Spironolacton: Fachinformation – Dosierung, Gegenanzeigen, Wechselwirkungen, Nebenwirkungen
Für Fachkreise
Anwendungsgebiete
1.1 Herzinsuffizienz
ALDACTONE ist angezeigt zur Behandlung der Herzinsuffizienz der NYHA-Klasse III–IV mit reduzierter Ejektionsfraktion, um das Überleben zu verlängern, Ödeme zu behandeln und die Notwendigkeit von Krankenhausaufenthalten wegen Herzinsuffizienz zu verringern.
ALDACTONE wird in der Regel in Verbindung mit anderen Herzinsuffizienztherapien angewendet.
1.2 Hypertonie
ALDACTONE ist angezeigt als Zusatztherapie zur Behandlung der Hypertonie, um den Blutdruck bei Patienten zu senken, die mit anderen Wirkstoffen nicht ausreichend eingestellt sind. Eine Senkung des Blutdrucks verringert das Risiko tödlicher und nicht tödlicher kardiovaskulärer Ereignisse, vor allem von Schlaganfällen und Myokardinfarkten. Dieser Nutzen wurde in kontrollierten Studien mit Antihypertensiva aus einer Vielzahl pharmakologischer Klassen beobachtet.
Die Kontrolle eines hohen Blutdrucks sollte Teil eines umfassenden kardiovaskulären Risikomanagements sein, das gegebenenfalls Lipidkontrolle, Diabetesmanagement, antithrombotische Therapie, Raucherentwöhnung, körperliche Bewegung und eine eingeschränkte Natriumzufuhr umfasst. Viele Patienten benötigen mehr als ein Arzneimittel, um die Blutdruckziele zu erreichen. Für spezifische Empfehlungen zu Zielen und Management siehe veröffentlichte Leitlinien, wie die des Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) des National High Blood Pressure Education Program.
Für zahlreiche Antihypertensiva aus einer Vielzahl pharmakologischer Klassen und mit unterschiedlichen Wirkmechanismen wurde in randomisierten kontrollierten Studien eine Senkung der kardiovaskulären Morbidität und Mortalität nachgewiesen, und es kann geschlossen werden, dass dieser Nutzen weitgehend auf die Blutdrucksenkung und nicht auf eine andere pharmakologische Eigenschaft der Arzneimittel zurückzuführen ist. Der größte und konsistenteste Nutzen hinsichtlich kardiovaskulärer Endpunkte war eine Verringerung des Schlaganfallrisikos, doch wurden regelmäßig auch Verringerungen von Myokardinfarkten und der kardiovaskulären Mortalität beobachtet.
Ein erhöhter systolischer oder diastolischer Druck verursacht ein erhöhtes kardiovaskuläres Risiko, und der absolute Risikoanstieg pro mmHg ist bei höheren Blutdruckwerten größer, sodass selbst moderate Senkungen einer schweren Hypertonie einen erheblichen Nutzen bringen können. Die relative Risikoreduktion durch Blutdrucksenkung ist in Populationen mit unterschiedlichem absolutem Risiko ähnlich, sodass der absolute Nutzen bei Patienten größer ist, die unabhängig von ihrer Hypertonie ein höheres Risiko haben (zum Beispiel Patienten mit Diabetes oder Hyperlipidämie), und bei solchen Patienten wäre ein Nutzen durch eine aggressivere Behandlung bis zu einem niedrigeren Blutdruckziel zu erwarten.
Einige Antihypertensiva haben bei schwarzen Patienten geringere blutdrucksenkende Wirkungen (als Monotherapie), und viele Antihypertensiva haben zusätzliche zugelassene Indikationen und Wirkungen (z. B. bei Angina pectoris, Herzinsuffizienz oder diabetischer Nierenerkrankung). Diese Überlegungen können die Auswahl der Therapie leiten.
1.3 Ödeme im Zusammenhang mit Leberzirrhose oder nephrotischem Syndrom
ALDACTONE ist angezeigt zur Behandlung von Ödemen in den folgenden Situationen:
- •Leberzirrhose, wenn die Ödeme nicht auf eine Flüssigkeits- und Natriumrestriktion ansprechen.
