spironolactone - heads of medicines agencies
TRANSCRIPT
spironolactone RO/W/0003/pdWS/001
Page 1/42
Rapporteur’s
Public Assessment Report
for paediatric studies submitted in accordance
with Article 45 of Regulation (EC) No1901/2006, as amended
Aldactone
(Spironolactone)
RO/W/0003/pdWS/001
List of product names and MAHs: Aldactone - Pfizer Limited, UK
Spironolactone Winthrop - Sanofi-aventis France
Osyrol - Sanofi-aventis Deutschland GmBH (Germany)
Rapporteur: Romania
Finalisation procedure (day 120): 07 November 2012
Date of finalisation of PAR 30 April 2013
Spironolactone Public Assessment Report RO/W/0003/pdWS/001 Page 2/42
ADMINISTRATIVE INFORMATION
Invented name of the medicinal
product(s):
See section VII
Aldactone,
Spironolactone Winthrop,
Osyrol
INN (or common name) of the active
substance(s):
Spironolactone
MAH (s): Pfizer Limited, UK Sanofi-aventis France (France)
Sanofi-aventis Deutschland GmBH (Germany)
Sanofi-aventis SPA (Italy)
Pharmaco-therapeutic group
(ATC Code):
C03DA01
Pharmaceutical form(s) and strength(s): Pfizer Limited, UK 25mg, 50mg, and 100mg tablets and film coated tablets
Sanofi-aventis
Tablets, 25 mg
Capsules, 25 mg
film coated tablets 50 mg, 75 mg and 100 mg
Rapporteur’s contact person:
Name Name Dana Gabriela Marin, MD
Tel: Phone: +40 21.317.11.02/317.11.15
Fax: +40 21.316.34.97/031.805.74.54
Email: [email protected]
Name of the assessor(s) Name: Dana Gabriela Marin, MD
Email: [email protected]
Spironolactone Public Assessment Report RO/W/0003/pdWS/001 Page 3/42
TABLE OF CONTENTS
I. Executive Summary ....................................................................................................... 5
II. RecommendatioN .......................................................................................................... 6
III. INTRODUCTION ............................................................................................................. 8
IV. SCIENTIFIC DISCUSSION ............................................................................................ 10
IV.1 Information on the pharmaceutical formulation used in the clinical study(ies) ....... 14
IV.2 Non-clinical aspects ................................................................................................................. 15
IV.3 Clinical aspects .......................................................................................................................... 15
V. MEMBER STATES Overall Conclusion AND RECOMMENDATION ........................... 37
VI. List of Medicinal products and marketing authorisation holders involved ............. 41
LIST OF ABBREVIATIONS
ACE - angiotensin converting enzyme
ACTH - Adrenocorticotropic Hormone AE - adverse event
BP - British Pharmacopoeia
BUN - blood urea nitrogen
BPD Bronchopulmonary Dysplasia
Spironolactone Public Assessment Report RO/W/0003/pdWS/001 Page 4/42
CDS - CORE DATA SHEET
CHF - Congestive Heart Failure
CLD - Chronic Lung Disease
CO - CLINICAL OVERVIEW
GNRH - Gonadotropin-Releasing Hormone
MAH Marketing Authorization Holder
MEDDRA - MEDICAL DICTIONARY FOR REGULATORY ACTIVITIES
MR - MINERALOCORTICOID RECEPTORS,
NYHA - NEW YORK HEART ASSOCIATION
PT - PREFERRED TERM
PRA - Plasma Renin Activity
RALES - Randomized Aldactone Evaluation Study
SAE - SERIOUS ADVERSE EVENT
SD - Standard Deviation
SE - STANDARD ERROR
SmPC - Summary Of Product Characteristics
USP - UNITED STATES PHARMACOPEIA
WHO - WORLD HEALTH ORGANIZATION
Spironolactone Public Assessment Report RO/W/0003/pdWS/001 Page 5/42
I EXECUTIVE SUMMARY
No SmPC and PL changes are proposed.
<Summary of outcome>
No change
Change
New study data: <section(s) xxxx, xxxx>
New safety information: <section(s) xxxx, xxxx>
Paediatric information clarified: <section(s) xxxx, xxxx>
New indication: <section(s) xxxx, xxxx>
Spironolactone Public Assessment Report RO/W/0003/pdWS/001 Page 6/42
This is an assessment of data for spironolactone, as part of the Article 45 EU worksharing
procedure for assessment of paediatric studies completed before the Paediatric Regulation entered into
force, 26 Jan 2007. Romania has been appointed as Rapporteur for this procedure.
