Accuzide^® (Tablets) Instructions for Use

ATC Code

C09BA06 (Quinapril and diuretics)

Active Substances

Hydrochlorothiazide (Rec.INN registered by WHO)

Quinapril (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Antihypertensive combination agent (ACE inhibitor + diuretic)

Pharmacological Action

A combined antihypertensive drug containing the ACE inhibitor Quinapril and the thiazide diuretic Hydrochlorothiazide.

ACE catalyzes the conversion of angiotensin I to angiotensin II, which has a vasoconstrictive effect and controls vascular tone, including by stimulating the secretion of aldosterone by the adrenal cortex. Quinapril competitively inhibits circulating plasma and tissue ACE and causes a decrease in vasopressor activity and aldosterone secretion. Elimination of the negative influence of angiotensin II on renin secretion via the feedback mechanism leads to an increase in plasma renin activity. In this case, the decrease in blood pressure is accompanied by a decrease in total peripheral vascular resistance and renal vascular resistance, while changes in heart rate, cardiac output, renal blood flow, glomerular filtration rate and filtration fraction are insignificant or absent. Quinapril increases exercise tolerance. With long-term use, it promotes the reverse development of myocardial hypertrophy in patients with arterial hypertension; improves blood supply to the ischemic myocardium. Enhances coronary and renal blood flow. Reduces platelet aggregation.

In addition, Quinapril somewhat reduces the loss of potassium caused by hydrochlorothiazide, which, due to its diuretic effect, also increases plasma renin activity, aldosterone secretion, reduces serum potassium levels and increases its excretion in the urine.

Hydrochlorothiazide is a diuretic that acts directly on the kidneys, increasing the excretion of sodium, chloride, water ions, as well as potassium and bicarbonate ions, and reducing the excretion of calcium ions. With long-term use, a decrease in total peripheral vascular resistance is noted. Thus, the use of a combination of quinapril and hydrochlorothiazide leads to a more pronounced decrease in blood pressure than therapy with each drug separately.

The antihypertensive effect of quinapril develops within 1 hour after oral administration, reaches a maximum after 2-4 hours and lasts for 24 hours during long-term treatment. In some cases, at least 2 weeks of therapy are required to achieve the maximum antihypertensive effect.

The diuretic effect of hydrochlorothiazide develops within 2 hours, reaches a maximum after about 4 hours and lasts about 6-12 hours.

Pharmacokinetics

Quinapril and Hydrochlorothiazide do not affect each other’s pharmacokinetics.

Quinapril

Absorption and Distribution

After oral administration, C_max of quinapril is reached within 1 hour. Quinapril is rapidly metabolized to quinaprilat, which is a potent ACE inhibitor. The absorption of quinapril is approximately 60%. C_max of quinaprilat in plasma is reached approximately 2 hours after oral administration of quinapril.

About 38% of the administered dose of quinapril circulates as quinaprilat. Approximately 97% of quinapril and quinaprilat circulate in plasma bound to proteins. Quinapril and its metabolites do not penetrate the blood-brain barrier.

Metabolism and Excretion

Quinapril is metabolized to quinaprilat by cleavage of the ester group (the main metabolite is the dibasic acid quinaprilat).

T_1/2 of quinapril from plasma is about 1 hour. Quinaprilat is excreted mainly by renal excretion, and its T_1/2 is about 3 hours.

Pharmacokinetics in Special Clinical Cases

In patients with renal failure, the T_1/2 of quinaprilat increases as creatinine clearance decreases.

The excretion of quinaprilat is also reduced in elderly patients (over 65 years of age) and closely correlates with renal function indicators, however, overall, no differences in the efficacy and safety of treatment between elderly and younger patients have been identified.

Hydrochlorothiazide

Absorption and Distribution

Hydrochlorothiazide is absorbed somewhat more slowly, C_max is reached in 1-2.5 hours. The degree of absorption is 50-80%.

Hydrochlorothiazide penetrates the placental barrier and is excreted in breast milk, but does not penetrate the blood-brain barrier.

Metabolism and Excretion

Hydrochlorothiazide is not metabolized in the liver and is excreted unchanged in the urine. T_1/2 ranges from 4 to 15 hours. About 61% of the orally administered dose is excreted unchanged within 24 hours.

