Losartan N (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

Agents acting on the renin-angiotensin system; angiotensin II receptor antagonists (ARBs), combinations; angiotensin II receptor antagonists and diuretics

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: leads to an increase in plasma renin activity, reduces plasma aldosterone concentration. Losartan indirectly causes activation of AT₂ receptors due to an increase in angiotensin II concentration. It does not suppress the activity of kininase II, an enzyme involved in the metabolism of bradykinin. Reduces total peripheral vascular resistance, pressure in the pulmonary circulation, reduces myocardial afterload, and has a diuretic effect. Prevents the development of myocardial hypertrophy, increases exercise tolerance in patients with chronic heart failure (CHF). Taking losartan once a day leads to a statistically significant decrease in systolic and diastolic blood pressure.

Losartan uniformly controls blood pressure throughout the day, and the antihypertensive effect corresponds to the natural circadian rhythm. The reduction in blood pressure at the end of the drug’s dose 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, the diuretic effect of which is associated with impaired reabsorption of sodium, chlorine, potassium, magnesium ions, and water in the distal nephron; delays the excretion of calcium ions and uric acid. It has an antihypertensive effect, which develops due to the expansion of arterioles. It has practically no effect on normal blood pressure. The diuretic effect occurs within 1-2 hours, reaches a maximum after 4 hours and lasts 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 angiotensin II concentration and reduces plasma potassium concentration. Taking losartan blocks all physiological effects of angiotensin II and, due to suppression of the effects of aldosterone, may help reduce potassium loss associated with diuretic use. Hydrochlorothiazide causes a slight increase in blood uric acid concentration; the combination of losartan and hydrochlorothiazide helps reduce the severity of hyperuricemia caused by the diuretic.

Pharmacokinetics

The pharmacokinetics of losartan and hydrochlorothiazide when used simultaneously 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 is reached after 1 hour and after 3-4 hours, respectively. Losartan and its active metabolite bind to plasma proteins (mainly albumin) by more than 99%. 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 ones, including two main metabolites formed by hydroxylation of the butyl group of the chain and a less significant metabolite, N-2-tetrazole glucuronide. The 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. The 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 mainly with bile through the intestines – 58% , by the kidneys – 35% . Does not accumulate.

When taken 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. Binding to plasma proteins is 64%. Penetrates the placental barrier. 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 in patients with arterial hypertension and left ventricular hypertrophy.

ICD codes

Dosage Regimen

Take orally, regardless of meals.

Initiate therapy with one tablet once daily. The recommended dose of the combination in terms of losartan is 50-100 mg once a day.

The maximum antihypertensive effect is typically achieved within 3 weeks of continuous therapy.

Do not exceed the maximum daily dose of 100 mg of losartan.

For patients not adequately controlled on losartan or hydrochlorothiazide monotherapy, switch to this combination.

For patients controlled on 25 mg of hydrochlorothiazide but who exhibit significant hypokalemia, transition to this combination.

Dosage adjustment in patients with hepatic impairment is not routinely required; however, initiate therapy with caution.

In patients with mild to moderate renal impairment (creatinine clearance 30-50 ml/min), initiate therapy with caution.

This combination is contraindicated in patients with severe renal impairment (creatinine clearance <30 ml/min).

For elderly patients, no initial dose adjustment is generally necessary.

The safety and efficacy in pediatric patients under 18 years of age have not been established.

Adverse Reactions

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

From the hematopoietic system: infrequently – anemia, Henoch-Schönlein purpura, ecchymosis, hemolysis, agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, thrombocytopenia.

From the nervous system: often – headache, dizziness, insomnia, increased fatigue; infrequently – migraine, anxiety, confusion, depression, sleep disorders, memory impairment, drowsiness, nervousness, paresthesia, tremor, fainting.

From the cardiovascular system: often – orthostatic hypotension (dose-dependent), palpitations, tachycardia; infrequently – second-degree AV block, chest pain, myocardial infarction, arrhythmias; rarely – vasculitis.

From the respiratory system: often – cough, upper respiratory tract infections, sinusitis, nasal mucosal edema, nasal congestion; infrequently – pharyngitis, laryngitis, rhinitis, dyspnea, bronchitis, nosebleed.

From the digestive system: often – diarrhea, dyspepsia, nausea, vomiting, abdominal pain; rarely – hepatitis, impaired liver function.

From the urinary system: infrequently – urinary tract infections, frequent urination, nocturia, glucosuria.

From the reproductive system: infrequently – decreased libido, decreased potency.

From the senses: infrequently – blurred vision, burning sensation in the eyes, conjunctivitis.

From the skin: often – alopecia, dry skin, erythema, photosensitivity, increased sweating; infrequently – urticaria, skin itching.

From the musculoskeletal system: often – myalgia, back pain; infrequently – arthralgia.

Other: often – asthenia, weakness, peripheral edema; infrequently – anorexia, exacerbation of gout.

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

Contraindications

Anuria; severe renal failure (creatinine clearance <30 ml/min); severe liver dysfunction; pregnancy; lactation (breastfeeding) period; children and adolescents under 18 years of age; hypersensitivity to the components of the drug; hypersensitivity to sulfonamide derivatives.

With caution

Disorders of water and electrolyte balance of the blood (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), simultaneous use of NSAIDs, including COX-2 inhibitors, diabetes mellitus, impaired liver function, impaired renal function (creatinine clearance from 30-50 ml/min), hypovolemia (including against the background of taking diuretics in high doses), 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 liver dysfunction.

With caution in mild and moderate liver dysfunction.

Use in Renal Impairment

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

With caution in mild and moderate renal impairment (creatinine clearance 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

During the use of losartan, reversible renal function disorders, including renal failure, may occur, which disappear after discontinuation of losartan. Drugs affecting the RAAS may lead to an increase in 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 disappear after discontinuation of therapy.

In patients with impaired renal function receiving therapy with NSAIDs (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 have their renal function monitored before and after starting treatment with this combination.

Patients should be monitored to promptly identify clinical signs of water and electrolyte imbalance, 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.

Therapy with thiazide diuretics may impair glucose tolerance. In some cases, dose adjustment of oral hypoglycemic agents and/or insulin may be required.

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

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

An increase in 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 hyperuricemia caused by the diuretic.

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 help increase 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 using 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 accompanied by an increased incidence of arterial hypotension, fainting, hyperkalemia, and renal dysfunction (including acute renal failure) compared with the use of a drug from one of the listed groups.

Reduced excretion of lithium ions 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.

The absorption of hydrochlorothiazide is impaired in the presence of cholestyramine and colestipol.

When used concomitantly with corticosteroids and ACTH, a pronounced decrease in electrolyte levels, in particular hypokalemia, is observed.

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

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

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

When used concomitantly with barbiturates, narcotic analgesics, antidepressants, and ethanol, the risk of orthostatic hypotension increases.

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 (for example, 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 using salicylates in high doses, 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 arrhythmia when using cardiac glycosides.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°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.