In accordance with Article 45 of the Paediatric Regulation, by January, the 26th 2008, any
paediatric studies already completed, by the date of entry into force, in respect of products authorised in
the Community shall be submitted by the marketing authorisation holder for assessment to the competent
authority.
The competent authority may update the Summary of Product Characteristics and Package
Leaflet, and may vary the marketing authorisation accordingly. Competent authorities shall exchange
information regarding the studies submitted and, as appropriate, their implications for any marketing
authorisations concerned.
Spironolactone belongs to a drug group called “Potassium-sparing diuretics – aldosterone
antagonists (antagonists of mineralocorticoid receptors)”, which are medicinal products used to block the
effects of mineralocorticoids.
Spironolactone is a synthetic steroid drug that competes for the cytoplasmic aldosterone receptor.
It increases the secretion of water and sodium, while decreasing the excretion of potassium, by competing
for the aldosterone sensitive Na+/K+ channel in the distal tubule of the nephron.
Approximately 5% of the filtered Na+ load is ultimately excreted in the urine.
Spironolactone effects both gonadal and adrenal steroidogenesis to elevate plasma gonadotrophin
levels in children and to act as antiandrogen at the target tissue level. For decades, Spironolactone has
been considered as an antagonist at the aldosterone receptors of the epithelial cells of the kidney and was
clinically used in the treatment of hyperaldosteronism and occasionally as a potassium-sparing diuretic.
Spironolactone may also be useful in the treatment of other conditions such as: portal hypertension,
cirrhosis, and left ventricular hypertrophy. 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.
Two MAHs have provided the documentation for spironolactone in accordance with Article 45
of the Regulation (EC) No 1901/2006, as amended on medicinal products for paediatric use.
The data package submitted by the MAHs under article 45 of the Paediatric Regulation
comprises a clinical study report for one exploratory safety study for 5% w/w spironolactone cream
conducted both in adolescents and adults, for one MAH and an extensive review of the published literature
in the clinical overview report. The study has been performed by Pfizer in USA in 1990. The MAH does
not manufacture or market the topical cream formulation in any country.
A short description of its recommended indications and posology in adult and children had been
provided and some variations in the indications and dosage recommendations are noted between member
states.
The MAH (s) have also conducted a literature search for publications relevant to paediatric
population and has included some published articles as supporting data.
II RECOMMENDATION
No SmPC and PL changes are proposed in this worksharing procedure and thus no further action
is required.
Based on the review of the presented paediatric data on spironolactone, the rapporteur considers
that the data from the submitted studies do not specifically indicate any need of major change of the
current paediatric information in the SmPCs.
The submitted paediatric studies do not influence the benefit-risk and that there is no
consequential regulatory action. However, in connection with this PdWS procedure the Rapporteur may
suggest that an update of the SPCs and PILs regarding paediatric population for all formulations which
contain spironolactone is needed in order to be in line with the revised SPC guideline (September 2009)
Spironolactone Public Assessment Report RO/W/0003/pdWS/001 Page 7/42
and QRD template to improve the information available on the use of medicinal products in the paediatric
population.
Spironolactone has been registered on a national basis in the EU member states and currently
there are some divergences between member states in regard to indications and dosage recommendations
of oral formulations of spironolactone. There is no agreement between the MSs on therapeutic indications
and the initial dose range of spironolactone in children 1 month-12 years of aged.
Since the pathology of different types of conditions for the use of spironolactone in adults and
children is not similar, the extrapolation of the efficacy in adults to all conditions in children is not
considered acceptable and separate indications for the paediatric population are recommended, when
appropriate.
An explicit wording in section 4.1, respective 4.2 for paediatric population is considered
necessary.
Based on the review of the available data there is no clinical evidence to restrict the use of
spironolactone to specific paediatric population. No age restriction should be applied.
The proposed amendment by one MAH for section 4.2, to change the initial dose range for
children from 1.5 -3 mg/kg/day to 1-4 mg/kg/day cannot be supported, based on the submitted data
package for this procedure.
The company’s proposal in section 4.2 of the SmPC was to change the initial recommended
dosage in children for spironolactone.
“Paediatric population
In general, the daily dose in children is 1.5 mg to 3 mg per kg body weight.”
The justification given was to be in line with the information available in Clinical Overview, dated 06-
Nov-2009 and with the Aldactone SmPC, France.
Further to the received Day 85 Member States comments, there were issues that have been needed
to be clarified.
The paediatric indications of spironolactone and the dosing information included in section 4.2
regarding the paediatric population are not very clear.
Spironolactone has been registered on a national basis in the EU member states and currently
there are some divergences between the various countries as regards posology and indications.
The indications and recommended doses are largely based on expert opinion and clinical
experience (spironolactone has been used for more than 50 years in children and adults).