Indications

• Arterial hypertension (in patients for whom combination therapy with quinapril and hydrochlorothiazide is indicated).

ICD codes

Dosage Regimen

Tablets

The drug is taken orally once a day, regardless of meals.

For patients not receiving a diuretic (regardless of whether quinapril monotherapy was performed or not), the recommended initial dose of Accuzide^® is 10 mg+12.5 mg once a day. If necessary, the dose can subsequently be increased to the maximum dose of 20 mg+25 mg once a day. Effective blood pressure control is usually achieved with Accuzide^® in the dose range from 10 mg+12.5 mg/day to 20 mg+12.5 mg/day.

In patients with mild renal impairment (creatinine clearance >60 ml/min), the initial dose of Accuzide^® is 10 mg+12.5 mg.

Accuzide^® should not be prescribed as initial therapy in patients with renal impairment with creatinine clearance <60 ml/min. In patients with moderate renal impairment (creatinine clearance 60-30 ml/min), Quinapril should be used at an initial dose of 5 mg with further titration.

In elderly patients, no dose adjustment of Accuzide^® is required. The initial dose of the drug is 10 mg+12.5 mg.

Adverse Reactions

Adverse reactions observed in patients receiving Quinapril in combination with hydrochlorothiazide

More than 1% of patients headache, dizziness, cough, persistent non-productive cough (resolved after discontinuation of therapy), increased fatigue, myalgia, viral infections, rhinitis, nausea, vomiting, upper respiratory tract infections, insomnia, bronchitis, dyspepsia, asthenia, pharyngitis, vasodilation symptoms, vertigo, chest pain, abdominal pain, back pain.

In general, adverse reactions were mild and transient, and did not depend on age, gender, race, or duration of therapy.

Laboratory parameters increase (more than 1.25 times compared to the upper limit of normal) in the concentration of creatinine and blood urea nitrogen, respectively, in 3% and 4% of patients receiving Quinapril and Hydrochlorothiazide.

Adverse reactions observed in 0.5-1% of patients receiving Quinapril in combination with hydrochlorothiazide

From the hematopoietic system hemolytic anemia, thrombocytopenia, leukopenia, agranulocytosis.

From the nervous system increased excitability, paresthesia, depression, drowsiness.

From the cardiovascular system palpitations, tachycardia, pronounced decrease in blood pressure, orthostatic hypotension, syncope, cardiac arrhythmias, myocardial infarction, ischemic stroke, peripheral edema (including generalized), hypertensive crisis, angina pectoris, heart failure.

From the respiratory system dyspnea, sinusitis.

From the digestive system dryness of the oral and throat mucosa, constipation or diarrhea, flatulence, pancreatitis, hepatitis, gastrointestinal bleeding, impaired liver function tests.

Allergic reactions skin rash, itching, urticaria, angioedema, intestinal angioedema, photosensitivity, erythema multiforme, exfoliative dermatitis, pemphigus, Stevens-Johnson syndrome, anaphylactic reactions.

From the musculoskeletal and connective tissue joint pain.

From the urinary system urinary tract infections, renal function impairment, acute renal failure.

From the reproductive system: decreased potency.

From the organ of vision visual impairment.

Other alopecia, hyperkalemia, increased sweating.

With simultaneous use of ACE inhibitors and gold preparations (sodium aurothiomalate for intravenous administration), a symptom complex has been described, including facial flushing, nausea, vomiting, decreased blood pressure, and flu-like syndrome.

Adverse reactions noted with the use of hydrochlorothiazide

From metabolism hypokalemia, hypomagnesemia, hypercalcemia and hypochloremic alkalosis, hyponatremia (confusion, seizures, lethargy, slowed thinking, increased fatigue, excitability, muscle cramps), hyperglycemia, glucosuria, hyperuricemia with the development of a gout attack.

Hypochloremic alkalosis (dryness of the oral mucosa, thirst, heart rhythm disturbances, mood or mental changes, muscle cramps and pain, nausea, vomiting, increased fatigue or weakness) can cause hepatic encephalopathy or hepatic coma.