- •Nephrotisches Syndrom, wenn die Behandlung der Grunderkrankung, die Einschränkung der Flüssigkeits- und Natriumzufuhr und die Anwendung anderer Diuretika zu einem unzureichenden Ansprechen führen.
Da ALDACTONE das Serumkalium erhöht, kann es zur Behandlung von Ödemen nützlich sein, wenn die Gabe anderer Diuretika eine Hypokaliämie verursacht hat.
1.4 Primärer Hyperaldosteronismus
ALDACTONE ist in den folgenden Situationen angezeigt:
- •Kurzfristige präoperative Behandlung von Patienten mit primärem Hyperaldosteronismus.
- •Langfristige Erhaltungstherapie bei Patienten mit umschriebenen aldosteronproduzierenden Nebennierenadenomen, die für eine Operation nicht in Frage kommen.
- •Langfristige Erhaltungstherapie bei Patienten mit bilateraler mikro- oder makronodulärer Nebennierenhyperplasie (idiopathischer Hyperaldosteronismus).
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1.1 Heart Failure
ALDACTONE is indicated for treatment of NYHA Class III–IV heart failure and reduced ejection fraction to increase survival, manage edema, and reduce the need for hospitalization for heart failure.
ALDACTONE is usually administered in conjunction with other heart failure therapies.
1.2 Hypertension
ALDACTONE is indicated as add-on therapy for the treatment of hypertension, to lower blood pressure in patients who are not adequately controlled on other agents. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes.
Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.
1.3 Edema Associated with Hepatic Cirrhosis or Nephrotic Syndrome
ALDACTONE is indicated for the management of edema in the following settings:
- •Cirrhosis of the liver when edema is not responsive to fluid and sodium restriction.
- •Nephrotic syndrome when treatment of the underlying disease, restriction of fluid and sodium intake, and the use of other diuretics produce an inadequate response.
Because it increases serum potassium, ALDACTONE may be useful for treating edema when administration of other diuretics has caused hypokalemia.
1.4 Primary Hyperaldosteronism
ALDACTONE is indicated in the following settings:
- •Short-term preoperative treatment of patients with primary hyperaldosteronism.
- •Long-term maintenance therapy for patients with discrete aldosterone-producing adrenal adenomas who are not candidates for surgery.
- •Long-term maintenance therapy for patients with bilateral micro or macronodular adrenal hyperplasia (idiopathic hyperaldosteronism).
Dosierung und Art der Anwendung
2.1 Allgemeine Hinweise
ALDACTONE kann mit oder ohne Nahrung eingenommen werden, sollte jedoch in Bezug auf die Nahrungsaufnahme stets gleich eingenommen werden [siehe Klinische Pharmakologie (12.3)].
2.2 Behandlung der Herzinsuffizienz
Bei Patienten mit einem Serumkalium ≤5,0 mEq/l und einer eGFR >50 ml/min/1,73 m² die Behandlung mit 25 mg einmal täglich beginnen. Bei Patienten, die 25 mg einmal täglich vertragen, kann die Dosis je nach klinischer Indikation auf 50 mg einmal täglich erhöht werden. Bei Patienten, die unter 25 mg einmal täglich eine Hyperkaliämie entwickeln, kann die Dosis auf 25 mg jeden zweiten Tag reduziert werden [siehe Warnhinweise und Vorsichtsmaßnahmen (5.1)]. Bei Patienten mit einer eGFR zwischen 30 und 50 ml/min/1,73 m² wegen des Risikos einer Hyperkaliämie einen Therapiebeginn mit 25 mg jeden zweiten Tag erwägen [siehe Anwendung bei besonderen Patientengruppen (8.6)].
2.3 Behandlung der essenziellen Hypertonie
Die empfohlene Anfangstagesdosis beträgt 25 bis 100 mg ALDACTONE, verabreicht als Einzeldosis oder in aufgeteilten Dosen, wird empfohlen. Die Dosis kann in zweiwöchigen Abständen titriert werden. Dosen über 100 mg/Tag bewirken im Allgemeinen keine zusätzliche Blutdrucksenkung.
