Veroshpiron capsules 100 mg No. 30

Instructions for Veroshpiron capsules 100 mg No. 30

Composition

active ingredient: spironolactone;

1 capsule contains 50 mg or 100 mg of spironolactone;

excipients:

Excipients of the capsule contents:

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

hard gelatin capsules 50 mg:

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

hard gelatin capsules 100 mg:

upper part of the capsule: sunset yellow FCF (E 110), titanium dioxide (E 171), gelatin;

lower part of the capsule: sunset yellow FCF (E 110), titanium dioxide (E 171), quinoline yellow (E 104), gelatin.

Dosage form

Capsules.

Main physicochemical properties:

Capsule 50 mg:

capsule contents: fine-grained, granulated powdery mixture of white color;

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

Capsule 100 mg:

capsule contents: fine-grained, granulated powdery mixture of white color;

capsule: hard gelatin, size No. 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 aldosterone antagonist. It acts on the distal tubules of the kidneys.

By blocking aldosterone, it suppresses water and Na+ retention and promotes K+ retention, which not only increases Na+ and Cl− excretion and reduces K+ excretion in the urine, but also reduces H+ excretion. As a result, the diuretic effect also has a hypotensive effect.

RALES study

The Randomized Aldactone Use Study (RALES) was a double-blind, multicenter study conducted in 1663 patients with an ejection fraction of 35% or less, with NYHA class IV heart failure diagnosed within 6 months prior to enrollment, and who had class III–IV heart failure at the time of randomization. All patients were taking loop diuretics, 97% of patients were taking an ACE inhibitor, and 78% were taking digoxin (beta-blockers were not widely available at the time of the study, with only 15% of patients receiving beta-blockers). Patients with a baseline serum creatinine increase of more than 2.5 mg/dL or a baseline serum potassium increase of more than 5.0 mEq/L were excluded. Patients with a serum potassium increase of more than 25% from baseline were also excluded. Patients were randomized 1:1 to spironolactone 25 mg once daily or placebo. Patients who tolerated 25 mg/day had their dose increased to 50 mg/day as clinically indicated. Patients who did not tolerate 25 mg/day had their dose reduced to 25 mg every other day. The primary endpoint in RALES was all-cause death. After a median follow-up of 24 months, RALES was terminated early because a planned interim analysis showed a significant reduction in mortality in the spironolactone group. Spironolactone reduced the risk of death by 30% compared with placebo (p < 0.001; 95% confidence interval 18% to 40%). In addition, spironolactone significantly reduced the risk of cardiac death, primarily sudden cardiac death and death from progressive heart failure, and the risk of hospitalization for cardiac disease. NYHA stage changes were more favorable in the spironolactone group. Gynecomastia and chest pain were observed in 10% of men receiving spironolactone compared with 1% of men in the placebo group (p < 0.001). The incidence of severe hyperkalemia was equally low in both groups of patients.

Pharmacokinetics

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

After administration of 100 mg of spironolactone daily for 15 days to healthy volunteers in the fed state, the time to peak plasma concentration (tmax), peak plasma concentration (Cmax) and 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, 13.8 and 16.5 hours, respectively.

The renal effects of a single dose of spironolactone peak at 7 hours and persist for at least 24 hours.

Indication

Congestive heart failure, in cases where the patient does not respond to treatment with other diuretics or there is a need to potentiate their effects.

Essential hypertension, mainly in cases of hypokalemia, usually in combination with other antihypertensive drugs.

Cirrhosis of the liver accompanied by edema and/or ascites.

Primary hyperaldosteronism.

Edema caused by nephrotic syndrome.

Hypokalemia, in cases where other therapy is not possible.

For the prevention of hypokalemia in patients receiving cardiac glycosides, in cases where other approaches are considered impractical or inappropriate.

Contraindication

Hypersensitivity to the active substance or to any of the excipients.

Anury.

Acute renal failure.

Severe renal impairment (glomerular filtration rate <10 ml/min).

Heart failure if the glomerular filtration rate is less than 30 ml/min or the serum creatinine concentration is more than 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 types of interactions

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

In addition to drugs that reliably cause hyperkalemia, concomitant use of the combination of trimethoprim/sulfamethoxazole (an antibiotic called co-trimoxazole) with spironolactone may lead to clinically significant hyperkalemia.

Taking with other diuretics increases diuresis.

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

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

Tricyclic antidepressants and antipsychotics may enhance the antihypertensive effect of spironolactone.

Antihypertensives: Spironolactone enhances the effect of antihypertensive drugs, the dose of which may need to be reduced and subsequently adjusted if necessary when taken simultaneously with spironolactone. Since ACE inhibitors reduce aldosterone production, drugs of this group should not be used concomitantly with spironolactone on a regular 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 narcotics may potentiate spironolactone-associated orthostatic hypotension.

Pressor amines (norepinephrine): Spironolactone reduces vascular responses to norepinephrine. For this reason, caution should be exercised when administering local or general anesthesia to patients receiving spironolactone.

