Hyzaar^® (Tablets) Instructions for Use

ATC Code

C09DA01 (Losartan and diuretics)

Active Substances

Hydrochlorothiazide (Rec.INN registered by WHO)

Losartan (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Antihypertensive agent, combination (diuretic + angiotensin II receptor antagonist)

Pharmacological Action

Combined antihypertensive agent. Losartan and Hydrochlorothiazide have an additive antihypertensive effect, reducing blood pressure to a greater extent than each component separately.

Losartan is a selective angiotensin II receptor antagonist (type AT₁) for oral administration. In vivo and in vitro, losartan and its pharmacologically active metabolite E-3174 block all physiologically significant effects of angiotensin II on AT₁ receptors, regardless of its synthesis pathway: it leads to an increase in plasma renin activity and reduces plasma aldosterone concentration. Losartan indirectly causes activation of AT₂ receptors by increasing the concentration of angiotensin II. It does not suppress the activity of kininase II, an enzyme involved in the metabolism of bradykinin. It reduces total peripheral vascular resistance, pressure in the pulmonary circulation, reduces myocardial afterload, and has a diuretic effect. It prevents the development of myocardial hypertrophy and increases exercise tolerance in patients with chronic heart failure (CHF). Taking losartan once daily leads to a statistically significant reduction in systolic and diastolic blood pressure.

Losartan provides uniform blood pressure control throughout the day, with the antihypertensive effect corresponding to the natural circadian rhythm. The reduction in blood pressure at the end of the drug’s effect was approximately 70-80% of the maximum effect of losartan, 5-6 hours after oral administration. There is no withdrawal syndrome.

Losartan does not have a clinically significant effect on heart rate and has a moderate and transient uricosuric effect.

Hydrochlorothiazide– a thiazide diuretic, whose diuretic effect is associated with impaired reabsorption of sodium, chloride, potassium, magnesium, and water ions in the distal part of the nephron; it delays the excretion of calcium ions and uric acid. It has an antihypertensive effect, which develops due to the dilation of arterioles. It has almost no effect on normal blood pressure. The diuretic effect begins within 1-2 hours, reaches a maximum in 4 hours, and lasts for 6-12 hours. The maximum antihypertensive effect occurs after 3-4 days, but it may take 3-4 weeks to achieve the optimal therapeutic effect.

Due to the diuretic effect, Hydrochlorothiazide increases plasma renin activity, stimulates aldosterone secretion, increases the concentration of angiotensin II, and reduces plasma potassium concentration. Taking losartan blocks all physiological effects of angiotensin II and, due to the suppression of aldosterone effects, may help reduce potassium loss associated with diuretic intake. Hydrochlorothiazide causes a slight increase in blood uric acid concentration; the combination of losartan and hydrochlorothiazide helps reduce the severity of diuretic-induced hyperuricemia.

Pharmacokinetics

The pharmacokinetics of losartan and hydrochlorothiazide when used concurrently do not differ from those during monotherapy.

Losartan

After oral administration, losartan is well absorbed from the gastrointestinal tract. It undergoes significant first-pass metabolism in the liver, forming a pharmacologically active carboxylated metabolite (E-3174) and inactive metabolites. Bioavailability is approximately 33%. Mean C_max of losartan and its active metabolite are reached in 1 hour and 3-4 hours, respectively. Losartan and its active metabolite are more than 99% bound to plasma proteins (mainly albumin). V_d of losartan is 34 L. It penetrates the blood-brain barrier very poorly.

Losartan is metabolized to form an active (E-3174) metabolite (14%) and inactive metabolites, including two main metabolites formed by hydroxylation of the butyl group chain and a less significant metabolite, N-2-tetrazole glucuronide. Plasma clearance of losartan and its active metabolite is approximately 10 ml/sec (600 ml/min) and 0.83 ml/sec (50 ml/min), respectively. Renal clearance of losartan and its active metabolite is about 1.23 ml/sec (74 ml/min) and 0.43 ml/sec (26 ml/min). T_1/2 of losartan and the active metabolite is 2 hours and 6-9 hours , respectively. It is excreted primarily in the bile through the intestine – 58% , and by the kidneys – 35% . It does not accumulate.

