Veroshpiron

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VERO-SPIRON (VEROSPIRON)

Composition:

Active substance: spironolactone;

1 capsule contains 50 mg or 100 mg of spironolactone;

Excipients:

Excipients in the capsule content:

sodium lauryl sulfate; magnesium stearate; maize starch; lactose monohydrate;

Hard gelatin capsules 50 mg:

capsule shell upper part: quinoline yellow (E 104), titanium dioxide (E 171), gelatin;
lower part: titanium dioxide (E 171), gelatin;

Hard gelatin capsules 100 mg:

capsule shell upper part: yellow sunset FCF (E 110), titanium dioxide (E 171), gelatin;
lower part: yellow sunset FCF (E 110), titanium dioxide (E 171), quinoline yellow (E 104), gelatin.

Pharmaceutical form. Capsules.

Main physicochemical properties:

Capsule 50 mg:

capsule content: fine-grained granulated powder-like mixture, white in color;

capsule: hard gelatin capsule size № 3; upper part: opaque, yellow; lower part: opaque, white.

Capsule 100 mg:

capsule content: fine-grained granulated powder-like mixture, white in color;

capsule: hard gelatin capsule size № 0; upper part: opaque, orange; lower part: opaque, yellow.

Pharmacotherapeutic group. Potassium-sparing diuretics, aldosterone antagonists. Spironolactone. ATC code C03D A01.

Pharmacological Properties

Pharmacodynamics

Spironolactone is a competitive antagonist of aldosterone. It acts on the distal renal tubules.

By blocking aldosterone, it inhibits water and Na+ retention and promotes K+ retention, which not only increases the excretion of Na+ and Cl− but also reduces K+ excretion in urine, as well as decreases H+ excretion. As a result, the diuretic effect also has antihypertensive activity.

RALES Study

Randomized Aldactone Evaluation Study (RALES) was a double-blind, multicenter trial involving 1663 patients with an ejection fraction of ≤35% and documented heart failure within 6 months prior to enrollment, classified as NYHA class IV, and who had heart failure classified as NYHA class III–IV at the time of randomization. All patients were receiving loop diuretics, 97% were receiving ACE inhibitors, and 78% were receiving digoxin (beta-blockers were not widely used at the time of the study; only 15% of patients received beta-blockers). Patients with baseline serum creatinine concentration >2.5 mg/dL or baseline serum potassium >5.0 mEq/L were excluded from the study. Patients who developed a 25% increase in serum potassium compared to baseline were also excluded during the study. Patients were randomized in a 1:1 ratio to receive either spironolactone 25 mg once daily or placebo. For patients who tolerated the 25 mg daily dose well, the dose could be increased to 50 mg daily based on clinical judgment. For patients who did not tolerate the 25 mg daily dose, the dose of spironolactone was reduced to 25 mg every other day. The primary endpoint in the RALES study was death from any cause. The RALES study was terminated early after a median follow-up of 24 months because an interim analysis revealed a significant reduction in mortality in the group receiving spironolactone. Spironolactone reduced the risk of death by 30% compared to placebo (p <0.001; 95% confidence interval from 18% to 40%). Additionally, spironolactone significantly reduced the risk of cardiac death, primarily sudden cardiac death and death due to progression of heart failure, as well as the risk of hospitalization for cardiac causes. Improvements in NYHA functional class were more favorable in the spironolactone group. Gynecomastia and breast pain occurred in 10% of men receiving spironolactone compared to 1% in the placebo group (p <0.001). The incidence of severe hyperkalemia was similarly low in both patient groups.

Pharmacokinetics

Spironolactone is rapidly and completely absorbed from the gastrointestinal tract. It is highly bound to plasma proteins (approximately 90%). Spironolactone undergoes rapid metabolism. Its active metabolites are 7α-thiomethylspironolactone and canrenone. Although the elimination half-life of spironolactone itself is short (1.3 hours), the half-lives of its active metabolites are longer (ranging from 2.8 to 11.2 hours). The metabolites are primarily excreted in urine; a small portion is excreted in feces. Spironolactone and its metabolites cross the placenta and are excreted in breast milk.

After administration of 100 mg spironolactone daily for 15 days to healthy volunteers in a non-fasting state, the time to reach peak plasma concentration (tmax), peak plasma concentration (Cmax), and elimination half-life (t1/2) of spironolactone were 2.6 hours, 80 ng/mL, and approximately 1.4 hours, respectively. For 7α-thiomethylspironolactone and canrenone, these values were 3.2 and 4.3 hours; 391 and 181 ng/mL; and 13.8 and 16.5 hours, respectively.

