Prezartan N - instructions for use, dose, side effects, contraindications

lactose monohydrate 111,50 mg, microcrystalline cellulose 58.00 mg, pregelatinized starch 3.00 mg, corn starch 12.00 mg, silicon dioxide colloid 1.00 mg, magnesium stearate 2.00 mg.

Sheath:

hypromellose 2.441 mg, titanium dioxide 0.60 mg, talc 1.50 mg, macrogol-6000 0.40 mg, dye quinoline yellow 0.058 mg.

Description:Oval, biconvex tablets, covered with a film coating of yellow color. On the cross-section: the core is from white to almost white.

Pharmacotherapeutic group:hypotensive combined agent (angiotensin II receptor antagonist [ARA II] + diuretic).

ATX: & nbsp

C.09.D.A.01 Losartan in combination with diuretics

Pharmacodynamics:Prezartan® H is a combined preparation, it includes losartan and hydrochlorothiazide, both components have an additive antihypertensive effect, reducing blood pressure (BP) more than each of the components individually.

Losartan

Losartan is a specific antagonist of angiotensin II receptors (subtype AT₁) for oral administration.Does not inhibit kinase II - an enzyme that catalyzes the reaction of the conversion of angiotensin I into angiotensin II.

Angiotensin II selectively binds to AT₁receptors located in many tissues (vascular smooth muscle, adrenal gland, kidneys and the heart) and performs several important biological functions, including vasoconstriction and the release of aldosterone. Angiotensin II also stimulates proliferation of smooth muscle cells.

Lozartan and its pharmacologically active metabolite (E 3174) as in vitro, and in vivo block all the physiological effects of angiotensin II, regardless of the source or route of synthesis. Losartan selectively binds to the AT₁receptors and does not bind or block receptors of other hormones and ion channels, which play an important role in regulating the function of the cardiovascular system. Besides, losartan does not inhibit angiotensin-converting enzyme (ACE) - kininase II, and, accordingly, does not interfere with the destruction of bradykinin, therefore side effects mediated by bradykinin (eg, angioedema) are rare.

When using losartan, the absence of negative feedback influence on renin secretion leads to an increase in renin plasma activity.Increased renin activity leads to an increase in angiotensin II in blood plasma. However, antihypertensive activity and a decrease in plasma aldosterone concentration are preserved, which indicates an effective blockade of angiotensin II receptors. Losartan and its active metabolite have a greater affinity for the angiotensin I receptors than for angiotensin II receptors. The active metabolite is 10-40 times more active than losartan.

After a single oral intake, the antihypertensive effect (systolic and diastolic blood pressure decreases) reaches a maximum after 6 hours, then gradually decreases within 24 hours.

The maximum antihypertensive effect develops in 3-6 weeks after the start of the drug.

Hydrochlorothiazide

Hydrochlorothiazide is a thiazide diuretic, it disrupts the reabsorption of sodium, chlorine, potassium, magnesium ions in the distal nephron, delays the excretion of calcium, uric acid. The increase in renal excretion of these ions is accompanied by an increase in the amount of urine (due to the osmotic binding of water). Hydrochlorothiazide reduces the volume of blood plasma, increases the activity of renin in the blood plasma and the secretion of aldosterone. When taken in high doses hydrochlorothiazide increases the excretion of bicarbonates, with prolonged intake reduces calcium excretion.

Antihypertensive effect develops due to a decrease in the volume of circulating blood (BCC), changes in the reactivity of the vascular wall, decrease of the pressor influence of vasoconstrictive amines (epinephrine, noradrenaline) and intensification of the depressor effect on the ganglion. Does not affect normal blood pressure. Diuretic effect occurs after 1-2 hours, reaches a maximum after 4 hours and lasts for 6-12 hours. Antihypertensive effect occurs in 3-4 days, but 3-4 weeks are necessary to achieve the optimal therapeutic effect.

Pharmacokinetics:

The pharmacokinetics of losartan and hydrochlorothiazide with simultaneous administration does not differ from that for their separate administration.

