Amlodipine + Valsartan + Hydrochlorothiazide Canon (Tablets) Instructions for Use

Marketing Authorization Holder

Canonpharma Production, CJS (Russia)

Contact Information

CANONPHARMA PRODUCTION CJSC (Russia)

ATC Code

C09DX01 (Valsartan, Amlodipine and Hydrochlorothiazide)

Active Substances

Hydrochlorothiazide (Rec.INN registered by WHO)

Amlodipine (Rec.INN registered by WHO)

Valsartan (Rec.INN registered by WHO)

Dosage Forms

	Amlodipine + Valsartan + Hydrochlorothiazide Canon	Film-coated tablets, 5 mg+160 mg+12.5 mg: 30 or 90 pcs.
		Film-coated tablets, 10 mg+160 mg+12.5 mg: 30 or 90 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, round, biconvex; the cross-section is white or almost white.

Excipients: colloidal silicon dioxide, crospovidone CL-F, magnesium stearate, povidone K30, microcrystalline cellulose (type 101), microcrystalline cellulose (type 102).

Film coating composition of the ready white film coating: hypromellose (hydroxypropyl methylcellulose), hyprolose (hydroxypropyl cellulose), talc, titanium dioxide.

10 pcs. – blister packs (3) – cardboard cartons.
90 pcs. – polymer jars (1) – cardboard cartons.

Film-coated tablets yellow, round, biconvex; the cross-section is white or almost white.

Excipients: colloidal silicon dioxide, crospovidone CL-F, magnesium stearate, povidone K30, microcrystalline cellulose (type 101), microcrystalline cellulose (type 102).

Film coating composition of the ready yellow film coating: hypromellose (hydroxypropyl methylcellulose), hyprolose (hydroxypropyl cellulose), talc, titanium dioxide, yellow iron oxide dye, quinoline yellow dye.

10 pcs. – blister packs (3) – cardboard cartons.
90 pcs. – polymer jars (1) – cardboard cartons.

Clinical-Pharmacological Group

Combined antihypertensive drug

Pharmacotherapeutic Group

Agents acting on the renin-angiotensin system; angiotensin II receptor antagonists, combinations; angiotensin II receptor antagonists, other combinations

Pharmacological Action

The drug Amlodipine + Valsartan + Hydrochlorothiazide Canon is a combination of three antihypertensive components with complementary mechanisms for controlling blood pressure in patients with essential arterial hypertension: Amlodipine (a dihydropyridine derivative) – a slow calcium channel blocker (CCB), Valsartan – an angiotensin II receptor antagonist (ARB), and Hydrochlorothiazide – a thiazide diuretic. The combination of these components leads to a more pronounced reduction in blood pressure compared to monotherapy with each drug.

Mechanism of action and pharmacodynamic effects

Amlodipine

Amlodipine, which is part of the drug Amlodipine + Valsartan + Hydrochlorothiazide Canon, inhibits the transmembrane influx of calcium ions into cardiomyocytes and vascular smooth muscle cells. The mechanism of the antihypertensive action of amlodipine is associated with a direct relaxing effect on vascular smooth muscle fibers, causing a decrease in total peripheral vascular resistance and a reduction in blood pressure. Experimental data show that Amlodipine binds to both dihydropyridine and non-dihydropyridine active sites of the receptor. The mechanism of myocardial and vascular smooth muscle contraction depends on the influx of calcium ions from the extracellular space through specific ion channels. When taken at therapeutic doses in patients with arterial hypertension (AH), Amlodipine causes vasodilation, leading to a reduction in blood pressure (in both standing and lying positions). The decrease in blood pressure is not accompanied by a significant change in heart rate or catecholamine activity during long-term use.

Plasma concentration correlates with the effect in both young and elderly patients.

In hypertension in patients with normal renal function, Amlodipine at therapeutic doses leads to a reduction in renal vascular resistance, an increase in glomerular filtration rate and effective renal plasma flow without changing the filtration fraction or the severity of proteinuria.

As with the use of other CCBs, during amlodipine administration in patients with normal left ventricular (LV) function, changes in hemodynamic parameters of heart function were observed at rest and during exercise: a slight increase in cardiac index without significant effect on the maximum rate of LV pressure rise, end-diastolic pressure and volume. Hemodynamic studies in intact animals and healthy volunteers have shown that the reduction in blood pressure under the influence of amlodipine in the therapeutic dose range is not accompanied by a negative inotropic effect, even with simultaneous use of beta-blockers in humans.

Amlodipine does not alter sinoatrial node function and does not affect atrioventricular conduction in intact animals and healthy volunteers. When amlodipine is used in combination with beta-blockers in patients with hypertension or angina, the reduction in blood pressure is not accompanied by undesirable changes in ECG parameters.

The clinical efficacy of amlodipine has been proven in patients with stable angina, vasospastic angina, and angiographically confirmed coronary artery disease.

Valsartan

Valsartan is an active and specific oral ARB. It acts selectively on the AT₁ receptor subtype, which is responsible for the known effects of angiotensin II. The increase in plasma concentration of unbound angiotensin II due to blockade of AT₁ receptors under the influence of valsartan may stimulate the unblocked AT₂ receptors, which counteract the effects of AT₁ receptor stimulation. Valsartan has no significant agonistic activity towards AT₁ receptors. The affinity of valsartan for AT₁ subtype receptors is approximately 20,000 times higher than for AT₂ subtype receptors.

Valsartan does not inhibit ACE, also known as kininase II, which converts angiotensin I to angiotensin II and causes the breakdown of bradykinin. Since ARB use does not involve ACE inhibition and the accumulation of bradykinin or substance P, the development of dry cough is unlikely. In comparative clinical studies of valsartan with an ACE inhibitor, the incidence of dry cough was significantly lower (p<0.05) in patients receiving Valsartan (in 2.6% of patients receiving Valsartan, and in 7.9% receiving an ACE inhibitor). In a clinical study, the incidence of dry cough with valsartan or a thiazide diuretic in patients with dry cough during prior ACE inhibitor therapy was 19.5% and 19.0%, respectively, compared to 68.5% of patients who received an ACE inhibitor.

Valsartan does not interact with or block receptors of other hormones or ion channels that are important for the regulation of cardiovascular functions.

The reduction in blood pressure during valsartan therapy in patients with AH is not accompanied by a change in heart rate.