The renal effect of a single dose of spironolactone peaks at 7 hours and persists for at least 24 hours.

Clinical characteristics.

Indications.

• Congestive heart failure, in cases where the patient does not respond to treatment with other diuretics or when potentiation of their effects is required.
• Essential arterial hypertension, primarily in cases of hypokalemia, usually in combination with other antihypertensive agents.
• Liver cirrhosis associated with edema and/or ascites.
• Primary hyperaldosteronism.
• Edema due to nephrotic syndrome.
• Hypokalemia, in cases where alternative therapy is not feasible.
• For prevention of hypokalemia in patients receiving cardiac glycosides, when other approaches are considered inappropriate or unsuitable.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients.
• Anuria.
• Acute renal failure.
• Severe impairment of kidney function (glomerular filtration rate <10 mL/min).
• Heart failure, if glomerular filtration rate is less than 30 mL/min or serum creatinine concentration exceeds 220 µmol/L.
• Hyperkalemia.
• Hyponatremia.
• Addison's disease.
• Concomitant use of eplerenone or other potassium-sparing diuretics.
• Pregnancy or breastfeeding.

Interaction with other medicinal products and other forms of interaction.

Concomitant administration of Veroshpiron with: other potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, aldosterone blockers, potassium supplements, as well as adherence to a potassium-rich diet or use of potassium-containing salt substitutes, may lead to the development of severe hyperkalemia.

In addition to medicinal products that definitively cause hyperkalemia, concomitant use of the trimethoprim/sulfamethoxazole combination (an antibiotic, so-called co-trimoxazole) with spironolactone may result in clinically significant hyperkalemia.

Administration with other diuretics enhances diuresis.

Immunosuppressants, cyclosporine, and tacrolimus may increase the risk of hyperkalemia induced by spironolactone.

Cholestyramine, ammonium chloride may also increase the risk of hyperkalemia and hyperchloremic metabolic acidosis.

Tricyclic antidepressants and antipsychotic drugs may enhance the antihypertensive effect of spironolactone.

Antihypertensive agents: spironolactone enhances the effect of antihypertensive drugs; therefore, their dosage may need to be reduced and subsequently adjusted as necessary when used concomitantly with spironolactone. Since ACE inhibitors reduce aldosterone production, these agents should not be used concomitantly with spironolactone on a long-term basis, especially in patients with established renal impairment.

Concomitant administration with nitroglycerin, other nitrates, or vasodilators may enhance the antihypertensive effect of spironolactone.

Alcohol, barbiturates, or narcotic drugs may potentiate spironolactone-related orthostatic hypotension.

Pressor amines (norepinephrine): spironolactone reduces vascular responses to norepinephrine. Therefore, caution should be exercised during local or general anesthesia in patients receiving spironolactone.

Nonsteroidal anti-inflammatory drugs (NSAIDs): in some patients, the use of nonsteroidal anti-inflammatory agents may reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics. Concomitant use of nonsteroidal anti-inflammatory drugs (e.g., acetylsalicylic acid, indomethacin, mefenamic acid) with potassium-sparing diuretics may lead to the development of severe hyperkalemia. Thus, careful monitoring of the patient is required when spironolactone is used concomitantly with NSAIDs to ensure the desired diuretic effect is achieved.

Glucocorticoids, adrenocorticotropic hormone (ACTH): may increase the rate of electrolyte excretion, particularly possibly leading to hypokalemia.

Digoxin: spironolactone may increase the half-life of digoxin, which may result in elevated serum digoxin concentrations and, consequently, increased toxicity. Dose reduction of digoxin may be necessary when spironolactone is administered. Close monitoring of the patient is required to prevent digoxin overdose or inadequate digitalization.

Effect of the drug on laboratory test results: several cases have been reported in the literature where spironolactone or its metabolites interfere with digoxin concentration measurements by radioimmunoassay. The clinical significance of this interaction is currently unclear.

In fluorometric analysis, spironolactone may interfere with the measurement of compounds with similar fluorescence parameters (e.g., cortisol, epinephrine).

Spironolactone binds to the androgen receptor and may increase prostate-specific antigen (PSA) levels in patients with prostate cancer receiving abiraterone. Concomitant use with abiraterone is not recommended.

Antipyrine: spironolactone accelerates antipyrine metabolism.

Lithium preparations: lithium preparations should generally not be used concomitantly with diuretics. Diuretics reduce renal clearance of lithium and increase the risk of lithium toxicity.

Carbenoxolone may cause sodium retention and, as a consequence, reduce the effectiveness of spironolactone. Concomitant use of carbenoxolone and spironolactone should be avoided.