2.4 Behandlung von Ödemen
Bei Patienten mit Zirrhose die Therapie im Krankenhaus beginnen und langsam titrieren [siehe Anwendung bei besonderen Patientengruppen (8.7)]. Die empfohlene Anfangstagesdosis beträgt 100 mg ALDACTONE, verabreicht als Einzeldosis oder in aufgeteilten Dosen, kann jedoch zwischen 25 und 200 mg täglich liegen. Bei Gabe als alleiniges Mittel zur Diurese mindestens fünf Tage lang verabreichen, bevor die Dosis erhöht wird, um die gewünschte Wirkung zu erzielen.
2.5 Behandlung des primären Hyperaldosteronismus
ALDACTONE zur Vorbereitung auf eine Operation in Dosen von 100 bis 400 mg täglich verabreichen. Bei Patienten, die als für eine Operation ungeeignet gelten, kann ALDACTONE als langfristige Erhaltungstherapie in der für den einzelnen Patienten ermittelten niedrigsten wirksamen Dosierung angewendet werden.
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2.1 General Considerations
ALDACTONE can be taken with or without food, but should be taken consistently with respect to food [see Clinical Pharmacology (12.3)].
2.2 Treatment of Heart Failure
In patients with serum potassium ≤5.0 mEq/L and eGFR >50 mL/min/1.73 m², initiate treatment at 25 mg once daily. Patients who tolerate 25 mg once daily may have their dosage increased to 50 mg once daily as clinically indicated. Patients who develop hyperkalemia on 25 mg once daily may have their dosage reduced to 25 mg every other day [see Warnings and Precautions (5.1)]. In patients with an eGFR between 30 and 50 mL/min/1.73 m², consider initiating therapy at 25 mg every other day because of the risk of hyperkalemia [see Use in Specific Populations (8.6)].
2.3 Treatment of Essential Hypertension
The recommended initial daily dose is 25 to 100 mg of ALDACTONE administered in either single or divided doses is recommended. Dosage can be titrated at two-week intervals. Doses greater than 100 mg/day generally do not provide additional reductions in blood pressure.
2.4 Treatment of Edema
In patients with cirrhosis, initiate therapy in a hospital setting and titrate slowly [see Use in Specific Populations (8.7)]. The recommended initial daily dosage is 100 mg of ALDACTONE administered in either single or divided doses, but may range from 25 to 200 mg daily. When given as the sole agent for diuresis, administer for at least five days before increasing dose to obtain desired effect.
2.5 Treatment of Primary Hyperaldosteronism
Administer ALDACTONE in doses of 100 to 400 mg daily in preparation for surgery. For patients who are considered unsuitable for surgery, ALDACTONE can be used as long-term maintenance therapy at the lowest effective dosage determined for the individual patient.
Darreichungsformen und Stärken
Tablets: 25 mg round, light yellow, film-coated, with SEARLE and 1001 debossed on one side and ALDACTONE and 25 on the other side.
Tablets: 50 mg oval, light orange, scored, film-coated, with SEARLE and 1041 debossed on the scored side and ALDACTONE and 50 on the other side.
Tablets: 100 mg round, peach-colored, scored, film-coated, with SEARLE and 1031 debossed on the scored side and ALDACTONE and 100 on the other side.
Gegenanzeigen
ALDACTONE ist kontraindiziert bei Patienten mit:
- •Hyperkaliämie
- •Morbus Addison
- •Gleichzeitiger Anwendung von Eplerenon
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ALDACTONE is contraindicated in the patients with:
- •Hyperkalemia
- •Addison's disease
- •Concomitant use of eplerenone
Nebenwirkungen
The following clinically significant adverse reactions are described elsewhere in the labeling:
- •Hyperkalemia [see Warnings and Precautions (5.1)]
- •Hypotension and Worsening Renal Function [see Warnings and Precautions (5.2)]
- •Electrolyte and Metabolic Abnormalities [see Warnings and Precautions (5.3)]
- •Gynecomastia [see Warnings and Precautions (5.4]
- •Impaired neurological function/ coma in patients with hepatic impairment, cirrhosis and ascites [see Use in Specific Populations (8.7)]
The following adverse reactions associated with the use of spironolactone were identified in clinical trials or postmarketing reports. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency, reliably, or to establish a causal relationship to drug exposure.
Digestive: Gastric bleeding, ulceration, gastritis, diarrhea and cramping, nausea, vomiting.
