Arifam, 5 mg+1.5 mg 30 pcs

Mechanism of action

Amlodipine is a calcium ion influx inhibitor, dihydropyridine derivative (slow calcium channel blocker, or calcium ion antagonist), which 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 direct relaxing effect on vascular smooth muscle.

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

Pharmacodynamic effects

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

Amlodipine has no adverse effect on lipid metabolism and does not cause changes in plasma lipid profile, therefore it is suitable for use in patients with bronchial asthma, diabetes mellitus and gout.

The antihypertensive activity of indapamide is associated with improvement of elastic properties of arteries and reduction of arteriolar and total peripheral vascular resistance.

In phase II and phase III clinical studies, a 24-hour hypotensive effect has been demonstrated when using indapamide in monotherapy at doses with no pronounced diuretic effect.

Indapamide reduces left ventricular hypertrophy.

Indapamide increases the dose of thiazide diuretics above the defined ones are accompanied by achievement of a plateau of therapeutic effect, but are accompanied by the occurrence of adverse reactions. If therapy does not produce the desired therapeutic effect, the drug dose should not be increased.

Indapamide has also been shown with short-, medium-, and long-term use in patients with arterial hypertension to:

• not affect parameters of lipid metabolism, including triglyceride levels.
• does not affect lipid metabolism, including triglyceride, cholesterol, LDL, and HDL levels
• does not affect carbohydrate metabolism, including in diabetic patients.

Pharmacokinetics

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

Amlodipine

Amlodipine is available in Arifam^® in immediate-release form.

Absorption and distribution

Amlodipine is well absorbed when taken orally at therapeutic doses, with C_max in plasma reached 6-12 h after oral administration. Absolute bioavailability ranges from 64% to 80%. V_d is about 21 l/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins. Simultaneous intake of food has no effect on the bioavailability of amlodipine.

Metabolism and excretion

The terminal T_1/2 of amlodipine from blood plasma is approximately 35-50 h, which is consistent with administration of the drug once daily. Amlodipine is actively metabolized in the liver to form inactive metabolites, with 10% of the original compound unchanged and 60% of the metabolites excreted in the urine.

Pharmacokinetics in special patient groups

There are very limited clinical data on the use of amlodipine in patients with severe hepatic impairment. In patients with hepatic impairment, the clearance of amlodipine is decreased, resulting in an increased T_1/2 and an increase in AUC of approximately 40-60%.

The use in elderly patients. The time to reach C_max of amlodipine in plasma does not differ in elderly and young adults. Clearance of amlodipine in elderly patients tends to decrease, resulting in increased AUC and T_1/2. The increases in AUC and T_1/2 in patients with congestive heart failure were consistent with the expected values for these age groups of patients.

Indapamide

Indapamide 1.5 mg in Arifam^® modified-release drug is distributed in a special carrier matrix that allows gradual release of indapamide.

Intake

The released portion of indapamide is quickly and completely absorbed from the gastrointestinal tract. Food intake slightly increases the rate of absorption, but does not affect the completeness of absorption.

The C_max of the drug in plasma is reached approximately 12 hours after oral administration of a single dose; repeated doses of the drug smooth out the fluctuations in plasma concentration between two doses of the drug. Intraindividual variability in absorption of the drug is observed.

Distribution

The binding of indapamide to plasma proteins is 79%. T_1/2 is 14-24 h (mean 18 h). C_ss is reached after 7 days. Repeated administration does not result in accumulation.

Elimination

The drug is excreted mainly in the urine (70% of the dose) and in the feces (22%) in the form of inactive metabolites.

Pharmacokinetics in special patient groups

Pharmacokinetic parameters do not change in patients with renal impairment.

Indications

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

Active ingredient

Amlodipine, Indapamide

Composition

Modified release film-coated white, round, biconvex, engraved with the company logo on one side.

Associates:

hypromellose-4 thous. – 84 mg,

Lactose monohydrate – 104.5 mg,

Magnesium stearate – 2.05 mg,

Povidone K-30 – 8.6 mg,

colloidal silicon dioxide – 0.82 mg,

calcium hydrophosphate dihydrate – 56.7 mg,

microcrystalline cellulose – 128.095 mg,

croscarmellose sodium – 10.5 mg,

corn starch pregelatinized – 6.3 mg.

Composition of the film coating:

Glycerol – 0.61992 mg, hypromellose-6 thousand. – 10.30445 mg, macrogol-6000 – 0.65797 mg, magnesium stearate – 0.61992 mg, titanium dioxide (E171) – 1.98375 mg.

How to take, the dosage

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

Patients with impaired renal function (see sections “Contraindications” and “Special Precautions”)

In severe renal impairment (CKG <30 ml/min) the drug is contraindicated. No adjustment of the drug dose is required in patients with mild to moderate renal impairment.

