Arifam® 1.5 mg/5 mg

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ARIFAM® 1.5 mg/5 mg (ARIFAM® 1.5 mg/5 mg) ARIFAM® 1.5 mg/10 mg (ARIFAM® 1.5 mg/10 mg)

Composition:

Active substances: indapamide, amlodipine;

One tablet contains 1.5 mg of indapamide and 6.935 mg of amlodipine besylate, equivalent to 5 mg of amlodipine, or 13.87 mg of amlodipine besylate, equivalent to 10 mg of amlodipine;

Excipients: hypromellose 4000 (E 464), lactose monohydrate, magnesium stearate (E 572), povidone (E 1201), colloidal anhydrous silicon dioxide, calcium hydrogen phosphate, microcrystalline cellulose (E 460), sodium croscarmellose (E 468), pregelatinized corn starch; film coating: glycerol (E 422), hypromellose (E 464), macrogol 6000, magnesium stearate (E 572), titanium dioxide (E 171), red iron oxide (E 172) (ARIFAM® 1.5 mg/10 mg).

Pharmaceutical form. Modified-release tablets.

Main physico-chemical properties:

ARIFAM® 1.5 mg/5 mg: white, film-coated, round tablet with an imprint «» on one side.

ARIFAM® 1.5 mg/10 mg: pink, film-coated, round tablet with an imprint «» on one side.

Pharmacotherapeutic group. Calcium channel blockers and diuretics. Amlodipine and diuretics. ATC code C08GA02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Indapamide is a sulfonamide derivative with an indole ring, pharmacologically related to thiazide diuretics, acting by inhibiting sodium reabsorption in the cortical segment of the kidneys. This increases urinary excretion of sodium and chlorides, and to a lesser extent – potassium and magnesium, thereby increasing diuresis and providing antihypertensive effect.

Amlodipine is a dihydropyridine calcium channel blocker (inhibitor of calcium ion influx) or calcium antagonist, which prevents transmembrane influx of calcium ions into smooth muscle cells of the myocardium and blood vessels. The mechanism of antihypertensive action of amlodipine is due to its ability to relax vascular smooth muscles.

Pharmacodynamic effects

Phase II and III clinical studies have demonstrated that when used as monotherapy, the antihypertensive effect of indapamide lasts for 24 hours. This effect is observed at doses where diuretic properties are minimal. The antihypertensive action of indapamide is associated with improved arterial elasticity, reduced arteriolar resistance, and decreased 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, whereas the incidence of adverse reactions increases. If there is no response to treatment, the dose should not be increased.

Also, in short-, medium-, and long-term studies involving patients with arterial hypertension, it has been demonstrated that indapamide:

• does not affect lipid metabolism (triglycerides, low- and high-density lipoproteins);
• does not affect carbohydrate metabolism, even in patients with diabetes mellitus and arterial hypertension.

In patients with arterial hypertension, administration of amlodipine once daily provides clinically significant reduction of arterial blood pressure over 24 hours in both supine and standing positions. Due to the slow onset of action of amlodipine, its use does not lead to acute hypotension. Administration of amlodipine has not been associated with any metabolic adverse reactions or changes in plasma lipid levels; therefore, it can be used in patients with asthma, gout, or diabetes mellitus.

Pharmacokinetics.

Concomitant administration of indapamide and amlodipine does not alter their pharmacokinetic properties compared to their individual use.

Indapamide

Indapamide 1.5 mg is formulated as an extended-release dosage form, provided by a matrix system in which the active substance is distributed, enabling uniform prolonged release of indapamide.

Absorption. Indapamide released from the tablet is rapidly and completely absorbed in the gastrointestinal tract. Food intake slightly increases the rate of absorption but does not affect the total amount of absorbed active substance. Maximum plasma concentration is reached approximately 12 hours after a single oral dose. Repeated administration reduces fluctuations in plasma indapamide levels between doses. There is inter-individual variability.