Nonsteroidal anti-inflammatory drugs (NSAIDs): In some patients, the use of nonsteroidal anti-inflammatory drugs 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, and mefenamic acid) with potassium-sparing diuretics may result in severe hyperkalemia. Therefore, when spironolactone is administered concomitantly with NSAIDs, the patient should be carefully monitored to ensure that the desired diuretic effect is achieved.

Glucocorticosteroids, adrenocorticotropic hormone (ACTH): The rate of electrolyte excretion may increase, in particular, hypokalemia is possible.

Digoxin: Spironolactone may increase the half-life of digoxin, which may lead to increased serum digoxin concentrations and, consequently, increased digoxin toxicity. A reduction in the dose of digoxin may be necessary when spironolactone is administered. The patient should be closely monitored to prevent digoxin overdose or insufficient digitalization.

Drug Interactions: Several cases of spironolactone or its metabolites affecting digoxin concentrations measured by radioimmunoassay have been reported. The clinical significance of this interaction is currently unclear.

In fluorimetric assays, spironolactone may interfere with the results of assays for compounds with similar fluorescence parameters (e.g., cortisol, epinephrine).

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

Antipyrine: Spironolactone accelerates the metabolism of antipyrine.

Carbenoxolone may cause sodium retention in the body and, as a result, reduce the effectiveness of spironolactone. The simultaneous 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 drugs.

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

Application features

Spironolactone should be used with extreme caution in patients whose underlying disease may predispose to the development of acidosis and/or hyperkalemia.

Patients with diabetic nephropathy are at increased risk of developing hyperkalemia.

Spironolactone may cause a transient increase in blood urea nitrogen (BUN), especially in the presence of renal impairment and hyperkalemia. Spironolactone may cause reversible hyperchloremic metabolic acidosis. Therefore, when using the drug in patients with renal and hepatic impairment, as well as in elderly patients, regular monitoring of serum electrolytes and renal function is necessary.

Concomitant use of spironolactone with drugs that cause hyperkalemia (e.g. other potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, aldosterone blockers, heparin, low molecular weight heparin, potassium supplements, a potassium-rich diet, use of salt substitutes containing potassium) may lead to the development of severe hyperkalemia.

Hyperkalemia can be fatal. It is critical to monitor and correct potassium levels in patients with severe heart failure receiving spironolactone. The drug should not be used with other potassium-sparing diuretics. Potassium supplements are contraindicated in patients with serum potassium levels above 3.5 mEq/L. The recommended frequency of monitoring potassium and creatinine is one week after starting or increasing the dose of spironolactone, monthly for the first 3 months, then quarterly for a year, and then every 6 months. If serum potassium levels exceed 5 mEq/L or creatinine levels exceed 4 mg/dL, spironolactone should be temporarily or permanently discontinued (see Dosage and Administration).

Patients with porphyria should use Verospiron with extreme caution, as many drugs provoke exacerbation of porphyria.

When taking the drug, drinking alcohol is prohibited.

In case of lactose intolerance, it should be taken into account that each 50 mg capsule contains 127.5 mg of lactose monohydrate and the 100 mg capsule contains 255.0 mg of lactose monohydrate. This medicine should not be used in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

This medicine contains less than 1 mmol sodium (23 mg) per capsule, i.e. essentially 'sodium-free'.

Veroshpiron capsules, 100 mg, contain the dye "sunset yellow" FCF (E 110), which may cause allergic reactions.

Use during pregnancy or breastfeeding

Pregnancy

Spironolactone has antiandrogenic effects in humans and should not be used during pregnancy (see Contraindications). Spironolactone or its metabolites cross the blood-placental barrier. Feminization of male fetuses was observed in pregnant rats treated with spironolactone, and endocrine disruption was observed in both male and female offspring after birth.

Breast-feeding

Metabolites of spironolactone have been detected in breast milk. If necessary, breastfeeding should be discontinued if spironolactone is used.

Ability to influence reaction speed when driving vehicles or other mechanisms

During the initial period of treatment, the duration of which is individual, it is forbidden to drive a car or other mechanisms, the work on which is associated with an increased risk of injury.

In the future, restrictions should be determined individually for each patient.

Method of administration and doses

Dosage regimens

Adults

Primary hyperaldosteronism

For diagnostic purposes

Long-term test: spironolactone is used at 400 mg/day for 3–4 weeks. When correction of hypokalemia and arterial hypertension is achieved, the presence of primary hyperaldosteronism can be assumed.

Short test: spironolactone is taken at 400 mg/day for 4 days. If the potassium content in the blood increases while taking Veroshpiron and decreases after its withdrawal, it can be assumed that there is primary hyperaldosteronism.

In preparation for surgical treatment, spironolactone is used in doses from 100 to 400 mg/day. For patients who are not scheduled for surgery, the drug can be used as long-term maintenance therapy in the lowest effective dose, which is determined individually. In the described situation, the initial dose can be reduced every 14 days until the minimum effective dose is reached. To reduce the severity of side effects with long-term use of the drug Veroshpiron is recommended to be used in combination with other diuretics.

