ARIFAM - instructions for use, doses, side effects, contraindications

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Dosage form: & nbspmodified release tablets coated with a film sheath

Composition:

1 tablet 5 mg + 1.5 mg with modified release, film-coated, contains: active ingredients: amlodipine besylate 6.935 mg, which corresponds to 5,000 mg of amlodipine, and indapamide 1,500 mg.

1 tablet of 10 mg + 1.5 mg with modified release, film-coated, contains: active ingredients: amlodipine besylate 13.870 mg, which corresponds to 10,000 mg of amlodipine, and indapamide 1,500 mg.

Excipients:

Core: hypromellose-4 thousand 84,000 / 84,000 mg, lactose monohydrate 104,500 / 104,500 mg, magnesium stearate 2,050 / 2,050 mg, povidone K-30 8,600 / 8,600 mg, silicon dioxide colloid 0,820 / 0,820 mg, calcium hydrophosphate dihydrate 56,700 / 56,700 mg, cellulose microcrystalline 128,095 / 121,160 mg, croscarmellose sodium 10,500 / 10,500 mg, corn starch pregelatinized 6,300 / 6,300 mg.

Film sheath: glycerol 0,61992 / 0,61992 mg, hypromellose-6 thousand 10,30445 / 10,30445 mg, macrogol-6000 0,65797 / 0,65797 mg, magnesium stearate 0,61992 / 0,61992 mg, titanium dioxide ( E171) 1.98375 / 1.75162 mg. Sheath of the tablet 10 mg + 1,5 mg additionally contains iron dye red oxide (E172) 0.23213 mg.

Description:

5 mg +1.5 mg: round, biconcave tablets of white color, with engraved company logo on one side;

10 mg + 1.5 mg: round, biconvex tablets of pink color, with an engraved company logo on one side.

Pharmacotherapeutic group:A combined hypotensive drug (BCCC + diuretic)

ATX: & nbsp

Amlodipine and diuretics

Pharmacodynamics:

Mechanism of action

Amlodipine is an inhibitor of calcium ion influx, a dihydropyridine derivative (slow calcium channel blocker, or calcium ion antagonist) that inhibits transmembrane influx of calcium ions into cardiomyocytes and smooth muscle cells of the vascular wall.

The mechanism of antihypertensive action of amlodipine is due to a direct relaxing effect on the smooth muscle of the vessels.

Indapamide is a sulfonamide derivative with an indole ring belonging to the pharmacological group of thiazide-like diuretics, which acts by decreasing the reabsorption of sodium in the cortical segment of the nephron loop. Indapamide increases the excretion of sodium and chloride in the urine and, to a lesser extent, the excretion of potassium and magnesium, thereby increasing diuresis and providing antihypertensive action.

Pharmacodynamic effects

In patients with arterial hypertension, the administration of amlodipine once a day provides a clinically significant reduction in arterial pressure in the supine position and standing for 24 hours. Due to the slow development of the effect amlodipine usually does not cause acute hypotension.

Amlodipine does not adversely affect the lipid metabolism and does not cause a change in the lipid profile of the blood plasma, so it is suitable for use in patients with bronchial asthma, diabetes and gout.

Antihypertensive activity of indapamide is associated with the improvement of the elastic properties of arteries and a reduction in arteriolar and general peripheral vascular resistance.

In clinical trials II and III phases with the use of indapamide in monotherapy in doses that did not exert a pronounced diuretic effect, a 24-hour antihypertensive effect was demonstrated.

Indapamide reduces hypertrophy of the left ventricle of the heart.

An increase in the dose of thiazide diuretics above certain is accompanied by the attainment of a plateau of therapeutic effect, but accompanied by the occurrence of adverse reactions. If therapy does not lead to the desired therapeutic effect, the dose should not be increased.

It was also shown that for short-term, medium-long duration and long-term use in patients with hypertension indapamide:

- does not affect lipid metabolism, including triglycerides, cholesterol, low-density lipoproteins and high-density lipoproteins;

- does not affect the metabolism of carbohydrates, including patients with diabetes mellitus.

