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Pharmacological Properties: The combination of active ingredients in Esantil Plus has an additional antihypertensive effect, lowering blood pressure more effectively than either component alone. Pharmacodynamics: Esantil-Plus is a potent, orally active, selective antagonist of the angiotensin II receptor (AT1 subtype). Angiotensin II is a potent vasoconstrictor formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system (RAS), which also stimulates aldosterone synthesis and secretion by the adrenal cortex, cardiac contractility, sodium reabsorption by the kidneys, sympathetic nervous system activity, and smooth muscle cell growth. Irbesartan blocks vasoconstriction and the aldosterone-secreting effect of angiotensin II by selectively binding to AT1 angiotensin II receptors. Irbesartan is a specific competitive antagonist of AT1 receptors with a much greater affinity (800 times greater) for AT1 receptors than for AT2 receptors, without agonist activity. Blockade of AT1 receptors removes the negative feedback of angiotensin II on renin secretion, but elevated plasma renin activity and circulating angiotensin II cannot overcome the effect of irbesartan on blood pressure. Irbesartan does not inhibit ACE or renin and does not affect other hormonal receptors or ion channels involved in cardiovascular regulation of blood pressure and sodium homeostasis. Since irbesartan does not inhibit ACE, it does not affect the bradykinin response. Hydrochlorothiazide is a thiazide diuretic. After oral administration, diuresis begins within 2 hours, with maximum effect occurring at 4 hours, while activity persists for about 6-12 hours. Thiazides act on the renal tubular portion of electrolyte reabsorption, directly increasing sodium and chloride excretion in approximately equal amounts. The diuretic effect of hydrochlorothiazide reduces plasma volume, increases plasma renin activity, increases aldosterone secretion, and consequently increases urinary loss of potassium and bicarbonate, and decreases serum potassium. The renin-aldosterone connection is mediated by angiotensin II, so coadministration of angiotensin II receptor antagonists restores the potassium loss associated with these diuretics. The mechanism of the antihypertensive effect of thiazides is not fully understood. Pharmacokinetics: Irbesartan is an orally active agent that does not require biotransformation to an active form. Oral absorption of irbesartan is rapid and complete with an average absolute bioavailability of 60-80%. Peak plasma concentrations of irbesartan are achieved 1.5-2 hours after oral administration. Food does not affect the bioavailability of irbesartan. Within the therapeutic dose range, irbesartan exhibits linear pharmacokinetics. The half-life of irbesartan is 11-15 hours. Steady-state concentrations are achieved within 3 days. Limited accumulation (<20%) of irbesartan is observed with once-daily dosing. Irbesartan is metabolized by glucuronide conjugation and oxidation. After oral or intravenous administration of 14C-labeled irbesartan, approximately 80% of the circulating plasma radioactivity can be attributed to unchanged irbesartan. The major circulating metabolite is the inactive irbesartan glucuronide conjugate (approximately 6%). Other oxidative metabolites are insignificant to the pharmacological activity of irbesartan. Irbesartan and its metabolites are excreted via biliary and urinary routes. After oral or intravenous administration of 14C-labeled irbesartan, approximately 20% of the radioactivity is recovered in urine, with the remainder in feces, as irbesartan or irbesartan glucuronide. In vitro studies of irbesartan oxidation by cytochrome P450 isoenzymes showed that irbesartan is primarily oxidized by 2C9; metabolism by 3A4 is insignificant. Irbesartan is neither metabolized by, nor significantly stimulates or inhibits, the enzymes commonly associated with drug metabolism (1A1, 1A2, 2A6, 2B6, 2D6, 2E1). No induction or inhibition of 3A4 was observed. 90% of irbesartan is bound to plasma proteins (primarily albumin and α1-acid glycoprotein) with insignificant binding to blood cellular components. The average volume of distribution is 53-93 liters. Total plasma and renal clearance are in the range of 157-176 and 3.0-3.5 mL/min, respectively. Clinically insignificant accumulation occurs with repeated dosing. Animal studies show that radiolabeled irbesartan crosses the blood-brain barrier and placenta poorly. Irbesartan is excreted in the milk of lactating rats. Hydrochlorothiazide: During observation of plasma levels over 24 hours, the plasma half-life varies between 5.6 and 14.8 hours. Hydrochlorothiazide is not metabolized but is rapidly excreted by the kidneys. At least 61% of the oral dose is excreted unchanged within 24 