Simartan-N (Tablets) Instructions for Use

Marketing Authorization Holder

Simpex Pharma, Pvt. Ltd. (India)

ATC Code

C09DA01 (Losartan and diuretics)

Active Substances

Hydrochlorothiazide (Rec.INN registered by WHO)

Losartan (Rec.INN registered by WHO)

Dosage Form

Simartan-N

Film-coated tablets, 25 mg+12.5 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets of a reddish-brown color, with a score on one side, round, biconvex; the core on the cross-section is white or almost white.

Excipients: microcrystalline cellulose – 100 mg, corn starch – 40.5 mg, povidone (PVP K30) – 2 mg, colloidal silicon dioxide – 3 mg, magnesium stearate – 2 mg, crospovidone – 25 mg.

Shell composition opadry brown (hypromellose – 5.4 mg, iron oxide red dye – 1.728 mg, macrogol – 1.08 mg, titanium dioxide – 0.792 mg) – 9 mg, propylene glycol – 1 mg.

10 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Antihypertensive combination agent (angiotensin II receptor antagonist + diuretic)

Pharmacological Action

The components of Simartan-N have an additive antihypertensive effect, reducing blood pressure to a greater extent than each component separately.

Due to the diuretic effect, Hydrochlorothiazide increases plasma renin activity (PRA), stimulates aldosterone secretion, increases angiotensin II concentration, and decreases serum potassium levels.

Losartan intake blocks all physiological effects of angiotensin II and, due to the suppression of aldosterone effects, may help reduce potassium loss associated with diuretic intake.

Losartan

Losartan is a specific angiotensin II receptor antagonist (subtype AT₁) for oral administration. It does not inhibit kininase II, the enzyme that catalyzes the conversion of angiotensin I to angiotensin II.

Angiotensin II selectively binds to AT₁ receptors located in many tissues (vascular smooth muscle, adrenal glands, kidneys, and heart) and performs several important biological functions, including vasoconstriction and aldosterone release.

Angiotensin II also stimulates smooth muscle cell proliferation.

Losartan and its pharmacologically active metabolite (E3174) block all physiological effects of angiotensin II, both in vitro and in vivo, regardless of the source or synthesis pathway.

Losartan selectively binds to AT₁ receptors and does not bind to or block receptors of other hormones and ion channels important in regulating cardiovascular function.

Furthermore, Losartan does not inhibit ACE and, accordingly, does not prevent the breakdown of bradykinin, so side effects indirectly related to bradykinin (e.g., angioedema) occur quite rarely.

When losartan is used, the lack of negative feedback on renin secretion leads to an increase in plasma renin activity.

Increased renin activity leads to an increase in plasma angiotensin II.

However, antihypertensive activity and a decrease in plasma aldosterone concentration persist, indicating effective blockade of angiotensin II receptors.

Losartan and its active metabolite have a greater affinity for angiotensin I receptors than for angiotensin II receptors.

The active metabolite is 10-40 times more active than losartan.

After a single oral dose, the antihypertensive effect (reduction in systolic and diastolic blood pressure) peaks at 6 hours, then gradually decreases over 24 hours.

The maximum antihypertensive effect develops 3-6 weeks after starting the drug.

In patients with arterial hypertension without concomitant diabetes mellitus with proteinuria (more than 2 g/day), the drug significantly reduces proteinuria, albumin excretion, and immunoglobulin G excretion.

Losartan at a dose of 150 mg/day does not affect serum triglyceride, total cholesterol, and high-density lipoprotein (HDL) cholesterol concentrations in patients with arterial hypertension.

At the same dose, Losartan does not affect fasting blood glucose levels.

Hydrochlorothiazide

The mechanism of the antihypertensive action of thiazides is unknown.

Thiazides usually do not affect normal blood pressure.

Hydrochlorothiazide affects electrolyte reabsorption in the distal renal tubules.

Hydrochlorothiazide increases the excretion of sodium and chloride ions approximately equally.

Natriuresis may be accompanied by a slight loss of potassium and bicarbonate ions.

After oral administration, the diuretic effect develops within 2 hours, peaks on average at 4 hours, and lasts from 6 to 12 hours.