When administered orally in doses up to 200 mg, losartan and its active metabolite have linear pharmacokinetics.

Hydrochlorothiazide

After oral administration, the absorption of hydrochlorothiazide is 60-80%. C_max in plasma is reached 1-5 hours after oral administration. Plasma protein binding is 64%. It crosses the placental barrier. It is excreted in breast milk. Hydrochlorothiazide is not metabolized and is rapidly excreted by the kidneys. T_1/2 is 5-15 hours. At least 61% of the orally administered dose is excreted unchanged within 24 hours.

Indications

Arterial hypertension (for patients who require combination therapy); reduction of cardiovascular morbidity and mortality risk in patients with arterial hypertension and left ventricular hypertrophy.

ICD codes

Dosage Regimen

Take orally once daily, with or without food.

The recommended starting dose is one Hyzaar^® 50/12.5 mg (losartan 50 mg/hydrochlorothiazide 12.5 mg) tablet daily.

For patients whose blood pressure is not adequately controlled with losartan monotherapy, switch directly to Hyzaar^® 50/12.5 mg once daily.

For patients whose blood pressure is controlled on 25 mg hydrochlorothiazide daily but who experience significant hypokalemia, switch to Hyzaar^® 50/12.5 mg to maintain similar blood pressure control with a lower dose of diuretic.

Dosage can be increased to a maximum of one Hyzaar^® 100/25 mg (losartan 100 mg/hydrochlorothiazide 25 mg) tablet daily after 2-3 weeks of therapy, based on blood pressure response.

The maximum recommended daily dose is losartan 100 mg combined with hydrochlorothiazide 25 mg.

For patients with intravascular volume depletion (e.g., those treated with high-dose diuretics), correct this condition prior to initiation or use a lower starting dose of Hyzaar^® 50/12.5 mg.

In patients with hepatic impairment, initiate therapy with caution; a lower starting dose may be required.

In patients with renal impairment (CrCl ≥30 mL/min), no initial dosage adjustment is necessary. Hyzaar^® is contraindicated in patients with severe renal impairment (CrCl <30 mL/min).

For elderly patients, no initial dosage adjustment is required, but a lower starting dose may be considered.

The full antihypertensive effect is typically attained within 3 weeks after initiation of therapy or a dosage change.

Monitor blood pressure regularly to determine the final therapeutic dose.

Adverse Reactions

Immune system disorders: rarely – anaphylactic reactions, angioedema (including edema of the larynx and tongue causing airway obstruction and/or edema of the face, lips, pharynx), urticarial rash.

Blood and lymphatic system disorders: infrequently – anemia, Henoch-Schönlein purpura, ecchymosis, hemolysis, agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, thrombocytopenia.

Nervous system disorders: frequently – headache, dizziness, insomnia, increased fatigue; infrequently – migraine, anxiety, confusion, depression, sleep disorders, memory impairment, somnolence, nervousness, paresthesia, tremor, syncope.

Cardiac disorders: frequently – orthostatic hypotension (dose-dependent), palpitations, tachycardia; infrequently – second-degree AV block, chest pain, myocardial infarction, arrhythmias; rarely – vasculitis.

Respiratory, thoracic and mediastinal disorders: frequently – cough, upper respiratory tract infections, sinusitis, nasal mucosal edema, nasal congestion; infrequently – pharyngitis, laryngitis, rhinitis, dyspnea, bronchitis, epistaxis.

Gastrointestinal disorders: frequently – diarrhea, dyspepsia, nausea, vomiting, abdominal pain; rarely – hepatitis, impaired liver function.

Renal and urinary disorders: infrequently – urinary tract infections, frequent urination, nocturia, glucosuria.

Reproductive system and breast disorders: infrequently – decreased libido, impotence.

Eye disorders: infrequently – blurred vision, burning sensation in the eyes, conjunctivitis.

