particular care should be taken in patients with ischaemic heart disease or cerebral circulatory insufficiency, with treatment being started at a low dose.

Hypertensive crisis. The safety and efficacy of amlodipine in hypertensive crisis has not been established.

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

In patients with severe cardiac insufficiency (grade IV) treatment should be started under medical supervision with a reduced initial dose. Treatment with β-blockers in hypertensive patients with coronary insufficiency should not be stopped: the ACE inhibitor should be added to the β-blocker.

Aortic or mitral valve stenosis/ hypertrophic cardiomyopathy. ACE inhibitors should be used with caution in patient with an obstruction in the outflow tract of the left ventricle.

Diabetic patients. In patients with insulin dependent diabetes mellitus (spontaneous tendency to increased levels of potassium), treatment should be started under medical supervision with a reduced initial dose.

The glycaemia levels should be closely monitored in diabetic patients previously treated with oral antidiabetic drugs or insulin, namely during the first month of treatment with an ACE inhibitor.

Monitoring of blood glucose is important in diabetic patients, particularly when potassium levels are low.

Ethnic differences. As with other ACE inhibitors, perindopril is apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of a higher prevalence of low-renin states in the black hypertensive population.

Surgery/anaesthesia. ACE inhibitors can cause hypotension in cases of anaesthesia, especially when the anaesthetic administered is an agent with hypotensive potential. It is therefore recommended that treatment with long-acting ACE inhibitors such as perindopril should be discontinued where possible one day before surgery.

Hepatic impairment. Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up (see the section “Undesirable effects”).

The half-life of amlodipine is prolonged and AUC values are higher in patients with impaired liver function; dosage recommendations have not been established. Amlodipine should therefore be initiated at the lower end of the dosing range and caution should be used, both on initial treatment and when increasing the dose. Slow dose titration and careful monitoring may be required in patients with severe hepatic impairment.

The effect of the combination Perindopres® Trio has not been tested in hepatic dysfunction. Considering the effect of each individual component of this combination, Perindopres® Trio is contraindicated in patients with severe hepatic impairment, and caution should be exercised in patients with mild to moderate hepatic impairment.

Uric acid. Tendency to gout attacks may be increased in hyperuricaemic patients.

Use in the elderly. Renal function and potassium levels should be tested before the start of treatment. The initial dose is subsequently adjusted according to blood pressure response, especially in cases of water and electrolyte depletion, in order to avoid sudden onset of hypotension. In the elderly increase of the dosage of amlodipine should take place with care (see the section “Posology and method of administration” and subsection “Pharmacokinetic properties”).

Choroidal effusion, acute myopia and secondary angle-closure glaucoma. Sulphonamide, or sulphonamide derivative, medicinal products can cause an idiosyncratic reaction resulting in choroidal effusion with visual field defect, transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of medicinal product initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue medicinal product intake as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulphonamide or penicillin allergy.

Important information about excipients.

This medicinal product contains less than 23 mg/ dose of sodium, i.e. it is practically free of sodium.

Fertility, pregnancy and lactation.

Pregnancy. Perindopres® Trio is contraindicated during pregnancy (see the section “Contraindications”).

Perindopril. The use of ACE inhibitors is contraindicated during the pregnancy. Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however, a small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy.

When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).

Should exposure to ACE inhibitors have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension (see the sections “Contraindications” and “Special warnings and precautions for use”).

Indapamide. There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of indapamide in pregnant women. Prolonged exposure to thiazide during the third trimester of pregnancy can reduce maternal plasma volume as well as uteroplacental blood flow, which may cause a foeto-placental ischemia and growth retardation. Moreover, rare cases of hypoglycaemia and thrombocytopenia in neonates have been reported following exposure near term. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

Amlodipine. The safety of amlodipine in human pregnancy has not been established.

In animal studies, reproductive toxicity was observed at high doses.

Breastfeeding. Perindopres® Trio is contraindicated during lactation. A decision must be made whether to discontinue breast-feeding during treatment or to discontinue the product during breast-feeding in view of the importance of therapy to the mother.

Perindopril: Because no information is available regarding the use of perindopril during breastfeeding, perindopril is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a new-born or preterm infant.

Indapamide: There is insufficient information on the excretion of indapamide/metabolites in human milk. Hypersensitivity to sulphonamide-derived medicines and hypokalaemia might occur. A risk to new-borns/infants cannot be excluded.

Indapamide is closely related to thiazide diuretics which have been associated, during breast-feeding, with decrease or even suppression of milk lactation.