Reproductive: Decreased libido, inability to achieve or maintain erection, irregular menses or amenorrhea, postmenopausal bleeding, breast and nipple pain.
Hematologic: Leukopenia (including agranulocytosis), thrombocytopenia.
Hypersensitivity: Fever, urticaria, maculopapular or erythematous cutaneous eruptions, anaphylactic reactions, vasculitis.
Metabolism: Hyperkalemia, electrolyte disturbances [see Warnings and Precautions (5.1, 5.3)], hyponatremia, hypovolemia.
Musculoskeletal: Leg cramps.
Nervous system/psychiatric: Lethargy, mental confusion, ataxia, dizziness, headache, drowsiness.
Liver/biliary: A very few cases of mixed cholestatic/hepatocellular toxicity, with one reported fatality, have been reported with spironolactone administration.
Renal: Renal dysfunction (including renal failure).
Skin: Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS), alopecia, pruritis.
Warnhinweise und Vorsichtsmaßnahmen
5.1 Hyperkalemia
ALDACTONE can cause hyperkalemia. This risk is increased by impaired renal function or concomitant potassium supplementation, potassium-containing salt substitutes or drugs that increase potassium, such as angiotensin converting enzyme inhibitors and angiotensin receptor blockers [see Drug Interactions (7.1)].
Monitor serum potassium within 1 week of initiation or titration of ALDACTONE and regularly thereafter. More frequent monitoring may be needed when ALDACTONE is given with other drugs that cause hyperkalemia or in patients with impaired renal function.
If hyperkalemia occurs, decrease the dose or discontinue ALDACTONE and treat hyperkalemia.
5.2 Hypotension and Worsening Renal Function
Excessive diuresis may cause symptomatic dehydration, hypotension and worsening renal function, particularly in salt-depleted patients or those taking angiotensin converting enzyme inhibitors and angiotensin II receptor blockers. Worsening of renal function can also occur with concomitant use of nephrotoxic drugs (e.g., aminoglycosides, cisplatin, and NSAIDs). Monitor volume status and renal function periodically.
5.3 Electrolyte and Metabolic Abnormalities
In addition to causing hyperkalemia, ALDACTONE can cause hyponatremia, hypomagnesemia, hypocalcemia, hypochloremic alkalosis, and hyperglycemia. Asymptomatic hyperuricemia can occur and rarely gout is precipitated. Monitor serum electrolytes, uric acid and blood glucose periodically.
5.4 Gynecomastia
ALDACTONE can cause gynecomastia. In RALES, patients with heart failure treated with a mean dose of 26 mg of spironolactone once daily, about 9% of the male subjects developed gynecomastia. The risk of gynecomastia increases in a dose-dependent manner with an onset that varies widely from 1–2 months to over a year. Gynecomastia is usually reversible.
Wechselwirkungen
7.1 Drugs and Supplements Increasing Serum Potassium
Concomitant administration of ALDACTONE with potassium supplementation or drugs that can increase potassium may lead to severe hyperkalemia. In general, discontinue potassium supplementation in heart failure patients who start ALDACTONE [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)]. Check serum potassium levels when ACE inhibitor or ARB therapy is altered in patients receiving ALDACTONE.
Examples of drugs that can increase potassium include:
- •ACE inhibitors
- •angiotensin receptor blockers
- •non-steroidal anti-inflammatory drugs (NSAIDs)
- •heparin and low molecular weight heparin
- •trimethoprim
7.2 Lithium
Like other diuretics, ALDACTONE reduces the renal clearance of lithium, thus increasing the risk of lithium toxicity. Monitor lithium levels periodically when ALDACTONE is coadministered [see Clinical Pharmacology (12.3)].
7.3 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
In some patients, the administration of an NSAID can reduce the diuretic, natriuretic, and antihypertensive effect of diuretics. Therefore, when ALDACTONE and NSAIDs are used concomitantly, monitor closely to determine if the desired effect of the diuretic is obtained [see Clinical Pharmacology (12.3)].
7.4 Digoxin
Spironolactone and its metabolites interfere with radioimmunoassays for digoxin and increase the apparent exposure to digoxin. It is unknown to what extent, if any, spironolactone may increase actual digoxin exposure. In patients taking concomitant digoxin, use an assay that does not interact with spironolactone.
