Instructions for use Corsar H DUO film-coated tablets 160 mg + 12.5 mg blister No. 30
Composition
active ingredients: valsartan, hydrochlorothiazide;
1 tablet contains:
80 mg valsartan and 12.5 mg hydrochlorothiazide or 160 mg valsartan and 12.5 mg hydrochlorothiazide, or 160 mg valsartan and 25 mg hydrochlorothiazide, or 320 mg valsartan and 12.5 mg hydrochlorothiazide, or 320 mg valsartan and 25 mg hydrochlorothiazide;
Excipients: microcrystalline cellulose, croscarmellose sodium, colloidal anhydrous silica, magnesium stearate, polyethylene glycol 6000 (macrogol 6000), hypromellose, titanium dioxide (E 171), talc.
Dosage form
Film-coated tablets.
Main physicochemical properties: round, biconvex tablets from white to almost white in color, film-coated.
Pharmacotherapeutic group
Agents acting on the renin-angiotensin system. Combined preparations of angiotensin II receptor blockers. Angiotensin II receptor blockers and diuretics. Valsartan and diuretics. ATC code C09D A03.
Pharmacological properties
Pharmacodynamics
The active hormone of the renin-angiotensin-aldosterone system (RAAS) is angiotensin II, formed from angiotensin I by angiotensin-converting enzyme (ACE). Angiotensin II binds to specific receptors located on cell membranes in various tissues. It has a wide range of physiological actions, including both direct and indirect participation in the regulation of blood pressure. As a potent vasoconstrictor, angiotensin II has a direct vasopressor effect. In addition, it promotes sodium retention and stimulates aldosterone secretion.
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 effects of angiotensin II. Increased levels of angiotensin II resulting from blockade of AT1 receptors by valsartan may stimulate free AT2 receptors, which counteracts the effect of AT1 receptors. Valsartan has no partial agonist activity at AT1 receptors and has a much higher (approximately 20,000-fold) affinity for AT1 receptors 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 observed. In clinical trials comparing valsartan with an ACE inhibitor, the incidence of dry cough was significantly lower (P
In controlled clinical trials, the incidence of cough in patients treated with the combination of valsartan and hydrochlorothiazide was 2.9%.
Valsartan does not interact with or block receptors for other hormones or ion channels that play an important role in regulating the functions of the cardiovascular system.
The use of the drug in patients with hypertension leads to a decrease in blood pressure without affecting the pulse rate.
In most patients, after oral administration of a single dose of the drug, the onset of antihypertensive activity is noted within 2 hours, and the maximum reduction in blood pressure is achieved within 4–6 hours. The antihypertensive effect persists for more than 24 hours after taking a single dose. With regular use of the drug, the maximum therapeutic effect is usually achieved within 2–4 weeks and is maintained at the achieved level during long-term therapy. The combination with hydrochlorothiazide reduces blood pressure more effectively.
Discontinuation of valsartan does not lead to recurrence of hypertension or other side effects.
Valsartan does not affect total cholesterol, triglycerides, serum glucose, or uric acid levels in patients with hypertension.
The point of action of thiazide diuretics is the cortical part of the distal convoluted renal tubules, where receptors are located that are highly sensitive to the action of diuretics, and where 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. Due to the diuretic effect, a decrease in the volume of circulating plasma is observed, as a result of which renin activity, aldosterone secretion, urinary potassium excretion and, consequently, a decrease in serum potassium concentration increase. The relationship between renin and aldosterone is mediated by angiotensin II, therefore, the use of an angiotensin II receptor antagonist will reduce the potassium loss associated with the use of a thiazide diuretic.
Pharmacokinetics
Valsartan
In the range of doses studied, the kinetics of valsartan are linear. With repeated use of the drug, no changes in kinetic parameters were noted. When taking the drug once a day, cumulation is insignificant. The drug concentrations in the blood plasma of women and men were the same. Valsartan is largely bound to serum proteins (94–97%), mainly to albumin. The volume of distribution at steady state is low (approximately 17 l). Compared with hepatic blood flow (approximately 30 l/h), plasma clearance of valsartan is relatively slow (approximately 2 l/h). The amount of valsartan excreted in the feces is 70% (of the dose taken orally), and almost 30% is excreted in the urine, mainly unchanged.