In most patients, the antihypertensive effect after a single oral dose of valsartan develops within 2 hours, with the maximum effect achieved within 4-6 hours. The duration of the antihypertensive effect is 24 hours. With repeated use, the maximum reduction in blood pressure, regardless of the dose taken, is usually achieved within 2-4 weeks and is maintained at the achieved level during long-term therapy. Abrupt discontinuation of valsartan is not accompanied by a sharp increase in blood pressure or other adverse clinical consequences. The use of valsartan in patients with chronic heart failure (NYHA functional class II-IV) leads to a significant reduction in the number of hospitalizations for cardiovascular diseases (which is especially pronounced in patients not receiving ACE inhibitors or beta-blockers).

In patients with clinically stable left ventricular failure or impaired LV function after myocardial infarction, valsartan therapy leads to a reduction in cardiovascular mortality.

Hydrochlorothiazide

The site of action of thiazide diuretics is the distal convoluted renal tubules. When thiazide diuretics act on the highly sensitive receptors of the distal tubules of the renal cortex, the reabsorption of sodium (Na+) and chloride (Cl^–) ions is suppressed. The suppression of the Na+ and Cl^– co-transport system apparently occurs due to competition for Cl^– ion binding sites in this system. As a result, the excretion of Na+ and Cl^– ions increases approximately equally. As a result of the diuretic action, a decrease in circulating plasma volume is observed, which consequently increases renin activity, aldosterone secretion, renal potassium excretion, and therefore a decrease in serum potassium levels.

Preclinical study data

Amlodipine

No teratogenicity or embryofetal toxicity was observed with oral administration of amlodipine maleate at a dose of 10 mg/kg/day in pregnant rats and rabbits during the main periods of organogenesis. However, the litter size was significantly reduced (by approximately 50%), and the frequency of intrauterine death of offspring increased (approximately 5 times). At the indicated doses, Amlodipine also increased the duration of gestation and labor in rats.

Valsartan and Amlodipine

In a study of embryofetal development in rats using oral amlodipine and valsartan at daily doses of 5 + 80 mg/kg, 10 + 160 mg/kg and 20 + 320 mg/kg, effects on both the mother and fetus were noted at high doses (developmental delays and abnormalities were noted against a background of significant maternal toxicity). The dose not accompanied by adverse effects on embryofetal development is 10 mg + 160 mg of amlodipine and valsartan per day, respectively. These doses are 4.3 and 2.7 times higher than the systemic exposure in humans when using the maximum recommended daily dose (10 mg + 320 mg for a patient weighing 60 kg).

Valsartan

In studies of embryofetal development in mice, rabbits, and rats, fetotoxicity was observed, which was associated with maternal toxicity in rats when valsartan was used at a daily dose of 600 mg/kg/day, which is approximately 18 times the maximum recommended daily dose for humans based on mg/kg body weight (calculation assumes an oral daily dose of 320 mg for a patient weighing 60 kg), and in rabbits when valsartan was used at a daily dose of 10 mg/kg, which is approximately 0.6 times the maximum recommended daily dose for humans based on mg/kg body weight (calculation assumes an oral daily dose of 320 mg for a patient weighing 60 kg). No maternal toxicity or fetotoxicity was observed in mice at daily doses up to 600 mg/kg, which is approximately 9 times the maximum recommended daily dose for humans based on mg/kg body weight (calculation assumes an oral daily dose of 320 mg for a patient weighing 60 kg).

Hydrochlorothiazide

No teratogenicity or effect of hydrochlorothiazide on fertility and fertilization was noted. In a study in 3 animal species that received Hydrochlorothiazide orally at doses at least 10 times the maximum recommended human dose (~1 mg/kg), no teratogenic potential was found. In rats, no dose-dependent fetotoxicity was observed with oral administration at doses of 0, 100, 300, and 1000 mg/kg. The lag in weight gain in suckling rat pups was due to high doses and the diuretic effect of hydrochlorothiazide and the corresponding effect on milk production.

Pharmacokinetics

Amlodipine

Absorption

After oral administration at therapeutic doses, the C_max of amlodipine in plasma is reached in 6-12 hours. The absolute bioavailability averages 64-80%. Food intake does not affect the bioavailability of amlodipine.

Distribution

The V_d is approximately 21 L/kg. In in vitro studies with amlodipine, it has been shown that in patients with arterial hypertension, approximately 97.5% of circulating amlodipine is bound to plasma proteins. Amlodipine crosses the placenta and is excreted in breast milk.

Metabolism

Amlodipine is extensively (approximately 90%) metabolized in the liver to form inactive metabolites.

Excretion

Elimination from plasma is biphasic with a T_1/2 of approximately 30 to 50 hours. C_ss in plasma is achieved after prolonged use for 7-8 days. 10% is excreted unchanged, 60% as metabolites.

Valsartan

Absorption

After oral administration, the C_max of valsartan in plasma is reached in 2-4 hours. The mean absolute bioavailability is 23%.

When taken with food, a reduction in bioavailability (by AUC value) of 40% and C_max in plasma of almost 50% is noted, although approximately 8 hours after oral administration of valsartan, the plasma concentration of valsartan in people who took it with food and in the group that received Valsartan on an empty stomach is similar. The reduction in AUC, however, is not accompanied by a clinically significant decrease in therapeutic effect, so Valsartan can be taken regardless of meal time.

Distribution

The V_d of valsartan at steady state after IV administration was about 17 L, indicating no extensive distribution into tissues. Valsartan is highly bound to serum proteins (94-97%), mainly albumin.

Metabolism

Valsartan does not undergo significant metabolism (about 20% of the administered dose is determined as metabolites). The hydroxyl metabolite is detected in plasma at low concentrations (less than 10% of the AUC of valsartan). This metabolite is pharmacologically inactive.

Excretion

The pharmacokinetic curve of valsartan is descending multi-exponential (T_1/2α <1 hour and T_1/2β about 9 hours). Valsartan is excreted mainly unchanged through the intestine (about 83% of the dose) and by the kidneys (about 13% of the dose). After IV administration, the plasma clearance of valsartan is about 2 L/h and its renal clearance is 0.62 L/h (about 30% of total clearance). The T_1/2 is 6 hours.

Hydrochlorothiazide

Absorption

Absorption of hydrochlorothiazide after oral administration is rapid (time to C_max about 2 hours). On average, the increase in AUC is linear and proportional to the dose in the therapeutic range. When taken with food, both increases and decreases in the systemic bioavailability of hydrochlorothiazide have been reported compared to taking the drug on an empty stomach. The magnitude of this effect is small and clinically insignificant. The absolute bioavailability of hydrochlorothiazide after oral administration is 70%.

