Instructions Valsartan N-Teva film-coated tablets 80 mg + 12.5 mg blister No. 30
Composition
active ingredients: valsartan, hydrochlorothiazide;
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, or valsartan 320 mg, hydrochlorothiazide 12.5 mg, or valsartan 320 mg, hydrochlorothiazide 25 mg;
excipients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, povidone K29-KZ2, talc, magnesium stearate, colloidal anhydrous silicon dioxide;
tablet shell 80/12.5 mg: Opadry II 85G34642 Pink (polyvinyl alcohol, talc, titanium dioxide (E 171), macrogol 3350, lecithin, red iron oxide (E 172), yellow iron oxide (E 172), black iron oxide (E 172));
tablet shell 160/12.5 mg: Opadry II 85G25455 Red (polyvinyl alcohol, talc, titanium dioxide (E 171), macrogol 3350, lecithin, red iron oxide (E 172), Sunset Yellow dye (E 110));
tablet shell 160/25 mg: Opadry II 85G23675 Orange (polyvinyl alcohol, talc, titanium dioxide (E 171), macrogol 3350, lecithin, red iron oxide (E 172), yellow iron oxide (E 172), black iron oxide (E 172));
tablet shell 320/12.5 mg: Opadry II pink 85G34643 (polyvinyl alcohol, talc, titanium dioxide (E 171), macrogol 3350, lecithin, red iron oxide (E 172), yellow iron oxide (E 172));
tablet shell 320/25 mg: Opadry II yellow 85G32408 (polyvinyl alcohol, talc, titanium dioxide (E 171), macrogol 3350, lecithin, iron oxide yellow (E 172), iron oxide red (E 172)).
Dosage form
Film-coated tablets.
Main physicochemical properties: 80/12.5 mg tablets – pink, oval, biconvex film-coated tablets, embossed with “V” on one side and “H” on the other;
160/12.5 mg tablets – red, oval, biconvex film-coated tablets, embossed with “V” on one side and “H” on the other;
160/25 mg tablets – orange, oval, biconvex film-coated tablets, embossed with “V” on one side and “H” on the other;
320/12.5 mg tablets – pink, oval, biconvex film-coated tablets, embossed with “H” on one side and “V” on the other;
320/25 mg tablets – yellow, oval, biconvex, film-coated tablets, embossed with “H” on one side and “V” on the other, with a breakline on one side and lines on the sides.
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 antagonist (ARB) 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 due to 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 (ACEI), 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% versus 7.9%, respectively). Patients previously treated with an ACE inhibitor developed dry cough, with valsartan and thiazide diuretics reporting this complication in 19.5% and 19% of patients, respectively, respectively, while cough was reported in 68.5% of patients treated with an ACE inhibitor (P<0.05).
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 decrease 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. Cancellation of valsartan does not lead to a sharp increase in blood pressure (rebound syndrome) or other side effects. Valsartan does not affect the level of total cholesterol, triglycerides, serum glucose or uric acid in patients with arterial 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 approximately equally. As a result of the diuretic effect, a decrease in the volume of circulating blood plasma is observed, resulting in increased renin activity, aldosterone secretion, urinary potassium excretion and, consequently, a decrease in serum potassium concentration. The relationship between renin and aldosterone is mediated by angiotensin II, so the appointment of ARA II will reduce the potassium loss associated with the use of a thiazide diuretic.
Pharmacokinetics.
Valsartan. After oral administration, valsartan and hydrochlorothiazide are rapidly absorbed, but the extent of absorption varies widely. The average absolute bioavailability of Valsartan H-Teva is 23%. The pharmacokinetic curve of valsartan has a descending multiexponential nature (t1/2α <1 h and t1/2β almost 9 hours). 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 concentration of the drug in the blood plasma in women and men was the same. Valsartan is largely bound to serum proteins (94-97%), mainly to albumin. The volume of distribution during the equilibrium 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 oral dose), 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 administration, plasma concentrations are similar in both the fasted and fed state. However, the decrease in AUC is not accompanied by a significant decrease in therapeutic effect.
