Hydrochlorothiazide, Irbesartan

Pharmacological properties

irbetan-n is a combination of the angiotensin ii irbesartan II receptor antagonist and the hydrochlorothiazide thiazide diuretic. the combination of these components has an additional antihypertensive effect, in which hell decreases significantly more than when using any component separately. irbesartan is a potent, oral active antagonist of angiotensin ii receptors (subtype at1) selective action. it can block all the actions of angiotensin ii that are provided by the at1 receptor, regardless of the source or method of synthesis of angiotensin ii. selective antagonism of angiotensin ii receptors (at1) causes an increase in plasma renin and angiotensin ii levels, as well as a decrease in the concentration of aldosterone in blood plasma. Irbesartan alone, when used in recommended doses in patients who do not have a risk of electrolyte imbalance, does not significantly affect serum potassium levels. irbesartan does not inhibit apf (kininase ii), an enzyme that generates angiotensin ii, and also breaks down bradykinin into inactive metabolites. irbesartan does not require metabolic activation.

Hydrochlorothiazide is a thiazide diuretic. The mechanism of the antihypertensive effect of thiazide diuretics at this time is not fully understood. Thiazides affect the re-absorption of electrolytes in the renal canals, directly enhancing the excretion of sodium and chloride in approximately equal amounts. Due to the diuretic effect of hydrochlorothiazide, plasma volume decreases, plasma renin activity, aldosterone secretion increase, as a result of which the loss of potassium and bicarbonate in the urine increases and the concentration of potassium in the blood serum decreases. Probably due to blocking of the renin-angiotensin-aldosterone system with the simultaneous use of irbesartan, there is a tendency to compensate for the loss of potassium. With the use of hydrochlorothiazide, diuresis begins after 2 hours, and the peak effect occurs at about 4 hours, while its effect lasts about 6-12 hours. The combination of hydrochlorothiazide and irbesartan determines a dose-dependent additional decrease in blood pressure within the therapeutic dose range. The addition of 12.5 mg of hydrochlorothiazide to 300 mg of irbesartan once a day for patients whose condition cannot be adequately controlled with 300 mg of irbesartan as monotherapy led to a placebo-corrected decrease in diastolic blood pressure to the minimum value (24 hours after the dose) 6.1 mmHg Art. The combination of 300 mg of irbesartan and 12.5 mg of hydrochlorothiazide led to a general decrease in systolic / diastolic blood pressure to 13.6 / 11.5 mm Hg. Art. excluding data obtained from placebo. The use of 150 mg of irbesartan and 12.5 hydrochlorothiazide once a day led to a decrease in the average systolic / diastolic blood pressure with correction of data on the results of taking a placebo to the level of 12.9 / 6.9 mm RT. Art. (24 hours after use) in patients with mild to moderate hypertension. The peak effect was observed after 3–6 hours. When assessing by outpatient monitoring of blood pressure, a combination of 150 mg of irbesartan and 12.5 mg of hydrochlorothiazide when applied once a day caused a consistent decrease in blood pressure over 24 hours with an average decrease in systolic / diastolic blood pressure during 24 hours excluding data obtained from placebo, 15.8 / 10.0 mm Hg. Art. The effect of lowering blood pressure with irbesartan in combination with hydrochlorothiazide appears after taking the first dose and lasts for 1–2 weeks, and the maximum effect occurs after 6–8 weeks. During long-term studies, the effect of irbesartan / hydrochlorothiazide lasted for a period exceeding one year.There is information that with the use of both irbesartan and hydrochlorothiazide, recovery of hypertension was not noted. The effect of a combination of irbesartan and hydrochlorothiazide on morbidity and mortality has not been studied. Epidemiological studies have shown that long-term treatment with hydrochlorothiazide reduces the risk of morbidity and mortality due to cardiovascular disease. The effectiveness of the drug does not depend on the age or gender of the patient. In patients of the Negroid race with hypertension, the response to monotherapy with irbesartan, as well as other drugs that affect the renin-angiotensin system, is significantly less. When irbesartan is used simultaneously with a low dose of hydrochlorothiazide (for example, 12.5 mg / day), the antihypertensive response in patients of the Negroid race approaches the response of representatives of other races.