Amlodipine: Amlodipine is excreted in human milk. The proportion of the maternal dose received by the infant has been estimated with an interquartile range of 3-7%, with a maximum of 15%. The effect of amlodipine on infants is unknown.

Fertility.

Perindopril and indapamide. Reproductive toxicity studies showed no effect on fertility in female and male rats. No effects on human fertility are anticipated.

Amlodipine. Reversible biochemical changes in the head of spermatozoa have been reported in some patients treated by calcium channel blockers. Clinical data are insufficient regarding the potential effect of amlodipine on fertility. In one animal study, adverse effects were found on male fertility.

Effects on ability to drive and use machines.

No studies on the effects of Perindopres® Trio on the ability to drive and use machines have been performed.

Perindopril and indapamide have no influence on the ability to drive and use machines but individual reactions related to low blood pressure may occur in some patients.

Amlodipine can have minor or moderate influence on the ability to drive and use machines. If patients suffer from dizziness, headache, fatigue, weariness or nausea, the ability to react may be impaired. As a result, the ability to drive or operate machinery may be impaired. Caution is recommended especially at the start of treatment.

Application method

The product is indicated for oral use.

One Perindopres® Trio tablet per day as a single dose, preferably to be taken in the morning and before a meal.

The fixed dose combination is not suitable for the initial therapy.

If a change of the dose of Perindopres® Trio fixed combination is required, titration should be done with the individual components.

Special populations.

Renal impairment (see sections “Contraindications” and “Special warnings for use”). In severe renal impairment (creatinine clearance below 30 ml/min), treatment is contraindicated. In patients with moderate renal impairment (creatinine clearance 30 to 60 ml/min), Perindopres® Trio at the doses of 8 mg/2.5 mg/5 mg and 8 mg/2.5 mg/10 mg is contraindicated. Usual medical follow-up should include frequent monitoring of creatinine and blood potassium.

Elderly patients (see section “Special warnings for use”). It should be considered that elimination of perindoprilat is decreased in the elderly (see subsection “Pharmacokinetics”). Elderly patients can be treated with Perindopres® Trio according to the renal function (see section “Contraindications”).

Hepatic impairment (see sections “Contraindications”, “Special warnings for use” and subsection “Pharmacokinetics”). Perindopres® Trio  is contraindicated in patients with severe hepatic impairment. In patients with mild to moderate hepatic impairment, Perindopres® Trio  should be administrated with caution, as dosage recommendations for amlodipine in these patients have not been established.

Pediatric population.

Information on the safety and efficacy of Perindopres® Trio in children is not available, therefore, it should not be used in this age group.

Overdose.

There is no information on overdosage with Perindopres® Trio in humans

For perindopril/indapamide combination, the most likely adverse reaction in cases of overdose is hypotension, sometimes associated with nausea, vomiting, cramps, dizziness, sleepiness, mental confusion, oliguria which may progress to anuria (due to hypovolaemia). Salt and water disturbances (low sodium levels, low potassium levels) may occur.

The first measures to be taken consist of rapidly eliminating the product(s) ingested by gastric lavage and/or administration of activated charcoal, then restoring fluid and electrolyte balance in a specialised centre until they return to normal.

If marked hypotension occurs, this can be treated by placing the patient in a supine position with the head lowered. If necessary an intravenous infusion of isotonic saline may be given, or any other method of volaemic expansion may be used.

Perindoprilat, the active form of perindopril, can be dialysed (see the section “Pharmacokinetic properties”).

For amlodipine, experience with intentional overdose in humans is limited.

Available data suggest that gross overdosage could result in excessive peripheral vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported.

Clinically significant hypotension due to amlodipine overdosage calls for active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of extremities and attention to circulating fluid volume and urine output.

A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade.

Gastric lavage may be worthwhile in some cases. In healthy volunteers the use of charcoal up to 2 hours after administration of amlodipine 10 mg has been shown to reduce the absorption rate of amlodipine. Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.

Undesirable effects.

The most commonly reported adverse reactions with perindopril, indapamide and amlodipine given separately are: dizziness, headache, paraesthesia, somnolence, dysgeusia, visual disturbances, tinnitus, vertigo, palpitations, flushing, hypotension (and effects related to hypotension), cough, dyspnoea, gastro-intestinal disorders (abdominal pain, constipation, diarrhoea, dyspepsia, nausea, vomiting, change of bowel habit), pruritus, rash, rash maculo-papular, muscle cramps, ankle swelling, asthenia, oedema and fatigue as well as hypokalaemia**.