Pharmacokinetics:

The simultaneous use of amlodipine and indapamide does not change their pharmacokinetic properties compared to the separate use of these agents.

Amlodipine:

Amlodipine is present in the Arifam® formulation in an immediate-release form.

Absorption, distribution, binding to plasma proteins

Amlodipine is well absorbed when administered in therapeutic doses, with the maximum concentration in the blood plasma is reached 6-12 hours after ingestion. Absolute bioavailability is from 64 to 80%. The volume of distribution is about 21 l / kg. Research in vitro showed that approximately 97.5 % circulating amlodipine binds to plasma proteins.

Simultaneous food intake does not affect the bioavailability of amlodipine.

Metabolism and excretion

The terminal half-life of amlodipine from the blood plasma is approximately 35-50 hours, which is consistent with the administration of the drug once a day. Amlodipine is actively metabolized in the liver with the formation of inactive metabolites, with 10% of the original compound in unchanged form and 60% of the metabolites are excreted in the urine.

Application for severe liver dysfunction.

There are very limited clinical data on the use of amlodipine in patients with severe impairment of liver function. In patients with hepatic insufficiency, the clearance of amlodipine decreases, which leads to an increase in the half-life and an increase in the area under the concentration-time curve (AUC) by approximately 40-60%.

Application in the elderly.

The time to reach the maximum concentrations of amlodipine in the blood plasma is not different in the elderly and young people. Amlodipine clearance in elderly patients tends to decrease, resulting in increased AUC and half-life. Increase AUC and half-life in patients with congestive heart failure corresponded to the expected values for these age groups of patients.

Indapamide:

Indapamide 1.5 mg in the Arifam® modified release formulation is distributed in a special carrier matrix, which allows for the gradual release indapamide.

Suction

The released proportion of indapamide is rapidly and completely absorbed in the gastrointestinal tract.

Food intake slightly increases the rate of absorption, but does not affect the completeness of absorption.

The maximum concentration of the drug in the blood plasma is reached approximately 12 hours after oral administration of a single dose; at repeated receptions of fluctuation of concentration of a preparation in a blood plasma in an interval between 2 methods of a preparation are smoothed out. The individual variability of the absorption indices of the preparation is observed inside.

Distribution

The binding of indapamide to plasma proteins is 79%. The half-life is (T_1/2) 14-24 hours (an average of 18 hours). The equilibrium concentration is achieved after 7 days. Repeated reception does not lead to accumulation.

Excretion

Drug withdrawal occurs mainly with urine (70% of the dose) and with feces (22%) in the form of inactive metabolites.

Patients, high-risk group

In patients with renal insufficiency, the pharmacokinetic parameters do not change.

Indications:

Arterial hypertension in patients who require therapy with amlodipine and indapamide.

Contraindications:

- Hypersensitivity to active substances, other sulfonamides, dihydropyridine derivatives or any of the excipients;

- tsevere renal failure (creatinine clearance <30 mL / min);

- thepatic insufficiency or hepatic encephalopathy;

- gand apokalemia;

- PThe period of breastfeeding;

- atAcute hypotension;

- wok (including cardiogenic shock);

- aboutobstruction of the left ventricular outflow tract (for example, aortic stenosis of a high degree);

- fromCardiac insufficiency after acute myocardial infarction with unstable hemodynamics;

- Mr.Galactose intolerance, lactase deficiency or glucose-galactose malabsorption (because the preparation contains lactose);

- dUp to 18 years of age.

Carefully:

Reduced circulating blood volume (diuretics, salt-free diet, vomiting, diarrhea), elderly age, patients with mild and moderate liver function abnormalities, patients with peripheral edema and ascites, coronary heart disease, chronic heart failure, patients with an elongated interval QT, bradycardia, chronic heart failure III-IV functional class by classification NYHA, diabetes mellitus, stenosis of the renal artery (including bilateral), the only functioning kidney, kidney failure, gout.

Pregnancy and lactation:

Given the effect of the individual components of this combination during pregnancy and lactation:

Arifam® is not recommended for use during pregnancy.