When valsartan is administered with food, the area under the concentration-time curve (AUC) is reduced by 48%, although approximately 8 hours after dosing, plasma concentrations are similar in the fed and fasted states. The decrease in AUC is not accompanied by a significant reduction in therapeutic effect.
Hydrochlorothiazide
Hydrochlorothiazide is rapidly absorbed after oral administration (tmax is approximately 2 hours). The pharmacokinetics of the drug in the distribution and elimination phases are generally described by a biexponential descending curve; the terminal elimination half-life (t1/2) is 6–15 hours. In the therapeutic dose range, the average AUC increases in direct proportion to the dose increase. With repeated administration, the pharmacokinetics of hydrochlorothiazide do not change; with once-daily administration, cumulation is insignificant.
The absolute bioavailability of hydrochlorothiazide when taken orally is 70%. Excretion occurs in the urine: more than 95% of the dose is excreted unchanged and approximately 4% - 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 have been observed compared with the corresponding figure when administered in the fasted state. The range of these changes is small and has no clinical significance.
Valsartan/hydrochlorothiazide
When used simultaneously with valsartan, the systemic bioavailability of hydrochlorothiazide is reduced by approximately 30%. The simultaneous use 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. In controlled clinical studies, a clear antihypertensive effect of this combination was found, which exceeded the effect of each component separately, as well as the effect of placebo.
Pharmacokinetics in specific patient groups
Elderly patients
In some elderly patients, the systemic exposure to valsartan was somewhat greater than in young patients, but this was not clinically significant. Some data suggest that the systemic clearance of hydrochlorothiazide is lower in the elderly than in healthy young volunteers.
Patients with renal impairment
No dose adjustment is required for patients with creatinine clearance 30–70 ml/min.
There are no data on the use of the drug ADENIZ-N in patients with severe renal impairment (creatinine clearance
In the presence of renal dysfunction, the mean peak plasma levels and AUC values of hydrochlorothiazide are increased and the urinary excretion rate is reduced. In patients with mild to moderate renal insufficiency, the mean t1/2 is almost doubled due to a significant decrease in renal clearance.
Renal excretion of hydrochlorothiazide occurs by passive filtration and active secretion into the renal tubular lumen. Renal function plays a major role in the pharmacokinetics of hydrochlorothiazide, as this drug is excreted exclusively by the kidneys.
In the presence of renal insufficiency, the mean peak plasma levels and AUC values of hydrochlorothiazide are increased, and the urinary excretion rate is reduced. In patients with mild to moderate renal insufficiency, a 3-fold increase in the AUC of hydrochlorothiazide is observed. In patients with severe renal insufficiency, an 8-fold increase in the AUC is observed. Hydrochlorothiazide is contraindicated in patients with severe renal insufficiency.
Liver dysfunction
The systemic exposure of 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.
Available epidemiological data suggest a cumulative dose-dependent association between hydrochlorothiazide exposure and the development of NSCLC. One study included 71,533 cases of basal cell carcinoma (including 1,430,833 controls) and 8,629 cases of squamous cell carcinoma (including 172,462 controls). High doses of hydrochlorothiazide (≥ 50,000 mg cumulative) were associated with an adjusted odds ratio (OR) of 1.29 (95% CI: 1.23–1.35) for basal cell carcinoma and 3.98 (95% CI: 3.68–4.31) for squamous cell carcinoma. A cumulative dose-response relationship was observed for both basal cell carcinoma and squamous cell carcinoma. Another study showed a possible association between lip cancer and hydrochlorothiazide use: 633 cases of lip cancer were matched to 63,067 population controls using a risk selection strategy. A cumulative dose-response relationship was demonstrated with an adjusted OR of 2.1 (95% CI: 1.27–2.6), increasing to OR 3.9 (3.0–4.9) for the high dose (25,000 mg) and OR 7.7 (5.7–10.5) for the highest dose (100,000 mg). For example, a cumulative dose of 100,000 mg corresponds to daily use of a fixed dose of 25 mg for a period of more than 10 years.
