Duopress (Tablets) Instructions for Use

Marketing Authorization Holder

Atoll LLC (Russia)

Manufactured By

Ozon, LLC (Russia)

ATC Code

C09DA03 (Valsartan and diuretics)

Active Substances

Hydrochlorothiazide (Rec.INN registered by WHO)

Valsartan (Rec.INN registered by WHO)

Dosage Forms

	Duopress	Film-coated tablets, 80 mg+12.5 mg: 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 150, 160, 180, 200, 210, 240, 270, 300 or 360 pcs.
		Film-coated tablets, 160 mg+12.5 mg: 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 150, 160, 180, 200, 210, 240, 270, 300 or 360 pcs.
		Film-coated tablets, 160 mg+25 mg: 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 150, 160, 180, 200, 210, 240, 270, 300 or 360 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, round, biconvex; a cross-section shows two layers – a white or almost white core and a film coating.

	1 tab.
Valsartan	80 mg
Hydrochlorothiazide	12.5 mg

Excipients: microcrystalline cellulose 71.2 mg, croscarmellose sodium 7 mg, povidone 5 mg, colloidal silicon dioxide 2.7 mg, magnesium stearate 1.6 mg.

Film coating composition: hypromellose 2.85 mg, macrogol-4000 0.75 mg, titanium dioxide 1.4 mg.

10 pcs. – contour cell packaging (aluminum/PVC) (1) – cardboard packs.
10 pcs. – contour cell packaging (aluminum/PVC) (2) – cardboard packs.
10 pcs. – contour cell packaging (aluminum/PVC) (3) – cardboard packs.
10 pcs. – contour cell packaging (aluminum/PVC) (4) – cardboard packs.
10 pcs. – contour cell packaging (aluminum/PVC) (5) – cardboard packs.
10 pcs. – contour cell packaging (aluminum/PVC) (6) – cardboard packs.
10 pcs. – contour cell packaging (aluminum/PVC) (7) – cardboard packs.
10 pcs. – contour cell packaging (aluminum/PVC) (8) – cardboard packs.
10 pcs. – contour cell packaging (aluminum/PVC) (9) – cardboard packs.
10 pcs. – contour cell packaging (aluminum/PVC) (10) – cardboard packs.
10 pcs. – contour cell packaging (aluminum/PVC) (12) – cardboard packs.
20 pcs. – contour cell packaging (aluminum/PVC) (1) – cardboard packs.
20 pcs. – contour cell packaging (aluminum/PVC) (2) – cardboard packs.
20 pcs. – contour cell packaging (aluminum/PVC) (3) – cardboard packs.
20 pcs. – contour cell packaging (aluminum/PVC) (4) – cardboard packs.
20 pcs. – contour cell packaging (aluminum/PVC) (5) – cardboard packs.
20 pcs. – contour cell packaging (aluminum/PVC) (6) – cardboard packs.
20 pcs. – contour cell packaging (aluminum/PVC) (7) – cardboard packs.
20 pcs. – contour cell packaging (aluminum/PVC) (8) – cardboard packs.
20 pcs. – contour cell packaging (aluminum/PVC) (9) – cardboard packs.
20 pcs. – contour cell packaging (aluminum/PVC) (10) – cardboard packs.
20 pcs. – contour cell packaging (aluminum/PVC) (12) – cardboard packs.
30 pcs. – contour cell packaging (aluminum/PVC) (1) – cardboard packs.
30 pcs. – contour cell packaging (aluminum/PVC) (2) – cardboard packs.
30 pcs. – contour cell packaging (aluminum/PVC) (3) – cardboard packs.
30 pcs. – contour cell packaging (aluminum/PVC) (4) – cardboard packs.
30 pcs. – contour cell packaging (aluminum/PVC) (5) – cardboard packs.
30 pcs. – contour cell packaging (aluminum/PVC) (6) – cardboard packs.
30 pcs. – contour cell packaging (aluminum/PVC) (7) – cardboard packs.
30 pcs. – contour cell packaging (aluminum/PVC) (8) – cardboard packs.
30 pcs. – contour cell packaging (aluminum/PVC) (9) – cardboard packs.
30 pcs. – contour cell packaging (aluminum/PVC) (10) – cardboard packs.
30 pcs. – contour cell packaging (aluminum/PVC) (12) – cardboard packs.
10 pcs. – polypropylene jars (1) – cardboard packs.
20 pcs. – polypropylene jars (1) – cardboard packs.
30 pcs. – polypropylene jars (1) – cardboard packs.
40 pcs. – polypropylene jars (1) – cardboard packs.
50 pcs. – polypropylene jars (1) – cardboard packs.
60 pcs. – polypropylene jars (1) – cardboard packs.
70 pcs. – polypropylene jars (1) – cardboard packs.
80 pcs. – polypropylene jars (1) – cardboard packs.
90 pcs. – polypropylene jars (1) – cardboard packs.
100 pcs. – polypropylene jars (1) – cardboard packs.
120 pcs. – polypropylene jars (1) – cardboard packs.
180 pcs. – polypropylene jars (1) – cardboard packs.