Treatment with thiazides can reduce glucose tolerance, and latent diabetes mellitus can manifest. When using high doses, plasma lipid concentrations may increase.

From the digestive system cholecystitis, sialadenitis, anorexia.

From the cardiovascular system arrhythmias, orthostatic hypotension, vasculitis.

From the hematopoietic organs aplastic anemia.

Allergic reactions purpura, necrotizing vasculitis, respiratory distress syndrome (including pneumonitis and non-cardiogenic pulmonary edema), photosensitivity, anaphylactic reactions up to shock.

From the organ of vision transient blurred vision, transient acute myopia and acute open-angle glaucoma.

From the urinary system renal function impairment, interstitial nephritis.

From the reproductive system decreased potency.

Post-marketing studies

From the cardiovascular system bradycardia, cor pulmonale, vasculitis, deep vein thrombosis.

From the digestive system gastrointestinal tumors, cholestatic jaundice, hepatitis, esophagitis, vomiting, diarrhea.

From the hematopoietic system anemia.

From metabolism weight loss.

From the musculoskeletal system myopathy, myositis, arthritis.

From the nervous system paralysis, hemiplegia, speech disorders, gait disturbance, meningism phenomena, amnesia.

From the respiratory system pneumonia, bronchial asthma.

From the skin urticaria, maculopapular rash, petechiae.

From the urinary system albuminuria, pyuria, hematuria, nephrosis.

Other shock, accidental injuries, panniculitis, generalized edema, hernia.

Contraindications

• History of angioedema as a result of previous therapy with ACE inhibitors, idiopathic and hereditary angioedema;
• Severe renal failure (creatinine clearance <30 ml/min);
• Anuria;
• Severe hepatic failure;
• Addison’s disease;
• Refractory hypokalemia, hypercalcemia and hyponatremia;
• Obstruction of the left ventricular outflow tract of the heart;
• Diabetes mellitus with chronic kidney disease with moderate renal failure (GFR <60 ml/min);
• Childhood and adolescence under 18 years of age (the efficacy and safety of the drug have not been established);
• Lactose intolerance, lactase deficiency, glucose-galactose malabsorption;
• Hypersensitivity to the active substances, auxiliary components of the drug;
• Hypersensitivity to sulfonamide derivatives.
• Simultaneous use with aliskiren in patients with diabetes mellitus, in patients with impaired renal function (GFR <60 ml/min/1.73 m²), in patients with hyperkalemia (>5 mmol/l), in patients with chronic heart failure with low blood pressure;
• Simultaneous use with angiotensin II receptor antagonists or other ACE inhibitors in patients with diabetes mellitus and target organ damage in the terminal stage, in patients with moderate to severe renal impairment (GFR <60 ml/min/1.73 m²), in patients with hyperkalemia (>5 mmol/l), in patients with chronic heart failure with low blood pressure.

With caution the drug should be prescribed to patients who have previously taken diuretics and are on a salt-restricted diet or are on hemodialysis; with severe chronic heart failure in patients with or without concomitant renal failure; with conditions accompanied by a decrease in circulating blood volume (including vomiting and diarrhea); bone marrow depression; aortic stenosis, cerebrovascular diseases (a sharp decrease in blood pressure during therapy with ACE inhibitors may worsen the course of these diseases); conditions after kidney transplantation, bilateral renal artery stenosis or stenosis of the artery of a single kidney; severe autoimmune systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma); impaired liver function or progressive liver diseases; diabetes mellitus; extensive surgical interventions and general anesthesia; with simultaneous use of other antihypertensive agents, as well as mTOR enzyme inhibitors and DPP-4 inhibitors; with simultaneous use of cardiac glycosides and other drugs that can lead to the development of torsades de pointes ventricular tachycardia; with water-electrolyte imbalance (hyperkalemia, hypokalemia, hyponatremia, hypercalcemia); with gout; symptomatic hyperuricemia; with angle-closure glaucoma; in old age.

Use in Pregnancy and Lactation

The use of Accuzide^® is contraindicated during pregnancy, in women planning a pregnancy, as well as in women of reproductive age who are not using reliable methods of contraception.

