Instructions Tiara Duo film-coated tablets 160 mg + 12.5 mg blister No. 84
Composition
active ingredients: 1 tablet contains: valsartan 80 mg, hydrochlorothiazide 12.5 mg or valsartan 160 mg, hydrochlorothiazide 12.5 mg, or valsartan 160 mg, hydrochlorothiazide 25 mg;
Excipients: microcrystalline cellulose, crospovidone, colloidal anhydrous silica, magnesium stearate, Opadry II 85F pink - for 80/12.5 mg and 160/25 mg tablets; Opadry II 85F white - for 160/12.5 mg tablets.
Dosage form
Film-coated tablets.
Main physicochemical properties:
Tiara Duo 80/12.5 mg: round tablets, coated with a pink shell, with a biconvex surface;
Tiara Duo 160/12.5 mg: round tablets, coated with a white or almost white coating, with a biconvex surface;
Tiara Duo 160/25 mg: round tablets, coated with a pink shell, with a biconvex surface.
Pharmacotherapeutic group
Angiotensin II antagonists 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 with the participation of 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 the secretion of aldosterone.
Valsartan is a potent and specific angiotensin II receptor (AR) antagonist for oral administration. It acts selectively on the AT1 receptor subtype, which mediates 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 effects of AT1 receptors. Valsartan does not have any 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 < 0.05) in patients treated with valsartan than in patients treated with an ACE inhibitor (2.6% vs. 7.9%, respectively). In patients previously treated with an ACE inhibitor, dry cough developed in 68.5% of cases (P < 0.05), compared with 19.5% of cases with valsartan and 19% with a thiazide diuretic.
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 known to play an important role in regulating cardiovascular function.
The drug in patients with arterial 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.
Withdrawal of valsartan does not lead to a sudden increase in blood pressure (rebound syndrome) or other adverse reactions.
Valsartan does not affect the levels of total cholesterol, triglycerides, serum glucose, or uric acid in patients with hypertension.
Thiazide diuretics affect the cortical part of the distal convoluted renal tubules, where receptors with high sensitivity to diuretics are located, 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. As a result of the diuretic effect, there is a decrease in circulating blood volume (CVL), which increases renin activity, aldosterone secretion, urinary potassium excretion, and therefore the concentration of potassium in the blood serum decreases. The relationship between renin and aldosterone is mediated by angiotensin II, so the use of ARA II will reduce the potassium loss associated with the use of a thiazide diuretic.
Valsartan. After oral administration of the drug, the absorption of valsartan and hydrochlorothiazide is rapid, but the extent of absorption varies widely. The average absolute bioavailability of Tiara Duo is 23%. The pharmacokinetic curve of valsartan has a descending multiexponential nature (t1/2α < 1 hour and t1/2β almost 9 hours). In the range of doses studied, the kinetics of valsartan are linear. With repeated administration of the drug, no changes in kinetic parameters were noted. 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 largely bound to serum proteins (94–97%), mainly to albumin. The volume of distribution at steady state is low (17 l). Compared with hepatic blood flow (30 l/h), plasma clearance of valsartan is relatively slow (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 from approximately 8 hours after administration, plasma concentrations of the drug are similar in both the fasted and fed state. The decrease in AUC is not accompanied by a significant decrease in therapeutic effect.
Hydrochlorothiazide. Absorption of hydrochlorothiazide after oral administration is rapid (tmax – 2 hours). The pharmacokinetics of the drug in the distribution and elimination phases are generally described by a biexponential descending curve; the terminal phase half-life is 6–15 hours. In the therapeutic dose range, the average area under the concentration-time curve (AUC) increases directly proportionally to the increase in dose. 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 with urine: more than 95% of the dose is unchanged and approximately 4% is excreted in the urine: more than 95% of the dose is unchanged and approximately 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 were observed compared with the corresponding indicator when taken in the fasted state. The range of these changes is small and has no clinical significance.
Valsartan/hydrochlorothiazide. When co-administered with valsartan, the systemic bioavailability of hydrochlorothiazide is reduced by 30%. Co-administration of hydrochlorothiazide, on the other hand, does not significantly affect the kinetics of valsartan. However, this interaction does not affect the efficacy of the combined use of valsartan and hydrochlorothiazide. In controlled clinical trials, a clear antihypertensive effect of this combination was found, which exceeded the effect of each of the components 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 younger patients, but this was not clinically significant.