Film-coated tablets from pink to light pink, round, biconvex; a cross-section shows two layers – a white or almost white core and a film coating.

	1 tab.
Valsartan	160 mg
Hydrochlorothiazide	12.5 mg

Excipients: microcrystalline cellulose 154.9 mg, croscarmellose sodium 14 mg, povidone 10 mg, colloidal silicon dioxide 5.4 mg, magnesium stearate 3.2 mg.

Film coating composition: hypromellose 5.7 mg, macrogol-4000 1.5 mg, iron oxide red dye 0.1 mg, titanium dioxide 2.7 mg.

Film-coated tablets white or almost white, round, biconvex; a cross-section shows two layers – a white or almost white core and a film coating.

	1 tab.
Valsartan	160 mg
Hydrochlorothiazide	25 mg

Excipients: microcrystalline cellulose 142.4 mg, croscarmellose sodium 14 mg, povidone 10 mg, colloidal silicon dioxide 5.4 mg, magnesium stearate 3.2 mg.

Film coating composition: hypromellose 5.7 mg, macrogol-4000 1.5 mg, titanium dioxide 2.8 mg.

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Antihypertensive combination agent (angiotensin II receptor blocker + diuretic)

Pharmacological Action

Duopress is an antihypertensive combination drug containing an angiotensin II receptor antagonist and a thiazide diuretic.

Valsartan

Valsartan is a selective, non-protein angiotensin II receptor antagonist for oral administration.

It exerts selective antagonistic action on AT₁ subtype receptors. The consequence of AT₁ receptor blockade is an increase in plasma angiotensin II concentration, which may stimulate the unblocked AT₂ subtype receptors, thereby balancing the effects associated with AT₁ receptor stimulation. Valsartan does not exhibit agonist activity towards AT₁ receptors. Its affinity for AT₁ subtype receptors is approximately 20,000 times greater than for AT₂ subtype receptors. Valsartan does not inhibit ACE, also known as kininase II, which converts angiotensin I to angiotensin II and degrades bradykinin. Due to the lack of effect on ACE, the effects of bradykinin and substance P are not potentiated, so the development of dry cough is unlikely when taking angiotensin II receptor antagonists. Valsartan does not interact with or block receptors of other hormones or ion channels involved in the regulation of cardiovascular function. In the treatment of arterial hypertension, Valsartan reduces blood pressure without affecting heart rate. After a single oral dose of valsartan, the antihypertensive effect develops within 2 hours, and the maximum reduction in blood pressure is achieved within 4-6 hours. The antihypertensive effect of valsartan persists for 24 hours. With repeated administration of valsartan, the maximum reduction in blood pressure, regardless of dose, is achieved after 2-4 weeks and is maintained at the achieved level during long-term therapy. Combination with hydrochlorothiazide allows for a significant additional reduction in blood pressure. Sudden discontinuation of valsartan is not accompanied by a withdrawal syndrome.

Hydrochlorothiazide

A thiazide diuretic, whose diuretic effect is associated with impaired reabsorption of sodium, chloride, potassium, magnesium ions, and water in the distal part of the nephron; delays the excretion of calcium ions and uric acid. It has an antihypertensive action, which is due to the dilation of arterioles. It has almost no effect on normal blood pressure levels. The diuretic effect develops 1-2 hours after oral administration of the drug, reaches a maximum after 4 hours, and persists for 6-12 hours. The antihypertensive effect occurs after 3-4 days, but 3-4 weeks may be required to achieve the optimal therapeutic effect.

