Valsartan 320/hydrochlorothiazide 25 macleods
UkraineTable of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT
Valsartan 160/hydrochlorothiazide 12.5 Macleods / Valsartan 160/hydrochlorothiazide 12.5 Macleods
Valsartan 160/hydrochlorothiazide 25 Macleods / Valsartan 160/hydrochlorothiazide 25 Macleods
Valsartan 320/hydrochlorothiazide 12.5 Macleods / Valsartan 320/hydrochlorothiazide 12.5 Macleods
Valsartan 320/hydrochlorothiazide 25 Macleods / Valsartan 320/hydrochlorothiazide 25 Macleods
Composition:
Active substances: valsartan and hydrochlorothiazide;
One tablet contains 160 mg of valsartan and 12.5 mg of hydrochlorothiazide, or 160 mg of valsartan and 25 mg of hydrochlorothiazide, or 320 mg of valsartan and 12.5 mg of hydrochlorothiazide, or 320 mg of valsartan and 25 mg of hydrochlorothiazide;
Excipients:
Dosage 160/12.5 mg: microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;
Coating: Opadry Brown 03F565001: hypromellose, titanium dioxide (E 171), polyethylene glycol 8000, talc, iron oxide red pigment (E 172);
Dosage 160/25 mg: microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;
Coating: Opadry Brown 03F57311: hypromellose, titanium dioxide (E 171), polyethylene glycol 8000, talc, iron oxide red pigment (E 172), iron oxide yellow pigment (E 172), iron oxide black pigment (E 172);
Dosage 320/12.5 mg: microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;
Coating: Opadry Pink 03F540000: hypromellose, titanium dioxide (E 171), polyethylene glycol 8000, talc, iron oxide red pigment (E 172), iron oxide black pigment (E 172);
Dosage 320/25 mg: microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;
Coating: Opadry Yellow 03F82329: hypromellose, titanium dioxide (E 171), polyethylene glycol 8000, talc, iron oxide yellow pigment (E 172).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
Tablets 160 mg/12.5 mg: biconvex, oval-shaped, film-coated tablets of dark red color, with "L17" embossed on one side and smooth on the other side;
Tablets 160 mg/25 mg: biconvex, oval-shaped, film-coated tablets of brown color, with "L18" embossed on one side and smooth on the other side;
Tablets 320 mg/12.5 mg: biconvex, oval-shaped, film-coated tablets of pink color, with "L19" embossed on one side and smooth on the other side;
Tablets 320 mg/25 mg: biconvex, oval-shaped, film-coated tablets of yellow color, with "L20" embossed on one side and smooth on the other side.
Pharmacotherapeutic group. Angiotensin II antagonists and diuretics. Valsartan and diuretics. ATC code C09DA03.
Pharmacological Properties
Pharmacodynamics
Valsartan
Valsartan is an active and specific angiotensin II receptor antagonist intended for oral administration. It acts selectively on AT1 subtype receptors, which are responsible for the effects of angiotensin II. Increased levels of angiotensin II resulting from AT1 receptor blockade by valsartan may stimulate unoccupied AT2 receptors, counterbalancing the effects mediated by AT1 receptors. Valsartan has no partial agonist activity at AT1 receptors and exhibits much greater (approximately 20,000 times) affinity for AT1 receptors than for AT2 receptors.
Valsartan does not inhibit angiotensin-converting enzyme (ACE), also known as kininase II, which converts angiotensin I to angiotensin II and degrades bradykinin. No adverse effects related to bradykinin have been observed. In clinical studies comparing valsartan with ACE inhibitors, the incidence of dry cough was significantly lower (P < 0.05) in patients treated with valsartan than in those receiving an ACE inhibitor (2.6% vs. 7.9%, respectively). In patients who previously experienced dry cough during ACE inhibitor therapy, this adverse effect occurred in 19.5% of cases when treated with valsartan and in 19% of cases when treated with a thiazide diuretic, whereas cough was observed in 68.5% of patients receiving ACE inhibitor therapy (P < 0.05).
In controlled clinical trials, the incidence of cough in patients receiving the combination of valsartan and hydrochlorothiazide was 2.9%.
Valsartan does not interact with or block receptors of other hormones or ion channels that play an important role in cardiovascular function regulation.
Administration of the drug to patients with hypertension leads to a reduction in arterial blood pressure without affecting pulse rate.
In most patients, after oral administration of a single dose, antihypertensive activity begins within 2 hours, and maximal reduction in blood pressure is achieved within 4–6 hours. The antihypertensive effect persists for more than 24 hours after a single dose. With regular administration, the maximal therapeutic effect is usually achieved within 2–4 weeks and is maintained at this level during long-term therapy. The combination with hydrochlorothiazide reduces blood pressure more effectively.
Discontinuation of valsartan does not lead to a sudden increase in blood pressure (rebound syndrome) or other adverse effects.
Valsartan does not affect total cholesterol, triglycerides, serum glucose, or uric acid levels in patients with arterial hypertension.
The site of action of thiazide diuretics is the cortical segment of the distal convoluted renal tubules, where receptors highly sensitive to diuretic action are located and where Na+ and Cl- ion transport is inhibited. The mechanism of action of thiazides involves inhibition of the Na+Cl- cotransporter, likely through competition for Cl- transport sites. As a result, urinary excretion of sodium and chloride ions increases to a similar extent. Due to the diuretic effect, plasma volume decreases, leading to increased renin activity, aldosterone secretion, potassium excretion in urine, and consequently, reduced serum potassium concentration. The renin-aldosterone relationship is mediated by angiotensin II; therefore, administration of an angiotensin II receptor antagonist reduces potassium loss associated with thiazide diuretic use.