Women of reproductive age taking Accuzide^® should use reliable methods of contraception.

If pregnancy occurs during treatment with Accuzide^®, the drug should be discontinued as soon as possible.

Prescription of ACE inhibitors during pregnancy is associated with an increased risk of developing anomalies of the cardiovascular and nervous system of the fetus. In addition, cases of oligohydramnios, premature birth, birth of children with arterial hypotension, impaired renal function, including acute renal failure, hypoplasia of the skull bones, limb contractures, craniofacial anomalies, pulmonary hypoplasia, intrauterine growth retardation, patent ductus arteriosus, as well as cases of intrauterine fetal death and neonatal death have been described with the use of ACE inhibitors during pregnancy. Often, oligohydramnios is diagnosed after the fetus has been irreversibly damaged.

Newborns who were exposed to ACE inhibitors in utero should be observed to detect arterial hypotension, oliguria and hyperkalemia. If oliguria occurs, blood pressure and renal perfusion should be maintained.

Thiazides cross the placental barrier and are found in cord blood. Non-teratogenic effects of thiazides include fetal and/or neonatal jaundice and thrombocytopenia, and the possibility of other adverse events observed in adults is also allowed.

ACE inhibitors, including Quinapril, penetrate into breast milk to a limited extent. Thiazide diuretics are excreted in breast milk. Given the possibility of developing serious adverse reactions in newborns, Accuzide^® should not be used during lactation, and if it is necessary to use it, breastfeeding should be discontinued.

Use in Hepatic Impairment

Contraindicated in severe hepatic failure.

Should be prescribed with caution in case of impaired liver function or progressive liver diseases.

Use in Renal Impairment

The use of the drug is contraindicated in severe renal failure (creatinine clearance less than 30 ml/min).

In patients with mild renal impairment (creatinine clearance >60 ml/min), the initial dose of Accuzide^® is 10 mg+12.5 mg.

Accuzide^® should not be prescribed as initial therapy in patients with renal impairment with creatinine clearance <60 ml/min. In patients with moderate renal impairment (creatinine clearance 60-30 ml/min), Quinapril should be used at an initial dose of 5 mg with further dose titration.

With caution the drug is prescribed for conditions after kidney transplantation, bilateral renal artery stenosis or stenosis of the artery of a single kidney.

Pediatric Use

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

Geriatric Use

In elderly patients, no dose adjustment of Accuzide^® is required. The initial dose of the drug is 10 mg+12.5 mg.

Special Precautions

Angioedema

Cases of angioedema of the face and neck have been described during treatment with ACE inhibitors, including in 0.1% of patients receiving Quinapril. If laryngeal wheezing or angioedema of the face, tongue or glottis, difficulty in swallowing food or breathing occurs, Accuzide^® should be discontinued immediately. The patient should be prescribed adequate treatment and observed until the edema disappears. Antihistamines may be used to reduce symptoms. Angioedema involving the larynx can be fatal. If edema of the tongue, glottis or larynx threatens to develop airway obstruction, adequate emergency therapy is necessary, including subcutaneous administration of a 1:1000 solution of epinephrine (adrenaline) (0.3-0.5 ml). Cases of intestinal angioedema have also been described during treatment with ACE inhibitors. Patients experienced abdominal pain (with/without nausea and vomiting); in some cases without preceding facial angioedema and with normal C1-esterase activity. The diagnosis was established using computed tomography of the abdominal area, ultrasound or at the time of surgery. Symptoms disappeared after discontinuation of ACE inhibitors.

In patients who have experienced angioedema not associated with an ACE inhibitor, the risk of its development may be increased when treated with drugs of this class.

Patients simultaneously receiving therapy with mTOR enzyme inhibitors (e.g., temsirolimus) and DPP-4 inhibitors (e.g., vildagliptin) may be at greater risk of developing angioedema.

ACE inhibitors cause angioedema more frequently in patients of Black race than in Caucasians. As with other ACE inhibitors, Quinapril may be less effective in lowering blood pressure in patients of Black race.