Distribution. Protein binding of indapamide to plasma proteins is 79%. The elimination half-life ranges from 14 to 24 hours (on average, 18 hours). Steady-state concentration is achieved within 7 days. Repeated dosing does not lead to accumulation.

Excretion. Excretion occurs mainly via urine (70% of the dose) and feces (22%) in the form of inactive metabolites.

High-risk patients. In patients with renal impairment, pharmacokinetic parameters are not altered.

Amlodipine

Amlodipine is formulated as an immediate-release dosage form.

Absorption, distribution, protein binding. After oral administration at therapeutic doses, amlodipine is well absorbed; maximum blood concentration is reached within 6–12 hours after intake. 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 elimination half-life of amlodipine in plasma is approximately 35–50 hours, corresponding to once-daily dosing. Amlodipine is extensively metabolized in the liver to inactive metabolites, excreted unchanged in urine (10%) and as metabolites (60%).

Use in patients with hepatic impairment. Clinical data on the use of amlodipine in patients with impaired liver function are limited. In patients with hepatic insufficiency, clearance of amlodipine is reduced, leading to an increase in elimination half-life and AUC by approximately 40–60%.

Use in elderly patients. Time to reach maximum plasma concentration of amlodipine is similar in elderly and younger patients. In elderly patients, there is a tendency toward reduced clearance of amlodipine, resulting in increased AUC and elimination half-life. Increased AUC and elimination half-life in patients with congestive heart failure were consistent with expectations for the studied age group.

Clinical characteristics.

Indications.

Treatment of essential hypertension in patients who require therapy with indapamide and amlodipine in doses available in fixed combinations.

Contraindications.

• Hypersensitivity to the active substances, other sulfonamides, dihydropyridine derivatives, or any excipients of the medicinal product;
• severe renal impairment (creatinine clearance < 30 mL/min);
• hepatic encephalopathy or severe hepatic dysfunction;
• hypokalemia;
• severe hypotension;
• shock (including cardiogenic shock);
• left ventricular outflow tract obstruction (e.g., severe aortic stenosis);
• heart failure with unstable hemodynamics following acute myocardial infarction.

Interaction with other medicinal products and other forms of interaction.

Interactions related to indapamide

Not recommended combinations

Lithium. Possible increase in plasma lithium concentration with symptoms of lithium toxicity similar to those observed during a low-salt diet (lithium excretion in urine is reduced). However, if diuretic therapy is truly necessary, plasma lithium levels should be closely monitored and the diuretic dose adjusted accordingly.

Combinations requiring precautions during use

Medicinal products that may provoke torsades de pointes ventricular tachycardia, such as, but not limited to:

• class IA antiarrhythmics (e.g., quinidine, hydroquinidine, disopyramide);
• class III antiarrhythmics (e.g., amiodarone, sotalol, dofetilide, ibutilide, bretylium);
• certain 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 medicinal products (e.g., bepridil, cisapride, difeminal, intravenous erythromycin, halofantrine, mizolastine, pentamidine, sparfloxacin, moxifloxacin, intravenous vinca alkaloids, methadone, astemizole, terfenadine).

Increased risk of ventricular arrhythmias, particularly torsades de pointes (hypokalemia is a risk factor). Before prescribing such combinations, hypokalemia should be ruled out and potassium levels corrected if necessary. Clinical status, plasma electrolyte levels, and ECG monitoring should be performed. In the presence of hypokalemia, medicinal products not associated with torsades de pointes should be used.

Nonsteroidal anti-inflammatory drugs (NSAIDs) (systemic use), including selective cyclooxygenase-2 inhibitors and high-dose acetylsalicylic acid (≥ 3 g/day). Concomitant use may reduce the antihypertensive effect of indapamide. In dehydrated patients, the risk of acute renal failure increases (reduced glomerular filtration rate). Fluid balance should be restored and renal function assessed before initiating treatment.

Angiotensin-converting enzyme (ACE) inhibitors. In patients with sodium deficiency, treatment with ACE inhibitors may lead to sudden arterial hypotension and/or acute renal failure (especially in patients with renal artery stenosis).

