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Home , Aldosterone, Androgen, Antiandrogen, Chlorothiazide, Eplerenone, Hyperaldosteronism

18th Expert Committee on the Selection and Use of Essential (21 to 25 March 2011) Section 16: -- review (Children)

Review of the role of Spironolactone in the therapy of children

Dr Fatemeh Tavakkoli M.D. Pharm. D Candidate, University of Maryland, School of Pharmacy, Baltimore, Maryland USA

Contents Introduction ...... 3 Background ...... 3 Table 1: available guidelines for Spironolactone...... 3 Public Health Burden ...... 5 Table 2: Indications and dose regimens for Spironolactone in children...... 6 Search methods for identification of safety and data ...... 7 Inclusion criteria:...... 7 Exclusion criteria: ...... 7 Results ...... 7 Description of the included studies (see appendix 3 for data extraction tables)...... 8 Systematic reviews:...... 8 Original articles (categorized based on therapeutic use of Spironolactone):...... 8 Spironolactone use in precocious (see table 4) ...... 8 Spironolactone use in (See table 5) ...... 10 Spironolactone use in (see table 6) ...... 10 Spironolactone use in (see table 7)...... 10 Spironolactone use in CHF & congenital (see table 8)...... 10 Spironolactone use in heart disease (see table 9) ...... 11 Spironolactone use in Alport Syndrome (see table 10)...... 11 Spironolactone use in Cystic (See table 11)...... 12 Co-administration of Spironolactone with other diuretics in (See table 12)...... 12 Spironolactone use in (see table 13)...... 13 Spironolactone use in mineralocortichoid excess (see table 14)...... 13 Spironolactone Safety (see table 15)...... 13 Co-administration of Spironolactone with other diuretics in infants with lung disease (See table 16)...... 14 Discussion: ...... 15 List of clinical trials, listed on ClinicalTrial.gov, including the use of Spironolactone in children:...... 16 Conclusion:...... 17 References:...... 18 Appendix 1: Search terms ...... 20 Pubmed...... 20 Embase ...... 20 Pubmed search ...... 20 Appendix 2: Search strategies...... 21 Pubmed...... 21 Pubmed Systematic Review...... 21 Embase ...... 21 Appendix 3: Data Extraction Tables ...... 22

2 Introduction At its meeting in October 2007, the WHO Subcommittee of the Expert Committee for the Selection and Use of Essential considered that the role of Spironolactone should be reviewed in light of potentially newer and more effective medicines for the next meeting. A review of the comparative efficacy, safety, and place in therapy of Spironolactone in children was requested [1]. Background Spironolactone is a synthetic that competes for the cytoplasmic . It increases the of water and , while decreasing the of , by competing for the aldosterone sensitive Na+/K+ channel in the distal tubule of the . Approximately 5% of the filtered Na+ load is ultimately excreted in the [2]. Spironolactone effects both gonadal and adrenal steroidogenesis to elevate plasma gonadotrophin levels in children and to act as at the target level [3]. For decades, Spironolactone has been considered as an antagonist at the aldosterone receptors of the epithelial cells of the and was clinically used in the treatment of hyperaldosteronism and occasionally as a potassium-sparing . Spironolactone may also be useful in the treatment of other conditions such as: , , and left ventricular hypertrophy [4]. Spironolactone not only inhibits production of several cytokines involved in the pathology of many disease, it can also be considered for prolong periods as an economically attractive alternative to modern anti-inflammatory agents [5]. To identify current paediatric guidelines and recommendations for Spironolactone, several resources were reviewed including: WHO publications, paediatric and pharmacology text books, WHO regional databases, FDA website, British National Formulary (BNF), Australian handbook, and international pharmacopoeias. (See table 1).

Table 1: available guidelines for Spironolactone

Source WHO model BNF for children, 2009 WHO .com formulary for Model children 2010 Formulary 2008

Paediatric Yes Yes Yes Yes specific guidelines Indications in congestive Diuresis in congestive heart Oedema , , , ascites, failure, ascites and oedema, Hypertension oedema, and nephritic reduction of syndrome reduction of induced by diuretics or hypokalemia induced amphotericin by other diuretics or amphotericin; primary hyperaldosteronism

Formulations : 25 mg Tablet: 25,50,100 mg Tablet: 25mg U.S.: Tablet:25, 50, Oral liquid: Oral suspensions: 100 mg 1mg/mL,2mg/mL, 5mg/5mL,10mg/5mL, : Tablet 25, 5mg/mL 25mg/5mL, 100 mg 50 mg/5mL, 100mg/5mL Dose Diuresis in congestive By mouth: Initially 1-3 Initial: oral, 1-3 heart failure, ascites, Neonate: 1-2 mg/kg daily in mg/kg daily in mg/kg or 30-90 oedema and nephrotic 1-2 divided doses; up to 7 1-2 divided mg/square meter of syndrome; reduction of mg/kg daily in resistant doses body surface/day 3 hypokalemia induced ascites as a single dose or by other diuretics or Child 1 month-12 years: 1-3 in 2-4 divide doses amphotericin. mg/kg in 1-2 divided doses; Oral: up to 9 mg/kg daily in Neonate 1–2 mg/kg resistant ascites daily in 1–2 divided Child 12-18 years: 50-100 doses. mg daily in 1-2 divided Infant or Child 1 doses; up to 9 mg/kg month–12 years 1–3 daily(max.400 mg daily) in mg/kg daily in 1–2 resistant ascites divided doses (maximum 100 mg daily). Primary hyperaldosteronism; resistant ascites. Oral: Neonate up to a maximum of 7 mg/kg daily may be used. Infant or Child 1 month–12 years up to a maximum of 9 mg/kg daily (total maximum 400 mg daily) may be used.

Spironolactone is currently listed in the WHO Model List of Essential Medicines on the complementary list. The administration of Spironolactone can cause side effects such as: fluid and imbalance (, ), mild , and transient elevation of serum . Hyperkalemia can be fatal and patient's potassium level needs to be checked while on Spironolactone. If hyperkalemia is severe, immediate medical attention is needed including intravenous administration of chloride , sodium bicarbonate solution, and/or the oral or parenteral administration of glucose with a rapid- acting preparation [6].

Detailed specification of Spironolactone active pharmaceutical ingredients, dosage forms & strength, publically available formulations, FDA registered formulations

Active ingredient [7]: Spironolactone Forms and strength available [7]: Tablet; oral: 25 mg, 50 mg, and 100 mg Commonly used brand names [8]: Aldactone, Dyrenium, Midamor, Novospiroton

Pharmacokinetics

Absorption / Distribution: Spironolactone is a steroidal diuretic showing incomplete oral behavior because of its low solubility and slow dissolution rate [9]. Spironolactone is best absorbed if administered with food. The diuretic effect is seen within 48 hours and its half life is about 5 days [10].

Metabolism / Excretion: Spironolactone is rapidly and extensively metabolized. The pharmacological activity of Spironolactone in humans is not known. The metabolites are excreted primarily in the urine and secondarily in [6].

4 : Spironolactone is a weak natriuretic agent. It blocks the - -aldosterone system. It can reduce pressure and its maximum hypotensive effects require 3-4 weeks to be fully expressed. It is associated with a dose-related increase in serum potassium levels [11].

Public Health Burden Spironolactone is currently used in the management of several in children including , hypertension, , Bartter's syndrome, and Congestive Heart Failure (CHF). The normal age of pubertal onset is between ages 8-12 for girls and 9-14 for boys. Precocious puberty is the onset of puberty before the age of 8 for girls and 9 for boys. Treatment usually includes that can delay further development. Possible complications of precocious puberty include short height and poly cystic ovarian syndrome [12]. Age of pubertal onset has declined significantly in many countries. Changes in age of pubertal onset can have potential influence on adolescent risk taking behavior, such as unprotected , substance abuse, and violence, especially in deprived communities contributing to health inequalities [13]. Precocious puberty can be due to several etiologies, dependent or gonadotropin independent [14]. The incidence of precocious puberty is about 0.01-0.05% affecting girls 4-10 more than boys and it is more common among African Americans than Caucasian children [15]. Treatment is usually indicated due to the major psychosocial on the affected child [16]. There are two approaches to treat familial male-limited precocious puberty (FMPP). The first is administration of and the second is a combination of Spironolactone and [17].

Recent reports from the WHO and the World Bank highlights the importance of chronic diseases such as hypertension as an obstacle to the achievement of good health status [18]. Hypertension is more prevalent in adults, however, in recent years, hypertension and its sequelae are being seen with increasing frequency in children. Hypertension in children is usually secondary to renovascular and renal parenchymal disease and its increased incidence is primarily related to the epidemic of pediatric obesity [19]. Until recently, the incidence of pediatric hypertension has been low, 1-3%, but average levels have risen substantially among American children [20]. The incidence of hypertension in infants has risen in recent years for two reasons: better monitoring methods and increasingly successful salvage of smaller newborns [21]. Hypertension can be seen in up to 3% of Neonatal Intensive Care Units (NICU) admissions [22].

Hypertension is among the more prevalent treatable diseases among children and it carries significant short-term and long-term morbidity and mortality [23]. Antihypertensive drugs are indicated in children with symptomatic hypertension, , established hypertensive target organ damage, stage 2 hypertension, and failure of non pharmacological measures such as weight control, dietary changes, and regular physical activity [24]. Spironolactone has been recommended as part of the antihypertensive drugs for outpatients' management of hypertension in children 1-17 years old. The recommended initial dose is 1 mg/kg/day with a maximum of 3.3 mg/kg/day up to 100 mg7day. All patients treated with diuretics should have their monitored shortly after initiating the therapy and periodically thereafter. Spironolactone may cause severe hyperkalemia, especially if given with ACE inhibitors or ARB [25].

Primary aldosteronism is the common cause of secondary hypertension, accounting for approximately 10% of the hypertensive population [26]. Primary aldosteronism is the most 5 common form of the endocrine hypertension and its early diagnosis and treatment is crucial [27].

Bartter's syndrome is a rare disease characterized by renal potassium wasting. Treatment of Bartter syndrome consists of potassium chloride with one of the following agents: Spironolactone, , , and [28].

CHF is associated with high burden of mortality and morbidity, reduced quality of life, and substantial healthcare cost. To reduce the fluid overload, diuretics are considered the first line of treatment. Spironolactone was the only aldosterone antagonist that was recommended for optimal patient management in 2001 European Society of Cardiology guidelines [29]. The most common cause of heart failure in children is volume overload secondary to a left-to-right shunt and the medical therapy is based on diuretics, angiotensin converting inhibitors, cardiac , and beta blockers[30]. The main cause of CHF in children in developed countries are: congenital heart defects and cardiomyopathies( 0.34 cases per 100000 of the age-specific population, with 52% occurring in the first year of life[31].

Current paediatric specific guidelines recommend a dose of 1-2g/kg of Spironolactone for the management of several clinical indications in children (see table 2).

