Fosinotec H (Tablets) Instructions for Use

Marketing Authorization Holder

Ranbaxy Laboratories, Ltd. (India)

ATC Code

C09BA09 (Fosinopril and diuretics)

Active Substances

Hydrochlorothiazide (Rec.INN registered by WHO)

Fosinopril (Rec.INN registered by WHO)

Dosage Form

Fosinotec H

Tablets 12.5 mg+20 mg: 20, 30 or 100 pcs.

Dosage Form, Packaging, and Composition

Tablets from white to almost white, round, flat, with beveled edges, engraved with “FH1” and a score for dividing on one side and smooth on the other.

Excipients: lactose 46.7 mg, crospovidone 6 mg, povidone 6 mg, isopropanol (consumed during production) q. s., microcrystalline cellulose 21 mg, colloidal silicon dioxide 3 mg, talc 4.8 mg.

10 pcs. – PVC/Polyamide/Aluminum blisters (2) – cardboard packs.
10 pcs. – PVC/Polyamide/Aluminum blisters (3) – cardboard packs.
10 pcs. – PVC/Polyamide/Aluminum blisters (10) – cardboard packs.

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Antihypertensive combination agent (ACE inhibitor + diuretic)

Pharmacological Action

Antihypertensive combination drug.

Fosinopril is an angiotensin-converting enzyme (ACE) inhibitor. In the body, fosinopril is converted to an active metabolite, fosinoprilat, which prevents the conversion of angiotensin I to angiotensin II. It has antihypertensive, vasodilating, diuretic, and potassium-sparing effects. Reduces total peripheral vascular resistance (TPVR) and blood pressure (BP). Suppresses aldosterone synthesis, inhibits tissue ACE.

Hydrochlorothiazide is a thiazide diuretic. It affects the mechanism of electrolyte reabsorption in the renal tubules, increasing the excretion of sodium and chloride ions to approximately the same extent, as well as potassium and bicarbonate ions. Increases plasma renin activity, aldosterone secretion, and reduces serum potassium ion levels.

Fosinopril and Hydrochlorothiazide have an additive effect. Fosinopril reduces the loss of potassium ions caused by hydrochlorothiazide intake. The antihypertensive effect begins to appear 1 hour after oral administration of the drug, the maximum effect develops in 2-6 hours. The reduction in BP after 24 hours is 60-90% of the maximum BP 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

The pharmacokinetics of fosinopril are linear.

Absorption after oral administration, absorption from the gastrointestinal tract is approximately 30-40%. The degree of absorption does not depend on food intake, but the rate of absorption may be slowed. The maximum plasma concentration of fosinoprilat is reached approximately 3 hours later and does not depend on the dose of fosinopril taken.

Distribution binding to plasma proteins is 95%. Fosinopril has a relatively small volume of distribution. Does not cross the blood-brain barrier.

Metabolism 50-100% of the absorbed fosinopril is hydrolyzed in the liver to fosinoprilat. In impaired liver function, the rate of hydrolysis may be slowed, while the degree of hydrolysis does not change significantly.

Elimination fosinoprilat is excreted through the intestines and kidneys. In patients with arterial hypertension and normal renal and hepatic function, the half-life of fosinoprilat is approximately 11.5 hours. In patients with chronic heart failure, T_1/2 is 14 hours. The clearance of fosinoprilat during hemodialysis and peritoneal dialysis averages 2% and 7%, respectively, relative to urea clearance values.

In patients with impaired renal function (creatinine clearance (CrCl) less than 80 ml/min), the total clearance of fosinoprilat is approximately half that of patients with normal renal function. At the same time, absorption, bioavailability, and plasma protein binding are not significantly altered.

In patients with impaired liver function (with alcoholic or biliary cirrhosis), the rate of fosinopril hydrolysis may be reduced, but the degree does not change significantly.

The total clearance of fosinoprilat in such patients is approximately half compared to patients with normal liver function.