Losartan

Ingestion losartan is well absorbed from the gastrointestinal tract (GIT) and at the same time is metabolized by "primary passage" through the liver by carboxylation with the participation of the CYP2C9 isoenzyme with the formation of an active metabolite.

Systemic bioavailability of losartan is approximately 33%.

The maximum concentration of losartan and its active metabolite is reached in the blood serum after approximately 1 hour and 3-4 hours after ingestion, respectively. Eating does not affect the bioavailability of losartan. More than 99% of losartan and its active metabolite bind to plasma proteins, mainly albumin. The volume of distribution of losartan is 34 liters. Losartan practically does not penetrate the blood-brain barrier. Approximately 14% of losartan administered to a patient intravenously or inwardly becomes an active metabolite. 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 ingested, approximately 4% of the dose taken is excreted by the kidneys unchanged and about 6% is excreted by the kidneys in the form of an active metabolite. Losartan and its active metabolite is characterized by linear pharmacokinetics when administered in doses up to 200 mg.

After oral administration, the plasma concentrations of losartan and its active metabolite decrease polyexponentially with a terminal half-life (T1 / 2) of losartan about 2 hours, and the active metabolite - about 6-9 hours.When taking the drug at a dose of 100 mg per day, neither losartan, nor its active metabolite significantly not cumulate in blood plasma.

Losartan and its metabolites are excreted through the intestine and the kidneys. In healthy volunteers after oral administration of 14C isotope-labeled losartan, about 35% of the radiolabel detected in the urine and 59% - in the feces.

Pharmacokinetics in specific patient groups

In patients with alcoholic liver cirrhosis of mild and moderate severity, the concentration of losartan was 5 times, and the active metabolite was 1.7 times higher than in healthy male volunteers.

When the creatinine clearance (CK) is above 10 ml / min, the concentration of losartan in the blood plasma does not differ from that with normal kidney function.

In patients undergoing hemodialysis, the value of the area under "concentration-time" curve (AUC) is approximately 2 times higher than in patients with normal renal function.

Neither losartan, nor its active metabolite is removed from the body by hemodialysis.

Concentrations of losartan and its active metabolite in the blood plasma of elderly patients with hypertension did not differ significantly from the values of these parameters in young male patients with hypertension.

Values of plasma concentrations of losartan in women with arterial hypertension are 2 times higher than the corresponding values in men with arterial hypertension.

The concentrations of the active metabolite in men and women do not differ. This pharmacokinetic difference is not clinically relevant.

Hydrochlorothiazide

After oral administration, the absorption and bioavailability of hydrochlorothiazide is about 70%. Connection with blood plasma proteins - 60-80%.

When ingestion of 12.5 mg of hydrochlorothiazide, the maximum plasma concentration is reached after 1.5-4 hours and is 70 ng / ml, and when administered 25 mg of hydrochlorothiazide, the maximum plasma concentration is reached after 2-5 hours and is 142 ng / ml.

In the therapeutic range of doses, the average AUC increases in direct proportion to the increase in dose, with the appointment of once a day, cumulation is negligible. Penetrates through the hematoplacental barrier and into breast milk. T1 / 2 - 5-6 hours. Hydrochlorothiazide slightly metabolized in the liver. Hydrochlorothiazide is excreted almost completely (more than 95%) by the kidneys in unchanged form. 50-70% of the dose taken internally is excreted within 24 hours.

Indications:

- Arterial hypertension (patients who are shown combined therapy).

- Reducing the risk of cardiovascular morbidity and mortality in patients with hypertension and left ventricular hypertrophy.

Contraindications:Increased sensitivity to the drug, other sulfonamide derivatives, anuria, severe renal impairment (creatinine clearance (CC) of less than 30 ml / min), hyperkalemia, severe liver function abnormalities (more than 9 points on the Child-Pugh), refractory hypokalemia, unmanageable diabetes, Addison's disease, dehydration, pregnancy, lactation, severe hypotension, age 18 years (effectiveness and safety have not been established), lactase deficiency, lactose intolerance and malabsorption syndrome.