There is a lack of comprehensive studies evaluating the therapeutic effects of Spironolactone in
children.
Physicians have established treatment protocols for paediatric use based on experience and the
available literature. Consensus seems to exist that dosing for the younger paediatric population should be
calculated per body weight. Indications are not specified separately for adults and children in all EU
member states and no side effects specific for the paediatric population have been identified.
Currently, in Europe products containing spironolactone are available only as 25 mg, 50 mg, 75
mg, and 100 mg tablets, capsules and film-coated tablets. No specific paediatric formulation is available.
A liquid formulation would be useful to overcome the possible difficulties of administering the
correct dose to small children especially during the initial period of dose titration.
If necessary in younger children, a suspension may be prepared by crushing tablets.
As part of the SmPC there is the following wording:
“in children < 6 years of age, the 25 mg spironolactone tablet (or part of the table) is to be crushed and
suspended in a liquid and the liquid will preferably be a syrup or 20% methylcellulose solution in order to
promote suspension”
From the performed studies such a suspension is stable for 1 month when refrigerated.
It should be clearly mentioned in the product information that only 25 mg dosage as tablets is
specifically use in children.
There are no data available regarding the stability of a potential solution by crushing 25 mg
capsules.
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The rapporteur acknowledges that the aim of this paediatric work-sharing procedure under Article
45 is to review the paediatric use of spironolactone, regardless of the availability of age appropriate
formulations for all paediatric subsets in the MSs.
However, the MAHs are encouraged to develop an age appropriate formulation for easier
administration and to ensure correct dosage during the titration period and during maintenance treatment
in small children.
The currently approved SmPC does not contain dosing wording for the paediatric use, presented
by age or relevant subsets.
The MAH (s) were requested to review the available evidence and to provide proposals for a
SmPC text with reference to the use of spironolactone in paediatric population in sections 4.1 and 4.2,
taking into account the current SmPC guidelines. Also the MAH(s) was asked to further justify and
discuss the pharmacokinetics of spironolactone in paediatric population at different ages.
Based on the submitted response no additional information has been provided.
The current data do not support any specific changes in section 4.1 regarding paediatric
indications. No clarification regarding the discrepancy in paediatric posology for the originator product
Aldactone 25 mg has been provided.
No discussion has been provided by the MAH of the originator product, concerning the different
initial recommended dosage noted in the French originator Aldactone 25 mg.
From the provided data there is a discrepancy regarding the therapeutic indications and the initial
recommended doses in children for Aldactone 25 mg referred to French Summary of Product
Characteristics (SmPC) and Core Data Sheet text. The Myasthenia gravis indication “Adjuvant treatment
in myasthenia” and the initial recommended posology in children up to 1 to 4 mg/kg/day, included in the
French SmPC for Aldactone 25 mg were not stated in the provided Core Data Sheet.
A closer review of the available paediatric information has not been performed by the MAH to
reflect the use of Spironolactone in the paediatric population.
Considering that there are significant differences in the product information of the originator
medicinal product registered in different MS, it is the responsibility of the MAH to consider how to
address this situation, taking into account that it is an objective of the Paediatric Regulation to give
children the same access to authorised medicinal products suitable for their use across the European
Community. The MAH may consider a range of regulatory options including submission of a series of
variations or initiation of a referral procedure in order to achieve a harmonised position.
Taking into consideration that spironolactone is acknowledged for the potential serious risk of
hyperkalaemia, which could be more severe in children, it should be ensured that all authorised SmPCs
and PLs are updated to contain adequate information. Such information may be required by prescribers
and carers in order to properly consider the benefits and risks in the different situations for which
spironolactone is taken into consideration for use in paediatric population. This will help to ensure that
spironolactone is used safely in children. For these reasons the Rapporteur would like to recommend that
spironolactone be considered for a SmPC harmonisation procedure.
III INTRODUCTION
In accordance with Article 45 of the Regulation (EC) No. 1901/2006, as amended on medicinal
products for paediatric use, the CMD(h) and the EMA require that for authorised medicinal products, that
contain spironolactone, any paediatric studies completed before 26 January 2007, which have not been
submitted yet to the Competent Authority where the product is authorized should be submitted for
assessment to European Health Agencies by 26 January 2008.
It is intended to describe and summarise the outcome of the presented studies and to draw
conclusions and suggestions with regards to the impact on the marketing authorisations.
The aim of this EU Worksharing project is the assessment of the clinically relevant information
on efficacy and safety data relative to spironolactone for the use in children, to enable progress on
medications in this population.
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Two MAH(s) are involved in this European Work-sharing of paediatric data on spironolactone
in accordance with Article 45 of the Regulation (EC) No 1901/2006, as amended on medicinal products
for paediatric use.