Pharmacokinetics
Valsartan/Hydrochlorothiazide
Systemic availability of hydrochlorothiazide is reduced by approximately 30% when co-administered with valsartan. The pharmacokinetics of valsartan are not significantly altered when co-administered with hydrochlorothiazide. This interaction does not affect the combined use of valsartan and hydrochlorothiazide, as the clear antihypertensive effect of the combination exceeds that achieved with monotherapy using either active substance or placebo.
Valsartan
Absorption. After oral administration, peak plasma concentration of valsartan is reached within 2–4 hours. The mean absolute bioavailability is 23%. Food intake reduces the exposure (as measured by AUC) of valsartan by approximately 40% and peak plasma concentration (Cmax) by approximately 50%, although about 8 hours after administration, plasma valsartan concentrations are similar whether taken with or without food. This reduction in AUC, however, is not associated with a clinically significant reduction in therapeutic effect; therefore, valsartan can be administered regardless of food intake.
Distribution. The steady-state volume of distribution of valsartan after intravenous administration is approximately 17 liters, indicating that valsartan is not extensively distributed into tissues. Valsartan is highly bound to plasma proteins (94–97%), primarily to serum albumin.
Metabolism. Valsartan undergoes minimal biotransformation, as only about 20% of the dose is recovered as metabolites. A hydroxylated metabolite has been detected in plasma at low concentrations (less than 10% of the AUC for valsartan). This metabolite is pharmacologically inactive.
Elimination. Valsartan exhibits multiphasic elimination kinetics (t½α < 1 hour and t½ß approximately 9 hours). Valsartan is eliminated predominantly via feces (about 83% of the dose) and urine (about 13% of the dose), mainly in unchanged form.
After intravenous administration, the plasma clearance of valsartan is approximately 2 L/h, and renal clearance is 0.62 L/h (about 30% of total clearance). The elimination half-life of valsartan is 6 hours.
Hydrochlorothiazide
Absorption. Hydrochlorothiazide is rapidly absorbed after oral administration (tmax approximately 2 hours). The increase in mean AUC is linear and dose-proportional within the therapeutic range. The effect of food on hydrochlorothiazide absorption is not clinically significant. Absolute bioavailability of hydrochlorothiazide after oral administration is 70%.
Distribution. Apparent volume of distribution is 4–8 L/kg. Circulating hydrochlorothiazide is bound to plasma proteins (40–70%), primarily to serum albumin. Hydrochlorothiazide also accumulates in erythrocytes at concentrations approximately three times higher than in plasma.
Elimination. Hydrochlorothiazide is excreted mainly in unchanged form. The terminal elimination half-life from plasma averages 6 to 15 hours. No changes in hydrochlorothiazide kinetics occur with repeated dosing, and accumulation is minimal with once-daily administration. More than 95% of the absorbed dose is excreted unchanged in urine. Renal clearance involves both passive filtration and active tubular secretion.
Pharmacokinetics in Specific Patient Populations
Elderly Patients. In some elderly patients, systemic exposure to valsartan was slightly higher than in younger patients, but this difference was not clinically significant. Limited data suggest that systemic clearance of hydrochlorothiazide is lower in elderly patients, both healthy and those with arterial hypertension, compared to healthy young volunteers.
Patients with Renal Impairment. Dose adjustment is not required in patients with creatinine clearance of 30–70 mL/min.
There are no data on the use of Valsartan/Hydrochlorothiazide Macleods in patients with severe renal impairment (creatinine clearance < 30 mL/min) or in patients undergoing hemodialysis. Valsartan is highly protein-bound and is not removed by hemodialysis; hydrochlorothiazide, on the contrary, is eliminated during hemodialysis. In renal impairment, mean peak plasma levels and AUC values of hydrochlorothiazide increase, while urinary excretion rate decreases. In patients with mild to moderate renal insufficiency, AUC of hydrochlorothiazide increases threefold. In patients with severe renal insufficiency, AUC increases eightfold. Hydrochlorothiazide is contraindicated in patients with severe renal impairment (see section "Contraindications").
Hepatic Impairment. Systemic exposure to valsartan in patients with mild (n = 6) and moderate (n = 5) hepatic impairment was twice as high as 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, and therefore dose reduction is not required.
Non-melanoma Skin Cancer (NMSC)
Available epidemiological data indicate a cumulative dose-dependent association between hydrochlorothiazide exposure and the development of NMSC. One study included 71,533 cases of basal cell carcinoma (with 1,430,833 individuals in the control group) and 8,629 cases of squamous cell carcinoma (with 172,462 individuals in the control group). High-dose hydrochlorothiazide (≥ 50,000 mg cumulative) was 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 and squamous cell carcinomas. Another study showed a possible association between lip cancer and hydrochlorothiazide use: 633 cases of lip cancer were matched with 63,067 population-based controls using a risk-set sampling 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) with high-dose use (~25,000 mg) and OR 7.7 (5.7–10.5) with the highest dose (~100,000 mg). For example, a cumulative dose of 100,000 mg corresponds to daily administration of a defined daily dose of 25 mg over a period exceeding 10 years.
Clinical characteristics.
Indications.
Essential arterial hypertension in patients whose blood pressure is not adequately controlled with monotherapy.
Contraindications.
- Hypersensitivity to any component of the medicinal product or to other sulfonamide derivatives.
- Severe impairment of liver function, liver cirrhosis, and cholestasis.
- Anuria.
- Refractory hypokalemia, hyponatremia, hypercalcemia, symptomatic hyperuricemia.
- Concomitant use of angiotensin receptor antagonists (ARBs), including valsartan, or angiotensin-converting enzyme (ACE) inhibitors with aliskiren in patients with diabetes mellitus (type I or type II) or renal impairment (eGFR < 60 mL/min/1.73 m²).
- Pregnancy, planned pregnancy (see "Use in pregnancy or breast-feeding").
- Hereditary angioedema or angioedema during previous treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor antagonists (ARBs).
Interaction with other medicinal products and other forms of interaction.