Pharmacokinetics

Valsartan

Valsartan is rapidly absorbed after oral administration, but the extent of absorption varies widely. The mean absolute bioavailability of valsartan is 23%. The time to reach maximum concentration (T_max) is 2 hours. When the drug is taken orally once daily, its accumulation is insignificant. Plasma concentrations of valsartan are the same in men and women. Valsartan is highly bound to serum proteins (94-97%), primarily serum albumin. The equilibrium volume of distribution of the drug is small, about 17 L. Plasma clearance is relatively low (approximately 2 L/h) compared to hepatic blood flow (approximately 30 L/h).

It is metabolized by the CYP2C9 isoenzyme. Valsartan does not undergo significant biotransformation; only about 20% of the dose is excreted as metabolites. Valeryl-4-hydroxy Valsartan is detected in plasma at low concentrations (less than 10% of the area under the concentration-time curve (AUC)). This metabolite is pharmacologically inactive.

The half-life (T_1/2) is 9 hours. It is excreted predominantly unchanged via the intestines (about 83%) and kidneys (about 13%). When valsartan is taken with food, the area under the concentration-time curve (AUC) decreases by 48%. However, 8 hours after administration, plasma concentrations of valsartan taken on an empty stomach or with food are the same. The decrease in AUC is not accompanied by a clinically significant reduction in the therapeutic effect of valsartan, so the drug can be taken regardless of meals.

Hydrochlorothiazide

After oral administration, the absorption of hydrochlorothiazide is 60-80%. The maximum concentration (C_max) of hydrochlorothiazide in the blood is reached 2 hours after oral administration. Binding to plasma proteins is 40-70%. Hydrochlorothiazide also accumulates in erythrocytes at a concentration approximately 3 times higher than in plasma.

Hydrochlorothiazide is not metabolized and is rapidly excreted by the kidneys (more than 95%). T_1/2 is 6-15 hours.

Valsartan/Hydrochlorothiazide

When used concomitantly with valsartan, the systemic bioavailability of hydrochlorothiazide is reduced by approximately 30%. Concomitant intake of hydrochlorothiazide, in turn, does not significantly affect the kinetics of valsartan. The noted interaction does not affect the efficacy of the simultaneous use of valsartan and hydrochlorothiazide. Clinical studies have shown a distinct antihypertensive effect of this combination, which exceeded the effect of each component separately.

Special patient groups

Patients with renal impairment

Given that renal clearance accounts for only 30% of total clearance, no dose adjustment is required in patients with renal impairment. There are currently no data on the use of the drug in patients with severe renal impairment (creatinine clearance less than 30 ml/min) and in patients on hemodialysis.

Since the degree of binding of valsartan to plasma proteins is high, its removal by hemodialysis is unlikely. At the same time, hemodialysis effectively removes Hydrochlorothiazide from the body. In the presence of renal impairment, mean peak plasma concentrations and AUC values of hydrochlorothiazide increase, and the excretion rate decreases. In patients with mild to moderate renal impairment, T_1/2 is almost doubled.

Patients with hepatic impairment

The AUC of valsartan in patients with mild (5-6 points on the Child-Pugh scale) and moderate (7-9 points on the Child-Pugh scale) hepatic impairment is twice that in healthy volunteers. There are currently no data on the use of the drug in patients with severe hepatic impairment (more than 9 points on the Child-Pugh scale). Since hepatic impairment does not have a clinically significant effect on the pharmacokinetics of hydrochlorothiazide, no dose adjustment is required in patients with hepatic impairment. The use of the drug is contraindicated in patients with severe hepatic impairment. The drug should be used with caution in patients with biliary obstruction.

Elderly patients

In some elderly patients, the AUC of valsartan was somewhat higher than in younger patients, but this is not clinically significant. In elderly patients (both without arterial hypertension and with arterial hypertension), the systemic clearance of hydrochlorothiazide is lower than in healthy young volunteers.

Indications

Arterial hypertension (in patients for whom combination therapy is indicated).

ICD codes

Open the list of ICD codes

ICD-10 code	Indication
I10	Essential [primary] hypertension

ICD-11 code	Indication
BA00.Z	Essential hypertension, unspecified

Dosage Regimen

The method of application and dosage regimen for a specific drug depend on its form of release and other factors. The optimal dosage regimen is determined by the doctor. It is necessary to strictly adhere to the compliance of the dosage form of a specific drug with the indications for use and dosage regimen.

Before starting therapy with Duopress, water and electrolyte imbalances should be corrected (see sections “With caution” and “Special precautions”).

Orally, regardless of meal time, frequency of administration – once a day. The tablet should be swallowed whole with liquid.

