INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Spinol-H (Spinol-H)

Composition:

Active substances: spironolactone, hydrochlorothiazide;

One film-coated tablet contains spironolactone 25 mg and hydrochlorothiazide 25 mg;

One film-coated tablet contains spironolactone 50 mg and hydrochlorothiazide 50 mg;

Excipients: lactose monohydrate; microcrystalline cellulose; corn starch; povidone K30; sodium starch glycolate; magnesium stearate; film coating: Opadry® II Orange 85F230087 [polyvinyl alcohol, polyethylene glycol, talc, yellow FCF aluminum lake (E 110), titanium dioxide (E 171), iron oxide yellow (E 172), tartrazine aluminum lake (E 102)].

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

tablets 25/25 mg: round, biconvex, film-coated tablets of orange color, with engraving "NOLX" on one side;

tablets 50/50 mg: round, biconvex, film-coated tablets of orange color, with a break line and engraving "NOLX 50" on one side.

Pharmacotherapeutic group. Combinations of diuretics with potassium-sparing agents.

ATC code C03EA01.

Pharmacological Properties

Pharmacodynamics

The medicinal product is a combination of two diuretics with different mechanisms and sites of action, providing additive diuretic and antihypertensive effects. In addition, spironolactone reduces potassium excretion from the body, which may be caused by hydrochlorothiazide administration.

The diuretic effect of spironolactone is due to its specific antagonistic action on aldosterone (a mineralocorticoid hormone of the adrenal cortex): it competitively binds to aldosterone receptors and disrupts sodium-potassium exchange in the distal convoluted tubules of the kidneys.

Hydrochlorothiazide promotes excretion of sodium and water primarily by reducing their reabsorption in the cortical diluting segment of the distal renal tubules.

Both spironolactone and hydrochlorothiazide reduce sodium content in the body, plasma volume, body weight, and arterial pressure. The diuretic and antihypertensive effects are enhanced when used concomitantly.

Spironolactone effectively reduces systolic and diastolic arterial pressure in patients with primary hyperaldosteronism. It is also effective in most cases of arterial (essential) hypertension, even when aldosterone secretion is within normal limits.

Non-melanoma skin cancer (NMSC).

Epidemiological data have shown an association between cumulative hydrochlorothiazide dose and the development of NMSC. One study included 71,533 patients with basal cell carcinoma (BCC) and 8,629 patients with squamous cell carcinoma (SCC), matched with 1,430,833 and 172,462 patients in the control group, respectively. With high-level use of hydrochlorothiazide (cumulative dose ≥ 50,000 mg), the adjusted odds ratio (OR) was 1.29 (95% CI [confidence interval]: 1.23–1.35) for BCC and 3.98 (95% CI: 3.68–4.31) for SCC. A clear dose-effect relationship for both BCC and SCC was observed. Another study demonstrated a possible link between lip cancer and hydrochlorothiazide use: 633 patients with lip cancer were identified among 63,067 patients in the control group (a risk-set sampling strategy was used). The dose-effect relationship was demonstrated by an adjusted OR of 2.1 (95% CI: 1.7–2.6). The OR increased to 3.9 (3.0–4.9) with high cumulative hydrochlorothiazide dose (~25,000 mg) and to 7.7 (5.7–10.5) with the highest cumulative dose (~100,000 mg) (see also section "Special Instructions").

Pharmacokinetics

No studies have been conducted on the pharmacokinetic parameters of spironolactone and hydrochlorothiazide when used in combination. The pharmacokinetic parameters of both agents were studied when administered separately.

The effects of hydrochlorothiazide develop on the day of administration; the maximum effect of spironolactone is observed on the third day.

Spironolactone

Absorption.

After oral administration, the extent of spironolactone absorption from the gastrointestinal tract is approximately 75%. Absolute bioavailability has not been established. After a 500 mg dose, maximum plasma concentration (C_max) was observed within 25–40 minutes.

When spironolactone is taken with food, its plasma concentration and the concentrations of its metabolites are significantly higher than when taken on an empty stomach.

Distribution.

Spironolactone and its metabolite canrenone are more than 90% bound to plasma proteins.

Metabolism.

Spironolactone is actively metabolized in the liver, resulting in several metabolites, including canrenone and 7-thiomethylspironolactone, which have pharmacological activity.

After a single oral dose, approximately 25–30% of the administered spironolactone dose is converted into canrenone, whose C_max is reached within 2–4 hours. After single-dose administration, a linear relationship is observed between spironolactone dose (ranging from 25 to 200 mg) and canrenone plasma levels.