Table 2: Indications and dose regimens for Spironolactone in children

Indication/s Dosage Diuresis in congestive heart failure, ascites, Diuresis in congestive heart failure, ascites, oedema, and nephritic syndrome reduction oedema and ; reduction of of hypokalemia induced by other diuretics hypokalemia induced by other diuretics or or amphotericin; primary amphotericin. hyperaldosteronism Oral: † Neonate 1–2 mg/kg daily in 1–2 divided doses. Infant or Child 1 month–12 years 1–3 mg/kg daily in 1–2 divided doses (maximum 100 mg daily). Primary hyperaldosteronism; resistant ascites. Oral: Neonate up to a maximum of 7 mg/kg daily may be used. Infant or Child 1 month–12 years up to a maximum of 9 mg/kg daily (total maximum 400 mg daily) may be used. Diuresis in congestive heart failure, ascites By mouth: and oedema, reduction of hypokalemia Neonate: 1-2 mg/kg daily in 1-2 divided doses; induced by diuretics or amphotericin †† up to 7 mg/kg daily in resistant ascites Child 1 month-12 years: 1-3 mg/kg in 1-2 divided doses; up to 9 mg/kg daily in resistant ascites Child 12-18 years: 50-100 mg daily in 1-2 divided doses; up to 9 mg/kg daily(max.400 mg daily) in resistant ascites † WHO model formulary for children, 2010 †† BNF for children 2009

6

Search methods for identification of safety and efficacy data An online database search for articles published from 1950 to present was conducted using search terms and children (see appendix 1 for detailed list of search terms). The relevant articles were studied and summarized in combination with other resources, such as National Clearinghouse Guidelines, paediatrics and pharmacology text books, communications with first authors and experts, international pharmacopoeias, and direct communication with FDA. The following databases were searched: • Electronic searches 1. library 2. Pubmed 3. Embase • Searching other resources: multiple sources were used wherever possible to validate the data.

Inclusion criteria:

• articles • Human subjects • Types of studies: 1. Systematic reviews 2. Randomized controlled trials which subjects were assigned to treatment or control group (-controlled or different from Mannitol) on the basis of random allocation. 3. Reviews 4. Observational studies • Types of participant: Children between 0-12 years old • Types of interventions: the treatment group received Mannitol at any dose for any duration at any time

Exclusion criteria:

• non English language articles • studies • Studies not targeting paediatric population • Studies including paediatric populations, but paediatric specific data not reported separately • Studies without clear specification of intervention or dose • Individual case reports Results See appendix 2 for Cochrane library, Pubmed, and Embase search strategies, number of citations found, and the flow charts for selecting the included articles.

7 Description of the included studies (see appendix 3 for data extraction tables)

Systematic reviews: We found only one relevant Cochrane systematic review.

BrionL.P. 2002. Cochrane Systematic review (see table 3): The aim of the review was to assess the risks and benefits of diuretics acting on distal segments of the renal tubule (distal diuretics) in pre-term infants with or developing chronic lung disease (CLD). Of the six studies included in the systematic review, 5 included Spironolactone as part of a treatment arm (4 RCTs and 1 double blind cross over study, total n=141). In each case spironolactone was administered in combination with a , either (2mg/kg/12hrs or 3mg/kg/day) or cholorothiazide (20mg/kg/day or 40mg/kg/day). The dose of Spironolactone administered ranged from 1.5 to 4 mg/kg/day. Only 1 RCT (n=33) investigated the effects of administering a thiazide plus spironolactone versus thiazide alone (Hoffman 2000). Overall, the review found that in preterm infants > 3 wks of age with CLD, a 4 week treatment with thiazide and spironolactone improved lung compliance and reduced the need for . Thiazide and spironolactone decreased the risk of and tended to decrease the risk for remaining intubated after 8 wks in infants who did not have access to , bronchodilators or aminophylline. However, it found little or no evidence to support any benefit of diuretic administration on need for ventilatory support, length of hospital stay or long-term outcome in patients receiving current therapy. Using spironolactone in addition to thiazide did not significantly affect the risk of needing sodium supplementation (RR 1.48, CI 0.77 to 2.85; RD +0.21, CI -0.12 to +0.54), the risk of needing potassium supplementation (RR 1.21, CI 0.59 to 2.47; RD +0.09, CI -0.25 to +0.43) or the risk of needing either sodium or potassium supplementation (RR 1.29, CI 0.7 to 2.36; RD + 0.15, CI -0.19 to +0.48) (1 RCT, n=33). The use of spironolactone did not affect the change in lung compliance, resistance or tidal volume within 2 weeks. The use of spironolactone did not affect the change in inspiratory oxygen. There is no evidence to support the hypothesis that adding spironolactone to thiazide improves the outcome of preterm infants with CLD.

Original articles (categorized based on therapeutic use of Spironolactone):

Spironolactone use in precocious puberty (see table 4)

Two clinical trials and 1 prospective cohort study investigated the therapeutic use of Spironolactone in children with precocious puberty. Overall, 27 children between the ages of 2.3 and 7.7 years were included in these studies. One of the clinical trials (Laue, 1993, n=8), used Spironolactone (2mg/kg/day in two divided doses, increased to 4mg/kg/day after 2 weeks and then increased again to 5.7 mg/kg/day two weeks later), combined with Testolactone (started as 20 mg/kg/day and increased to 30 mg/kg/day at two weeks and to 40 mg/kg/day at 4 weeks). No specific side effects were reported and the study concluded that the combined therapy is an effective treatment for boys with familial male precocious puberty in whom central activation of the hypothalamic luteinizing releasing hormone (LHRH) has not yet occurred and in whom gonadotropin secretion remains prepubertal. The authors hypothesized that improved preservation of height potential may result from earlier institution of Spironolactone and Testolactone to prevent age advancement and from prompt suppression with if secondary LHRH dependent precocious puberty should develop. 8 Another (Laue, 1989) divided the 9 subjects into two groups. Group 1 (n=4) received Spironolactone (2 mg/kg/day in two divided doses). After 2 weeks, the dose was increased to 4mg/kg/day and again 2 weeks later, increased to 5.7mg/kg/day. After six months of treatment, Spironolactone was discontinued in two patients and six months later a combination of Spironolactone and Testolactone was initiated. The remaining two patients in this group were initiated on the combination therapy with Spironolactone and Testolactone upon finishing 6 months of montherapy with Spironolactone. Group 2 (n=5) received Testolactone alone for the initial six months and then Testolactone and Spironolactone for the second 6 months. Dosage was similar to group 1. No abnormalities in electrolytes or in hepatic, renal, or hematologic function were observed during treatment. All 4 patients in group 1 had mild gynecomasteia which was resolved either on discontinuation of Spironolactone or upon addition of Testolactone to their therapy. 1/5 in group 2 experienced transient abdominal discomfort which was resolved spontaneously. This study reported that in group 1, growth rate declined from 15.1±3.2 cm/year before treatment to 9.3±1.5 cm/year during Spironolactone and to 6.1±1.3 cm7year during combination therapy with Spironolactone and Testolactone. The rate of bone maturation declined from 2.43±0.14 -year/chronological year before treatment to 2.16±0.17 during Spironolactone therapy and to 0.60±0.23 during combined therapy.

In group 2, growth rate declined from 13.9±1.1 to 6.8±1.9 cm7year during Testolactone therapy and to 5.8±0.8 cm/year during combined therapy with Spironolactone and Testolactone. The rate of bone maturation fell from 2.25±0.26 bone age-year/chronological year to 1.21±0.46 during Testolactone therapy and to 0.78±0.48 during the combined therapy. Overall in group 1 &2, the basal gonadotropin levels did not change significantly after treatment. The peak (LH )level after stimulation with LHRH however, increased significantly after combination therapy (29.7±8.5 vs. 4.5±1.0 IU/liter before treatment). The basal plasma did not change significantly after treatment, except for moderate decline after treatment with Spironolactone alone (13.8±0.9 vs. 8.9±0.5 nmol/L). Testicular volume and did not change during treatment with Spironolactone, Testolactone, or both combined. * 6/9 continued to receive the combination therapy for an additional 12 months and maintained normal prepubertal rates of growth and bone maturation. The mean predicted height (± SEM) increased progressively during the combined treatment although the difference between the pre-treatment and post-treatment predictions was not significant (169.5±2.8 at the end of treatment vs. 166.2±4.5 cm before treatment, p=0.29). The authors concluded that blockade of both action and synthesis with the combination of Spironolactone and Testolactone is an effective short-term treatment for familial precocious puberty.

The Prospective Cohort Study (Leschek, 1999) included 10 children and the intervention included co-administration of Spironolactone and Testolactone and Deslorelin (LHRH analog). Spironolactone was given daily in two oral doses (1.5 mg/kg/day fro the first 1-2 weeks and 3.0 mg/kg/day during the second 1-2 weeks and 5.7 mg/kg/day thereafter). Testolactone started at 20 mg/kg/day for the first 1-2 weeks and increased every 1-2 weeks to 30 mg/kg/day and then 40 mg/kg/day. Deslorelin started at the onset of the secondary central precocious puberty at a dose of 4 microgram/kg/day. This study reported that 7/10 had improvement and 2/4 boys with aggressive behaviour had improved behavior. However, rarely gastrointestinal upset was noted with Testolactone. This study concluded that long term treatment with Spironolactone, Testolactone, and deslorelin safely normalizes the rate of growth and bone maturation and improves predicted height in boys with FMPP( familial male-limited precocious puberty).

9 Although no RCT evaluated the therapeutic benefits of Spironolactone in precocious puberty, it seems reasonable to recommend a combination therapy of Spironolactone and Testolactone in children with precocious puberty.

Spironolactone use in hypertension (See table 5)

One retrospective study evaluated the therapeutic effect of Spironolactone in 20 children with hyperaldosteronism. Eighteen participants were within our target population (0-12 years) and 16/20 had hypertension. 8/16 was treated with directed monotherapies with spironolactone (12.5 to 100 mg/day), (5 to 15 mg), and suppression (, 0.5 mg, , 6.25-15 mg/day). This study reported that all 8 treated patients maintained a blood pressure below the 90th percentile. No side effects were reported. This study concluded that compared to the combination of direct therapies, directed montherapy is often successful in controlling blood pressure in Glucocorticoid-remediable aldosteronism (GRA). Due to the study design, small sample size, and the administration of spironolactone as part of a combination therapy regimen, it is not possible to make a definite conclusion about the use of spironolactone in children with hypertension due to hyperaldosteronism.

Spironolactone use in hyperaldosteronism (see table 6)

One Clinical trial investigated the therapeutic effect of Spironolactone in 35 infants between 1 week and 10 months old. 4/15 participants in the study group (n=15) received spironolactone (1-3 mg/kg/24 h. The control group (n=20) received no treatment. No specific benefit or was stated. This study reported that the 4 patients receiving Spironolactone showed improved diuresis and decreased serum aldosterone. Due to the nature of the study and the small sample size, it is not possible to make a definite recommendation.