Carefully:disorders of water and electrolyte balance of blood (hyponatremia hypochloraemic alkalosis, hypomagnesemia, hypokalemia), bilateral renal artery stenosis or artery stenosis single kidney, disorders of certain functions kidney (CK more than 30 ml / min.), human liver (less than 9 points on the scale of Child -Pyu), diabetes, hypercalcemia, hyperuricaemia and / or gout, allergic history (in some patients angioedema previously developed while taking other drugs,including angiotensin-converting enzyme (ACE) inhibitors) and bronchial asthma, systemic blood diseases (including systemic lupus erythematosus), decreased circulating blood volume (bcc) (including against the background of high doses of diuretics), simultaneous use of non-steroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase-P (COX-2) inhibitors, cardiac glycosides, elderly age, ischemic heart disease.

Pregnancy and lactation:

The use of Prezartan® H during pregnancy is contraindicated. It is known that drugs acting directly on the renin-angiotensin-aldosterone system (RAAS), when used in the II and III trimesters of pregnancy, can cause developmental defects or even the death of the developing fetus. Therefore, when diagnosing a pregnancy, use Prezartan® H should be stopped as soon as possible.

It is not known whether losartan with breast milk. Thiazides penetrate the placental barrier and are detected in the blood of the umbilical cord. Thiazides are excreted in breast milk.

It is not recommended to take Prezartan® H during lactation.If Prasartan® H is needed during lactation, then breastfeeding should be discontinued.

Dosing and Administration:Inside, regardless of food intake.

Arterial hypertension

The initial and maintenance dose is 1 tablet of Prezartan® H (12.5 mg + 50 mg) once a day. The maximum antihypertensive effect is achieved within three weeks of therapy. To achieve a more pronounced effect may increase the dose to 2 x H Prezartan® drug tablets (12.5 mg + 50 mg), 1 time per day. The maximum daily dose is 2 tablets of Prezartan® N.

In patients with reduced circulating blood volume (e.g., in patients receiving large doses of diuretics), the recommended initial dose of losartan in patients with hypovolemia is 25 mg once a day. In connection with this therapy with Prezartan® H, it is necessary to start after the abolition of diuretics and correction of hypovolemia.

In elderly patients and patients with moderate renal failure, including those on dialysis, there is no need for correction of the initial dose. Reducing the risk of cardiovascular morbidity and mortality in patients with hypertension and left ventricular hypertrophy

The standard initial dose of losartan is 50 mg once a day.Patients who failed to achieve the target blood pressure when taking losartan 50 mg / day require a combination of losartan with low doses of hydrochlorothiazide (12.5 mg) and, if necessary, a dose of losartan to 100 mg should be added in combination with hydrochlorothiazide at a dose of 12.5 mg / day, further - to increase up to 2 tablets of the drug Presartan® H 50 / 12.5 mg total (100 mg of losartan and 25 mg of hydrochlorothiazide per day once).

Side effects:

Losartan in combination with hydrochlorothiazide is well tolerated, as shown in controlled clinical trials, the most frequent adverse reactions were systemic and non-systemic dizziness, general weakness / fatigue.

From the side of the blood and lymphatic system: thrombocytopenia, anemia, aplastic anemia, hemolytic anemia, leukopenia, agranulocytosis.

From the immune system: anaphylactic reactions, angioedema, including edema of the larynx and vocal cords with the development of airway obstruction and / or edema of the face, lips, pharynx and / or tongue have been observed rarely in patients taking losartan; some of these patients had indications of angioedema development in the anamnesis when using other medicines, incl. ACE inhibitors.

From the side of metabolism and nutrition: anorexia, hyperglycaemia, hyperuricemia, disturbances of water-electrolyte balance of blood, incl. hyponatremia and hypokalemia.

From the side of the psyche: insomnia, increased excitability.