Distribution

The distribution and elimination kinetics are generally described as a bi-exponential declining function with a T_1/2 of 6-15 hours. With multiple administrations, the kinetics of hydrochlorothiazide do not change and with once-daily administration, accumulation is minimal. The apparent V_d is 4-8 L/kg. 40-70% of hydrochlorothiazide circulating in plasma is bound to plasma proteins, mainly albumin. Hydrochlorothiazide also accumulates in erythrocytes at concentrations approximately 3 times higher than those in plasma.

Metabolism

Hydrochlorothiazide is excreted predominantly unchanged.

Excretion

The T_1/2 of the terminal phase is 6-15 hours. With repeated use of the drug, the kinetics of hydrochlorothiazide do not change, and with once-daily administration, accumulation is minimal. More than 95% of the absorbed dose of hydrochlorothiazide is excreted unchanged by the kidneys.

Amlodipine + Valsartan + Hydrochlorothiazide

After oral administration of the Amlodipine + Valsartan + Hydrochlorothiazide combination in healthy volunteers, the C_max of amlodipine, valsartan, and hydrochlorothiazide is reached at 6-8, 3, and 2 hours, respectively. The rate and extent of absorption of the three active substances from the drug are equivalent to the bioavailability of amlodipine, valsartan, and hydrochlorothiazide when each is taken as separate tablets.

Linearity (non-linearity)

The pharmacokinetic parameters of amlodipine, valsartan, and hydrochlorothiazide are characterized by linearity.

Pharmacokinetics in special patient groups

Renal impairment

In patients with impaired renal function, the pharmacokinetic parameters of amlodipine do not change significantly.

No correlation was found between renal function (determined by GFR) and systemic exposure to valsartan (AUC) in patients with varying degrees of renal impairment. No initial dose adjustment is required in patients with mild to moderate renal impairment.

In renal impairment, the mean C_max in plasma and AUC values of hydrochlorothiazide increase, and the elimination rate decreases. In patients with mild to moderate renal impairment, the T_1/2 almost doubles. The renal clearance of hydrochlorothiazide in patients with renal impairment is significantly reduced compared to normal values (about 300 ml/min).

The drug Amlodipine + Valsartan + Hydrochlorothiazide Canon is contraindicated in patients with severe renal impairment (GFR <30 ml/min/1.73 m²), anuria.

Hepatic impairment

In patients with impaired liver function, the clearance of amlodipine is reduced, leading to an increase in AUC of approximately 40-60%. On average, in patients with mild (Child-Pugh class A) and moderate (Child-Pugh class B) hepatic impairment, the bioavailability (by AUC) of valsartan is doubled compared to healthy volunteers (of corresponding age, sex, and body weight). Since hepatic impairment does not have a clinically significant effect on the pharmacokinetic parameters of hydrochlorothiazide, no dose adjustment is required in patients with hepatic impairment.

The drug Amlodipine + Valsartan + Hydrochlorothiazide Canon is contraindicated in patients with severe hepatic impairment (Child-Pugh class C), biliary cirrhosis and cholestasis; the drug should be used with caution in patients with mild to moderate hepatic impairment.

Elderly patients

The time to reach C_max of amlodipine in blood plasma is the same in young and elderly patients. In elderly patients, the clearance of amlodipine is slightly reduced, leading to an increase in AUC and T_1/2.

In elderly patients, the systemic exposure to valsartan was somewhat more pronounced than in young patients, which, however, is not clinically significant.

There are limited data on the reduction of systemic clearance of hydrochlorothiazide in patients over 65 years of age (healthy volunteers or patients with hypertension) compared to young patients.

Children

The pharmacokinetic features of the use of the drug Amlodipine + Valsartan + Hydrochlorothiazide Kanon in children under 18 years of age have not been established.

Indications

Adults from 18 years

• Grade II and III arterial hypertension.

ICD codes

Dosage Regimen

Take orally, regardless of meals, with a small amount of water.

The recommended daily dose is 1 tablet containing Amlodipine + Valsartan + Hydrochlorothiazide in a fixed combination at a dose of 5 mg + 160 mg + 12.5 mg, 10 mg + 160 mg + 12.5 mg, once daily.

A patient receiving monotherapy with amlodipine, valsartan, and hydrochlorothiazide in separate tablets can be switched to therapy with Amlodipine + Valsartan + Hydrochlorothiazide Kanon containing the same doses of active components; with insufficient blood pressure control on dual combination therapy (Valsartan + Hydrochlorothiazide, Amlodipine + Valsartan and Amlodipine + Hydrochlorothiazide), the patient can be switched to triple combination treatment with Amlodipine + Valsartan + Hydrochlorothiazide Kanon in appropriate doses.

If dose-dependent adverse effects develop during dual combination therapy with any components of the drug, the use of Amlodipine + Valsartan + Hydrochlorothiazide Kanon containing a lower dose of the active substance that caused this adverse effect may be used to achieve comparable blood pressure reduction.

The dose can be increased 2 weeks after the start of therapy.

The maximum antihypertensive effect of Amlodipine + Valsartan + Hydrochlorothiazide Kanon is noted 2 weeks after dose increase.

Special patient groups

Elderly patients

Correction of the initial dose of the drug is not required. In patients of this category, the possibility of using the initial dose of the drug containing the lowest dose of amlodipine, i.e., 1 tablet containing Amlodipine + Valsartan + Hydrochlorothiazide at a dose of 5 mg + 160 mg + 12.5 mg, should be considered.

Patients with impaired renal function

For patients with mild to moderate renal impairment (GFR from ≥30 to ≤90 ml/min/1.73 m²), no initial dose adjustment is required. The drug should not be used in patients with severe renal impairment (GFR <30 ml/min/1.73 m²) due to the presence of hydrochlorothiazide in the drug.

The use of thiazide diuretics in monotherapy in patients with severe renal impairment (GFR <30 ml/min/1.73 m²) is ineffective; however, simultaneous use with “loop” diuretics in patients of this category is possible.

Patients with impaired hepatic function

Due to the presence of amlodipine, valsartan, and hydrochlorothiazide in the composition, Amlodipine + Valsartan + Hydrochlorothiazide Kanon is contraindicated in patients with severe hepatic impairment (class C according to the Child-Pugh classification) and should be used with caution in patients with mild to moderate hepatic impairment (class A and B according to the Child-Pugh classification) and obstructive biliary tract disease. In patients of this category, the possibility of using the initial dose containing the lowest dose of amlodipine, i.e., 1 tablet containing Amlodipine + Valsartan + Hydrochlorothiazide at a dose of 5 mg + 160 mg + 12.5 mg, should be considered.

Children

Since the safety and efficacy of the drug in children and adolescents under 18 years of age have not been established, the drug is not recommended for use in patients of this category.

