Spironolactone-darnitsa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SPIRONOLACTONE-DARNITSA (SPIRONOLACTONE-DARNITSA)

Composition:

Active substance: spironolactone;

1 tablet contains spironolactone 25 mg;

Excipients: potato starch, lactose monohydrate, povidone, calcium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: flat cylindrical tablets with a bevel, white or white with a creamy shade.

Pharmacotherapeutic group. Potassium-sparing diuretics. Aldosterone antagonists. Spironolactone. ATC code C03DA01.

Pharmacological properties.

Pharmacodynamics.

The active ingredient of the medicinal product – spironolactone – is a competitive antagonist of aldosterone that acts on the distal renal tubules. By blocking aldosterone, it inhibits retention of water and Na+ ions and promotes retention of K+ ions, thereby not only increasing excretion of Na+ and Cl− ions and reducing excretion of K+ ions in urine, but also decreasing excretion of H+ ions. As a result, the diuretic effect also has antihypertensive action.

Pharmacokinetics.

After oral administration, the medicinal product is rapidly and completely absorbed from the gastrointestinal tract. Bioavailability is 92–99%, and it may slightly increase when taken with food.

Maximum concentration of spironolactone in blood plasma is observed within 2.6 hours and amounts to 80 ng/ml. Protein binding in plasma is about 90%. The elimination half-life is 1.3 hours.

Spironolactone is metabolized in the liver. Its active metabolites are 7α-thiomethylspironolactone and canrenone. Canrenone is responsible for the anti-aldosterone effect and accounts for approximately 50% of all spironolactone metabolites. Peak plasma concentration and time to reach it are as follows: for 7α-thiomethylspironolactone – 391 ng/ml and 3.2 hours; for canrenone – 181 ng/ml and 4.3 hours. The respective elimination half-lives are 13.8 hours and 16.5 hours. Spironolactone and its metabolites cross the placenta and are excreted into breast milk.

Excretion from the body occurs predominantly via renal excretion of metabolites, with a small portion excreted in feces. Spironolactone is characterized by a cumulative effect.

Clinical characteristics.

Indications.

• Primary hyperaldosteronism.
• Congestive heart failure when other diuretics are ineffective or not tolerated, or when it is necessary to enhance their efficacy.
• Essential arterial hypertension, particularly in the presence of hypokalemia, usually in combination with other antihypertensive drugs.
• Liver cirrhosis associated with edema and/or ascites.
• Edema due to nephrotic syndrome.
• Hypokalemia – when alternative therapies cannot be used.
• Prevention of hypokalemia in patients receiving cardiac glycosides, when other treatment options are considered inappropriate or unsuitable.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients.
• Acute renal failure, severe impairment of renal excretory function (glomerular filtration rate < 10 mL/min), anuria.
• Hyperkalemia, hyponatremia.
• Addison's disease.
• Concomitant use with potassium-sparing diuretics and potassium supplements due to the risk of developing hyperkalemia.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of spironolactone with other medicinal products may result in:

with antihypertensive agents (especially ganglion blockers, nicardipine, nimodipine) – excessive reduction in blood pressure; when used concomitantly, the dose of antihypertensive agents should be reduced, with subsequent dose adjustment if necessary. Since angiotensin-converting enzyme (ACE) inhibitors reduce aldosterone production, medicinal products of this class should not be used in combination with spironolactone on a long-term basis, especially in patients with impaired renal function;

with ammonium chloride, cholestyramine – increased risk of developing hyperkalemia and hyperchloremic metabolic acidosis;

with potassium-sparing diuretics, potassium supplements, ACE inhibitors, angiotensin II receptor blockers, aldosterone receptor blockers, anticholinesterase agents, tacrolimus, cyclosporine – increased risk of developing hyperkalemia; concomitant use with potassium-sparing diuretics and potassium supplements is contraindicated due to the risk of hyperkalemia;

with other diuretics – enhanced diuretic effect;

with nonsteroidal anti-inflammatory drugs (NSAIDs) – increased risk of hyperkalemia and renal failure, accompanied by reduced diuretic, natriuretic, and antihypertensive effects of spironolactone; when used concomitantly with acetylsalicylic acid, prostaglandin synthesis is also inhibited, and with antipyrine – its hepatic metabolism is enhanced;

with glucocorticoids, adrenocorticotropic hormone (ACTH) – enhanced diuretic and natriuretic effects of spironolactone and paradoxical increase in potassium excretion;

with α- and β-adrenomimetics, carbenoxolone – reduced effect of spironolactone;

with antipsychotics, tricyclic antidepressants – enhanced effect of spironolactone;

with barbiturates, narcotic drugs, ethanol – occurrence of orthostatic hypotension;

with terfenadine – increased risk of ventricular arrhythmia due to hypokalemia and imbalance of other electrolytes;