Carbamazepine, when used concomitantly with diuretics, may cause clinically significant hyponatremia.

Heparin, low-molecular-weight heparin: concomitant use with spironolactone may lead to severe hyperkalemia.

Coumarin derivatives: the drug reduces the effectiveness of this group of agents.

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

Mitotane. Spironolactone may reduce plasma mitotane levels in patients with adrenocortical carcinoma receiving mitotane; therefore, it should not be used concomitantly with mitotane.

Special precautions for use.

• Spironolactone should be used with particular caution in patients whose underlying disease may provoke the development of acidosis and/or hyperkalemia.
• Patients with diabetic nephropathy have an increased risk of developing hyperkalemia.
• Administration of spironolactone may cause a transient increase in blood urea nitrogen (BUN), particularly in the presence of impaired renal function and hyperkalemia. Spironolactone may cause reversible hyperchloremic metabolic acidosis. Therefore, when administering the drug to patients with impaired renal or hepatic function, as well as in elderly patients, regular monitoring of serum electrolytes and renal function is required.
• Concomitant use of spironolactone with agents that may cause hyperkalemia (e.g., other potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, aldosterone blockers, heparin, low-molecular-weight heparin, potassium supplements, potassium-rich diet, potassium-containing salt substitutes) may lead to the development of severe hyperkalemia.
• Hyperkalemia may result in death. It is critically important to monitor and correct potassium levels in patients with severe heart failure receiving spironolactone. The drug 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 monitoring frequency for potassium and creatinine is: one week after initiation of spironolactone or dose increase, monthly during the first 3 months, then quarterly for one year, and thereafter every 6 months. If serum potassium exceeds 5 mEq/L or creatinine exceeds 4 mg/dL, spironolactone should be temporarily or permanently discontinued (see section "Dosage and administration").
• Verospiron should be used with particular caution in patients with porphyria, as many drugs may provoke porphyria exacerbation.
• Consumption of alcohol is prohibited during treatment with this drug.
• In patients with lactose intolerance, it should be noted that each 50 mg capsule contains 127.5 mg of lactose monohydrate, and each 100 mg capsule contains 255.0 mg of lactose monohydrate. This medicinal product should not be used in patients with rare hereditary conditions such as galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption syndrome.
• This medicinal product contains less than 1 mmol (23 mg) of sodium per capsule, i.e., it is practically sodium-free.
• Verospiron 100 mg capsules contain the colorant "Yellow Sunset" FCF (E 110), which may cause allergic reactions.

Use during pregnancy or breastfeeding.

Pregnancy

Spironolactone exhibits antiandrogenic effects in humans and therefore should not be used during pregnancy (see section "Contraindications"). Spironolactone and its metabolites cross the placental barrier. In pregnant rats treated with spironolactone, feminization of male fetuses was observed, and endocrine disturbances were noted in offspring of both sexes after birth.

Breastfeeding

Spironolactone metabolites have been detected in breast milk. If spironolactone therapy is required, breastfeeding should be discontinued.

Ability to influence reaction rate while driving or operating machinery.

During the initial period of treatment, the duration of which is individual, driving vehicles and operating machinery, particularly those associated with a high risk of injury, is prohibited.

Subsequently, restrictions should be determined individually for each patient.

Method of Administration and Dosage

Dosage Regimens

Adults

Primary Hyperaldosteronism

For diagnostic purposes

Prolonged test: spironolactone is administered at a dose of 400 mg/day for 3–4 weeks. Correction of hypokalemia and arterial hypertension during this period suggests the presence of primary hyperaldosteronism.

Short test: spironolactone is taken at a dose of 400 mg/day for 4 days. An increase in serum potassium levels during drug administration and a subsequent decrease after discontinuation suggest the presence of primary hyperaldosteronism.

Treatment

Prior to surgical treatment, spironolactone is administered in doses ranging from 100 to 400 mg/day. In patients not scheduled for surgery, the drug may be used as long-term maintenance therapy at the lowest effective dose, which should be individually determined. In such cases, the initial dose may be gradually reduced every 14 days until the minimum effective dose is reached. To reduce the severity of adverse effects during prolonged use of Verospiron, it is recommended to use it in combination with other diuretics.

Edema associated with congestive heart failure or nephrotic syndrome

The initial daily dose is 100 mg and may range from 25* to 200 mg/day, administered once or twice daily.

When higher doses are required, Verospiron may be used in combination with other classes of diuretics acting in more proximal segments of renal tubules. In such cases, the dosage of Verospiron should be adjusted accordingly.