Spironolactone use in Bartter syndrome (see table 7)

One observational study was identified that included 13 children with Bartter's syndrome between the ages of 2 and 32 months investigating the therapeutic effect of Spironolactone. Spironolactone (2 mg/kg/day) was administered if hypokaemia was not corrected despite initial potassium supplement (4 to 8mmol/kg/day) . Subsequently, salicylates (10 mg/kg/day) or Indomethacin (3-5 mg/kg/day) was added if hypokalemia was still not corrected. This study reported a significant growth catch-up in 4 patients and increase in serum potassium in 8 patients who received Indomethacin therapy. One patient died of severe pneumonia with respiratory failure from hypokalemic myopathy. Seven patients continued to show growth failure and 3 were hypokalemic in spite of sufficient supplemental potassium therapy. One patient developed renal failure despite the standard therapy. This study concluded that early diagnosis, close follow up, and compliance with treatment may lead to appropriate growth and development of children with Bartter’s syndrome. Due to the nature of the study and the small sample size, it is not possible to make a definite recommendation for the inclusion of Spironolactone in children with barter's syndrome.

Spironolactone use in CHF & congenital heart disease (see table 8)

One RCT and one investigated the therapeutic effect of Spironolactone in 24 children, between the ages of 1-12 years, with CHF and congenital heart disease. In the RCT study, patients were divided into two groups: Group A (n=10) received potassium (1-3 mEq/kg/day) in addition to (same dose as group B) and cholorothiazide same dose as 10 group B). Group B (n=11) received Spironolactone (1-2 mg/kg/day every 12 h) in addition to digoxin (0.05 mg/kg/day divided to 3 equal doses followed by maintenance dose of 0.005 mg/kg every 12 h) and cholorothiazide (10-20 mg/kg/day every 12 h). Overall, Group B patients who have continued treatment including Spironolactone were progressing well clinically when seen at follow-up. This study reported that Mean daily weight fell fro group B but not for group A. Both groups showed significant decrease in hepatomegaly but the decrease was consistently greater in group B after day 2. Significant decrease in respiratory rates began on study day 4 in group B but not until day 6 in group A. There was no significant difference between the numbers of episodes between the two groups. In group B the 2nd and 3rd mean plasma Na+ values were significantly lower than 1st decreasing from 138.7(±0.78) to 136.1(±0.77) to 134.4(±1.75). There was no significant difference for duration of time in the study; group A (10.1± 1.62) and group B (11.0± 0.83) days. The authors concluded that the addition of Spironolactone hastens and enhances the response to standard treatment with digoxin and cholorothiazide in infants with CHF. In the Case series study, Spironolactone was administered with various doses( patient 1 received 4mg/kg/day and then increased to 5mg/kg/day, patient 2 received 2.3 mg/kg/day and patient 3 received 1.4 mg/kg7day and then 2.8mg/kg/day). This study reported that patient 1 did not achieve remission of loss and normalization of serum protein levels until the addition of Spironolactone to treatment. Authors suggested that a clinical trial of , a selective aldosterone inhibitor, in patients with PLE may be the appropriate next step to answer whether the blocking of aldosterone receptors accounts for spironolactone's diuretic effect and whether long term remission can be achieved. Due to the small sample size for the first study and the nature and small sample size of the second study and the fact that Spironolactone was used in a combination therapy in the RCT study, it is not possible to make a definite conclusion for the beneficial therapeutic effect of Spironolactone in children with CHF or congenital heart disease.

Spironolactone use in heart disease (see table 9)

One Prospective study and 1 Retrospective studies evaluated the effect of Spironolactone in patients (overall age range of 10 days- 52 years) with heart disease such as long QT syndrome. The overall number of participants was 28 and 22/28 were within our targeted age range. The Prospective study (Etheridge, 2003) administered Spironolactone (3.5±1.2 mg/kg/day) and KCl (3.3±1.5 mEq/kg/day) for four weeks. This study concluded that long-term oral potassium administration increases serum potassium in patients with long QT syndrome type 2; however no specific conclusion regarding the effectiveness of Spironolactone was made. The retrospective study (Motz, 2005) used Aldactone plus hydrochlorothiazide or furosemide (each 1-2 mg/kg/day) and digoxin. This study concluded that none of the infants, with significant left-to-right shunt, improved while receiving diuretics, Spironolactone, and digoxin alone, but improved after the addition of (Propranolol, metoprolol). Due to the nature of the studies, small sample size, and inconclusive data, it is not possible to make a recommendation for inclusion of Spironolactone in therapy of children with heart diseases.

Spironolactone use in Alport Syndrome (see table 10)

A clinical study including 5 patients, with the age range of 11-19 years old, with Alport syndrome investigated the effect of 25 mg/day Spironolactone. Only one of the participants was within our target population. It was stated that Spironolactone in addition to angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blocker (ARB) was helpful in 11 reducing urinary protein excretion. No specific side effect was reported. This study reported that before the start of Spironolactone, U-P/C showed no significant reduction but after the start of Spironolactone, U-P/C was significantly reduced at every time point (p<0.05) and gradually reduced to a minimum (0.13± 0.06 g/g) at 18 months. EGFR remained virtually unchanged throughout the Spironolactone therapy (before Spironolactone treatment: 129.2± 21.4 ml/min and 18 months later 110.1± 30.1 ml/min, p=0.115). Blood pressure dropped 3 months after Spironolactone treatment (systolic BP from 110.8± 5.0 to 91.2 ±6.6 mmHg and diastolic BP from 58.2 ±2.7 to 51.0± 3.0 mmHg). Although serum potassium level was significantly higher 3 months after Spironolactone treatment, none of the patients developed serious hyperkalemia. This study demonstrated that adding Spironolactone to ACEI and ARB may be effective for lowering in Alport syndrome. However, a large-scale study with longer follow-up is required to demonstrate whether the results shown in our study translate to improved renal survival for patients with Alport syndrome. Due to the nature of the study and very small sample size, a definite conclusion regarding the inclusion of Spironolactone in the treatment protocol of children with Alport syndrome can not be made.

Spironolactone use in Cystic fibrosis (See table 11)

One observational study including 2 seven months old infants evaluated the therapeutic effect of Spironolactone on the relative changes in electrolyte excretion by the sweat glands and the kidneys in cystic fibrosis. A combination therapy was initiated including: methopyrapone (125mg/4h) and dexamethasone (0.375mg/8h) and Spironolactone (12.5 mg/6h).Duration of this combination therapy was not stated. No specific benefit or side effect is stated. This study reports that similar patterns of increased excretion of Na and Cl and changes in K/Na ratio occurred in urine and sweat, but the magnitude per cent of change in salt excretion and K/Na were greater for renal excretion. Due to the nature of the study and small sample size, it is not possible to make a definite recommendation for the inclusion of Spironolactone in the management of children with cystic fibrosis.

Co-administration of Spironolactone with other diuretics in nephritic syndrome (See table 12)

One prospective cohort study investigated the effect of a combination therapy including furosemide and Spironolactone in 30 children between the ages of 1.4-15 years. 28/30 was within our target age range. The study was done in two phases. Phase one included 10 children and 8/10 were within our target population. Phase two included 20 children, all within our target population. VE ( intravascular volume expansion= fractional excretion of sodium(FeNa)>1%) group received IV furosemide at 1mg/kg/dose(max 40 mg) twice daily and oral Spironolactone at 2.5 mg/kg /dose twice daily(max 100mg twice daily, dose based around 25 mg tablets or its multiples) for sever oedema. VC(intravascular contraction= FeNa<1%) group received IV albumin(25%) at 0.5 g/kg twice daily over 2-3 hours followed by IV furosemide at 1 mg/kg per dose(max 40 mg) at the end of albumin infusion for severe oedema.

One intravascular expansion (VE) patient in phase 2, who only received diuretic, had electrolyte abnormalities and was switched to albumin. This study concluded that there was no difference in hospital stay and weight loss between the VE and intravascular contraction (VC) groups. FeNa is useful in distinguishing VC versus VE in children with nephritic syndrome with severe edema. The use of diuretics alone in VE patients is safe and effective. However, the nature of the study and the small sample size, does not allow a definite

12 recommendation for the inclusion of Spironolactone in the management of children with nephritic syndrome.

Spironolactone use in hypertrichosis (see table 13)

One clinical trial including 12 patients, with mean age 6.9(1.2) years, investigated the effect of Spironolactone in children with hypertrichosis. Spironolactone started at an oral dose of 25 and increased to 100 mg x m (-2) x day8-1) twice daily for one year. No side effects were encountered and Spironolactone therapy was well tolerated and no side effects were observed. This study concluded that Spironolactone may be used safely in the treatment of hypertrichosis. It reduces hair growth to some extent in a number of children, however due to the small sample size; it is not possible to make a recommendation for the use of Spironolactone in children with hypertrichosis.

Spironolactone use in mineralocortichoid excess (see table 14)

One case series including 3 children between the ages of 4-9 years with mineralocortichoid excess evaluated the therapeutic effect of Spironolactone. Administration of Spironolactone 100 mg/day orally for 3 days was compared with 3 different protocols: Study 1: ACTH (40 units over 360 min). Study 2: Dietary sodium manipulation (low sodium diet 10 mEq/day, high sodium diet 150 mEq/day, and regular sodium diet 80 mEq/Day). Study 3: Aldosterone (1 mg/day for 3 days) and hydro (20 mg/day fro 5 days). No specific benefit or side effect was stated. This study reported that Spironolactone administration in patient 1 and 2 resulted in fall of BP to the similar level to that achieved with low sodium diet and significantly lower than that achieved with a regular sodium diet. After 3 days of Spironolactone administration, (PRA) and 24 hour urinary PH1 aldosterone remained suppressed. Continuous IV hydrocortisone administration caused an increase in blood pressure and decrease in serum potassium demonstrating the abnormal mineralocortichoid activity of in these patients. Addition of Spironolactone resulted in a decrease in BP, rise in serum potassium, and gradual increase in plasma renin activity. Due to the nature of the study and the very small sample size, it is not possible to make a recommendation for the therapeutic use of Spironolactone in children with mineralocortichoid excess.

Spironolactone Safety (see table 15)

One RCT, one clinical trial, one prospective observational study, and one retrospective study evaluated the safety of Spironolactone in children. The RCT (Walker, 1964) included 16 infants between 6-47 days old. 3/16 received a single dose of Spironolactone (50mg) and their urine volume and the urine sodium, potassium, , and was compared to their urine sample 24 hours before the administration of Spironolactone. No specific benefit or side effect was reported. Three infants who received Spironolactone had a moderately large increase in urine volume and sodium excretion. This study did not make any specific conclusion for Spironolactone. The clinical trial (Atkinson, 1988) included 30 infants who were divided into 4 groups: 1) Single dose of furosemide (n=6), 2) furosemide plus Spironolactone and hydrochlorothiazide (n=7), 3) Spironolactone (n=12) (2-4 mg/kg/day) and hydrochlorothiazide (1-2 mg/kg/day) for 5 consecutive days (n=29), 4) no diuretic (control). No specific side effect was stated. This study concluded that hypercalciuria was observed in all but the control group. Treatment with any of these diuretics in neonates may be associated with abnormal renal losses of calcium, sodium, chloride, and potassium. Neonates requiring long term treatment with diuretics,

13 require special consideration, including monitoring of mineral excretion and renal ultrasonography.