Limited data suggest that in elderly patients (both healthy and those suffering from arterial hypertension), the systemic clearance of hydrochlorothiazide is lower 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 Tiara Duo in patients with severe renal impairment (creatinine clearance < 30 ml/min) and patients on 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.
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 impairment, the mean elimination half-life is almost doubled due to a significant reduction 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, which is understandable given that this drug is excreted exclusively by the kidneys.
In the presence of renal impairment, the mean peak plasma levels and AUC of hydrochlorothiazide are increased and the urinary excretion rate is decreased. A three-fold increase in the AUC of hydrochlorothiazide has been observed in patients with mild to moderate renal impairment. An eight-fold increase in the AUC has been observed in patients with severe renal impairment. Hydrochlorothiazide is contraindicated in patients with severe renal impairment.
Non-melanoma skin cancer (NMSC).
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 hazard 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: 1.7–2.6), increasing to OR 3.9 (3.0–4.9) at the high dose (25,000 mg) and OR 7.7 (5.7–10.5) at the highest dose (100,000 mg). For example, a cumulative dose of 100,000 mg corresponds to daily use of a defined daily dose of 25 mg over a period of more than 10 years.
Indication
Essential hypertension in patients whose blood pressure is not adequately controlled by monotherapy.
Contraindication
Hypersensitivity to any of the components of the drug Tiara Duo or to other sulfonamide derivatives.
Severe liver dysfunction, cirrhosis and cholestasis.
Severe renal impairment (creatinine clearance < 30 ml/min), anuria.
Refractory hypokalemia, hyponatremia, hypercalcemia, symptomatic hyperuricemia.
Concomitant use of ARBs, including valsartan, or ACE inhibitors with aliskiren in patients with diabetes mellitus (type I and II) or renal impairment (glomerular filtration rate (GFR) < 60 ml/min/1.73 m2).
Pregnant women or women planning to become pregnant (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, particularly hydrochlorothiazide. Due to the lack of experience with the concomitant use of valsartan and lithium, this combination is not recommended. If such a combination proves necessary, careful monitoring of plasma lithium levels is recommended.
Concomitant use requiring caution
Other antihypertensive drugs
The drug Tiara Duo may enhance the effect of other drugs with antihypertensive properties (for example, guanethidine, methyldopa, vasodilators, ACE inhibitors, ARBs, β-blockers, calcium channel blockers and dopamine reuptake inhibitors).
Pressor amines (e.g., noradrenaline, adrenaline)
There may be a reduced response to pressor amines such as norepinephrine, which is not sufficient to prohibit their use.
Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid > 3 g/day, and nonselective NSAIDs
NSAIDs may weaken the antihypertensive effect of both ARA II and hydrochlorothiazide when used simultaneously. In addition, the simultaneous use of Tiara Duo 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 BCC (especially 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 the RAAS with ARBs, ACE inhibitors, or aliskiren
When ARBs, including valsartan, are used concomitantly with other RAAS-blocking medicinal products such as ACE inhibitors or aliskiren, the incidence of hypotension, syncope, hyperkalaemia and renal dysfunction (including acute renal failure) is increased compared with monotherapy. Dual blockade of the RAAS with ACE inhibitors, ARBs or aliskiren is not recommended. If dual RAAS blockade is necessary, it should be carried out only under specialist supervision and with close monitoring of renal function, electrolytes and blood pressure.
The concomitant use of ARBs, including valsartan, or ACE inhibitors with aliskiren is contraindicated in patients with severe renal impairment (GFR < 60 ml/min), patients with diabetes mellitus (types I and II), and patients with diabetic nephropathy.
Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, and other substances that may increase potassium levels
If it is necessary to use a medicinal product that affects potassium levels in combination with valsartan, monitoring of potassium levels in the blood plasma is recommended.
With simultaneous use of ARA II with other drugs that can increase the content of potassium in the blood serum (for example, potassium-sparing diuretics, potassium-based drugs, heparin), the risk of developing hyperkalemia increases. In such cases, the drug Tiara Duo, containing valsartan, should be used with caution and potassium levels should be monitored.