Hydrochlorothiazide

Absorption: after oral administration, absorption from the gastrointestinal tract is 60-80%. Maximum plasma concentration is reached 1-5 hours after oral administration.

Distribution binding to plasma proteins is 64%. Does not cross the blood-brain barrier.

Metabolism and excretion Hydrochlorothiazide is not metabolized and is rapidly excreted by the kidneys. T_1/2 is 5-15 hours.

Indications

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

ICD codes

Dosage Regimen

The tablets are taken orally, regardless of meal time, with a sufficient amount of liquid.

The dose is selected individually. The usual dose is 1 tablet once a day.

For mild or moderate renal impairment (CrCl greater than 30 ml/min, serum creatinine approximately 3 mg/dl or 265 µmol/L), the usual dose of Fosinotec H is recommended. For CrCl less than 30 ml/min, the use of the drug is not recommended. Patients with severe renal impairment are prescribed “loop” diuretics.

For hepatic impairment, dose adjustment is not required.

When prescribing the drug to elderly patients, it should be taken into account that they may be more sensitive to the drug’s action due to slowed metabolism, so the dose of Fosinotec H is recommended to be selected individually.

Adverse Reactions

Side effects observed with the use of Fosinotec H are similar to the side effects noted with the use of each drug separately.

General

Allergic reactions angioedema, urticaria.

From the CNS dizziness, headache, feeling of fatigue, drowsiness, depression.

From the nervous system paresthesia.

From the skin skin rash, skin itching.

From the urinary system frequent urination, dysuria.

From the musculoskeletal system muscle pain, joint pain, cramps.

From the digestive system nausea, vomiting, diarrhea, heartburn, abdominal pain, gastritis, esophagitis.

From the respiratory system cough, nasal congestion, pharyngitis, rhinitis.

From the sensory organs hearing loss.

From the cardiovascular system orthostatic hypotension, flushing, syncope, peripheral edema, heart rhythm disturbances, chest pain.

From the reproductive system decreased sexual function, change in libido.

From laboratory parameters decreased levels of potassium, sodium, chloride, magnesium, glucose ions; increased levels of calcium ions, uric acid in the blood; increased concentration of cholesterol and triglycerides; neutropenia.

Other chills.

Side effects described with the use of fosinopril

From the CNS stroke, cerebral ischemia, dizziness, headache, weakness; with high doses – insomnia, anxiety, depression, confusion, vestibular disorders.

From the nervous system paresthesia.

From the digestive system nausea, diarrhea, intestinal obstruction, pancreatitis, hepatitis, cholestatic jaundice, abdominal pain, vomiting, constipation, decreased appetite, change in body weight, stomatitis, glossitis, intestinal edema.

From the respiratory system dry cough, pulmonary infiltrates, bronchospasm, shortness of breath, rhinorrhea, pharyngitis, dysphonia.

From the sensory organs hearing and vision disorders, tinnitus.

From the cardiovascular system marked decrease in BP, orthostatic collapse, tachycardia, palpitation, arrhythmia, angina pectoris, myocardial infarction.

From laboratory parameters increased urea concentration, increased liver enzyme activity, hyperbilirubinemia, hypercreatininemia, hyperkalemia, hyponatremia; decreased hemoglobin and hematocrit, increased erythrocyte sedimentation rate (ESR).

Side effects described with the use of hydrochlorothiazide:

Allergic reactions dermatitis.

From the CNS weakness, increased fatigue, dizziness, headache.

From the urinary system hypercreatininemia, acute interstitial nephritis.

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

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

From laboratory parameters hypokalemia, hypomagnesemia, hyponatremia, hyperuricemia, hypercalcemia, hyperglycemia, neutropenia, thrombocytopenia.

Other calf muscle cramps, exacerbation of gout, progression of myopia.