Pharmacokinetics

Absorption

Losartan

When taken orally, Losartan is well absorbed and undergoes metabolism during the first pass through the liver, resulting in the formation of an active carboxylated metabolite and inactive metabolites.

Systemic bioavailability is approximately 33%.

Mean C_max of losartan and its active metabolite is reached at 1 hour and 3-4 hours, respectively.

When losartan was taken with food, no clinically significant effect on the plasma concentration profile of losartan was identified.

Hydrochlorothiazide

When taken orally, Hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract.

The time to reach C_max is 1.5-3 hours.

Distribution

Losartan

Losartan and its active metabolite are more than 99% bound to plasma proteins (mainly albumin).

The V_d of losartan is 34 L.

Studies in rats have shown that Losartan practically does not penetrate the blood-brain barrier.

Hydrochlorothiazide

Hydrochlorothiazide is 40-60% bound to plasma proteins, crosses the placental (but not the blood-brain) barrier, and passes into breast milk.

Metabolism

Losartan

Approximately 14% of the losartan dose administered intravenously or orally is converted to its active metabolite.

In addition to the active metabolite, biologically inactive metabolites are formed as a result of hydroxylation of the butyl side chain, including two main metabolites and one minor one – N-2-tetrazole-glucuronide.

Elimination

Losartan

The plasma clearance of losartan and its active metabolite is about 600 ml/min and 50 ml/min, respectively.

The renal clearance of losartan and its active metabolite is approximately 74 ml/min and 26 ml/min, respectively.

When losartan is taken orally, about 4% of the dose is excreted unchanged by the kidneys, and about 6% of the dose is excreted as the active metabolite.

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

After oral administration, plasma concentrations of losartan and its active metabolite decline polyexponentially with a terminal T_1/2 of approximately 2 and 6-9 hours, respectively.

With a single daily dose of 100 mg, neither Losartan nor its active metabolite accumulates significantly in plasma.

Losartan and its metabolites are excreted in the bile through the intestine and by the kidneys.

Hydrochlorothiazide

Hydrochlorothiazide is not metabolized and is rapidly excreted by the kidneys.

T_1/2 varies from 5.6 to 14.8 hours.

At least 61% of the orally administered dose is excreted unchanged within 24 hours.

Pharmacokinetics in specific patient groups

Losartan+Hydrochlorothiazide

Elderly patients

Plasma concentrations of losartan and its active metabolite and the absorption rate of hydrochlorothiazide in elderly hypertensive patients do not differ significantly from these parameters in young hypertensive patients.

Losartan

Gender

Plasma concentrations of losartan were 2 times higher in women with hypertension compared to men with hypertension.

This apparent pharmacokinetic difference has no clinical significance.

Concentrations of the active metabolite did not differ between men and women.

Impaired liver and kidney function

After oral administration to patients with mild to moderate alcoholic liver cirrhosis, plasma concentrations of losartan and its active metabolite were 5 and 1.7 times higher, respectively, than in young male volunteers.

Plasma concentrations of losartan in patients with CC above 10 ml/min did not differ from those in patients with preserved renal function.

When comparing AUC in patients with normal renal function, the AUC of losartan in patients on hemodialysis was approximately 2 times higher.

Plasma concentrations of the active metabolite do not change in patients with impaired renal function or patients on hemodialysis.

Losartan and its active metabolite cannot be removed by hemodialysis.

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

Simartan-N is taken orally, regardless of meal time.

Arterial hypertension – 1 tab. of Simartan-N once daily. If there is no therapeutic effect within 2-4 weeks, the dose of Simartan-N may be increased to 2 tabs. once daily. The maximum dose is 2 tabs. of Simartan-N once daily. Typically, the antihypertensive effect is achieved within 3 weeks after starting therapy.

Reduction of cardiovascular morbidity and mortality risk in patients with arterial hypertension and left ventricular hypertrophy – 1 tab. once daily. If there is no therapeutic effect (target blood pressure values are not achieved while taking 1 tab.), the dose of Simartan-N may be increased to 2 tabs. once daily. The maximum dose is 2 tabs. once daily.

No initial dose adjustment is required for elderly patients and patients with moderate renal failure (CC 30-50 ml/min).

Use in patients with reduced circulating blood volume (CBV) – before starting therapy with the drug, it is necessary to restore CBV and/or plasma sodium levels.