The MAH (s) submitted a review of the clinically relevant information on efficacy and safety
related to spironolactone in children. in accordance with Article 45 of the Regulation (EC)No 1901/2006,
as amended on medicinal products for paediatric use. Short clinical expert overviews have also been
provided.
The supportive documentation available for this purpose was the following:
- The own clinical paediatric studies and
- Literature searches on standard medical databases (i.e. Embase, Medline and Cochrane).
The aim of this EU Work-sharing project is the proper assessment of paediatric data on
spironolactone and the update the summary of product characteristics accordingly.
A line listing and annex II, including SPC wording of sections 4.1 and 4.2 related to the
paediatric use of the medicinal products have been submitted for all concerned MAH (s).
The Rapporteur assessed the data submitted by the MAHs, and also performed his own research
of the literature.
IV SCIENTIFIC DISCUSSION
Product background
Spironolactone received first regulatory approval in Canada on 08 December 1959. In Europe the
first marketing authorization (MA) for spironolactone was granted on 24 March 1962 in Italy.
Currently the reference product for spironolactone is marketed in 12 countries in Europe
(Belgium, France, Greece, Iceland, Ireland, Luxembourg, Malta, Norway, Portugal, Spain, Sweden, and
the United Kingdom).
Spironolactone is a steroid with a structure resembling that of the natural adrenocorticoid
hormone, aldosterone. It acts as a competitive inhibitor of aldosterone on the distal portion of the renal
tubule, thereby increasing sodium and water excretion and reducing potassium excretion.
Aldosterone acts on kidney tubules and collecting ducts, causing a reabsorption of sodium,
bicarbonate, and water. Conversely, aldosterone decreases reabsorption of potassium, which, with H+, is
then lost in the urine. Enhancement of sodium reabsorption by aldosterone also occurs in gastrointestinal
mucosa and in sweat and salivary glands. Elevated aldosterone levels may cause alkalosis and
hypokalemia, whereas retention of sodium and water leads to an increase in blood volume and blood
pressure.
Spironolactone competitively inhibits the binding of aldosterone to the cytosolic
mineralocorticoid receptors (MR), situated in the epithelial cells of the more distal tubule and collecting
duct. This receptor is a member of the superfamily of receptors for steroid hormones, thyroid hormones,
vitamin D, and retinoids.
Spironolactone binds to aldosterone receptors and may also reduce the intracellular formation of
active metabolites of aldosterone. Amiloride and triamterene do not block the aldosterone receptor but
instead directly interfere with Na+ entry through the epithelial sodium ion channels (ENaC) in the apical
membrane of the collecting tubule. Since K+ secretion is coupled with Na
+ entry in this segment, these
agents are also effective potassium-sparing diuretics.
Unlike the MR-aldosterone complex, the MR-spironolactone complex is not able to induce the
synthesis of AIPs (aldosterone-induced proteins). Since spironolactone blocks the biological effects of
aldosterone, this agent also is referred to as aldosterone antagonists. MR antagonists are the only diuretics
that do not require access to the tubular lumen to induce diuresis.
The effects of MR antagonists on urinary excretion are very similar to those induced by renal
epithelial Na+-channel inhibitors. However, unlike that of the Na
+-channel inhibitors, the clinical efficacy
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of MR antagonists is a function of endogenous levels of aldosterone. The higher the levels of endogenous
aldosterone, the greater are the effects of MR antagonists on urinary excretion.
MR antagonists have little or no effect on renal hemodynamics and do not alter
tubuloglomerular feedback (TGF).
The actions of the aldosterone antagonists depend on renal prostaglandin production and
consequently the actions of K+-sparing diuretics can be inhibited by NSAIDs under certain conditions.
Spironolactone has some affinity toward progesterone and androgen receptors and thereby
induces side effects such as gynecomastia, impotence, and menstrual irregularities.
Mechanism of action
Spironolactone inhibits the effect of aldosterone by competing for intracellular aldosterone
receptors in the cortical collecting duct. This decreases the reabsorption of sodium and water, while
decreasing the secretion of potassium. Spironolactone has a fairly slow onset of action, taking several days
to develop, and, so, the effect diminishes slowly. This is because steroid pathways alter gene transcription,
and it will take several days for the gene products to change (in this case the ENaC and ROMK channels
will be decreased).
Spironolactone has anti-androgen activity by directly binding to and blocking androgens from
interacting with the androgen receptor, by blocking androgen production, and by increasing estrogen
levels. Production of androgens is decreased by inhibiting 17α-hydroxylase and 17,20-desmolase, which
are enzymes in the testosterone biosynthesis pathway. Estrogen levels are increased by enhancing the
peripheral conversion of testosterone to estradiol and by displacing estradiol from sex hormone-binding
globulin (SHBG).