From the central nervous system: dysgeusia, headache, migraine, paresthesia.

From the side of the organ of vision: xantopsy, transient disturbance of vision focusing.

From the heart: palpitation, tachycardia.

From the side of the vessels: dose-dependent orthostatic effects, necrotizing angiitis (vasculitis), cutaneous vasculitis.

From the respiratory system, chest and mediastinum: cough, nasal congestion, pharyngitis, upper respiratory tract infections, respiratory distress syndrome (including pneumonitis and pulmonary edema).

From the digestive system: dyspepsia, abdominal pain, irritation of the gastric mucosa, spasms, diarrhea, constipation, nausea, vomiting, pancreatitis, sialadenitis.

From the liver and bile ducts: hepatitis, jaundice (cholestatic).

From the skin and subcutaneous fat: skin rash, itching, purpura (including purple Shenlaine-Henoch), toxic epidermal necrolysis, urticaria, erythroderma, photosensitization, exacerbation of the systemic lupus erythematosus.

From the musculoskeletal system and connective tissue: back pain, muscle cramps, muscle spasms, myalgia, arthralgia.

From the side of the kidneys and urinary tract: glucosuria, impaired renal function, interstitial nephritis.

From the genitals and the breast: erectile dysfunction / impotence.

Common violations: pain in the chest, peripheral edema, fever, weakness, malaise.

Laboratory indicators: hyperkalemia, increased activity of "liver" transaminases.

The following side effects were reported for losartan and hydrochlorothiazide used in monotherapy.

LOSARTANE

Side effects, occurring with a frequency of more than 1%:

Common violations: asthenia, fatigue, pain in the chest, peripheral edema.

From the side of the cardiovascular system, palpitation, tachycardia

From the digestive system: abdominal pain, diarrhea, dyspepsia, nausea.

From the musculoskeletal system: pain in the back, legs, cramps calf muscles.

From the nervous system: dizziness, headache, insomnia.

On the part of the respiratory system: cough, bronchitis, stuffy nose, pharyngitis, sinusitis, upper respiratory tract infections

Side effects, occurring with a frequency of less than 1%

From the cardiovascular system: Orthostatic hypotension (dose-dependent), epistaxis, bradycardia, arrhythmias, angina pectoris, vasculitis, myocardial infarction.

From the digestive system: anorexia, dryness of the oral mucosa, toothache, vomiting, flatulence, gastritis, constipation, hepatitis, a violation of liver function.

From the skin: dry skin, erythema, ecchymosis, photosensitivity, increased sweating, alopecia.

Allergic reactions: urticaria, skin rash, itching, angioedema (including swelling of the larynx and tongue, causing airway obstruction and / or swelling of the face, lips, pharynx).

On the part of the hematopoiesis system: anemia (insignificant decrease in hemoglobin and hematocrit, an average of 0.11 g% and 0.09 volume%

respectively, rarely having clinical significance), thrombocytopenia, eosinophilia, purpura Shenlen-Henoch.

From the musculoskeletal system: arthralgia, arthritis, pain in the shoulder, knee, fibromyalgia.

From the nervous system and sensory organs: anxiety, sleep disorders, drowsiness, memory impairment, peripheral neuropathy, paresthesia, hyposthenia, tremor, ataxia, depression, fainting, ringing in the ears, impaired taste, visual impairment, conjunctivitis, migraine.

From the genitourinary and reproductive system: imperative urges for urination, urinary tract infections, impaired renal function, decreased libido, impotence.

Other: exacerbation of gout.

Laboratory indicators: often - hyperuricemia (the content of potassium in the blood plasma is more than 5.5 mmol / l); infrequent - increased concentration

urea and residual nitrogen and creatinine in serum; very rarely - a moderate increase in the activity of "liver" transaminases: aspartate aminotransferase (ACT) and alanine aminotransferase (ALT), hyperbilirubinemia.