Interactions with the combination of valsartan and hydrochlorothiazide
Concomitant use not recommended
Lithium
Increased reversible serum lithium concentrations and signs of lithium toxicity have been reported with concomitant use of ACE inhibitors and thiazide diuretics, including hydrochlorothiazide. Due to lack of experience with the concomitant use of valsartan and lithium, this combination is not recommended. If such combination is necessary, careful monitoring of plasma lithium levels is advised.
Concomitant use requiring special caution
Other antihypertensive agents
The medicinal product may enhance the hypotensive effect of other antihypertensive agents (such as guanethidine, methyldopa, vasodilators, ACE inhibitors, angiotensin receptor blockers, beta-blockers, calcium channel blockers, direct renin inhibitors, and dopamine reuptake inhibitors).
Pressor amines (e.g., noradrenaline, adrenaline)
A reduced response to pressor amines is likely. The clinical significance of this effect is not well established and insufficient 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 use of valsartan/hydrochlorothiazide and NSAIDs may lead to worsening of renal function and increased serum potassium levels. Therefore, monitoring of renal function at the beginning of treatment and adequate fluid replacement are recommended.
In elderly patients, patients with reduced blood volume (including those receiving diuretic therapy), or patients with impaired renal function, concomitant use of NSAIDs (or COX-2 inhibitors) with ARBs increases the risk of worsening renal function, including acute renal failure. Combined use of these agents requires caution and monitoring of renal function.
Interactions related to valsartan
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with ARBs, ACE inhibitors, or aliskiren
Caution is required when ARBs, including valsartan, are used concomitantly with other agents that block the RAAS, such as ACE inhibitors or aliskiren.
This is due to an increased incidence of hypotension, syncope, hyperkalemia, and renal dysfunction (including acute renal failure) compared to monotherapy. Therefore, dual blockade of the RAAS by combined use of ACE inhibitors, angiotensin receptor blockers, or aliskiren is not recommended. If dual RAAS blockade is considered absolutely necessary, treatment should be conducted only under specialist supervision and accompanied by monitoring of renal function, electrolyte levels, and blood pressure.
Concomitant use of angiotensin receptor antagonists (ARBs), including valsartan, or angiotensin-converting enzyme (ACE) inhibitors with aliskiren in patients with diabetes mellitus (type I or type II), diabetic nephropathy, or renal impairment (eGFR < 60 mL/min/1.73 m²) is contraindicated (see "Contraindications" and "Adverse reactions").
Concomitant use not recommended
Potassium-sparing diuretics, potassium-containing dietary supplements, potassium-containing salt substitutes, and other substances that may increase potassium levels
If it is necessary to use a medicinal product affecting potassium levels in combination with valsartan, monitoring of plasma potassium levels is recommended.
Concomitant use of angiotensin II receptor antagonists with other medicinal products capable of increasing serum potassium levels (e.g., potassium-sparing diuretics, potassium-containing medicinal products, heparin) increases the risk of hyperkalemia. In such cases, Valsartan/Hydrochlorothiazide Macleods should be used with caution and potassium levels should be monitored.
Transporters
Based on in vitro studies, valsartan is a substrate of the hepatic uptake transporter OATP1B1/OATP1B3 and the hepatic efflux transporter MRP2. The clinical relevance of these data is unknown. Concomitant use of inhibitors of uptake transporters (e.g., rifampicin, cyclosporine) or efflux transporters (e.g., ritonavir) may increase systemic exposure to valsartan. Appropriate precautions should be taken at the initiation or discontinuation of concomitant use of these medicinal products.
Absence of interactions
No clinically significant interactions were observed during studies with valsartan when administered concomitantly with any of the following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, and glyburide. Digoxin and indomethacin may interact with hydrochlorothiazide (see interactions related to hydrochlorothiazide).
Interactions related to hydrochlorothiazide
Concomitant use requiring special caution
MEDICINAL PRODUCTS ASSOCIATED WITH POTASSIUM LOSS AND HYPOKALEMIA
The hypokalemic effect of hydrochlorothiazide may be enhanced when used concomitantly with potassium-wasting diuretics, corticosteroids, laxatives, adrenocorticotropic hormones (ACTH), amphotericin, carbenoxolone, penicillin G, salicylic acid and its derivatives, antiarrhythmic agents.
If the above-mentioned medicinal products are prescribed in combination with valsartan/hydrochlorothiazide, monitoring of serum potassium levels is recommended (see "Special precautions for use").
MEDICINAL PRODUCTS THAT MAY INDUCE TORSADES DE POINTES VENTRICULAR TACHYCARDIA
Due to the risk of hypokalemia, hydrochlorothiazide should be used cautiously concomitantly with medicinal products that may induce torsades de pointes ventricular tachycardia, particularly class Ia and III antiarrhythmics, as well as certain antipsychotics.
MEDICINAL PRODUCTS AFFECTING SERUM SODIUM LEVELS
The hyponatremic effect of diuretics may be enhanced when used concomitantly with medicinal products such as antidepressants, antipsychotics, antiepileptics, etc. Long-term use of these agents should be prescribed cautiously.
MEDICINAL PRODUCTS THAT MAY CAUSE TORSADES DE POINTES (TORSADES DE POINTES)
- Class Ia antiarrhythmic agents (e.g., quinidine, hydroquinidine, disopyramide)
- Class III antiarrhythmic agents (e.g., amiodarone, sotalol, dofetilide, ibutilide)
- Certain neuroleptics (e.g., thioridazine, chlorpromazine, levomepromazine, trifluoperazine, zuclopenthixol, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol)
- Others (e.g., bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, ketanserin, mizolastine, pentamidine, sparfloxacin, terfenadine, intravenous vinca alkaloids)
Due to the risk of hypokalemia, hydrochlorothiazide should be used cautiously concomitantly with medicinal products that may cause torsades de pointes.
Cardiac glycosides
Hypokalemia or hypomagnesemia induced by thiazides may occur as an adverse effect predisposing to cardiac arrhythmias induced by cardiac glycosides (see "Special precautions for use").