hours. Hydrochlorothiazide crosses the placenta but not the blood-brain barrier and is excreted in breast milk. Indications: Esantil-Plus is indicated for the treatment of hypertension. This fixed-dose combination is not indicated for initiating therapy. Contraindications: Esantil is contraindicated in patients with hypersensitivity to any component of this product. Due to the hydrochlorothiazide component, this agent is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs. Precautions: Fetal/neonatal morbidity and mortality: Drugs that directly act on the renin-angiotensin system can cause fetal and neonatal morbidity and death when used in pregnant women. There are reports in the world literature of several dozen cases in patients receiving angiotensin-converting enzyme inhibitors. Upon confirmation of pregnancy, the drug should be immediately discontinued. Use of drugs that directly act on the renin-angiotensin system in the second and third trimesters of pregnancy is associated with fetal and neonatal injuries, including hypotension, skull hypoplasia, anuria, reversible and irreversible renal damage, and lethality. Oligohydramnios has also been reported, likely due to impaired fetal renal function; in this case, oligohydramnios is associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although a causal relationship with the drug has not been established. Hypotension in hypovolemic and salt-depleted patients: Severe arterial blood pressure reduction was rarely observed in patients with uncomplicated hypertension treated with irbesartan alone (<0.1%) or with the irbesartan-hydrochlorothiazide combination (approximately 1%). Initiation of antihypertensive therapy may cause symptomatic hypotension in patients with intravascular hypovolemia or salt depletion, e.g., in patients treated with potent diuretics or undergoing dialysis. Such hypovolemia should be corrected before the use of antihypertensive agents. In case of hypotension, the patient should be placed in a supine position and, if necessary, given an intravenous infusion of normal saline. Transient hypotensive effect is not a contraindication to continuation of treatment, and it can be continued without any difficulty after blood pressure normalization. Hydrochlorothiazide: Liver: Thiazides should be used with caution in patients with impaired liver function or progressive liver disease, as even minor changes in fluid and electrolyte balance may precipitate hepatic coma. Hypersensitivity reactions: Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, although they are more common in patients with such a history. Systemic lupus erythematosus: Thiazide diuretics can exacerbate systemic lupus erythematosus. Impaired renal function: In susceptible individuals, changes in renal function are expected as a result of suppression of the renin-angiotensin-aldosterone system. In patients whose renal function is dependent on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin-converting enzyme is associated with oliguria and/or progressive azotemia and (rarely) acute renal failure and/or death. Irbesartan is likely to behave similarly. In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or BUN were observed. The use of irbesartan in patients with unilateral or bilateral renal artery stenosis is not known, but a similar outcome is expected. Use in children: Safety and efficacy in children have not been established. Use in the elderly: Clinical studies of the combination of irbesartan and hydrochlorothiazide did not include sufficient numbers of subjects aged 65 and over to determine whether treatment effects differ from those in younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for an elderly patient should usually start at the lowest dose. Pregnancy and lactation: Pregnancy categories C (first trimester) and D (second and third trimesters). It is not known whether irbesartan is excreted in human milk, although irbesartan and some of its metabolites are secreted in the milk of lactating rats at low concentrations. Because of the potential for adverse effects in the infant, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Effect on ability to drive and operate machinery: Studies on the effect on ability to drive and operate machinery have not been conducted. Based on its pharmacodynamic properties, it can be assumed that irbesartan will have little effect on this ability. When driving or operating machinery, consider the possible occurrence of dizziness and drowsiness during treatment. Adverse Reactions: In general, the combination of irbesartan and hydrochlorothiazide is well tolerated. Most adverse events were mild and transient and did not require discontinuation of treatment. In placebo-controlled trials in patients with hypertension, the incidence of adverse events in the irbesartan/hydrochlorothiazide