In patients receiving ACE inhibitors during desensitizing therapy with hymenoptera venom (wasps, bees), persistent life-threatening anaphylactoid reactions may develop. Temporary discontinuation of the ACE inhibitor promotes regression of symptoms; however, they may recur upon resumption of ACE inhibitor therapy.

Anaphylactoid reactions may also develop when ACE inhibitors are administered to patients undergoing LDL apheresis with dextran sulfate or to patients on hemodialysis using high-flux membranes such as polyacrylonitrile. Alternative lipid-lowering therapy or other hemodialysis membranes should be used.

Arterial Hypotension

Accuzide^® may cause transient arterial hypotension, but not more frequently than with monotherapy with either component of the drug. Symptomatic hypotension is rare in the treatment of uncomplicated arterial hypertension with quinapril; however, it may develop as a result of ACE inhibitor therapy in patients with reduced blood volume, for example, after treatment with diuretics, adherence to a sodium-restricted diet, or during hemodialysis. If symptomatic hypotension occurs, the patient should be placed in a horizontal position and, if necessary, intravenous infusion with 0.9% sodium chloride solution should be administered. Transient arterial hypotension is not a contraindication to further use of the drug, but in such cases, it is advisable to reduce its dose.

Chronic Heart Failure

In patients with chronic heart failure with or without renal impairment, ACE inhibitor therapy for arterial hypertension may lead to an excessive decrease in blood pressure, which may be accompanied by oliguria, azotemia, and, in rare cases, acute renal failure and even death. Treatment of such patients with Accuzide^® should be initiated under careful medical supervision and observation during the first 2 weeks and when increasing the drug dose.

Agranulocytosis

In rare cases, ACE inhibitor therapy may be accompanied by the development of agranulocytosis and suppression of bone marrow hematopoiesis in patients with uncomplicated arterial hypertension, but more often in patients with impaired renal function, especially with connective tissue diseases. In these cases, the white blood cell count should be monitored.

If any symptoms of infection appear (e.g., sore throat, fever), patients should consult a doctor immediately, as such symptoms may be a manifestation of neutropenia.

Systemic Lupus Erythematosus

Thiazide diuretics may sometimes cause exacerbation of SLE.

Renal Impairment

Accuzide^® should not be used in patients with severe renal impairment (creatinine clearance less than 30 ml/min), as thiazide diuretics contribute to the progression of azotemia and have a cumulative effect with prolonged use in such patients. The drugs of choice for this group of patients receiving quinapril therapy are “loop” diuretics. For this reason, the fixed combination of Hydrochlorothiazide/Quinapril should not be used in patients with severe renal failure.

The T_1/2 of quinaprilat increases with decreasing creatinine clearance. Patients with a creatinine clearance of less than 60 ml/min but more than 30 ml/min should be started on a lower initial dose of Quinapril. In such patients, the dose of Accuzide^® should be increased based on the patient’s clinical condition, with regular monitoring of renal function, although clinical studies have not shown further deterioration of renal function during treatment with Accuzide^®.

In patients with arterial hypertension without obvious signs of pre-existing renal impairment, the use of quinapril, especially in combination with a diuretic, has been noted to increase blood urea nitrogen and serum creatinine levels, which is usually mild and generally transient. Such changes are most likely in patients with pre-existing renal impairment. In such cases, a reduction in the dose of Accuzide^® may be required. Renal function should be monitored in all patients with arterial hypertension. Accuzide^® should not be used as initial therapy in patients with a creatinine clearance of less than 60 ml/min.

Effect on the RAAS

In some patients, suppression of RAAS activity may lead to impaired renal function. In patients with severe heart failure, renal function may depend on RAAS activity; therefore, treatment with ACE inhibitors, including Quinapril, may lead to oliguria and/or progressive azotemia, and in rare cases, to acute renal failure and/or death.

Dual Blockade of the RAAS

The use of angiotensin II receptor antagonists, ACE inhibitors, or aliskiren may lead to dual blockade of the RAAS. This effect may manifest as a decrease in blood pressure, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Blood pressure, renal function, and plasma electrolyte levels should be carefully monitored in patients taking Accuzide^® and other drugs affecting the RAAS. The concomitant use of RAAS-active agents and quinapril should be avoided. The use of this combination should be limited to individual cases with careful monitoring of renal function and plasma potassium levels.