For patients with arterial hypertension in whom prior diuretic therapy has led to sodium deficiency, the following should be done:

• discontinue diuretic therapy 3 days before starting ACE inhibitors and, if necessary, resume diuretic treatment afterward;
• or initiate ACE inhibitor therapy with a low starting dose, gradually increasing it.

For patients with congestive heart failure, ACE inhibitor therapy should be initiated at the lowest dose, possibly after reducing the dose of concomitant potassium-wasting diuretics.

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

Other compounds that may cause hypokalemia: intravenous amphotericin B, glucocorticoids and mineralocorticoids (systemic use), tetracosactide, stimulant laxatives. The risk of hypokalemia increases (additive effect). Plasma potassium levels should be monitored and corrected as needed. This is particularly important when concomitantly treating with cardiac glycosides. Non-stimulant laxatives are recommended.

Cardiac glycosides. Hypokalemia and/or hypomagnesemia may enhance the toxicity of cardiac glycosides. Monitoring of plasma potassium and magnesium levels and ECG control are recommended, with treatment adjustment if necessary.

Baclofen. Enhanced antihypertensive effect. At the start of treatment, fluid balance should be restored and renal function monitored.

Allopurinol. Concomitant use with indapamide may increase the frequency of allopurinol hypersensitivity reactions.

Combinations requiring attention

Potassium-sparing diuretics (amiloride, spironolactone, triamterene). Despite the rationale for prescribing this combination to certain patients, hypokalemia or hyperkalemia may occur (especially in patients with renal impairment or diabetes mellitus). Plasma potassium levels should be monitored, ECG monitoring performed, and therapy reviewed if necessary.

Metformin. Increased risk of metformin-associated lactic acidosis due to possible development of functional renal impairment related to diuretic use, particularly loop diuretics. Metformin should not be prescribed if plasma creatinine exceeds 15 mg/L (135 µmol/L) in men and 12 mg/L (110 µmol/L) in women.

Iodinated contrast agents. In patients with dehydration caused by diuretic use, the risk of acute renal failure increases, especially with high doses of iodinated contrast agents. Fluid balance should be restored before administering iodinated contrast agents.

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

Calcium (salts). Hypercalcemia may occur due to reduced urinary calcium excretion.

Cyclosporine, tacrolimus. Increased plasma creatinine levels may occur without changes in circulating cyclosporine levels, even in the absence of water and sodium deficiency.

Corticosteroids, tetracosactide (systemic action). Possible reduction in antihypertensive effect (water and sodium retention caused by corticosteroids).

Interactions related to amlodipine

Dantrolene (infusion). In animal studies, intravenous verapamil and dantrolene administration resulted in ventricular fibrillation with fatal outcome and cardiovascular collapse combined with hyperkalemia. In patients predisposed to malignant hyperthermia or undergoing its treatment, concomitant use of calcium channel blockers such as amlodipine is not recommended due to the risk of hyperkalemia.

Concomitant use of amlodipine with grapefruit or grapefruit juice is not recommended, as in some patients bioavailability may increase, leading to enhanced 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 lead to a significant increase in amlodipine concentration. 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 monitoring is recommended for such patients.

CYP3A4 inducers.

Concomitant use with known CYP3A4 inducers may alter amlodipine plasma concentrations. Therefore, blood pressure should be monitored and dose adjustments made during and after concomitant use with CYP3A4 inducers, particularly strong CYP3A4 inducers (e.g., rifampicin, St. John's wort (hypericum perforatum)).

Effect of amlodipine on other medicinal products. Amlodipine's antihypertensive effects may potentiate the hypotensive action of other antihypertensive agents (additive effect). Clinical interaction studies have shown that amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.

Tacrolimus. There is a risk of increased blood tacrolimus levels when used concomitantly with amlodipine. To avoid tacrolimus toxicity when used with amlodipine, blood levels should be monitored and the dose adjusted if necessary.

mTOR (mechanistic target of rapamycin) inhibitors. mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. When used concomitantly with mTOR inhibitors, amlodipine may enhance their effects.