Depending on the clinical situation, the recommended daily dose of the drug is 1 tablet of Duopress containing Valsartan/Hydrochlorothiazide in a dose of 80 mg+12.5 mg, 160 mg+12.5 mg or a maximum of 160 mg+25 mg. The maximum antihypertensive effect of Duopress develops within 2-4 weeks of therapy.

For patients with impaired renal function (creatinine clearance more than 30 ml/min (0.5 ml/sec)), no dose adjustment of the drug is required.

Duopress is not recommended for patients with severe hepatic impairment (more than 9 points on the Child-Pugh scale).

In patients with mild or moderate hepatic impairment without concomitant cholestasis, the dose of valsartan should not exceed 80 mg.

Adverse Reactions

Classification of the frequency of side effects by the World Health Organization (WHO): very common > 1/10; common from > 1/100 to < 1/50; uncommon from > 1/1000 to < 1/100; rare from > 1/10000 to < 1/1000; very rare < 1/10000, including isolated reports; frequency unknown (insufficient data to estimate frequency)

Adverse events were generally mild and transient in nature.

From the central and peripheral nervous system: common – headache; uncommon – paresthesia, increased fatigue; very rare – dizziness; frequency unknown – syncope.

From the respiratory system: uncommon – cough; frequency unknown – non-cardiogenic pulmonary edema.

From the cardiovascular system: uncommon – pronounced decrease in blood pressure, peripheral edema.

From the digestive tract: uncommon – nausea; very rare – diarrhea.

From the musculoskeletal system: uncommon – myalgia; very rare – arthralgia.

From the genitourinary system: frequency unknown – impaired renal function.

Laboratory parameters: frequency unknown – increased serum uric acid concentration, increased serum bilirubin and creatinine concentration, hypokalemia, hyponatremia, neutropenia, increased blood urea nitrogen concentration.

From metabolism: uncommon – dehydration.

From the organ of vision: uncommon – decreased visual acuity.

From the organ of hearing: uncommon – tinnitus.

The following adverse events were observed in patients with arterial hypertension without an obvious connection to drug intake: abdominal pain, anxiety, arthritis, asthenia, back pain, bronchitis (including acute), chest pain, postural dizziness, dyspepsia, shortness of breath, dry oral mucosa, epistaxis, erectile dysfunction, gastroenteritis, headache, increased sweating, hypoesthesia, influenza-like condition, insomnia, ligament sprain, muscle cramps, muscle hypertonia, nasal congestion, nasopharyngitis, nausea, neck pain, peripheral edema, otitis media, limb pain, palpitations, laryngeal and pharyngeal pain, pyrexia, pollakiuria, hyperthermia, sinusitis, somnolence, upper respiratory tract infections, urinary tract infection, vertigo, viral infections, visual impairment.

The following are adverse events associated with the use of each component separately.

Valsartan

From the blood system: frequency unknown – decreased hemoglobin, hematocrit, thrombocytopenia.

From the immune system: frequency unknown – hypersensitivity/allergic reactions, including serum sickness.

From metabolism: frequency unknown – increased serum potassium.

From the organ of hearing: uncommon – vertigo.

From the cardiovascular system: frequency unknown – vasculitis.

From the liver and biliary tract: frequency unknown – increased activity of “liver” transaminases.

From the skin: frequency unknown – angioedema, skin rash, pruritus.

From the kidneys and urinary tract: frequency unknown – renal failure.

The following adverse events were observed during clinical trials of valsartan in patients with arterial hypertension regardless of their causal relationship to the drug: arthralgia, asthenia, back pain, diarrhea, dizziness, headache, insomnia, decreased libido, nausea, edema, pharyngitis, rhinitis, sinusitis, upper respiratory tract infections, viral infections.

Hydrochlorothiazide

From metabolism: very common – increased plasma lipid concentration (especially against the background of high doses of hydrochlorothiazide), common – hypomagnesemia and hyperuricemia, rare – hypercalcemia, hyperglycemia, glucosuria and worsening of diabetes mellitus, very rare – hypochloremic alkalosis.

From the blood system: rare – thrombocytopenia, sometimes in combination with purpura, very rare – agranulocytosis, bone marrow depression, hemolytic anemia, leukopenia, frequency unknown – aplastic anemia.

From the immune system: very rare – hypersensitivity reactions.

From the psyche: rare – sleep disorders, depression.