Calcium salts and vitamin D
Concomitant use of thiazide diuretics, including hydrochlorothiazide, with vitamin D or calcium salts may lead to increased serum calcium levels. Concomitant use of thiazide diuretics with calcium salts may cause hypercalcemia in patients predisposed to hypercalcemia (e.g., patients with hyperparathyroidism, malignant tumors, or conditions caused by vitamin D deficiency) due to increased tubular reabsorption of calcium.
Antidiabetic medicinal products (oral agents and insulin)
Thiazides may alter glucose tolerance. Adjustment of antidiabetic agent dosage may be required.
Metformin should be used with caution due to the risk of lactic acidosis potentially caused by functional renal impairment associated with hydrochlorothiazide use.
Beta-blockers and diazoxide
Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta-blockers may increase the risk of hyperglycemia. Thiazide diuretics, including hydrochlorothiazide, may potentiate the hyperglycemic effect of diazoxide.
MEDICINAL PRODUCTS USED IN THE TREATMENT OF GOUT (probenecid, sulfinpyrazone, and allopurinol)
Dose adjustment of gout medications may be necessary because hydrochlorothiazide may increase serum uric acid levels. The dose of probenecid or sulfinpyrazone may need to be increased if required. Concomitant use of thiazide diuretics may increase the frequency of hypersensitivity reactions to allopurinol.
Anticholinergic agents and other medicinal products affecting gastrointestinal motility
The bioavailability of thiazide diuretics may increase when used concomitantly with anticholinergic agents (e.g., atropine, biperiden), particularly due to reduced gastrointestinal motility and delayed gastric emptying. Conversely, prokinetic agents such as cisapride may reduce the bioavailability of thiazide diuretics.
Amantadine
Thiazides, including hydrochlorothiazide, increase the risk of adverse effects caused by amantadine.
Ion-exchange resins
Absorption of thiazide diuretics, including hydrochlorothiazide, is impaired when used concomitantly with cholestyramine or colestipol.
This may lead to subtherapeutic effects of thiazide diuretics. To minimize interaction, hydrochlorothiazide should be administered at least 4 hours before or 4–6 hours after the resin.
Cytotoxic agents (e.g., cyclophosphamide, methotrexate)
Thiazides may reduce renal excretion of cytotoxic agents and potentiate their myelosuppressive effect.
Non-depolarizing skeletal muscle relaxants (e.g., tubocurarine)
Thiazides, including hydrochlorothiazide, enhance the effect of skeletal muscle relaxants such as curare derivatives.
Cyclosporine
Concomitant use with cyclosporine may increase the risk of hyperuricemia and symptoms resembling gout flare-ups.
Alcohol, anesthetics, and sedatives
Concomitant use of thiazide diuretics with agents that may also lower blood pressure (e.g., due to reduced sympathetic central nervous system activity or direct vasodilatory action) may potentiate orthostatic hypotension.
Methyldopa
Cases of hemolytic anemia have been reported with concomitant use of hydrochlorothiazide and methyldopa.
Carbamazepine
Hyponatremia may develop in patients receiving hydrochlorothiazide concomitantly with carbamazepine. Such patients should be informed about the possibility of hyponatremic reactions and appropriately monitored.
Contrast agents containing iodine
In cases of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially with high doses of iodine-containing agents. Adequate fluid replacement should be ensured prior to administration.
Special precautions for use.
Changes in serum electrolyte balance
Potassium
Thiazide diuretics may cause hypokalemia or exacerbate pre-existing hypokalemia.
Correction of hypokalemia is recommended before initiating thiazide therapy. Concomitant hypomagnesemia may lead to hypokalemia that is difficult to correct.
Since Valsartan/Hydrochlorothiazide Macleods contains an angiotensin II receptor antagonist, caution should be exercised when co-administering Valsartan/Hydrochlorothiazide Macleods with potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other medicinal products that may increase potassium levels (e.g., heparin). Cases of hypokalemia have been reported during treatment with thiazide diuretics. Regular monitoring of serum potassium and magnesium levels is recommended in patients with conditions involving increased potassium loss. Electrolyte balance should be monitored in all patients receiving thiazide diuretics.
Patients with sodium deficiency and/or reduced circulating blood volume (CBV)
Treatment with thiazide diuretics is often associated with the development of hyponatremia or worsening of pre-existing hyponatremia and hypochloremic alkalosis. This may be accompanied by neurological symptoms (e.g., vomiting, confusion, apathy). Thiazide diuretics should only be administered after correction of hyponatremia. Serum sodium concentration should be monitored regularly.
Thiazides enhance urinary excretion of magnesium, which may result in hypomagnesemia.
Patients receiving thiazide diuretics should be monitored for clinical signs of fluid or electrolyte imbalance. In patients with marked sodium deficiency and/or reduced circulating blood volume (e.g., those receiving high doses of diuretics), symptomatic arterial hypotension may occur in isolated cases after initiation of treatment with the medicinal product. Sodium levels and/or circulating blood volume should be corrected prior to starting therapy.
In case of hypotension, the patient should be placed in a supine position and, if necessary, intravenous infusion of saline solution should be administered. Treatment may be resumed immediately after stabilization of blood pressure.
Calcium
Thiazide diuretics reduce calcium excretion in urine and may cause elevated serum calcium levels. Thiazide diuretics should only be used after correction of hypercalcemia or treatment of conditions causing hypercalcemia. Serum calcium concentration should be monitored regularly.
Patients with severe chronic heart failure with congestion or other conditions involving activation of the renin-angiotensin-aldosterone system (RAAS)
In patients whose renal function primarily depends on RAAS activity (e.g., patients with severe congestive heart failure), treatment with agents acting on the RAAS may lead to oliguria and/or progressive azotemia, rarely resulting in acute renal failure and/or fatal outcomes. Evaluation of patients with heart failure or after myocardial infarction should always include assessment of renal function.