Pharmacokinetics The simultaneous use of hydrochlorothiazide and irbesartan does not affect the pharmacokinetics of any of the components of the drug. Irbesartan and hydrochlorothiazide are orally active drugs and, when active, do not require biological transformation. After oral administration of the drug, the absolute oral bioavailability is 60–80 and 50–80% for irbesartan and hydrochlorothiazide, respectively. Food does not affect the bioavailability of the drug. The peak plasma concentration is reached after 1.5–2 hours after oral administration for irbesartan and after 1-2 hours for hydrochlorothiazide. The binding of irbesartan to plasma proteins is about 96%, and the binding to the cellular components of the blood is so low that it can be neglected. The volume of distribution of irbesartan is 53–93 liters. Hydrochlorothiazide binds to plasma proteins by 68%, and its confirmed distribution volume is 0.83–1.14 l / kg. Irbesartan demonstrates a linear and proportional dosage pharmacokinetics within the range of doses from 10 to 600 mg. There was an increase in absorption at doses of 600 mg; the mechanism of this process is not clear. The total excretion from the body by the kidneys is 157–176 and 3.0–3.5 ml / min, respectively. Final t_½ irbesartan is 11-15 hours. Stable equal plasma concentrations are reached within 3 days after the start of the regimen of taking one dose per day. Limited accumulation of irbesartan (20%) was observed in blood plasma after repeated administration of a daily dose. As part of the study, slightly higher plasma levels of irbesartan were observed in female patients with hypertension. However the differences between T_½ and no accumulation of irbesartan has been detected. Dosage of the drug does not require correction depending on the age or gender of the patient. AUC and C Values_max for irbesartan, they were also slightly higher in elderly patients (≥65 years old) than in young patients (18–40 years old). However, the final value of T_½ not significantly different. For elderly patients, dose adjustment is not required. The average value of T_½ according to the data obtained, hydrochlorothiazide from blood plasma is 5–15 hours. After oral administration, the amount of unchanged irbesartan in blood plasma is 80–85%, which is determined by the indicator ¹⁴C. Irbesartan is metabolized by the liver due to its combination with glucuronides and oxidation. The main metabolite that is in the circulation is irbesartan glucuronide (approximately 6%). In vitro studies show that irbesartan is primarily oxidized by the cytochrome enzyme P450 CYP 2C9; the isoenzyme CYP 3A4 has a negligible effect that can be neglected. Irbesartan and its metabolites are excreted both through the liver and kidneys. Both after oral and intravenous administration ¹⁴With irbesartan, about 20% of the radioactive dose is excreted in the urine, and the remainder with feces. Less than 2% of the dose is excreted in the urine in the form of unchanged irbesartan. 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 placental barrier, but does not pass through the BBB and passes into breast milk.

Renal failure: in patients with renal failure or in patients undergoing hemodialysis, the pharmacokinetics of irbesartan do not significantly change. Irbesartan is not excreted by hemodialysis. It has been reported that in patients with creatinine clearance of 20 ml / min T_½ hydrochlorothiazide increased to 21 hours

Liver failure: in patients with mild to moderate sever cirrhosis, the pharmacokinetics of irbesartan are not significantly altered. Studies involving patients with severe liver failure have not been conducted.

Indications

Treatment of essential ag.

This fixed-dose combination is indicated for adult patients whose blood pressure cannot be adequately controlled by irbesartan or hydrochlorothiazide alone.

Application

The drug is used 1 time per day, regardless of food intake.

With clinical feasibility, the possibility of a direct transition from monotherapy to fixed combinations may be considered:

Irbetan-N 150 mg / 12.5 mg can be used in patients whose blood pressure is not adequately controlled by hydrochlorothiazide or irbesartan at a dose of 150 mg;

• Irbetan-N 300 mg / 12.5 mg can be used in patients whose blood pressure is not adequately controlled with 300 mg irbesartan or 150 mg / 12.5 mg Irbetan-N.

If necessary, Irbetan-N can be used with other antihypertensive drugs (see INTERACTIONS).