Indication
Treatment of essential hypertension in adults.
The fixed-dose combination of the drug ADENIZ-N is indicated for patients whose blood pressure is not adequately controlled by valsartan or hydrochlorothiazide monotherapy.
Contraindication
- Hypersensitivity to any of the components of the drug ADENIZ-N or to other sulfonamide derivatives;
- severe liver dysfunction, biliary cirrhosis and cholestasis;
- severe renal dysfunction (creatinine clearance
- anuria;
- refractory hypokalemia, hyponatremia, hypercalcemia, symptomatic hyperuricemia;
- concomitant use of angiotensin receptor antagonists (ARBs), including valsartan, or ACE inhibitors with aliskiren in patients with diabetes mellitus (type I and II) or renal impairment (GFR 2);
- pregnancy, planning pregnancy (see section "Use during pregnancy or breastfeeding");
- hereditary angioedema or angioedema during previous use of ACE inhibitors or ARBs.
Interaction with other medicinal products and other types of interactions
Interactions associated with both valsartan and hydrochlorothiazide
Concomitant use is not recommended.
Lithium
Reversible 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 the use of this combination proves necessary, careful monitoring of plasma lithium levels is recommended.
Concomitant use requires caution
Other antihypertensive drugs
The drug ADENIZ-N may enhance the effect of other drugs with antihypertensive properties (e.g. guanethidine, methyldopa, vasodilators, ACE inhibitors, angiotensin receptor antagonists, β-blockers, calcium channel blockers, direct renin inhibitors and dopamine reuptake inhibitors).
Pressor amines (e.g., noradrenaline, adrenaline)
There may be a reduced response to pressor amines such as norepinephrine, but this is not sufficient to preclude their use.
Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid > 3 g/day, and nonselective NSAIDs
NSAIDs may attenuate the antihypertensive effect of both angiotensin II antagonists and hydrochlorothiazide when used concomitantly. In addition, concomitant administration of ADENIZ-N and NSAIDs may lead to impaired renal function and an increase in plasma potassium levels. Therefore, monitoring of renal function at the beginning of treatment is recommended, as well as adequate hydration of the patient.
In elderly patients, patients with reduced circulating blood volume (including those receiving diuretic therapy) or with renal dysfunction, the simultaneous use of NSAIDs (or COX-2 inhibitors) with ARA II increases the risk of renal dysfunction, including acute renal failure. The combined use of these drugs requires caution and monitoring of renal function.
Interactions related to valsartan
Dual blockade of RAAS with ARA, ACE inhibitors or aliskiren
Caution is required when ARBs, including valsartan, are co-administered with other drugs that block the RAAS, such as ACE inhibitors or aliskiren.
The concomitant use of ARBs, including valsartan, or ACE inhibitors with aliskiren is contraindicated in patients with diabetes mellitus (types I and II), diabetic nephropathy, or renal impairment (GFR 2).
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 levels is recommended.
The risk of hyperkalemia increases when angiotensin II receptor antagonists are used concomitantly with other medicinal products that may increase serum potassium (e.g. potassium-sparing diuretics, potassium supplements, heparin). In such cases, ADENIZ-N, which contains valsartan, should be used with caution and potassium levels should be monitored.
Conveyors
In vitro studies have shown that valsartan is a substrate for the hepatic uptake transporter OATP1B1/OATP1B3 and the hepatic efflux transporter MRP2. The clinical significance of these findings is not yet fully understood. Concomitant use of inhibitors of the uptake transporter (e.g. rifampicin, cyclosporine) or efflux transporter (e.g. ritonavir) may increase systemic exposure to valsartan. Appropriate precautions should be taken when initiating or discontinuing concomitant use of these medicinal products.
Lack of interaction
In drug interaction studies with valsartan, no clinically significant interactions were observed between valsartan and the following drugs: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide. Digoxin and indomethacin may interact with the hydrochlorothiazide component of ADENIZ-N (see "Interactions related to hydrochlorothiazide").