From the nervous system: rare – headache, paresthesia, dizziness.

From the cardiovascular system: common – orthostatic hypotension (may be enhanced by alcohol, sedatives or analgesics), rare – arrhythmias.

From the respiratory system: very rare – respiratory distress syndrome, including pulmonary edema and pneumonitis.

From the digestive system: common – decreased appetite, moderately severe nausea, vomiting; rare – abdominal discomfort, constipation, diarrhea; very rare – pancreatitis.

From the liver and biliary tract: rare – intrahepatic cholestasis and jaundice.

From the skin: common – urticaria and other types of skin rash; rare – photosensitivity; very rare – necrotizing vasculitis and toxic epidermal necrolysis, lupus-like reactions, exacerbation of skin manifestations of systemic lupus erythematosus; frequency unknown – erythema multiforme.

From the genital organs and mammary gland: common – impotence.

From the organ of vision: visual impairment (especially in the first few weeks of therapy); frequency unknown – acute attack of angle-closure glaucoma.

From the kidneys and urinary tract: frequency unknown – acute renal failure, impaired renal function.

From the muscular system: frequency unknown – muscle cramps.

Other: frequency unknown – fever, asthenia.

Contraindications

Hypersensitivity to valsartan, hydrochlorothiazide and other sulfonamide derivatives or to other components of the drug;
Pregnancy, pregnancy planning, lactation period;
Severe hepatic impairment (more than 9 points on the Child-Pugh scale);
Anuria, severe renal impairment (creatinine clearance less than 30 ml/min (0.5 ml/sec));
Age under 18 years (efficacy and safety of valsartan in children has not been established);
Concomitant use with aliskiren in patients with type 2 diabetes mellitus.

With caution

Concomitant use of potassium preparations, potassium-sparing diuretics, potassium-containing salt substitutes and other agents that can increase blood potassium levels (e.g., heparin), chronic heart failure of NYHA functional class III-IV, renal failure (creatinine clearance more than 30 ml/min (0.5 ml/sec)), bilateral or unilateral renal artery stenosis or stenosis of the artery of a single kidney, condition after kidney transplantation; conditions accompanied by a decrease in circulating blood volume (CBV) and/or sodium ions (including diarrhea, vomiting, high doses of diuretics); moderately severe hepatic impairment, primary hyperaldosteronism, stenosis of the aortic and mitral valves, hypertrophic obstructive cardiomyopathy (HOCM), systemic lupus erythematosus (SLE), diabetes mellitus, hyperuricemia, hypercholesterolemia and hypertriglyceridemia, obstructive biliary tract diseases and cholestasis, angle-closure glaucoma; conditions accompanied by water and electrolyte imbalances: nephropathy accompanied by salt loss, and prerenal (cardiogenic) renal impairment, in patients with hypokalemia, hypomagnesemia, hyponatremia, hypercalcemia.

Use in Pregnancy and Lactation

Like any other drug affecting the RAAS, Duopress should not be used in women planning pregnancy. When prescribing any drug affecting the RAAS, the physician should inform women of childbearing potential about the potential danger of using these drugs during pregnancy.

The use of Duopress during pregnancy is contraindicated, since, given the mechanism of action of angiotensin II receptor antagonists, the risk to the fetus cannot be excluded. The effect of ACE inhibitors (drugs affecting the RAAS) on the fetus, when prescribed in the second and third trimesters of pregnancy, leads to fetal damage and death. According to retrospective data, the use of ACE inhibitors in the first trimester of pregnancy increases the risk of having children with congenital defects. There are reports of spontaneous abortions, oligohydramnios and impaired renal function in newborns whose mothers unintentionally received Valsartan during pregnancy. Intrauterine administration of thiazide diuretics, including Hydrochlorothiazide, led to the development of jaundice or thrombocytopenia in the fetus or in the neonatal period, as well as to the development of other adverse events that are subsequently observed in adults. If pregnancy is diagnosed during treatment with Duopress, the drug should be discontinued as soon as possible.

It is not known whether Valsartan passes into breast milk. Experimental studies have shown that Valsartan is excreted in the milk of lactating animals.

Hydrochlorothiazide crosses the placenta and is excreted in breast milk, so the drug is not recommended for use during breastfeeding.

Use in Hepatic Impairment

Duopress is not recommended for patients with severe hepatic impairment (more than 9 points on the Child-Pugh scale).