The prospective study (Buck, 2005) included 100 patients between the ages of 4 days-21 years old. 87% of these patients were below that age of one. The participants received different doses of Spironolactone with the average initial dose: 1.8± 0.7 mg/kg/day (range 0.5-4.2) once (n=53) or twice (n=43) a day. Two subjects received doses every 8 hours and two other subjects received doses every 6 hours. Patients with chronic lung disease received higher initial dose than those with heart disease (2±0.8 vs. 1.7±0.5 mg/kg/day).This study reported alteration in potassium levels in 26 children and discontinuation of Spironolactone in one of these children. The average serum potassium level after initiation of treatment was (4.3±0.8 mEq/L with higher values in patients with CLD vs. HD (4.7±0.7 vs., 4.2±0.7 mEq/L). This study showed that Spironolactone was a frequent part of combination diuretic regimen used in the management of pediatric cardiac and pulmonary disease. The most common was alteration in serum potassium level, resulting from the combined effects of Spironolactone with other diuretics, , or ACEI. While hyperkalemia was more common initially, hypokalemia was a more significant problem with long-term diuretic use. Potassium concentrations should be carefully monitored, particularly in children receiving multiple diuretics. Additional research is needed to define the and optimal dosing interval of Spironolactone, as well as determine its long-term effects on potassium.

The retrospective study (Jenis, 1969) included 15 autopsies of subjects between the ages of 5- 75 years who had received 0.025-23.6 grams of Spironolactone. 2/15 was within our target population. Distinctive laminated intracytoplasmic inclusions develop in the human following prolonged Spironolactone therapy. The result of this study suggest a hypothesis: as a consequence of chronic administration of Spironolactone and the sodium diuresis which ensues, there is an activation of the endogenous renin-angiotensin system. Due to the nature of these studies and lack of robust conclusion regarding the safety of Spironolactone in children, it is not possible to make a recommendation for inclusion or exclusion of Spironolactone in the therapy of children.

One article was identified [32] that investigated the age related reference values for the first weeks of life in 34 preterm infants and the possible influence of therapy with dexamethasone(0.1-0.5 mg/kg/day), Spironolactone(3 mg/kg/day), and catecholamines( 2.5 micrograms/kg/min, dobutamine 7.5 microgram/kg/min). However, because the duration of therapy and the indication for Spironolactone administration were not stated, we did not include it in our safety data table. This study reported that therapy with dexamethasone, Spironolactone or catecholamines showed no influence on creatinine excretion. This study concluded that it might be necessary to lower dosage of renal excreted drugs in very immature and mechanically ventilated infants according to the creatinine .

Co-administration of Spironolactone with other diuretics in infants with lung disease (See table 16)

1 double blind cross-over study including 16 infants with bronchopulmonary dysplasia (BPD) investigated the effect of a combination therapy, including Spironolactone with a dose of 1.5 mg/kg/dose twice daily. The patients were divided into two groups: Group 1(n=10) received

14 successively placebo, theophylline, and theophylline plus diuretics(cholorothiazide 20mg/kg/dose combined with Spironolactone 1.5 mg/kg/dose twice daily). Group 2(n=9), received theophylline, placebo, and placebo plus diuretics(cholorothiazide 20mg/kg/dose combined with Spironolactone 1.5 mg/kg/dose twice daily) on successive 4-day periods. No specific benefit or side effect was stated, however, this study showed that oral diuretics and theophylline have synergistic effects in infants with BPD (improved airway resistance, dynamic compliance, maximal expiratory flow at functional residual capacity, and time constant at functional residual capacity significantly more than theophylline alone). The authors suggest that combined orally administered diuretics and theophylline are of benefit in some infants with BPD. Due to the small sample size and the nature of the intervention, it is not possible to make a definite recommendation for inclusion of Spironolactone in infants with BPD. Discussion: Spironolactone has been the drug of choice to treat primary aldosteronism for more than four decades. Serum potassium and creatinine should be monitored frequently during the first 4-6 weeks of therapy, especially in patients with renal insufficiency and mellitus. Spironolactone increases the half life of digoxin. Spironolactone should not be co administered with salicylates because salicylates can interfere with the tubular secretion of an active and decrease the effectiveness of Spironolactone [33].

Treatment of childhood hypertension is difficult for several reasons, lack of extensive scientific data for pharmacokinetics and efficacy of antihypertensive drugs in children, lack of manufactures' recommendations for the use of antihypertensive agents in children, and a lack of age-appropriate formulation for children. Therefore, the clinical decisions to treat pediatric hypertension relies either on limited data from older studies of agents are no longer considered first line of treatment or to adapt drugs studied in adults for pediatric use[34].

Although no specific study investigated the side effects of Spironolactone in children comprehensively, because Spironolactone is a non-selective aldosterone , endocrine-related adverse effects, such as gynecomasteia, are relatively common with this medicine. The selective aldosterone receptor antagonist eplerenone is associated with fewer endocrine-related side effects [2]. The side effects of Spironolactone are related to its antagonistic action against the testosterone receptor; it causes gynecomasteia, mastalgia, impotence, and menstrual irregularities [35]. Spironolactone side effects include: potassium retention, GI irritation, , gynecomasteia, hyperchloremic , , anorexia, , hyponatremia. It is contraindicated in renal failure and should be used with caution if ClCr<10 ml/min. Drug interactions include. Hyperkalemia when used with other potassium sparing drugs; may decrease hypoprothrombinemia effects of anticoagulants [36]. Potassium sparing diuretics can alter digoxin pharmacokinetics [37] (. Spironolactone is one the drugs have been shown to interact with digoxin when co-administered; however, most of data available is derived from the adult patients. Due to the difference in pharmacokinetic and Pharmacodynamics between children and adults, a direct extrapolation of adult population to the pediatric population is not permitted [38]. Spironolactone can also interact with ACE inhibitors (can cause hyperkalemia) and potassium supplements [39]. Eplerenone is a new selective aldosterone receptor antagonist that has been approved for patients with left ventricular dysfunction and clinical evidence of heart failure following acute . Compared to Spironolactone, it has greater selectivity for aldosterone receptors than for steroid receptors, and has superior pharmacokinetic properties [40] (. Spironolactone and eplerenone have similar potencies and mineralocortichoid effects but 15 eplerenone may have fewer endocrine disturbances due to its lower binding affinity for and androgen receptors [41].

Spironolactone has been the subject of a large RCT in adult population and Randomized Aldactone Evaluation Study(RALES), by Pitt et al in 1999, was the first trial( RCT) that showed the beneficial effect Spironolactone in adult patients with CHF.822/1663 patients received Spironolactone(25 mg daily) and 841 received placebo. The treatment group showed a 30% decrease in death [42].

Eplerenone has also been the subject of a RCT and Eplerenone post-Acute Myocardial Infarction heart failure Efficacy and Survival Study (EPHESUS), by Pitt et al in 2003, investigated the effects of eplerenone against placebo in adult patients with myocardial infarction complicated by left ventricular dysfunction. Compare to placebo, the of death from any cause was 0.85 in eplerenone group and the relative risk of death or hospitalization for cardiovascular events was 0.87.The reduction in the risk of sudden death from cardiac causes was statistically significant [43].

List of clinical trials, listed on ClinicalTrial.gov, including the use of Spironolactone in children:

Four clinical trials were listed as completed [44]:

1) "Treatment of boys with precocious puberty"(NCT00001202). Sponsored by Eunice Kennedy Shriver national Institute of Child health and Human Development (NICHD) and included boys≤10 years with familial male precocious puberty treated with Spironolactone, Testolactone, and Desrolerin. The estimated study completion date was recorded as January 2004; however, we could not find any published data for this trial.

2)"Effects of Spironolactone on in patients with chronic heart failure"(NCT00664222). Sponsored by the Tottori University Hospital and included patients with CHF (age was not specified) treated with Spironolactone (25 mg/day) plus furosemide (20 mg/day) for 16 weeks. This trail was listed as completed; however, we could not find any published data for this clinical trial.

3) Effects of Spironolactone on circulating Matrix Metalloproteinases (MMPs) in patients with chronic heart failure"(NCT00663195). Sponsored by the Tottori University Hospital and included patients with CHF (age was not specified) treated with Spironolactone (25 mg/day) plus furosemide (20 mg/day) for 16 weeks. This trail was listed as completed; however, we could not find any published data for this clinical trial.

4)"Spironolactone combined with captopril and for the treatment of patients with pulmonary arterial hypertension associated with congenital heart disease-focus on pulmonary artery"(NCT00240656). Sponsored by Hebei medical University, China. The age of the participants was not stated and although listed as completed, e could not find any published data for this trial.

16 Conclusion: Spironolactone is currently used in the management of several diseases including precocious puberty, hypertension, primary aldosteronism, Bartter's syndrome, and CHF. There is a lack of comprehensive studies evaluating the therapeutic effects of Spironolactone in children. We only identified one systematic review assessing the risks and benefits of diuretics acting on the distal segments of the renal tubule in preterm infants with or developing chronic lung disease. This systematic review concluded that preterm infants older than 3 weeks of age with chronic lung disease, acute and chronic administration of distal diuretics improve pulmonary mechanics, however, spironolactone was not administered alone, sample size was small, and the overall findings were not conclusive. Precocious puberty is a clinical situation that dictates major psychosocial stress on the affected child and the parents. Therefore, although no RCT evaluated the therapeutic benefits of Spironolactone in precocious puberty, it seems reasonable to recommend a combination therapy of spironolactone and testolactone in children with precocious puberty. In most studies that were identified, spironolactone was used as part of a combination therapy. Moreover, the majority of the identified studies are of different designs, such as retrospective, prospective, observational studies, and case series which makes it difficult to come into a definite conclusion about spironolactone's place in the therapy of children with different diseases such as hypertension, primary aldosteronism, Bartter's syndrome, Alport syndrome, CHF and congenital heart diseases, mineralocortichoid excess, hypertrichosis, nephritic syndrome, BPD, and cystic fibrosis. Eplerenone is a new selective aldosterone receptor antagonist that has been approved for heart failure. Although both Spironolactone and eplerenone have been evaluated for their efficacy, no studies have directly compared these two drugs [45]. Therefore, it is not clear if Eplerenone could be recommended for children. Overall there is a lack of pediatric specific safety and efficacy data for spironolactone and adult related data is used to implement guidelines for the use of spironolactone in children.