Adverse Reactions

The frequency of side effects is classified according to WHO recommendations: very common – not less than 10%; common – not less than 1%, but less than 10%; uncommon – not less than 0.1%, but less than 1%; rare – not less than 0.01%, but less than 0.1%; very rare – 0.01%, including isolated reports; frequency not established (cannot be calculated from available data).

In clinical studies with losartan/hydrochlorothiazide, no adverse events specific to this combination drug were observed. Adverse events were limited to those previously reported with losartan and hydrochlorothiazide separately. The following adverse events have been observed during post-marketing use of losartan/hydrochlorothiazide.

Digestive system disorders: rarely – hepatitis.

Laboratory parameters: rarely – hyperkalemia, increased activity of “liver” transaminases.

The following adverse events have been observed with the use of losartan and hydrochlorothiazide separately.

Losartan

Blood and lymphatic system disorders: uncommon – anemia, Henoch-Schönlein purpura, ecchymosis, hemolytic anemia.

Allergic reactions: rarely — anaphylactic reactions, angioedema, urticaria.

Metabolism and nutrition disorders: anorexia, gout.

Nervous system disorders: common – headache, dizziness, insomnia; uncommon – anxiety, paresthesia, peripheral neuropathy, tremor, migraine, syncope, anxiety disorders, panic disorders, confusion, depression, somnolence, sleep disorder, memory impairment.

Eye disorders: uncommon – visual impairment, sensation of dryness and burning in the eyes, conjunctivitis, decreased visual acuity.

Ear and labyrinth disorders: uncommon – vertigo, tinnitus.

Respiratory system disorders: common – nasal congestion, cough, upper respiratory tract infections (fever, sore throat, sinusopathy, sinusitis, pharyngitis); uncommon – pharyngitis, laryngitis, dyspnea, bronchitis, rhinitis, epistaxis, pharyngeal discomfort.

Gastrointestinal disorders: common – nausea, diarrhea, dyspepsia, abdominal pain; uncommon – dry mouth, toothache, vomiting, flatulence, gastritis, constipation.

Musculoskeletal and connective tissue disorders: common – cramps, myalgia, back pain, leg pain; uncommon – arthralgia, arm pain, shoulder pain, knee pain, arthritis, fibromyalgia, muscle weakness, joint swelling, musculoskeletal pain.

Cardiac disorders: uncommon – pronounced decrease in blood pressure, orthostatic hypotension (dose-dependent), palpitations, tachycardia or bradycardia, arrhythmias, angina pectoris, chest pain, second-degree AV block, cerebrovascular events, myocardial infarction, vasculitis.

Renal and urinary disorders: uncommon – nocturia, frequent urination, urinary tract infections, decreased libido, impotence.

Skin and subcutaneous tissue disorders: uncommon – dry skin, erythema, facial flushing, photosensitivity, pruritus, rash, hyperhidrosis, alopecia, dermatitis.

General disorders: common – asthenia, increased fatigue; uncommon – facial edema, fever.

Laboratory parameters: common – hyperkalemia, decreased hematocrit and hemoglobin; uncommon – increased urea and creatinine concentration; very rarely – increased activity of “liver” transaminases.

Hydrochlorothiazide

Blood and lymphatic system disorders: uncommon – agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, purpura, thrombocytopenia.

Allergic reactions: rarely – anaphylactic reactions; very rarely – urticaria, Stevens-Johnson syndrome, erythema multiforme, erythroderma, reversible non-phigoid reactions, exfoliative dermatitis, allergic alveolitis, eosinophilic pneumonia, angioedema of the larynx, pharynx, tongue, face, lips, mucous membranes (including fatal outcomes).

Metabolism and nutrition disorders: uncommon – loss of appetite, hyperglycemia, hyperuricemia, water-electrolyte balance disorders (particularly hypokalemia and hyponatremia, hypomagnesemia and hypochloremia, as well as hypercalcemia). Thiazide treatment may reduce glucose tolerance, and latent diabetes mellitus may become manifest; very rarely – metabolic alkalosis.

Nervous system disorders: common – headache; uncommon – dizziness, insomnia.

Eye disorders: rarely – decreased tear production, visual impairment; very rarely – conjunctivitis; frequency not established – acute myopia, secondary angle-closure glaucoma.

