Pharmacological properties
Pharmacodynamics. The active hormone of the renin-angiotensin-aldosterone system is angiotensin II, formed from angiotensin I with the participation of apF. Angiotensin II binds to specific receptors located on cell membranes in various tissues. It has a wide range of physiological effects, including primarily both direct and indirect participation in the regulation of blood pressure. Being a potent vasoconstrictor, angiotensin II causes a direct vasopressor response. In addition, it stimulates the secretion of aldosterone and promotes sodium retention.
Valsartan is a potent and specific angiotensin II receptor antagonist for oral administration. It acts selectively on the AT1 receptor subtype, which is responsible for the known effects of angiotensin II. Increased plasma levels of angiotensin II due to blockade of AT1 receptors by valsartan may stimulate free AT2 receptors, which balances the effect of AT1 receptors. Valsartan does not exhibit pronounced agonist activity towards AT1 receptors. The affinity of valsartan for AT1 receptors is approximately 20,000 times higher than for AT2 receptors.
Valsartan does not inhibit ACE, also known as kininase II, which converts angiotensin I to angiotensin II and destroys bradykinin. No bradykinin-related side effects have been reported. In clinical trials comparing valsartan with an ACE inhibitor, the incidence of dry cough was significantly (p<0.05) lower in patients receiving valsartan than in patients receiving an ACE inhibitor (2.6% and 7.9%, respectively). In a clinical trial involving patients who had previously developed dry cough while receiving an ACE inhibitor, this complication occurred in 19.5% of patients receiving valsartan and 19.0% of patients receiving a thiazide diuretic, while in the group of patients receiving ACE inhibitor therapy, cough was recorded in 68.5% of patients (p<0.05). Valsartan does not interact with or block receptors for other hormones or ion channels that are important for regulating cardiovascular function.
When treating patients with hypertension with valsartan, a decrease in blood pressure is noted without affecting heart rate.
After oral administration of a single dose of the drug in most patients, the onset of antihypertensive activity is recorded within 2 hours, and the maximum decrease in blood pressure is achieved after 4-6 hours. After taking the drug, the antihypertensive effect persists for 24 hours. With continuous use of the drug, the maximum decrease 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. When used simultaneously with hydrochlorothiazide, an additional decrease in blood pressure is achieved.
The point of action of thiazide diuretics is the cortical part of the distal convoluted renal tubules, where receptors are highly sensitive to the action of diuretics and the transport of Na and Cl ions is inhibited. The mechanism of action of thiazides is associated with the inhibition of the Na + Cl - pump, which, apparently, occurs due to competition for Cl - transport sites. As a result, the excretion of sodium and chlorine ions increases to approximately the same extent. As a result of the diuretic action, the volume of circulating blood plasma decreases, resulting in increased renin activity, aldosterone secretion, urinary potassium excretion and, consequently, a decrease in plasma potassium concentration. The relationship between renin and aldosterone is mediated by angiotensin II, so the appointment of an angiotensin II receptor antagonist will reduce the potassium loss associated with the use of hydrochlorothiazide.
Pharmacokinetics
Valsartan. After oral administration, valsartan is rapidly absorbed, but the extent of absorption varies considerably. The average absolute bioavailability of Co-Diovan is 23%. The pharmacokinetic curve of valsartan has a descending multiexponential character (t 1/2 α 1 h and t 1/2 β about 9 h).
In the range of doses studied, the kinetics of valsartan are linear. With repeated use of the drug, no changes in kinetic parameters were observed. When taking the drug once a day, cumulation is insignificant. The drug concentrations in blood plasma in women and men were the same.
Valsartan is highly (94-97%) bound to plasma proteins, mainly albumin. The equilibrium volume of distribution is small (about 17 l). Compared with hepatic blood flow (about 30 l/h), plasma clearance of valsartan is relatively slow (about 2 l/h). The excretion of valsartan with feces is 70% of the dose taken. About 30% is excreted in the urine, mainly unchanged.
When valsartan is administered with food, the AUC decreases by 48%, starting approximately 8 hours after dosing, and plasma concentrations are similar in both the fasted and fed state. However, the decrease in AUC is not accompanied by a clinically significant decrease in therapeutic effect.