The decline in canrenone plasma concentration is characterized by biphasic kinetics. During the first phase, lasting 3 to 12 hours, the plasma concentration of canrenone decreases more rapidly than during the second phase, which lasts from 12 to 96 hours. Data on canrenone clearance indicate that its accumulation in the body is higher with repeated administration of spironolactone at a dose of 25 mg four times daily compared to 100 mg once daily.

Excretion.

Within 6 days, 53% of the administered spironolactone dose is excreted in urine and approximately 20% in bile.

Hydrochlorothiazide

Absorption.

After oral administration, hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract. After single oral doses of 25 mg, 50 mg, 100 mg, and 200 mg, the extent of absorption ranged from 50–63% and was independent of dose. C_max is reached within 1–2 hours after administration. The onset of action occurs within 1 hour, and the duration of action is 4–5 hours. When hydrochlorothiazide is taken with food, its plasma concentration is significantly lower than when taken on an empty stomach.

Distribution.

Hydrochlorothiazide distributes into extracellular fluid and accumulates minimally in peripheral tissues, except in the kidneys. It is 40% bound to plasma proteins and accumulates in erythrocytes (the mechanism of this phenomenon is unknown). The ratio of its concentration in erythrocytes to plasma is 3.5:1. The volume of distribution of hydrochlorothiazide is approximately 3–4 L/kg.

Metabolism.

Hydrochlorothiazide undergoes minimal metabolism in the liver. A significant portion of the administered dose is excreted unchanged in urine.

Excretion.

Hydrochlorothiazide is almost completely excreted unchanged by the kidneys and appears in urine within 1 hour after administration. After oral doses of 25 mg to 65 mg, approximately 50–70% of the administered dose is excreted in urine within 24 hours. The elimination half-life is approximately 4–5 hours. When administered at doses of 12.5 mg, 25 mg, 50 mg, and 75 mg, its renal clearance ranges from 319 to 345 mL/min.

Special Patient Groups

Patients with hepatic impairment.

Pharmacokinetic studies of the spironolactone/hydrochlorothiazide combination in patients with hepatic impairment have not been conducted. The medicinal product should be used with caution in patients with mild to moderate liver dysfunction. Use of the medicinal product is contraindicated in patients with severe or progressive liver disease (see section "Contraindications").

Patients with renal impairment.

Pharmacokinetic studies of the spironolactone/hydrochlorothiazide combination in patients with renal impairment have not been conducted. Use of the medicinal product is contraindicated in patients with anuria, acute renal failure, and severe renal function impairment (see section "Contraindications").

Elderly patients.

Pharmacokinetic studies of the spironolactone/hydrochlorothiazide combination in elderly patients have not been conducted. The medicinal product should be used with caution in patients with impaired liver and/or kidney function (see sections "Contraindications" and "Special Instructions").

Children.

Pharmacokinetic studies of the spironolactone/hydrochlorothiazide combination in children have not been conducted. Safety and efficacy in children have not been established.

Clinical characteristics.

Indications.

Edema:

In congestive heart failure:

relief of edema and excess sodium in the body when other agents are insufficiently effective or not tolerated;
management of diuretic-induced hypokalemia when use of other agents is inappropriate;
in patients with congestive heart failure receiving cardiac glycosides, when other agents are insufficiently effective or inappropriate;

In liver cirrhosis associated with edema and/or ascites (plasma aldosterone levels may be markedly elevated in this condition):

supportive therapy along with bed rest and restriction of fluid and sodium intake;

In nephrotic syndrome (combination of spironolactone and hydrochlorothiazide does not affect the underlying pathological process):

when response to glucocorticoid therapy and other diuretics is inadequate.

Essential hypertension:

when other agents are insufficiently effective or inappropriate;
management of diuretic-induced hypokalemia when use of other agents is inappropriate.

Fixed-dose combination products are not intended for initial treatment. Effective doses of each component should be established separately for the patient. If the fixed combination contains a dose previously determined during titration, use of the combination agent may be more convenient for treatment. If dose adjustment is required during maintenance therapy, separate formulations of spironolactone and hydrochlorothiazide should be used.

Contraindications.

Hypersensitivity to active substances, thiazide diuretics, other sulfonamide derivatives, and/or excipients of the medicinal product.
Acute renal failure, severe renal impairment (glomerular filtration rate [GFR] less than 30 mL/min/1.73 m²), anuria.
Severe or progressive liver disease.
Addison’s disease.
Hyperkalemia.
Hypercalcemia.
Concomitant use with eplerenone (see sections "Special precautions for use" and "Interaction with other medicinal products and other types of interactions").
Concomitant use with heparin, low-molecular-weight heparin (see sections "Special precautions for use" and "Interaction with other medicinal products and other types of interactions").
Pregnancy and breastfeeding (see section "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other types of interactions.