The drug Arifam® is contraindicated for use during breastfeeding.

Pregnancy

Amlodipine:

Safety of amlodipine in pregnant women is not established. In experimental animal studies, a toxic effect on the reproductive system was established with the use of the drug in high doses.

Indapamide:

At the moment, there is insufficient data on the use of indapamide during pregnancy (less than 300 cases have been described). Long-term exposure to thiazides during the third trimester of pregnancy can cause hypovolemia in the mother, as well as reduce uteroplacental blood flow, which can lead to fetoplacental ischemia and delayed fetal development.In addition, rare cases of hypoglycemia and thrombocytopenia in newborns were registered with diuretics shortly before birth. Studies in animals showed no direct or indirect toxic effects on reproductive function.

Breastfeeding period

Amlodipine:

The ability of amlodipine to penetrate breast milk has not been studied.

Indapamide:

It is not known whether indapamide or its metabolites with breast milk. Taking thiazide diuretics causes a decrease in the amount of breast milk or suppression of lactation. A newborn can develop hypersensitivity to sulfonamide derivatives and hypokalemia.

The risk to the newborn / infant can not be ruled out.

Fertility

Amlodipine:

In some patients who received blockers of slow calcium channels, reversible biochemical changes in the heads of spermatozoa were observed. There is insufficient clinical data on the potential effect of amlodipine on reproductive function. In a study in rats, undesirable effects on fertility in males were identified.

Indapamide:

Studies of reproductive toxicity have not shown an effect on reproductive function in rats of both sexes. It can be assumed that there is no effect on human fertility.

Dosing and Administration:

Inside, 1 tablet 1 time per day, preferably in the morning. The tablet should be swallowed without chewing and drinking with water.

Special patient groups

Patients with impaired renal function (see the sections "Contraindications" and "Special instructions")

With severe kidney damage (creatinine clearance less than 30 ml / min), the drug is contraindicated.

Correction of the dose of the drug in patients with mild and moderate renal dysfunction is not required.

Application in elderly patients (see sections "Special instructions" and "Pharmacokinetics")

The drug Arifam® can be administered to elderly patients with renal function.

Patients with impaired hepatic function (see the sections "Contraindications" and "Special instructions")

In severe liver disease therapy with Arifam® is contraindicated.

Recommendations for the dosage of amlodipine have not been established for patients with mild to moderate liver dysfunction, so the dose should be selected with caution and treatment should be started with the lowest dose (see sections "Special instructions" and "Pharmacokinetics").

Children and teens

At present, there is no data on the safety and efficacy of Arifam® in children and adolescents.

Side effects:

The most frequently observed adverse reactions during treatment with amlodipine and indapamide include drowsiness, dizziness, headache, palpitations, redness of the face, abdominal pain, nausea, edema of the lower leg, swelling and fatigue.

During treatment with amlodipine and indapamide, the following undesirable reactions were observed. The frequency is classified as follows: very often (≥1 / 10); often (≥1 / 100, <1/10); infrequently (≥1 / 1,000, <1/100); rarely (≥1 / 10,000, <1/1 000); very rarely (<1/10 000), the frequency is unknown (the frequency can not be estimated from the available data).