In patients with mild or moderate hepatic impairment without concomitant cholestasis, the dose of valsartan should not exceed 80 mg.

Use in Renal Impairment

The drug should be prescribed with caution to patients with impaired renal function (creatinine clearance more than 30 ml/min (0.5 ml/sec)).

The use of the drug is contraindicated in anuria, severe renal impairment (creatinine clearance less than 30 ml/min (0.5 ml/sec)).

Pediatric Use

Contraindicated in children under 18 years of age, because the efficacy and safety of valsartan in children has not been established.

Special Precautions

Duopress can be used as initial therapy in patients who may require several antihypertensive drugs to achieve target blood pressure values. The choice of Duopress for initial therapy of arterial hypertension should be based on an assessment of the potential benefit-risk ratio.

Chronic heart failure of NYHA functional class III-IV, including after myocardial infarction

In patients whose renal function depends on the state of the RAAS (e.g., patients with chronic heart failure), therapy with ACE inhibitors and angiotensin II receptor antagonists may be accompanied by oliguria and/or progressive azotemia, in rare cases – acute renal failure. Examination of patients with circulatory failure and patients who have had myocardial infarction should include an assessment of renal function.

Patients with hyponatremia and/or reduced CBV

In patients with severe hyponatremia and/or reduced CBV (e.g., due to taking high doses of diuretics), in rare cases, pronounced arterial hypotension may develop at the beginning of therapy with Duopress. Before starting treatment, it is recommended to correct sodium levels in the body and/or replenish CBV, otherwise therapy should be started under strict medical supervision.

If arterial hypotension with clinical manifestations develops, the patient should be placed in a horizontal position with legs elevated, CBV should be replenished, and water and electrolyte imbalances should be corrected. Therapy with Duopress can be continued only after blood pressure parameters have stabilized.

Changes in serum electrolyte levels

Thiazide diuretics, due to their ability to reduce serum potassium and magnesium levels, should be used with caution in patients with conditions accompanied by water and electrolyte imbalances: nephropathy accompanied by salt loss, and prerenal (cardiogenic) renal impairment. If clinical manifestations of hypokalemia occur (muscle weakness, paresis, changes in ECG parameters), treatment with Duopress should be discontinued. Before starting the drug, hypokalemia and hypomagnesemia should be corrected. All patients taking drugs containing thiazide diuretics require regular monitoring of plasma electrolyte levels, especially potassium.

When using Duopress, the ability of thiazide diuretics to cause hyponatremia and hypochloremic alkalosis, as well as to exacerbate existing hyponatremia, should be taken into account. Hyponatremia in these cases is rarely accompanied by neurological symptoms. Regular monitoring of plasma sodium levels is necessary.

Renal artery stenosis

In patients with unilateral or bilateral renal artery stenosis or stenosis of the artery of a single kidney, taking Duopress may be accompanied by an increase in serum urea and creatinine concentrations, so Duopress should be used with caution in such patients.

Impaired renal function

In patients with impaired renal function (creatinine clearance more than 30 ml/min (more than 0.5 ml/sec)), no dose adjustment of the drug is required. Periodic monitoring of serum potassium, creatinine and uric acid concentrations is recommended.

There is no experience with the use of Duopress in patients with recent kidney transplantation.

Impaired liver function

Duopress should not be used in patients with severe (more than 9 points on the Child-Pugh scale) hepatic impairment; in the presence of biliary tract obstruction and cholestasis, Duopress should be used with caution.

Primary hyperaldosteronism

Duopress is not recommended for patients with primary hyperaldosteronism.

Systemic lupus erythematosus (SLE)

There are reports of exacerbation of connective tissue diseases (e.g., SLE) with the use of thiazide diuretics, including Hydrochlorothiazide.

Other metabolic disorders

Thiazide diuretics, including Hydrochlorothiazide, can impair glucose tolerance and increase serum concentrations of cholesterol, triglycerides and uric acid.

Decreased uric acid clearance can lead to hyperuricemia and the development of gout in predisposed patients, in the presence of concomitant calcium metabolism disorders. Thiazide diuretics reduce renal calcium excretion and can cause a slight increase in plasma calcium levels in the absence of concomitant calcium metabolism disorders. Marked hypercalcemia during therapy with a thiazide diuretic (more than 12 mg/dl) or not responding to drug withdrawal may indicate the presence of a concomitant calcium metabolism disorder. In several patients with hypercalcemia and hypophosphatemia during long-term use of thiazide diuretics, pathological changes in the parathyroid glands were determined.