In the therapeutic dose range, the mean AUC increases in direct proportion to the increase in dose. The pharmacokinetics of hydrochlorothiazide do not change with repeated administration; with once-daily administration, cumulation is insignificant.
When taken orally, the absolute bioavailability of hydrochlorothiazide is 60-80%. It is excreted in the urine: 95% of the dose is unchanged and about 4% is excreted in the form of a hydrolysate - 2-amino-4-chloro-m-benzenedisulfonamide.
When hydrochlorothiazide is administered with food, both an increase and a decrease in its systemic bioavailability (compared to the corresponding figure when taken in the fasted state) were observed. The range of these changes is small and clinically insignificant.
Valsartan / hydrochlorothiazide. When taken simultaneously with valsartan, the systemic bioavailability of hydrochlorothiazide is reduced by approximately 30%. The simultaneous administration of hydrochlorothiazide does not significantly affect the kinetics of valsartan. However, this interaction does not affect the effectiveness of the combined use of valsartan and hydrochlorothiazide. Controlled clinical studies have revealed a clear antihypertensive effect of this combination, exceeding the effect of each component separately and the placebo effect.
Pharmacokinetics in specific patient groups
Elderly patients. In some elderly patients, the systemic exposure to valsartan was greater than in younger patients, but this was not clinically significant. Limited data suggest that in elderly patients (both healthy and hypertensive) the systemic clearance of hydrochlorothiazide is lower than in healthy young volunteers.
Patients with renal impairment. Patients with creatinine clearance 30-70 ml/min do not require dose adjustment. There are no data on the use of Co-Diovan in patients with severe renal impairment (creatinine clearance 30 ml/min) and in patients undergoing hemodialysis. Valsartan is highly bound to plasma proteins and is not removed by hemodialysis. Hydrochlorothiazide, on the contrary, is removed from the body by hemodialysis.
Renal excretion of hydrochlorothiazide occurs by passive filtration and active secretion into the lumen of the renal tubules. The state of renal function plays a major role in the pharmacokinetics of hydrochlorothiazide.
Patients with hepatic impairment. The systemic exposure to valsartan in patients with mild (n = 6) and moderate (n = 5) hepatic impairment was 2-fold greater than in healthy volunteers. There are no data on the use of valsartan in patients with severe hepatic impairment.
Liver disease does not significantly affect the pharmacokinetics of hydrochlorothiazide, so a dose reduction is not required.
Indication
Ag in patients whose blood pressure is not adequately controlled with monotherapy.
Application
The recommended dose of Co-Diovan is 1 tablet of 80 mg / 12.5 mg / day. If blood pressure is not reduced sufficiently after 3-4 weeks of treatment, it is recommended to consider continuing treatment at a dose of 1 tablet of 160 mg / 12.5 mg / day. Tablets of 160 mg / 25 mg are prescribed to patients who do not achieve a sufficient reduction in blood pressure when using tablets of 160 mg / 12.5 mg. If in the future, when using tablets of 160 mg / 25 mg, blood pressure is not reduced sufficiently, it is recommended to consider continuing treatment at a dose of 320 mg / 12.5 mg. Tablets of 320 mg / 25 mg are prescribed to patients who do not achieve a sufficient reduction in blood pressure when using tablets of 320 mg / 12.5 mg.
The maximum daily dose is 320 mg / 25 mg.
The maximum antihypertensive effect is achieved within 2-4 weeks. Some patients may require 4-8 weeks of treatment.
Co-Diovan can be taken regardless of meals. The tablets should be swallowed with a small amount of water.
In patients with mild to moderate hepatic insufficiency of non-biliary origin and without cholestasis, the dose of valsartan should not exceed 80 mg.
Contraindication
Hypersensitivity to any of the components of the drug Co-Diovan or to other sulfonamide derivatives. Severe liver dysfunction, cirrhosis and cholestasis. Anuria, severe renal dysfunction (creatinine clearance 30 ml/min). Refractory hypokalemia, hyponatremia, hypercalcemia and symptomatic hyperuricemia.