Therefore, the possibility of developing renal failure due to RAAS suppression with the use of the combination of valsartan/hydrochlorothiazide cannot be excluded. Such patients should not take this medicinal product.
Renal artery stenosis
Since serum urea and creatinine levels may increase, the use of the medicinal product is not recommended in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery to a single kidney.
Primary hyperaldosteronism
The medicinal product is not recommended for use in patients with primary hyperaldosteronism, as their RAAS is not activated.
Aortic or mitral valve stenosis, hypertrophic obstructive cardiomyopathy
Particular caution is required in patients with aortic or mitral valve stenosis or hypertrophic obstructive cardiomyopathy (HOCM).
Renal impairment
Dose adjustment is not required in patients with mild to moderate renal impairment (creatinine clearance > 30 mL/min).
Valsartan/Hydrochlorothiazide Macleods should be used with caution in patients with severe renal impairment (creatinine clearance < 30 mL/min). Thiazide diuretics may precipitate azotemia in patients with chronic renal dysfunction. They are ineffective as monotherapy in severe renal impairment (creatinine clearance < 30 mL/min), but may be used with appropriate caution in combination with loop diuretics, even in patients with creatinine clearance < 30 mL/min.
Concomitant use of angiotensin receptor blockers, including Valsartan/Hydrochlorothiazide Macleods, or angiotensin-converting enzyme (ACE) inhibitors with aliskiren is contraindicated in patients with renal impairment (creatinine clearance < 60 mL/min).
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.
Renal transplantation
Currently, there are no data on the safety of using the medicinal product in patients who have recently undergone kidney transplantation.
Hepatic impairment
Caution is required when treating patients with hepatic impairment. The medicinal product should be used with caution in patients with mild or moderate hepatic impairment without cholestasis (see section "Dosage and administration" and "Pharmacological properties"). Liver disease does not significantly alter the pharmacokinetic parameters of hydrochlorothiazide.
Thiazides may cause electrolyte imbalances, hepatic encephalopathy, and hepatorenal syndrome. Therefore, Valsartan/Hydrochlorothiazide Macleods should be prescribed to such patients only after careful consideration of the risk-benefit ratio and with monitoring of clinical and laboratory parameters. Valsartan/Hydrochlorothiazide Macleods is contraindicated in patients with biliary cirrhosis or cholestasis.
Systemic lupus erythematosus
Thiazide diuretics, including hydrochlorothiazide, may exacerbate or activate systemic lupus erythematosus.
Other metabolic disorders
Thiazide diuretics may affect glucose tolerance and increase serum cholesterol, triglycerides, and uric acid levels, potentially exacerbating hyperuricemia and leading to gout. Diabetics may require adjustment of insulin or oral hypoglycemic agent doses.
Thiazides may reduce urinary calcium excretion and cause transient and mild increases in serum calcium levels in the absence of known calcium metabolism disorders. Marked hypercalcemia may indicate hyperparathyroidism. Thiazide use should be discontinued prior to parathyroid function testing.
Photosensitivity
Cases of photosensitivity reactions have been reported with thiazide diuretics (see section "Adverse reactions"). If a photosensitivity reaction occurs during treatment with the medicinal product, discontinuation of therapy is recommended. If re-administration of the diuretic is necessary, protection of susceptible areas from sunlight or artificial UV radiation is recommended.
Pregnancy
Angiotensin II receptor antagonists should not be initiated during pregnancy. Women planning pregnancy should be switched to alternative antihypertensive therapies with an established safety profile during pregnancy unless continuation of angiotensin II receptor antagonist therapy is considered necessary. If pregnancy is detected, treatment with angiotensin II receptor antagonists should be discontinued immediately, and alternative therapy should be initiated if needed.
General disorders
Caution should be exercised when administering the medicinal product to patients with a history of hypersensitivity to other angiotensin II receptor antagonists. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergies or asthma.
Angioedema
Angioedema (including angioedema of the larynx and glottis leading to airway obstruction, and/or angioedema of the face, lips, pharynx, and/or tongue) has been observed in patients receiving valsartan; some of these patients had a history of angioedema with other drugs, including other angiotensin II receptor antagonists and ACE inhibitors. If angioedema occurs, treatment with angiotensin II receptor antagonists should be discontinued immediately. Re-administration of the medicinal product is contraindicated.
Choroidal effusion, acute myopia, and secondary acute angle-closure glaucoma
The use of hydrochlorothiazide, a sulfonamide, has been associated with idiosyncratic reactions that may lead to choroidal effusion with visual field defects, acute transient myopia, and acute angle-closure glaucoma. Symptoms include acute decrease in visual acuity or eye pain, typically occurring within hours to a week after administration of the drug. Untreated acute angle-closure glaucoma may result in permanent vision loss.
Treatment with hydrochlorothiazide should be discontinued as soon as possible. Emergency medical or surgical intervention may be required. Risk factors for developing acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.
Patients with heart failure, previous myocardial infarction
In patients whose renal function depends on the activity of the renin-angiotensin-aldosterone system (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 some cases, acute renal failure and fatal outcomes. 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 NMSC (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 NMSC.
Patients taking hydrochlorothiazide should be informed about the risk of NMSC. Regular skin examinations for new lesions are recommended, and any suspicious changes should be reported immediately. Preventive measures to minimize the risk of skin cancer, such as limiting exposure to sunlight and ultraviolet radiation and using adequate protection when exposed to sunlight, are recommended. Suspicious skin lesions should be promptly evaluated, including histological examination and biopsies. The use of hydrochlorothiazide should also be reconsidered in patients who have experienced NMSC.
Fertility
There is no information on the effect of valsartan on human fertility. Studies in rats did not show any effect of valsartan on fertility.
No dose adjustment is required for elderly patients.
Hydrochlorothiazide may reduce plasma protein-bound iodine levels. Hydrochlorothiazide may increase the concentration of free bilirubin in serum.