Adjunctive therapy in the treatment of severe heart failure (NYHA class III–IV with ejection fraction ≤35%)

Based on results from randomized trials of aldactone use (RALES: see section "Pharmacodynamics"), if serum potassium does not exceed 5.0 mEq/L and serum creatinine concentration does not exceed 2.5 mg/dL, the initial dose of spironolactone should be 25* mg/day in addition to standard baseline therapy. In patients who tolerate the drug well at a dose of 25 mg/day, the dose may be increased to 50 mg/day based on clinical indications. For patients who do not tolerate the 25 mg/day dose, the dose may be reduced to 25* mg every other day (see section "Special Instructions").

Adjunctive therapy in the treatment of arterial hypertension when previously used antihypertensive drugs are insufficiently effective

The initial dose of spironolactone used concomitantly with other antihypertensive agents is 25* mg/day. If target blood pressure levels are not achieved after 4 weeks, the dose may be doubled. In patients with arterial hypertension receiving drugs that may cause hyperkalemia (e.g., ACE inhibitors or angiotensin receptor blockers), serum potassium and creatinine levels should be assessed before initiating spironolactone. Verospiron should not be used in patients with serum potassium exceeding 5.0 mmol/L or serum creatinine concentration exceeding 2.5 mg/dL. Serum potassium and creatinine levels should be closely monitored for 3 months after starting spironolactone.

Ascites and edema due to liver cirrhosis

If the urinary Na+/K+ ratio is greater than 1, the daily dose is 100 mg. If this ratio is less than 1, the daily dose should range from 200 to 400 mg/day.

Maintenance dose should be individually determined.

Hypokalemia

The drug is prescribed at a dose of 25*–100 mg/day when potassium supplements or other potassium-sparing measures are insufficient.

Children

The initial daily dose is 1–3 mg/kg body weight, administered as a single dose or in 2–4 divided doses. For maintenance therapy or when used concomitantly with other diuretics, the dose of Verospiron should be reduced to 1–2 mg/kg body weight. Capsule form is suitable for children aged 5 years and older who are able to swallow capsules. If use in children under 5 years is necessary, the tablet form should be used. The 25 mg Verospiron tablet should be crushed, dissolved, and administered as a suspension.

Elderly Patients

Treatment should be initiated with lower doses, gradually increasing until maximum effect is achieved. It should be noted that elderly individuals may have hepatic and renal impairments affecting drug metabolism and excretion.

Additionally, when administering the drug to elderly patients, the risk of hyperkalemia should be considered (see section "Special Instructions").

*When the single dose is 25 mg, Verospiron 25 mg tablets are recommended.

Method of Administration

Spironolactone is generally taken after meals, once or twice daily. It is recommended to take the daily dose or the first part of the daily dose in the morning.

Children

To be used in children aged 5 years and older as prescribed by a physician.

Overdose.

Symptoms

Spironolactone overdose may cause conditions and symptoms consistent with adverse reactions observed during its use (e.g., drowsiness, confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, diarrhea). In some cases, hyponatremia or hyperkalemia may occur, particularly in patients with impaired renal function; in patients with severe liver disease, overdose may lead to hepatic coma.

Treatment is symptomatic; there is no specific antidote. Water-electrolyte and acid-base balance should be maintained by administering potassium-wasting diuretics; intravenous glucose with insulin may be given, and in severe cases, hemodialysis may be performed.

Adverse reactions.

Adverse reactions are the result of competitive antagonism of aldosterone, which increases potassium excretion, and the antiandrogenic effect of spironolactone.

Adverse reactions are listed by system organ classes according to the Medical Dictionary for Regulatory Activities (MedDRA), using MedDRA frequency definitions: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000), and frequency not known (cannot be estimated from the available data).

1In patients with renal insufficiency and in patients who are concurrently receiving potassium-containing medications.

2In elderly patients, in patients with diabetes mellitus, and in patients who are concurrently receiving ACE inhibitors.

3In patients with hepatic cirrhosis.

4In patients with renal insufficiency and in patients receiving potassium supplements concurrently with spironolactone.

5When the drug is used in high doses (450 mg/day).

6Generally, with prolonged use.

Adverse effects usually resolve after discontinuation of spironolactone.

Reporting of suspected adverse reactions

Reporting adverse reactions following drug registration is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of drug efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua/.

Shelf life. 5 years.

Storage conditions. Store in a place inaccessible to children.

Store at a temperature not exceeding 30 °C.

Packaging.

10 capsules in a blister pack, 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Gedeon Richter Plc., Hungary.

Manufacturer's address and location of its business operations.

H-1103 Budapest, Demrédi street 19-21, Hungary.