Side effects
The most frequently reported adverse reactions in clinical trials and laboratory studies with valsartan and hydrochlorothiazide compared to placebo and in individual post-marketing reports are listed below by system organ class. Adverse reactions that may occur with the use of each component separately, but which are not reported in clinical trials, may occur during treatment with the combination of valsartan + hydrochlorothiazide.
Adverse reactions are presented by frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (≥1/10,000 to <1/1,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Frequency of adverse reactions with valsartan/hydrochlorothiazide
Metabolic disorders, metabolism
Uncommon - dehydration.
neurological disorders
Very rare - dizziness. Uncommon - paresthesia, confusion, disorientation, nervousness, mood changes, xanthopsia. Not known - fainting.
From the organ of vision
From the side of the organs of hearing and vestibular apparatus
Infrequently - ringing in the ears.
vascular disorders
Uncommon: hypotension.
Respiratory, thoracic and mediastinal disorders
Uncommon: cough, respiratory distress, pneumonitis. Not known: non-cardiogenic pulmonary oedema.
Gastrointestinal disorders
Very rarely - diarrhea, thirst, inflammation of the salivary glands, cholecystitis.
Musculoskeletal and connective tissue disorders
Uncommon: muscle pain. Very rare: arthralgia.
Skin and subcutaneous tissue disorders
Frequency unknown - purpura, toxic epidermal necrolysis, eczema.
From the heart
Frequency unknown - heart failure.
Hepatobiliary system
Frequency unknown - hypochloraemic alkalosis, which may induce hepatic encephalopathy or hepatic coma.
From the urinary system
Frequency unknown - renal dysfunction, interstitial nephritis.
General disorders and administration site conditions
Uncommon - fatigue, anaphylactic reactions, shock.
research
Unknown - increased levels of uric acid, bilirubin and creatinine in blood plasma, hypokalemia, hyponatremia, increased blood urea nitrogen, neutropenia, hyperuricemia, which can provoke gout attacks in patients with asymptomatic disease, decreased glucose tolerance, which can cause manifestation of latent diabetes mellitus.
The following reactions were observed in clinical trials in patients with hypertension, regardless of their causal relationship to the study drug: abdominal pain (including upper), anxiety, arthritis, back pain, bronchitis, acute bronchitis, chest pain, dizziness, dyspepsia, shortness of breath, dry mouth, epistaxis, impotence, gastroenteritis, headache, increased sweating, hypoesthesia, influenza, insomnia, sprain, muscle cramps, muscle strain, nausea, nasal congestion, sinus congestion, neck pain, peripheral edema, otitis media, pain in extremity, palpitations, pharyngolaryngeal pain, pollakiuria, fever, nasopharyngitis, sinusitis, drowsiness, tachycardia, upper respiratory tract infection, urinary tract infection, vertigo, viral infections, visual disturbances. It is not known whether these effects were causally related to therapy.
Additional information on individual components
Adverse reactions that previously occurred with the use of each component separately may also be potential side effects when using Co-Diovan, even if they were not observed in clinical trials or during the post-marketing period.
Frequency of adverse reactions when using valsartan
Blood and lymphatic system disorders
Not known - decreased hemoglobin, decreased hematocrit, thrombocytopenia.
On the part of the immune system
Unknown - other hypersensitivity/allergic reactions, including serum sickness.
Metabolic disorders, metabolism
Not known - increased plasma potassium levels, hyponatremia.
From the side of the organs of hearing and vestibular apparatus
Uncommon - vestibular dizziness.
vascular disorders
Unknown - vasculitis.
Gastrointestinal disorders
Uncommon - abdominal pain.
Hepatobiliary system
Unknown - increased liver function tests.
Skin and subcutaneous tissue disorders
Not known - angioedema, rash, itching.
From the urinary system
Unknown - renal failure.
The following reactions were recorded during clinical trials in patients with hypertension, regardless of their causal relationship to the study drug: arthralgia, asthenia, back pain, diarrhea, dizziness, headache, insomnia, decreased libido, nausea, edema, pharyngitis, rhinitis, sinusitis, upper respiratory tract inflammation, viral infections.