Cyclosporine. Interaction studies between cyclosporine and amlodipine have not been conducted in healthy volunteers or other populations, except in kidney transplant patients, where fluctuations in cyclosporine trough concentrations increased (on average from 0 to 40%). In kidney transplant patients receiving amlodipine, cyclosporine blood levels should be monitored and the dose reduced if necessary.

Simvastatin. Administration of amlodipine at doses ≥10 mg in combination with 80 mg simvastatin resulted in a 77% increase in simvastatin concentration compared to simvastatin monotherapy. Patients taking amlodipine should limit their simvastatin dose to 20 mg daily.

Special precautions for use.

Special warnings

Hepatic encephalopathy. In patients with impaired liver function, the use of thiazide-like diuretics, particularly in the presence of electrolyte imbalance, may precipitate hepatic encephalopathy, which may progress to hepatic coma. In such cases, the use of Arifam should be discontinued immediately due to the presence of indapamide in its composition.

Photosensitivity. Photosensitivity reactions have been reported during treatment with thiazide and thiazide-like diuretics (see section "Adverse reactions"). If a photosensitivity reaction occurs during treatment, drug administration is recommended to be discontinued. If re-initiation of treatment is necessary, protection of exposed skin from sunlight or artificial ultraviolet sources is recommended.

Precautions for use

Hypertensive crisis. Specific studies on the safety and efficacy of amlodipine in hypertensive crisis have not been conducted.

Water and electrolyte balance

• Plasma sodium levels. Plasma sodium levels should be determined before initiating treatment and at regular intervals thereafter. Decreased plasma sodium levels may initially be asymptomatic; therefore, monitoring is required. Monitoring should be performed more frequently in elderly patients and in those with hepatic cirrhosis (see sections "Adverse reactions" and "Overdose"). Any diuretic therapy may cause hyponatremia, sometimes with very serious consequences. Hyponatremia associated with hypovolemia may lead to dehydration and orthostatic hypotension. Concomitant chloride ion loss may lead to secondary compensatory metabolic alkalosis; the frequency and severity of this effect are minor.

Plasma potassium levels. Decreased plasma potassium levels leading to hypokalemia represent a major risk during treatment with thiazide and thiazide-like diuretics. Hypokalemia may cause muscle disorders. Cases of rhabdomyolysis, predominantly with severe hypokalemia, have been reported. Hypokalemia (< 3.4 mmol/L) should be prevented in patients at high risk, such as elderly patients, poorly nourished patients and/or those taking multiple medications, patients with cirrhosis accompanied by edema and ascites, and patients with ischemic heart disease (IHD) and heart failure. In these patients, hypokalemia increases the cardiotoxicity of cardiac glycosides and the risk of arrhythmias. Patients with congenital or drug-induced QT interval prolongation also belong to the risk group. In such patients, hypokalemia and bradycardia may predispose to severe arrhythmias, including torsades de pointes, which may be fatal. In all the above-mentioned cases, more frequent monitoring of plasma potassium levels is required. The first determination of plasma potassium levels should be performed within the first week of treatment. If hypokalemia is detected, plasma potassium levels should be corrected. Hypokalemia associated with low serum magnesium concentration may be refractory to treatment unless serum magnesium levels are also corrected.

• Magnesium in plasma

Thiazides and related diuretics, including indapamide, have been shown to increase urinary excretion of magnesium, which may lead to hypomagnesemia (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

• 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 development of hypercalcemia may be associated with undiagnosed hyperparathyroidism. In such cases, treatment should be discontinued and parathyroid function should be evaluated.

Blood glucose levels. Due to the presence of indapamide in the formulation, monitoring of blood glucose levels is important in patients with diabetes mellitus, especially in the presence of hypokalemia.