7.5 Cholestyramine
Hyperkalemic metabolic acidosis has been reported in patients given ALDACTONE concurrently with cholestyramine.
7.6 Acetylsalicylic Acid
Acetylsalicylic acid may reduce the efficacy of spironolactone. Therefore, when ALDACTONE and acetylsalicylic acid are used concomitantly, ALDACTONE may need to be titrated to higher maintenance dose and the patient should be observed closely to determine if the desired effect is obtained [see Clinical Pharmacology (12.3)].
7.7 Abiraterone
Spironolactone binds to the androgen receptor and may increase prostate-specific antigen (PSA) levels in abiraterone-treated prostate cancer patients. Concomitant use of spironolactone and abiraterone is not recommended.
7.8 Mitotane
Avoid concomitant use of ALDACTONE and mitotane. Spironolactone reduces mitotane plasma levels [see Clinical Pharmacology (12.3)].
Schwangerschaft, Stillzeit, Kinder, ältere Menschen
8.1 Pregnancy
Risk Summary
Based on mechanism of action and findings in animal studies, spironolactone may affect sex differentiation of the male during embryogenesis (see Data). Rat embryofetal studies report feminization of male fetuses and endocrine dysfunction in females exposed to spironolactone in utero. Limited available data from published case reports and case series did not demonstrate an association of major malformations or other adverse pregnancy outcomes with spironolactone. There are risks to the mother and fetus associated with heart failure, cirrhosis and poorly controlled hypertension during pregnancy (see Clinical Considerations). Because of the potential risk to the male fetus due to anti-androgenic properties of spironolactone and animal data, avoid spironolactone in pregnant women or advise a pregnant woman of the potential risk to a male fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively.
Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk
Pregnant women with congestive heart failure are at increased risk for preterm birth. Stroke volume and heart rate increase during pregnancy, increasing cardiac output, especially during the first trimester. Clinical classification of heart disease may worsen with pregnancy and lead to maternal death. Closely monitor pregnant patients for destabilization of their heart failure.
Pregnant women with symptomatic cirrhosis generally have poor outcomes including hepatic failure, variceal hemorrhage, preterm delivery, fetal growth restriction and maternal death. Outcomes are worse with coexisting esophageal varices. Pregnant women with cirrhosis of the liver should be carefully monitored and managed accordingly.
Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death.
Data
Animal Data
Teratology studies with ALDACTONE have been carried out in mice and rabbits at doses of up to 20 mg/kg/day. On a body surface area basis, this dose in the mouse is substantially below the maximum recommended human dose and, in the rabbit, approximates the maximum recommended human dose. No teratogenic or other embryotoxic effects were observed in mice, but the 20 mg/kg dose caused an increased rate of resorption and a lower number of live fetuses in rabbits. Because of its antiandrogenic activity and the requirement of testosterone for male morphogenesis, ALDACTONE may have the potential for adversely affecting sex differentiation of the male during embryogenesis. When administered to rats at 200 mg/kg/day between gestation days 13 and 21 (late embryogenesis and fetal development), feminization of male fetuses was observed. Offspring exposed during late pregnancy to 50 and 100 mg/kg/day doses of ALDACTONE exhibited changes in the reproductive tract including dose-dependent decreases in weights of the ventral prostate and seminal vesicle in males, ovaries and uteri that were enlarged in females, and other indications of endocrine dysfunction, that persisted into adulthood. ALDACTONE has known endocrine effects in animals including progestational and antiandrogenic effects.
8.2 Lactation
Risk Summary
Spironolactone is not present in breastmilk; however, limited data from a lactating woman at 17 days postpartum reports the presence of the active metabolite, canrenone, in human breast milk in low amounts that are expected to be clinically inconsequential. In this case, there were no adverse effects reported for the breastfed infant after short term exposure to spironolactone; however, long term effects on a breastfed infant are unknown. There are no data on spironolactone effects on milk production. Consider the developmental and health benefits of breastfeeding along with the mother's clinical need for spironolactone and any potential adverse effects on the breastfed child from spironolactone or from the underlying maternal condition.
8.4 Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
8.5 Geriatric Use
ALDACTONE is substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, monitor renal function.