Hydrochlorothiazide. Absorption of hydrochlorothiazide after oral administration is rapid (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 phase half-life is 6-15 hours. In the therapeutic dose range, the average AUC value increases in direct proportion to the increase in dose. With repeated administration, the pharmacokinetics of hydrochlorothiazide do not change; when administered once a day, 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 in the form of a hydrolysate - 2-amino-4-chloro-m-benzenedisulfonamide. When hydrochlorothiazide is taken simultaneously with food, both an increase and a decrease in its systemic bioavailability were noted compared with the corresponding indicator when taken on an empty stomach. 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 approximately 30%. Co-administration of hydrochlorothiazide does not significantly affect the kinetics of valsartan. However, this interaction does not affect the efficacy of the combined use of valsartan and hydrochlorothiazide. Controlled clinical trials have shown a clear antihypertensive effect of this combination, which exceeded the effect of each component separately, as well as the effect of placebo.
Pharmacokinetics in specific patient groups
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 Valsartan H-Teva in patients with severe renal impairment (creatinine clearance <30 ml/min) or patients on haemodialysis. Valsartan is highly bound to plasma proteins and is not removed by haemodialysis; hydrochlorothiazide, on the contrary, is removed from the body by haemodialysis. In the presence of renal dysfunction, the mean peak plasma levels and AUC values of hydrochlorothiazide increase, and the urinary excretion rate decreases. In patients with mild and moderate renal insufficiency, the mean half-life 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.
Hepatic impairment. The systemic exposure of valsartan in patients with mild (n=6) and moderate (n=5) hepatic impairment was 2-fold higher 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.
Non-melanoma skin cancer (NMSC). Available epidemiological data suggest a cumulative dose-dependent association between hydrochlorothiazide exposure and the development of NMSC. One study included 71,533 cases of basal cell carcinoma (BCC) (including 1,430,833 controls) and 8,629 cases of squamous cell carcinoma (SCC) (including 172,462 controls). High-dose hydrochlorothiazide (≥50,000 mg cumulative) was associated with an adjusted hazard ratio (OR) of 1.29 (95% CI: 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for SCC. A cumulative dose-response relationship was observed for both BCC and SCC. Another study showed a possible association between lip cancer and hydrochlorothiazide use: 633 lip cancer cases 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) 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 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 or to other sulfonamide derivatives, as well as to peanut or soy.
Severe liver dysfunction, biliary cirrhosis and cholestasis.
Anury.
Refractory hypokalemia, hyponatremia, hypercalcemia, symptomatic hyperuricemia.
Concomitant use of angiotensin receptor antagonists (ARBs), including valsartan, or angiotensin-converting enzyme inhibitors (ACEIs) with aliskiren in patients with diabetes mellitus (type I and II) or renal impairment (GFR <60 ml/min/1.73 m2).
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 combination proves necessary, careful monitoring of plasma lithium levels is recommended.
Concomitant use requires caution
Other antihypertensive drugs: Valsartan H-Teva may enhance the effect of other drugs with antihypertensive properties (such as guanethidine, methyldopa, vasodilators, ACE inhibitors, ARBs, beta-blockers, calcium channel blockers and direct renin inhibitors).
Non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors, acetylsalicylic acid >3 g/day and non-selective NSAIDs. NSAIDs may reduce the antihypertensive effect of both ARA II and hydrochlorothiazide when used concomitantly. In addition, concomitant administration of Valsartan H-Teva and NSAIDs may lead to deterioration of renal function and an increase in plasma potassium levels. Therefore, monitoring of renal function at the start 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 worsening renal function, 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. Caution is advised when ARBs, including valsartan, are used concomitantly with other RAAS-blocking agents such as ACE inhibitors or aliskiren. This has been associated with an increased incidence of hypotension, loss of consciousness, hyperkalaemia and renal dysfunction (including acute renal failure) compared with monotherapy. Therefore, dual blockade of the RAAS by the combined use of ACE inhibitors, ARBs or aliskiren is not recommended. If dual blockade of the RAAS is considered absolutely necessary, treatment should only be carried out 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 in patients with diabetes mellitus (type I and II), diabetic nephropathy or renal impairment (GFR <60 ml/min/1.73 m2) is contraindicated (see section "Contraindications").