Pharmacokinetics:
Absorption – Spironolactone is incompletely but fairly rapidly absorbed from the gastrointestinal
tract and the extent of absorption will depend on the particle size and formulation and is improved after
food. Bioavailability is estimated from 60 to 90%. Time to peak plasma concentration is approximately
one hour.
Distribution – Although the plasma half life of spironolactone itself is short (1.3 hours) the half
lives of the active metabolites are longer (ranging from 2.8 to 11.2 hours).
Spironolactone is estimated to be 90% protein bound. Volume of distribution, extent of tissue
accumulation and ability to cross the blood brain barrier are not known. Spironolactone or its metabolites
may cross the placental barrier and canrenone is secreted breast milk. Spironolactone is known to have a
slow onset of action two to three days and a slow diminishment of action.
Metabolism – The main site of biotransformation is the liver where it is metabolised, to 80%
sulphur containing metabolities such as 7 alpha- thiomethylspironolactone and canrenone (20%). Many of
these metabolities also have a diuretic-activity. Canrenone, which is an active metabolite, has a biphasic
plasma half life of about 4 - 17 hours.
Elimination – Spironolactone is excreted in the urine and faeces in the form of metabolites.
The renal action of a single dose of spironolactone reaches its peak after 7 hours, and activity
persists for at least 24 hours.
A review of the comparative efficacy, safety, and place in therapy of Spironolactone in children
has been performed.
The search methods for identification of safety and efficacy data included an electronic search in
the following database: Cochrane library, Pubmed, Embase for articles published from 1950 to present.
The relevant articles were studied and summarized in combination with other resources, such as National
Clearinghouse Guidelines, paediatrics and pharmacology text books.
Spironolactone is well established in the current pediatric clinical practice. Spironolactone is listed
in the WHO Model List of Essential Medicines List for Children on the complementary list as an oral
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liquid (1 to 20 mg/mL) or as a 25 mg tablet. The 1998 edition of the Pediatric Hospital Level Standard
Treatment Guidelines and Essential Drug List for South Africa includes spironolactone under treatment
guidelines for heart failure (2 to 4 mg/kg/day in two divided doses) and ascites (3 to 5 mg/kg/day as a
single daily dose) associated with cirrhosis, portal hypertension, and chronic liver failure.
In Europe, only the current French Summary of Product Characteristics (SmPC) for Aldactone
(spironolactone 25 mg, scored, film-coated tablet) contains therapeutic indications in children and for all
the other currently approved medicinal products which contain spironolactone, the use in children is
included in section 4.2 with adapted posology.
As it previously mentioned the French Summary of Product Characteristics (SmPC) for Aldactone
(spironolactone 25 mg, scored, film-coated tablet) contains therapeutic indications in children which are:
- Treatment of primary hyperaldosteronism
- Hyperaldosteronism secondary to effective diuretic treatment
- Essential hypertension
- Edematous states that may accompany hyperaldosteronism:
- Edema and ascites in heart failure
- Nephrotic syndrome
- Cirrhotic ascites
- Adjuvant treatment in myasthenia; spironolactone spares potassium and decreases the exaggerated
requirements for potassium.
Also, there are publications available to support the currently used of spironolactone in the
management of several diseases in children including: precocious puberty, Bartter's syndrome, and
Congestive Heart Failure (CHF).
Spironolactone use in precocious puberty
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
medications that can delay further development. Possible complications of precocious puberty include
short height and poly cystic ovarian syndrome. 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 sex, substance abuse, and violence, especially in deprived communities
contributing to health inequalities. Precocious puberty can be due to several etiologies, gonadotropin
dependent or gonadotropin independent. 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. Treatment is usually indicated due to the major psychosocial stress on the affected child. There
are two approaches to treat familial male-limited precocious puberty (FMPP). The first is administration
of ketoconazole and the second is a combination of Spironolactone and Testolactone.
Spironolactone use in hypertension Recent reports from the WHO highlights the importance of chronic diseases such as hypertension
as an obstacle to the achievement of good health status. 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. Until recently, the
incidence of pediatric hypertension has been low, 1-3%, but average blood pressure levels have risen
substantially among American children. The incidence of hypertension in infants has risen in recent years
for two reasons: better monitoring methods and increasingly successful salvage of smaller newborns.
Hypertension can be seen in up to 3% of Neonatal Intensive Care Units (NICU) admissions.
Hypertension is among the more prevalent treatable diseases among children and it carries
significant short-term and long-term morbidity and mortality. Antihypertensive drugs are indicated in
children with symptomatic hypertension, secondary 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.