Cardiac disorders: uncommon – necrotizing vasculitis.

Respiratory system disorders: uncommon – respiratory distress syndrome (including pneumonitis and non-cardiogenic pulmonary edema).

Digestive system disorders: uncommon – sialadenitis, gastrointestinal mucosa irritation, nausea, vomiting, diarrhea, constipation, jaundice (intrahepatic cholestasis), pancreatitis.

Skin and subcutaneous tissue disorders: uncommon – photosensitivity, urticaria, toxic epidermal necrolysis, lupus-like syndrome.

Musculoskeletal and connective tissue disorders: uncommon – muscle cramps.

Renal and urinary disorders: uncommon – glucosuria, interstitial nephritis, renal function impairment, renal failure.

General disorders: uncommon – increased body temperature.

Contraindications

• Hypersensitivity to any component of the drug;
• Hypersensitivity to sulfonamide derivatives;
• Anuria;
• Severe renal impairment (CC less than 30 ml/min);
• Severe hepatic impairment (more than 9 points on the Child-Pugh scale), cholestasis;
• Age under 18 years (efficacy and safety of use have not been established);
• Dehydration;
• Refractory hypokalemia and hyperkalemia;
• Poorly controlled diabetes mellitus;
• Addison’s disease;
• Primary hyperaldosteronism;
• Pregnancy, breastfeeding period;
• Concomitant use with aliskiren and aliskiren-containing drugs in patients with diabetes mellitus and/or renal impairment (glomerular filtration rate (GFR) less than 60 ml/min/1.73 m²).

With caution

Patients with disorders of water and electrolyte balance, for example, due to diarrhea or vomiting (hyponatremia, hypochloremic alkalosis, hypomagnesemia, hypokalemia).

Patients with renal failure (CC 30-50 ml/min); hepatic failure (less than 9 points on the Child-Pugh scale); bilateral renal artery stenosis or stenosis of the artery of a single kidney; coronary artery disease; heart failure with life-threatening arrhythmias; cerebrovascular diseases; aortic stenosis, mitral stenosis, hypertrophic obstructive cardiomyopathy; diabetes mellitus, hypercalcemia: with a burdened allergic history and bronchial asthma; as well as with systemic connective tissue diseases (including systemic lupus erythematosus); hypovolemia (including against the background of high-dose diuretic use); and also, with simultaneous prescription with NSAIDs, including COX-2 inhibitors; acute attack of myopia and secondary angle-closure glaucoma; history of angioedema: symptomatic increase in plasma uric acid concentration, gout; condition after kidney transplantation (no experience of use), chronic heart failure of functional class IV according to the NYHA classification; use in patients of the Black race.

Use in Pregnancy and Lactation

Use of Simartan-N is contraindicated during pregnancy.

Use of drugs that have a direct effect on the RAAS during the second and third trimesters of pregnancy can harm the developing fetus or even cause its death. As soon as pregnancy is established, Simartan-N should be discontinued.

Although there are no data on the use of Simartan-N in pregnant women, animal studies have demonstrated that the use of losartan can cause harm and death to the fetus and newborn, which is likely related to the drug’s effect on the RAAS. In the human fetus, renal perfusion, which depends on the development of the RAAS, begins in the second trimester; thus, the risk of developmental impairment and fetal death increases when Simartan-N is used during the second or third trimester of pregnancy.

Thiazides cross the placental barrier and are detected in cord blood. The use of diuretics in healthy pregnant women is not recommended, as it increases the risk of adverse events in the fetus such as fetal jaundice and neonatal jaundice, and in the mother – thrombocytopenia.

There are no data on whether Losartan is excreted in human milk. It is known that thiazides cross the placental barrier and are detected in cord blood. Due to the risk of adverse events in infants, a balanced decision must be made in all cases regarding drug use during breastfeeding, taking into account the importance of therapy for the mother.

If it is decided that Simartan-N is needed during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

Use with caution in patients with hepatic insufficiency (less than 9 points on the Child-Pugh scale).

Use is contraindicated in patients with severe hepatic impairment (more than 9 points on the Child-Pugh scale) and cholestasis.

Use in Renal Impairment

Use with caution in patients with renal insufficiency (CrCl 30-50 ml/min).