The patient should be warned to consult a doctor if there are signs of anuria/ oliguria, hot flashes, as well as depression, dark urine, nausea, vomiting, muscle cramps, confusion, which may indicate the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

The following undesirable effects have been observed during clinical trials and/or post-marketing use of perindopril, indapamide or amlodipine and ranked under the following frequency: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10 000, < 1/1 000); very rare (< 1/10 000); not known (frequency cannot be estimated from the available data).

Infections and infestations. Rhinitis: perindopril – very rare, amlodipine – uncommon.

Blood and lymphatic system disorders. Eosinophilia: perindopril – uncommon*; agranulocytosis: perindopril and indapamide – very rare; aplastic anaemia: indapamide – very rare; pancytopenia: perindopril – very rare; leukopenia: perindopril, indapamide, amlodipine – very rare; neutropenia: perindopril – very rare; haemolytic anaemia: perindopril, indapamide – very rare; thrombocytopenia: perindopril, indapamide, amlodipine – very rare.

Immune system disorders. Hypersensitivity: amlodipine – very rare, indapamide – uncommon.

Endocrine disorders. SIADH: perindopril - rare.

Metabolism and nutrition disorders. Hypoglycaemia: perindopril – uncommon*; hyperkalaemia reversible on discontinuation: perindopril – uncommon*; hyponatraemia: perindopril and indapamide – uncommon*; hyperglycaemia: amlodipine – very rare; hypercalcaemia: indapamide – very rare; potassium depletion with hypokalaemia**, particularly serious in certain high-risk populations: indapamide – common, hypochloraemia (indapamide - rare), hypomagnesaemia (indapamide - rare).

Psychiatric disorders. Insomnia: amlodipine – uncommon; mood altered (including anxiety): amlodipine, perindopril – uncommon; depression: perindopril and amlodipine – uncommon; sleep disorder: perindopril – uncommon; confusional state: perindopril – very rare, amlodipine – rare.

Nervous system disorders. Dizziness: perindopril and amlodipine – common; headache: perindopril and amlodipine – common, indapamide – rare; paraesthesia: perindopril – common, indapamide – rare, amlodipine – uncommon; somnolence: perindopril – uncommon*, amlodipine – common; hypoesthesia: amlodipine – uncommon; dysgeusia: perindopril – common, amlodipine – uncommon; tremor: amlodipine – uncommon; syncope: perindopril – uncommon*, indapamide not known, amlodipine – uncommon; hypertonia: amlodipine – very rare; neuropathy peripheral: amlodipine – very rare; extrapyramidal disorder (extrapyramidal syndrome): amlodipine – not known; stroke possibly secondary to excessive hypotension in high-risk patients: perindopril – very rare; possibility of onset of hepatic encephalopathy in case of hepatic insufficiency: indapamide – not known.

Eye disorders. Visual impairment: perindopril and amlodipine – common, indapamide not known; diplopia: amlodipine – common; myopia: indapamide not known; vision blurred: indapamide not known; choroidal effusion: indapamide - not known.

Ear and labyrinth disorders. Tinnitus: perindopril – common, amlodipine – uncommon; vertigo: perindopril – common, indapamide – rare.

Cardiac disorders. Palpitations: perindopril – uncommon*, amlodipine – common; tachycardia: perindopril – uncommon*; angina pectoris: perindopril – very rare; arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation): perindopril and indapamide – very rare, amlodipine – uncommon; myocardial infarction, possibly secondary to excessive hypotension in high risk patients: perindopril and amlodipine – very rare; torsade de pointes, potentially fatal: indapamide – not known.

Vascular disorders. Flushing: amlodipine – common, perindopril – rare; hypotension (and effects related to hypotension): perindopril – common, indapamide – very rare, amlodipine – uncommon; vasculitis: perindopril – uncommon*, amlodipine – very rare, Raynaud’s phenomenon: perindopril – not known.

Respiratory, thoracic and mediastinal disorders. Cough: perindopril – common, amlodipine – uncommon; dyspnoea: perindopril and amlodipine – common; bronchospasm: perindopril – uncommon; eosinophilic pneumonia: perindopril – very rare.

Gastrointestinal disorders. Abdominal pain: perindopril and amlodipine – common; constipation: perindopril and amlodipine – common, indapamide – rare; diarrhoea: perindopril and amlodipine – common; dyspepsia: perindopril and amlodipine – common; nausea: perindopril and amlodipine – common, indapamide – rare; vomiting: perindopril – common, indapamide and amlodipine – uncommon; dry mouth: perindopril and amlodipine – uncommon, indapamide – rare; change of bowel habits: amlodipine – common; gingival hyperplasia: amlodipine – very rare; pancreatitis: perindopril, indapamide and amlodipine – very rare; gastritis: amlodipine – very rare.

Hepatobiliary disorders. Hepatitis: perindopril and amlodipine – very rare, indapamide – not known; jaundice: amlodipine – very rare; hepatic function abnormal: indapamide – very rare.

Skin and subcutaneous tissue disorders. Pruritus: perindopril – common, amlodipine – uncommon; rash: perindopril – common, amlodipine – uncommon; rash maculo-papular: indapamide – common; urticaria: perindopril and amlodipine – uncommon, indapamide – very rare; angioedema: perindopril – uncommon, indapamide and amlodipine – very rare; alopecia: amlodipine – uncommon; purpura: indapamide and amlodipine – uncommon; skin discoloration: amlodipine – uncommon; hyperhidrosis: perindopril and amlodipine – uncommon; exanthema: amlodipine – uncommon; photosensitivity reactions: perindopril – uncommon*, indapamide – not known, amlodipine – very rare; psoriasis aggravation: perindopril – rare; pemphigoid: perindopril – uncommon*; erythema multiform: perindopril and amlodipine – very rare; Stevens-Johnson syndrome: indapamide and amlodipine – very rare; exfoliative dermatitis: amlodipine – very rare; toxic epidermal necrolysis: indapamide – very rare, amlodipine – not known; Quincke’s oedema: amlodipine – very rare.

Musculoskeletal and connective tissue disorders. Muscle spasm: perindopril and amlodipine – common; ankle swelling: amlodipine – common; arthralgia: perindopril – uncommon*, amlodipine – uncommon; myalgia: perindopril – uncommon*, amlodipine – uncommon; back pain: amlodipine – uncommon; possible worsening of pre-existing systemic lupus erythematosus: indapamide – not known.

Renal and urinary disorders. Micturition disorder: amlodipine – uncommon; nocturia: amlodipine – uncommon; pollakiuria: amlodipine – uncommon; acute renal failure: perindopril – rare, indapamide – very rare; renal failure: perindopril – uncommon, indapamide – very rare; anuria/oliguria (rare - perindopril).

Reproductive system and breast disorders. Erectile dysfunction: perindopril, amlodipine and indapamide – uncommon; gynaecomastia: amlodipine – uncommon.

General disorders. Asthenia: perindopril and amlodipine – common; fatigue: indapamide – rare, amlodipine – common; oedema: amlodipine – very common; chest pain: perindopril – uncommon*, amlodipine – uncommon; pain: amlodipine – uncommon; malaise: perindopril – uncommon*, amlodipine – uncommon; oedema peripheral: perindopril – uncommon*; pyrexia: perindopril – uncommon*.

Investigations. Weight increased: amlodipine – uncommon; weight decreased: amlodipine – uncommon; blood urea increased: perindopril – uncommon*; blood creatinine increased: perindopril – uncommon*; blood bilirubin increased: perindopril – rare; hepatic enzyme increased: perindopril – rare, indapamide – not known, amlodipine – very rare; haemoglobin decreased and haematocrit decreased: perindopril – very rare; Electrocardiogram QT prolonged: indapamide – not known; blood glucose increased: indapamide – not known; blood uric acid increased: indapamide – not known.

Injury, poisoning and procedural complications. Fall: perindopril – uncommon*.

*Frequency calculated from clinical trials for adverse events detected from spontaneous report.

**In phase II and III comparison studies of 1.5 and 2.5 mg of indapamide, plasma potassium analysis showed a dose-dependent effect of indapamide:

Indapamide 1.5 mg: plasma potassium < 3.4 mmol/L was observed in 10 % of patients and < 3.2 mmol/L in 4% of patients after 4-6 weeks of treatment. After 12 weeks of treatment, the mean reduction in plasma potassium was 0.23 mmol/L.

Indapamide 2.5 mg: plasma potassium < 3.4 mmol/L was observed in 25 % of patients and < 3.2 mmol/L in 10% of patients after 4-6 weeks of treatment. After 12 weeks of treatment, the mean reduction in plasma potassium was 0.41 mmol/L.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the state pharmacovigilance system.

Shelf life. 1.5 years.

Storage conditions.

Store in the original package below 25 ºC.

Keep out of reach of children.

Nature and contents of container.

10 tablets in a blister; 3 blisters in a pack.

Prescription status.Upon prescription.

Manufacturer.PRJSC Pharmaceutical company Darnitsa.

Manufacturer’s location and place of business.

13 Boryspilska Street, 02093, City of Kyiv, Ukraine.

Date of the last revision.February 23, 2022

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Specialized edition for medical institutions and doctors.