Renal failure. Due to the presence of hydrochlorothiazide in the composition, the drug is not recommended for patients with severe renal impairment (creatinine clearance 30 ml / min). In the treatment of such patients, loop diuretics rather than thiazides are preferred. For patients with renal failure who have creatinine clearance ≥30 ml / min, dose adjustment is not required.

Liver failure. Irbetan-N is not recommended for patients with severe hepatic impairment. Patients with hepatic insufficiency thiazides should be used with caution. For patients with mild or moderate hepatic insufficiency, dose adjustment is not required.

Elderly patients. For elderly patients, there is no need for dose adjustment.

Contraindications

Hypersensitivity to the components of the drug or to sulfonamide derivatives (hydrochlorothiazide is a sulfonamide derivative), severe renal failure (creatinine clearance 30 ml / min), persistent form of hypokalemia, hypercalcemia, severe liver failure, liver cirrhosis and cholestasis.

Side effects

From the digestive system and metabolism: nausea and vomiting; diarrhea; dyspepsia, dysgeusia, hyperkalemia, electrolyte imbalance (including hypokalemia and hyponatremia), hyperuricemia, glucosuria, hyperglycemia, increased levels of cholesterol and tg, pancreatitis, anorexia, constipation, irritation of the gastric mucosa, sialadenitis, loss of appetite.

From the nervous system: dizziness; orthostatic dizziness; headache, tinnitus, paresthesia, rash actions, anxiety, depression, sleep disturbance.

On the part of the respiratory system: cough, shortness of breath (including pneumonitis and pulmonary edema).

On the part of the kidneys and urinary system: impaired urination; impaired renal function (including special cases of renal failure in patients at risk), interstitial nephritis.

On the part of the skin and subcutaneous tissues: hypersensitivity reactions (including angioedema, rash, urticaria), anaphylactic reactions, toxic epidermal necrolysis, necrotic angiitis (vasculitis, skin vasculitis), skin reactions (like lupus erythematosus), relapse of cutaneous lupus erythematosus, reactions photosensitivity.

From the cardiovascular system: loss of consciousness, decreased blood pressure, tachycardia, edema, hyperemia, arrhythmias, postural hypotension.

From the side of musculoskeletal and connective tissue: swelling of the extremities; arthralgia, myalgia, weakness, muscle cramps.

From the circulatory and lymphatic systems: aplastic anemia, inhibition of bone marrow function, neutropenia / agranulocytosis, hemolytic anemia, leukopenia, thrombocytopenia.

From the hepatobiliary system: hepatitis, impaired liver function, intrahepatic cholestatic jaundice.

From the reproductive system: impaired sexual function, changes in libido.

From the side of the organ of vision: temporary blurred vision, xanthopsia.

General disorders: fatigue; chest pain; fever.

Laboratory studies: increased blood urea nitrogen, creatinine and creatine kinase; a decrease in the content of potassium and sodium in blood plasma.

special instructions

Low hell - low blood volume patients. irbetan-n is rarely associated with a symptomatic decrease in hell in patients with ag who have no other risk factors for lowering hell. a symptomatic decrease in hell can occur in patients in whom, due to intensive diuretic therapy, limited salt intake with food, diarrhea or vomiting, blood volume and / or sodium content decreased. such conditions should be adjusted before starting treatment with the drug.

Renal artery stenosis - Renovascular hypertension. There is an increased risk of a severe form of lowering blood pressure and renal failure when patients with bilateral renal artery stenosis or artery stenosis of a single functioning kidney are treated with ACE inhibitors or angiotensin II receptor antagonists.

Renal failure and kidney transplantation. When the drug is used in patients with impaired renal function, periodic monitoring of plasma calcium, creatinine and uric acid levels is recommended. There is no experience with the use of the drug in patients who have recently had a kidney transplant. Irbetan-N should not be prescribed to patients with severe renal failure (creatinine clearance of 30 ml / min). In patients with impaired renal function, azotemia associated with thiazide diuretics may occur. Dose adjustment is not required in patients with renal failure in whom creatinine clearance is ≥30 ml / min. In patients with mild to moderate renal failure (creatinine clearance ≥30 ml / min, but 60 ml / min), this fixed-dose combination should be used with caution.