8.6 Use in Renal Impairment
ALDACTONE is substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Patients with renal impairment are at increased risk of hyperkalemia. Monitor potassium closely.
8.7 Use in Hepatic Impairment
ALDACTONE can cause sudden alterations of fluid and electrolyte balance which may precipitate impaired neurological function, worsening hepatic encephalopathy and coma in patients with hepatic disease with cirrhosis and ascites. In these patients, initiate ALDACTONE in the hospital [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].
Clearance of spironolactone and its metabolites is reduced in patients with cirrhosis. In patients with cirrhosis, start with lowest initial dose and titrate slowly [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].
Überdosierung
The oral LD₅₀ of ALDACTONE is greater than 1000 mg/kg in mice, rats, and rabbits.
Acute overdosage of ALDACTONE may be manifested by drowsiness, mental confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, or diarrhea. Rarely, instances of hyponatremia, hyperkalemia, or hepatic coma may occur in patients with severe liver disease, but these are unlikely due to acute overdosage. Hyperkalemia may occur, especially in patients with impaired renal function.
Treatment: Induce vomiting or evacuate the stomach by lavage. There is no specific antidote. Treatment is supportive to maintain hydration, electrolyte balance, and vital functions. Patients who have renal impairment may develop hyperkalemia. In such cases, discontinue ALDACTONE.
Klinische Pharmakologie
12.1 Mechanism of Action
Spironolactone and its active metabolites are specific pharmacologic antagonists of aldosterone, acting primarily through competitive binding of receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule. Spironolactone causes increased amounts of sodium and water to be excreted, while potassium is retained. Spironolactone acts both as a diuretic and as an antihypertensive drug by this mechanism. It may be given alone or with other diuretic agents that act more proximally in the renal tubule.
12.2 Pharmacodynamics
Aldosterone antagonist activity: Increased levels of the mineralocorticoid, aldosterone, are present in primary and secondary hyperaldosteronism. Edematous states in which secondary aldosteronism is usually involved include congestive heart failure, hepatic cirrhosis, and nephrotic syndrome. By competing with aldosterone for receptor sites, spironolactone provides effective therapy for the edema and ascites in those conditions. Spironolactone counteracts secondary aldosteronism induced by the volume depletion and associated sodium loss caused by active diuretic therapy.
12.3 Pharmacokinetics
Absorption
The mean time to reach peak plasma concentration of spironolactone and the active metabolite, canrenone, in healthy volunteers is 2.6 and 4.3 hours, respectively.
Effect of food: Food increased the bioavailability of spironolactone (as measured by AUC) by approximately 95.4%. Patients should establish a routine pattern for taking ALDACTONE with regard to meals [see Dosage and Administration (2.1)].
Distribution
Spironolactone and its metabolites are more than 90% bound to plasma proteins.
Elimination
The mean half-life of spironolactone is 1.4 hour. The mean half-life values of its metabolites including canrenone, 7-α-(thiomethyl) spirolactone (TMS), and 6-β-hydroxy-7-α-(thiomethyl) spirolactone (HTMS) are 16.5, 13.8, and 15 hours, respectively.
Metabolism: Spironolactone is rapidly and extensively metabolized. Metabolites can be divided into two main categories: those in which sulfur of the parent molecule is removed (e.g., canrenone) and those in which the sulfur is retained (e.g., TMS and HTMS). In humans, the potencies of TMS and 7-α-thiospirolactone in reversing the effects of the synthetic mineralocorticoid, fludrocortisone, on urinary electrolyte composition were approximately a third relative to spironolactone. However, since the serum concentrations of these steroids were not determined, their incomplete absorption and/or first-pass metabolism could not be ruled out as a reason for their reduced in vivo activities.
Excretion: The metabolites are excreted primarily in the urine and secondarily in bile.
Specific Populations
The impact of age, sex, race/ethnicity, and renal impairment on the pharmacokinetics of spironolactone have not been specifically studied.
Auszug – vollständiger Text im Originaldokument. Original auf DailyMed (FDA/NLM)
Quelle: U.S. Food and Drug Administration (FDA), Prescribing Information, über DailyMed (NLM); gemeinfrei. Keine Werbung, keine Therapieempfehlung. Bei Fragen zur eigenen Behandlung: Ärztin, Arzt oder Apotheke.