Adverse Reactions

Summary of the safety profile

The safety profile below is based on data obtained from the simultaneous use of amlodipine, valsartan, and hydrochlorothiazide, as well as during monotherapy with amlodipine, valsartan, and hydrochlorothiazide.

Amlodipine + Valsartan + Hydrochlorothiazide

The safety of the Amlodipine + Valsartan + Hydrochlorothiazide combination at the maximum dose of 10 mg + 320 mg + 25 mg was studied in a trial involving 2271 patients, 582 of whom received Valsartan in combination with hydrochlorothiazide and amlodipine.

No new adverse reactions (AR) were identified with the use of the Amlodipine + Valsartan + Hydrochlorothiazide combination compared to monotherapy with individual components.

No new risks were identified relative to those previously established during long-term therapy with the drug. Good tolerability was noted regardless of gender, age, and race.

With the use of the Amlodipine + Valsartan + Hydrochlorothiazide combination, changes in laboratory parameters were minimal, corresponded to the mechanism of action of each component, and did not differ from those during monotherapy with individual components. Valsartan, which is part of dual and triple combination therapy with hydrochlorothiazide, reduces its hypokalemic effect.

ARs previously registered with the use of each component in monotherapy may occur with the use of the Amlodipine + Valsartan + Hydrochlorothiazide combination, even if they were not registered in clinical trials of this drug.

Tabulated summary of adverse reactions

Adverse reactions are presented in the table according to the affected organ systems and organ classes in the sequence of the Medical Dictionary for Regulatory Activities (MedDRA). The frequency of occurrence was distributed according to the following categories: very common (>1/10), common (>1/100 but <1/10), uncommon (>1/1000 but <1/100), rare (>1/10000 but <1/1000), very rare (<1/10000), frequency unknown (cannot be estimated from the available data).

Description of selected adverse reactions

In clinical trials with the use of valsartan in patients with hypertension, the following adverse events were noted (regardless of their causal relationship with the study drug): insomnia, decreased libido, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, viral infections.

Contraindications

• Hypersensitivity to amlodipine, valsartan, hydrochlorothiazide, other sulfonamide derivatives and dihydropyridines, or to any of the excipients included in the drug;
• Hereditary angioedema or angioedema in patients during previous therapy with an angiotensin II receptor antagonist (ARA II);
• Severe hepatic impairment (class C according to the Child-Pugh scale), biliary cirrhosis and cholestasis;
• Severe renal impairment (GFR <30 ml/min/1.73 m² body surface area), anuria, hemodialysis;
• Hypokalemia, hyponatremia, hypercalcemia refractory to adequate therapy, as well as hyperuricemia with clinical manifestations;
• Severe arterial hypotension (systolic BP <90 mm Hg), collapse, cardiogenic shock;
• left ventricular outflow tract obstruction (including severe aortic stenosis);
• Hemodynamically unstable heart failure after acute myocardial infarction;
• Concomitant use with aliskiren and with drugs containing aliskiren in patients with diabetes mellitus and/or moderate to severe renal impairment (GFR <60 ml/min/1.73 m² body surface area);
• Pregnancy, pregnancy planning (see section “Pregnancy and lactation”);
• Period of breastfeeding (see section “Pregnancy and lactation”).

With caution

• Unilateral or bilateral renal artery stenosis or stenosis of the artery of a solitary kidney;
• Conditions accompanied by a decrease in circulating blood volume (CBV) and disturbances in water and electrolyte balance: salt-losing nephropathy, prerenal (cardiogenic) renal impairment;
• Hypokalemia, hypomagnesemia, hyponatremia, hypochloremia, hypercalcemia;
• Mitral or aortic stenosis, hypertrophic obstructive cardiomyopathy;
• Chronic heart failure (CHF) NYHA functional class III-IV, acute coronary syndrome, condition after recent myocardial infarction;
• Acute myocardial infarction (in the acute period and within 1 month after it), acute coronary syndrome, unstable angina;
• Mild to moderate hepatic impairment (Child-Pugh class A or B), obstructive biliary tract diseases;
• Diabetes mellitus;
• Systemic lupus erythematosus;
• Hyperuricemia;
• Increased concentration of cholesterol and triglycerides;
• History of allergic reaction to penicillin and sulfonamides;
• Status after kidney transplantation;
• Elderly age;
• Concomitant use with potassium-containing dietary supplements, potassium-sparing diuretics and other drugs, salt substitutes, as well as with other drugs that can increase potassium levels;
• Concomitant use with inhibitors or inducers of the CYP3A4 isoenzyme;
• Primary hyperaldosteronism;
• Concomitant use of drugs that can cause polymorphic ventricular tachycardia of the “torsades de pointes” type;
• Gout;
• History of non-melanoma skin cancer (NMSC) (see section “Special precautions”);
• Concomitant use of drugs that can cause hypokalemia, and lithium preparations.

Use in Pregnancy and Lactation

The use of the drug Amlodipine + Valsartan + Hydrochlorothiazide Canon during pregnancy and breastfeeding is contraindicated.

Women of childbearing potential

Like any other drug that has a direct effect on the RAAS, the drug Amlodipine + Valsartan + Hydrochlorothiazide Canon should not be used in women planning pregnancy. When choosing any drug that affects the RAAS, the physician should inform the patient with preserved reproductive potential about the possible risk of using the drug during pregnancy.

Pregnancy

As for any other drug that has a direct effect on the RAAS, the use of the drug Amlodipine + Valsartan + Hydrochlorothiazide Canon during pregnancy is contraindicated.

Given the mechanism of action of ARBs, a risk to the fetus cannot be ruled out.

It is known that the use of ACE inhibitors (a class of specific drugs acting on the RAAS) in the second and third trimesters of pregnancy leads to fetal damage and death. According to a retrospective analysis, the use of ACE inhibitors in the first trimester of pregnancy is associated with a potential risk of fetal malformations. Hydrochlorothiazide crosses the placenta. Cases of spontaneous abortion, oligohydramnios and impaired renal function in newborns have been described with inadvertent use of valsartan by pregnant women.

Data on the use of amlodipine in pregnant women are insufficient to judge its effect on the fetus. In preclinical studies, reproductive toxicity was demonstrated when amlodipine was used in animals at doses 8 times the maximum recommended dose of 10 mg. The potential risk to humans is unknown.

In utero exposure to thiazide diuretics, including Hydrochlorothiazide, is associated with the development of jaundice or thrombocytopenia in the fetus or newborn, and may also be associated with other adverse reactions noted in adults. If pregnancy is diagnosed during treatment with Amlodipine + Valsartan + Hydrochlorothiazide Canon, the drug should be discontinued as soon as possible.