Liver failure. With caution, thiazides should be used in patients with impaired liver function or progressive liver disease, since minor changes in the balance of fluid and electrolytes can accelerate the onset of hepatic coma. There is no clinical experience with the use of the drug Irbetan-N in patients with liver failure.

Stenosis of the aortic and mitral valve, obstructive hypertrophic cardiomyopathy.As with other vasodilators, special precautions are needed for patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Primary aldosteronism. In patients with primary aldosteronism, as a rule, there is no hypotensive effect when using drugs that act by inhibiting the renin-angiotensin system. Therefore, the use of the drug Irbetan-N in this category of patients is not recommended.

Effect on metabolism and endocrine system. During therapy with thiazide diuretics, glucose tolerance may be impaired, and signs of diabetes mellitus in the latent stage may also appear. There is a need for dosage adjustment of insulin or oral hypoglycemic drugs for patients with diabetes.

Increased cholesterol and triglyceride levels are associated with thiazide diuretic therapy; however, at a dosage of 12.5 mg of hydrochlorothiazide, which is contained in the Irbetan-N preparation, a minimal effect or the absence of any effect was reported. Some patients receiving thiazide diuretic therapy may experience hyperuricemia or signs of gout.

Electrolyte imbalance. As with any patient taking diuretics, it is necessary to periodically check the level of electrolytes in the blood serum.

Thiazides, including hydrochlorothiazide, can cause imbalance in fluid or electrolytes (hypokalemia, hyponatremia and hypochloremic alkalosis). Characteristic signs of fluid or electrolyte imbalance that you should pay attention to are dry mouth, thirst, weakness, lethargy, drowsiness, anxiety, pain or muscle cramps, muscle weakness, decreased blood pressure, oliguria, tachycardia, and such gastrointestinal disturbances, like nausea or vomiting.

Although hypokalemia can develop with thiazide diuretics, concurrent therapy with irbesartan can weaken the hypokalemia that occurs with diuretics. The highest risk of hypokalemia in patients with cirrhosis of the liver, intense diuresis, in patients who are orally taking the wrong amount of electrolytes or are being treated with corticosteroids or ACTH. Conversely, hyperkalemia can occur due to the presence of irbesartan in the composition of the drug Irbetan-N, especially with renal failure and / or heart failure, as well as diabetes. Appropriate monitoring of plasma potassium levels in patients for whom there is such a risk is recommended. Caution is required when using diuretics that do not remove potassium, and additional potassium preparations or salt substitutes that contain potassium.

There is no evidence that irbesartan can weaken or prevent the occurrence of hyponatremia due to the use of diuretics. Sodium chloride deficiency is generally noted in a mild form and, as a rule, it does not require treatment.

Thiazides can reduce urinary calcium excretion and cause a temporary and insignificant increase in serum calcium in the absence of known calcium metabolism disorders. A pronounced form of hypercalcemia may indicate a latent stage of hyperparathyroidism. Before conducting parathyroid function tests, thiazide administration must be stopped. There is evidence that thiazides increase the excretion of magnesium in the urine, which can lead to hypomagnesemia.

Lithium. It is not recommended to use lithium and Irbetan-N at the same time.

Anti-Doping Control. Hydrochlorothiazide, which is contained in the drug, can give a positive result when conducting anti-doping control.

General precautions.In the treatment with ACE inhibitors or angiotensin II receptor antagonists that affect this system, in patients whose vascular tone and renal function depend mainly on the activity of the renin-angiotensin-aldosterone system (for example, in patients with severe congestive heart failure or initial kidney disease, including renal artery stenosis), acute hypotension, azotemia, oliguria or acute renal failure may occur.

As with any antihypertensive drug, an excessive decrease in blood pressure in patients with ischemic cardiopathy or ischemic cardiovascular disease can lead to myocardial infarction or stroke. Hypersensitivity reactions to hydrochlorothiazide can occur in patients who have a history of or are not allergic or AD, but they are more likely to occur in patients with a history of this pathology. An exacerbation or activation of systemic lupus erythematosus has been reported with thiazide diuretics.

Photosensitivity reactions have been reported with thiazide diuretics. If a photosensitivity reaction occurs during treatment, it is recommended to discontinue treatment. If the repeated use of such diuretics is considered necessary, it is recommended to protect open areas of the body from sunlight or artificial radiation in the UV spectrum.