Frequency of adverse reactions with hydrochlorothiazide
Hydrochlorothiazide has been widely used for many years, often in higher doses than those contained in Co-Diovan. The following adverse reactions have been reported in patients receiving thiazide diuretics, including hydrochlorothiazide, as monotherapy.
From the side of metabolism, metabolism
Very common - when used in high doses, increased blood lipid levels; common - hypomagnesemia, hyperuricemia; rare - hypercalcemia, hyperglycemia, glucosuria and metabolic disorders in patients with diabetes mellitus; very rare - hypochloremic alkalosis.
Blood and lymphatic system disorders
Rarely - thrombocytopenia, sometimes with purpura; very rarely - agranulocytosis, leukopenia, hemolytic anemia, bone marrow depression; unknown - aplastic anemia.
On the part of the immune system
Very rare - hypersensitivity reactions.
Mental disorders
Rarely - depression, sleep disorders.
neurological disorders
Rarely - headache, dizziness, paresthesia.
From the organ of vision
Uncommon: blurred vision in the first few weeks after starting treatment; not known: acute angle-closure glaucoma.
cardiac disorders
Rarely - cardiac arrhythmia.
vascular disorders
Often - postural hypotension, which can be aggravated by alcohol consumption, the use of anesthetics, and sedatives.
Very rare: respiratory failure, including pneumonia and pulmonary edema.
Gastrointestinal disorders
Often - loss of appetite, mild nausea and vomiting; rarely - constipation, feeling of gastrointestinal discomfort, diarrhea; very rarely - pancreatitis.
Hepatobiliary system
Rarely - intrahepatic cholestasis or jaundice.
Skin and subcutaneous tissue disorders
Common: urticaria and other types of rash; rare: photosensitivity; very rare: necrotizing vasculitis and toxic epidermal necrolysis, lupus-like skin reactions, reactivation of cutaneous lupus erythematosus; not known: erythema multiforme.
Reproductive system and mammary gland disorders
Often - impotence.
From the urinary system
Not known - acute renal failure, renal dysfunction.
General disorders and administration site conditions
Unknown - increased body temperature, fatigue.
Musculoskeletal and connective tissue disorders
Not known - muscle spasms.
Special instructions
Changes in the balance of blood plasma electrolytes. Caution should be exercised when using Co-Diovan with potassium salts, potassium-sparing diuretics, potassium-containing salt substitutes, as well as with drugs that may cause an increase in blood potassium levels (e.g. heparin). There are reports of hypokalemia during treatment with thiazide diuretics. It is recommended to frequently check the potassium content in the blood plasma.
Thiazide diuretics may cause hyponatremia and hypochloremic alkalosis. Thiazides cause increased urinary magnesium excretion, which may lead to hypomagnesemia.
Patients with a deficiency in the body of sodium and / or circulating blood volume. In patients with a severe deficiency of sodium and / or circulating blood volume, for example, receiving diuretics in high doses, in some cases at the beginning of treatment with the drug Co-Diovan symptomatic hypotension may occur. Therefore, before starting treatment with the drug, correction of the content of sodium in the body and / or circulating blood volume should be carried out. In the event of arterial hypotension, the patient should be placed in a supine position and, if necessary, an intravenous infusion of saline solution should be carried out. After stabilization of blood pressure, treatment with the drug Co-Diovan can be continued.
Patients with severe chronic heart failure or other conditions with increased activity of the renin-angiotensin-aldosterone system
In patients whose renal function depends on the activity of the renin-angiotensin-aldosterone system (e.g., severe congestive heart failure), treatment with ACE inhibitors has been associated with oliguria and/or progressive azotemia and, rarely, acute renal failure. The use of Co-Diovan in patients with severe chronic heart failure is not justified.
Since it cannot be excluded that due to suppression of the renin-angiotensin-aldosterone system, the use of Co-Diovan may also be associated with impaired renal function, it should not be used in such patients.
Renal artery stenosis: The drug should not be used in patients with unilateral or bilateral renal artery stenosis or stenosis caused by a solitary kidney, as these patients may experience increases in plasma urea and creatinine levels.