with carbamazepine – increased risk of hyponatremia;

with digoxin – increased risk of glycoside intoxication due to prolonged elimination half-life;

with lithium preparations – increased risk of lithium intoxication due to reduced renal clearance of lithium; these medicinal products should not be used concomitantly;

with indirect anticoagulants (coumarin derivatives), mitotane, pressor amines (epinephrine), cardiac glycosides – reduced effect of the latter;

with heparin, low-molecular-weight heparin – development of severe hyperkalemia;

with triptorelin, buserelin, gonadorelin – enhanced effect of the latter;

with the combination trimethoprim/sulfamethoxazole (antibiotic, so-called co-trimoxazole) – development of clinically significant hyperkalemia;

with immunosuppressants, cyclosporine, and tacrolimus – increased risk of hyperkalemia induced by spironolactone;

with cholestyramine, ammonium chloride – increased risk of hyperkalemia and hyperchloremic metabolic acidosis;

with nitroglycerin, other nitrates, or vasodilators – enhanced antihypertensive effect of spironolactone;

with pressor amines (norepinephrine) – reduced vascular response to norepinephrine. Therefore, caution should be exercised during local or general anesthesia in patients taking spironolactone;

with antipyrine – accelerated metabolism of antipyrine;

with carbenoxolone – sodium retention and, consequently, reduced efficacy of spironolactone. Concomitant use of carbenoxolone and spironolactone should be avoided;

with abiraterone – when used concomitantly, spironolactone binds to the androgen receptor, potentially increasing prostate-specific antigen (PSA) levels in patients with prostate cancer receiving abiraterone. Concomitant use with abiraterone is not recommended;

with aliskiren – reduces plasma concentration of furosemide when administered orally. Reduced furosemide effect may occur in patients receiving both aliskiren and oral furosemide; therefore, monitoring for reduced diuretic effect is recommended, with appropriate dose adjustments.

Spironolactone may enhance the effect of GnRH (gonadotropin-releasing hormone) analogs: triptorelin, buserelin, gonadorelin.

Special precautions for use.

Administration of the medicinal product, especially in patients with impaired renal function, may cause transient increases in plasma blood urea nitrogen levels and hyperkalemia, which can lead to cardiac arrhythmias and reversible hyperchloremic metabolic acidosis. The medicinal product should be used with caution in patients with impaired renal or hepatic function and in elderly patients. Periodic monitoring of plasma electrolyte levels and renal function parameters is recommended. If hyperkalemia develops, spironolactone therapy should be discontinued.

The medicinal product should be used with caution in patients who have conditions that may predispose to the development of acidosis and/or hyperkalemia.

Concomitant use of spironolactone with medicinal products that induce hyperkalemia (e.g., other potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, aldosterone antagonists, heparin, low-molecular-weight heparin, potassium supplements, potassium-rich diet, or use of potassium-containing salt substitutes) may lead to severe hyperkalemia.

Hyperkalemia may result in fatal outcomes. Careful monitoring and correction of potassium levels are critically important in patients with severe heart failure receiving spironolactone. The medicinal product should not be used concomitantly with other potassium-sparing diuretics. Potassium supplements are contraindicated in patients with serum potassium levels above 3.5 mEq/L. Recommended frequency for monitoring serum potassium and creatinine levels is one week after initiation or dose increase of spironolactone, monthly for the first 3 months, then quarterly for one year, and thereafter every 6 months. If serum potassium exceeds 5 mEq/L or serum creatinine exceeds 4 mg/dL, spironolactone should be temporarily or permanently discontinued.

The medicinal product should be used with caution in patients with diabetes mellitus, particularly in the presence of diabetic nephropathy.

Spironolactone therapy may interfere with the measurement of cortisol, epinephrine, and digoxin concentrations (using radioimmunoassay methods).

Prolonged, unjustified use of the medicinal product should be avoided, as studies in animals receiving maximum doses of spironolactone have shown an increased risk of developing carcinoma and myeloid leukemia.

Alcoholic beverages are contraindicated during treatment with this medicinal product.

Spironolactone-Darnytsia contains lactose; therefore, the medicinal product is contraindicated in patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Spironolactone should be used with particular caution in patients with porphyria, as many medicinal products may provoke porphyria exacerbations.

Use during pregnancy or breastfeeding.

The medicinal product is contraindicated during pregnancy and breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

During the initial period of treatment, the duration of which is individual, driving or operating machinery is contraindicated.

Dosage and Administration.

The medicinal product should be administered orally to adults and children. The daily dose should be taken once or twice after meals. Administration of the daily dose as a single dose or the first dose of the medicinal product in case of twice-daily administration is recommended in the morning.