Patients in the elderly (see sections “Special Precautions” and “Pharmacokinetics”)

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

Patients with impaired liver function (see “Contraindications” and “Special Precautions”)

The therapy with Arifam^® is contraindicated in severe liver damage. There are no dosing recommendations for amlodipine for patients with mild to moderate hepatic impairment; therefore, the dose should be adjusted with caution and treatment should be started with the lowest dose possible (see sections “Special Precautions” and “Pharmacokinetics”).

Children and adolescents

There are currently no data on the safety and effectiveness of Arifam^® in children and adolescents.

Interaction

Amlodipine

Dantrolene: Ventricular fibrillation and cardiovascular collapse with fatal outcome have been observed in animals on the background of hyperkalemia after administration of verapamil and IV administration of dantrolene. Due to the risk of hyperkalemia, it is recommended to avoid co-administration of slow calcium channel blockers such as amlodipine in patients with predisposition to malignant hyperthermia and in the treatment of malignant hyperthermia.

The administration of amlodipine with grapefruit or grapefruit juice is not recommended because the bioavailability of amlodipine may be increased in some patients, resulting in increased BP-lowering effects.

CYP3A4 cytochrome 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 lead to a significant increase in amlodipine concentration. Clinical manifestations of these pharmacokinetic abnormalities may be more pronounced in elderly patients. Clinical monitoring and dose adjustment may be required.

CYP3A4 inducers: There is no information about the effect of cytochrome CYP3A4 inducers on amlodipine. Concomitant use of CYP3A4 inducers (e.g., rifampicin, St. John’s wort) may lead to decreased plasma concentrations of amlodipine. Amlodipine should be used with caution together with CYP3A4 inducers.

The effect of amlodipine on other drugs

Amlodipine has additional hypotensive effect when taken simultaneously with other drugs with antihypertensive effect.

In clinical studies of drug interactions, amlodipine did not affect the pharmacokinetics of 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 simvastatin concentration compared with simvastatin monotherapy. In patients receiving amlodipine, the dose of simvastatin should not exceed 20 mg/day.

Indapamide

Combinations of drugs not recommended

Lithium preparations

. When indapamide and lithium preparations are used concomitantly, there may be increased plasma lithium levels with signs of overdose, as with a salt-free diet (decreased excretion of lithium in the urine). However, if the use of diuretics is necessary, close monitoring of plasma lithium and dosage adjustment is required.

Combinations for which precautions are required

Pirouette-type tachycardia-inducing drugs:

• Class IA antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmic drugs (amiodarone, sotalol, dofetilide, ibutilide);
• some antipsychotics: phenothiazines (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluorperazine), benzamides (amisulpride, sulpiride, sultopride, thiapride), butyrophenones (droperidol, haloperidol);
• others: Bepridil, cisapride, difemanil, erythromycin for IV administration, halofantrine, misolastin, pentamidine, sparfloxacin, moxifloxacin, vincamycin for IV administration.

Elevated risk of ventricular arrhythmias, especially pirouette tachycardia (hypokalemia as a risk factor)

Prior to prescribing drugs that cause pirouette tachycardia with Arifam^®, the patient should be evaluated for hypokalemia and corrected if necessary. Monitoring of clinical condition, plasma electrolytes and ECG is required.

In the presence of hypokalemia, drugs that do not cause pirouette-type tachycardia should be used.

NSAIDs (systemic use) including selective COX-2 inhibitors, salicylic acid at high doses (≥3 g/day)

Possible decrease of antihypertensive effect of indapamide. Risk of acute renal failure in patients with dehydration (decreased glomerular filtration). Hydration and monitoring of renal function should be performed at the beginning of treatment.

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 already decreased sodium levels (especially in patients with renal artery stenosis).

In arterial hypertension, if prior treatment with diuretics may have caused a reduction in sodium levels, it is necessary:

• 3 days before starting treatment with an ACE inhibitor, discontinue diuretics. Thereafter, if necessary, diuretics may be restarted;
• or an ACE inhibitor should be started at a low starting dose and the dose gradually increased.

In chronic heart failure, treatment with ACE inhibitors should be started at a low dose with possible prior reduction of diuretics.

In all cases renal function (plasma creatinine level) should be monitored during the first weeks of ACE inhibitor treatment.

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

An increased risk of hypokalemia (additive effect). Plasma potassium concentration should be monitored and, if necessary, its correction. This is especially relevant in concomitant treatment with cardiac glycosides. Laxatives that do not stimulate intestinal motility should be used.

Cardiac glycosides

Hypokalemia increases the toxic effects of cardiac glycosides. Plasma potassium concentration and ECG values should be monitored and treatment should be adjusted if necessary.

Baclofen

Augmentation of the antihypertensive effect. Hydration and monitoring of renal function should be performed at the beginning of treatment.