Use is contraindicated in patients with severe renal impairment (CrCl less than 30 ml/min).

Pediatric Use

Use in children and adolescents under 18 years of age is contraindicated (efficacy and safety have not been established).

Special Precautions

Simartan-N can be prescribed in combination with other antihypertensive agents.

Losartan

Due to inhibition of the RAAS, changes in renal function, including renal failure, have been observed in some susceptible patients; these changes were reversible and resolved after discontinuation of therapy.

Manifestation of hypersensitivity reactions such as angioedema is possible, therefore patients with a history of angioedema (swelling of the face, lips, pharynx/larynx, and/or tongue) require careful monitoring during drug use.

Simartan-N, like some drugs affecting the RAAS, may increase blood urea and serum creatinine concentrations in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. These changes in renal function were reversible and resolved after discontinuation of therapy. Pharmacokinetic data indicate that the plasma concentration of losartan is significantly increased in patients with hepatic cirrhosis, therefore patients with a history of liver disease should use the drug at a lower dose.

During treatment with Simartan-N, as with any antihypertensive therapy, a pronounced decrease in blood pressure may occur. Patients should be examined for clinical signs of reduced circulating blood volume and water-electrolyte imbalance, including hyponatremia, hypochloremic alkalosis, hypomagnesemia, or hypokalemia, which may occur due to episodes of diarrhea or vomiting, as a result of diuretic therapy, or with restricted salt intake. In such patients, plasma electrolyte levels should be monitored.

Concomitant use with potassium preparations, potassium-sparing diuretics is not recommended (see section “Drug Interactions”).

In patients with primary hyperaldosteronism, the use of antihypertensive drugs affecting the RAAS, including Simartan-N, is not effective.

A sharp decrease in blood pressure during therapy with Simartan-N, as with other antihypertensive drugs, in patients with ischemic cardiovascular and cerebrovascular diseases may lead to the development of acute myocardial infarction or stroke.

In patients with heart failure, both with and without renal impairment, the use of Simartan-N, like other agents affecting the RAAS, increases the risk of a sharp decrease in blood pressure and the development of acute renal failure.

Caution should be exercised when using Simartan-N in patients with aortic stenosis, mitral stenosis, and hypertrophic obstructive cardiomyopathy.

It should be taken into account that angiotensin II receptor antagonists, including Losartan, are less effective for the treatment of arterial hypertension in Black patients than in other patients.

Hydrochlorothiazide

As with the use of any antihypertensive drugs, symptomatic arterial hypotension may be observed in some patients. In some patients, Hydrochlorothiazide may exacerbate water-electrolyte imbalances (decreased circulating blood volume, hyponatremia, hypochloremic alkalosis, hypomagnesemia, hypokalemia), impair glucose tolerance, reduce renal calcium excretion, cause a transient slight increase in plasma calcium levels, increase cholesterol and triglyceride concentrations, and provoke the occurrence of hyperuricemia and/or gout (since Losartan reduces uric acid concentration, the severity of diuretic-induced hyperuricemia is reduced).

May yield positive results in doping control. Hydrochlorothiazide, due to its effect on calcium metabolism, may distort the results of parathyroid function tests.

There are reports of exacerbation or progression of systemic lupus erythematosus during the use of thiazide diuretics.

Thiazide diuretics should be used with caution in patients with impaired liver function or progressive liver disease, as this may lead to the development of intrahepatic cholestasis, which, in combination with water-electrolyte imbalance, can lead to the development of hepatic coma.

Thiazide therapy may impair glucose tolerance; in some cases, adjustment of the dose of hypoglycemic agents, including insulin, may be required. Marked hypercalcemia may indicate latent hyperparathyroidism. Due to the influence of thiazides on calcium metabolism, their use may distort the results of parathyroid function tests; before testing parathyroid function, the thiazide diuretic should be discontinued.

Acute myopia and angle-closure glaucoma

Cases of transient myopia and acute onset of angle-closure glaucoma have been reported with the use of hydrochlorothiazide. Risk factors for acute angle-closure glaucoma may include a history of allergic reactions to sulfonamide derivatives and penicillin. Symptoms: sudden onset, acute decrease in vision or eye pain, usually occurring within hours to a week after starting therapy. An untreated attack of angle-closure glaucoma can lead to permanent vision loss. The first step is to discontinue hydrochlorothiazide. If intraocular pressure does not decrease after discontinuation of hydrochlorothiazide, medical or surgical treatment may be required.