The duration of treatment is individual and may last several years in some cases. It is necessary to use the medicinal product at the lowest effective daily dose with continuous monitoring of serum electrolyte levels and kidney function parameters.

Adults.

Primary hyperaldosteronism.

For preoperative preparation, the medicinal product should be administered at a dose of 100–400 mg per day.

If surgical treatment is not possible, spironolactone may be used long-term as maintenance therapy at the lowest effective dose, which is determined individually.

In this case, the initial dose may be reduced every 14 days until the minimum effective dose is achieved. During long-term treatment, it is recommended to use the medicinal product in combination with other diuretics to reduce adverse effects.

Congestive heart failure, edema due to nephrotic syndrome.

The medicinal product should be administered at an initial dose of 100 mg per day in one or two doses. The daily dose may also range from 25 to 200 mg.

If higher doses are prescribed, the medicinal product may be used in combination with other diuretics acting in more proximal segments of renal tubules. In this case, the dose of spironolactone should be adjusted accordingly.

Essential arterial hypertension.

The medicinal product should be administered at an initial dose of 50–100 mg per day in one or two doses in combination with other antihypertensive medicinal products. Treatment should continue for at least 2 weeks, as maximum antihypertensive effect is achieved by the end of this period. Further dose adjustment is individual, depending on the effect achieved.

Cirrhosis of the liver accompanied by edema or ascites.

If the urinary Na+/K+ ratio is greater than 1, the medicinal product should be administered at an initial dose of 100 mg per day. The maximum daily dose is 100 mg/day. If this ratio is less than 1, the medicinal product should be administered at a dose of 200 mg per day, with a maximum daily dose of 400 mg/day.

Hypokalemia.

The medicinal product should be administered at a dose of 25–100 mg per day to patients who do not respond adequately to dietary potassium supplements or other potassium-replacement therapies.

Children.

The medicinal product should be administered at a dose of 1–3 mg/kg body weight per day in one or two doses. For maintenance therapy in combination with other diuretics, the daily dose is 1–2 mg/kg body weight.

If necessary, for administration to children under 3 years of age, the tablet should be crushed, dissolved, and given to the child as a suspension.

Elderly patients.

The medicinal product is recommended to be administered at lower doses, with gradual increase until maximum effect is achieved. It should be taken into account that this patient group may have hepatic and renal impairments that can affect the metabolism and elimination of the medicinal product.

Children.

The medicinal product is used in pediatric practice as prescribed by a physician.

Overdose.

Symptoms: drowsiness/laziness, confusion, electrolyte disturbances.

Treatment: symptomatic therapy. Maintain water-electrolyte and acid-base balance; use potassium-wasting diuretics, administer intravenous glucose with insulin; in severe cases – perform hemodialysis. There is no specific antidote.

Adverse reactions.

Cardiovascular system: arterial hypotension, arrhythmia (in patients with renal insufficiency and those receiving potassium preparations), vasculitis.

Blood and lymphatic system: leukopenia (including agranulocytosis), thrombocytopenia, megaloblastic or aplastic anemia, eosinophilia.

Nervous system and psyche: headache, drowsiness, dizziness, ataxia, paralysis, paraplegia, lethargy, mental depression, confusion.

Respiratory system, thoracic organs and mediastinum: voice hoarseness.

Gastrointestinal tract: nausea, vomiting, decreased appetite, abdominal and stomach pain, diarrhea, constipation, intestinal colic, gastritis, gastric and duodenal ulcer, gastrointestinal bleeding.

Hepatobiliary system: hepatitis, liver function abnormalities.

Urinary system: acute renal failure.

Musculoskeletal system and connective tissue: osteomalacia, muscle spasm, leg muscle cramps.

Metabolism and nutrition: hyperkalemia, hyponatremia, hypercreatininemia, increased plasma urea levels, hyperuricemia, porphyria, metabolic hyperchloremic acidosis or alkalosis, dehydration.

Endocrine system: hirsutism.

Reproductive system and mammary glands: decreased libido, erectile dysfunction, gynecomastia, menstrual cycle disorders, dysmenorrhea, amenorrhea, postmenopausal metrorrhagia, breast swelling and pain in women, infertility (when using high doses – 450 mg per day), benign mammary gland tumors.

Immune system, skin and subcutaneous tissue: hypersensitivity reactions, including rash, pruritus, urticaria, drug fever; hypertrichosis, alopecia, lupus-like syndrome, erythema, annular erythema, eczema, Stevens-Johnson syndrome.

General: asthenia, increased fatigue.

Shelf life.

3 years.

Storage conditions.

Store in original packaging at temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 tablets in a blister pack; 3 blisters per carton.

Prescription category.

Prescription only.

Manufacturer.

JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's location and address of business activity.

13 Boryspylska Street, Kyiv, 02093, Ukraine.