MedDRA Classes and systems of organs	Unwanted reactions	Frequency
MedDRA Classes and systems of organs	Unwanted reactions	Indapamide	Amlodipine
Violations from the blood and lymphatic systems	Leukocytopenia	Rarely	Rarely
	Thrombocytopenia	Rarely	Rarely
	Agranulocytosis	Rarely	-
	Aplastic anemia	Rarely
	Hemolytic anemia	Rarely
Immune system disorders	Allergic reactions		Rarely
Disorders from the metabolism and nutrition	Hypokalemia	Often In clinical trials, hypokalemia (plasma potassium level <3.4 mmol / L) was noted 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 decrease in potassium level in plasma was 0.23 mmol / L (see section "Special instructions")
	Hyperglycaemia	-	Rarely
	Hypercalcemia	Rarely	-
	Hyponatremia with hypovolaemia¹	Frequency unknown
Violations psyche	Insomnia	-	Infrequently
	Mood changes (including alarm)		Infrequently
	Depression	-	Infrequently
	Confusion consciousnesses		Rarely
Violations from the nervous systems	Drowsiness		Often (especially at the beginning of treatment)
	Dizziness		Often (especially at the beginning of treatment)
	Headache	Rarely	Often (especially at the beginning of treatment)
	Tremor	-	Infrequently
	Changes in taste	-	Infrequently
	Fainting	Frequency unknown	Infrequently
	Decreased sensitivity		Infrequently
	Paresthesia	Rarely	Infrequently
	Vertigo	Rarely	-
	Hypertonus	-	Rarely
	Peripheral Neuropathy		Rarely
Impaired vision of the eye	Visual impairment (including diplopia)		Infrequently
	Myopia	Frequency unknown
	Unclear vision	Frequency unknown
	Decreased visual acuity	Frequency unknown
Abnormalities from the organ of hearing and labyrinth disorders	Noise in ears		Infrequently
Heart Disease	Palpitation	-	Often
	Myocardial infarction	-	Rarely
	Arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation)	Rarely	Rarely
	Tachycardia of the "pirouette" type (potentially with a lethal outcome).	Frequency is unknown (see "Interactions with other drugs and other interactions" and "Special instructions")
Vascular disorders	Tides of blood to the skin of the face		Often
	Arterial hypotension	Rarely	Infrequently
	Vasculitis	-	Rarely
Infringements from respiratory system, chest and mediastinal organs	Dyspnea	-	Infrequently
	Rhinitis	-	Infrequently
	Cough		Rarely
Violations from side of the gastrointestinal tract	Abdominal pain	-	Often
	Nausea	Rarely	Often
	Vomiting	Infrequently	Infrequently
	Dyspepsia	-	Infrequently
	Changes in bowel function (including diarrhea and constipation)		Infrequently
	Dry mouth	Rarely	Infrequently
	Pancreatitis	Rarely	Rarely
	Gastritis	-	Rarely
	Hyperplasia of gums	-	Rarely
	Constipation	Rarely	Infrequently
Violations from sides of the liver and bile ducts	Hepatitis	Frequency unknown	Rarely
	Jaundice	-	Rarely
	Increased activity of "liver" enzymes	Frequency unknown	Rarely²
	Impaired liver function	Rarely
	Possible development of hepatic encephalopathy in the case of liver failure	Frequency unknown (see the sections "Contraindications" and "Special instructions")
Disturbances from the skin and subcutaneous tissue	Maculopapular rash	Often
	Purpura	Infrequently	Infrequently
	Alopecia	-	Infrequently
	Skin discoloration		Infrequently
	Hyperhidrosis	-	Infrequently
	Itching	-	Infrequently
	Skin rash	-	Infrequently
	Exanthema	-	Infrequently
	Angioedema	Rarely	Rarely
	Hives	Rarely	Rarely
	Toxic epidermal necrolysis	Rarely
	Stevens-Johnson Syndrome	Rarely	Rarely
	Erythema multiforme		Rarely
	Exfoliative dermatitis		Rarely
	Edema Quincke	-	Rarely
	Photosensitivity	The cases of photosensitivity reactions are described (see the section and "Special instructions")	Rarely
	Perhaps exacerbation of already existing acute systemic lupus erythematosus	Frequency unknown
Disorders from the side of the skeletal-muscular and connective tissue	Swelling of the shins	-	Often
	Arthralgia	-	Infrequently
	Myalgia	_	Infrequently
	Muscle Cramps	-	Infrequently
	Backache	-	Infrequently
Disorders from the kidneys and urinary tract ways	Violation of urination		Infrequently
	Nocturia	-	Infrequently
	Increasing urination		Infrequently
	Renal insufficiency	Rarely
Violations of the genitals and mammary gland	Impotence	-	Infrequently
Violations of the genitals and mammary gland	Gynecomastia		Infrequently
Are common disorders and symptoms	Edema	-	Often
	Increased fatigue	Rarely	Often
	Chest pain	-	Infrequently
	Asthenia	-	Infrequently
	Pain	-	Infrequently
	Malaise	-	Infrequently
Laboratory and instrumental data	Weight gain		Infrequently
	Weight loss	-	Infrequently
	Interval lengthening QT on an electrocardiogram (ECG)	Frequency unknown (see the sections "Interaction with other medicines and other types of interaction "and" Special instructions ")
	Increase in uric acid and blood glucose levels during treatment	Frequency unknown The advisability of prescribing these diuretics to patients with gout or diabetes should be carefully evaluated