Allopurinol

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

Combinations of drugs requiring attention

Caliberating diuretics (amiloride, spironolactone, triamterene)

. Although in some patients the use of the combination is reasonable, hypokalemia or hyperkalemia may occur (especially in patients with renal insufficiency and diabetes mellitus). Plasma potassium concentration and ECG parameters should be monitored and, if necessary, treatment should be revised.

Metformin

Functional renal insufficiency, which may occur with diuretics, especially loop diuretics, increases the risk of lactic acidosis when metformin is concomitantly administered. Metformin should not be used if plasma creatinine levels exceed 15 mg/L (135 µmol/L) in men and 12 mg/L (110 µmol/L) in women.

Iodine-containing contrast agents

In dehydration caused by diuretics, there is an increased risk of acute renal failure, especially when using iodine-containing contrast agents in high doses. Fluid loss should be compensated before administration of an iodine-containing drug.

Tricyclic antidepressants, neuroleptics

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

Calcium salts

There is a risk of hypercalcemia due to decreased urinary calcium excretion.

Cyclosporine, tacrolimus

There is a risk of increased plasma creatinine levels without any change in circulating cyclosporine concentrations, even in the absence of water/sodium loss.

Corticosteroids, tetracosactide (systemic use)

Decreased antihypertensive effect (water/sodium retention due to corticosteroid administration).

Special Instructions

Hepatic encephalopathy

The thiazide-like diuretics may cause hepatic encephalopathy, especially in case of electrolyte imbalance in impaired hepatic function. Because of the presence of indapamide in the composition, the use of Arifam^® should be immediately discontinued if this phenomenon develops.

Photosensitivity

There have been reports of photosensitivity reactions when using thiazide and thiazide-like diuretics (see section “Adverse effects”). If photosensitivity reaction occurred during treatment, it is recommended to stop treatment. If reapplication of the diuretic is considered necessary, it is recommended to protect exposed parts of the body from exposure to the sun or artificial ultraviolet rays.

Hypertensive crisis

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

Water-electrolyte balance

The content of sodium ions in plasma. Prior to treatment it is necessary to determine the content of sodium ions in blood plasma. This parameter should be controlled regularly while taking the drug. All diuretics may cause hyponatremia, which sometimes leads to serious complications. Hyponatremia at the initial stage may not be accompanied by clinical symptoms, so regular laboratory control is necessary. More frequent monitoring of sodium ions is indicated in elderly patients and patients with liver cirrhosis (see sections “Side effects” and “Overdose”).

The content of plasma potassium ions. Depletion of potassium stores with development of hypokalemia is the main risk associated with thiazide and thiazide-like diuretics administration. It is necessary to prevent the development of hypokalemia (< 3.4 mmol/l), in patients at high risk, namely the elderly, weakened and/or receiving combined drug therapy, patients with cirrhosis, peripheral edema and ascites, CHD, heart failure. In these patients, hypokalemia increases cardiotoxicity of cardiac glycosides and risk of arrhythmias.

Persons with prolonged QT interval are also at risk, regardless of the origin of this disorder – congenital or iatrogenic. Hypokalemia, as well as bradycardia, are factors contributing to severe arrhythmias, particularly potentially fatal pirouette tachycardia.

In all of the above situations, plasma potassium concentrations should be measured more frequently. The first measurement of plasma potassium ions should be done within the first week of initiating treatment.

In case of hypokalemia, appropriate treatment should be prescribed.

The plasma calcium content. Thiazide and thiazide-like diuretics may decrease urinary calcium excretion and cause a slight and temporary increase in plasma calcium levels. True hypercalcemia may be associated with previously undiagnosed hyperparathyroidism. Until parathyroid function is investigated, treatment should be discontinued.

Plasma glucose content

In connection with the presence of indapamide, blood glucose levels should be controlled in patients with diabetes mellitus, especially in the presence of hypokalemia.

Heart failure

In patients with heart failure, treatment should be used with caution. In a long-term placebo-controlled study in patients with severe heart failure (NYHA class III and IV) the incidence of pulmonary edema was higher in the 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 may increase the risk of cardiovascular events and death.

The thiazide and thiazide-like diuretics are only fully effective in normal or mildly impaired renal function (plasma creatinine levels below 25 mg/L, i.e., 220 µmol/L in adult patients). In elderly patients the normal plasma creatinine level should be calculated depending on age, body weight and sex.

At the beginning of treatment, patients may have a decrease of CPP due to hypovolemia, which in turn is caused by loss of water and sodium ions due to diuretic therapy. This may lead to increased plasma concentrations of urea and creatinine. Such transient functional renal failure is not clinically relevant in normal renal function, but may exacerbate pre-existing renal failure.