Lactose. The drug contains lactose. Patients with rare hereditary galactose intolerance, Lapp lactase deficiency or malabsorption of glucose-galactose should not take this medicine.

Use during pregnancy and lactation

Pregnancy. In the first trimester of pregnancy, the use of angiotensin II receptor antagonists is not recommended. The use of angiotensin II receptor antagonists is contraindicated in the second and third trimester of pregnancy.

Thiazides cross the placental barrier and enter the umbilical cord blood. They can cause a decrease in placental perfusion, a violation of the electrolyte content in the fetus and, possibly, other reactions that occur in adults. When using thiazides in pregnant women, cases of thrombocytopenia in newborns or jaundice in the fetus or newborn have been reported. Since the drug contains hydrochlorothiazide, its use in the first trimester of pregnancy is not recommended. Before a planned pregnancy, it is necessary to switch to the appropriate alternative treatment, which has a safety profile proven for use during pregnancy.

Lactation. During breastfeeding, the use of the drug Irbetan-N is contraindicated.

Children. The drug is not recommended for use in children due to insufficient data on safety and effectiveness.

The ability to influence the reaction rate when driving vehicles or other mechanisms. Studies of the effect on the ability to drive vehicles and work with other mechanisms have not been conducted. Based on the pharmacodynamic properties of the drug, its effect on this ability is unlikely. When driving vehicles or working with mechanisms, it must be borne in mind that drowsiness or fatigue may occur during treatment of hypertension.

Interactions

Other antihypertensive drugs. the antihypertensive effect of the drug irbetan-n may be enhanced by the simultaneous administration of other antihypertensive agents. irbesartan and hydrochlorothiazide (in doses up to 300 mg of irbesartan / 25 mg of hydrochlorothiazide) have been safely used with other antihypertensive drugs, including calcium channel blockers and α-adrenergic blockers.pretreatment with high doses of diuretics can lead to a decrease in blood volume and a risk of lowering hell if treatment with irbesartan with thiazide diuretics is started, unless the reduction in blood volume has been eliminated in advance.

Lithium. Temporary increases in plasma lithium concentration and toxicity have been reported during the simultaneous use of lithium with ACE inhibitors. Very rare cases of similar effects have been reported with irbesartan. In addition, thiazides reduce the excretion of lithium by the kidneys, so when using this drug, the risk of toxic effects of lithium may increase. Thus, it is not practical to combine lithium and Irbetan-N. If such a combination is necessary, careful monitoring of serum lithium levels is recommended.

Potassium-excreting drugs. The effect of potassium excretion due to hydrochlorothiazide is mitigated by the effect of potassium conservation due to irbesartan. However, it is believed that this effect of hydrochlorothiazide on potassium in the blood plasma is possible due to other drugs associated with potassium loss and hypokalemia (for example, other diuretics that remove potassium, laxatives, amphotericin, carbenoxolone, penicillin G sodium). And vice versa, based on the experience of using other drugs that suppress the renin-angiotensin system, the simultaneous use of diuretics that do not remove potassium, supplements containing potassium, salt substitutes that contain potassium, or other drugs that increase plasma potassium levels blood (e.g. sodium heparin), can lead to increased serum potassium levels. Appropriate monitoring of plasma potassium levels in patients at this risk is recommended.

Medicines that are affected by a violation of the potassium content in blood plasma. Periodic monitoring of potassium in the blood plasma is recommended when the drug is used simultaneously with drugs, the toxicity of which increases with a violation of the potassium content in the blood serum (for example, digitalis glycosides, antiarrhythmic drugs).

NSAIDs. When angiotensin II antagonists are used simultaneously with NSAIDs (i.e., with selective COX-2 inhibitors, acetylsalicylic acid (3 g / day) and non-selective NSAIDs), a weakening of the antihypertensive effect may occur.

As with ACE inhibitors, the simultaneous use of angiotensin II antagonists and NSAIDs may increase the risk of impaired renal function, including the possible occurrence of acute renal failure and increased levels of potassium in the blood plasma, especially in patients with pre-existing adverse renal function. The combination should be used with caution, especially in elderly patients. Patients should receive fluid in the proper amount, and it is also necessary to pay attention to monitoring renal function after the start of such combination therapy and during treatment.