¹ leads to dehydration and orthostatic hypotension. Concomitant loss of chloride ions can lead to secondary compensatory metabolic alkalosis: the frequency and severity of this effect are negligible.

² most often in combination with cholestasis.

When using amlodipine, extremely rare cases of extrapyramidal syndrome were observed.

Overdose:

There is no information about the overdose of Arifam®.

Amlodipine:

Information on intentional overdose in humans is limited.

The available data demonstrate that a significant overdose can lead to excessive peripheral vasodilation and, possibly, reflex tachycardia. There have been cases of pronounced and probably prolonged systemic hypotension up to the development of shock with a fatal outcome.

With clinically significant hypotension due to an overdose of amlodipine, active support of the functioning of the cardiovascular system is needed, including frequent monitoring of cardiac and respiratory functions, lifting of the limbs and monitoring the volume of circulating blood and diuresis.

To restore the vascular tone and arterial pressure, the use of vasoconstrictors can be effective in the absence of contraindications to their use. Intravenous administration of calcium gluconate can contribute to the elimination of calcium channel blockade.

In some cases, it may be advisable to wash the stomach. In healthy volunteers, the use of activated charcoal for up to 2 hours after taking 10 mg of amlodipine reduced the absorption rate of amlodipine.

Because the amlodipine is highly associated with proteins, dialysis is unlikely to be effective.

Indapamide:

Indapamide did not show toxicity when administered in doses up to 40 mg, i.e. 27 times higher than the therapeutic dose.

The signs of acute poisoning are mainly water-electrolyte disorders (hyponatremia, hypokalemia). In the clinical picture, nausea, vomiting, hypotension, muscle spasms, vertigo, drowsiness, confusion, polyuria or oliguria may be noted, possibly up to anuria (due to hypovolemia).

Initial measures of emergency care include the rapid removal of the substances taken (a) by washing the stomachand / or the appointment of activated carbon, followed by the restoration of the water-electrolyte balance to the norm in a specialized department.

Interaction:

Amlodipine:

Dantrolene (iv introduction): the animals observed ventricular fibrillation and cardiovascular collapse with a lethal outcome against hyperkalemia after receiving verapamil and intravenous dantrolene. Because of the risk of developing hyperkalemia, it is recommended that joint use of slow calcium channel blockers, such as amlodipine, in patients with a predisposition to malignant hyperthermia, as well as in the treatment of malignant hyperthermia.

Reception of amlodipine with grapefruit or grapefruit juice is not recommended, as in some patients the bioavailability of amlodipine may increase, which leads to an increase in the effects of lowering blood pressure.

Inhibitors of cytochrome CYP3A4: Simultaneous use of amlodipine with strong or moderate inhibitors CYP3A4 (protease inhibitors, antifungal agents from the azole group, macrolides, such as erythromycin or clarithromycin, verapamil or diltiazem) can lead to a significant increase in the concentration of amlodipine. Clinical manifestations of these pharmacokinetic abnormalities may be more pronounced in elderly patients. Clinical status monitoring and dose adjustment may be required.

Inductors CYP3A4: Information on the influence of cytochrome inducers CYP3A4 per amlodipine absent. Simultaneous application of inducers CYP3A4 (e.g., rifampicin, St. John's wort pitted) can lead to a decrease in the concentration of amlodipine in the blood plasma. Amlodipine should be used with caution in conjunction with inducers CYP3A4.