Heart failure. Arifam should be administered with caution in patients with heart failure. In a long-term placebo-controlled study involving patients with severe heart failure (NYHA 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, as they may 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 impairment is mild (plasma creatinine level < 25 mg/L, i.e., < 220 µmol/L in adults). In elderly patients, plasma creatinine levels should be adjusted according to age, body weight, and sex. Hypovolemia caused by loss of water and sodium due to diuretic use at the beginning of treatment is associated with decreased glomerular filtration rate. This may lead to increased plasma urea and creatinine levels. This transient functional renal impairment has no consequences in patients with normal renal function, but may exacerbate pre-existing renal impairment.

Amlodipine can be used in standard doses in patients with renal impairment. Plasma concentration fluctuations of amlodipine do not depend on the severity of renal impairment. Amlodipine is not dialyzable. Studies evaluating the efficacy of the combined drug Arifam in patients with renal dysfunction have not been conducted. For patients with impaired renal function, the dose of the drug should be adjusted according to the dosing recommendations for each individual component when used as monotherapy.

Blood uric acid levels. In patients with a history of gout, there is a risk of increased frequency of gout attacks due to elevated blood uric acid levels caused by the presence of indapamide in the formulation.

Hepatic function. In patients with impaired liver function, prolonged elimination half-life and increased AUC (area under the concentration-time curve) of amlodipine are observed; dosing recommendations are lacking. Therefore, treatment with amlodipine should be initiated at the lowest dose. The drug should be used with caution at the beginning of treatment and when increasing the dose. Targeted studies evaluating the efficacy of the combined drug Arifam in patients with hepatic dysfunction have not been conducted. Due to the properties of indapamide and amlodipine, Arifam is contraindicated in patients with severe hepatic impairment. The drug should be used with caution in patients with mild to moderate hepatic impairment.

Elderly patients. Arifam should be used in elderly patients with consideration of renal function (see sections "Method of administration and dosage" and "Pharmacokinetics").

Choroidal effusion, acute myopia (short-sightedness), and secondary angle-closure glaucoma. Medicinal products containing sulfonamide or sulfonamide derivatives may cause an idiosyncratic reaction leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and usually occur within hours or weeks after starting the drug. Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is prompt discontinuation of the drug. If intraocular pressure remains uncontrolled, medical or surgical intervention may be required. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Athletes.

Athletes should be aware that the drug contains an active substance that may lead to a positive doping test.

Excipients. The medicinal product contains lactose. Arifam should not be administered to patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.

Sodium content. Arifam contains less than 1 mmol of sodium (23 mg) per tablet, i.e., nearly "sodium-free".

Use during pregnancy or breastfeeding.

Considering the effects of the components of the combined drug Arifam on pregnancy and breastfeeding:

• use of the drug during pregnancy is not recommended;
• the drug is not recommended during breastfeeding.

Pregnancy

Warnings related to indapamide. Data on the use of indapamide in pregnant women are lacking or limited (< 300 cases). Prolonged use of a thiazide diuretic during the third trimester of pregnancy may result in reduced circulating blood volume (CBV) in the pregnant woman and uteroplacental perfusion, which may lead to fetoplacental ischemia and delayed fetal development. In rare cases, neonates have shown hypoglycemia and thrombocytopenia. Animal studies have not revealed direct or indirect toxic effects on reproductive function.

Warnings related to amlodipine. Safety studies of amlodipine use in pregnant women have not been conducted. In animal studies, toxic effects on reproductive function were observed with high doses.

Breastfeeding

Warnings related to indapamide. Data on the passage of indapamide/metabolites into breast milk are insufficient. Hypersensitivity to sulfonamide derivatives and hypokalemia may develop. Risk to neonates/infants cannot be excluded. Indapamide belongs to thiazide-like diuretics, the use of which during breastfeeding is associated with reduced or even suppressed lactation.

Warnings related to amlodipine.

Amlodipine passes into breast milk. The fraction of the maternal dose received by the infant has been estimated as an interquartile range of 3–7% with a maximum of 15%. The effect of amlodipine on infants is unknown.