Kidney transplantation. There is no experience with the use of hydrochlorothiazide+losartan in patients who have recently undergone kidney transplantation.

Coronary artery disease and cerebrovascular disease. As with treatment with any antihypertensive drugs, excessive lowering of blood pressure in patients with coronary artery disease or cerebrovascular disease may lead to myocardial infarction or stroke.

Heart failure. In patients whose renal function depends on the state of the RAAS (e.g., in CHF functional class III-IV according to NYHA, with or without renal impairment), therapy with drugs affecting the RAAS may be accompanied by sharp arterial hypotension, oliguria and/or progressive azotemia, and in rare cases, acute renal failure. The development of these disorders due to suppression of RAAS activity during the use of ARBs cannot be ruled out.

Aortic and/or mitral valve stenosis, hypertrophic obstructive cardiomyopathy. Simartan-N, like other vasodilators, should be used with caution in patients with hemodynamically significant aortic and/or mitral valve stenosis, or with hypertrophic obstructive cardiomyopathy.

Interaction with drugs affecting the RAAS. Dual blockade of the RAAS with angiotensin II receptor antagonists, ACE inhibitors, or aliskiren-containing drugs is associated with an increased risk of arterial hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Blood pressure, renal function, and electrolyte levels should be monitored in patients who are using several drugs affecting the RAAS simultaneously. The concomitant use of aliskiren with drugs containing Hydrochlorothiazide+Losartan is not recommended in patients with diabetes mellitus and in patients with renal impairment (eGFR <60 ml/min/1.73 m²).

Effect on ability to drive and operate machinery

Some adverse effects of the drug, such as dizziness, weakness, drowsiness, and blurred vision, may negatively affect the ability to drive vehicles and tractors and perform potentially hazardous activities requiring increased concentration and speed of psychomotor reactions. At the beginning of therapy with the drug (the duration of this period is determined individually), it is recommended to refrain from driving vehicles and performing work requiring increased concentration and speed of psychomotor reactions (due to the possible development of dizziness and drowsiness); subsequently, caution should be exercised.

Overdose

Symptoms: Losartan – marked decrease in blood pressure, tachycardia, bradycardia (resulting from vagal stimulation).

Hydrochlorothiazide – electrolyte loss (hypokalemia, hypochloremia, hyponatremia); dehydration (excessive diuresis).

Treatment: symptomatic and supportive therapy. If the drug was taken recently, gastric lavage should be performed; if necessary, correction of water-electrolyte disturbances is carried out. Losartan and its active metabolite are not removed by hemodialysis.

It has not been established to what extent Hydrochlorothiazide can be removed from the body by hemodialysis.

Drug Interactions

Losartan

Clinical pharmacokinetic studies have not revealed clinically significant interactions with hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, ketoconazole, and erythromycin. Rifampicin decreases the concentration of the active metabolite. The clinical significance of this interaction has not been established.

The combination of losartan, like other agents blocking angiotensin II or its effects, with potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride, eplerenone), potassium supplements or potassium salts may lead to an increase in serum potassium levels.

As with the use of other agents affecting lithium excretion, treatment with losartan may be accompanied by reduced excretion and increased serum concentration of lithium, therefore, during concomitant treatment with lithium preparations, its serum concentration should be monitored.

NSAIDs, including selective COX-2 inhibitors, may reduce the effect of diuretics and other antihypertensive agents. Therefore, the antihypertensive effect of angiotensin II receptor antagonists may be attenuated by NSAIDs, including COX-2 inhibitors.

In some patients with impaired renal function receiving therapy with NSAIDs, including COX-2 inhibitors, treatment with angiotensin II receptor antagonists may cause further deterioration of renal function. These effects are usually reversible.