17 References:

1) WHO Technical Report Series. THE SELECTION AND USE OF ESSENTIAL MEDICINES. Report of the WHO Expert Committee, October 2007. Page:93 2) Volz EM, Felker GM. How to use diuretics in heart failure.Curr Treat Options Cardiovasc Med. 2009 Dec; 11(6):426-32. 3) Loriaux D.L., Menard R., Taylor A., Santen R. Spironolactone and endocrine dysfunction. Annals of internal Medicine 1976 85:5 (630-636) 4) Doggrell SA, Brown L. The spironolactone renaissance. Expert Opin Investig Drugs. 2001 May;10(5):943-54. 5) Bendtzen K, Hansen PR, Rieneck K; Spironolactone/Arthritis Study Group. Spironolactone inhibits production of proinflammatory cytokines, including tumour necrosis factor-alpha and interferon-gamma, and has potential in the treatment of arthritis.Clin Exp Immunol. 2003 Oct;134(1):151-8.). 6) Facts & Comparisons.com 7) Drugs @FDA 8) Drugs.com 9) Limayem Blouza I, Charcosset C, Sfar S, Fessi H. Preparation and characterization of spironolactone-loaded nanocapsules for paediatric use. Int J Pharm. 2006 Nov 15;325(1- 2):124-31. Epub 2006 Jun 23. 10) Yachha SK, Khanna V. Ascites in childhood disease. Indian J Pediatr. 2006 Sep;73(9):819-24. 11) Sica DA. Pharmacokinetics and pharmacodynamics of blocking agents and their effects on potassium . Heart Fail Rev. 2005 Jan;10(1):23-9.) 12) Mayoclinic.com 13) Downing J, Bellis MA. Early pubertal onset and its relationship with sexual risk taking, substance use and anti-social behaviour: a preliminary cross-sectional study. BMC Public Health. 2009 Dec 3;9:446. 14) Hettinger CA, Cheville JC, Lteif AN, Bradley NA, Kramer SA. Department of Urology, Mayo Clinic, Rochester, MN 55905, USA. Precocious puberty in a 7-year-old : a novel case. J Pediatr Urol. 2009 Oct;5(5):412-4. Epub 2009 Jun 13.) 15) Muir A.Precocious puberty. Pediatr Rev. 2006 Oct;27(10):373-81 16) Brämswig J, Dübbers A.Disorders of pubertal development. Dtsch Arztebl Int. 2009 Apr;106(17):295-303; quiz 304. Epub 2009 Apr 24. 17) Leschek E.W. Familial male-limited precocious puberty. Endocrinologist 2004 14:3(148-151). 18) Sanchez RA, Ayala M, Baglivo H, Velazquez C, Burlando G, Kohlmann O, Jimenez J, Jaramillo PL, Brandao A, Valdes G, Alcocer L, Bendersky M, Ramirez AJ, Zanchetti A; America Expert Group.Latin American guidelines on hypertension. Latin American Expert Group. J Hypertens. 2009 May;27(5):905-22.) 19) Kiessling S.G. and Chisti A. Management of pediatric hypertension. Therapy 2009 6:1(51-63). 20) Mitsnefes MM.Hypertension in children and adolescents. Pediatr Clin North Am. 2006 Jun;53(3):493-512, viii.) 21) Goble MM.Hypertension in infancy. Pediatr Clin North Am. 1993 Feb;40(1):105-22. 22) Fanaroff JM, Fanaroff AA. Semin. Blood pressure disorders in the neonate: and hypertension. Fetal Neonatal Med. 2006 Jun;11(3):174-81. Epub 2006 Mar 3.) 23) Seikaly MG. Hypertension in children: an update on treatment strategies. Curr Opin Pediatr. 2007 Apr;19(2):170-7. 24) Andreade H., Antonio N., Rodrigues D., Da Silva A.M., and providencia L.A. High blood pressure in the pediatric age group. 18 Revista Portuguesa de Cardiologia 2010 29:3(413-432). 25) The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents.National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. Pediatrics. 2004 Aug;114(2 Suppl 4th Report):555-76. 26) Schirpenbach C, Reincke M. Primary aldosteronism: current knowledge and controversies in Conn's syndrome. Nat Clin Pract Endocrinol Metab. 2007 Mar;3(3):220-7. 27) Boscaro M, Ronconi V, Turchi F, Giacchetti G.Diagnosis and management of primary aldosteronism. Curr Opin Endocrinol Diabetes Obes. 2008 Aug;15(4):332-8. 28) Chan J.C.M, Cooper S.M. Bartter's Syndrome. International Journal of pediatric nephrology 1981 2:1(47-52) 29) Maggioni, Aldo P. Review of the new ESC guidelines for the pharmacological management of chronic heart failure. European Heart Journal Supplements82205) 7(Supplement J), J15-J20 30) Odland HH, Thaulow EM.Heart failure therapy in children. Expert Rev Cardiovasc Ther. 2006 Jan;4(1):33-40. 31) Josheph D. Kay, Steven D. Colan, Thomas P. Graham, Jr. Congestive heart failure in pediatric patients. Am Heart J 2001; 142:923-8 32) Sonntag J., Prankel b. and Waltz, S. Serum creatinine concentration, urinary creatinine excretion and creatinine clearance during the first 9 weeks in preterm infants with a birth weight below 1500 g. European journal of pediatrics 1996 155:9(815-819) 33) Young WF Jr Adrenal causes of hypertension: pheochromocytoma and primary aldosteronism..Rev Endocr Metab Disord. 2007 Dec;8(4):309-20. 34) Flynn JT. Pharmacologic management of childhood hypertension: current status, future challenges. Am J Hypertens. 2002 Feb; 15(2 Pt 2):30S-33S. 35) Moo TA, Zarnegar R, Duh QY.Prediction of successful outcome in patients with primary aldosteronism. Curr Treat Options Oncol. 2007 Aug;8(4):314-21. 36) Barnes S, Shields B, Bonney W, Hardin J, Abdulla R.The pediatric cardiology pharmacopoeia: 2004 update. Pediatr Cardiol. 2004 Nov-Dec;25(6):623-46. 37) Marcus FI. Pharmacokinetic interactions between digoxin and other drugs. J Am Coll Cardiol. 1985 May;5(5 Suppl A):82A-90A 38) Koren G. Interaction between digoxin and commonly coadministered drugs in children. Pediatrics. 1985 Jun;75(6):1032-7. 39) Balfour I. Management of Chronic Congestive Heart Failure in Children. Curr Treat Options Cardiovasc Med. 2004 Oct;6(5):407-416. 40) Nunez L., Caballero R., Vaquero M., and Tamargo J. of eplerenone. Revista Espanola de Cardiologia Suplementos 2006 6:B(31B-47B) 41) Moffett BS, Chang AC. Future pharmacologic agents for treatment of heart failure in children. Pediatr Cardiol. 2006 Sep-Oct; 27(5):533-51.) 42) Anand K, Mooss AN, Mohiuddin SM. Aldosterone inhibition reduces the risk of sudden cardiac death in patients with heart failure. J Renin Angiotensin Aldosterone Syst. 2006 Mar;7(1):15-9. 43) Struthers AD. Aldosterone blockade in heart failure. J Renin Angiotensin Aldosterone Syst. 2004 Sep;5 Suppl 1:S23-7.) 44) ClinicalTrial.gov 45) Marcy TR, Ripley TL.Aldosterone antagonists in the treatment of heart failure. Am J Health Syst Pharm. 2006 Jan 1;63(1):49-58)

19 Appendix 1: Search terms

Pubmed

1. "Child"[Mesh] OR "Maternal-Child Health Centers"[Mesh] OR "Child Nutrition Sciences"[Mesh] OR "Child Health Services"[Mesh] OR "Child Nutritional Physiological Phenomena"[Mesh] OR "Child Nutrition Disorders"[Mesh] OR "Child Mortality"[Mesh] OR "Child Welfare"[Mesh] OR "Child Care"[Mesh] OR "Child Reactive Disorders"[Mesh] OR "Child Guidance"[Mesh] OR "Child Reactive Disorders"[Mesh] OR "Child Behavior Disorders"[Mesh] OR "Child, Orphaned"[Mesh] OR "Child, Institutionalized"[Mesh] OR "Child, Hospitalized"[Mesh] OR "Child Development"[Mesh] OR "Child Behavior"[Mesh] OR "Developmental Disabilities"[Mesh] OR "Mental Disorders Diagnosed in Childhood"[Mesh] OR "Disabled Children"[Mesh] OR "children" [TIAB] OR "newborn*" [TIAB] OR "childhood" [TIAB] OR "baby" [TIAB] OR "babies"[TIAB] OR "toddler"[TIAB] OR "toddlers"[TIAB] OR "infants"[TIAB] OR "infant"[TIAB] OR "infantile" [TIAB] OR "young patient" [TIAB] OR "young patients"[TIAB] OR "Pediatric Nursing"[Mesh] OR "Pediatric Assistants"[Mesh] OR "Hospitals, Pediatric"[Mesh] OR "Intensive Care Units, Pediatric"[Mesh] OR "Pediatrics"[Mesh] OR "Pediatricians" [TIAB] OR "paediatricians" [TIAB] OR "Pediatrician" [TIAB] OR "paediatrician" [TIAB] OR "Pediatrics" [TIAB] OR "paediatrics" [TIAB] OR "Pediatric" [TIAB] OR "paediatric" [TIAB]

2. "Spironolactone"[Mesh]

Embase

1. "Spironolactone"[Mesh]

2. 'child'/exp OR 'child' OR 'children'/exp OR 'children' OR 'youth'/exp OR 'youth' OR youth* OR newborn* OR 'newborn'/exp OR 'newborn' OR 'new born' OR 'childhood disease'/exp OR 'childhood disease' OR 'baby'/exp OR 'baby' OR babies OR 'infant'/exp OR 'infant' OR infant* OR childhood* OR toddler* OR kid OR kids OR 'young patient' OR boy* OR girl* OR 'young age' OR pediatr* OR paediatr* OR 'child death'/exp OR 'child death' OR 'child health'/exp OR 'child health' OR 'child care'/exp OR 'child care' OR 'childhood mortality'/exp OR 'childhood mortality' OR 'child hospitalization'/exp OR 'child hospitalization' OR 'pediatric hospital'/exp OR 'pediatric hospital' OR child*

3. 'review'/exp OR 'review' OR 'medline'/exp OR medline OR 'medlars'/exp OR medlars OR 'pubmed'/exp OR pubmed OR 'scisearch'/exp OR scisearch OR 'psychlit'/exp OR psychlit OR 'psyclit'/exp OR psyclit OR 'psychinfo'/exp OR psychinfo OR 'electronic databases' OR 'electronic database' OR hand NEAR/5 search* OR manual* NEAR/5 search* OR bibliographic NEAR/5 database* OR pooled NEAR/5 analys* OR pooling OR peto OR sesimonian OR fixed NEAR/5 effect OR 'mantel haenszel' OR 'meta analysis'/exp OR 'meta analysis' OR 'retracted article'/exp OR 'retracted article' OR systematic* NEAR/5 review* OR systematic* NEAR/5 overview* OR quantitative* NEAR/5 review* OR quantitative* NEAR/5 overview* OR methodologic* NEAR/5 review* OR methodologic* NEAR/5 overview* OR integrative NEAR/5 review* OR research NEAR/5 integration OR quantitative* NEAR/5 synthesi* OR embase:ti

Pubmed Systematic review search

Search term: "Spironolactone"[MeSH] AND systematic [sb]