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Hypertension in children is defined as average systolic BP or diastolic BP that is ≥ 95th percentile
for ender, age, and height on at least three separate occasions. Primary (essential) hypertension in children
is usually mild or Stage 1 hypertension. It is often associated with a positive family history of
hypertension or CVD risk factors or co-morbidities. Renal parenchymal and renovascular diseases are the
most common (60% to 70%) causes of secondary hypertension in children.
The most common causes of hypertension by age group, are:
Newborn infants: renal artery thrombosis, renal artery stenosis, congenital renal
abnormality, coarctation of the aorta
Infancy to 6 years: renal parenchymal and structural renal disease, coarctation of the
aorta, renal artery stenosis
6 to 10 years: renal parenchymal disease, renal artery stenosis, primary hypertension
Adolescence: primary hypertension, renal parenchymal disease
Left-ventricular hypertrophy is the most prominent clinical evidence of target-organ damage in
paediatric hypertension, and can be seen in as many as 41% of paediatric patients. Paediatric patients with
severe cases of hypertension are also at increased risk of developing hypertensive encephalopathy,
seizures, cerebrovascular events, and congestive heart failure.
Due in part to the increasing prevalence of childhood obesity as well as growing awareness of the
disease, the prevalence and rate of diagnosis of hypertension in children and adolescents appears to be
increasing from the estimated > 1% in the 1980s to 2.2% - 3.6% at present. This increase also reflects an
epidemiologic shift from secondary hypertension, most often caused by renal and renovascular diseases, to
primary hypertension as the main cause of paediatric hypertension.
Current management of Hypertension
In children and adolescents therapeutic lifestyle changes are the first-line treatments for hypertension and
pre-hypertension. Weight reduction is the primary goal for obesity-related hypertension, and may limit
future increases in blood pressure. Evidence based benefits of regular physical activity; restriction of
sedentary activities, as well as dietary modifications have been recognized.
The pharmacological intervention is usually initiated after insufficient response to lifestyle modification,
with a single drug. Five groups of anti-hypertensive drugs recommended for use in children are:
1) diuretics, 2) beta-blockers, 3) angiotensin-converting enzyme inhibitors, 4) calcium channels blockers,
and recently also 5) angiotensin receptor blockers.
The goal for antihypertensive treatment in children should be reduction of BP to below the 95th percentile
unless concurrent conditions are present, in which case BP should be lowered to below the 90th percentile.
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 mg/day. All patients treated with diuretics should have their electrolytes
monitored shortly after initiating the therapy and periodically thereafter. Spironolactone may cause severe
hyperkalemia, especially if given with ACE inhibitors or angiotensin receptor blocker (ARB).
Spironolactone use in hyperaldosteronism
Primary aldosteronism is the common cause of secondary hypertension, accounting for
approximately 10% of the hypertensive population. Primary aldosteronism is the most common form of
the endocrine hypertension and its early diagnosis and treatment is crucial.
Spironolactone use in Bartter syndrome 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, triamterene, propranolol, and prostaglandin.
Spironolactone use in CHF & congenital heart disease
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Congestive Heart Failure (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. 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 enzyme inhibitors, cardiac glycosides,
and beta blockers. 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.
Current paediatric specific guidelines recommend a dose of 1-2g/kg of Spironolactone for the
management of several clinical indications in children.
Indications and dose regimens for
Spironolactone in children Indication/s Dosage
Diuresis in congestive heart failure, ascites,
oedema, and nephritic syndrome reduction
of hypokalemia induced by other diuretics
or amphotericin; primary
hyperaldosteronism
†
Diuresis in congestive heart failure, ascites,
oedema and nephrotic syndrome; reduction of
hypokalemia induced by other diuretics or
amphotericin.
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
and oedema, reduction of hypokalemia
induced by diuretics or amphotericin ††
By mouth:
Neonate: 1-2 mg/kg daily in 1-2 divided doses;
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 (British National Formulary) for children 2009
The effect of spironolactone use in Alport Syndrome, Cystic fibrosis, hypertrichosis and in co-
administration with other diuretics in nephritic syndrome or in infants with lung disease has been
investigated in several published observational studies
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.
Spironolactone Public Assessment Report RO/W/0003/pdWS/001 Page 14/42
There is a lack of comprehensive studies evaluating the therapeutic effects of Spironolactone in
children.
However, spironolactone has been a frequent part of combination diuretic regimen used in the
management of pediatric cardiac and pulmonary disease and 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
diabetes mellitus.
It was 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.
In safety studies 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).