Interactions related to hydrochlorothiazide
Concomitant use requiring caution
Drugs associated with potassium loss and hypokalemia
Drugs associated with potassium loss and hypokalemia (e.g., kaliuretic diuretics, corticosteroids, laxatives, adrenocorticotropic hormone (ACTH), amphotericin, carbenoxolone, penicillin G, salicylic acid and its derivatives, antiarrhythmics).
If it is necessary to prescribe the above-mentioned drugs with the 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 and the level of potassium in the blood plasma.
Drugs that may cause the development of induced torsades de pointes
Due to the risk of hypokalemia, hydrochlorothiazide should be used with caution simultaneously with drugs that may cause the development of torsades de pointes, in particular with class Ia and class III antiarrhythmics and some neuroleptics.
Drugs that affect plasma sodium levels
The hyponatremic effect of diuretics may be enhanced by concomitant administration of such drugs as antidepressants, antipsychotics, antiepileptic drugs, etc. Caution should be exercised when prescribing ADENIZ-N with long-term use of such drugs.
Drugs that can cause torsades de pointes
- Class Ia antiarrhythmic drugs (e.g. quinidine, hydroquinidine, disopyramide).
- Class III antiarrhythmic drugs (e.g. amiodarone, sotalol, dofetilide, ibutilide).
- Some neuroleptics (e.g. thioridazine, chlorpromazine, levopromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol).
- Others (e.g. bepridil, cisapride, diphemanil, erythromycin intravenously, gelofantrine, ketanserin, mizolastine, pentamidine, sparfloxacin, terfenadine, vincamine intravenously).
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 an adverse effect, contributing to the development of digitalis-induced cardiac arrhythmias.
Calcium salts and vitamin D
The use of thiazide diuretics, including hydrochlorothiazide, with vitamin D or calcium salts may lead to an increase in plasma calcium levels. Concomitant use of thiazide diuretics with calcium salts may cause hypercalcemia in patients predisposed to hypercalcemia (e.g., patients with hyperparathyroidism, malignancy, or vitamin D-mediated conditions) by increasing tubular calcium reabsorption.
Antidiabetic drugs (oral antidiabetic drugs and insulin)
Thiazide therapy may affect glucose tolerance. Dose adjustment of the antidiabetic agent 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-blockers increases the risk of hyperglycemia. Thiazide diuretics, including hydrochlorothiazide, may potentiate the hyperglycemic effect of diazoxide.
Medicines used to treat 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 (e.g. atropine, biperiden), presumably by reducing gastrointestinal motility and gastric emptying rate. On the other hand, prokinetics such as cisapride are expected to reduce the bioavailability of thiazide diuretics.
Amantadine
Thiazides, including hydrochlorothiazide, increase the risk of adverse effects caused by amantadine.
Ion exchange resins
The absorption of thiazide diuretics, including hydrochlorothiazide, is reduced by cholestyramine or colestipol. This may result in subtherapeutic effects of the thiazide diuretic. However, spacing the administration of hydrochlorothiazide and the resin so that hydrochlorothiazide is taken at least 4 hours before or 4 to 6 hours after the resin minimizes the risk of interaction.
Cytotoxic agents (e.g., cyclophosphamide, methotrexate)
Thiazides, including hydrochlorothiazide, may reduce the renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Nondepolarizing skeletal muscle relaxants (e.g., tubocurarine)
Thiazides, including hydrochlorothiazide, enhance the effect of curare derivatives.
Cyclosporine
Concomitant use with cyclosporine may increase the risk of hyperuricemia and gout-like complications.
Alcohol, anesthetics and sedatives
In the case of simultaneous use of thiazide diuretics with drugs that can also lower blood pressure (for example, by reducing sympathetic activity of the central nervous system or direct vasodilation), orthostatic hypotension may be potentiated.
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. Such patients should be informed of the possibility of a hyponatremic reaction and monitored appropriately.
Contrast agents containing iodine
In case of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially with high doses of iodine-containing preparations. The patient should be adequately rehydrated before use.