The following interactions may occur when used concomitantly with other agents.

Alcohol, barbiturates, narcotics — concomitant use may enhance orthostatic hypotension. Such combination should be avoided, especially at the beginning of treatment.

Amphotericin B — concomitant use may increase the risk of thiazide-induced hypokalemia. Monitoring of plasma potassium levels is recommended when used together.

Antidiabetic agents — thiazide-induced hyperglycemia may compromise plasma glucose control when used concomitantly. Insulin and other antidiabetic agent requirements may increase, decrease, or remain unchanged. Hyperglycemia and glucosuria may appear in patients with prediabetes. Cases of erythema multiforme have been reported with concomitant use of hydrochlorothiazide and glibenclamide. Monitoring of plasma glucose levels is recommended, and dosage adjustment of antidiabetic agents and potassium supplementation may be necessary.

Antineoplastic agents (including cyclophosphamide and methotrexate) — concomitant use may reduce renal clearance of cytotoxic agents and enhance their myelosuppressive effects. Hematological parameters should be monitored, and dosage adjustment of cytotoxic agents may be required.

Antipyrine — concomitant use may enhance its metabolism.

Atorvastatin / furosemide / acetylsalicylic acid — cases of hepatitis, pancreatitis, and fatal outcomes have been reported with concomitant use of this combination and hydrochlorothiazide/spironolactone.

Bile acid sequestrants — concomitant use may lead to intestinal binding of thiazide diuretics and reduced gastrointestinal absorption by 43–85%. Administration of hydrochlorothiazide 4 hours after bile acid reduces its absorption by 30–35%. Hyperchloremic metabolic acidosis, often associated with hyperkalemia, has also been reported with concomitant use of spironolactone and ammonium chloride or cholestyramine. The medicinal product should be administered 2–4 hours before or 6 hours after bile acid sequestrants. Monitoring of blood pressure is recommended, and dosage adjustment may be necessary.

Calcium preparations and vitamin D supplements — concomitant use may reduce renal calcium excretion and enhance bone resorption. Monitoring of plasma calcium levels is recommended, especially with high-dose use, and dosage adjustment or discontinuation of calcium and/or vitamin D supplements may be necessary.

Carbamazepine — concomitant use may enhance hyponatremia. Caution and monitoring of plasma sodium levels are recommended.

Corticosteroids, adrenocorticotropic hormone (ACTH) — concomitant use may lead to electrolyte depletion, particularly hypokalemia. Monitoring of plasma potassium levels is recommended, and dosage adjustment of corticosteroids and ACTH may be necessary.

Digoxin — concomitant use may increase digoxin half-life, leading to elevated plasma digoxin levels and risk of digoxin toxicity. Thiazide-induced electrolyte disturbances (e.g., hypokalemia, hypomagnesemia) may enhance digoxin toxicity, potentially leading to fatal arrhythmias. Monitoring of plasma digoxin levels is required, and dosage adjustment of digoxin and potassium supplementation may be necessary.

Diuretics and antihypertensive agents — concomitant use may potentiate antihypertensive effects. Cases of hyperkalemia have been reported with concomitant use of spironolactone and angiotensin-converting enzyme (ACE) inhibitors, angiotensin-II receptor blockers, and aldosterone inhibitors. Dosage of antihypertensive agents, particularly ganglionic blockers, should be reduced by 50%.

Agents capable of causing hyperkalemia — concomitant use may lead to severe hyperkalemia.

Agents affecting gastrointestinal motility (e.g., atropine, metoclopramide, domperidone) — concomitant use with anticholinergic agents may increase bioavailability of thiazide diuretics, while use with prokinetic agents may reduce it. Dosage adjustment of the medicinal product may be required.

Eplerenone — concomitant use may lead to severe hyperkalemia. Concomitant use is contraindicated.

Agents for treatment of gout (allopurinol, uricosurics, xanthine oxidase inhibitors) — thiazide-induced hypercalcemia may compromise gout control. Concomitant use of hydrochlorothiazide with allopurinol may increase frequency of hypersensitivity reactions to allopurinol. Dosage adjustment of anti-gout agents may be required.

Heparin, low-molecular-weight heparin — concomitant use may lead to severe hyperkalemia. Concomitant use is contraindicated.

Lithium — concomitant use may reduce renal clearance of lithium and enhance its toxicity. Combined use has been associated with acute renal failure (sometimes fatal). Concomitant use is not recommended. If necessary, lithium dose should be reduced by 50%, and plasma lithium levels should be closely monitored.