Fertility

Warnings related to indapamide. Reproductive toxicity studies showed no effect on fertility in male and female rats. An effect on human fertility is not expected.

Warnings related to amlodipine. In some patients, reversible biochemical changes in the sperm head have been observed with calcium channel blockers. Clinical data on the potential effect of amlodipine on fertility are insufficient. In one animal study, adverse reactions affecting male fertility were observed.

Ability to affect reaction speed when driving or operating machinery.

Arifam has a minor or moderate influence on the ability to drive vehicles and operate machinery:

• Indapamide does not affect alertness, but various reactions related to decreased blood pressure may occur in individual cases, especially at the beginning of treatment or when used concomitantly with other antihypertensive drugs.

As a result, the ability to drive vehicles or operate other machinery may be impaired.

• Amlodipine may have a minor or moderate effect on the ability to drive vehicles and operate machinery. If patients taking amlodipine experience adverse reactions such as dizziness, headache, fatigue, or nausea, their reaction ability may be reduced. Caution is recommended, especially at the beginning of treatment.

Dosage and Administration.

For oral use.

One tablet daily as a single dose, preferably in the morning before food. The tablet should be swallowed whole, without chewing, with water. The maximum daily dose is 1 tablet (1.5 mg/10 mg).

Fixed-dose combination therapy is not intended for initiation of treatment.

If dose adjustment is required, individual titration of each component of the combination should be performed.

Special patient groups

Patients with renal impairment (see sections "Contraindications" and "Special precautions for use").
Aripham is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min). Dose adjustment is not required in patients with mild to moderate renal impairment.

Geriatric patients (see sections "Special precautions for use" and "Pharmacokinetics").
Aripham should be used in elderly patients with consideration of renal function.

Patients with hepatic impairment (see sections "Contraindications" and "Special precautions for use").
Aripham is contraindicated in patients with severe hepatic impairment. For patients with mild to moderate hepatic impairment, dosage recommendations for amlodipine have not been established; therefore, the dose should be carefully titrated, starting with the lowest dose (see sections "Special precautions for use" and "Pharmacokinetics").

Children.
The safety and efficacy of Aripham in children have not been established. Data are lacking.

Overdose.
There is no information available on Aripham overdose in humans.

Overdose with indapamide

Symptoms. No toxic effects were observed following indapamide doses up to 40 mg, which is 27 times higher than the therapeutic dose. Symptoms of acute poisoning are mainly related to disturbances in water-electrolyte balance (hyponatremia, hypokalemia). Clinically, nausea, vomiting, arterial hypotension, seizures, vertigo, drowsiness, confusion, polyuria or oliguria may occur, potentially leading to anuria (due to hypovolemia).

Treatment. Emergency measures include rapid removal of the ingested substance by gastric lavage and/or administration of activated charcoal, followed by correction of water-electrolyte imbalance under hospital conditions.

Overdose with amlodipine

Data on intentional human overdose are limited.

Symptoms. Available data suggest that ingestion of very high doses may lead to excessive peripheral vasodilation and possible reflex tachycardia. Profound, possibly prolonged systemic hypotension has been reported, leading to shock with fatal outcome.

Rare cases of non-cardiogenic pulmonary edema following amlodipine overdose have been reported, which may present with delayed onset (24–48 hours after administration) and may require mechanical ventilation. Early resuscitative measures (including fluid loading) to maintain perfusion and cardiac output may act as triggering factors.

Treatment. Clinically significant hypotension due to amlodipine overdose requires active cardiovascular support, including continuous monitoring of cardiac and respiratory function, placing the patient in a supine position with legs elevated, and monitoring of circulating blood volume and urine output. Administration of vasoconstrictors may be beneficial to restore vascular tone and blood pressure, provided there are no contraindications. Intravenous calcium gluconate may help counteract calcium channel blockade effects. In some cases, gastric lavage may be beneficial. Administration of activated charcoal within 2 hours after a 10 mg dose of amlodipine reduces its absorption rate. Since amlodipine is highly protein-bound, hemodialysis is unlikely to be effective.

Adverse Reactions

When indapamide and amlodipine are used separately, according to their registered safety profiles, the most commonly reported adverse reactions include hypokalemia, somnolence, dizziness, headache, visual disturbances, diplopia, palpitations, flushing, dyspnea, abdominal pain, nausea, dyspepsia, altered defecation rhythm, diarrhea, constipation, hypersensitivity reactions (mainly dermatological), particularly in individuals predisposed 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 frequency of occurrence: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

Infections and infestations: rhinitis (uncommon – amlodipine).

Blood and lymphatic system disorders: 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).

Immune system disorders: hypersensitivity (very rare – amlodipine).

Metabolism and nutrition disorders: hypokalemia (see section "Special precautions for use") (common – indapamide); hyperglycemia (very rare – amlodipine); hypercalcemia (very rare – indapamide); hyponatremia with hypovolemia* (uncommon – indapamide); hypochloremia (rare – indapamide); hypomagnesemia (rare – indapamide).

Psychiatric disorders: insomnia (uncommon – amlodipine); mood changes (including anxiety) (uncommon – amlodipine); depression (uncommon – amlodipine); confusion (rare – amlodipine).

Nervous system disorders: somnolence (common (especially at the beginning of treatment) – amlodipine); dizziness (common (especially at the beginning of treatment) – amlodipine); headache (rare – indapamide; common (especially at the beginning of treatment) – amlodipine); tremor (uncommon – amlodipine); dysgeusia (uncommon – amlodipine); syncope (frequency not known – indapamide; uncommon – amlodipine); hypesthesia (uncommon – amlodipine); paresthesia (rare – indapamide; uncommon – amlodipine); hypertonia (very rare – amlodipine); peripheral neuropathy (very rare – amlodipine); extrapyramidal disorders (extrapyramidal syndrome) (frequency not known – amlodipine); hepatic encephalopathy may occur in case of hepatic insufficiency (frequency not known – indapamide) (see sections "Contraindications" and "Special precautions for use").

Eye disorders: visual disturbances (frequency not known – indapamide; common – amlodipine); diplopia (common – amlodipine); myopia (frequency not known – indapamide); acute angle-closure glaucoma (frequency not known – indapamide); blurred vision (frequency not known – indapamide); choroidal effusion (frequency not known – indapamide).

Ear and labyrinth disorders: tinnitus (uncommon – amlodipine); vertigo (rare – indapamide).

Cardiac disorders: palpitations (common – amlodipine); myocardial infarction (very rare – amlodipine); arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation) (very rare – indapamide; uncommon – amlodipine); torsade de pointes (potentially fatal) (frequency not known – indapamide) (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Vascular disorders: flushing (common – amlodipine); arterial hypotension (very rare – indapamide; uncommon – amlodipine); vasculitis (very rare – amlodipine).

Respiratory, thoracic and mediastinal disorders: dyspnea (common – amlodipine); cough (uncommon – amlodipine).

Gastrointestinal disorders: abdominal pain (common – amlodipine); nausea (rare – indapamide; common – amlodipine); vomiting (uncommon – indapamide; uncommon – amlodipine); dyspepsia (common – amlodipine); altered defecation rhythm (common – amlodipine); dry mouth (rare – indapamide; uncommon – amlodipine); pancreatitis (very rare – indapamide and amlodipine); gastritis (very rare – amlodipine); gingival hyperplasia (very rare – amlodipine); diarrhea (common – amlodipine); constipation (rare – indapamide; common – amlodipine).

Hepatobiliary disorders: hepatitis (frequency not known – indapamide; very rare – amlodipine); jaundice (very rare – amlodipine); liver function abnormalities (very rare – indapamide).