Acute respiratory toxicity
Very rare cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported after administration of hydrochlorothiazide. Pulmonary edema usually develops within minutes or hours after taking hydrochlorothiazide. Initial symptoms include dyspnea, fever, worsening of pulmonary function, and hypotension. If ARDS is suspected, the medicinal product should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be prescribed to patients who have previously experienced ARDS after taking hydrochlorothiazide.
Use during pregnancy or breastfeeding.
Pregnancy
Valsartan
The medicinal product should not be used in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this medicinal product, its use should be discontinued immediately and replaced with another medicinal product approved for use during pregnancy.
It is known that the use of angiotensin II receptor antagonists during the second and third trimesters causes fetotoxicity in humans (reduced renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia).
If angiotensin II receptor antagonists were used from the second trimester of pregnancy, ultrasound monitoring of the kidneys and skull is recommended.
Newborns whose mothers took angiotensin II receptor antagonists require careful monitoring for hypotension.
Hydrochlorothiazide
Experience with the use of hydrochlorothiazide during pregnancy is limited, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide, its use during the second and third trimesters of pregnancy may impair fetoplacental circulation and cause effects in the fetus and newborn such as jaundice, electrolyte imbalance, and thrombocytopenia.
The physician prescribing a medicinal product acting on the RAAS should inform the woman about the potential risks during pregnancy.
Due to the mechanism of action of angiotensin II receptor antagonists, the risk of embryopathy and fetal disease cannot be excluded. According to retrospective data, the use of ACE inhibitors during the first trimester is associated with a potential risk of congenital malformations. In addition, fetal injury and fatal outcomes have been reported due to the use of drugs directly affecting the renin-angiotensin-aldosterone system (RAAS) during the second and third trimesters. In humans, fetal renal perfusion, which depends on RAAS development, begins during the second trimester. Thus, the risk associated with valsartan treatment is higher during the second and third trimesters. Reports of spontaneous abortions, oligohydramnios, and renal dysfunction in newborns have occurred when pregnant women inadvertently took valsartan.
Newborns exposed to the medicinal product in utero should be carefully monitored for adequate urine output, hyperkalemia, and blood pressure. If necessary, appropriate medical measures (e.g., rehydration) should be taken to remove the medicinal product from the circulation.
Intrauterine exposure to thiazide diuretics, including hydrochlorothiazide, may cause jaundice or thrombocytopenia in the fetus and newborn or other adverse reactions observed in adults.
Breastfeeding period
If use of the medicinal product is essential, breastfeeding should be discontinued. There is no information on the use of valsartan during breastfeeding. Hydrochlorothiazide passes into human milk in small amounts. Thiazides in high doses cause diuresis, which may suppress milk production. During breastfeeding, it is preferable to use alternative treatment methods with better-established safety profiles, especially when breastfeeding a newborn or premature infant.
Ability to affect reaction speed when driving or operating machinery.
At the beginning of treatment with the medicinal product (the duration is determined individually by the physician), driving and performing work that could lead to an accident are prohibited due to the possibility of dizziness or fatigue. The extent of the restriction at a later stage is determined by the physician.
Method of Administration and Dosage
The recommended dose of Valsartan/Hydrochlorothiazide Macleods is 1 tablet of 160 mg/12.5 mg once daily. If blood pressure is not adequately controlled after 3–4 weeks of treatment, consideration should be given to continuing therapy with a dose of 1 tablet of 160 mg/25 mg once daily. Tablets of 320 mg/12.5 mg should be prescribed to patients in whom adequate blood pressure reduction is not achieved with tablets of 160 mg/25 mg. Tablets of 320 mg/25 mg should be prescribed to patients in whom adequate blood pressure reduction is not achieved with tablets of 320 mg/12.5 mg.
The maximum daily dose is 320 mg/25 mg.
If there is no response to treatment with the medicinal product after 8 weeks, the use of an additional or alternative medicinal agent should be considered.
Maximum antihypertensive effect is achieved within 2–4 weeks. For some patients, 4–8 weeks of treatment may be required.
Valsartan/Hydrochlorothiazide Macleods may be taken independently of food intake. Tablets should be taken with a small amount of water.
Population-specific considerations
Renal impairment. Dose reduction may be required in patients with renal impairment. Since the medicinal product contains hydrochlorothiazide, it is contraindicated in patients with anuria, and caution is required when administering to patients with severe renal impairment (creatinine clearance < 30 mL/min).
There are no data on the use of valsartan in patients with end-stage renal disease (creatinine clearance < 10 mL/min) or in patients undergoing dialysis.
Hepatic impairment. Dose reduction may be required in patients with hepatic impairment. Since the medicinal product contains hydrochlorothiazide, it should be used with caution in patients with hepatic impairment. Since the product contains valsartan, it is contraindicated in patients with biliary cirrhosis or cholestasis.
The dose of valsartan in patients with mild to moderate non-biliary hepatic impairment without cholestasis should not exceed 80 mg.
Elderly patients. Dose adjustment in elderly patients is not required.
Children.
Valsartan/Hydrochlorothiazide Macleods is not recommended for use in children under 18 years of age due to lack of data on safety and efficacy.
Overdose.
Symptoms
Overdose may lead to marked hypotension, which may result in decreased level of consciousness, vascular collapse, and/or shock. In addition, hydrochlorothiazide overdose may lead to signs and symptoms such as nausea, drowsiness, hypovolemia, and electrolyte imbalance, accompanied by cardiac arrhythmias and muscle spasms. The most characteristic signs of overdose also include tachycardia, hypotension, shock, weakness, confusion, dizziness, muscle cramps, paresthesia, exhaustion, disturbances of consciousness, vomiting, thirst, polyuria, oliguria, anuria, alkalosis, and elevated blood urea nitrogen levels (primarily due to renal impairment).
