Fozide 20 (Tablets) Instructions for Use

Marketing Authorization Holder

Bristol-Myers Squibb S.r.L. (Italy)

ATC Code

C09BA09 (Fosinopril and diuretics)

Active Substances

Hydrochlorothiazide (Rec.INN registered by WHO)

Fosinopril (Rec.INN registered by WHO)

Dosage Form

Fozide 20

Tablets 20 mg+12.5 mg: 28 pcs.

Dosage Form, Packaging, and Composition

Tablets of a yellowish-orange color, round, biconvex, with an engraving “1493” on one side and a score on the other side of the tablet.

Excipients: lactose, croscarmellose sodium, povidone, sodium stearyl fumarate, yellow iron oxide, red iron oxide.

14 pcs. – blisters (2) – cardboard packs.

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Antihypertensive combination agent (ACE inhibitor + diuretic)

Pharmacological Action

Antihypertensive drug. It is a combination of an ACE inhibitor (Fosinopril) and a thiazide diuretic (Hydrochlorothiazide).

Fosinopril is a prodrug ester that is hydrolyzed in the body by esterases to form the active metabolite fosinoprilat. Due to the specific ability of the phosphinyl group to bind to ACE, Fosinopril inhibits the conversion of angiotensin I to angiotensin II, which has a pronounced vasoconstrictive effect. As a result of the decrease in angiotensin II concentration, a secondary increase in plasma renin activity and a direct decrease in aldosterone secretion occur, which in turn leads to a slight increase in serum potassium ions (on average 0.1 mEq/L) with a simultaneous loss of sodium ions and fluid by the body.

Furthermore, Fosinopril inhibits the metabolic degradation of bradykinin, which has a potent vasodilatory effect, and this also plays an important role in the therapeutic action of the drug.

Hydrochlorothiazide impairs the reabsorption of sodium, chloride, and water ions in the distal tubules of the nephron. It helps to reduce elevated blood pressure. It increases the excretion of potassium, magnesium, and bicarbonate ions; it retains calcium ions in the body.

Fosinopril reduces the loss of potassium ions caused by the intake of hydrochlorothiazide.

The maximum reduction in blood pressure is achieved 2-6 hours after oral administration of the drug and lasts for 24 hours. The reduction in blood pressure parameters after 24 hours is 60-90% of the maximum blood pressure reduction, which allows the drug to be taken once a day.

Pharmacokinetics

The pharmacokinetics of fosinopril and hydrochlorothiazide when taken simultaneously do not differ from those when they are prescribed separately.

Fosinopril

Absorption

After oral administration, absorption is 30-40%. The extent of absorption does not depend on food intake, but the rate of absorption may be slowed. C_max of fosinoprilat in plasma is reached in 3 hours and does not depend on the dose of fosinopril taken. After a single or multiple oral doses, C_max and AUC are directly proportional to the total dose of fosinopril taken.

Distribution

Plasma protein binding is 95%. Fosinoprilat has a relatively small V_d and is minimally bound to cellular components of blood.

Metabolism

Hydrolysis of fosinopril to form the pharmacologically active fosinoprilat occurs primarily in the liver.

Elimination

Fosinoprilat is excreted unchanged equally by the kidneys and liver. T_1/2 is 11.5 hours.

Pharmacokinetics in special clinical cases

In patients with impaired renal function (creatinine clearance less than 80 ml/min/1.73 m²), the total clearance of fosinoprilat from the body is approximately half that of patients with normal renal function, while absorption, bioavailability, and protein binding are not significantly altered. Reduced renal excretion is compensated by increased hepatic excretion. A moderate increase in plasma AUC values (less than double compared to normal) was observed in patients with varying degrees of renal failure, including end-stage renal failure (creatinine clearance less than 10 ml/min/1.73 m²).

The clearance of fosinoprilat during hemodialysis and peritoneal dialysis averages 2% and 7% (relative to urea clearance values), respectively.