In patients with renal insufficiency, amlodipine can be used in normal doses. Changes in amlodipine plasma concentrations do not correlate with the degree of renal impairment. Amlodipine is not excreted by dialysis.

The effects of the combined drug Arifam^® in impaired renal function have not been studied. If renal function is impaired, the dose of the drug should be adjusted taking into account the content of the individual components.

Uracilic acid

The presence of indapamide in patients with hyperuricemia may increase the risk of gout attacks.

Hepatic function

In patients with impaired hepatic function the T_1/2 and AUC of amlodipine are increased. There are no dosing recommendations for these patients. Amlodipine should be started with the lowest dose and precautions should be observed, both at the beginning of treatment and when increasing the dose.

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

Patients in the elderly

Patients in the elderly may take Arifam® with renal function in mind (see sections “Dosing regimen” and “Pharmacological effects”).

Excipients

Arifam^® should not be used for the treatment of patients with rare hereditary diseases associated with galactose intolerance, lactase deficiency and glucose-galactose malabsorption.

Impact on driving and operating machinery

Arifam^® has little to moderate effect on driving and operating machinery.

Arlodipine has mild to moderate effect on the ability to drive vehicles and operate machinery. If patients receiving amlodipine experience dizziness, headache, fatigue, or nausea, their ability to respond may be impaired. Caution is advised, especially at the beginning of treatment.

Indapamide does not affect alertness, but in individual cases, various reactions associated with a decrease in BP may occur, especially at the beginning of treatment or with the addition of another antihypertensive drug. As a result, the ability to drive vehicles and operate machinery may be impaired.

Contraindications

• severe renal failure (CK < 30 ml/min);
• severe hepatic failure or hepatic encephalopathy;
• hypokalemia;
• severe hypotension;
• shock (including cardiogenic shock);
• left ventricular outflow tract obstruction (e.g., high degree aortic stenosis);
• heart failure after acute myocardial infarction with unstable hemodynamics;
• Galactose intolerance, lactase deficiency, or glucose-galactose malabsorption (because the drug contains lactose.
• Breast-feeding
• Children under 18 years of age
• High sensitivity to the active ingredients, other sulphonamides, dihydropyridine derivatives or any of the excipients.

. The preparation should be used with caution in the decrease of circulatory blood pressure (diuretics, salt-free diet, vomiting, diarrhea), patients with light and moderate liver dysfunction, peripheral edema and ascites, patients with CHD, chronic heart failure, patients with prolonged QT interval, bradycardia, chronic heart failure class III-IV by NYHA classification, diabetes, stenosis of the renal artery (including bilateral).

In patients with a single functioning kidney, with renal insufficiency, gout, elderly patients.

Side effects

The most commonly observed adverse reactions during treatment with amlodipine and indapamide include drowsiness, dizziness, headache, palpitations, facial flushing, abdominal pain, nausea, shingles, edema and fatigue.

The adverse reactions reported below have been observed during treatment with amlodipine and indapamide. The frequency is classified as follows: very common (≥1/10); common (≥1/100, < 1/10); infrequent (≥1/1000, < 1/100); rare (≥1/10 000, < 1/1000); very rare (< 1/10 000), frequency unknown (frequency cannot be estimated from available data).

–

¹ leads to dehydration and orthostatic hypotension. Concomitant loss of chlorine ions may lead to secondary compensatory metabolic alkalosis: the frequency and severity of this effect is minor.

² most often in combination with cholestasis.

In the use of amlodipine exceptionally rare cases of extrapyramidal syndrome have been observed.

Overdose

There is no information on overdose of Arifam^®.

Amlodipine

Information about intentional overdose in humans is limited.

The evidence demonstrates that a significant overdose may result in excessive peripheral vasodilation and possibly reflex tachycardia. Cases of severe and probably prolonged systemic hypotension up to and including shock with fatal outcome have been observed.

In clinically significant hypotension due to amlodipine overdose, active support of cardiovascular function, including frequent monitoring of cardiac and respiratory function, limb elevation, and control of blood pressure and diuresis is necessary.

The use of vasoconstrictors may be effective to restore vascular tone and BP if there are no contraindications for their use. IV administration of calcium gluconate may help to eliminate calcium channel blockade.

In some cases gastric lavage may be appropriate. In healthy volunteers, the use of activated charcoal for 2 h after taking 10 mg amlodipine resulted in a decrease in the absorption rate of amlodipine.

Because amlodipine is highly protein-bound, dialysis is unlikely to be effective.

Indapamide

Indapamide showed no toxicity when used at doses up to 40 mg, which is 27 times the therapeutic dose.

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

The initial emergency measures include rapid elimination of the ingested substance(s) by gastric lavage and/or administration of activated charcoal, followed by restoration of water-electrolyte balance to normal in a specialized department.