Norepinephrine — concomitant use may reduce vascular response to norepinephrine. The medicinal product should be used with caution in patients undergoing regional or general anesthesia. Discontinuation of the medicinal product should be considered prior to elective surgery.

Nonsteroidal anti-inflammatory drugs (NSAIDs) — concomitant use may reduce natriuretic efficacy of diuretics due to inhibition of intrarenal prostaglandin synthesis and reduced diuretic effect of spironolactone. NSAID-induced inhibition of prostaglandin synthesis, leading to reduced renal blood flow, combined with thiazide-induced reduction in glomerular filtration rate, may result in acute renal failure, especially in patients with heart failure. Cases of hyperkalemia have been reported with concomitant use of indomethacin and potassium-sparing diuretics. However, acetylsalicylic acid has been shown not to alter the effect of spironolactone on blood pressure, plasma electrolyte levels, blood urea nitrogen, or plasma renin activity in hypertensive patients. Careful monitoring of plasma potassium levels, renal function, and blood pressure is recommended, and dosage adjustment of NSAIDs may be necessary.

Selective serotonin reuptake inhibitors (SSRIs) (e.g., citalopram, escitalopram, sertraline) — concomitant use may lead to hyponatremia. Use with caution and monitoring of plasma sodium levels is recommended.

Curare-like muscle relaxants (e.g., tubocurarine) — concomitant use may enhance their effects.

Topiramate — concomitant use may lead to hypokalemia and thiazide-induced increase in topiramate plasma concentration. Monitoring of plasma potassium and topiramate levels is recommended, and dosage adjustment of topiramate and potassium supplementation may be necessary.

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

Interaction with food.

It has been established that concomitant administration with food increases Cmax and AUC of spironolactone and its active metabolite, canrenone. In 9 patients receiving 200 mg of spironolactone with food, statistically significant increases in AUC(0–24) and Cmax were observed: 2-fold for spironolactone and 1.4-fold for canrenone. The clinical significance of this increased exposure has not been established.

When the medicinal product is taken with food, monitoring for signs potentially related to excessive exposure, such as elevated plasma potassium levels and other serious symptoms, is recommended, especially in patients with impaired renal or hepatic function, elderly patients, pregnant women, and breastfeeding women (see section "Overdose").

Interaction in laboratory tests.

Thiazides may reduce protein-bound iodine levels without affecting thyroid function. The medicinal product should be discontinued before testing parathyroid function. Hydrochlorothiazide has been shown to increase 24-hour uptake and absorbed levels of 131I in the thyroid gland.

Spironolactone or its metabolites have been reported to interfere with radioimmunoassay determination of digoxin. Concomitant administration of spironolactone and digoxin in healthy volunteers resulted in a 2–4-fold increase in plasma spironolactone concentration within 2–24 hours. Plasma digoxin concentration also increased. Concomitant use of these agents should be performed under medical supervision, and dosage adjustment of both spironolactone and digoxin may be required.

Special precautions for use.

Use only for "indications".

The medicinal product should be used only in conditions specified in the section "Indications".

Use of potassium supplements.

Concomitant use of potassium supplements, other potassium-sparing diuretics, or adherence to a diet high in potassium is not recommended during treatment with this medicinal product, as this may lead to hyperkalemia.

Risk of carcinogenicity.

Carcinogenic effects of spironolactone were observed in chronic toxicity studies in animals. During the post-marketing period, cases of breast cancer and other neoplasms (in the intestine, pancreas, etc.) have been reported.

Risk of non-melanoma skin cancer (NMSC).

In two epidemiological studies based on data from the Danish National Cancer Registry, an increased risk of NMSC (basal cell carcinoma [BCC] and squamous cell carcinoma [SCC]) was observed with increasing cumulative dose of hydrochlorothiazide. A possible mechanism for the development of NMSC may be the photosensitizing effect of hydrochlorothiazide.

Patients taking hydrochlorothiazide should be informed about the risk of developing NMSC and advised to regularly check their skin for new lesions and immediately report any suspicious skin changes to their physician. To reduce the risk of skin cancer, patients should be informed about preventive measures, such as limiting exposure to sunlight and ultraviolet radiation and ensuring adequate skin protection when such exposure occurs. Suspicious skin lesions should be promptly investigated, including biopsy with histological examination. For patients with risk factors (e.g., fair skin, personal or family history of skin cancer, long-term immunosuppressive therapy), reconsideration of the appropriateness of hydrochlorothiazide use may also be necessary (see also section "Adverse reactions").