Contraindications

• Hereditary or idiopathic angioedema (including history after taking other ACE inhibitors);
• Severe renal failure (CrCl less than 30 ml/min/1.73 m²);
• Anuria;
• Gout;
• Severe disturbances of water-electrolyte balance or acid-base state;
• Pregnancy and lactation;
• Childhood and adolescence under 18 years;
• Hypersensitivity to fosinopril and other components of the drug, other ACE inhibitors, to thiazide diuretics or sulfonamide derivatives;
• Lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

With caution the drug should be prescribed for arterial hypotension, for connective tissue diseases (including systemic lupus erythematosus, scleroderma), impaired liver function or progressive liver disease (severe water-electrolyte balance disorders can cause hepatic coma), metabolic acidosis, impaired renal function, bilateral renal artery stenosis or stenosis of the artery of a single kidney (an increase in blood urea nitrogen and serum creatinine concentration is possible), impaired hematopoiesis (agranulocytosis, neutropenia), conditions accompanied by a decrease in circulating blood volume (diarrhea, vomiting), aortic stenosis, cerebrovascular diseases (including cerebral circulation insufficiency), coronary artery disease, chronic heart failure, when following a salt-restricted diet, conditions after kidney transplantation, diabetes mellitus, as well as to elderly patients.

Use in Pregnancy and Lactation

The use of Fosinotec H is contraindicated during pregnancy. The use of ACE inhibitors in the II and III trimester can cause damage or even death of the fetus (possible development of impaired fetal renal function, decreased BP, skull bone hypoplasia, oligohydramnios, limb contractures, lung hypoplasia).

Fosinopril is excreted in breast milk. If it is necessary to use Fosinotec H during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

In case of impaired liver function, dose adjustment is not required.

Use in Renal Impairment

For mild or moderate degree of renal impairment (CrCl greater than 30 ml/min, serum creatinine approximately 3 mg/dl or 265 µmol/L), the usual dose of Fosinotec H is recommended. For CrCl less than 30 ml/min, the use of the drug is not recommended. Patients with severe renal impairment are prescribed “loop” diuretics.

Pediatric Use

Contraindicated in children under 18 years of age.

Geriatric Use

When prescribing the drug to elderly patients, it should be taken into account that they may be more sensitive to the drug’s action due to slowed metabolism, so the dose of Fosinotec H is recommended to be selected individually.

Special Precautions

Before starting therapy with Fosinotec H, it is necessary to correct the water-electrolyte balance. Fosinopril can cause symptomatic arterial hypotension, which is most likely in patients with reduced circulating blood volume as a result of previous long-term treatment with diuretics, salt restriction, dialysis, diarrhea or vomiting.

Arterial hypotension is not an absolute contraindication for further use of Fosinotec H. The maximum decrease in BP is noted in the early stages of treatment and usually stabilizes by the second week of therapy. With further use of the drug, no decrease in its therapeutic efficacy is observed.

When using ACE inhibitors, including Fosinopril, angioedema may develop. With edema of the tongue, pharynx, larynx, airway obstruction may develop. Patients should discontinue the drug and immediately inform the attending physician about the appearance of edema on the face, eyes, lips and tongue, about laryngeal muscle spasm or difficulty breathing. In such cases, prompt emergency measures are necessary.

Caution should also be exercised when prescribing Fosinotec H during desensitization procedures.

During hemodialysis using high-permeability membranes, as well as during low-density lipoprotein apheresis with adsorption on dextran sulfate, anaphylactic reactions may occur. In these cases, a different type of dialysis membrane or other drug treatment should be used.

In patients with impaired renal function, especially in the presence of systemic connective tissue diseases, agranulocytosis and bone marrow suppression may develop. In this case, the content of leukocyte cells in the peripheral blood should be monitored. Such patients should be warned about the need to report any signs of infection – fever, sore throat.

In patients with arterial hypertension with renal artery stenosis of one or both kidneys, as well as with the simultaneous use of diuretics during treatment with ACE inhibitors, the level of blood urea nitrogen and serum creatinine may increase. These effects are reversible and disappear after discontinuation of treatment. In such patients, it is necessary to monitor renal function during the first two weeks of treatment. A dose reduction of the drug may be required.