20 Appendix 2: Search strategies

Pubmed

1) Search "Child"[Mesh] OR "Maternal-Child Health Centers"[Mesh] OR "Child Nutrition Sciences"[Mesh] OR "Child Health Services"[Mesh] OR "Child Nutritional Physiological Phenomena"[Mesh] OR "Child Nutrition Disorders"[Mesh] OR "Child Mortality"[Mesh] OR "Child Welfare"[Mesh] OR "Child Care"[Mesh] OR "Child Reactive Disorders"[Mesh] OR "Child Guidance"[Mesh] OR "Child Reactive Disorders"[Mesh] OR "Child Behavior Disorders"[Mesh] OR "Child, Orphaned"[Mesh] OR "Child, Institutionalized"[Mesh] OR "Child, Hospitalized"[Mesh] OR "Child Development"[Mesh] OR "Child Behavior"[Mesh] OR "Developmental Disabilities"[Mesh] OR "Mental Disorders Diagnosed in Childhood"[Mesh] OR "Disabled Children"[Mesh] OR "children" [TIAB] OR "newborn*" [TIAB] OR "childhood" [TIAB] OR "baby" [TIAB] OR "babies"[TIAB] OR "toddler"[TIAB] OR "toddlers"[TIAB] OR "infants"[TIAB] OR "infant"[TIAB] OR "infantile" [TIAB] OR "young patient" [TIAB] OR "young patients"[TIAB] OR "Pediatric Nursing"[Mesh] OR "Pediatric Assistants"[Mesh] OR "Hospitals, Pediatric"[Mesh] OR "Intensive Care Units, Pediatric"[Mesh] OR "Pediatrics"[Mesh] OR "Pediatricians" [TIAB] OR "paediatricians" [TIAB] OR "Pediatrician" [TIAB] OR "paediatrician" [TIAB] OR "Pediatrics" [TIAB] OR "paediatrics" [TIAB] OR "Pediatric" [TIAB] OR "paediatric" [TIAB] Results: 1866521 2) Search "Spironolactone"[Mesh] Results: 4891 3) Search #1 AND #2 Results: 216

Pubmed Systematic Review

1) Search "Spironolactone"[MeSH] AND systematic [sb] 2) Results: 32

Embase

1) Search 'spironolactone'/exp OR 'spironolactone' Results: 19,685 2) Search 'child'/exp OR 'child' OR 'children'/exp OR 'children' OR 'youth'/exp OR 'youth' OR youth* OR newborn* OR 'newborn'/exp OR 'newborn' OR 'new born' OR 'childhood disease'/exp OR 'childhood disease' OR 'baby'/exp OR 'baby' OR babies OR 'infant'/exp OR 'infant' OR infant* OR childhood* OR toddler* OR kid OR kids OR 'young patient' OR boy* OR girl* OR 'young age' OR pediatr* OR paediatr* OR 'child death'/exp OR 'child death' OR 'child health'/exp OR 'child health' OR 'child care'/exp OR 'child care' OR 'childhood mortality'/exp OR 'childhood mortality' OR 'child hospitalization'/exp OR 'child hospitalization' OR 'pediatric hospital'/exp OR 'pediatric hospital' OR child* Results: 3,192,056 3) Search 'review'/exp OR 'review' OR 'medline' OR 'medline'/exp OR medline OR 'medlars' OR 'medlars'/exp OR medlars OR 'pubmed' OR 'pubmed'/exp OR pubmed OR 'scisearch' OR 'scisearch'/exp OR scisearch OR 'psychlit' OR 'psychlit'/exp OR psychlit OR 'psyclit' OR 'psyclit'/exp OR psyclit OR 'psychinfo' OR 'psychinfo'/exp OR psychinfo OR 'electronic databases' OR 'electronic database' OR hand NEAR/5 search* OR manual* NEAR/5 search* OR bibliographic NEAR/5 database* OR pooled NEAR/5 analys* OR pooling OR peto OR sesimonian OR fixed NEAR/5 effect OR 'mantel haenszel' OR 'meta analysis'/exp OR 'meta analysis' OR 'retracted article'/exp OR 'retracted article' OR systematic* NEAR/5 review* OR systematic* NEAR/5 overview* OR quantitative* NEAR/5 review* OR quantitative* NEAR/5 overview* OR methodologic* NEAR/5 review* OR methodologic* NEAR/5 overview* OR integrative NEAR/5 review* OR research NEAR/5 integration OR quantitative* NEAR/5 synthesi* OR embase:ti Results: 18,041,264 4) Search #1 AND #2 AND #3 Results: 2,264

21 Appendix 3: Data Extraction Tables

Table 3: Brion, 2002, Cochrane Systematic review Clinical question: to assess the risks and benefits of diuretics acting on distal segments of the renal tubule in preterm infants with or developing chronic lung disease. Total number of studies included in review: 6 Studies including Spironolactone: 4 RCTs (total n=131), 1 double blind cross over study (n=10)

Citation & Study Age # of Intervention & Comparison Outcomes Benefits Side Results/Comments Date Design range patients Dose effects Hoffman, Double- 26-36 33 Study group Control group Pulmonary None stated None The use of Spironolactone did not affect the 2000 blind weeks (n=17) received (n=16) received mechanics, stated change in lung compliance, resistance or tidal randomized Spironolactone the same dose of electrolyte volume within 2 weeks. The use of Pennsylvania placebo- (1.5 mg/kg per cholorothiazide balance, and the Spironolactone did not affect the change in Hospital, USA controlled dose orally twice and a placebo need for sodium or inspiratory oxygen trial daily) and potassium Using Spironolactone in addition to thiazide did cholorothiazide supplementation not significantly affect the risk of needing (20 mg/kg per sodium supplementation (RR 1.48, CI 0.77 to dose orally twice 2.85; RD +0.21, CI -0.12 to +0.54), the risk of daily) needing potassium supplementation (RR 1.21, CI 0.59 to 2.47; RD +0.09, CI -0.25 to +0.43) or the risk of needing either sodium or potassium supplementation (RR 1.29, CI 0.7 to 2.36; RD + 0.15, CI -0.19 to +0.48) Kao, 1994 Double- Infants 49 (43 Diuretic group Placebo group To determine The None Chronic diuretic therapy significantly improved Intensive care blind (11.1±4 completed (n=22) received (n=21) whether patients respiratory stated lung compliance at 4 wks (WMD 0.62ml/cm nursery,, randomized .0 - the study) cholorothiazide * 9/21 infants benefit from score H2O/kg, CI 0.38 to 0.86, n=43) and at 20 wks Children's placebo- 12.1±3. (40 mg/kg) and with evidence of continuing diuretic improved (WMD 0.25ml/cm H2O/kg, CI 0.02 to 0.48) Hospital, controlled 9 Spironolactone pulmonary administration significantly Long-term diuretic therapy in stable infants Oakland, trial weeks) (4 mg/kg per edema, until they no in the with oxygen-dependent bronchopulmonary California day ) respiratory longer require diuretic dysplasia, after extubation, improves their ** 3/22 infants distress, or oxygen. group pulmonary function and decrease their with evidence of excessive weight Secondary functional inspired oxygen requirements, pulmonary gain received outcomes: natural but does not decrease the number of days edema, furosemide(1 history of BPD, by that they require supplemental oxygen. respiratory mg/kg IV or measuring The improvement in pulmonary function distress, or 2mg/kg orally) pulmonary associated with diuretic therapy is not excessive weight mechanics during maintained after treatment is discontinued. gain received 1st year of life furosemide(1 mg/kg IV or 2mg/kg orally)

22 Citation & Study Age # of Intervention & Comparison Outcomes Benefits Side Results/Comments Date Design range patients Dose effects Engelhardt Randomized Infants( 21 Treatment Control group Dynamic lung No None Although co-administration of 1989, placebo- 7.8 ±2.1 group(n=12) (n=9) received compliance, total beneficial stated hydrochlorothiazide and Spironolactone controlled - 8.8± received a 1:1 no treatment pulmonary effect of significantly increased urine output, neither trial but was 4.2 mixture of resistance, and Spironolacto lung mechanics nor oxygenation was improved not blinded weeks) hydro- haemoglobin ne/ by the intervention. oxygen saturation hydrochlorot and were measured the hiazide Spironolactone(3 first and last day of combination mg/kg/day of each study period on lung both function was compounds) for detected 1 week Albersheim, Randomized Premat 35 Treatment Placebo Survival at None stated None There was a significant difference in the 1989, British double-blind ure group(n=19) group(n=15) discharge. stated proportion of infants discharged alive between Columbia's control trial infants( received received equal Secondary the treatment group (84%) and the placebo Children 36.5± hydrochlorothiaz volume of the outcomes: total no. group (47%). Hospital, 4.7- ide(2 mg/kg drug vehicle for of ventilator days; All in this study were a consequence Canada 40.5± every 12 hours) 8 weeks hospital days; chronic respiratory failure 9.0 and pulmonary Long term diuretic therapy improves outcome days) Spironolactone(1 function; O2 in infants with bronchopulmonary dysplasia .5 mg/kg every requirement; no. of (BPD). Hydrochlorothiazide and 12 hours doses of Spironolactone therapy in infants with BPD enterally) for 8 furosemide needed resulted in improved total weeks clinically compliance over time, with decreased lung damage and increased survival rate. Kao, 1984 Cross-over Preterm 10 2)Thiazide(40 2) vice versa 2) pulmonary 2) Patients None Patients did not require oxygen. Baseline values design infants mg7kg/day (n=5) mechanics did not stated were similar between patients initially started (gestati q12h) and require on placebo and those started on diuretics onal Spironolactone(3 oxygen. age: mg/kg/day q12h) Baseline 29.0±3. for one week pulmonary 2 followed by one values were weeks) week similar placebo(n=5) between both groups

23 Table 4: Spironolactone use in precocious puberty

Citation & Study Age # of Intervention & Dose Comparison Outcomes considered Benefits Side Results/Comments Date Design range patients effects Laue, 1993 Clinical 2.4-7.6 8 Spironolactone + None Rates of growth and bone None None was The authors conclude that NIH, USA trial years Testolactone maturation(height, stated reported this combined therapy is Dose: testicular volume, pubic effective treatment for boys Spironolactone( 2mg/kg/day hair stage) and hormone with familial male in two divided doses and measurements(, precocious puberty in whom increased to 4mg/kg/day testosterone, LH, FSH, central activation of the after 2 weeks and again ) hypothalamic LHRH neuron increased to 5.7 mg/kg/day has not yet occurred and in two weeks later). whom gonadotropin Testolactone(started as 20 secretion remains mg/kg/day and increased to prepubertal. 30 mg/kg/day at two weeks The authors hypothesize and to 40 mg/kg/day at 4 that improved preservation weeks) of height potential may result from earlier institution of Spironolactone and Testolactone to prevent bone age advancement and from prompt suppression with deslorelin if secondary LHRH dependent precocious puberty should develop. Laue, 1989 Clinical 3.3-7.7 9 Group 1(4/9): Group 2(5/9): Rates of growth and bone No All 4 Group 1: growth rate The Clinical trial years Spironolactone (2 mg/kg/day Testolactone maturation, levels of abnormali patients in declined from 15.1±3.2 Center at in two divided doses). After alone for the gonadotropin and sex ties in group 1 cm/year before treatment to NIH, USA 2 weeks, the dose was initial six , testicular electrolyt had mild 9.3±1.5 cm/year during increased to 4mg/kg/day and months and volume and pubic hair es or in gynecoma Spironolactone and to again 2 weeks later, then hepatic, steia 6.1±1.3 cm7year during increased to 5.7mg/kg/day. Testolactone renal, or which was combination therapy with After six months of and hematolo resolved Spironolactone and treatment, Spironolactone Spironolacton gic either on Testolactone. The rate of was discontinued in two e for the function discontinu bone maturation declined patients and six months later second 6 were ation of from 2.43±0.14 bone age- a combination of months. observed Spironolac year/chronological year Spironolactone and Dosage was during tone or before treatment to