Influence of amlodipine on other drugs

Amlodipine has an additional antihypertensive effect with simultaneous administration with other drugs with antihypertensive effect.

In clinical trials of drug interactions amlodipine did not affect the pharmacokinetics atorvastatin, digoxin, warfarin or cyclosporine.

Simvastatin: Simultaneous use of multiple doses of amlodipine 10 mg and simvastatin 80 mg resulted in a 77% increase in the concentration of simvastatin compared with simvastatin monotherapy. In patients receiving amlodipine, the dose of simvastatin should not exceed 20 mg per day.

Indapamide:

Combinations of medicines, whose application is not recommended

Lithium preparations:

With the simultaneous use of indapamide and lithium preparations, an increase in the level of lithium in the blood plasma with signs of an overdose can be observed, as with a salt-free diet (reduced excretion of lithium in the urine). However, if the use of diuretics is necessary, careful monitoring of lithium in plasma and dosage adjustment are required.

Combinations, when applying which precautions are required

Drugs that cause tachycardia such as "pirouette":

- antiarrhythmic drugs Ia class (quinidine, hydroquinidine, disopyramide),

- antiarrhythmic drugs of III class (amiodarone, sotalol, dofetilide, ibutilide);

- some antipsychotics:

phenothiazines (chlorpromazine, cyamemazine, levomepromazine. thioridazine, trifluoroperazine);
benzamides (amisulpride, sulpiride, sultopride, tiapride); butyrophenones (droperidol, haloperidol);

- other: bepridil, cisapride, difemanyl, erythromycin for intravenous administration, halofantrine, misolastine, pentamidine. sparfloxacin, moxifloxacin, vinkamycin for iv administration.

Increased risk of ventricular arrhythmias, especially tachycardia such as "pirouette" (hypokalemia as a risk factor)

Before the appointment of drugs that cause tachycardia such as "pirouette", against the background of taking the drug Arifam ®, a study should be conducted to identify hypokalemia and correct if necessary. Monitoring of the clinical state, plasma electrolytes and ECG is required.

In the presence of hypokalemia should be used drugs that do not cause tachycardia such as "pirouette."

Non-steroidal anti-inflammatory drugs (systemic use), including selective inhibitors of cyclooxygenase-2, high doses of salicylic acid (≥ 3 g / day):

Possible reduction in the antihypertensive effect of indapamide.

The risk of developing acute renal failure in patients with dehydration (reduced glomerular filtration). At the beginning of the treatment, hydration and monitoring of kidney function should be performed.

Angiotensin-converting enzyme (ACE) inhibitors:

The risk of sudden hypotension and / or acute renal failure at the beginning of treatment with an ACE inhibitor against the background of an already reduced sodium level (especially in patients with renal artery stenosis).

With arterial hypertension, if the previous treatment with diuretics could cause a decrease in the sodium level, it is necessary:

- 3 days before the start of treatment with an ACE inhibitor, stop taking diuretics. In the future, if necessary, the reception of diuretics can be resumed;

- or prescribe an ACE inhibitor in a low initial dose and gradually increase the dose.

With chronic heart failure treatment with ACE inhibitors should be started with low doses with a possible preliminary reduction in the dose of diuretics.

In all cases should monitor the function of the kidneys (the level of creatinine in the blood plasma) during the first weeks of treatment with an ACE inhibitor.

Other drugs that cause hypokalemia: amphotericin B (IV), gluco- and mineralocorticoids (systemic administration), tetracosactide, laxatives, stimulating intestinal motility:

Increased risk of hypokalemia (additive effect).

Concentration of potassium in blood plasma and, if necessary, its correction should be monitored. This is especially true with concomitant treatment with cardiac glycosides. Use laxatives that do not stimulate intestinal motility.

Cardiac glycosides:

Hypokalemia increases the toxic effects of cardiac glycosides.

Concentration of potassium in the blood plasma and ECG parameters should be monitored, as well as correction of treatment if necessary.

Baclofen:

Increased antihypertensive effect.

At the beginning of the treatment, hydration and monitoring of kidney function should be performed.