HYDROCHLOROTHYASIDE

Violation of water-electrolyte balance: hypokalemia, hypomagnesemia, hypercalcemia and hypochloraemic alkalosis: dryness of the oral mucosa, thirst, irregular heart rhythm, changes in mood or psyche, convulsions and muscle pain, nausea, vomiting, unusual fatigue or weakness. Hypochloremic alkalosis can cause hepatic encephalopathy or hepatic coma. Hyponatremia: confusion, convulsions, lethargy, slowing down the process of thinking, increased fatigue, excitability, muscle cramps.

Metabolic disorders: hyperglycemia, glucosuria, hyperuricemia with the development of an attack of gout. Treatment with thiazides can impair glucose tolerance, and latent diabetes mellitus can manifest. When using high doses, lipid concentrations in the serum can increase.

From the digestive system: cholecystitis or pancreatitis, cholestatic jaundice, diarrhea, sialadenitis, constipation, anorexia.

From the cardiovascular system: arrhythmias, orthostatic hypotension, vasculitis.

From the nervous system: dizziness, temporarily blurred vision, headache, paresthesia.

From the hematopoiesis: (very rare): leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia.

Allergic reactions: urticaria, purpura, necrotizing vasculitis, Stevens-Johnson syndrome, respiratory distress syndrome (including pneumonitis and noncardiogenic pulmonary edema), photosensitivity, anaphylactic reactions up to shock.

Other phenomena: decreased potency, impaired renal function, interstitial nephritis.

Overdose:

Losartan

Symptoms: marked decrease in blood pressure, tachycardia; bradycardia due to parasympathetic (vagal) stimulation.

Treatment: forced diuresis, symptomatic therapy, hemodialysis is ineffective.

Hydrochlorothiazide

Symptoms: the most frequent symptoms are a consequence of a deficiency of electrolytes (hypokalemia, hypochloraemia, hyponatremia) and dehydration due to excessive diuresis. With the simultaneous administration of cardiac glycosides, hypokalemia can aggravate the course of arrhythmias.

Treatment: symptomatic.

Interaction:

Losartan

Can be used concomitantly with other antihypertensive agents.

Mutually enhances the effect of beta-blockers and sympatholytics. The combined use of losartan with diuretics causes an additive effect.

There were no pharmacokinetic interactions of losartan with hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, ketoconazole and erythromycin. Reportedly rifampicin and fluconazole reduce the concentration of the active metabolite in the blood plasma. The clinical significance of these interactions is still unknown.

As with other agents that inhibit angiotensin II or its effect, the combined use of losartan with potassium-sparing diuretics (eg, spironolactone, triamterene, amiloride), potassium preparations, potassium-containing salts, increases the risk of hyperkalemia.

Non-steroidal anti-inflammatory drugs (NSAIDs), including selective inhibitors of COX-2, can reduce the effect of diuretics and other antihypertensive agents: ACE inhibitors and angiotensin II receptor antagonists.

In patients with impaired renal function receiving NSAID therapy (including COX-2 inhibitors),therapy with angiotensin II receptor antagonists can lead to further impairment of renal function, including acute renal failure, which is usually reversible. Simultaneous reception of these medicines should be carried out with caution in patients with impaired renal function.

With the combined use of antagonists of angiotensin II and lithium receptors, an increase in the concentration of lithium in the blood plasma is possible. Considering this, it is necessary to weigh the benefits and risks of joint use of losartan with lithium salts. In case of necessity of joint application of preparations, it is necessary to regularly monitor the concentration of lithium in blood plasma.

Hydrochlorothiazide

With thiazide diuretics, such medicines as ethanol, barbiturates and narcotic drugs, may potentiate the risk of developing orthostatic hypotension.

Hypoglycemic agents (for oral administration and insulin) - dosage correction of hypoglycemic agents may be required.

Other antihypertensives - additive effect.

Kolestyramin and colestipol - in the presence of anion exchange resins, hydrochlorothiazide absorption is impaired. Kolestyramine and colestipol in a single dose bind hydrochlorothiazide and reduce its absorption in the gastrointestinal tract by 85% and 43%, respectively.