In patients with severe heart failure, oliguria and/or progressive azotemia with or without renal failure, treatment with ACE inhibitors may cause an excessive hypotensive effect, which may increase oliguria or azotemia, and in rare cases, lead to death. Therefore, in such patients, the use of Fosinotec H should be started with minimal therapeutic doses and under strict control of BP, especially during the first two weeks of treatment.

Hydrochlorothiazide can cause hypokalemia, hyponatremia and hypochloremic alkalosis. In the presence of fosinopril, the risk of hypokalemia is reduced.

Hydrochlorothiazide promotes a decrease in the excretion of calcium ions from the body, an increase in the excretion of magnesium ions in the urine, which can lead to hypomagnesemia.

Periodic monitoring of serum electrolyte levels is necessary.

The concentration of uric acid in the blood may increase, and in some patients taking thiazide diuretics, an acute attack of gout may develop. In diabetic patients, the need for insulin may change, latent forms of diabetes may become manifest during the use of thiazide diuretics. An increase in the concentration of triglycerides and cholesterol is associated with treatment with thiazide diuretics.

The cough caused by ACE inhibitors, including Fosinopril, is usually non-productive and persistent, and resolves after discontinuation of the drugs. Cough caused by ACE inhibitors should be considered as one of the options in the differential diagnosis of cough.

In rare cases, the use of ACE inhibitors can lead to the appearance of cholestatic jaundice with the development of fulminant hepatocellular necrosis.

Overdose

Symptoms marked decrease in BP, bradycardia, shock, disturbance of water-electrolyte balance, acute renal failure, stupor.

Treatment lay the patient down with legs elevated. In mild cases, gastric lavage, induction of vomiting, administration of adsorbents and sodium sulfate within 30 minutes after taking the drug are indicated. With a marked decrease in BP – intravenous administration of vasopressors, catecholamines, angiotensin II; with bradycardia – use of an artificial pacemaker. The drug is not removed by hemodialysis and peritoneal dialysis.

Drug Interactions

With simultaneous use of Fosinotec H with potassium preparations, potassium-sparing diuretics (spironolactone, amiloride, triamterene), the risk of hyperkalemia increases. Control of serum potassium levels is necessary (once every 2-3 weeks).

Other antihypertensive agents, diuretic agents, narcotic analgesics, and general anesthetics used simultaneously enhance the antihypertensive effect of Fosinotec H.

Fosinotec H, when used simultaneously, enhances the hypoglycemic effect of sulfonylurea derivatives and insulin.

With simultaneous use of Fosinotec H with allopurinol, cytotoxic agents, immunosuppressants, procainamide, the risk of leukopenia increases.

Non-steroidal anti-inflammatory drugs reduce the severity of the antihypertensive effect of Fosinotec H.

With simultaneous intake of Fosinotec H with lithium salts, an increase in serum lithium levels and the risk of lithium toxicity is possible. With simultaneous use with Fosinotec H, an increase in the doses of probenecid or sulfinpyrazone used to treat gout may be required, since Hydrochlorothiazide can increase the concentration of uric acid in the blood. Antacid agents (aluminum or magnesium hydroxide), simethicone may reduce the absorption of Fosinotec H. These drugs should be taken at least 2 hours apart.

Colestyramine resin and colestipol may reduce the absorption of hydrochlorothiazide. Fosinotec H should be taken at least 1 hour before or 4-6 hours after taking these agents.

Hydrochlorothiazide may increase serum calcium ion levels by reducing its excretion from the body. When used concomitantly with Fosinotec H, a reduction in the dose of calcium supplements may be required.

The bioavailability of the drug does not change when used concomitantly with chlorthalidone, nifedipine, propranolol, cimetidine, metoclopramide, propantheline bromide, digoxin, acetylsalicylic acid, and warfarin. The absorption of hydrochlorothiazide is increased when taken concomitantly with drugs that reduce gastrointestinal motility.

Storage Conditions

Store in a dry place at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

The shelf life is 2 years.

Dispensing Status

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.