Treatment
In all cases of overdose, general supportive measures should be implemented, including monitoring of the patient and measures to stabilize cardiovascular function.
Therapeutic interventions depend on the time of ingestion and the type and severity of symptoms; stabilization of circulation is of primary importance.
If the drug has been taken recently, vomiting should be induced. If a significant time has passed since ingestion, the patient should be given an adequate amount of activated charcoal.
In the event of hypotension, the patient should be placed in a supine position, and immediate restoration of fluid and electrolyte balance should be ensured by intravenous administration of isotonic saline solution. Valsartan cannot be removed from the body by hemodialysis due to its high plasma protein binding, but hemodialysis is effective for elimination of hydrochlorothiazide from the body.
Adverse reactions
Adverse reactions reported in clinical trials and laboratory abnormalities occurring more frequently with valsartan and hydrochlorothiazide than with placebo, as well as post-marketing reports, are listed below by system organ class. During treatment with Valsartan/Hydrochlorothiazide Macleods, adverse reactions may occur which are known to be associated with each individual component, but which were not observed in clinical trials.
The frequency of adverse reactions is defined as follows, starting with the most frequent: very common (<u>> 1/10), common (<u>> 1/100, < 1/10), uncommon (<u>> 1/1000, < 1/100), rare (<u>> 1/10,000, < 1/1000), very rare (< 1/10,000), including isolated case reports.
Table 1
Frequency of adverse reactions during administration of valsartan/hydrochlorothiazide
| Infections and infestations |
|
| Uncommon: |
viral infections, fever. |
| Metabolism and nutrition disorders |
|
| Uncommon: |
dehydration. |
| Not known: |
hypokalaemia, hyponatraemia. |
| Nervous system disorders |
|
| Common: |
headache, fatigue, dizziness. |
| Uncommon: |
asthenia, dizziness, insomnia, anxiety, paraesthesia. |
| Rare: |
depression. |
| Not known: |
syncope. |
| Eye disorders |
|
| Uncommon: |
blurred vision. |
| Rare: |
conjunctivitis. |
| Ear and labyrinth disorders |
|
| Uncommon: |
otitis media, tinnitus. |
| Cardiac disorders |
|
| Uncommon: |
palpitations, tachycardia. |
| Vascular disorders |
|
| Uncommon: |
oedema, arterial hypotension, hyperhidrosis. |
| Respiratory, thoracic and mediastinal disorders |
|
| Common: |
cough, rhinitis, pharyngitis, upper respiratory tract infections. |
| Uncommon: |
bronchitis, dyspnoea, sinusitis, pharyngolaryngeal pain, dry mouth. |
| Very rare: |
epistaxis. |
| Not known: |
non-cardiogenic pulmonary oedema. |
| Gastrointestinal disorders |
|
| Common: |
diarrhoea. |
| Uncommon: |
abdominal pain, dyspepsia, nausea, gastroenteritis. |
| Musculoskeletal and connective tissue disorders |
|
| Common: |
back pain, arthralgia. |
| Uncommon: |
limb pain, chest pain, neck pain, arthritis, sprains and deformities, muscle cramps, myalgia. |
| Renal and urinary disorders |
|
| Uncommon: |
urinary frequency, urinary tract infections. |
| Very rare: |
renal function impairment. |
| Reproductive system disorders |
|
| Common: |
erectile dysfunction. |
| General disorders |
|
| Uncommon: |
increased fatigue. |
| Investigations |
|
| Not known: |
elevated plasma uric acid levels, elevated plasma bilirubin and creatinine levels, hypokalaemia, hyponatraemia, increased blood urea nitrogen, neutropenia. |
A reduction in serum potassium levels by more than 20% was observed in 3.7% of patients receiving the medicinal product and in 3.1% of patients receiving placebo.
Elevations in creatinine and blood urea nitrogen were observed in 1.9% and 14.7% of patients receiving the medicinal product, respectively, and in 0.4% and 6.3% of patients receiving placebo, respectively, in controlled clinical trials.
During clinical trials in patients with hypertension, the following events were observed regardless of causal relationship to the investigational medicinal product: hyposthesia, influenza, insomnia, ligament sprain, muscle strain, nasal congestion, nasopharyngitis, neck pain, peripheral edema, and sinus congestion.
The following reactions were associated with monotherapy with valsartan but were not observed with the combination of valsartan/hydrochlorothiazide.
Rarely, therapy with valsartan may be associated with decreased hemoglobin and hematocrit levels. In controlled clinical trials, significant (>20%) reductions in hematocrit and hemoglobin levels were observed in 0.8% and 0.4% of patients, respectively. Decreased hematocrit or hemoglobin levels were observed in 0.1% of patients receiving placebo.
Neutropenia was observed in 1.9% of patients receiving valsartan and in 1.6% of patients receiving ACE inhibitors.
In controlled clinical trials, significant increases in serum creatinine, potassium, and total bilirubin levels were observed in 0.8%, 4.4%, and 6% of patients receiving valsartan, respectively, and in 1.6%, 6.4%, and 12.9% of patients receiving ACE inhibitors, respectively.
Elevated liver function parameters were infrequently observed in patients receiving valsartan.
There is no need for special laboratory monitoring in patients with essential hypertension receiving valsartan therapy.
The following reactions were observed during clinical trials in patients with hypertension: upper abdominal pain, anxiety, arthritis, back pain, bronchitis, acute bronchitis, chest pain, dizziness, dyspepsia, dyspnea, dry mouth, epistaxis, impotence, gastroenteritis, headache, increased sweating, hyposthesia, influenza, insomnia, ligament sprain, muscle cramps, muscle strain, nausea, nasal congestion, nasal sinus congestion, neck pain, edema, peripheral edema, otitis media, limb pain, palpitations, pharyngolaryngeal pain, polyuria, increased temperature, nasopharyngitis, sinusitis, somnolence, tachycardia, upper respiratory tract infections, urinary tract infections, vertigo, viral infections, and visual disturbances. It is unknown whether these effects were causally related to therapy.