In patients with impaired liver function (alcoholic or biliary cirrhosis), the rate of hydrolysis of fosinopril may be reduced without changing its extent. The total clearance of fosinoprilat is approximately half that of patients with normal liver function. In this category of patients, there is evidence of a compensatory increase in the excretion of the active substance by the kidneys with a simultaneous decrease in the hepatic clearance of fosinopril.

In patients over 65 years of age, no significant differences in the pharmacokinetic parameters of fosinoprilat are observed compared to young patients (20-35 years).

Hydrochlorothiazide

Absorption

After oral administration, it is 50-80% absorbed. Time to reach C_max in plasma is 1-2.5 hours.

Distribution

Plasma protein binding is 68%. V_d is 3.6-7.8 L/kg.

Hydrochlorothiazide accumulates in erythrocytes (concentration in erythrocytes is 1.6-1.8 relative to plasma concentration).

Metabolism

Hydrochlorothiazide is metabolized to a very small extent.

Elimination

T_1/2 ranges from 5 to 15 hours. In patients with normal renal function, elimination occurs almost exclusively by the kidneys. Overall, 50-75% of an orally administered dose is excreted unchanged in the urine.

Pharmacokinetics in special clinical cases

In severe renal impairment (creatinine clearance less than 20 ml/min/1.73 m²), T_1/2 may increase to 21 hours.

Indications

• Arterial hypertension (in cases where combination therapy is optimal).

ICD codes

Dosage Regimen

The drug is prescribed as 1 tablet once a day.

In mild to moderate renal impairment (creatinine clearance greater than 30 ml/min/1.73 m², serum creatinine 3 mg/dL or 265 µmol/L) and/or hepatic impairment, as well as in elderly patients (over 65 years), no dose adjustment is required.

In severe renal impairment (creatinine clearance less than 30 ml/min/1.73 m²), Fozide 20 should not be prescribed. In this case, the use of loop diuretics is recommended.

The drug is taken in the morning, regardless of meal time, with a sufficient amount of fluid.

Adverse Reactions

Side effects observed with the use of Fozide 20 are similar to the side effects noted with the use of each component separately.

From the central and peripheral nervous system 2% – dizziness, headache, feeling of fatigue; 0.5-2% – paresthesia, drowsiness, depression, hearing loss.

From the cardiovascular system 0.5-2% – chest pain, orthostatic hypotension, syncope, edema, sensation of facial flushing, cardiac arrhythmias.

From the digestive system 0.5-2% – nausea, vomiting, diarrhea, heartburn, abdominal pain, gastritis, esophagitis.

From the respiratory system 2% – cough; 0.5-2% – sensation of nasal congestion, pharyngitis, rhinitis.

Allergic reactions 0.5-2% – skin rash, itching, angioedema.

From the musculoskeletal system 2% – bone pain, myalgia, arthralgia; 0.5-2% – cramps.

From the reproductive system 0.5-2% – decreased sexual function, change in libido.

From the urinary system 0.5-2% – increased urination, dysuria, increased plasma creatinine and urea concentrations.

From laboratory parameters 0.5-2% – decreased concentration of potassium, sodium, chloride, magnesium ions, decreased glucose concentration, increased calcium ion concentration, increased cholesterol and triglyceride levels.

Other 0.5-2% – chills, neutropenia.

Side effects described with the use of fosinopril

From the cardiovascular system arterial hypotension, orthostatic collapse, tachycardia, arrhythmias, angina pectoris, myocardial infarction.

From the central and peripheral nervous system dizziness, headache, weakness, stroke, cerebral ischemia, hearing and vision disorders, tinnitus; when used in high doses – insomnia, anxiety, depression, confusion, vestibular disorders, paresthesia.

From the respiratory system dry cough, bronchospasm, dyspnea, rhinorrhea, pharyngitis, dysphonia, pulmonary infiltrates.