Primary hyperaldosteronism
The drug should not be used in patients with primary aldosteronism, since their renin-angiotensin system is not activated.
Aortic and mitral valve stenosis, hypertrophic obstructive cardiomyopathy
As with other vasodilators, special caution is required in patients with aortic and mitral valve stenosis or hypertrophic obstructive cardiomyopathy.
Renal impairment: No dose adjustment is required in patients with mild to moderate renal impairment (creatinine clearance ≥30 mL/min).
Co-Diovan should be used with caution in severe renal insufficiency (creatinine clearance 30 ml/min). Thiazides may provoke azotemia in patients with chronic renal impairment. They are ineffective as monotherapy in severe renal insufficiency (creatinine clearance 30 ml/min), but they can be used with caution in combination with loop diuretics even in patients with creatinine clearance 30 ml/min.
Kidney transplantation: There is currently no experience of the safe use of the drug in patients who have recently undergone kidney transplantation.
Hepatic impairment. In patients with mild to moderate hepatic impairment without cholestasis, no dose adjustment is required. However, Co-Diovan should be used with caution. Liver disease does not significantly alter the pharmacokinetics of hydrochlorothiazide.
Other metabolic disorders. Thiazides may alter glucose tolerance and increase plasma cholesterol, triglycerides, and uric acid levels. In diabetic patients, dosage adjustment of insulin or oral hypoglycemic agents may be necessary. Thiazides may reduce urinary calcium excretion and cause transient and minor increases in plasma calcium in the absence of calcium metabolism disorders. Significant hypercalcemia may indicate underlying hyperparathyroidism. Thiazides should be discontinued before parathyroid function tests are performed.
photosensitivity
Photosensitivity has been reported with thiazide diuretics. If a photosensitivity reaction occurs during treatment, it is recommended that treatment be discontinued. If repeated use of the diuretic is considered necessary, it is recommended that exposed skin be protected from sunlight or artificial ultraviolet radiation.
general
Caution should be exercised when using the drug in patients with a history of hypersensitivity to other angiotensin II receptor antagonists. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergies and asthma.
angioedema
Angioedema (including swelling of the larynx and glottis leading to airway obstruction and/or swelling of the face, lips, pharynx and/or tongue) has been reported in patients treated with valsartan. Some of these patients had a history of angioedema with other drugs, including other angiotensin II receptor antagonists. If angioedema develops, treatment with angiotensin II receptor antagonists should be discontinued immediately. Re-administration is contraindicated.
Acute angle-closure glaucoma
The use of hydrochlorothiazide and a sulfonamide has been associated with an idiosyncratic reaction that may lead to acute transient myopia and acute angle-closure glaucoma. A sharp decrease in visual acuity or eye pain has been reported. These symptoms usually last for several hours per week while taking the drug. Untreated glaucoma can lead to irreversible vision loss.
The drug should be discontinued as soon as possible. Medical or surgical treatment may be necessary. A risk factor for the development of acute glaucoma is an allergic reaction to the use of sulfonamides or penicillin.
No dosage adjustment is required for elderly patients.
Hydrochlorothiazide may reduce the level of protein-bound iodine in the blood plasma. Hydrochlorothiazide may increase the concentration of free bilirubin in the blood plasma.
Use during pregnancy and breastfeeding
pregnancy
valsartan
The use of angiotensin II receptor antagonists is not recommended during the first trimester of pregnancy. The use of angiotensin II receptor antagonists is contraindicated throughout pregnancy.
Epidemiological evidence on the teratogenic risk following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive, but a small increase cannot be excluded. Although there are no data from controlled epidemiological studies with angiotensin II receptor antagonists, teratogenic risks may exist for this class of drugs.
Unless continued angiotensin II receptor antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy.
When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.
The use of angiotensin II receptor antagonists during the second and third trimesters of pregnancy is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalemia).
If angiotensin II receptor antagonists have been used, ultrasound check of renal function and skull is recommended from the second trimester of pregnancy.