In general the dose range varied between 2-4 mg/kg/day. It was 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 chronic lung
disease (CLD) vs. heart disease (HD) (4.7±0.7 vs., 4.2±0.7 mEq/L).
The most common adverse effect was alteration in serum potassium level, resulting from the
combined effects of Spironolactone with other diuretics, aspirin, 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 pharmacokinetics and optimal dosing interval of
Spironolactone, as well as determine its long-term effects on potassium.
I.1 Information on the pharmaceutical formulation used in clinical studies
In the submitted study the pharmaceutical formulations was topical 5%: spironolactone cream.
Currently this formulation is not manufactured or marketed in any country.
Spironolactone received first regulatory approval on 08 December 1959 in Canada.
In Europe, the first marketing authorization (MA) for spironolactone was granted on 24 March
1962 in Italy.
International Birth Date: 08 December 1959
Country of First Approval: Canada
European Harmonized Birth Date: 01 March 1962
Spironolactone is approved in 85 countries and is currently marketed in 65 countries.
Spironolactone Public Assessment Report RO/W/0003/pdWS/001 Page 15/42
In Europe, products containing spironolactone are available only for oral administration as 25 mg,
50 mg, 75 mg, and 100 mg tablets, capsules and film-coated tablets.
Spironolactone s available in Europe for oral administration as: tablets, film-coated tablets and
capsules. .
Spironolactone 100 mg/gram granules for oral suspension from Pfizer was available only in Japan
(approval date 13-Jun-1996, launch date 01-Apr-1978, currently status – withdrawn, withdrawal date 18-
Sep-2008). It was stated that the withdrawal was not due to safety reasons.
Currently no specific paediatric formulation is available.
The current SmPC in France for Aldactone (spironolactone 25 mg, scored, film-coated tablet)
states that in children <6 years of age, the 25 mg spironolactone tablet (or part of the table) is to be
crushed and suspended in a liquid and the liquid will preferably be a syrup or 20% methylcellulose
solution in order to promote suspension.
A search of the published biopharmaceutical literature found additional methods for
extemporaneously compounding liquid oral formulations of spironolactone that may be suitable for use in
pediatric patients.
Suspensions of spironolactone at concentrations of 2.5, 5.0, and 10.0 mg/mL were prepared by
grinding film-coated tablets to a fine powder, adding Purified Water USP, titrating the mixture to form a
fine paste, adding Cherry Syrup NF, and homogenizing the suspension. Such a suspension is stable for 1
month when refrigerated.
I.2 Non-clinical aspects
Non-clinical studies have not been provided or summarized by the MAHs on spironolactone. It
is noted that no literature review has been conducted by the MAHs to identify preclinical studies relevant
for the paediatric use of this active substance.
I.3 Clinical aspects
A) Summary of clinical program sponsored by Pfizer Limited
1. Introduction
The MAH has no efficacy studies on file to support the beneficial effects of spironolactone in
paediatric population.
Pfizer Limited included in this submission one completed exploratory safety clinical study,
multicenter, double-blind, placebo -controlled for 5% w/w spironolactone cream conducted both in
adolescents and adults, in USA, 1990.
The supportive documentation available for this work-sharing procedure was the following: the
published paediatric studies for spironolactone from literature searches on standard medical databases
(1990-2007), a critical expert overview and Aldactone Company Core Safety Information.
Pfizer Limited has reviewed the results of this study and has concluded that no changes to the
Aldactone (spironolactone) SmPC are required. The MAH stated that the submitted paediatric studies do
not influence the benefit risk for their product and that there is no consequential regulatory action.
The completed paediatric safety study is the following:
Study Code: S84-96-06-016, dated 28 March 1996
Protocol Number: S84-89-02-016
Study Title: A Multicenter, Double-Blind, Vehicle Controlled Study of Topical 5%
Spironolactone Cream in the Treatment of Nodulocystic Acne
Pfizer Study Report Number: S84-96-06-016, dated 28 March 1996
Spironolactone Public Assessment Report RO/W/0003/pdWS/001 Page 16/42
Additionally, the MAH submitted an extensive review of the biomedical literature found in
published references reporting the efficacy of spironolactone in pediatric patients, and confirming that the
use of spironolactone is well established in current pediatric clinical practice. Established dosing regimens
generally range from 1 to 4 mg/kg/day.
WHO Model List of Essential Medicines for Children, October 2007.
Mather LK, Wickman A. Stability of extemporaneously compounded spironolactone
suspensions. Am J Hosp Pharm 1989.
Pramar Y, Das Gupta V. Formulation of an oral liquid dosage form of spironolactone: effect
of cosolvents and excipients. Pharm Res 1991;8(10, Suppl):S168.