From the digestive system nausea, diarrhea, vomiting, abdominal pain, constipation, decreased appetite, stomatitis, glossitis, intestinal obstruction, pancreatitis, hepatitis, cholestatic jaundice, increased activity of liver transaminases, hyperbilirubinemia.

Allergic, toxic-allergic and immunopathological reactions skin rash, itching, angioedema of the face, extremities, lips, tongue, glottis and/or larynx.

From the urinary system development or worsening of renal failure, proteinuria, hypercreatininemia, increased urea concentration.

From laboratory parameters hyperkalemia, hyponatremia, decreased hemoglobin and hematocrit levels, increased ESR.

Side effects described with the use of hydrochlorothiazide

From the digestive system dry mouth, nausea, vomiting, diarrhea; hemorrhagic pancreatitis, acute cholecystitis (against the background of cholelithiasis).

From the central and peripheral nervous system weakness, fatigue, dizziness, headache, paresthesia may occur.

From the cardiovascular system orthostatic hypotension, tachycardia, vasculitis, thrombosis, thromboembolism.

From metabolism hypokalemia, hypomagnesemia, hyponatremia, hyperuricemia, hypercalcemia, hyperglycemia, exacerbation of gout.

From the urinary system acute interstitial nephritis, hypercreatininemia.

From the hematopoietic system neutropenia, thrombocytopenia.

From the organ of vision progression of myopia.

Allergic reactions allergic dermatitis.

Contraindications

• History of angioedema with the use of ACE inhibitors;
• Severe renal impairment (creatinine clearance less than 30 ml/min/1.73 m²);
• Anuria;
• Gout;
• Electrolyte imbalance;
• Pregnancy;
• Lactation (breastfeeding);
• Children and adolescents under 18 years of age;
• Hypersensitivity to the components of the drug, to other ACE inhibitors, to sulfonamide derivatives, including thiazides.

Use in Pregnancy and Lactation

Fozide 20 is contraindicated for use during pregnancy. The use of fosinopril in the second and third trimesters of pregnancy causes damage (impaired development of fetal kidneys, decreased blood pressure in the fetus and newborns, impaired renal function, hyperkalemia, skull hypoplasia, oligohydramnios, limb contractures, skull deformation, lung hypoplasia) or death of the developing fetus.

Since fosinoprilat is excreted in breast milk, if it is necessary to use Fozide 20 during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

In hepatic impairment, no dose adjustment is required.

Use in Renal Impairment

In mild to moderate renal impairment (creatinine clearance greater than 30 ml/min/1.73 m², serum creatinine 3 mg/dL or 265 µmol/L), no dose adjustment is required.

In severe renal impairment (creatinine clearance less than 30 ml/min/1.73 m²), Fozide 20 should not be prescribed. In this case, the use of loop diuretics is recommended.

Pediatric Use

The drug is contraindicated in children and adolescents under 18 years of age.

Special Precautions

Fozide 20 should be prescribed with caution in arterial hypotension, connective tissue diseases (SLE, scleroderma), impaired liver function or progressive liver disease (minor changes in water-electrolyte balance can cause hepatic coma), metabolic acidosis, renal impairment, stenosis of the renal artery of one or both kidneys (concentrations of blood urea nitrogen and serum creatinine may increase), hematopoietic disorders (agranulocytosis, neutropenia), conditions accompanied by a decrease in circulating blood volume (diarrhea, vomiting), aortic stenosis, cerebrovascular diseases, coronary artery disease, chronic heart failure, status after kidney transplantation, diabetes mellitus, when following a salt-restricted diet, as well as in elderly patients.

If angioedema develops while taking Fozide 20, the drug should be discontinued immediately. Patients should be warned that if swelling of the face, eyes, lips and tongue, narrowing of the larynx, or difficulty breathing occurs, they should immediately stop taking the drug and consult a doctor.

Caution should be exercised when prescribing the drug to patients receiving desensitizing therapy, as there is a risk of developing anaphylactoid reactions.