Dual blockade of the RAAS – combined use of angiotensin II receptor antagonists, ACE inhibitors, or aliskiren (a direct renin inhibitor) – leads to a significant increase in the frequency of adverse events such as arterial hypotension, syncope, hyperkalemia, impaired renal function, acute renal failure, therefore regular monitoring of blood pressure, renal function, and electrolyte levels in the blood is necessary in patients taking Simartan-N and other drugs affecting the RAAS. The drug should not be used concomitantly with aliskiren in patients with diabetes mellitus. Concomitant use of the drug and aliskiren should be avoided in patients with renal impairment (eGFR less than 60 ml/min/1.73 m²). The highest risk is in patients with an established diagnosis of atherosclerosis, heart failure, diabetes mellitus (with any complication). The issue of using dual blockade of the RAAS (e.g., by simultaneous prescription of an ACE inhibitor and an angiotensin II receptor antagonist) should be decided on a case-by-case basis with careful monitoring of renal function.

Fluconazole, an inhibitor of the CYP2C9 isoenzyme, reduces plasma concentrations of the active metabolite and increases concentrations of losartan; however, the pharmacodynamic significance of this phenomenon has not been established. It has been shown that patients who do not metabolize Losartan to the active metabolite have a very rare and specific defect of the CYP2C9 isoenzyme.

Hydrochlorothiazide

When hydrochlorothiazide is prescribed concomitantly with ethanol, barbiturates, narcotic analgesics, the risk of orthostatic hypotension increases;

• With oral hypoglycemic agents and insulin, dose adjustment of the hypoglycemic agents may be required;
• With other antihypertensive agents, an additive effect is possible;
• With cholestyramine and colestipol – impaired absorption of hydrochlorothiazide.

A single dose of cholestyramine or colestipol can reduce the absorption of hydrochlorothiazide in the gastrointestinal tract by 85% and 43%, respectively.

When hydrochlorothiazide is prescribed concomitantly with corticosteroids, adrenocorticotropic hormone, glycyrrhizic acid (contained in licorice root), amphotericin B, electrolyte loss may be enhanced, exacerbating hypokalemia

• With pressor amines (norepinephrine, epinephrine), a slight reduction in the effect of pressor amines is possible, which does not preclude their use;
• With non-depolarizing muscle relaxants – enhancement of their action;
• With NSAIDs (including COX-2 inhibitors), a reduction in the diuretic, natriuretic, antihypertensive effect of diuretics is possible.

Do not use concomitantly with lithium preparations, as diuretics reduce the renal clearance of lithium and increase the risk of lithium intoxication.

Drugs used to treat gout (probenecid, sulfinpyrazone and allopurinol) – dose adjustment may be required (increase in the dose of probenecid and sulfinpyrazone), since Hydrochlorothiazide may increase serum uric acid concentration. Concomitant use of thiazide diuretics may increase the frequency of hypersensitivity reactions to allopurinol.

Anticholinergic agents (e.g., atropine, biperiden) – increased bioavailability of thiazide diuretics due to reduced gastrointestinal motility and gastric emptying rate.

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

Thiazide diuretics may enhance the toxic effect of salicylates on the central nervous system when used in high doses.

Isolated cases of hemolytic anemia have been reported with the concomitant use of hydrochlorothiazide and methyldopa.

Concomitant treatment with cyclosporine may increase the risk of hyperuricemia and gout.

Hypokalemia or hypomagnesemia caused by the use of thiazide diuretics may contribute to the development of arrhythmia when used concomitantly with cardiac glycosides.

Concomitant use of thiazide diuretics with antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide, amiodarone, sotalol, dofetilide, ibutilide), some antipsychotic drugs (neuroleptics) (thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol) and other drugs (bepridil, cisapride, difemanil, erythromycin, halofantrine, mizolastine, pentamidine, terfenadine, vincamine, pentamidine) may be accompanied by the development of hypokalemia, which, in turn, can cause the development of torsades de pointes arrhythmia.

Thiazide diuretics may lead to hypercalcemia due to reduced calcium excretion, therefore serum calcium levels should be monitored.

Due to the influence of thiazide diuretics on calcium metabolism, their use may distort the results of parathyroid function tests.

When used concomitantly with carbamazepine, there is a risk of symptomatic hyponatremia.

With the development of dehydration during the use of diuretics, there is a possibility of acute renal failure, especially when used concomitantly with iodine-containing drugs.

Ethanol, barbiturates, and narcotic analgesics may potentiate the risk of orthostatic hypotension.

Storage Conditions

Store in a light-protected place, out of the reach of children, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 2 years.

Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

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.