Concomitant use is not recommended.
Potassium-sparing diuretics, potassium-containing food supplements, salt substitutes containing potassium and other substances that may increase potassium levels. In the case of using 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 serum potassium (for example, potassium-sparing diuretics, potassium-based drugs, heparin), the risk of developing hyperkalemia increases. In such cases, Valsartan N-Teva, which contains valsartan, should be used with caution and potassium levels should be monitored.
Transporters. 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 agents.
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 the drug (see interactions related to hydrochlorothiazide).
Interactions related to hydrochlorothiazide
Concomitant use requires 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, ACTH, amphotericin, carbenoxolone, penicillin G, salicylic acid and derivatives, and antiarrhythmics. If these drugs are to be administered in combination with hydrochlorothiazide and valsartan, monitoring of plasma potassium levels is recommended.
Drugs affecting serum sodium levels. The hyponatremic effect of diuretics may be enhanced by concomitant use of drugs such as antidepressants, antipsychotics, antiepileptics, etc. Caution is advised with prolonged use of these drugs.
Drugs that may cause torsades de pointes
Class Ia antiarrhythmic drugs (e.g. quinidine, hydroquinidine, disopyramide).
Class III antiarrhythmic drugs (e.g. amiodarone, sotalol, dofetilide, ibutilide).
Some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol).
Others (e.g. bepridil, cisapride, diphemanil, erythromycin intravenously, halofantrine, ketanserin, mizolastine, pentamidine, sparfloxacin, terfenadine, vincamine intravenously).
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 increase 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 agents (oral agents 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.
Beta-blockers and diazoxide: Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta-blockers increases the risk of hyperglycemia. Thiazide diuretics, including hydrochlorothiazide, may potentiate the hyperglycemic effect of diazoxide.
Medicines used in the treatment of gout (probenecid, sulfinpyrazone and allopurinol). The dose of medicines that promote the excretion of uric acid may need to be adjusted, as hydrochlorothiazide may increase the level of uric acid in the blood plasma. The dose of probenecid or sulfinpyrazone may need to be increased. Concomitant use of thiazide diuretics, including hydrochlorothiazide, may increase the frequency of hypersensitivity reactions to allopurinol.
Anticholinergics and other agents 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 agents such as cisapride may be expected to reduce the bioavailability of thiazide-type diuretics.
Amantadine: Thiazides, including hydrochlorothiazide, increase the risk of adverse effects caused by amantadine.
Ion exchange resins. 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 the resin so that hydrochlorothiazide is taken at least 4 hours before or 4 to 6 hours after the resin 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.
Non-depolarizing skeletal muscle relaxants (e.g. tubocurarine). Thiazides, including hydrochlorothiazide, potentiate the effects of skeletal muscle relaxants such as curare derivatives.
Cyclosporine: Concomitant administration with cyclosporine may increase the risk of hyperuricemia and gout-like complications.
Alcohol, barbiturates and anesthetics: When thiazide diuretics are used concomitantly with drugs that can also lower blood pressure (e.g. by reducing the activity of the sympathetic central nervous system or by 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.
Iodine-containing contrast media: In case of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially with high doses of iodine-containing agents. The patient should be adequately rehydrated before use.
Application features
Serum 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 cause hypokalemia that is more difficult to correct.
Patients with sodium and/or volume depletion. Thiazide diuretics may cause hyponatremia and hypochloremic alkalosis. This may be accompanied by neurological symptoms (vomiting, confusion, apathy). Thiazide diuretics should only be used after correction of hyponatremia. Patients receiving thiazide diuretics (including hydrochlorothiazide) should be observed for clinical signs of fluid or electrolyte imbalance. Serum sodium levels should be monitored regularly.