and placebo groups did not differ. In controlled clinical trials, discontinuation of combination therapy with irbesartan and hydrochlorothiazide due to adverse events was required in only 3.6%. This incidence was significantly lower (p=0.023) than the 6.8% of patients treated with placebo who discontinued treatment. In these placebo-controlled trials, the following adverse events occurred in >=1% of patients during combination therapy with irbesartan and hydrochlorothiazide: General: chest pain 2%, asthenia 7%, influenza 3% Cardiovascular: edema 1%, tachycardia 1% Gastrointestinal: abdominal pain 2%, dyspepsia/heartburn 2%, nausea/vomiting 3% Immunology: allergy 1% Musculoskeletal: skeletal muscle pain 7% Nervous system: dizziness 8%, orthostatic dizziness 1% Urinary system: abnormal urination 2% The following adverse events occurred with an incidence of 1% or more but were more frequent in the placebo group: headache, sinus disorders, cough, upper respiratory tract infections, pharyngitis, diarrhea, rhinitis, urinary tract infection, rash, anxiety/nervousness, and muscle spasms. The following adverse events have been reported in post-marketing studies: urticaria; angioedema (including swelling of the face, lips, larynx, and/or tongue). Hyperkalemia was rarely reported. Laboratory Parameters: In controlled clinical trials, clinically significant changes in standard laboratory parameters were rarely associated with the use of irbesartan-hydrochlorothiazide combination. Creatinine, Blood Urea Nitrogen (BUN): In patients with essential hypertension treated with irbesartan-hydrochlorothiazide combination alone, a slight increase in BUN and serum creatinine was observed in 2.3% and 1.1%, respectively. Hemoglobin: A clinically insignificant average decrease of approximately 0.2 g/dL was observed in patients treated with irbesartan-hydrochlorothiazide combination alone, compared to a decrease of 0.4 g/dL in patients receiving placebo. Liver function tests: Rare elevations of liver enzymes and/or serum bilirubin were observed. If you experience any side effects, consult your doctor. Drug Interactions: No pharmacokinetic (or pharmacodynamic) interactions were observed when irbesartan was studied with hydrochlorothiazide, digoxin, warfarin, and nifedipine. The following drugs, when used with hydrochlorothiazide, may interact with thiazide diuretics: Alcohol, sleeping pills, or narcotics: Potentiation of orthostatic hypotension may occur. Antidiabetic drugs (oral agents and insulin): Dosage adjustments of antidiabetic drugs may be necessary. Other antihypertensive drugs: Additive or potentiating effect. Cholestyramine and colestipol resins: Anion exchange resins impair the absorption of hydrochlorothiazide. A single dose of cholestyramine or colestipol binds to hydrochlorothiazide and reduces its absorption from the gastrointestinal tract by 85% and 43%, respectively. Corticosteroids, ACTH: Enhanced loss of electrolytes, especially hypokalemia. Pressor amines (e.g., norepinephrine): Decreased response to pressor amines, but not sufficient to preclude their use. Skeletal muscle relaxants, nondepolarizing agents (e.g., tubocurarine): Possible increased effect. Lithium: Usually not used with diuretics. Diuretics reduce the renal clearance of lithium and increase the risk of lithium toxicity. Nonsteroidal anti-inflammatory drugs: In some patients, the use of nonsteroidal anti-inflammatory drugs may reduce the diuretic, natriuretic, and antihypertensive effects of thiazide, potassium-sparing, and loop diuretics. Therefore, when co-administered with CO-IRDA and NSAIDs, adequate monitoring of the patient is necessary to determine if the desired effect is achieved. Dosage and Administration: The recommended starting dose of Esantil-Plus is 150 mg once daily. For patients requiring further reduction in blood pressure, titration up to 300 mg once daily may be necessary. A lower starting dose of irbesartan (75 mg) is recommended for patients with intravascular volume depletion (e.g., patients receiving potent diuretics or undergoing hemodialysis). Overdosage: No data on overdosage in humans are available for irbesartan. However, daily doses of 900 mg for 8 weeks have been well tolerated. The most likely manifestation of overdosage is expected to be hypotension and tachycardia; bradycardia may also occur with overdosage. Irbesartan is not removed by hemodialysis. The most frequent signs and symptoms of hydrochlorothiazide overdosage in humans are caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. With the use of digitalis, hypokalemia may exacerbate cardiac arrhythmias. The extent of removal of hydrochlorothiazide by hemodialysis has not been established. Storage Conditions: Store at room temperature up to 25°C in its original packaging. Keep out of reach of children.