Newborns whose mothers have taken angiotensin II receptor antagonists should be closely observed for the development of arterial hypotension.
Hydrochlorothiazide
Experience with the use of hydrochlorothiazide during pregnancy is limited, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanisms of action of hydrochlorothiazide, its administration during the second and third trimesters of pregnancy may lead to impaired fetoplacental circulation and cause effects in the fetus and newborn such as jaundice, electrolyte imbalance and thrombocytopenia.
If the use of the drug is absolutely necessary, breastfeeding should be discontinued. There is no information on the use of valsartan during breastfeeding. Hydrochlorothiazide passes into breast milk in small quantities. Thiazides in high doses cause diuresis, which may suppress milk production. During breastfeeding, especially while breastfeeding a newborn or preterm infant, alternative treatments with better established safety profiles are preferable.
Children. Co-Diovan is not recommended for use in children due to a lack of data on its safety and effectiveness.
The ability to influence the reaction speed when driving vehicles or working with other mechanisms. At the beginning of the use of the drug (the period is determined individually by the doctor), it is forbidden to drive vehicles and perform work that may lead to an accident. Later, the degree of prohibition is determined by the doctor.
Interactions
Interactions associated with both valsartan and hydrochlorothiazide
Concomitant use is not recommended.
Lithium: Transient increases in plasma lithium concentrations and toxicity have been reported with concomitant use of ACE inhibitors and thiazides, including hydrochlorothiazide. Due to the lack of experience with the concomitant use of valsartan and lithium, this combination is not recommended. If such a combination is necessary, careful monitoring of plasma lithium levels is recommended.
Concomitant use requiring caution
Other antihypertensive drugs
Co-Diovan may enhance the effect of other drugs with antihypertensive properties (e.g. ACE inhibitors, β-adrenergic blockers, calcium channel blockers).
Pressor amines (e.g., noradrenaline, adrenaline)
There may be a reduced response to pressor amines, which is not sufficient to preclude their use.
NSAIDs, including selective COX-2 inhibitors, acetylsalicylic acid 3 g/day, and non-selective NSAIDs
NSAIDs may attenuate the antihypertensive effect of both angiotensin II antagonists and hydrochlorothiazide when used concomitantly. In addition, concomitant administration of Co-Diovan and nonsteroidal anti-inflammatory drugs may lead to decreased renal function and increased plasma potassium levels. Therefore, monitoring of renal function at the start of treatment and adequate hydration of the patient are recommended.
Interactions related to valsartan
Concomitant use is not recommended.
Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, and other substances that may increase potassium levels
If the use of a medicinal product that affects potassium levels is considered necessary in combination with valsartan, monitoring of plasma potassium is recommended.
lack of interaction
Studies have not shown any clinically significant drug interactions between valsartan and any of the following: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide. Digoxin and indomethacin may interact with the hydrochlorothiazide component of valsartan (see Interactions related to hydrochlorothiazide).
Interactions related to hydrochlorothiazide
Concomitant use requiring caution
Drugs associated with potassium loss and hypokalemia (e.g., kaliuretic diuretics, corticosteroids, laxatives, ACTH, amphotericin, carbenoxolone, penicillin G, salicylic acid and derivatives).
If it is necessary to prescribe these drugs with a combination of hydrochlorothiazide and valsartan, it is recommended to monitor the level of potassium in the blood plasma. These drugs may enhance the effect of hydrochlorothiazide on the level of potassium in the blood plasma.
Drugs that can cause torsades de pointes:
Class Ia antiarrhythmics (quinidine, hydroquinidine, disopyramide); Class III antiarrhythmics (amiodarone, sotalol, dofetilide, ibutilide); Some neuroleptics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol); Others (e.g. bepridil, cisapride, diphemanil, erythromycin IV, halofantrine, ketanserin, mizolastine, pentamidine, sparfloxacin, terfenadine, vincamine IV).
Due to the risk of hypokalemia, hydrochlorothiazide should be used with caution simultaneously with drugs that can cause torsades de pointes.
digitalis glycosides
Thiazide-induced hypokalemia or hypomagnesemia may occur as a side effect, contributing to the development of digitalis-induced cardiac arrhythmias.