Clinical aspects

Maternal and/or embryofetal risk associated with the disease. Hypertension during pregnancy increases the risk of preeclampsia, gestational diabetes mellitus, preterm birth, as well as complications during childbirth (e.g., the need for cesarean section, development of postpartum hemorrhage). With arterial hypertension, the risk of intrauterine growth retardation and intrauterine fetal death increases.

Fetal/neonatal risk. Oligohydramnios in pregnant women taking drugs affecting the RAAS in the second and third trimesters can lead to deterioration of fetal renal function, resulting in anuria and renal failure, fetal lung hypoplasia, fetal skeletal deformities, including skull bone hypoplasia, arterial hypotension and fetal death.

In case of inadvertent use of ARB drugs during pregnancy, the need for appropriate fetal monitoring should be considered. Newborns whose mothers received ARB therapy should be carefully monitored for the development of arterial hypotension.

Breastfeeding period

It is not known whether Valsartan is excreted in breast milk. Excretion of amlodipine in breast milk has been noted. It is estimated that the infant receives within 3-7%, maximum 15% of the maternal dose. The effect of amlodipine on infants has not been studied. In preclinical studies, excretion of valsartan in the milk of lactating rats was noted. Hydrochlorothiazide is also excreted in breast milk in small amounts. The use of the drug during breastfeeding is contraindicated.

Fertility

There are no data on the effect of amlodipine, valsartan or hydrochlorothiazide on human fertility. In preclinical studies, no effect of amlodipine or valsartan on fertility in rats was noted.

Use in Hepatic Impairment

The drug Amlodipine + Valsartan + Hydrochlorothiazide Canon is contraindicated in patients with severe hepatic impairment (Child-Pugh class C) and should be used with caution in patients with mild to moderate hepatic impairment (Child-Pugh class A and B) and obstructive biliary tract disease.

Use in Renal Impairment

The drug should not be used in patients with severe renal impairment (GFR <30 ml/min/1.73 m²). For patients with mild to moderate renal impairment (GFR from ≥30 to ≤90 ml/min/1.73 m²), no initial dose adjustment is required.

Pediatric Use

Since the safety and efficacy of the drug in children and adolescents under 18 years of age have not been established, the drug is not recommended for use in patients of this category.

Geriatric Use

No initial dose adjustment of the drug is required.

Special Precautions

Sodium deficiency and/or reduced circulating blood volume (CBV)

In controlled studies, when using the drug at the maximum daily dose (10 mg + 320 mg + 25 mg) in patients with grade II and III hypertension, a pronounced decrease in blood pressure, including orthostatic hypotension, was observed in 1.7% of cases (compared with 1.8%, 0.4% and 0.2% against the background of combination therapy with Valsartan + Hydrochlorothiazide at a dose of 320 mg + 25 mg, Amlodipine + Valsartan at a dose of 10 mg + 320 mg and Amlodipine + Hydrochlorothiazide at a dose of 10 mg + 25 mg, respectively).

In patients with a pronounced deficiency of CBV and/or hyponatremia, for example, those receiving high doses of diuretics, in rare cases, symptomatic arterial hypotension may develop at the beginning of therapy with the drug. Before starting treatment with Amlodipine + Valsartan + Hydrochlorothiazide Canon, sodium levels and/or CBV should be corrected or therapy should be started under close medical supervision.

In case of development of arterial hypotension, the patient should be placed with the foot end elevated and, if necessary, intravenous infusion of 0.9% sodium chloride solution should be performed. After blood pressure stabilizes, treatment with Amlodipine + Valsartan + Hydrochlorothiazide Canon can be continued.

Renal impairment

The drug should not be used in patients with severe renal impairment (GFR <30 ml/min/1.73 m²) due to the presence of hydrochlorothiazide in the drug. In patients with chronic kidney disease, thiazide diuretics can cause azotemia. For patients with mild to moderate renal impairment (GFR ≥30 – ≤90 ml/min/1.73 m²), no initial dose adjustment is required. Concomitant use with aliskiren and drugs containing aliskiren in patients with diabetes mellitus and/or moderate or severe renal impairment (GFR <60 ml/min/1.73 m²), with anuria or on dialysis, is contraindicated.

Renal artery stenosis

In patients with unilateral or bilateral renal artery stenosis or stenosis of the artery of a solitary kidney, taking the combination Amlodipine + Valsartan + Hydrochlorothiazide may be accompanied by an increase in serum urea and creatinine concentrations, so the drug Amlodipine + Valsartan + Hydrochlorothiazide Canon should be used with caution in such patients.

There are no data on the use of the drug in patients with a transplanted kidney.

Hepatic impairment

Valsartan is excreted unchanged through the intestines with bile, while Amlodipine undergoes intensive metabolism in the liver. Due to the presence of valsartan, amlodipine and hydrochlorothiazide in the drug, the drug should be used with caution in patients with mild to moderate hepatic impairment (Child-Pugh class A and B) or obstructive biliary tract diseases. The use of the drug in patients with severe hepatic impairment (Child-Pugh class C) is contraindicated.

Angioedema

The occurrence of hypersensitivity reactions while taking hydrochlorothiazide is most likely in patients with a history of allergic reactions and bronchial asthma.

When using valsartan, the development of angioedema, including laryngeal and vocal cord edema, leading to airway obstruction and/or swelling of the face, lips, pharynx and/or tongue, has been noted; in some of these patients, a history of angioedema has been noted when using other drugs, including ACE inhibitors. If angioedema develops, the drug should be discontinued immediately without resuming therapy.

Circulatory failure NYHA functional class III-IV, including after myocardial infarction

In general, in patients with CHF NYHA functional class III-IV, CCBs should be used with caution, as these drugs may increase the risk of cardiovascular complications.

The use of ACE inhibitors or ARBs in cases where renal function depends on the activity of the renin-angiotensin-aldosterone system (RAAS) (e.g., in patients with heart failure) has been associated with the development of oliguria and/or progressive azotemia, and in rare cases has led to acute renal failure and/or death. When assessing the condition of a patient with acute cardiovascular failure or myocardial infarction, the state of renal function must be determined in all cases.

Caution should be exercised when using the drug in patients with heart failure and coronary artery disease, since available data in this population are limited.

Acute myocardial infarction

At the beginning of therapy with amlodipine (or when increasing its dose), exacerbation of angina and development of acute myocardial infarction are possible, especially in patients with severe coronary artery disease.

Aortic and mitral valve stenosis

As with all other vasodilators, caution should be exercised when using the drug in patients with mitral or severe aortic stenosis.

Primary hyperaldosteronism

It is not recommended to prescribe therapy with the drug Amlodipine + Valsartan + Hydrochlorothiazide Canon in patients with primary hyperaldosteronism due to impaired functional state of the RAAS.