Application features
Electrolyte changes
Potassium
Thiazide diuretics may cause hypokalemia or complicate pre-existing hypokalemia.
Correction of hypokalemia is recommended before initiating thiazide therapy. Concomitant hypomagnesemia may make hypokalemia more difficult to correct.
Since ADENIZ-N contains an angiotensin II receptor antagonist, caution should be exercised when ADENIZ-N is used concomitantly with potassium salts, potassium-sparing diuretics, salt substitutes containing potassium, or other medicinal products that may increase potassium levels (e.g. heparin). Cases of hypokalaemia have been reported during treatment with thiazide diuretics. It is recommended that serum potassium and magnesium levels be monitored regularly in patients with conditions associated with increased potassium loss. Electrolyte balance should be monitored in all patients receiving thiazide diuretics.
Patients with sodium and/or circulating blood volume (CV) deficiency
Treatment with thiazide diuretics is often associated with the development of hyponatremia or with exacerbation of pre-existing hyponatremia and hypochloremic alkalosis. This may be accompanied by neurological symptoms (vomiting, confusion, apathy). Thiazide diuretics should be used only after correction of hyponatremia. It is also necessary to regularly monitor the concentration of sodium in the blood serum.
Thiazides increase the urinary excretion of magnesium, which can ultimately lead to hypomagnesemia.
In patients with severe sodium and/or volume depletion, such as those receiving high doses of diuretics, symptomatic hypotension may occasionally occur after initiation of ADENIZ-N. Therefore, sodium and/or volume depletion should be corrected before initiating therapy with this drug.
In case of hypotension, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of saline. Treatment may be resumed as soon as blood pressure has stabilized.
Thiazide diuretics reduce urinary calcium excretion and may cause an increase in serum calcium. Thiazide diuretics should be used only after correction of hypercalcemia or treatment of the underlying condition. Serum calcium should be monitored regularly.
Patients with severe chronic heart failure or other conditions with increased RAAS activity
In patients whose renal function may depend on RAAS activity (e.g., patients with 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 ADENIZ-N in patients with severe chronic heart failure is not justified.
Since it cannot be excluded that due to inhibition of the RAAS, the use of the drug ADENIZ-N may also be associated with impaired renal function, the drug should not be used in such patients.
Renal artery stenosis
The drug ADENIZ-N should be used with extreme caution in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, as blood urea and plasma creatinine levels may increase in such patients.
Primary hyperaldosteronism
ADENIZ-N should not be used in patients with primary hyperaldosteronism, as their renin-angiotensin system is not activated.
Aortic and mitral valve stenosis, hypertrophic obstructive cardiomyopathy (HOCM)
As with other vasodilators, patients with aortic and mitral valve stenosis or HFMD require special caution.
Kidney dysfunction
For patients with mild to moderate renal impairment (creatinine clearance ≥ 30 ml/min), no dose adjustment is required.
The drug ADENIZ-N is contraindicated in patients with severe renal insufficiency (creatinine clearance ˂ 30 ml/min). Thiazide diuretics can 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 due caution in combination with loop diuretics even in patients with creatinine clearance ˂ 30 ml/min.
In patients with impaired renal function (creatinine clearance < 60 ml/min), concomitant use of angiotensin receptor blockers, including ADENIZ-N or ACE inhibitors, with aliskiren is contraindicated.
There is no experience with the use of valsartan in patients with end-stage renal disease (creatinine clearance < 10 ml/min) or in patients undergoing dialysis.
Kidney transplantation
There are currently no data on the safety of the drug in patients who have recently undergone a kidney transplant.
Liver dysfunction
Caution is required when treating patients with impaired liver function. For patients with mild to moderate liver function disorders without cholestasis, dose adjustment is not required. However, ADENIZ-N should be used with caution. Liver disease does not significantly alter the pharmacokinetic parameters of hydrochlorothiazide.
Thiazides can cause electrolyte imbalance, hepatic encephalopathy and hepatorenal syndrome. Therefore, ADENIZ-N should be prescribed to such patients only after a risk-benefit assessment and monitoring of clinical and laboratory parameters. ADENIZ-N is contraindicated in patients with biliary cirrhosis or cholestasis.