Corticosteroids, ACTH (adrenocorticotropic hormone) or glycyrrhizic acid (found in licorice root) - a marked decrease in the electrolyte content, in particular, the risk of hypokalemia.

Pressing amines (for example, epinephrine, norepinephrine) - decrease in the severity of response to the reception of pressor amines.

Muscle relaxants of nondepolarizing action type (eg, tubocurarine) - an increase in the effect of muscle relaxants.

Lithium - diuretics reduce renal clearance of lithium and increase the risk of developing toxic effects of lithium; simultaneous use is not recommended.

NSAIDs (including COX-2 inhibitors) - can reduce the diuretic, natriuretic and antihypertensive effect of diuretics.

In some patients with impaired renal function (eg, elderly patients or patients with dehydration, including those taking diuretics) receiving NSAID therapy, including COX-2 inhibitors, treatment with angiotensin II receptor antagonists, or ACE inhibitors may cause further impairment of kidney function, including development of acute renal failure. These effects are reversible.The simultaneous use of these drugs should be conducted with caution in patients with impaired renal function.

In connection with the effect on calcium metabolism, their reception may distort the results of the study of parathyroid gland function.

Special instructions:

Prezartan® H can be used concomitantly with other antihypertensive agents.

Losartan

Prior to the use of the drug, a correction

BCC.

Drugs that affect RAAS can increase the concentration of urea in the blood and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney.

During the treatment period, the potassium content in the blood should be regularly monitored, especially in elderly patients, with renal dysfunction.

Hydrochlorothiazide

Hydrochlorothiazide may increase symptomatic arterial hypotension and disturbances in water-electrolyte balance (decrease in the volume of circulating blood, hyponatremia, hypochloraemic alkalosis, hypomagnesemia, hypokalemia), impair glucose tolerance (hypoglycemic dose for ingestion and / or insulin may be required)reduce the excretion of calcium by the kidneys and cause a transient, insignificant increase in the calcium content in the blood plasma (pronounced hypercalcemia may indicate latent hyperparathyroidism). Due to the effect of thiazide diuretics on calcium metabolism, their administration may distort the results of the parathyroid gland function, therefore, before the study of parathyroid function, the thiazide diuretic should be canceled.

Hydrochlorothiazide can increase the concentration of cholesterol and triglycerides, provoke the appearance of hyperuricemia and / or gout. Because the losartan reduces the concentration of uric acid, its combination with hydrochlorothiazide reduces the severity of hyperuricemia caused by a diuretic.

Other effects

In patients receiving thiazide diuretics, hypersensitivity reactions can be observed even in the absence of an anamnesis indicating the presence of allergic reactions or bronchial asthma. There are reports of the development of exacerbation or progression of systemic lupus erythematosus against the background of the use of thiazide diuretics.

Effect on the ability to drive transp. cf. and fur:There were no special clinical studies to assess the effect of the drug on the ability to drive vehicles and work with machinery. It should be borne in mind the possibility of drowsiness and dizziness, so you need to be careful when performing work that requires increased attention, especially at the beginning of treatment, with an increase in the dose of the drug and in the management of vehicles.

Form release / dosage:

Film coated tablets 12.5 mg + 50 mg.

Packaging:

Primary packaging: 14 tablets in a blister of aluminum foil and PVC film.

Secondary packaging: 2 blisters together with instructions for use in a cardboard box.

Storage conditions:In a dry, the dark place at a temperature of no higher than 25 ° C. Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-001049

Date of registration:21.10.2011

The owner of the registration certificate:Ipka Laboratories Ltd.Ipka Laboratories Ltd. India

Manufacturer: & nbsp

IPCA LABORATORIES, Ltd. India

Representation: & nbspIPKA LABORATORIES LTD. IPKA LABORATORIES LTD. India

Information update date: & nbsp23.12.2015

Illustrated instructions

Instructions

Prezartan® H (Presartan® N)