Changes in serum electrolyte levels

Amlodipine/Valsartan/Hydrochlorothiazide. Periodic determinations of serum electrolyte levels should be performed at appropriate intervals to detect possible electrolyte imbalance. Periodic determination of serum electrolytes and, in particular, potassium, should be performed at appropriate intervals to detect possible electrolyte imbalance, especially in patients with other risk factors, such as renal impairment, therapy with other drugs, or a history of previous electrolyte imbalance.

Valsartan. When using the drug concomitantly with dietary supplements containing potassium, potassium-sparing diuretics, potassium-containing salt substitutes or with other drugs that can cause hyperkalemia (e.g., heparin), caution should be exercised and regular monitoring of blood potassium levels should be carried out.

Hydrochlorothiazide. Pre-existing hypokalemia and hypomagnesemia should be corrected before starting therapy with thiazide diuretics. Therapy with thiazide diuretics can lead to the development of hypokalemia or worsen pre-existing hypokalemia. Thiazide diuretics should be used with caution in conditions accompanied by potassium loss (e.g., nephropathy, cardiogenic renal impairment). In case of symptomatic hypokalemia (e.g., muscle weakness, paresthesia, ECG changes), the drug should be discontinued. Serum potassium and magnesium levels should be periodically determined. In order to timely detect possible disturbances in water and electrolyte balance during therapy with thiazide diuretics, it is necessary to monitor electrolyte levels (especially potassium) in all patients.

Therapy with thiazide diuretics can lead to the development of hyponatremia, hypochloremic alkalosis or worsen existing hyponatremia. Isolated cases of neurological symptoms in patients with hyponatremia (nausea, progressive disorientation, apathy) have been reported. Therapy with Amlodipine + Valsartan + Hydrochlorothiazide Canon should be started only after correction of previously diagnosed hyponatremia. If hyponatremia develops while taking Amlodipine + Valsartan + Hydrochlorothiazide Canon, therapy should be discontinued until the serum sodium level normalizes.

Regular monitoring of plasma electrolyte levels should be carried out when using the drug Amlodipine + Valsartan + Hydrochlorothiazide Canon.

Systemic lupus erythematosus

When using thiazide diuretics, including Hydrochlorothiazide, exacerbation or activation of the course of systemic lupus erythematosus has been reported.

Other metabolic disorders

Thiazide diuretics, including Hydrochlorothiazide, can cause changes in glucose tolerance, as well as an increase in serum cholesterol and TG concentrations. In patients with diabetes mellitus, dose adjustment of insulin or oral hypoglycemic drugs may be required. Like other diuretics, Hydrochlorothiazide can cause or worsen an increase in serum uric acid levels due to a decrease in its clearance and lead to the development of hyperuricemia, as well as the occurrence of gout symptoms in predisposed patients.

Thiazide diuretics cause a decrease in calcium excretion and, accordingly, a moderate increase in blood calcium levels in the absence of diagnosed calcium metabolism disorders. Hydrochlorothiazide should be used with caution in patients with hypercalcemia. Severe hypercalcemia (>12 mg/dl), not resolved by discontinuation of hydrochlorothiazide, may be a sign of a latent mechanism of hypercalcemia development not associated with the use of hydrochlorothiazide. Pathological changes in the parathyroid glands have been noted in some patients with hypercalcemia and hypophosphatemia receiving long-term therapy with thiazide diuretics. If hypercalcemia is detected, additional examinations are required to clarify the diagnosis.

Photosensitivity

Cases of photosensitivity reactions have been reported with the use of thiazide diuretics. If photosensitivity occurs while taking Amlodipine + Valsartan + Hydrochlorothiazide Canon, treatment should be discontinued. If continuation of diuretic intake is necessary, the skin should be protected from exposure to sunlight or artificial ultraviolet rays.

Choroidal effusion/acute myopia/acute angle-closure glaucoma

Thiazide and thiazide-like diuretics can cause an idiosyncratic reaction leading to the development of choroidal effusion with visual field impairment, acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and usually occur within several hours or weeks after starting the drug. If left untreated, an acute attack of angle-closure glaucoma can lead to permanent vision loss. First of all, it is necessary to discontinue the drug as soon as possible. If IOP remains uncontrolled, emergency medical treatment or surgery may be required. A risk factor for the development of an acute attack of angle-closure glaucoma is a history of allergic reactions to thiazide-like diuretics and penicillins.

Use in patients over 65 years of age

Therapy in patients over 65 years of age should be carried out with caution, including more frequent blood pressure monitoring, since available data in this population are limited.

Non-melanoma skin cancer

In two epidemiological studies using data from the Danish National Cancer Registry, an increased risk of non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma of the skin) was noted with increasing cumulative dose of hydrochlorothiazide exposure. The risk of non-melanoma skin cancer increases with long-term use of hydrochlorothiazide, the potential mechanism of which may be the photosensitizing effect of hydrochlorothiazide.

Patients taking Hydrochlorothiazide should be informed about the risk of non-melanoma skin cancer and recommended to regularly examine the skin for the appearance of new formations, as well as to promptly report the appearance of suspicious skin lesions. To reduce the risk of skin cancer, the patient should be recommended preventive measures, such as limiting exposure to sunlight and adequate sun protection. Suspicious skin lesions should be examined immediately, possibly including histological examination of a biopsy. The possibility of using hydrochlorothiazide in patients with a history of non-melanoma skin cancer should be reconsidered (see section “Adverse reactions”). Based on available data from epidemiological studies, an association has been noted between the cumulative dose of hydrochlorothiazide and non-melanoma skin cancer. One study included 71,533 cases of basal cell carcinoma and 8,629 cases of squamous cell carcinoma of the skin, matched with 1,430,833 and 172,462 control subjects in the population, respectively. A high cumulative dose of hydrochlorothiazide (≥50,000 mg) was associated with an adjusted risk ratio (RR) for basal cell carcinoma of 1.29 (95% confidence interval (CI): 1.23-1.35) and 3.98 (95% CI: 3.68-4.31) for squamous cell carcinoma of the skin. A clear dose-effect relationship was noted for both basal cell carcinoma and squamous cell carcinoma of the skin. Another study using a case-control design showed a possible association between lip cancer (squamous cell carcinoma of the skin) and exposure to hydrochlorothiazide: 633 cases of lip cancer matched with 63,067 control subjects in the population. A clear dose-effect relationship was noted with an adjusted RR of 2.1 (95% CI: 1.7-2.6), which increased to 3.9 (95% CI: 3.0-4.9) for high doses (~25,000 mg), and 7.7 (95% CI: 5.7-10.5) for the highest cumulative dose (~100,000 mg). For example, a cumulative dose of 100,000 mg corresponds to >10 years of daily use at the established daily dose of 25 mg (see section “Adverse reactions”).