Renal Artery Stenosis

In clinical studies of patients with arterial hypertension and bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, treatment with ACE inhibitors in some cases resulted in increased blood urea nitrogen and serum creatinine levels. These changes were almost always reversible and disappeared after discontinuation of the ACE inhibitor and/or diuretic. In such cases, renal function should be monitored during the first few weeks of treatment with Accuzide^®.

Hepatic Impairment

Accuzide^® should be used with caution in patients with impaired liver function or progressive liver disease, as minor changes in fluid and electrolyte balance may precipitate hepatic coma.

Fluid and Electrolyte Balance

Serum electrolyte levels should be monitored regularly to detect possible electrolyte imbalances. In patients receiving quinapril monotherapy, as with other ACE inhibitors, serum potassium levels may increase.

Hyperkalemia (>5.8 mmol/L) was noted in approximately 2% of patients taking Quinapril, but in most cases, this deviation was isolated and resolved during treatment. Risk factors for hyperkalemia include renal impairment, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes. Concomitant use of a potassium-sparing diuretic with Accuzide^®, which contains a thiazide diuretic, is not recommended. Treatment with thiazide diuretics, conversely, is accompanied by hypokalemia, hyponatremia, and hypochloremic alkalosis. These imbalances sometimes manifest with symptoms such as dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle weakness, muscle pain or cramps, low blood pressure, oliguria, tachycardia, nausea, confusion, seizures, and vomiting.

Hypokalemia can also enhance the toxic effect of cardiac glycosides. The risk of hypokalemia is particularly high in liver cirrhosis, forced diuresis, inadequate intake of drugs that improve myocardial metabolism, concomitant therapy with corticosteroids or ACTH, and concomitant use with drugs that increase the risk of hypokalemia during thiazide diuretic use. The opposing effects of the components of Accuzide^® on serum potassium levels result in no change in its value in many patients.

In individual cases, the effect of one component of Accuzide^® may predominate over the other. Serum electrolyte levels should be determined periodically before and during treatment to detect possible electrolyte imbalances.

Chloride deficiency associated with thiazide diuretic therapy is usually mild and only in exceptional cases requires specific treatment (e.g., in liver or kidney disease).

In hot weather, patients with peripheral edema may develop hyponatremia. In this case, adequate replacement therapy is necessary.

Thiazide diuretics reduce calcium excretion.

In rare cases, patients on long-term thiazide therapy have developed pathological changes in the parathyroid glands, accompanied by hypercalcemia and hypophosphatemia. More serious complications of hyperparathyroidism (nephrolithiasis, bone resorption, and peptic ulcer) have not been described. Thiazide diuretics should be discontinued before testing parathyroid function.

Thiazide diuretics increase urinary magnesium excretion and can cause hypomagnesemia.

Thiazide diuretics may increase serum levels of cholesterol, triglycerides, and uric acid. These effects are usually mild; however, in susceptible patients, thiazide diuretics may trigger the development of gout or diabetes mellitus.

Diabetes Mellitus

Hyperglycemia induced by high doses of thiazide diuretics (including hydrochlorothiazide at doses >100 mg/day) may impair plasma glucose control. A decrease in plasma potassium levels leads to increased glucose tolerance. Plasma glucose levels should be monitored; potassium supplements should be prescribed if necessary to maintain plasma potassium levels, and hypoglycemic therapy should be adjusted. ACE inhibitor therapy may be accompanied by the development of hypoglycemia in diabetic patients receiving insulin or oral hypoglycemic agents. More careful monitoring and adjustment of the dose of hypoglycemic agents may be required when treating diabetic patients. ACE inhibitor therapy may be accompanied by the development of hypoglycemia in diabetic patients receiving insulin or oral hypoglycemic agents. More careful monitoring may be required when treating diabetic patients.

Cough

The development of a cough has been observed during treatment with ACE inhibitors, including Quinapril. Typically, it is non-productive, persistent, and resolves after discontinuation of therapy. A possible association with ACE inhibitors should be considered in the differential diagnosis of cough.