Effects on the reproductive system and mammary glands.

Spironolactone may cause dose- and duration-dependent gynecomastia, which usually resolves after discontinuation of treatment. In rare cases, gynecomastia may persist after the drug is discontinued. If this complication occurs, the medicinal product should be discontinued.

Effects on metabolism.

Rarely, acidosis may develop during treatment with the medicinal product.

Cases of transient hyperchloremic metabolic acidosis, usually in combination with hyperkalemia, have been reported in patients with decompensated liver cirrhosis (even with normal renal function). The medicinal product should be used with caution in patients with acute hepatic dysfunction.

Hyperchloremic alkalosis occurs infrequently and rarely in severe form. Chloride deficiency can be corrected by administration of ammonium chloride (except in cases of renal or hepatic disease) and largely prevented by normal intake of sodium/chloride.

Effects on water and electrolyte balance.

Regular monitoring of plasma electrolyte levels should be performed during treatment with the medicinal product, especially in elderly patients and in patients with impaired renal or hepatic function.

Hyperkalemia.

Hyperkalemia (sometimes fatal) may occur during treatment with the medicinal product, both with excessive potassium intake and in the absence of such intake, particularly in elderly patients, patients with impaired renal function, and patients with diabetes mellitus. Potassium supplements should not be taken during treatment. Concomitant use of the medicinal product with other potassium-sparing diuretics, angiotensin-converting enzyme (ACE) inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin II receptor antagonists, eplerenone, or other aldosterone blockers is not recommended, even when a diuretic is used, as this is associated with the development of severe hyperkalemia (see section "Interaction with other medicinal products and other forms of interaction"). Concomitant use of the medicinal product with heparin, low-molecular-weight heparin, or other agents, or under conditions that cause hyperkalemia, may lead to severe hyperkalemia (see sections "Contraindications", "Interaction with other medicinal products and other forms of interaction").

Hyperkalemia in patients with diabetes mellitus. The medicinal product should be used with caution in patients with diabetes mellitus due to an increased risk of hyperkalemia. Renal function and plasma potassium levels should be checked before starting treatment and repeated within the first few weeks in patients at risk, especially in elderly patients. Monitoring of plasma potassium and creatinine levels is recommended before treatment initiation, one week after starting or increasing the dose, monthly for the first 3 months, then quarterly for one year, and thereafter every 6 months.

Correction of hyperkalemia can be achieved by rapid intravenous administration of 20–50% glucose solution with insulin, using 0.25–0.5 units of insulin per 1 gram of glucose. This measure may be repeated if necessary. The medicinal product should be discontinued and potassium intake restricted.

Hyperkalemia in patients with moderate or severe heart failure. Since hyperkalemia in patients with heart failure may be fatal, plasma potassium levels should be monitored during treatment with the medicinal product.

Concomitant use of other diuretics should be avoided.

Potassium supplements should be avoided when plasma potassium levels exceed 3.5 mEq/L. Data are lacking for patients with plasma creatinine levels > 2.5 mg/dL or a recent increase in creatinine levels > 25%.

Monitoring of plasma potassium and creatinine levels is recommended before treatment initiation, one week after starting or increasing the dose, monthly for the first 3 months, then quarterly for one year, and thereafter every 6 months. The medicinal product should be discontinued if plasma potassium levels exceed 5 mEq/L or plasma creatinine levels exceed 4 mg/dL.

Hypokalemia.

Hypokalemia may occur during treatment with the medicinal product, especially during enhanced diuresis, severe cirrhosis, or concomitant use of agents that increase the risk of hypokalemia. Plasma potassium levels should be monitored when the medicinal product is used concomitantly with agents that increase the risk of hypokalemia (aminoglycoside antibiotics, cisplatin, foscarnet, and amphotericin B). Treatment with cardiac glycosides may potentiate the metabolic effects of hypokalemia, particularly on the heart. If this complication occurs, the medicinal product should be discontinued, and treatment should be switched either to hydrochlorothiazide with potassium supplementation (if necessary), or to spironolactone.

Hyponatremia.

Hyponatremia may occur or be exacerbated when the medicinal product is used concomitantly with other diuretics, manifesting as dry mouth, thirst, lethargy, and drowsiness.

Careful monitoring of patients with sodium deficiency and signs of electrolyte imbalance is required during treatment with the medicinal product.

The syndrome of salt depletion may develop during treatment, which may manifest as confusion, similar to hepatic coma. If this complication occurs, the medicinal product should be discontinued and sodium replacement provided.

Use in patients with hepatic impairment.