Skin and subcutaneous tissue disorders: frequently – alopecia, dry skin, erythema, photosensitivity, increased sweating; infrequently – urticaria, skin itching.

Musculoskeletal and connective tissue disorders: frequently – myalgia, back pain; infrequently – arthralgia.

General disorders and administration site conditions: frequently – asthenia, weakness, peripheral edema; infrequently – anorexia, exacerbation of gout.

Investigations: frequently – hyperkalemia, slight decrease in hemoglobin and hematocrit concentration; infrequently – moderate increase in plasma urea and creatinine concentration, hyperglycemia, hyperuricemia, water-electrolyte balance disorders; rarely – increased ALT activity; very rarely – increased AST activity and bilirubin concentration.

Contraindications

Anuria; severe renal failure (CrCl <30 ml/min); severe hepatic impairment; pregnancy; lactation (breastfeeding); children and adolescents under 18 years of age; hypersensitivity to the drug components; hypersensitivity to sulfonamide derivatives.

With caution

Water-electrolyte balance disorders (hyponatremia, hypochloremic alkalosis, hypomagnesemia, hypokalemia), bilateral renal artery stenosis, stenosis of the artery of a single functioning kidney, condition after kidney transplantation, hypercalcemia, hyperuricemia and/or gout, burdened allergic history, bronchial asthma, systemic connective tissue diseases (including systemic lupus erythematosus), concurrent use of NSAIDs, including COX-2 inhibitors, diabetes mellitus, impaired liver function, impaired renal function (CrCl from 30-50 ml/min), hypovolemia (including against the background of taking high doses of diuretics), acute attack of angle-closure glaucoma.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

Contraindicated in severe hepatic impairment.

With caution in mild to moderate hepatic impairment.

Use in Renal Impairment

Contraindicated in severe renal failure (CrCl<30 ml/min).

With caution in mild to moderate renal impairment (CrCl from 30-50 ml/min).

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

The drug is approved for use in elderly patients.

Special Precautions

Reversible renal function impairments, including renal failure, which resolve after discontinuation of losartan, may occur during losartan use. Drugs affecting the RAAS may lead to increased plasma urea and creatinine concentrations in patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney. These changes in renal function may be reversible and resolve after discontinuation of therapy.

In patients with impaired renal function receiving NSAID therapy (including COX-2 inhibitors), therapy with angiotensin II receptor antagonists may lead to further deterioration of renal function, including acute renal failure, which is usually reversible, as well as increase plasma potassium concentration in patients with pre-existing renal impairment. This combination should be used with caution, especially in elderly patients. Patients should receive adequate fluids, and renal function should be monitored before and after starting treatment with this combination.

Patients should be monitored to promptly identify clinical signs of water-electrolyte balance disorders, such as dehydration, hyponatremia, hypochloremic alkalosis, hypomagnesemia, or hypokalemia, which may develop against the background of concomitant diarrhea or vomiting. In such patients, monitoring of plasma electrolyte levels is necessary.

Thiazide diuretic therapy may impair glucose tolerance. In some cases, dose adjustment of oral hypoglycemic agents and/or insulin may be required.

Thiazides can reduce renal calcium excretion and cause a transient and slight increase in plasma calcium concentration. Marked hypercalcemia may indicate latent hyperparathyroidism.

Due to the effect of thiazides on calcium metabolism, their use may distort the results of parathyroid function tests; therefore, the thiazide diuretic should be discontinued before testing parathyroid function.

Increased blood cholesterol and triglyceride levels may also be associated with thiazide diuretic therapy.

In some patients, the use of thiazide diuretics may lead to hyperuricemia and/or the development of gout. Since losartan reduces uric acid concentration, its combination with hydrochlorothiazide reduces the severity of diuretic-induced hyperuricemia.

Hydrochlorothiazide is a sulfonamide that can cause an idiosyncratic reaction leading to the development of an acute attack of angle-closure glaucoma.