Anaphylactoid reactions have also been reported with the use of Fozide 20 during hemodialysis using high-flux membranes or during low-density lipoprotein apheresis with dextran sulfate adsorption. In such patients, the possibility of using a different type of dialysis membrane or other drug treatment should be considered.

To reduce the risk of arterial hypotension, the water-electrolyte balance should be corrected before prescribing Fozide 20.

A transient episode of hypotension with subsequent stabilization of blood pressure is not a reason to discontinue treatment. The maximum decrease in blood pressure is noted in the early stages of treatment and usually stabilizes by the 2nd week of treatment. With further use of the drug, no decrease in its therapeutic efficacy is observed.

In patients with chronic heart failure, regardless of the degree of renal impairment, excessive reduction in blood pressure may be observed with the use of fosinopril, which may lead to oliguria or azotemia, and in rare cases to the development of acute renal failure. Treatment of arterial hypertension in such patients should be started with the minimum therapeutic dose of the drug, strictly controlling the level of blood pressure, especially during the first 2 weeks, as well as with any increase in the dose of the drug.

While taking Fozide 20, blood glucose levels may increase, so adjustment of the dose of hypoglycemic drugs may be required.

While taking Fozide 20, dose adjustment of probenecid or sulfinpyrazone may also be required, as the concentration of uric acid in the blood may increase.

While taking hydrochlorothiazide, the concentration of calcium ions in the blood serum may increase due to a decrease in its excretion. A dose reduction of concurrently taken calcium preparations may be required.

Before surgery, patients taking Fozide 20 require correction of water-electrolyte balance.

Elderly patients may be more sensitive to the action of the drug due to slower metabolism.

Control of laboratory parameters

While taking Fozide 20, the number of leukocytes in the peripheral blood should be periodically monitored, especially in patients with impaired renal function against the background of collagenoses (systemic lupus erythematosus or scleroderma), as it has been reported that in rare cases, ACE inhibitors cause agranulocytosis and bone marrow suppression, especially in this category of patients.

Use in pediatrics

The safety and efficacy of Fozide 20 in children and adolescents under 18 years of age have not been established.

Effect on the ability to drive vehicles and operate machinery

While taking Fozide 20, caution should be exercised when engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms pronounced decrease in blood pressure, bradycardia, shock, water-electrolyte imbalance, acute renal failure, stupor.

Treatment induced vomiting, gastric lavage, restoration of water-electrolyte balance, compensation of arterial hypertension. Hemodialysis and peritoneal dialysis are not effective.

Drug Interactions

When prescribing Fozide 20 in combination with other antihypertensive drugs, an additive effect is possible.

With simultaneous use, Fozide 20 may enhance the hypotensive effect of drugs used in anesthesia, opioid analgesics, barbiturates, and ethanol.

Concomitant use of Fozide 20 and potassium-sparing diuretics or potassium preparations may lead to an increase in plasma potassium concentration.

When prescribing Fozide 20, it should be taken into account that NSAIDs may reduce the antihypertensive effect of ACE inhibitors and weaken the effect of hydrochlorothiazide.

Hydrochlorothiazide may enhance the effect of non-depolarizing muscle relaxants (e.g., tubocurarine).

Concomitant use of antacids may reduce the absorption of fosinopril and hydrochlorothiazide, leading to a decrease in their serum concentrations.

Cholestyramine resin and colestipol may delay or reduce the absorption of hydrochlorothiazide.

In patients receiving Fozide 20 simultaneously with lithium salts, the serum lithium concentration may increase.

The bioavailability of fosinopril does not change with concomitant use with chlorthalidone, nifedipine, propranolol, cimetidine, metoclopramide, propantheline, digoxin, acetylsalicylic acid, and warfarin.

Storage Conditions

List B. The drug should be stored in a dry place at a temperature from 15°C (59°F) to 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.