Conveyors
In vitro data indicate 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 fully understood. Concomitant use of inhibitors of uptake transporters (e.g. rifampin, cyclosporine) or efflux transporters (e.g. ritonavir) may lead to increased systemic exposure to valsartan. Caution is advised when initiating or ending concomitant treatment with such medicinal products.
Lack of interaction
In drug interaction studies with valsartan, no clinically significant interactions were observed between valsartan and any of the following drugs: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide. Digoxin and indomethacin may interact with the hydrochlorothiazide component of Tiara Duo (see interactions related to hydrochlorothiazide).
Interactions related to hydrochlorothiazide
Concomitant use requiring caution
Medicinal products associated with potassium loss and hypokalemia The hypokalemic effect of hydrochlorothiazide may be enhanced by concomitant use of kaliuretic diuretics, corticosteroids, laxatives, adrenocorticotropic hormones (ACTH), amphotericin, carbenoxolone, penicillin G, salicylic acid and derivatives, and antiarrhythmics.
If it is necessary to prescribe these drugs with the combination of hydrochlorothiazide and valsartan, it is recommended to monitor the level of potassium in the blood plasma.
Drugs that can induce torsades de pointes
Due to the risk of hypokalemia, hydrochlorothiazide should be used with caution concomitantly with drugs that may induce torsades de pointes, in particular class Ia and III antiarrhythmics and some antipsychotics.
Drugs that affect serum 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 with prolonged use of these 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, 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 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. The simultaneous 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) due to increased tubular calcium reabsorption.
Antidiabetic agents (oral medications 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.
β-blockers and diazoxide
Concomitant use of thiazide diuretics, including hydrochlorothiazide, with β-blockers may increase the risk of hyperglycemia. Thiazide diuretics, including hydrochlorothiazide, may potentiate the hyperglycemic effect of diazoxide.
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 and other drugs affecting gastric motility The bioavailability of thiazide diuretics may be increased by anticholinergics (e.g. atropine, biperiden), probably by reducing gastrointestinal motility and gastric emptying rate. Conversely, prokinetic drugs such as cisapride may be expected to reduce the bioavailability of thiazide-type diuretics.
Amantadine
Thiazides, including hydrochlorothiazide, may increase the risk of adverse reactions 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, staggering the timing of hydrochlorothiazide and resin administration so that hydrochlorothiazide is administered at least 4 hours before or 4 to 6 hours after the resin administration may minimize 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 effects of skeletal muscle relaxants such as curare derivatives.
Cyclosporine
Concomitant use with cyclosporine may increase the risk of hyperuricemia and gout-like complications.
Alcohol, anesthetics and sedative medications.
When thiazide diuretics are used concomitantly with drugs that can also lower blood pressure (e.g., through decreased sympathetic central nervous system activity or direct vasodilator action), potentiation of orthostatic hypotension is possible.
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 drugs. 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 Tiara Duo contains ARA II, caution should be exercised when using this medicinal product Tiara Duo with potassium salts, potassium-sparing diuretics, salt substitutes containing potassium, or other medicinal products that may increase potassium levels (e.g. heparin). Cases of hypokalemia have been reported during treatment with thiazide diuretics. It is recommended to regularly monitor serum potassium and magnesium levels in patients with conditions involving increased potassium loss. Electrolyte balance should be monitored in all patients receiving thiazide diuretics.
Patients with sodium and/or BCC 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 only be used after correction of hyponatremia. Serum sodium concentration should be monitored regularly.
Thiazides increase the urinary excretion of magnesium, which can ultimately lead to hypomagnesemia.
In patients with severe sodium and/or volume depletion (e.g. those receiving high doses of diuretics), symptomatic hypotension may occasionally occur after initiation of Tiara Duo. Therefore, sodium and/or volume depletion should be corrected before initiating therapy with this medicinal product.
In case of hypotension, the patient should be placed in the supine position and, if necessary, an intravenous infusion of saline should be given. Treatment can be continued as soon as the blood pressure has stabilized.