Thiazides (including hydrochlorothiazide) increase the urinary excretion of magnesium, which may result in 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 therapy with the drug. Therefore, correction of sodium and/or volume depletion should be considered before initiating therapy with this drug.
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 may be continued as soon as blood pressure has stabilized.
Calcium: Thiazide diuretics reduce calcium excretion, which may cause hypercalcemia. 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, rarely with acute renal failure and/or fatal outcome. Evaluation of patients with heart failure or after myocardial infarction should always include assessment of renal function. Use of the drug 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 may also be associated with impaired renal function, Valsartan N-Teva 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 renal artery to a solitary kidney, as blood urea and plasma creatinine levels may increase in such patients.
Primary hyperaldosteronism: Valsartan H-Teva 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: As with other vasodilators, patients with aortic and mitral valve stenosis or hypertrophic obstructive cardiomyopathy (HOCM) require special caution.
Renal impairment. For patients with mild to moderate renal impairment (creatinine clearance >30 ml/min), no dose adjustment is required (see section “Dosage and administration”). The drug should be used with caution in severe renal impairment (creatinine clearance <30 ml/min). Thiazide diuretics may provoke azotemia in patients with chronic renal impairment. They are ineffective as monotherapy in severe renal impairment (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. Periodic monitoring of serum potassium, creatinine and uric acid is recommended when using the drug in patients with renal impairment.
The concomitant use of ARA II, including valsartan, or ACE inhibitors with aliskiren in patients with impaired renal function (GFR <60 ml/min/1.73 m2) is contraindicated (see sections 4.3 and 4.5). 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 currently no experience regarding the safety of the drug in patients who have recently undergone kidney transplantation.
Systemic lupus erythematosus: Thiazide diuretics (including hydrochlorothiazide) have been reported to exacerbate or activate the manifestations of systemic lupus erythematosus.
Other metabolic disorders. Thiazide diuretics (including hydrochlorothiazide) may alter glucose tolerance and increase serum cholesterol, triglycerides and uric acid levels, which may exacerbate hyperuricemia and lead to gout. Therefore, Valsartan H-Teva is not recommended for use in patients with hyperuricemia and/or gout. Patients with diabetes mellitus may require adjustment of the dosage of insulin or oral hypoglycemic agents. Thiazides may reduce urinary calcium excretion and cause a transient, slight increase in serum calcium in the absence of disturbances of calcium metabolism. 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 precautions: Caution should be exercised when administering the drug to patients with a history of hypersensitivity to other ARBs. 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 whom had a history of angioedema with other drugs, including ACE inhibitors. If angioedema develops, treatment with this drug should be discontinued immediately. Re-administration is contraindicated.
Choroidal effusion, acute myopia and secondary angle-closure glaucoma. Sulfonamide drugs 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 acute angle-closure glaucoma may lead to irreversible vision loss. Initial treatment includes discontinuation of the drug as soon as possible. If intraocular pressure remains uncontrolled, a decision may be made to consider prompt medical or surgical treatment. Risk factors for acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillins.
Acute Respiratory Toxicity: Very rare cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported following the administration of hydrochlorothiazide. Pulmonary edema usually develops within minutes to hours of hydrochlorothiazide administration. Initial symptoms include dyspnea, fever, worsening pulmonary function, and hypotension. If ARDS is suspected, the drug should be discontinued and appropriate treatment instituted. Hydrochlorothiazide should not be given to patients who have previously experienced ARDS after taking hydrochlorothiazide.
Patients with heart failure, prior myocardial infarction. In patients whose renal function depends on the activity of the RAAS (e.g. patients with severe heart failure), treatment with ACE inhibitors or ARBs 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). Increased risk of developing NMSC (basal cell carcinoma)