Calcium salts and vitamin D
The use of thiazide diuretics, including hydrochlorothiazide, simultaneously with vitamin D or calcium salts may lead to an increase in plasma calcium levels.
Antidiabetic agents (oral agents and insulin)
Thiazide therapy may affect glucose tolerance. Dose adjustment of the antidiabetic medicinal product may be necessary.
Metformin should be used with caution due to the risk of lactic acidosis induced by possible functional renal failure associated with hydrochlorothiazide.
Concomitant use of thiazide diuretics, including hydrochlorothiazide, with β-adrenergic blockers may increase the risk of hyperglycemia. Thiazides, including hydrochlorothiazide, may potentiate the hyperglycemic effect of diazoxide.
Medicines used in the treatment of gout (probenecid, sulfinpyrazone and allopurinol)
It may be necessary to adjust the dose of drugs that promote the excretion of uric acid, since hydrochlorothiazide may increase the level of uric acid in the blood plasma. It may be necessary to increase the dose of probenecid or sulfinpyrazone. Concomitant use of thiazide diuretics, including hydrochlorothiazide, may increase the frequency of hypersensitivity reactions to allopurinol.
Anticholinergics (e.g. atropine, biperiden)
The bioavailability of thiazide diuretics may be increased by anticholinergic agents, probably due to a decrease in gastrointestinal motility and gastric emptying rate.
amantadine
Thiazides, including hydrochlorothiazide, may increase the risk of side effects caused by amantadine.
Cholestyramine and colestipol resins
The absorption of thiazide diuretics, including hydrochlorothiazide, is impaired in the presence of anionic resins.
Cytotoxic agents (e.g., cyclophosphamide, methotrexate)
Thiazides, including hydrochlorothiazide, may reduce the excretion of cytotoxic agents and enhance their myelosuppressive effect.
Non-depolarizing skeletal muscle relaxants (e.g. tubocurarine)
Thiazides, including hydrochlorothiazide, enhance the effect of curare derivatives.
cyclosporine
Concomitant administration with cyclosporine increases the risk of hyperuricemia and gout-like complications.
Alcohol, anesthetics and sedatives
Potentiation of orthostatic hypotension may occur.
methyldopa
There have been isolated reports of hemolytic anemia in patients receiving concomitant treatment with methyldopa and hydrochlorothiazide.
carbamazepine
Hyponatremia may develop in patients receiving hydrochlorothiazide concomitantly with carbamazepine. Patients should be warned of the possibility of a hyponatremic reaction and monitored appropriately.
Contrast agents containing iodine
In case of dehydration caused by diuretics, there is an increased risk of developing acute renal failure, especially with high doses of iodine-containing drugs. The patient should be adequately rehydrated before use.
Overdose
Overdose of valsartan can lead to severe hypotension, which, in turn, can contribute to a decrease in the level of consciousness, the development of heart failure and / or shock.
The following signs and symptoms may occur in case of hydrochlorothiazide overdose: nausea, drowsiness, hypovolemia, electrolyte imbalance and, as a result, arrhythmia and muscle spasms. The most characteristic signs and symptoms of overdose are also tachycardia, arterial hypotension, shock, weakness, confusion, dizziness, muscle spasm, paresthesia, exhaustion, disorders of consciousness, vomiting, thirst, polyuria, oliguria, anuria, alkalosis, increased blood urea nitrogen (mainly renal failure).
Therapeutic measures depend on the length of time since the overdose, as well as the type and severity of symptoms; the primary measure is to normalize hemocirculation.
If the drug has been taken recently, vomiting should be induced. If a long time has passed since the drug was taken, the patient should be given a sufficient amount of activated charcoal.
In case of hypotension, the patient should be placed in a horizontal position and immediately ensure the restoration of water-salt balance by intravenous administration of isotonic saline solution.
Valsartan cannot be removed from the body by hemodialysis due to its binding to plasma proteins, but hemodialysis is effective for removing hydrochlorothiazide from the body.
Storage conditions
At a temperature not exceeding 30 °C, in the original packaging to protect from moisture.