Calcium
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 with acute renal failure and death. Evaluation of patients with heart failure or after myocardial infarction should always include assessment of renal function.
The use of Tiara Duo 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 Tiara Duo may also be associated with impaired renal function, Tiara Duo 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 of the artery to a solitary kidney, as blood urea and plasma creatinine levels may increase in such patients.
Primary hyperaldosteronism.
Tiaru Duo should not be used in patients with primary hyperaldosteronism, as their RAAS is not activated.
Aortic and mitral valve stenosis, hypertrophic obstructive cardiomyopathy.
As with other vasodilators, patients with aortic and mitral valve stenosis or hypertrophic obstructive cardiomyopathy require special caution.
Kidney dysfunction.
No dose adjustment is required for patients with renal impairment with creatinine clearance ≥30 mL/min.
When using the drug Tiara Duo in patients with renal failure, periodic monitoring of serum potassium, creatinine, and uric acid levels is recommended.
Thiazide diuretics may provoke azotemia in patients with chronic renal impairment. In patients with renal impairment (creatinine clearance < 60 ml/min), concomitant use of angiotensin receptor blockers, in particular Tiara Duo, 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 is no experience to date regarding 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. In patients with mild to moderate liver function disorders without cholestasis, dose adjustment is not required, but Tiara Duo should be used with caution. Liver disease does not significantly alter the pharmacokinetic parameters of hydrochlorothiazide.
Thiazides may cause electrolyte imbalance, hepatic encephalopathy and hepatorenal syndrome. Therefore, Tiara Duo should be prescribed to such patients only after a risk-benefit assessment and monitoring of clinical and laboratory parameters.
The drug Tiara Duo is contraindicated in patients with biliary cirrhosis or cholestasis.
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, Tiara Duo is not recommended for use in patients with hyperuricemia and/or gout. For diabetic patients, 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.
Photosensitivity reactions have been reported with thiazide diuretics. If a photosensitivity reaction occurs during treatment, it is recommended to discontinue treatment. If repeated use of the diuretic is considered necessary, it is recommended to protect exposed skin from sunlight or artificial ultraviolet radiation.
Pregnancy.
ARBs should not be initiated during pregnancy. Unless continued ARB 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, ARBs should be stopped immediately, and, if appropriate, alternative therapy should be started.
General warnings.
Caution should be exercised when using the drug in patients with a history of hypersensitivity to other ARA II. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergies and asthma.
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 taking valsartan. Some of these patients had a history of angioedema with other medicinal products, including other ARBs, including ACE inhibitors. If angioedema develops, ARB treatment should be discontinued immediately. Re-administration is contraindicated.
Choroidal effusion, acute myopia, and secondary angle-closure glaucoma.
The use of hydrochlorothiazide, sulfonamides or sulfonamide derivatives has been associated with the occurrence of an idiosyncratic reaction that may lead to choroidal effusion with visual field defect, transient myopia, acute transient myopia and acute angle-closure glaucoma.
The use of hydrochlorothiazide, sulfonamides, or sulfonamide derivatives may cause an idiosyncratic reaction resulting in choroidal effusion with visual field defect, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and usually occur within hours to weeks of starting the drug. Untreated glaucoma can lead to irreversible vision loss.
The main treatment is to stop taking the drug as soon as possible. If the intraocular pressure remains uncontrolled, medical or surgical treatment should be initiated. A risk factor for the development of acute angle-closure glaucoma is an allergic reaction to the use of sulfonamides or penicillin.
Double blockade of RAAS.
There is evidence that the concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Therefore, dual blockade of the RAAS through the combination of ACE inhibitors, angiotensin II receptor blockers or aliskiren is not recommended (see section 4.5). If treatment with two RAAS blockers is considered absolutely necessary, it should only be carried out under specialist supervision and with frequent and careful monitoring of renal function, electrolytes and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
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 NMSC. It is recommended that such patients regularly examine their skin for new lesions and promptly report any suspicious skin changes. Possible preventive measures to minimize the risk of skin cancer include limiting exposure to sunlight and ultraviolet rays and using adequate protection when exposed to sunlight. Suspicious skin lesions should be promptly investigated, including histological examination and biopsy. Use of hydrochlorothiazide