Skin and subcutaneous tissue disorders: maculopapular rash (common – indapamide); purpura (uncommon – indapamide; uncommon – amlodipine); alopecia (uncommon – amlodipine); skin discoloration (uncommon – amlodipine); hyperhidrosis (uncommon – amlodipine); pruritus (uncommon – amlodipine); rash (uncommon – amlodipine); exanthema (uncommon – amlodipine); angioedema (very rare – indapamide; very rare – amlodipine); urticaria (very rare – indapamide; uncommon – amlodipine); toxic epidermal necrolysis (very rare – indapamide; frequency not known – amlodipine); Stevens-Johnson syndrome (very rare – indapamide; very rare – amlodipine); erythema multiforme (very rare – amlodipine); exfoliative dermatitis (very rare – amlodipine); Quincke's edema (very rare – amlodipine); photosensitivity reactions (cases of photosensitivity reactions reported – indapamide; very rare – amlodipine) (see section "Special precautions for use").

Musculoskeletal and connective tissue disorders: ankle swelling (common – amlodipine); arthralgia (uncommon – amlodipine); myalgia (frequency not known – indapamide; uncommon – amlodipine); muscle cramps (frequency not known – indapamide; common – amlodipine); muscle weakness (frequency not known – indapamide); rhabdomyolysis (frequency not known – indapamide); back pain (uncommon – amlodipine); possible exacerbation of existing systemic lupus erythematosus (frequency not known – indapamide).

Renal and urinary disorders: urinary disorders (uncommon – amlodipine); nocturia (uncommon – amlodipine); polyuria (uncommon – amlodipine); renal failure (very rare – indapamide).

Reproductive system and breast disorders: erectile dysfunction (uncommon – amlodipine; uncommon – indapamide); gynecomastia (uncommon – amlodipine).

General disorders and administration site conditions: edema (very common – amlodipine); fatigue (rare – indapamide; common – amlodipine); chest pain (uncommon – amlodipine); asthenia (common – amlodipine); pain (uncommon – amlodipine); malaise (uncommon – amlodipine).

Investigations: weight gain (uncommon – amlodipine); weight loss (uncommon – amlodipine); QT interval prolongation on ECG (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction") (frequency not known – indapamide); increased blood glucose levels (frequency not known – indapamide) (the appropriateness of prescribing these diuretics should be carefully considered before administration to patients with gout or diabetes mellitus); increased blood uric acid levels (frequency not known – indapamide) (the appropriateness of prescribing these diuretics should be carefully considered before administration to patients with gout or diabetes mellitus); increased liver enzymes (frequency not known – indapamide; very rare** – amlodipine).

* May lead to dehydration and orthostatic hypotension. Concomitant loss of chloride ions may lead to secondary compensatory metabolic alkalosis; the frequency and severity of this effect are negligible.

** Mostly due to cholestasis.

Description of selected adverse reactions

During Phase II and III studies comparing doses of 1.5 mg and 2.5 mg of indapamide, analysis of plasma potassium levels showed a dose-dependent effect:

• 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 decrease in plasma potassium level was 0.23 mmol/L.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system.

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 30 °C. Keep out of reach of children.

Packaging.

15 tablets in a blister pack made of aluminum foil and PVC film. 2 or 6 blisters per cardboard packaging.

Prescription status.

Prescription only.

Manufacturer.

Les Laboratoires Servier Industrie / Les Laboratoires Servier Industrie.

Manufacturer's location and address of place of business.

905 route de Saran, 45520 Gidy, France / 905 route de Saran, 45520 Gidy, France.

Manufacturer.

Servier (Ireland) Industries Ltd / Servier (Ireland) Industries Ltd.

Manufacturer's location and address of place of business.

Moneylands, Gorey Road, Arklow, Co. Wicklow, Ireland / Moneylands, Gorey Road, Arklow, Co. Wicklow, Ireland.

Marketing authorization holder.

Les Laboratoires Servier / Les Laboratoires Servier.

Address of marketing authorization holder.

50, rue Carnot, 92284 Suresnes cedex, France / 50, rue Carnot, 92284 Suresnes cedex, France.

For any information regarding this medicinal product, please contact LLC "Servier Ukraine" at tel.: (044) 490 3441, fax: (044) 490 3440.