Surgery

ACE inhibitors should be used with caution in patients undergoing surgery or general anesthesia, as they block angiotensin II formation induced by compensatory renin secretion. This may lead to arterial hypotension, which is corrected by increasing blood volume. Before surgery, the patient should inform the anesthesiologist that they are taking an ACE inhibitor.

Blood Volume

Patients should be warned that insufficient fluid intake and increased sweating may lead to an excessive decrease in blood pressure due to a reduction in blood volume. Other causes of dehydration, such as vomiting or diarrhea, can also lead to a drop in blood pressure.

Acute Myopia and Angle-Closure Glaucoma

Hydrochlorothiazide (a sulfonamide derivative) can lead to the development of acute transient myopia and acute angle-closure glaucoma. Symptoms include sudden onset of decreased vision or eye pain and usually occur within the first hours to weeks after starting therapy. Without appropriate treatment, angle-closure glaucoma can lead to permanent vision loss. The primary treatment for this condition is immediate discontinuation of hydrochlorothiazide. Emergency medical or surgical intervention may be needed if intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of allergic reactions to sulfonamides and penicillin.

Effect on Driving and Operating Machinery

Caution should be exercised when driving vehicles or performing other work requiring increased attention, especially at the beginning of treatment.

Overdose

There is no information on Accuzide^® overdose and no specific data on its treatment.

Symptoms: marked decrease in blood pressure, disturbances in fluid and electrolyte balance (hyponatremia, hypochloremia, hypokalemia), decreased blood volume due to forced diuresis. When used concomitantly with cardiac glycosides, the risk of arrhythmia increases.

Treatment: the drug should be discontinued; gastric lavage, oral administration of activated charcoal, intravenous infusion of 0.9% sodium chloride solution, measures to restore fluid and electrolyte balance, and standard symptomatic and supportive therapy are indicated. Hemodialysis and peritoneal dialysis have a small effect on the elimination of quinapril and quinaprilat.

Drug Interactions

Tetracycline and Other Drugs Interacting with Magnesium

When used concomitantly with Accuzide^®, the absorption of tetracycline is reduced by approximately 28-37% due to the presence of magnesium carbonate as an excipient in the drug. This interaction should be taken into account when Accuzide^® is used concomitantly with tetracycline or other drugs capable of interacting with magnesium.

Lithium Preparations

Lithium preparations should generally not be prescribed in combination with diuretics, as the latter reduce the renal clearance of lithium and increase the risk of adverse effects. Increased serum lithium concentrations and symptoms of lithium toxicity have been observed in patients receiving lithium preparations and ACE inhibitors. These changes are associated with sodium loss under the influence of ACE inhibitors. When prescribing Accuzide^®, the risk of lithium intoxication may be increased. Caution is required with this combination.

Diuretics

Concomitant use of quinapril with diuretics enhances the antihypertensive effect.

Ethanol, Barbiturates, or Narcotic Analgesics

Concomitant use with Accuzide^® may increase the risk of orthostatic hypotension (due to the presence of hydrochlorothiazide in the drug).

Hypoglycemic Drugs

Dose adjustment of hypoglycemic agents may be required when used concomitantly with Accuzide^®. Hyperglycemia induced by thiazide diuretics may impair blood glucose control. A decrease in plasma potassium levels leads to increased glucose tolerance. Blood glucose levels should be monitored; potassium supplements should be prescribed if necessary to maintain its plasma concentration, and hypoglycemic therapy should be adjusted.

Other Antihypertensive Agents

The thiazide diuretic contained in Accuzide^® may enhance the effect of other antihypertensive agents, especially ganglionic blockers or beta-blockers. The antihypertensive effect of the thiazide diuretic, in turn, may be enhanced after sympathectomy.

Corticosteroids, ACTH

Concomitant use with Accuzide^® leads to increased loss of electrolytes, especially potassium.

Pressor Amines

Concomitant use with Accuzide^® may reduce the effect of adrenomimetics (e.g., norepinephrine), but this effect is not significant.

Non-Depolarizing Muscle Relaxants

The effect of non-depolarizing muscle relaxants may be enhanced when used concomitantly with Accuzide^®.