Edema due to congestive heart failure or nephrotic syndrome

The initial daily dose is 100 mg and can vary from 25* to 200 mg/day, in 1 or 2 divided doses.

In case of higher doses, Verospiron can be used in combination with other groups of diuretics that act in more proximal parts of the renal tubules. In this case, the dosage of Verospiron should be adjusted.

Adjunctive therapy in the treatment of severe heart failure (New York Heart Association (NYHA) class III–IV and with an ejection fraction ≤35%)

Based on the results of randomized studies of the use of Aldactone (RALES: see the section "Pharmacodynamics"), it was established that if the serum potassium content does not exceed 5.0 mEq/L and the serum creatinine concentration does not exceed 2.5 mg/dL, the initial dose of spironolactone should be 25* mg/day on the background of basic standard therapy. In patients who tolerate the drug well at a dose of 25 mg/day, the dose can be increased to 50 mg/day according to clinical indications. In patients who do not tolerate the drug at a dose of 25 mg/day, the dose of the drug can be reduced to 25* mg once every 2 days (see the section "Special instructions for use").

Additional therapy in the treatment of arterial hypertension in case of insufficient effectiveness of previously used antihypertensive drugs

The initial dose of spironolactone when used simultaneously with other antihypertensive drugs is 25* mg/day. If after 4 weeks the blood pressure does not reach the target values, the dose of the drug can be doubled. In patients with arterial hypertension who are receiving drugs that can cause the development of hyperkalemia (for example, ACE inhibitors or angiotensin receptor blockers), the content of potassium and creatinine in the blood serum should be assessed before starting spironolactone. Veroshpiron should not be used in patients whose serum potassium content exceeds 5.0 mmol/l and the concentration of creatinine in the blood serum exceeds 2.5 mg/dl. Within 3 months after starting spironolactone, the content of potassium and creatinine in the blood should be carefully monitored.

Ascites and edema due to cirrhosis of the liver

If the ratio of Na+/K+ in the urine is more than 1, the daily dose is 100 mg. If this ratio is less than 1, the dose of the drug should be in the range from 200 to 400 mg/day.

The maintenance dose should be determined individually.

Hypokalemia

The drug is prescribed at a dose of 25*–100 mg/day if the use of potassium supplements or other potassium-sparing methods is insufficient.

Children

The initial daily dose is 1-3 mg/kg of body weight once or in 2-4 doses. When carrying out maintenance therapy or when used simultaneously with other diuretics, the dose of Veroshpiron should be reduced to 1-2 mg/kg of body weight. It is advisable to use the drug in the form of capsules for children over 5 years of age, when they can swallow the capsule. If it is necessary to use the drug for children under 5 years of age, the drug should be used in the form of tablets. A 25 mg Veroshpiron tablet should be crushed, dissolved and given to the child as a suspension.

Elderly patients

It is recommended to start treatment with lower doses and then gradually increase them until the maximum effect is achieved. It should be taken into account that elderly people may have liver and kidney disorders that affect the metabolism of the drug and its excretion.

In addition, when using the drug in elderly patients, the risk of developing hyperkalemia should be taken into account (see section "Special warnings and precautions for use").

*If the single dose is 25 mg, it is recommended to use Veroshpiron, 25 mg tablets.

Method of application

Spironolactone is usually taken after meals, once or twice a day. It is recommended that the daily dose or the first part of the daily dose be taken in the morning.

Children

Use as directed by a doctor for children over 5 years of age.

Overdose

Symptoms

Spironolactone overdose may cause conditions and symptoms that are considered adverse reactions and are observed against the background of its administration (for example, drowsiness, confusion, maculopapular or erythematous rashes, nausea, vomiting, dizziness, diarrhea). In some cases, hyponatremia or hyperkalemia is possible, especially 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 prescribing potassium-sparing diuretics; parenteral administration of glucose with insulin, and in severe cases, hemodialysis.

Side effects

Adverse reactions are listed by system organ class according to the MedDRA Medical Dictionary of Regulatory Activities using the following MedDRA frequency definitions: very common (≥ 1/10), common (≥ 1/100, <1/10), uncommon (≥ 1/1000, <1/100), rare (≥ 1/10000, <1/1000), unknown frequency (cannot be estimated from the available data).

1In patients with renal insufficiency and in patients concomitantly receiving potassium supplements.

2In elderly patients, with diabetes mellitus and in patients concomitantly taking ACE inhibitors.

3In patients with liver cirrhosis.

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

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

6Usually with prolonged use.

Usually, after stopping spironolactone, the unwanted effects disappear.

Reporting of suspected adverse reactions

Reporting adverse reactions after registration of a medicinal product is of great importance. This allows monitoring of the benefit/risk ratio when using this 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 efficacy of a medicinal product via the automated pharmacovigilance information system at the link: https://aisf.dec.gov.ua/.

Expiration date

5 years.

Storage conditions

Keep out of reach of children.

Store at a temperature not exceeding 30 °C.

Packaging

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

Vacation category

According to the recipe.

Producer

Gedeon Richter OJSC, Hungary.

Address

H-1103, Budapest, Demrei Street 19-21, Hungary.