Allopurinol:

Simultaneous use with indapamide may increase the risk of hypersensitivity reactions to allopurinol.

Combinations of drugs requiring attention

Potassium-sparing diuretics (amiloride, spironolactone, triamterene):

Although in some patients, the use of combinations is advisable, hypokalemia or hyperkalemia may occur (especially in patients with renal insufficiency and diabetes mellitus). It is necessary to observe the concentration of potassium in the blood plasma and the parameters of the ECG, and, if necessary, revise the treatment.

Metformin:

Functional renal failure, which can occur against the background of diuretics, especially loop, with the simultaneous appointment of metformin increases the risk of lactic acidosis. Do not use metformin, if the level of creatinine in the blood plasma exceeds 15 mg / L (135 μmol / L) in men and 12 mg / L (110 μmol / L) in women.

Iodine-containing contrast agents:

With dehydration caused by diuretics, there is an increased risk of developing acute renal failure, especially when using high doses of iodine-containing contrast agents.

Before the introduction of the iodine-containing drug, the loss of fluid should be compensated.

Tricyclic antidepressants, antipsychotics:

There is an increased risk of orthostatic hypotension and increased antihypertensive effect (additive effect).

Salts of calcium:

As a result of the decrease in the excretion of calcium in the urine, there is a risk of hypercalcemia.

Cyclosporin, tacrolimus:

There is a risk of an increase in the level of creatinine in the blood plasma without any changes in the concentration of circulating cyclosporine, even in the absence of loss of water / sodium.

Corticosteroids, tetracosactide (systemic application):

Reduction of antihypertensive effect (water / sodium retention due to corticosteroids).

Special instructions:

Hepatic encephalopathy:

If there is a violation of the liver, thiazide-like diuretics can cause hepatic encephalopathy, especially in the case of electrolyte imbalance.In connection with the presence of indapamide, in the development of this phenomenon, the use of Arifam^® should be stopped immediately.

Photosensitivity:

The cases of photosensitivity reactions with the use of thiazide and thiazide-like diuretics are described (see the "Side effect" section). If photosensitivity reaction occurs during treatment, it is recommended to stop treatment.

If reassignment of a diuretic is deemed necessary, it is recommended that the exposed parts of the body be protected from sun exposure or artificial ultraviolet rays.

Hypertensive crisis

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

Water-electrolyte balance:

- Content of sodium ions in blood plasma:

Before the start of treatment it is necessary to determine the content of sodium ions in the blood plasma.

Against the background of taking the drug should regularly monitor this figure. All diuretics can cause hyponatraemia, which sometimes leads to serious complications. Hyponatremia at the initial stage may not be accompanied by clinical symptoms, so regular laboratory monitoring is necessary.More frequent monitoring of sodium ions is indicated in elderly patients and patients with cirrhosis of the liver (see "Side effects" and "Overdose" sections).

- The content of potassium ions in blood plasma:

Depletion of potassium stores with the development of hypokalemia is the main risk associated with the use of thiazide and thiazide-like diuretics. It is necessary to prevent the development of hypokalemia (<3.4 mmol / l), in patients with high risk, namely, elderly, weakened and / or receiving concomitant medication, patients with cirrhosis, peripheral edema and ascites, patients with coronary heart disease, heart failure. In such patients, hypokalemia increases the cardiotoxicity of cardiac glycazides and the risk of arrhythmia.

Persons with an elongated interval QT also belong to the risk group, regardless of the origin of this disorder - congenital or iatrogenic. Hypokalemia, as well as bradycardia, are factors contributing to the occurrence of severe arrhythmia, in particular, a potentially fatal tachycardia such as pirouette.

In all of the above situations, the concentration of potassium in the plasma should be measured more oftenblood. The first measurement of the level of potassium ions in blood plasma should be carried out within the first week from the beginning of treatment.

When hypokalemia occurs, appropriate treatment should be prescribed.

- Calcium in the blood plasma:

Thiazide and thiazide-like diuretics can reduce the excretion of calcium in the urine and cause a slight and temporary increase in the level of calcium in the blood plasma. True hypercalcemia can be associated with previously unidentified hyperparathyroidism.