In patients receiving thiazide diuretics, hypersensitivity reactions may occur even in the absence of a history of allergic reactions or bronchial asthma. There are reports of exacerbation or progression of systemic lupus erythematosus during the use of thiazide diuretics.

Effect on ability to drive vehicles and operate machinery

Caution should be exercised when driving vehicles and working with other technical devices that require increased concentration and speed of psychomotor reactions.

Drug Interactions

Concomitant use with potassium-sparing diuretics (spironolactone, eplerenone, triamterene, amiloride), potassium preparations or potassium-containing salt substitutes, as well as the use of other drugs that contribute to an increase in plasma potassium concentration, increase the risk of hyperkalemia.

NSAIDs, including selective COX-2 inhibitors, may reduce the effect of diuretics and other antihypertensive agents, including losartan.

The antihypertensive effect of losartan, like other antihypertensive agents, may be reduced when used with indomethacin.

Dual blockade of the RAAS, i.e., adding an ACE inhibitor to therapy with an angiotensin II receptor antagonist, is possible only in individual cases under careful monitoring of renal function.

In patients with atherosclerosis, heart failure, or diabetes mellitus with target organ damage, dual blockade of the RAAS (with simultaneous use of angiotensin II receptor antagonists, ACE inhibitors, or aliskiren) is associated with an increased frequency of arterial hypotension, syncope, hyperkalemia, and renal function impairments (including acute renal failure) compared to the use of a drug from one of the listed groups.

A decrease in lithium ion excretion is possible. Therefore, when angiotensin II receptor antagonists are used concomitantly with lithium salts, serum lithium concentrations should be carefully monitored.

When used concomitantly with thiazide diuretics, drugs such as ethanol, barbiturates, and opioid analgesics may potentiate the risk of orthostatic hypotension.

Concomitant use may enhance the hypoglycemic effect of oral hypoglycemic agents (sulfonylurea derivatives) and/or insulin in patients with diabetes mellitus; with such combinations, an increase in glucose tolerance is possible, which may require adjustment of the doses of oral hypoglycemic agents and/or insulin.

Concomitant use with other antihypertensive agents – additive effect.

Absorption of hydrochlorothiazide is impaired in the presence of cholestyramine and colestipol.

Concomitant use with corticosteroids and ACTH results in a pronounced decrease in electrolyte levels, in particular hypokalemia.

A decrease in the therapeutic effect of hydrochlorothiazide is observed against the background of the use of pressor amines (e.g., epinephrine (adrenaline), norepinephrine (noradrenaline)).

Hydrochlorothiazide enhances the effect of non-depolarizing muscle relaxants (e.g., tubocurarine chloride).

Diuretics reduce the renal clearance of lithium and increase the risk of lithium toxicity. Concomitant use is not recommended.

Concomitant use with barbiturates, narcotic analgesics, antidepressants, and ethanol increases the risk of orthostatic hypotension.

Drugs used to treat gout (probenecid, sulfinpyrazone, and allopurinol): Hydrochlorothiazide can increase serum uric acid concentration, so dose adjustment of uricosuric drugs may be required – increasing the dose of probenecid or sulfinpyrazone. Concomitant use of thiazide diuretics may increase the frequency of hypersensitivity reactions to allopurinol.

Concomitant use with cyclosporine may increase the risk of hyperuricemia and lead to exacerbation of gout.

Anticholinergic agents (e.g., atropine, biperiden) increase the bioavailability of thiazide diuretics by reducing gastrointestinal motility and gastric emptying rate.

Thiazide diuretics may reduce the renal excretion of cytotoxic drugs (cyclophosphamide, methotrexate) and enhance their myelosuppressive effect.

In case of high-dose salicylate use, Hydrochlorothiazide may enhance their toxic effect on the central nervous system.

There is limited data on the development of hemolytic anemia with the concomitant use of hydrochlorothiazide and methyldopa.

Thiazide diuretic-induced hypokalemia or hypomagnesemia may lead to the development of arrhythmias when used with cardiac glycosides.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.