The medicinal product should be used with caution in patients with mild to moderate hepatic impairment, as disturbances in water and electrolyte balance may lead to the development of hepatic coma. In the treatment of cirrhosis with edema/ascites requiring high doses of the medicinal product, the dose should be reduced once the maximum diuretic effect is achieved to avoid dehydration. If confusion develops, the medicinal product should be temporarily discontinued.

Effects on the nervous system.

Renal clearance of lithium is reduced and its toxicity is increased when used concomitantly with thiazide diuretics. Acute renal failure (sometimes fatal) has been reported. Concomitant use is not recommended. If such use is necessary, a reduction in the lithium dose may be required (see section "Interaction with other medicinal products and other forms of interaction").

Effects on vision.

Hydrochlorothiazide may cause idiosyncratic reactions leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms usually occur from several hours to several weeks after starting treatment and include sudden decrease in visual acuity or eye pain. Untreated acute angle-closure glaucoma may lead to irreversible vision loss. If this complication occurs, the medicinal product should be discontinued immediately. If intraocular pressure remains uncontrolled, surgical or operative treatment should be considered. Risk factors for acute angle-closure glaucoma include a history of hypersensitivity to sulfonamide derivatives or penicillins.

Use in patients with renal impairment.

Use of the medicinal product in patients with renal impairment may lead to its accumulation, and in patients with severe renal failure — to azotemia. The medicinal product should be used with caution in patients with severe renal impairment. The medicinal product is contraindicated in patients with acute renal failure, severe renal impairment (creatinine clearance less than 30 mL/min), or anuria.

Effects on reproductive function.

Spironolactone reduced fertility in female mice and increased the duration of the estrous cycle in female rats.

Effects on the skin.

Photosensitivity reactions have been reported during treatment with thiazide diuretics. If such reactions occur, use of the medicinal product should be discontinued.

Risk of acute respiratory toxicity.

Very rare, severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported after hydrochlorothiazide administration. Pulmonary edema usually develops within minutes or hours after hydrochlorothiazide intake. Initial symptoms include dyspnea, fever, worsening of lung condition, and hypotension. If ARDS is suspected, the medicinal product should be discontinued and appropriate treatment initiated. The medicinal product should not be used in patients who have previously experienced ARDS after hydrochlorothiazide.

Other.

Orthostatic hypotension may occur during treatment with the medicinal product, which may be exacerbated by concomitant use of alcohol, barbiturates, or narcotic drugs.

With prolonged use of thiazides, hypercalcemia and hypophosphatemia due to pathological changes in the parathyroid gland have been observed in some patients.

Exacerbation of systemic lupus erythematosus has been reported during treatment with sulfonamide derivatives, including thiazides (see section "Adverse reactions").

Treatment with thiazides may increase plasma uric acid levels. The medicinal product should be used with caution in patients with hyperuricemia or a history of gout. Dose adjustment of anti-gout medications may be necessary during concomitant use.

Treatment with thiazides may increase plasma glucose levels in patients with diabetes or pre-diabetes. Dose adjustment of insulin or hypoglycemic agents may be necessary during concomitant use.

Warnings regarding excipients.

The medicinal product contains lactose and therefore should not be used in patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

The medicinal product contains aluminium lake of tartrazine (E 102) and aluminium lake of sunset yellow FCF (E 110), which may cause allergic reactions.

Use during pregnancy or breastfeeding.

Adequate and well-controlled studies on the use of the medicinal product in pregnant women have not been conducted. In preclinical studies, spironolactone caused endocrine effects, including progestogenic and antiandrogenic effects.

The main metabolite of spironolactone, canrenone, passes into breast milk. Thiazides pass into breast milk in small amounts and, in high doses, may suppress lactation due to enhanced diuresis. Breastfeeding should be discontinued if the medicinal product is used.

The medicinal product is contraindicated during pregnancy or breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Somnolence and dizziness may occur during treatment with the medicinal product. Patients should exercise caution when driving or operating machinery until their response to treatment is known.

Dosage and Administration

The medicinal product is intended for oral administration.

The optimal dose is determined by titration of its components.

The optimal dose of the medicinal product should be evaluated within 2 weeks.

A pharmacokinetic interaction between the medicinal product and food is possible, and dose adjustment may be required.

Edema in adults (congestive heart failure, hepatic cirrhosis, or nephrotic syndrome)

The usual maintenance daily dose of the medicinal product is 50–100 mg of each component, administered once or in several doses. Doses of 50–200 mg of each component per day may be used depending on the response to initial titration.

Edema in children

The usual maintenance daily dose of the medicinal product should provide 1.65–3.3 mg of spironolactone per kilogram of body weight.