Hypersensitivity reactions

The occurrence of hypersensitivity reactions during the use of hydrochlorothiazide was most often noted in patients with a history of allergic reactions and bronchial asthma. Angioedema, including edema of the larynx and vocal folds leading to airway obstruction, and/or edema of the face, lips, pharynx and/or tongue, occurred in patients receiving Valsartan; some of these patients had previously experienced angioedema while using other drugs, including ACE inhibitors. Administration of Duopress in case of angioedema development should be immediately discontinued; resumption of Duopress use is prohibited.

Acute attack of angle-closure glaucoma

Cases of transient myopia and acute development of angle-closure glaucoma have been reported during the use of hydrochlorothiazide. Risk factors for the acute development of angle-closure glaucoma may include a history of allergic reactions to sulfonamide and penicillin. Symptoms: sudden onset, sharp decrease in visual acuity or eye pain, usually occurring within a period of several hours to a week after starting therapy. Untreated angle-closure glaucoma can lead to permanent vision loss. First of all, it is necessary to stop taking hydrochlorothiazide. Additional drug or surgical treatment may be required if intraocular pressure does not decrease after drug withdrawal.

Effect on ability to drive vehicles and operate machinery

Patients should exercise caution when driving vehicles and working with machinery requiring increased attention and speed of reactions, as dizziness or weakness may develop.

Overdose

Valsartan

Symptoms: pronounced decrease in blood pressure, which can lead to dizziness, collapse and/or shock with fatal outcome.

Treatment: symptomatic, it is recommended to induce vomiting and perform gastric lavage, prescribe activated charcoal. In case of a pronounced decrease in blood pressure, the patient should be placed in a horizontal position with legs elevated, circulating blood volume (CBV) should be replenished, and water and electrolyte imbalances should be corrected. Hemodialysis is ineffective.

Hydrochlorothiazide

Symptoms: the most frequent symptoms are a consequence of electrolyte deficiencies (hypokalemia, hypochloremia, hyponatremia) and dehydration due to excessive diuresis: nausea, drowsiness, arrhythmia, muscle cramps. With the simultaneous use of cardiac glycosides, hypokalemia may worsen the course of arrhythmias.

Treatment: symptomatic.

Drug Interactions

Interactions for valsartan and hydrochlorothiazide

Drugs to be avoided during concomitant use

Lithium preparations

Concomitant use of lithium preparations with ACE inhibitors or thiazide diuretics has been associated with a reversible increase in serum lithium concentrations and a related increase in toxic manifestations. Experience with the concomitant use of valsartan and lithium preparations is currently lacking, so monitoring of serum lithium levels is recommended in this case.

Drugs requiring caution during concomitant use

Antihypertensive agents

Potentiation of the antihypertensive effect may occur with the concomitant use of other blood pressure-lowering agents (ACE inhibitors, beta-blockers, slow calcium channel blockers, guanethidine, methyldopa, vasodilators, direct renin inhibitors, angiotensin II receptor antagonists).

Pressor amines

A reduction in the effect of pressor amines (norepinephrine, epinephrine) may occur, which does not require discontinuation of concomitant use.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors

A reduction in the diuretic and antihypertensive effects of Duopress may occur with the concomitant use of NSAIDs, for example, salicylic acid derivatives, indomethacin. Concomitant hypovolemia can lead to acute renal failure.

Interactions for valsartan

Drugs to be avoided during concomitant use

Concomitant use of angiotensin II receptor antagonists with other drugs affecting the RAAS (ACE inhibitors, aliskiren) leads to an increased incidence of arterial hypotension, hyperkalemia, and impaired renal function. Monitoring of blood pressure, renal function, and plasma electrolyte levels is necessary when prescribing Duopress with other drugs affecting the RAAS. Concomitant use of potassium-sparing diuretics, potassium-containing dietary supplements, potassium-containing salt substitutes; and other drugs that increase serum potassium levels (e.g., heparin) requires precautions (including regular monitoring of blood potassium levels).

Nonsteroidal anti-inflammatory drugs (NSAIDs)

When valsartan is used concomitantly with NSAIDs (selective COX-2 inhibitors), a reduction in its antihypertensive effect may occur. Concomitant use of angiotensin II receptor antagonists and NSAIDs, especially in patients with impaired renal function and/or hypovolemia (including during diuretic therapy), may lead to the development of acute renal failure. If concomitant use of valsartan with NSAIDs is necessary, renal function should be assessed and water-electrolyte imbalances corrected before starting therapy.