24 Citation & Study Age # of Intervention & Dose Comparison Outcomes considered Benefits Side Results/Comments Date Design range patients effects Testolactone was initiated. similar to treatment. upon 2.16±0.17 during The remaining two patients group 1. addition of Spironolactone therapy and in this group were initiated Testolacto to 0.60±0.23 during on the combination therapy ne to their combined therapy. with Spironolactone and therapy. Group 2: growth rate Testolactone upon finishing 1/5 in declined from 13.9±1.1 to 6 months of montherapy group 2 6.8±1.9 cm7year during with Spironolactone. experience Testolactone therapy and to d transient 5.8±0.8 cm/year during abdominal combined therapy with discomfort Spironolactone and which was Testolactone. The rate of resolved bone maturation fell from spontaneo 2.25±0.26 bone age- usly. year/chronological year to 1.21±0.46 during Testolactone therapy and to 0.78±0.48 during the combined therapy. Group 1 &2: the basal gonadotropin levels did not change significantly after treatment. The peak LH level after stimulation with LHRH however, increased significantly after combination therapy (29.7±8.5 vs. 4.5±1.0 IU/liter before treatment). The basal plasma testosterone did not change significantly after treatment, except for moderate decline after treatment with Spironolactone alone (13.8±0.9 vs. 8.9±0.5 nmol/L). Testicular volume and pubic hair did not change during treatment

25 Citation & Study Age # of Intervention & Dose Comparison Outcomes considered Benefits Side Results/Comments Date Design range patients effects with Spironolactone, Testolactone, or both combined. * 6/9 continued to receive the combination therapy for an additional 12 months and maintained normal prepubertal rates of growth and bone maturation. The mean predicted height (± SEM) increased progressively during the combined treatment although the difference between the pre-treatment and post-treatment predictions was not significant(169.5±2.8 at the end of treatment vs. 166.2±4.5 cm before treatment, p=0.29) The authors concluded that blockade of both androgen action and estrogen synthesis with the combination of Spironolactone and Testolactone is an effective short-term treatment for familial precocious puberty. Leschek, Prospect 2.3-5.6 10 Co-administration of None stated Growth rate, rate of bone 7/10 had Rarely Long term treatment with 1999, ive years Spironolactone and maturation, predicted acne gastrointes Spironolactone, NIH, USA Cohort Testolactone and Deslorelin height improvem tinal upset Testolactone, and deslorelin Study (LHRH analog). ent and was noted safely normalizes the rate of Spironolactone was given 2/4 boys with growth and bone maturation daily in two oral doses (1.5 with Testolacto and improves predicted mg/kg/day fro the first 1-2 aggressiv ne height in boys with weeks and 3.0 mg/kg/day e FMPP( familial male- during the second 1-2 weeks behaviour limited precocious puberty)

26 Citation & Study Age # of Intervention & Dose Comparison Outcomes considered Benefits Side Results/Comments Date Design range patients effects and 5.7 mg/kg/day had thereafter). improved Testolactone started at 20 behavior mg/kg/day for the first 1-2 weeks and increased every 1- 2 weeks to 30 mg/kg/day and then 40 mg/kg/day. Deslorelin started at the onset of the secondary central precocious puberty at a dose of 4 microgram/kg/day.

Table 5: Spironolactone use in hypertension

Citation & Date Study Design Age # of patients Intervention & Dose Comparison Outcomes Benefits Side Results/Comments range considered effects

Dulby, 2001, Retrospective 1 month- 18/20 within 8/16 were treated with Combination Blood All 8 None stated Directed International registry study 18 years our age directed monotherapies with of directed pressure treated montherapy is for Glucocorticoid- range Spironolactone(12.5-100 therapies patients often successful remediable 16/20 had mg/day), Amiloride(5-15 maintained in controlling aldosteronism(GRA) hypertension mg), and glucocorticoid a blood blood pressure in suppression( dexamethasone, pressure GRA. 0.5 mg, hydrocortisone, 6.25- below the 15 mg/day) 90th percentile

27 Table 6: Spironolactone use in hyperaldosteronism

Citation & Study Design Age range # of patients Intervention & Comparison Outcomes Benefits Side effects Results/Comments Date Dose considered

Baylen, 1980 Clinical trial Study group : Study 4/15 received No treatment Body weight, None stated None stated In 4 patients Children's 1 week -10 group(n=15) spironolactone81- serum receiving Hospital months 3 mg/kg/24 h) osmolality, Spironolactone, medical Control urine volume resulted in Center, Control group(n=20) and sodium improved diuresis Cincinnati, group: 1.5- to potassium and decreased 9.5 months concentration serum aldosterone. ratio, and The authors serum conclude that aldosterone because they and renin observed hyperaldosteronism in infants with a variety of congenital and acquired cardiac lesions, it is an important factor in fluid and salt retention in infants with heart failure and occurrence of hyperaldosteronism should be considered in the management of infants with such failure and signs of fluid retention refractory to treatment.

28 Table 7: Spironolactone use in Bartter syndrome

Citation & Study Design Age range # of patients Intervention & Comparison Outcomes Benefits Side effects Results/Comments Date Dose considered

Yaser Khalil, Observational 2-32 months 13 Initial potassium Not stated Growth Significant One patient Early diagnosis, 2002 study? supplement (4- catch-up growth catch- dies of sever close follow up, and Al-Adan, 8mmol/kg/day) (weight and up in 4 patients pneumonia compliance with Mubarak Al- followed by height), and increase in with treatment may lead Kabeer, Al- spirinolactone (2 serum serum respiratory to appropriate Jahra mg/kg/day) if potassium potassium in 8 failure from growth and Hospitals, hypokalemia was level. patients who hypokalemic development of Kuwait not corrected. received myopathy. children with Subsequently, indomethacin Seven patients Bartter’s syndrome salicylates(10 therapy. continued to mg/kg/day) or show growth Indomethacin(3-5 failure and 3 mg/kg/day) was were added if hypokalemic hypokalemia was in spite of still not corrected sufficient supplemental potassium therapy. One patient developed renal failure despite the standard therapy.

29 Table 8: Spironolactone use in CHF & congenital heart disease

Citation & Study Design Age range # of Intervention & Comparison Outcomes Benefits Side effects Results/Comments Date patients Dose considered

Hobbins. Randomized 1-12 21 Group B(n=11) Group A(n=10) Clinical Group B 5/10 in group A Mean daily weight 1981, control trial months received received progress: patients who and 3/11 in group fell fro group B but Cardiology Spironolactone( 1-2 potassium(1-3 Daily clinical have continued B vomited within not for group A. ward, mg/kg/day every 12 mEq/kg/day) in observation of treatment one hour of Both groups showed Hospital for h) in addition to addition to , including ingestion of significant decrease Sick digoxin(0.05 digoxin(same weight, Spironolactone medications. in hepatomegaly but Children, mg/kg/day divided dose as group hepatomegaly, were Electrocardiogram the decrease was Canada to 3 equal doses B) and and vomiting. progressing and clinical consistently greater followed by cholorothiazide well clinically assessment in group B after day maintenance dose same dose as when seen at indicated no 2. of 0.005 mg/kg group B) follow-up adverse effect of Significant decrease every 12 h) and treatment in either in respiratory rates cholorothiazide(10- group. began on study day 20 mg/kg/day every 4 in group B but not 12 h) until day 6 in group A. There was no significant difference between the numbers of vomiting episodes between the two groups. In group B the 2nd and 3rd mean plasma Na+ values were significantly lower than 1st decreasing from 138.7(±0.78) to 136.1(±0.77) to 134.4(±1.75). There was no significant difference for duration of time in the study; group A 30 Citation & Study Design Age range # of Intervention & Comparison Outcomes Benefits Side effects Results/Comments Date patients Dose considered

(10.1± 1.62) and group B (11.0± 0.83) days. The authors concluded that the addition of Spironolactone hastens and enhances the response to standard treatment with digoxin and cholorothiazide in infants with CHF.

Ringel, Case series 1-10 years 3 Spironolactone , None Duration of Patient 1 did None stated Authors suggest that 2003 various remission of not achieve a clinical trial of Johns doses( patient 1 protein losing remission of eplerenone, a Hopkins received enteropathy protein loss selective Hospital, 4mg/kg/day and and aldosterone USA then increased to normalization inhibitor, in patients 5mg/kg/day, patient of serum with PLE may be 2 received 2.3 protein levels the appropriate next mg/kg/day and until the step to answer patient 3 received addition of whether the 1.4 mg/kg7day and Spironolactone blocking of then 2.8mg/kg/day) to treatment aldosterone receptors accounts for spironolactone's diuretic effect and whether long term remission can be achieved.

31 Table 9: Spironolactone use in heart disease

Citation & Date Study Age range # of patients Intervention & Dose Comparison Outcomes Benefits Side effects Results/Comments Design considered

Etheridge, 2003, 2/8 (11 11-52 Prospective Spirinolactone( 3.5±1.2 None stated ECG and QT This No serious Long-term oral University of Utah and 12 years study mg/kg/day) and interval analysis regimen complication potassium years old) KCl(3.3±1.5 resulted in was administration mEq/kg/day) for four an associated increase serum weeks. increase in with therapy potassium in serum patients with long potassium QT syndrome type from 2. 4.0±0.3 to 5.2±0.3 mEq/L. Therapy was well tolerated without significant side effects Motz, 2005 20 Infants(10 Retrospective Aldactone plus Same regimen plus Variability in None No infant None of these Departements of days-9.2 study hydrocholorothiazid or beta- heart rate with stated suffered any infants, with pediatric months) furosemide each 1-2 blocker(metoprolol reduced serious side significant left-to- cardiology, mg/kg/day and digoxin or propranolol neurohumoral effects, right shunt, Elisabeth starting with 0.2- stimulation became improved while Children’s 0.5 mg/kg/day and correlated with severely receiving diuretics, Hospital, George- final dose of 1.5-2 improved clinical bradycardic, spirinolactone, and Albercht mg/kg/day) for 1-2 condition. or needed digoxine alone, but university, weeks any other improved after the George-August additional addition of beta university, intervention. blocker (propranolol Germany or metoprolol).