Essential hypertension

Since the medicinal product potentiates the effect of antihypertensive agents, especially ganglion blockers, the dosage of such agents should be reduced by at least 50% when used concomitantly.

Children

The safety and efficacy of the medicinal product in children have not been established.

Limited use in children for edema is permitted (see section "Dosage and Administration").

Overdose

Symptoms: nausea, vomiting, drowsiness, dizziness, decreased level of consciousness, coma, confusion, diarrhea, maculopapular and erythematous rashes. These symptoms usually resolve after discontinuation of the medicinal product. Exacerbation of hyperkalemia is possible. Cases of thrombocytopenic purpura and granulocytopenia have been reported.

Treatment: In case of overdose, administration of the medicinal product should be discontinued and potassium intake should be restricted. There is no specific antidote.

Adverse reactions.

The most common adverse reactions are gynecomastia and gastrointestinal disorders. These effects are usually reversible after discontinuation of the drug. In rare cases, symptoms of gynecomastia may persist.

Spironolactone

The most common adverse reactions are gynecomastia and gastrointestinal disorders.

The following adverse reactions have also been reported with spironolactone use:

Blood and lymphatic system disorders:

Leukopenia (including agranulocytosis), thrombocytopenia, anemia.

Immune system disorders:

Hypersensitivity reactions, including drug fever, urticaria, maculopapular and erythematous rashes, anaphylactic reactions, vasculitis, pruritus, rash.

Metabolism and nutrition disorders:

Electrolyte imbalance (hypochloremic alkalosis, hyponatremia, hypokalemia, hyperkalemia) (see section "Special precautions").

Nervous system disorders:

Confusion, libido disorders.

Central and peripheral nervous system disorders:

Ataxia, dizziness, headache, somnolence, lethargy.

Gastrointestinal disorders:

Gastrointestinal bleeding, ulcer, gastritis, diarrhea, cramps, nausea, vomiting.

Hepatobiliary disorders:

Mixed cholestatic/hepatocellular toxicity (sometimes with fatal outcome).

Musculoskeletal and connective tissue disorders:

Calf muscle cramps, rhabdomyolysis, myalgia, weakness.

Reproductive system and breast disorders:

Gynecomastia (see section "Special precautions"), erectile dysfunction, inability to achieve and maintain erection, abnormal spermatogenesis (reduced sperm motility and count), irregular menstruation or amenorrhea, postmenopausal bleeding, breast pain, benign breast neoplasm, breast cancer (including in male patients).

Skin and subcutaneous tissue disorders:

Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), alopecia, hypertrichosis.

Renal and urinary disorders:

Renal function impairment (including acute renal failure).

General disorders and administration site conditions:

Malaise.

Hydrochlorothiazide

The following adverse reactions have been reported with hydrochlorothiazide use:

Benign, malignant and unspecified neoplasms (including cysts and polyps):
NMSC (BCC and SCC).

Blood and lymphatic system disorders:

Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenic purpura.

Immune system disorders:

Hypersensitivity reactions, including anaphylactic reactions, necrotizing vasculitis, respiratory distress including pneumonitis and pulmonary edema; photosensitization, fever, urticaria, rash, purpura (including thrombocytopenic).

Metabolism and nutrition disorders:

Hypokalemia, hyperglycemia, glucosuria, hypomagnesemia, hyponatremia, hyperuricemia, azotemia.

Nervous system disorders:

Vertigo, paresthesia, dizziness, headache, restlessness.

Eye disorders:

Choroidal effusion, acute myopia, acute angle-closure glaucoma (see section "Special precautions"), transient visual blurring, xanthopsia.

Respiratory, thoracic and mediastinal disorders:

Very rare: acute respiratory distress syndrome (ARDS) (see section "Special precautions").

Cardiovascular disorders:

Hypotension, including orthostatic hypotension, which may be potentiated by concomitant use of alcohol, barbiturates, narcotics, or antihypertensive agents.

Gastrointestinal disorders:

Pancreatitis, jaundice (intrahepatic cholestatic), diarrhea, vomiting, sialadenitis, cramps, constipation, gastric irritation, nausea, anorexia.

Musculoskeletal and connective tissue disorders:

Muscle cramps.

Skin and subcutaneous tissue disorders:

Erythema multiforme, pruritus, alopecia.

Renal and urinary disorders:

Renal failure, renal function impairment, interstitial nephritis.

General disorders and administration site conditions:

Weakness.

Post-marketing experience.