Additional information on the interaction of irbesartan. According to studies, the pharmacokinetics of irbesartan hydrochlorothiazide is not impaired. Irbesartan is mainly excreted by CYP 2C9 and to a lesser extent due to glucuronidation. No significant pharmacokinetic or pharmacodynamic interaction was observed with irbesartan combined with warfarin, a drug that is metabolized by CYP 2C9. The effect of CYP 2C9 inducers such as rifampicin on the pharmacokinetics of irbesartan has not been established. Due to the parallel use of irbesartan, the pharmacokinetics of digoxin have not changed.

Additional information on the interaction of hydrochlorothiazide.When combined with thiazide diuretics, interaction with the following drugs is possible:

Ethanol: Orthostatic hypotension may occur.

Antidiabetic drugs (oral agents and insulins): dose adjustment of an antidiabetic drug may be necessary.

Colestyramine and colestipol resins: in the presence of anionic exchange resins, the absorption of hydrochlorothiazide is impaired.

Corticosteroids, ACTH: a decrease in the volume of electrolytes, especially hypokalemia, may intensify.

Digitalis glycosides: thiazide-induced hypokalemia or hypomagnesemia contributes to the development of cardiac arrhythmias induced by digitalis glycosides.

NSAIDs: the use of NSAIDs in some patients can reduce the diuretic, natriuretic and antihypertensive effect of thiazide diuretics.

Pressor amines (e.g. norepinephrine): the action of pressor amines may be weakened, but not so much as to preclude their use.

Non-depolarizing muscle relaxants (e.g. tubocurarine): the effect of non-depolarizing muscle relaxants can be enhanced by hydrochlorothiazide.

Medicines for the treatment of gout: it may be necessary to adjust the dose of drugs used for gout, since hydrochlorothiazide can increase the level of uric acid in blood plasma. An increase in the dose of probenecid or sulfinpyrazone may be necessary. With the combined use of thiazide diuretics, the number of cases of hypersensitivity reactions to allopurinol may increase.

Calcium salts: thiazide diuretics can increase plasma calcium levels as a result of decreased excretion. If it is necessary to prescribe additional preparations containing calcium or drugs that do not remove calcium (for example, therapy with vitamin D), the level of calcium in the blood serum should be monitored and the dosage of calcium should be adjusted accordingly.

Other forms of interaction: the hyperglycemic effect of beta-adrenoreceptor blockers and diazoxide may be enhanced by thiazides. Anticholinergics (e.g., atropine, biperiden) can increase the bioavailability of thiazide-type diuretics by lowering the tone of the gastrointestinal tract and the rate of gastric emptying. Thiazides may increase the risk of adverse effects caused by amantadine. Thiazides can reduce the renal excretion of cytotoxic drugs (e.g. cyclophosphamide, methotrexate) and enhance their inhibitory effect on bone marrow function.

Overdose

There is no specific information on the treatment of an overdose of irbetan-n. the patient should be closely monitored, and treatment should be symptomatic and supportive. treatment depends on the time that has passed since the use of the drug, and the severity of the symptoms. measures contemplated include induction of vomiting and / or gastric lavage. in the treatment of overdose, it may be useful to take activated charcoal. it is often necessary to control serum electrolytes and creatinine levels. if arterial hypotension occurs, the patient should be given a horizontal position, quickly apply saline solutions and replenish the volume of fluid.

The most likely manifestations of an overdose of irbesartan are arterial hypotension and tachycardia; bradycardia is also possible.

An overdose of hydrochlorothiazide is associated with the elimination of electrolytes (hypokalemia, hypochloremia, hyponatremia) and dehydration due to intense diuresis. The most likely signs and symptoms of an overdose are nausea and drowsiness.Hypokalemia can lead to muscle cramps and / or increase cardiac arrhythmia due to the parallel use of digitalis glycosides or some antiarrhythmic drugs.

Irbesartan is not excreted by hemodialysis. The volume in which hydrochlorothiazide is excreted by hemodialysis has not been established.

Storage conditions

At a temperature not exceeding 25 ° C.