Dual blockade of the RAAS with ARB, ACE inhibitor, or aliskiren use

Concomitant use of angiotensin II receptor antagonists with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR <60 ml/min/1.73 m² body surface area) and is not recommended in other patients. Simultaneous therapy with ACE inhibitors and ARBs should not be conducted in patients with diabetic nephropathy and is not recommended in other patients.

Other

The drug should be used with caution in patients with previously established cases of hypersensitivity to other angiotensin II receptor antagonists.

Influence on the ability to drive vehicles and machinery

Some side effects of the drug, including dizziness or visual disturbances, may adversely affect the ability to drive vehicles and perform potentially hazardous activities requiring increased concentration and speed of psychomotor reactions. Patients taking the drug Amlodipine + Valsartan + Hydrochlorothiazide Canon should exercise caution when driving vehicles and operating machinery.

Overdose

Symptoms

With an overdose of valsartan, pronounced decrease in blood pressure and dizziness can be expected.

Overdose of hydrochlorothiazide is associated with electrolyte depletion (hypokalemia, hypochloremia) and hypovolemia caused by excessive diuresis. The most common signs and symptoms of overdose are nausea and drowsiness. Hypokalemia may lead to muscle spasms and/or exacerbate arrhythmia associated with the concomitant use of cardiac glycosides or certain antiarrhythmic drugs.

Treatment

In case of clinically significant arterial hypotension due to amlodipine overdose, active measures to support the cardiovascular system are necessary, including frequent monitoring of cardiovascular and respiratory functions, positioning with elevated legs, and careful monitoring of circulating blood volume and diuresis.

If there are no contraindications, a vasoconstrictor may be used (with caution) to restore vascular tone and blood pressure. If the drug was taken recently, induction of vomiting or gastric lavage should be considered. Administration of activated charcoal to healthy volunteers immediately after or within 2 hours of amlodipine intake significantly reduced its absorption. Intravenous administration of calcium gluconate may be effective in counteracting the effects of calcium channel blockade.

The degree of removal of hydrochlorothiazide by hemodialysis has not been established.

Valsartan and Amlodipine are not removed by hemodialysis, whereas hemodialysis may be effective for removing hydrochlorothiazide.

Drug Interactions

General drug interactions for valsartan and/or hydrochlorothiazide

Lithium preparations

Concomitant use of lithium preparations with ACE inhibitors, ARBs, or thiazide diuretics has been associated with a reversible increase in serum lithium concentrations and related increased toxic manifestations. The risk of toxic manifestations associated with lithium use may be further increased with concomitant use of the drug Amlodipine + Valsartan + Hydrochlorothiazide Canon, as the renal clearance of lithium is slowed by thiazide diuretics. Therefore, careful monitoring of serum lithium levels is recommended in case of concomitant use.

Amlodipine

Simvastatin

Multiple concomitant administration of simvastatin 80 mg/day and amlodipine 10 mg/day leads to a 77% increase in simvastatin exposure. It is recommended to reduce the simvastatin dose to 20 mg/day in patients taking Amlodipine.

CYP3A4 isoenzyme inhibitors

Concomitant use of amlodipine 5 mg/day with diltiazem 180 mg/day in elderly hypertensive patients resulted in a 1.6-fold increase in systemic exposure to amlodipine. When amlodipine is used with potent CYP3A4 isoenzyme inhibitors (e.g., ketoconazole, itraconazole, ritonavir), a more pronounced increase in systemic exposure to amlodipine is possible. Amlodipine should be used with caution with CYP3A4 isoenzyme inhibitors.

Grapefruit juice

Due to inhibition of the CYP3A4 isoenzyme upon concomitant intake with grapefruit juice, amlodipine exposure may increase. However, in a clinical study of 20 healthy volunteers, no significant changes in pharmacokinetics were detected with a single dose of amlodipine 10 mg taken with 240 ml of grapefruit juice.

CYP3A4 isoenzyme inducers (anticonvulsants (e.g., carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone), herbal preparations containing St. John’s wort)

There are no data on the quantitative effect of CYP3A4 isoenzyme inducers on Amlodipine.

The adequacy of the clinical response should be monitored in patients receiving concomitant therapy with amlodipine and a CYP3A4 isoenzyme inducer. Since the use of amlodipine with CYP3A4 isoenzyme inducers (e.g., rifampicin, herbal preparations containing St. John’s wort) may lead to a significant decrease in its plasma concentration, caution should be exercised when using amlodipine with CYP3A4 isoenzyme inducers.

Dantrolene (with intravenous administration)

Ventricular fibrillation and cardiovascular collapse with fatal outcome were observed in animals against the background of hyperkalemia that occurred after verapamil administration and intravenous dantrolene. Due to the risk of hyperkalemia, it is recommended to avoid concomitant use of calcium channel blockers, such as Amlodipine, in patients at risk for malignant hyperthermia.

No clinically significant interaction was observed with amlodipine monotherapy with thiazide diuretics, beta-blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, atorvastatin, sildenafil, aluminum and magnesium hydroxide gel with simethicone, cimetidine, NSAIDs, antibiotics, and oral hypoglycemic drugs.

Ethanol

Concomitant single and multiple administration of amlodipine 10 mg does not affect the pharmacokinetics of the latter.

Valsartan

Dual blockade of the RAAS with ARB, ACE inhibitor, or aliskiren use

Concomitant use of ARBs, including valsartan, with other drugs affecting the RAAS leads to an increased incidence of arterial hypotension, hyperkalemia, and impaired renal function compared to monotherapy.

Dual blockade of the RAAS by simultaneous use of an ACE inhibitor, ARB, or aliskiren is not recommended in the general population. However, if combination therapy with these drugs, including the drug Amlodipine + Valsartan + Hydrochlorothiazide Canon, is absolutely necessary, such use should be under close medical supervision, with frequent monitoring of blood pressure, renal function, and plasma electrolyte levels. Simultaneous therapy with ACE inhibitors and ARBs should not be conducted in patients with diabetic nephropathy and is not recommended in other patients.

Concomitant use of drugs containing ARBs, including the drug Amlodipine + Valsartan + Hydrochlorothiazide Canon, with other agents affecting the RAAS, including aliskiren, is contraindicated in patients with diabetes mellitus and/or moderate or severe renal impairment (GFR <60 ml/min/1.73 m²) and is not recommended in other patients.