Angioedema
Angioedema (including laryngeal and glottis swelling resulting in airway obstruction and/or swelling of the face, lips, pharynx and/or tongue) has been reported in patients treated with valsartan, some of whom had a history of angioedema with other drugs, including other angiotensin II receptor antagonists, including ACE inhibitors. If angioedema develops, treatment with angiotensin II receptor antagonists should be discontinued immediately. Re-administration of ADENIZ-N is contraindicated.
Systemic lupus erythematosus
Thiazide diuretics have been reported to exacerbate or activate the manifestations of systemic lupus erythematosus.
Other metabolic disorders
Thiazide diuretics may alter glucose tolerance and increase serum cholesterol, triglycerides and uric acid levels, which may exacerbate hyperuricemia and lead to gout. Therefore, ADENIZ-N is not recommended for use in patients with hyperuricemia and/or gout. For patients with diabetes mellitus, dosage adjustment of insulin or oral hypoglycemic agents may be required. Thiazides may reduce urinary calcium excretion and cause transient and slight increases in serum calcium in the absence of calcium metabolism disorders. Significant hypercalcemia may indicate that the patient has underlying hyperparathyroidism. Thiazides should be discontinued before performing tests to assess parathyroid function.
Photosensitivity reactions have been reported with thiazide diuretics. If a photosensitivity reaction occurs during treatment, it is recommended to discontinue treatment. If re-administration of the diuretic is considered necessary, it is recommended to protect exposed skin from sunlight or artificial ultraviolet radiation.
Pregnancy
Angiotensin II receptor antagonists should not be initiated during pregnancy 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.
General recommendations
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.
Acute angle-closure glaucoma
The use of hydrochlorothiazide and a sulfonamide has been associated with an idiosyncratic reaction resulting in choroidal effusion with visual field defect, transient myopathy, and acute angle-closure glaucoma. Acute visual loss or eye pain has been reported. These symptoms usually occur within a few hours to a week of drug administration. Untreated acute angle-closure glaucoma can lead to irreversible vision loss.
The drug should be discontinued immediately. If intraocular pressure remains uncontrolled, medical or surgical treatment may be necessary. A risk factor for the development of acute angle-closure glaucoma is an allergic reaction to the use of sulfonamides or penicillins.
Patients with heart failure, previous myocardial infarction
In patients whose renal function depends on RAAS activity (e.g. patients with severe heart failure), treatment with ACE inhibitors or angiotensin receptor antagonists may be associated with oliguria and/or progressive azotemia and, in rare cases, with acute renal failure and fatal outcome. Evaluation of patients with heart failure or after myocardial infarction should always include assessment of renal function.
Non-melanoma skin cancer (NMSC)
An increased risk of NSCLC (basal cell carcinoma and squamous cell carcinoma) with increasing cumulative dose of hydrochlorothiazide was observed in two epidemiological studies based on the Danish National Cancer Registry. The photosensitizing effect of hydrochlorothiazide may be a potential mechanism for the development of NSCLC.
Patients taking hydrochlorothiazide should be informed of the risk of NMSD. It is recommended that such patients regularly examine their skin for new lesions and immediately report any suspicious skin changes to their physician.
Possible preventive measures to minimize the risk of skin cancer include limiting exposure to sunlight and ultraviolet radiation, and using adequate protection when exposed to sunlight. Suspicious lesions should be investigated promptly, including histological examination and biopsy. The use of hydrochlorothiazide should also be reconsidered in patients with a history of NMSC.
Dual blockade of RAAS
There is evidence that the concomitant use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren increases the risk of hypotension, hyperkalemia and decreased renal function (including the occurrence of acute renal failure). For dual blockade of the RAAS, the concomitant use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren is not recommended.
When the combination of these drugs (dual blockade) is considered absolutely necessary, treatment should only be carried out under medical supervision and with frequent and careful monitoring of renal function, fluid and electrolyte balance and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients
