Instructions for use Arifam 1.5 mg/10 mg modified-release tablets 1.5 mg + 10 mg blister No. 30
Composition
active ingredients: indapamide, amlodipine;
1 tablet contains 1.5 mg of indapamide and 6.935 mg of amlodipine besylate, corresponding to 5 mg of amlodipine, or 13.87 mg of amlodipine besylate, corresponding to 10 mg of amlodipine;
excipients: hypromellose 4000 (E 464), lactose monohydrate, magnesium stearate (E 572), povidone (E 1201), colloidal anhydrous silica, calcium hydrogen phosphate, microcrystalline cellulose (E 460), croscarmellose sodium (E 468), pregelatinized corn starch; film coating: glycerol (E 422), hypromellose (E 464), macrogol 6000, magnesium stearate (E 572), titanium dioxide (E 171), iron oxide red (E 172) (Arifam® 1.5 mg/10 mg).
Dosage form
Modified-release tablets.
Main physicochemical properties:
Arifam® 1.5 mg/5 mg: white, round, film-coated tablet, embossed with "" on one side.
Arifam® 1.5 mg/10 mg: pink, round, film-coated tablet, embossed with "" on one side.
Pharmacotherapeutic group
Calcium channel blockers and diuretics. Amlodipine and diuretics. ATC code C08G A02.
Pharmacological properties
Pharmacodynamics
Mechanism of action
Indapamide is a sulfonamide derivative with an indole ring, pharmacologically related to thiazide diuretics, which acts by inhibiting sodium reabsorption in the cortical segment of the kidney. This increases the urinary excretion of sodium and chloride and, to a lesser extent, potassium and magnesium, thereby increasing urine output and providing an antihypertensive effect.
Amlodipine is a calcium ion influx inhibitor of the dihydropyridine group (slow calcium channel blocker or calcium ion antagonist), which prevents the transmembrane influx of calcium ions into myocardial and vascular smooth muscle. The mechanism of antihypertensive action of amlodipine is its ability to relax vascular smooth muscle.
Pharmacodynamic effects
Clinical trials of phase II and III have shown that when indapamide is used as monotherapy, the antihypertensive effect lasts for 24 hours. This effect is manifested at doses in which diuretic properties are minimal. The antihypertensive effect of indapamide is associated with an improvement in arterial elasticity, a decrease in arteriolar resistance and total peripheral vascular resistance. Indapamide reduces left ventricular hypertrophy.
When the recommended dose is exceeded, the therapeutic effect of thiazide and thiazide-like diuretics does not increase, while the number of side effects increases. In the absence of a treatment effect, the dose should not be increased.
Also, in short-, medium- and long-term studies in patients with hypertension, it was demonstrated that indapamide:
does not affect lipid metabolism (triglycerides, low- and high-density lipoproteins);
does not affect carbohydrate metabolism, even in diabetic patients with arterial hypertension.
In patients with arterial hypertension, taking amlodipine once a day provides a clinically significant reduction in blood pressure for 24 hours in both the supine and standing positions. Due to the slow onset of action of amlodipine, its use does not lead to acute hypotension. Taking amlodipine was not associated with the occurrence of any metabolic adverse reactions or changes in plasma lipid levels, so it can be used in patients with asthma, gout and diabetes mellitus.
Pharmacokinetics
The simultaneous administration of indapamide and amlodipine does not change their pharmacokinetic properties compared to their separate use.
Indapamide
Indapamide 1.5 mg is presented in a prolonged-release dosage form, which is provided by a matrix system in which the active substance is distributed and which enables uniform prolonged release of indapamide.
Absorption. Indapamide released from the tablet is rapidly and completely absorbed from the gastrointestinal tract. Food intake slightly increases the rate of absorption, but does not affect the amount of active substance absorbed. Maximum plasma concentrations are reached approximately 12 hours after oral administration of a single dose; repeated administration reduces the fluctuation in indapamide plasma levels between two doses of the drug. There is intra-individual variability.
Distribution. The binding of indapamide to plasma proteins is 79%. The half-life is from 14 to 24 hours (average – 18 hours). The level of stable concentration is reached after 7 days. Repeated administration does not lead to cumulation.
Excretion: Excretion occurs mainly in the urine (70% of the dose) and feces (22%) as inactive metabolites.
High-risk patients: Pharmacokinetic parameters are not altered in patients with renal insufficiency.
Amlodipine
Absorption, distribution, plasma protein binding. After oral administration in therapeutic doses, amlodipine is well absorbed, with peak blood concentrations occurring 6–12 hours after administration. Absolute bioavailability is 64–80%. 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. Food intake does not affect the bioavailability of amlodipine.
Biotransformation/Excretion: The plasma half-life of amlodipine is approximately 35-50 hours, corresponding to a single daily dose. Amlodipine is extensively metabolized by the liver to inactive metabolites and is excreted in the urine as unchanged drug (10%) and as metabolites (60%).
Use in patients with hepatic impairment. Clinical data on the use of amlodipine in patients with hepatic impairment are limited. In patients with hepatic impairment, the clearance of amlodipine is reduced, resulting in an increase in half-life and AUC by approximately 40-60%.
Use in elderly patients. The time to reach maximum plasma concentrations of amlodipine is similar in elderly and younger patients. There is a tendency for amlodipine clearance to decrease in elderly patients, resulting in an increase in AUC and half-life. In patients with congestive heart failure, the increase in AUC and half-life was expected for the age group studied.
Indication
Treatment of essential hypertension in patients who require treatment with indapamide and amlodipine in doses available in fixed combinations.
Contraindication
Hypersensitivity to the active substances, other sulfonamides, dihydropyridine derivatives or any excipients of the drug;
severe renal failure (creatinine clearance < 30 ml/min);
hepatic encephalopathy or severe liver dysfunction;
hypokalemia;
severe hypotension;
shock (including cardiogenic);
obstruction of the left ventricular outflow tract (e.g. severe aortic stenosis);
heart failure with unstable hemodynamics after acute myocardial infarction.
Interaction with other medicinal products and other types of interactions
Interactions related to indapamide
Not recommended combinations
Lithium: Increased plasma lithium concentrations may occur with symptoms of overdose similar to those seen with a salt-free diet (reduced urinary lithium excretion). However, if diuretic use is absolutely necessary, careful monitoring of plasma lithium levels and adjustment of the diuretic dose are necessary.
Combinations requiring precautions for use
Drugs that can cause the development of paroxysmal ventricular tachycardia of the "pirouette" type, such as, but not limited to:
Class IA antiarrhythmic drugs (e.g. quinidine, hydroquinidine, disopyramide);
class III antiarrhythmic drugs (e.g. amiodarone, sotalol, dofetilide, ibutilide, bretylium);
some antipsychotics:
phenothiazines (e.g. chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine);
benzamides (e.g. amisulpride, sulpiride, sultopride, tiapride);
butyrophenones (e.g. droperidol, haloperidol);
other antipsychotics (e.g. pimozide);
other medicines (e.g. bepridil, cisapride, diphemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, sparfloxacin, moxifloxacin, intravenous vincamine, methadone, astemizole, terfenadine).
The risk of ventricular arrhythmias, in particular torsades de pointes (hypokalemia is a risk factor), increases. Before prescribing this combination, check for hypokalemia and correct potassium levels if necessary. The patient's clinical condition, plasma electrolyte levels and ECG monitoring should be monitored. In the presence of hypokalemia, drugs that do not cause torsades de pointes should be used.
Non-steroidal anti-inflammatory drugs (NSAIDs) (systemic use), including selective cyclooxygenase-2 inhibitors and acetylsalicylic acid in high doses (≥ 3 g/day). With simultaneous use, the antihypertensive effect of indapamide may be weakened. In dehydrated patients, the risk of acute renal failure (decreased glomerular filtration) increases. Before starting treatment, water balance should be restored and renal function checked.
Angiotensin-converting enzyme (ACE) inhibitors: In the presence of sodium deficiency, treatment with angiotensin-converting enzyme inhibitors may cause sudden hypotension and/or acute renal failure (especially in patients with renal artery stenosis).
For patients with arterial hypertension in whom previous diuretic therapy has led to sodium deficiency, it is necessary to:
3 days before starting treatment with ACE inhibitors, stop taking diuretics and then, if necessary, resume taking the diuretic
For patients with congestive heart failure, the ACE inhibitor should be initiated at the lowest dose, possibly after reducing the dose of the concomitant potassium-sparing diuretic.
In all cases, renal function (plasma creatinine level) should be monitored during the first weeks of treatment with ACE inhibitors.
Other compounds that may cause hypokalemia: intravenous amphotericin B, gluco- and mineralocorticoids (systemic administration), tetracosactide, laxatives that stimulate peristalsis. The risk of hypokalemia increases (additive effect). The level of potassium in the blood plasma should be monitored and corrected if necessary. This should be especially remembered during concomitant treatment with cardiac glycosides. It is recommended to use laxatives that do not stimulate peristalsis.
Digitalis preparations. Hypokalemia and/or hypomagnesemia contribute to the toxicity of digitalis. Monitoring of plasma potassium and magnesium levels and ECG monitoring are recommended, and treatment adjustments are made if necessary.
Baclofen. The antihypertensive effect is increased. At the beginning of treatment, the patient's water balance should be restored and renal function should be monitored.
Allopurinol: Concomitant use with indapamide may lead to an increased incidence of hypersensitivity reactions to allopurinol.
Combinations that require attention
Potassium-sparing diuretics (amiloride, spironolactone, triamterene). Although this combination is reasonable in some patients, hypokalemia or hyperkalemia may occur (especially in patients with renal insufficiency or diabetes mellitus). Plasma potassium levels should be monitored, ECG monitoring should be performed, and therapy should be reviewed if necessary.
Metformin: The risk of metformin-induced lactic acidosis is increased due to the possible development of functional renal failure associated with the use of diuretics, especially loop diuretics. Metformin should not be prescribed if the plasma creatinine level exceeds 15 mg/L (135 μmol/L) in men and 12 mg/L (110 μmol/L) in women.
Iodine contrast media. In the presence of dehydration caused by the use of diuretics, the risk of developing acute renal failure increases, especially when taking large doses of iodinated contrast media. Water balance should be restored before the use of iodinated contrast media.
Imipramine-like antidepressants, neuroleptics. Increased antihypertensive effect and risk of orthostatic hypotension (additive effect).
Calcium (salts). Hypercalcemia may occur due to decreased urinary calcium elimination.
Cyclosporine, tacrolimus: Plasma creatinine levels may increase without changes in circulating cyclosporine levels, even in the absence of water and sodium depletion.
Corticosteroids, tetracosactide (systemic action). Possible reduction of the antihypertensive effect (water and sodium retention under the influence of corticosteroids).
Interactions related to amlodipine
Dantrolene (infusion). In animal studies, fatal ventricular fibrillation and cardiovascular collapse in association with hyperkalemia have been observed after intravenous administration of verapamil and dantrolene. In patients predisposed to malignant hyperthermia and in the treatment of malignant hyperthermia, it is recommended that concomitant use of calcium channel blockers such as amlodipine be avoided due to the risk of hyperkalemia.
It is not recommended to use amlodipine with grapefruit or grapefruit juice, as bioavailability may increase in some patients, leading to increased hypotensive effect.
CYP3A4 inhibitors. Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) may result in significant increases in amlodipine concentrations. These pharmacokinetic changes are clinically more pronounced in elderly patients. Therefore, clinical monitoring and dose adjustment may be necessary. There is an increased risk of hypotension in patients taking clarithromycin in combination with amlodipine. Close observation is recommended in such patients.
CYP3A4 inducers.
When used concomitantly with known CYP3A4 inducers, the plasma concentration of amlodipine may change. Therefore, blood pressure should be monitored and the dose adjusted during and after concomitant use with CYP3A4 inducers, particularly with strong CYP3A4 inducers (e.g. rifampicin, St. John's wort (hypericum perforatum)).
Effect of amlodipine on other medicinal products. The hypotensive effects of amlodipine potentiate the hypotensive effects of other medicinal products with antihypertensive properties (additive effect). Clinical interaction studies have shown that amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin or warfarin.
Mechanistic target of rapamycin (mTOR) inhibitors. mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are substrates of CYP3A. Amlodipine is a weak CYP3A inhibitor. When used concomitantly with mTOR inhibitors, amlodipine may potentiate the effects of the latter.
Cyclosporine: No interaction studies have been conducted with cyclosporine and amlodipine in healthy volunteers or other populations, except in renal transplant patients, who showed an increase in the fluctuation of cyclosporine trough concentrations (on average from 0 to 40%). In renal transplant patients receiving amlodipine, cyclosporine blood levels should be monitored and the dose reduced if necessary.
Simvastatin: Coadministration of amlodipine in multiples of 10 mg with simvastatin 80 mg resulted in a 77% increase in simvastatin concentrations compared to simvastatin alone. Patients taking amlodipine should limit the dose of simvastatin to 20 mg daily.
Application features
Special precautions
Hepatic encephalopathy: In patients with impaired liver function, the use of thiazide-like diuretics, especially in the presence of electrolyte imbalance, may cause hepatic encephalopathy, which may progress to hepatic coma. In such cases, Arifam should be discontinued immediately due to the presence of indapamide.
Photosensitivity: Photosensitivity reactions have been reported with thiazide and thiazide-like diuretics (see section 4.8). If photosensitivity reactions occur during treatment, discontinuation of the drug is recommended. If re-administration is necessary, it is recommended to protect exposed areas from the sun or artificial ultraviolet light sources.
Precautions for use
Hypertensive crisis: No studies have been conducted to determine the safety and efficacy of amlodipine in hypertensive crisis.
Water and electrolyte balance
Plasma sodium levels. Plasma sodium levels should be determined before starting treatment and at regular intervals thereafter. A decrease in plasma sodium levels may initially be asymptomatic, therefore monitoring is necessary. In elderly patients and those suffering from cirrhosis of the liver, monitoring should be carried out more frequently (see sections “Adverse reactions” and “Overdose”). Any diuretic treatment can cause hyponatremia, sometimes with very serious consequences. Hyponatremia in combination with hypovolemia can lead to dehydration and orthostatic hypotension. The concomitant loss of chloride ions can lead to secondary compensatory metabolic alkalosis; the frequency and severity of this effect are insignificant.
Plasma potassium levels. A decrease in plasma potassium levels with hypokalaemia is the main risk with thiazide and thiazide-like diuretics. Hypokalaemia may cause muscle disorders. Rhabdomyolysis has been reported, mainly with severe hypokalaemia. Hypokalaemia (< 3.4 mmol/l) should be avoided in patients at high risk, such as the elderly, malnourished and/or heavily medicated patients, patients with cirrhosis of the liver with oedema and ascites, patients with ischaemic heart disease (IHD) and heart failure. In such cases, hypokalaemia increases the cardiotoxicity of cardiac glycosides and the risk of arrhythmias. Patients with a prolonged QT interval of congenital or iatrogenic origin are also at risk. In such patients, hypokalemia and bradycardia may contribute to the development of severe arrhythmias, including torsades de pointes, which may be fatal. In all of the above cases, more frequent monitoring of plasma potassium levels is necessary. The first determination of plasma potassium levels should be performed within the first week of treatment. If hypokalemia is detected, the plasma potassium level should be corrected. Hypokalemia, which is detected in connection with low serum magnesium levels, may be refractory to treatment if serum magnesium levels are not corrected.
Magnesium in blood plasma
Thiazides and related diuretics, including indapamide, have been shown to increase urinary magnesium excretion, which may lead to hypomagnesemia (see sections 4.5 and 4.8).
Plasma calcium levels. Thiazide and thiazide-like diuretics may reduce urinary calcium excretion and lead to a slight and transient increase in plasma calcium levels. The occurrence of hypercalcemia may be associated with undiagnosed hyperparathyroidism. In such cases, treatment should be discontinued and parathyroid function should be monitored.
Heart failure. Arifam should be used with caution in patients with heart failure. In a long-term placebo-controlled study in patients with severe heart failure (New York Heart Association functional class III and IV), the incidence of pulmonary edema was higher with amlodipine than with placebo. Calcium antagonists, including amlodipine, should be used with caution in patients with congestive heart failure because they increase the risk of cardiovascular events and death.
Renal function: Thiazide and thiazide-like diuretics are most effective when renal function is not impaired or only mildly impaired (plasma creatinine < 25 mg/l, i.e. 220 µmol/l in adults). In elderly patients, plasma creatinine levels are adjusted for age, weight and sex. Hypovolemia caused by water and sodium loss due to diuretics at the start of treatment is associated with a decrease in glomerular filtration rate. This may lead to increases in plasma urea and creatinine. This transient functional renal insufficiency is of no consequence in patients with normal renal function, but may aggravate existing renal insufficiency.
Patients with renal insufficiency can use amlodipine in normal doses. Fluctuations in the concentration of amlodipine in the blood plasma do not depend on the severity of renal insufficiency. Amlodipine is not dialyzable. Studies on the effectiveness of the combined drug Arifam in patients with renal dysfunction have not been conducted. For people with impaired renal function, the dose of the drug should be selected in accordance with the dosage of each individual component when used as monotherapy.
Blood uric acid levels. In patients with a history of gout, there is a possibility of an increase in the number of gout attacks due to an increase in blood uric acid levels due to the presence of indapamide in the composition of the drug.
Liver function. In patients with impaired liver function, amlodipine half-life is prolonged and AUC (area under the curve on the graph of the drug concentration in the blood versus time of observation) is increased; no dosage recommendations are available. Therefore, treatment with amlodipine should be started at the lowest dose. The drug should be used with caution at the beginning of treatment and when increasing the dose. Targeted studies of the efficacy of the combined drug Arifam in patients with liver dysfunction have not been conducted. Due to the properties of indapamide and amlodipine, Arifam is contraindicated in patients with severe liver dysfunction. The drug should be used with caution in patients with mild to moderate liver dysfunction.
Elderly patients: Arifam should be used in elderly patients taking into account renal function (see sections “Method of administration and dosage” and “Pharmacokinetics”).
Choroidal effusion, acute myopia (short-sightedness) and secondary angle-closure glaucoma. Sulfonamide- or sulfonamide-derived drugs may 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 eye pain and usually occur within hours to weeks of starting the drug. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue the drug as soon as possible. If intraocular pressure remains uncontrolled, prompt medical or surgical treatment may be necessary. Risk factors for acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
Athletes.
Athletes should take into account that the drug contains an active substance that may cause a positive reaction in doping control.
Excipients: The medicinal product contains lactose. Arifam should not be administered to patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
Sodium level: Arifam contains less than 1 mmol sodium (23 mg) per tablet, i.e. essentially “sodium-free”.
Use during pregnancy or breastfeeding
Considering the effect of the components of the combined drug Arifam on the course of pregnancy and breastfeeding:
the use of the drug during pregnancy is not recommended;
The drug is not recommended during breastfeeding.
Pregnancy
Precautions related to amlodipine. Studies on the safety of amlodipine in pregnant women have not been conducted. In animal studies, reproductive toxicity was observed at high doses.
Breast-feeding
Precautions related to indapamide. There is insufficient data on the excretion of indapamide/metabolites in breast milk. Hypersensitivity to sulfonamide derivatives and hypokalemia may develop. A risk to the newborn/infants cannot be excluded. Indapamide belongs to the thiazide-like diuretics, the use of which during breastfeeding has been associated with a decrease or even suppression of lactation.
Precautions related to amlodipine.
Amlodipine is excreted in human milk. The proportion of the initial maternal dose received by the infant was estimated to be 3–7% interquartile range with a maximum of 15%. The effects of amlodipine on infants are unknown.
Fertility
Precautions related to indapamide: Reproductive toxicity studies have shown no effect on fertility in male and female rats. No effect on human fertility is expected.
Precautions related to amlodipine. Reversible biochemical changes in the head of sperm have been observed in some patients receiving calcium channel blockers. Clinical data on the potential effect of amlodipine on fertility are insufficient. One animal study showed adverse reactions affecting male fertility.
The ability to influence the reaction speed when driving or working with other mechanisms
Arifam has minor or moderate influence on the ability to drive and use machines:
Indapamide does not affect alertness, but in individual cases various reactions associated with a decrease in blood pressure may occur, especially at the beginning of treatment or when used simultaneously with other antihypertensive drugs.
As a result, the ability to drive vehicles or operate other automated systems may be impaired.
Amlodipine may have minor or moderate influence on the ability to drive and use machines. If patients taking amlodipine experience adverse reactions such as dizziness, headache, fatigue or nausea, their reactions may be reduced. Caution is recommended, especially at the beginning of treatment.
Method of administration and doses
For oral use.
One tablet per day, preferably in the morning before meals. The tablet is swallowed whole, without chewing, with water. The maximum daily dose is 1 tablet (1.5 mg/10 mg).
The use of a fixed combination is not intended for initiation of therapy.
If dosage changes are necessary, individual titration of each component of the combination should be performed.
Special patient groups
Patients with renal impairment (see sections "Contraindications" and "Special instructions for use"). In severe renal impairment (creatinine clearance < 30 ml/min), treatment with the drug is contraindicated. For patients with mild and moderate renal impairment, no adjustment of the recommended dose is required.
Elderly patients (see sections "Special warnings and precautions for use" and "Pharmacokinetics").
In elderly patients, Arifam should be used taking into account renal function.
Patients with impaired liver function (see sections "Contraindications" and "Features of use"). In severe liver function disorders, treatment with the drug is contraindicated. For patients with mild and moderate liver function disorders, dosage recommendations for amlodipine have not been established, therefore the dose should be selected with caution and treatment should be started with the lowest dose (see sections "Features of use" and "Pharmacokinetics").
Children
The safety and efficacy of Arifam in children have not been studied. Data are lacking.
Overdose
There is no information on overdose with Arifam in humans.