32 Table 10: Spironolactone use in Alport Syndrome

Citation & Study Design Age range # of patients Intervention & Comparison Outcomes Benefits Side effects Results/Comments Date Dose considered

Kaito, 2006, Clinical study 11-19 years 1/5 patients is Spironolactone 25 None stated Urinary Spironolactone There were Before the start of Kobe within our mg/day protein/creatinine in addition to no adverse Spironolactone, U- University target ratio(U-P/C) and angiotensin events P/C showed no Hospital, population(11 estimated converting significant reduction Japan y/o) glomerular enzyme but after the start of filteration inhibitors Spironolactone, U- rates(EGFRs), in (ACEI) and P/C was other words, the angiotensin significantly possibility of receptor reduced at every reducing urinary blocker (ARB) time point (p<0.05) protein excretion was helpful and gradually as well as slowing reducing reduced to a down disease urinary protein minimum (0.13± progression with excretion. 0.06 g/g) at 18 Spironolactone months. treatment EGFR remained virtually unchanged throughout the Spironolactone therapy(before Spironolactone treatment: 129.2± 21.4 ml/min and 18 months later 110.1± 30.1 ml/min, p=0.115). Blood pressure dropped 3 months after Spironolactone treatment (systolic BP from 110.8± 5.0 to 91.2 ±6.6 mmHg and diastolic BP from 58.2 ±2.7 to 51.0± 3.0 mmHg). Although serum 33 Citation & Study Design Age range # of patients Intervention & Comparison Outcomes Benefits Side effects Results/Comments Date Dose considered

potassium level was significantly higher 3 months after Spironolactone treatment, none of the patients developed serious hyperkalemia. This study demonstrated that adding Spironolactone to ACEI and ARB may be effective for lowering proteinuria in Alport syndrome. However, a large- scale study with longer follow-up is required to demonstrate whether the results shown in our study translate to improved renal survival for patients with Alport syndrome.

34 Table 11: Spironolactone use in Cystic fibrosis

Citation & Study Design Age range # of patients Intervention & Comparison Outcomes Benefits Side effects Results/Comments Date Dose considered

May, 1965 Observational 7 months 2 Combination Non stated Relative Non stated Non stated Similar patterns of A special study therapy: changes in increased excretion clinical methopyrapone electrolyte of Na and Cl and research unit (125mg/4h) and excretion by changes in K/Na USA dexamethasone the sweat ratio occurred in (0.375mg/8h) and glands and urine and sweat, but Spironolactone the kidneys the magnitude per (12.5 mg/6h). in cystic cent of change in Duration of this fibrosis salt excretion and combination K/Na were greater therapy is not for renal excretion stated

35 Table 12: Co-administration of Spironolactone with other diuretics in nephritic syndrome

Citation & Study Age # of Intervention & Comparison Outcomes Benefits Side Results/Comments Date& setting Design range patients Dose considered effects

Kapur, 2009 Prospective Phase 30 VE (intra- VC(intravascul Hospital stay None One VE There was no difference in hospital stay Pediatric Cohort study one age Phase vascular volume ar contraction= and weight stated patient in and weight loss between the VE and VC nephrology range= one: 10 expansion = FeNa<1%) loss phase 2 groups. FeNa is useful in distinguishing service at the 1.4-15 patients fractional group received who only VC versus VE in children with nephritic Children's years and 8/10 excretion of IV received syndrome with severe oedema. The use of hospital, are sodium (FeNa) albumin(25%) diuretic diuretics alone in VE patients is safe and Michigan Phase 2 within >1%) group at 0.5 g/kg had effective. mean our age received IV twice daily electrolyte age= range. furosemide at over 2-3 hours abnormalit 7.6± 4.7 Phase 2: 1mg/kg/dose(m followed by IV ies and years 20 ax 40 mg) twice furosemide at was patients daily and oral 1 mg/kg per switched and Spirono- dose(max 40 to albumin 20/20 at 2.5 mg/kg mg) at the end are /dose twice of albumin within daily(max infusion for our age 100mg twice severe oedema range daily, dose around 25 mg tablets or its multiples) for severe oedema

36 Table 13: Spironolactone use in hypertrichosis

Citation & Study Design Age range # of patients Intervention & Comparison Outcomes Benefits Side effects Results/Comments Date Dose considered

Darendeliler, Clinical trial Mean age 12 Spironolactone None Hair growth Spironolactone No side Spironolactone may 1996 6.9(1.2) years started at an oral therapy was effects were be used safely in the Istanbul dose of 25 and well tolerated encountered treatment of faculty of increased to 100 and no side hypertrichosis. It medicine, mg x m (-2) x effects were reduces hair growth department day8-1) twice observed to some extent in a of pediatrics, daily for one year. number of children. Turkey

37 Table 14: Spironolactone use in mineralocortichoid excess

Citation & Study Design Age range # of patients Intervention & Comparison Outcomes Benefits Side effects Results/Comments Date Dose considered Dimartino- Case series 4-9 years 3 Study 4: Study 1: Blood Not stated Not stated Spironolactone Nardi, 1987, Spironolactone ACTH(40 units pressure administration in New York 100 mg/day orally over 360 min) patient 1 and 2 Hospital- for 3 days Study 2: Dietary resulted in fall of BP Cornell sodium to the similar level to medical manipulation(low that achieved with low Center, NY sodium diet 10 sodium diet and mEq/day, high significantly lower sodium diet 150 than that achieved mEq/day, regular with a regular sodium sodium diet 80 diet. mEq/Day) After 3 days of Study 3: Spironolactone Aldosterone( I administration, plasma mg7day for 3 renin activity (PRA) days) and hydro and 24 hour urinary cortisone(20 PH1 aldosterone mg/day for 5 remained suppressed. days) Continuous IV hydrocortisone administration caused an increase in blood pressure and decrease in serum potassium demonstrating the abnormal mineralocortichoid activity of cortisol in these patients. Addition of Spironolactone resulted in a decrease in BP, rise in serum potassium, and gradual increase in plasma renin activity.

38

Table 15: Spironolactone Safety

Citation & Study Age # of Intervention Comparison Outcomes Benefits Side Results/Comments Date Design range patients & Dose considered effects

Walker. Randomiz 6-47 16 3/16 received A control 24 hour urine None No A moderately large increase in urine volume 1964, ed clinical days a single dose urine flow, Na, K, stated clinical and sodium excretion was observed in the 3 Newborn trial of 50 mg collection a Cl, side infants who received Spironolactone but the Nursery of Spironolacton day before Creatinine, effects small sample size did not allow statistical the e administration CH20 were analysis. Winnipeg of diuretics noted No specific conclusion for Spironolactone was General made. Hospital

Atkinson, Clinical Infants( 30 Spironolacton 1)Single dose Urinary None None Hypercalciuria was observed in all but the 1988 trial gestatio e alone(2-4 of calcium stated stated control group. Treatment wit any of these Neonatal nal mg/kg/day) furosemide(n= excretion diuretics in neonates may be associated with intensive age= n=12 6) abnormal renal losses of calcium, sodium, care unit, 26.4±0. chloride, and potassium. Neonates requiring McMaster 6) 2) furosemide long term treatment with diuretics, require university, Postnat plus special consideration, including monitoring of Canada al Spironolacton mineral excretion and renal ultrasonography. age>1 e and week hydrochlorothi azide (n=7) 3) Spironolacton e(2-4 mg/kg/day) and hydrochlorothi azide(1-2 mg/kg/day) for 5 consecutive days (n=29) 39 4) no diuretic ( control)

Buck, 2005, Prospectiv 4 days- 100( 78 Spironolacton None stated Serum Not stated Alteratio The average serum potassium level after University of e 21 % <1 e, the average potassium n in initiation of treatment was(4.3±0.8 mEq/L with Virginia Observatio years year initial dose: concentratio potassiu higher values in patients with CLD vs. children's nal study old) 1.8± 0.7 n m HD(4.7±0.7 vs., 4.2±0.7 mEq/L) Hospital, mg/kg/day (n=26). This study showed that Spironolactone was a USA (range 0.5- Spironola frequent part of combination diuretic regimen 4.2) once ctone was used in the management of pediatric cardiac (n=53) or discontin and pulmonary disease. The most common twice (n=43) ued in adverse effect was alteration in serum a day. Two one child potassium level, resulting from the combined subjects with effects of Spironolactone with other diuretics, received cardiomy aspirin, or ACEI. While hyperkalemia was doses every 8 opathy more common initially, hypokalemia was a hours and two due to more significant problem with long-term other subjects lack of diuretic use. Potassium concentrations should received efficacy be carefully monitored, particularly in children doses every 6 (patient's receiving multiple diuretics. Additional hours. had research is needed to define the Patients with worsenin pharmacokinetics and optimal dosing interval chronic lung g cardiac of Spironolactone, as well as determine its disease function). long-term effects on potassium. received higher initial dose than those with heart disease (2±0.8 vs. 1.7±0.5 mg/kg/day). 66 patients received furosemide, 37 received and 12 received both.

Jenis,1969, Retrospect 5-75 15(2/15 Spironolacton None stated Adrenal None None Distinctive laminated intracytoplasmic

40 Walter Reed ive( autops years within e(0.025-23.6 inclusions stated stated inclusions develop in the human adrenal gland general y) our grams) following prolonged Spironolactone therapy. Hospital, target The result of this study suggest a hypothesis: as Washington, populati a consequence of chronic administration of DC on) Spironolactone and the sodium diuresis which ensues, there is an activation of the endogenous renin-angiotensin system. Since Spironolactone is a synthetic foreign steroidal compound, it may interfere with the normal membrane turnover causing a progressive accumulation of granular membranes and exaggeration of normal phenomenon..

41 Table 16: Co-administration of Spironolactone with other diuretics in infants with lung disease

Citation & Study Age # of Intervention Comparison Outcomes Benefits Side Results/Comments Date& setting Design range patients & Dose considered effects

Kao, 1987 Double-blind Infants( 16 Group Group PFT at the start There was None This study showed that oral diuretics and Intensive care cross over gestatio * 2 1(n=10) 2(n=9) of the study and no stated theophylline have synergistic effects in Nursery at trial nal age= patients received Received at the end of each difference infants with BPD (improved airway Oakland 28.5± participa successively theophylline, 4-day period between resistance, dynamic compliance, maximal Children's 3.4 ted placebo, placebo, and the fluid expiratory flow at functional residual Hospital, weeks) more theophylline, placebo plus intake of capacity, and time constant at functional California than and diuretics(cho the two residual capacity significantly more than once in theophylline lorothiazide groups. theophylline alone). The authors suggest the plus 20mg/kg/dos No infants that combined orally administered study. diuretics(cho e combined required diuretics and theophylline are of benefit in lorothiazide with supplemen some infants with BPD. 20mg/kg/dos Spironolacto tal e combined ne 1.5 diuretics with mg/kg/dose or Spironolacto twice daily) bronchodil ne 1.5 on ators mg/kg/dose successive 4- during the twice daily) day periods. study.

42