Results of some pharmacoepidemiological studies suggest that hydrochlorothiazide use is associated with an increased risk of BCC and SCC. Systematic review and meta-analysis suggest with high uncertainty that long-term use of hydrochlorothiazide (>3 years) led to:

122 additional cases (95% CI: 112–133) of BCC per 1000 patients treated with hydrochlorothiazide compared to those not treated (meta-analysis of 3 observational studies);
31 additional cases (95% CI: 24–37) of SCC per 1000 patients treated with hydrochlorothiazide compared to those not treated (meta-analysis of 2 observational studies).

Very rare adverse reactions have been reported during the post-marketing period. Although a clear causal relationship between these events and the use of the spironolactone/hydrochlorothiazide combination has not been established.

Infections and infestations:

Pneumonia, otitis media.

Benign, malignant and unspecified neoplasms (including cysts and polyps):

Breast cancer (in men and women), malignant neoplasm (2 cases), uterine leiomyoma, pancreatic adenocarcinoma (1 case), metastatic liver cancer (1 case), lung malignant neoplasm, lymphoma.

Blood and lymphatic system disorders:

Thrombocytopenia, agranulocytosis, anemia, leukopenia.

Immune system disorders:

Hypersensitivity reactions.

Endocrine disorders:

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) (2 cases), abnormal plasma ADH levels, hyperthyroidism.

Metabolism and nutrition disorders:

Hyponatremia, hypomagnesemia, hyperkalemia, hypochloremia, hypercalcemia, dehydration, decreased appetite, metabolic acidosis, increased abdominal fat tissue (after 1 year of treatment), hypoglycemia.

Psychiatric disorders:

Confusion, disorientation, depression (1 case), aggression, agitation, abnormal behavior, suicide attempt (1 case).

Nervous system disorders:

Somnolence, dizziness/balance disorders, coma (including hepatic) (1 case), loss (1 case)/change/suppression of consciousness, syncope, seizures (1 case), cerebrovascular disorder, including acute, brain edema, paresthesia.

Ear and labyrinth disorders:

Vertigo.

Cardiac disorders:

Bradycardia (2 cases), myocardial infarction, tachycardia (1 case), arrhythmia, atrioventricular block, atrial fibrillation, intraventricular block, right bundle branch block, heart failure (including congestive) (1 case), right ventricular failure, polymorphic ventricular tachycardia of the torsade de pointes type.

Vascular disorders:

Orthostatic hypotension, hypotension, circulatory collapse, atherosclerosis (1 case), hemorrhagic shock (1 case), bleeding (1 case).

Respiratory, thoracic and mediastinal disorders:

Dyspnea, pulmonary fibrosis (1 case), respiratory failure, pulmonary embolism (1 case), pulmonary edema, interstitial lung disease, cough.

Gastrointestinal disorders:

Vomiting, nausea, diarrhea, acute pancreatitis (necrotizing, recurrent), abdominal pain, gastrointestinal bleeding (rectal bleeding), constipation, melena.

Hepatobiliary disorders:

Jaundice, cholestasis, hepatitis, hepatomegaly, steatosis/necrosis/liver failure (1 case each).

Skin and subcutaneous tissue disorders:

Purpura, pruritus, maculopapular and erythematous rashes, photosensitization, bullous dermatitis, eczema, toxic epidermal necrolysis/rash, pemphigoid.

Musculoskeletal and connective tissue disorders:

Rhabdomyolysis, myalgia, muscle weakness, systemic lupus erythematosus.

Renal and urinary disorders:

Renal failure (acute, chronic), renal function impairment, interstitial nephritis, oliguria (1 case), anuria.

General disorders and administration site conditions:

Malaise, asthenia, pyrexia, chest pain, edema (peripheral and others), sudden death (1 case).

Investigations:

Decreased body weight, increased levels of creatinine, gamma-glutamyltransferase, aspartate aminotransferase, alanine aminotransferase, transaminases in plasma, increased body weight due to increased peripheral edema.

Reporting of suspected adverse reactions.

Reporting of adverse reactions after marketing authorization of the medicinal product is important. It allows 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 suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in a place inaccessible to children.

Packaging.

10 tablets in a blister; 2 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

UORLД MEDICIN ILAC SAN. VE TIC. A.S., Turkey /
WORLD MEDICINE ILAC SAN. VE TIC. A.S., Turkey.

Manufacturer's address and location of business activity.

15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey.

Marketing Authorization Holder.

LLC «WORLD MEDICINE», Ukraine /
WORLD MEDICINE, LLC, Ukraine.

Spinol-n

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Spinol-H (Spinol-H)

Composition:

Pharmacological Properties

Clinical characteristics.

Special precautions for use.

Dosage and Administration

Adverse reactions.