Overdose when using indapamide
Symptoms. When using indapamide in doses up to 40 mg, which is 27 times higher than the therapeutic dose, no toxic effects were detected. Symptoms of acute poisoning are mainly manifested in the form of disturbances of water and electrolyte balance (hyponatremia, hypokalemia). Clinically, nausea, vomiting, arterial hypotension, convulsions, vertigo, drowsiness, confusion, polyuria or oliguria, which can lead to anuria (due to hypovolemia), are possible.
Treatment. First aid measures include rapid removal of the ingested substance by gastric lavage and/or administration of activated charcoal, followed by normalization of water and electrolyte balance in a hospital setting.
Amlodipine overdose
Data on deliberate human overdose are limited.
Non-cardiogenic pulmonary edema has been reported rarely following amlodipine overdose, which may have a delayed onset (24-48 hours after administration) and may require mechanical ventilation. Early resuscitation measures (including fluid overload) to maintain perfusion and cardiac output may be precipitating factors.
Treatment. Clinically significant hypotension caused by amlodipine overdose requires active cardiovascular care, including frequent monitoring of cardiac and respiratory function, positioning the patient in a horizontal position with elevation of the lower extremities, and monitoring of BCC and urine output. The administration of a vasoconstrictor may be useful to restore vascular tone and blood pressure in the absence of contraindications. Intravenous calcium gluconate is likely to help reverse the effects of calcium channel blockade. Gastric lavage may be useful in some cases. Administration of activated charcoal within 2 hours of a 10 mg dose of amlodipine reduces the rate of absorption of the latter. Since amlodipine is highly protein bound, hemodialysis is unlikely to be effective.
Side effects
When indapamide and amlodipine are used separately, according to the registered safety profile, the most frequently reported adverse reactions are hypokalemia, drowsiness, dizziness, headache, visual disturbances, diplopia, palpitations, flushing, shortness of breath, abdominal pain, nausea, dyspepsia, change in the rhythm of defecation, diarrhea, constipation, hypersensitivity reactions, mainly dermatological, in individuals with a tendency to allergic and asthmatic reactions and maculopapular rashes, ankle swelling, muscle cramps, edema, fatigue and asthenia.
During treatment with indapamide and amlodipine, adverse reactions have been reported with the following frequencies: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, ≤ 1/100); rare (≥ 1/10000, ≤ 1/1000); very rare (≤ 1/10000); frequency unknown (cannot be estimated from the available data).
Infections and infestations: rhinitis (uncommon - amlodipine).
From the blood and lymphatic system: leukopenia (very rare - indapamide and amlodipine); thrombocytopenia (very rare - indapamide and amlodipine); agranulocytosis (very rare - indapamide); aplastic anemia (very rare - indapamide); hemolytic anemia (very rare - indapamide).
On the part of the immune system: hypersensitivity (very rarely - amlodipine).
From the side of metabolism and metabolism: hypokalemia (see section "Peculiarities of use") (often - indapamide); hyperglycemia (very rarely - amlodipine); hypercalcemia (very rarely - indapamide); hyponatremia with hypovolemia* (uncommon - indapamide); hypochloremia (rarely - indapamide); hypomagnesemia (rarely - indapamide).
Psychiatric: insomnia (uncommon - amlodipine); mood changes (including anxiety) (uncommon - amlodipine); depression (uncommon - amlodipine); confusion (rarely - amlodipine).
Nervous system: drowsiness (often (especially at the beginning of treatment) - amlodipine); dizziness (often (especially at the beginning of treatment) - amlodipine); headache (rarely - indapamide; often (especially at the beginning of treatment) - amlodipine); tremor (uncommon - amlodipine); dysgeusia (uncommon - amlodipine); fainting (frequency unknown - indapamide; uncommon - amlodipine); hypoesthesia (uncommon - amlodipine); paresthesia (rarely - indapamide; uncommon - amlodipine); hypertonicity (very rarely - amlodipine); peripheral neuropathy (very rarely - amlodipine); extrapyramidal disorders (extrapyramidal syndrome) (frequency unknown - amlodipine); In case of liver failure, hepatic encephalopathy may occur (frequency unknown - indapamide) (see sections "Contraindications" and "Special instructions for use").
On the part of the organs of vision: visual impairment (frequency unknown - indapamide; often - amlodipine); diplopia (often - amlodipine); myopia (frequency unknown - indapamide); acute angle-closure glaucoma (frequency unknown - indapamide); blurred vision (frequency unknown - indapamide); choroidal effusion (frequency unknown - indapamide).
From the organs