NSAIDs

In some patients, NSAIDs may cause attenuation of the diuretic, natriuretic, and antihypertensive effects of “loop,” potassium-sparing, and thiazide diuretics. Therefore, when used concomitantly with Accuzide^®, the effectiveness of therapy should be monitored.

Furthermore, in elderly patients, patients with reduced blood volume (including those receiving diuretic therapy), or patients with impaired renal function, the concomitant use of NSAIDs (including selective COX-2 inhibitors) with ACE inhibitors, including quinapril, may lead to deterioration of renal function, including possible acute renal failure. Renal function should be regularly monitored in patients receiving NSAIDs and Quinapril concomitantly.

A weakening of the antihypertensive effect of ACE inhibitors, including quinapril, may also be observed when used concomitantly with NSAIDs.

Agents that Increase Blood Potassium Levels

Quinapril reduces aldosterone concentration, which in turn may lead to hyperkalemia. Therefore, when treating with Accuzide^®, potassium supplements and potassium-containing salt substitutes should be used with caution, monitoring serum potassium levels. Since Accuzide^® contains a diuretic, the addition of a potassium-sparing diuretic is not recommended.

Digoxin

Fluid and electrolyte disturbances caused by thiazide diuretics (i.e., hypokalemia, hypomagnesemia) increase the risk of digoxin intoxication symptoms, which can lead to fatal arrhythmias.

Ion-Exchange Resins

The absorption of hydrochlorothiazide is impaired in the presence of cholestyramine and colestipol. With single concomitant administration, these drugs bind Hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by 85% and 43%, respectively.

Drugs for Treating Gout (Allopurinol, Uricosuric Drugs, Xanthine Oxidase Inhibitors)

Hyperuricemia induced by thiazide diuretics may impair the control of gout in patients managed with allopurinol and probenecid. Concomitant use of hydrochlorothiazide and allopurinol may increase the frequency of hypersensitivity reactions to allopurinol.

Other Drugs

No signs of clinically significant pharmacokinetic interaction of quinapril with propranolol, hydrochlorothiazide, or cimetidine have been identified.

Twice-daily administration of quinapril did not significantly affect the anticoagulant effect of a single dose of warfarin (assessed by prothrombin time).

Concomitant multiple administration of atorvastatin 10 mg with quinapril 80 mg did not lead to significant changes in the steady-state pharmacokinetic parameters of atorvastatin.

Antihypertensive drugs, narcotic analgesics, and general anesthetics enhance the antihypertensive effect of quinapril.

Quinapril increases the risk of leukopenia when used concomitantly with allopurinol, cytostatic agents, immunosuppressants, and procainamide.

A symptom complex including facial flushing, nausea, vomiting, decreased blood pressure, and a flu-like syndrome has been described with the concomitant use of ACE inhibitors and gold preparations (sodium aurothiomalate, intravenous).

Caution should be exercised with the concomitant use of cardiac glycosides and other drugs that can lead to the development of torsades de pointes ventricular tachycardia due to the possibility of developing hypokalemia and, consequently, an enhanced toxic effect of these drugs.

The use of angiotensin II receptor antagonists, ACE inhibitors, or aliskiren may lead to dual blockade of the RAAS activity. This effect may manifest as decreased blood pressure, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy.

Quinapril and Hydrochlorothiazide should not be used concomitantly with aliskiren in patients with diabetes mellitus, in patients with moderate to severe renal impairment ( GFR <60 mL/min/1.73 m²), in patients with hyperkalemia ( >5 mmol/L), and in patients with chronic heart failure with low blood pressure.

Quinapril and Hydrochlorothiazide should not be used concomitantly with angiotensin II receptor antagonists or other ACE inhibitors in patients with diabetes mellitus and end-stage target organ damage, in patients with moderate to severe renal impairment ( GFR <60 mL/min/1.73 m²), in patients with hyperkalemia ( >5 mmol/L), and in patients with chronic heart failure with low blood pressure.

Patients receiving concomitant therapy with mTOR enzyme inhibitors (e.g., temsirolimus) and DPP-4 inhibitors (e.g., vildagliptin) may be at an increased risk of developing angioedema. Caution should be exercised when using these drugs concomitantly with Accuzide^®.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years.

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.