Before the study of parathyroid function, treatment should be discontinued.

The content of glucose in the blood plasma:

In connection with the presence of indapamide, it is necessary to monitor the level of glucose in the blood in patients with diabetes mellitus, especially in the presence of hypokalemia.

Heart failure:

Patients with heart failure should be treated with caution. In a long-term placebo-controlled study in patients with severe heart failure (Class III and IV according to classification NYHA), the incidence of pulmonary edema was higher in the group receiving amlodipine, than in the placebo group. Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, because they can increase the risk of cardiovascular events and death.

Kidney function:

Thiazide and thiazide-like diuretics are fully effective only with normal or slightly impaired renal function (creatinine level in the blood plasma is below 25 mg / L, ie 220 μmol / L in adult patients). In elderly patients, the normal level of creatinine in the plasma should be calculated depending on age, body weight and sex.

At the beginning of treatment, patients may experience a decrease in glomerular filtration rate due to hypovolemia, which in turn is caused by loss of water and sodium ions on the background of taking diuretic drugs. This can lead to an increase in the concentration of urea and creatinine in the blood plasma. Such transient functional renal failure is not clinically important in normal renal function, but it can strengthen existing renal failure.

In patients with renal insufficiency amlodipine can be used in usual doses.Changes in the concentration of amlodipine in the blood plasma do not correlate with the degree of impaired renal function. Amlodipine Mr.e is excreted from the body by dialysis.

Effects of the combined preparation Arifam ® in the violation of kidney function have not been studied. If the renal function is impaired, the dose of the drug should be selected taking into account the content of individual components.

Uric acid:

In connection with the presence of indapamide, patients with hyperuricemia may increase the risk of developing gout attacks.

Function of the liver:

In patients with impaired hepatic function T_1/2 and AUC Amlodipine increased. Recommendations for dosing for such patients are not established. Admission of amlodipine should start with the lowest doses and observe precautions, both at the beginning of treatment, and with increasing doses.

Effects of combined intake of amlodipine + indapamide in cases of impaired liver function have not been studied. Taking into account the effects of separate use of indapamide and amlodipine, Arifam® is contraindicated for use in patients with severe liver dysfunction, and caution should be exercised in treating patients with mild to moderate liver dysfunction.

Elderly patients

Elderly patients can take Arifam® taking into account the function of the kidneys (see the sections "Dosage and Administration" and "Pharmacodynamics").

Excipients:

Arifam® should not be used to treat patients with rare hereditary diseases associated with galactose intolerance, lactase deficiency and glucose-galactose malabsorption.

Effect on the ability to drive transp. cf. and fur:

Arifam® has little or moderate influence on the ability to manage vehicles and work with mechanisms.

Amlodipine has little or moderate influence on the ability to drive vehicles and work with mechanisms. If patients receiving amlodipine, dizziness, headache, fatigue or nausea, the ability to respond may be compromised. It is recommended to be careful, especially at the beginning of treatment.

Indapamide does not affect care, but in some cases, there may be various reactions associated with a decrease in blood pressure, especially at the beginning of treatment or with the addition of another antihypertensive drug.

As a result, the ability to drive vehicles and work with machinery can be impaired.

Form release / dosage:

Tablets with modified release, film-coated, 5 mg + 1.5 mg and 10 mg + 1.5 mg.

Packaging:

For 14 or 15 tablets per blister (PVC / Al). Two blisters with instructions for medical use in a pack of cardboard.

Packing for hospitals:

For 15 tablets per blister (PVC / Al). For 6 blisters with instructions for medical use in a pack of cardboard.

Storage conditions:

At a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004188

Date of registration:15.03.2017

Expiration Date:15.03.2022

The owner of the registration certificate:Servier LaboratoriesServier Laboratories France

Manufacturer: & nbsp

Les Laboratoires Servier Industrie France

Representation: & nbspServier Laboratories Servier Laboratories France

Information update date: & nbsp07.04.2017

Illustrated instructions

Instructions

ARIFAM® (ARIFAM®)