Transporter proteins

Based on in vitro studies on liver cultures, Valsartan is a substrate for the transporter proteins OATP1B1 and MRP2. Concomitant administration of valsartan with inhibitors of the OATP1B1 transporter protein (rifampicin, cyclosporine) and with inhibitors of the MRP2 transporter protein (ritonavir) may increase the systemic exposure to valsartan (maximum plasma concentration and AUC).

Absence of drug interaction

No clinically significant interactions were observed during valsartan monotherapy with the following drugs: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, Hydrochlorothiazide, amlodipine, glibenclamide.

Interactions for hydrochlorothiazide

Lithium

Cases of reversible increases in plasma lithium concentrations and its toxic effects have been reported with concomitant use with ACE inhibitors and diuretics. Studies on the concomitant use of hydrochlorothiazide with valsartan and lithium preparations have not been conducted. Therefore, monitoring of blood lithium levels is recommended when hydrochlorothiazide and lithium-containing drugs are used concomitantly.

Other antihypertensive agents

Thiazide diuretics enhance the antihypertensive effect of other antihypertensive drugs (including guanethidine, methyldopa, beta-blockers, vasodilators, slow calcium channel blockers, ACE inhibitors, angiotensin II receptor antagonists, renin inhibitor).

Curare-like muscle relaxants

Thiazide diuretics, including Hydrochlorothiazide, potentiate the effect of non-depolarizing muscle relaxants.

Drugs affecting plasma potassium levels

The risk of hypokalemia caused by diuretics may be increased with the concomitant use of corticosteroids, ACTH, amphotericin, carbenoxolone, penicillin, acetylsalicylic acid or its derivatives, and antiarrhythmic drugs.

Drugs affecting plasma sodium levels

The hyponatremic effect caused by diuretics may be increased with the concomitant use of antidepressants, antipsychotics, anticonvulsants, etc. Caution should be exercised during long-term concomitant use of hydrochlorothiazide with the aforementioned drugs.

Hypoglycemic agents

Thiazide diuretics may impair glucose tolerance, which may require adjustment of the doses of insulin and oral hypoglycemic agents.

Cardiac glycosides

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

NSAIDs

Concomitant use of NSAIDs and hydrochlorothiazide may lead to a reduction in the diuretic and antihypertensive effects of the latter. Concomitant hypovolemia may provoke the development of acute renal failure.

N- and m-cholinergic blockers

N- and m-cholinergic blockers (including atropine, biperiden) may increase the bioavailability of hydrochlorothiazide, which is associated with reduced gastrointestinal motility and gastric emptying rate. Accordingly, gastrointestinal motility stimulants (cisapride) may reduce the bioavailability of hydrochlorothiazide.

Anion exchange resins

The absorption of hydrochlorothiazide is impaired in the presence of cholestyramine and colestipol. Hydrochlorothiazide should be taken either 4 hours before or 4-6 hours after taking these compounds.

Vitamin D and calcium salts

Concomitant intake of hydrochlorothiazide with vitamin D or calcium preparations may lead to hypercalcemia due to enhanced calcium reabsorption.

Cyclosporine

Concomitant use of hydrochlorothiazide and cyclosporine increases the risk of hyperuricemia and exacerbation of gout.

Methyldopa

Cases of hemolytic anemia have been reported with the concomitant administration of hydrochlorothiazide and methyldopa.

Pressor amines

Hydrochlorothiazide may reduce the body’s response to the administration of pressor amines (norepinephrine). The clinical significance of this interaction is minor and does not preclude their combined use.

Other types of interactions

Concomitant administration of thiazide diuretics, including Hydrochlorothiazide, may lead to an increased frequency of hypersensitivity reactions to allopurinol; an increased risk of adverse effects of amantadine; enhancement of the hyperglycemic effect of diazoxide; a reduction in the renal excretion of drugs with cytotoxic action (e.g., cyclophosphamide, methotrexate), potentiating their myelosuppressive effect.

Ethanol, barbiturates, and narcotic drugs

Concomitant use with hydrochlorothiazide may potentiate the development of orthostatic hypotension.

Storage Conditions

In a light-protected place at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

The shelf life is 3 years.

Dispensing Status

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.

Medical Disclaimer

Medixlife (Author)

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