In the post-marketing period, there have been reports of syncope and very rare cases of angioneurotic edema, rash, loss of consciousness, and other hypersensitivity reactions such as serum sickness and vasculitis, as well as cases of renal dysfunction.
Bullous dermatitis has been reported, with frequency unknown.
Additional information regarding individual components
Adverse reactions observed with valsartan and hydrochlorothiazide when used separately may also potentially occur with the medicinal product Valsartan/Hydrochlorothiazide Macleods, even if they were not observed in clinical trials or during the post-marketing period.
Table 2
Frequency of adverse reactions during administration of valsartan
| From the blood and lymphatic system |
|
| Unknown: |
decreased hemoglobin levels, decreased hematocrit, thrombocytopenia. |
| From the immune system |
|
| Unknown: |
other hypersensitivity reactions/allergic reactions, including serum sickness. |
| Metabolism and nutrition disorders |
|
| Unknown: |
increased plasma potassium levels, hyponatremia. |
| From the ear and labyrinthine disorders |
|
| Uncommon: |
vestibular vertigo. |
| Vascular disorders |
|
| Unknown: |
vasculitis. |
| Gastrointestinal disorders |
|
| Uncommon: |
abdominal pain, gastroenteritis. |
| Hepatobiliary disorders |
|
| Unknown: |
elevated liver function tests. |
| From the skin and subcutaneous tissue |
|
| Unknown: |
edema, angioneurotic edema, rash, pruritus, bullous dermatitis. |
| From the urinary system |
|
| Unknown: |
renal failure, acute renal failure. |
| Musculoskeletal and connective tissue disorders |
|
| Common: |
arthralgia. |
| Nervous system disorders |
|
| Uncommon: |
asthenia, insomnia, dizziness. |
| Rare: |
neuralgia. |
| From the reproductive system |
|
| Uncommon: |
decreased libido. |
| Cardiac disorders |
|
| Very rare: |
cardiac arrhythmia |
There has been one reported case of angioneurotic edema.
Adverse reactions observed during clinical trials in patients with hypertension, regardless of their causal relationship to the investigational drug: arthralgia, asthenia, back pain, diarrhea, dizziness, headache, insomnia, decreased libido, nausea, edema, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, viral infections.
Adverse reactions associated with the use of hydrochlorothiazide
Hydrochlorothiazide has been widely used for many years, often at higher doses than those contained in the medicinal product Valsartan/Hydrochlorothiazide Macleods. The adverse reactions listed below have been reported in patients receiving thiazide diuretics, including hydrochlorothiazide as monotherapy.
Table 3
Frequency of adverse reactions during the use of hydrochlorothiazide
| From metabolism and endocrine system |
|
| Very common: |
with high doses – increased blood lipid levels, hypokalemia. |
| Common: |
hyponatremia, hypomagnesemia, hyperuricemia. |
| Uncommon: |
hypercalcemia, hyperglycemia, glucosuria, and worsening of metabolic control in patients with diabetes mellitus. |
| Rare: |
hypochloremic alkalosis. |
| Blood and lymphatic system disorders |
|
| Uncommon: |
thrombocytopenia, sometimes with purpura. |
| Rare: |
agranulocytosis, leukopenia, hemolytic anemia, bone marrow suppression. |
| Not known: |
aplastic anemia. |
| Immune system disorders |
|
| Rare: |
hypersensitivity reactions. |
| Psychiatric disorders |
|
| Uncommon: |
depression, sleep disturbances. |
| Nervous system disorders |
|
| Uncommon: |
headache, dizziness, paresthesia. |
| Eye disorders |
|
| Uncommon: |
blurred vision during the first few weeks after starting treatment. |
| Not known: |
choroidal effusion, acute angle-closure glaucoma. |
| Cardiac disorders |
|
| Uncommon: |
arrhythmia. |
| Vascular disorders |
|
| Common: |
postural hypotension, which may be enhanced by alcohol, anesthetics, or sedatives. |
| Respiratory, thoracic and mediastinal disorders |
|
| Rare: |
acute respiratory distress syndrome (ARDS), respiratory failure including pneumonia and pulmonary edema. |
| Gastrointestinal disorders |
|
| Common: |
loss of appetite, mild nausea and vomiting. |
| Uncommon: |
constipation, gastrointestinal discomfort, diarrhea. |
| Rare: |
pancreatitis. |
| Hepatobiliary disorders |
|
| Uncommon: |
intrahepatic cholestasis or jaundice. |
| Skin and subcutaneous tissue disorders |
|
| Common: |
urticaria and other types of rash. |
| Uncommon: |
photosensitivity. |
| Rare: |
necrotizing vasculitis and toxic epidermal necrolysis, skin reactions resembling lupus erythematosus, reactivation of cutaneous lupus erythematosus. |
| Not known: |
erythema multiforme. |
| Reproductive system disorders |
|
| Common: |
impotence. |
| Renal and urinary disorders |
|
| Not known: |
acute renal failure, renal dysfunction. |
| General disorders |
|
| Not known: |
fever, fatigue. |
| Musculoskeletal and connective tissue disorders |
|
| Not known: |
muscle cramps. |
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
|
| Not known: |
non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma). |
Shelf life. 2 years.
Storage conditions.
Store at a temperature not exceeding 25 °C in the original packaging.
Keep out of reach of children.
Packaging.
90 tablets in a bottle; 1 bottle in a cardboard box.
10 tablets in a blister pack; 3 or 9 blisters in a cardboard box.
Prescription status. Prescription only.
Manufacturer.
MACLEODS PHARMACEUTICALS LIMITED.
Manufacturer's address and place of business.
Phase II, Plot No. 12, 15, 21, 23, 24, 25, 26, 27, 28 and 30, Survey No. 366, Premier Industrial Estate, Kachigam, Daman, 396210, India.