Drugs and substances affecting serum potassium levels

Caution should be exercised and serum potassium levels should be regularly monitored when used concomitantly with potassium-containing dietary supplements, potassium-sparing diuretics, eplerenone, potassium-containing salt substitutes, or other drugs that may cause an increase in blood potassium levels (e.g., heparin, etc.).

NSAIDs, including selective COX-2 inhibitors

Use of angiotensin II receptor antagonists concurrently with NSAIDs, including COX-2 inhibitors, may lead to attenuation of the antihypertensive effect of the drug. Moreover, in elderly patients with concomitant hypovolemia (including due to diuretic use) or impaired renal function, concomitant use of ARBs and NSAIDs, including selective COX-2 inhibitors, may lead to deterioration of renal function. In patients taking NSAIDs, monitoring of renal function is recommended upon initiation of concomitant therapy with valsartan or upon dose adjustment.

Transport proteins

According to an in vitro study with human liver tissue, Valsartan is a substrate of the transport protein OATP1B1 and MRP2. Concomitant use of valsartan with inhibitors of the transport protein OATP1B1 (rifampicin, cyclosporine) and with an inhibitor of the transport protein MRP2 (ritonavir) may lead to increased systemic exposure to valsartan. It has been established that with valsartan monotherapy, there is no clinically significant interaction with the following drugs: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide.

Hydrochlorothiazide

The following drug reactions, due to hydrochlorothiazide, may develop when using the drug.

Other antihypertensive drugs

Thiazide diuretics enhance the antihypertensive effect of other antihypertensive drugs (including guanethidine, methyldopa, beta-blockers, vasodilators, CCBs, ACE inhibitors, ARBs, direct renin inhibitors).

Beta-blockers

Concomitant use with thiazide diuretics may increase the risk of hyperglycemia.

Curare-like muscle relaxants

Thiazide diuretics, including Hydrochlorothiazide, potentiate the action of curare-like muscle relaxants (e.g., tubocurarine chloride).

Drugs affecting serum potassium levels

The risk of hypokalemia increases with concomitant use of other diuretics, corticosteroids, ACTH, amphotericin B, carbenoxolone, penicillin, acetylsalicylic acid derivatives (in doses >3 g), laxatives, as well as antiarrhythmic drugs. Careful monitoring of serum potassium levels is necessary when these drugs are used concomitantly with thiazide diuretics.

Drugs affecting blood sodium levels

The hyponatremic effect caused by diuretics may be enhanced by concomitant use with antidepressants, antipsychotics, anticonvulsants, etc. Caution should be exercised with long-term concomitant use of the drug Amlodipine + Valsartan + Hydrochlorothiazide Canon with the aforementioned drugs.

Hypoglycemic agents

Use of hydrochlorothiazide is associated with altered glucose tolerance, therefore, in patients with diabetes mellitus, dose adjustment of insulin and oral hypoglycemic agents may be required. Since lactic acidosis may develop with the use of hydrochlorothiazide with metformin (due to impaired renal function during hydrochlorothiazide therapy), caution should be exercised when using the drug Amlodipine + Valsartan + Hydrochlorothiazide Canon in patients receiving metformin treatment.

Cardiac glycosides

Hypokalemia and hypomagnesemia (adverse effects of thiazide diuretics) may contribute to the development of cardiac arrhythmias in patients receiving cardiac glycosides.

NSAIDs, including selective COX-2 inhibitors

Reduction of the diuretic and antihypertensive effect of the thiazide component of the drug is possible with concomitant use with NSAIDs, including selective COX-2 inhibitors, for example, with salicylic acid derivatives, indomethacin. Concomitant hypovolemia may lead to the development of acute renal failure.

Amantadine

Concomitant use with thiazide diuretics (including Hydrochlorothiazide) may increase the side effects of amantadine.

Antineoplastic drugs

Concomitant use of thiazide diuretics (including hydrochlorothiazide) may reduce the renal excretion of cytotoxic agents and enhance their myelosuppressive effect.

Anticholinergic agents H- and M-cholinoblockers

H- and M-cholinoblockers (including atropine, biperiden) may increase the bioavailability of hydrochlorothiazide, which is apparently associated with slowed gastrointestinal motility and gastric emptying rate. Accordingly, gastrointestinal motility stimulants (cisapride) may reduce the bioavailability of hydrochlorothiazide.

Anion exchange resins

The absorption of thiazide diuretics, including hydrochlorothiazide, is decreased in the presence of cholestyramine and colestipol. However, the following adjustment of the timing of administration of these drugs may reduce the risk of this interaction: Hydrochlorothiazide should be taken at least 4 hours before or 4-6 hours after taking anion exchange resins.

Vitamin D

Concomitant intake of hydrochlorothiazide with vitamin D or calcium salts may contribute to an increase in serum calcium levels.

Cyclosporine

Concomitant use of hydrochlorothiazide and cyclosporine increases the risk of hyperuricemia and the appearance of gout-like symptoms.

Calcium salts

Concomitant use with thiazide diuretics may lead to hypercalcemia due to increased tubular reabsorption of calcium.

Diazoxide

Thiazide diuretics may enhance the hyperglycemic effect of diazoxide.

Methyldopa

Cases of hemolytic anemia have been reported in the literature with concomitant use of hydrochlorothiazide and methyldopa.

Ethanol, barbiturates, and narcotic drugs

Concomitant use with hydrochlorothiazide may contribute to the development of orthostatic hypotension.

Pressor amines

Hydrochlorothiazide may reduce the response to the administration of pressor amines (norepinephrine). The clinical significance of this effect is doubtful and should not preclude concomitant use of the drugs.

Iodinated contrast agents

Dehydration of the body while taking thiazide diuretics increases the risk of acute renal failure, especially when using iodinated contrast agents, fluid loss must be compensated.

Drugs capable of causing polymorphic ventricular tachycardia of the "torsades de pointes" type

Thiazide diuretics should be used with caution together with drugs capable of causing polymorphic ventricular tachycardia of the "torsades de pointes" type, in particular, with class Ia and III antiarrhythmic drugs, and some antipsychotic drugs, due to the risk of hypokalemia.

Drugs used to treat gout (probenecid, sulfinpyrazone, allopurinol)

Dose adjustment of uricosuric drugs may be required, as Hydrochlorothiazide increases serum uric acid concentration. An increase in the dose of probenecid or sulfinpyrazone may be required. Concomitant use with thiazide diuretics (including Hydrochlorothiazide) may increase the risk of hypersensitivity reactions to allopurinol.

Storage Conditions

The drug should be stored in the secondary packaging (cardboard box), at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.