Salgado AC, Rosa ML, Duarte MA, et al. Stability of spironolactone in an extemporaneously
prepared aqueous suspension: the importance of microbiological quality of compounded paediatric
formulations. Eur J Hosp Pharm Sci 2005;11:68-73.
Allen LV, Erickson MA. Stability of ketoconazole, metolazone, metronidazole, procainamide
hydrochloride, and spironolactone in extemporaneously compounded oral liquids. Am J Health-Syst
Pharm 1996;53:2073-2078.
Witte MK, Stork JE, Blumer JL. Diuretic therapeutics in the pediatric patient. Am J Cardiol
1986;57:44A-53A.
Baylen BG, Johnson G, Tsang R, et al. The occurrence of hyperaldosteronism in infants with
congestive heart failure. Am J Cardiol 1980;45:305-310.
Hobbins SM, Fowler RS, Row RD, et al. Spironolactone therapy in infants with congestive
heart failure secondary to congenital heart disease. Arch Disease Childhood 1981;56:934-938.
Kao LC, Warburton D, Sargent CW, et al. Furosemide acutely decreases airway resistance in
chronic bronchopulmonary dysplasia. J Pediatr 1983;103:624-629.
van der Vorst MMJ, Kist JE, van der Heijden AJ, Burggraaf J. Diuretics in pediatrics. Pediatr
Drugs 2006;8(4)245-264.
Pitt B, Zanna R, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in
patients with severe heart failure. N Engl J Med 1999;341(10):709-717.
Buck ML. Clinical experience with spironolactone in pediatrics. Ann Pharmacother
2005;39:823-828.
New MI, Levine LS. Mineralocorticoid hypertension in childhood. Mayo Clin Proc
1997;52:323-328.
Batista MC, Mendonca BB, Kater CE, et al. Spironolactone-reversible rickets associated with
11 beta-hydroxysteroid dehydrogenase syndrome. J Pediatr 1986;109(6):989-993.
New MR, Stoner E, DiMartino-Nardi J. Apparent mineralocorticoid excess causing hypertension
and hypokalemia in children. Clin Exp Hypertens Part A Theory and Practice 1986;8(4):751-772.
Flynn JT, Daniels SR. Pharmacologic treatment of hypertension in children and
adolescents. J Pediatr 2006;149(6):746-754.
Spironolactone Public Assessment Report RO/W/0003/pdWS/001 Page 17/42
Temple ME, Nahata MC. Treatment of pediatric hypertension. Pharmacotherapy,
2000;20(2):140-150.
Miller K. Pharmacological management of hypertension in paediatric patients: a
comprehensive review of the efficacy, safety and dosage guidelines of the available
agents. Drug 1994;48(6):868-997.
Lurbe E, Cifkova R, Cruickshank JK, et al. Management of high blood pressure in children
and adolescents: recommendations of the European Society of Hypertension. J Hypertens
2009;27:1719-1742.
Feld LG, Lieberman E, Mendoza SA, et al. Management of hypertension in the child with
chronic renal disease. J Pediatr 1996;129:S18-S26.
Hanna JD, Chan JCM, Gill JR. Hypertension and the kidney. J Pediatr 1991;118(3):327-340.
Sharma M, Nair MNG, Jatana SK, et al. Congestive heart failure in infants and children.
MJAFI 2003;59:228-233.
Buchhorn R, Bartmus D, Siekmeyer W et al. Beta-blocker therapy of severe congestive
heart failure in infants with left to right shunts. Am J Cardiol 1998;81(11):1366-1368.
Chéron G, Le Masne A. Traitement de I’insuffisance cardiaqu aiguë du nourrisson. Arch
Pediatr 1996;3:176-179.
Wimmer M, Bachl G, Schlemmer M, et al. Experiences with Aldactone- in pediatric
cardiology. Pädiatrie und Pädologie 1979;14:363-372.
Kapur G, Valentini RP, Imam AA, et al. Treatment of severe edema in children with
nephrotic syndrome with diuretics along – a prospective study. Clin J Am Soc Nephrol 2009;4:907-
Yachha SK, Khanna V. Ascites in childhood liver disease. Indian J Pediatr 2006;73(9):819-
824.
Gottlieb B, Laurent LP. Spironolactone in the treatment of myasthenia gravis. Lancet
1962;2(7201):528-529.
2. Clinical studies
One clinical study which had not been previously submitted regarding the safety of spironolactone
in paediatric patients is assessed:
Study Code: S84-96-06-016
Protocol Number: S84-89-02-016
Study Title: A Multicenter, Double-Blind, Vehicle Controlled Study of Topical 5%
Spironolactone Cream in the Treatment of Nodulocystic Acne
Sponsor: G.D. Searle & Co, USA
Study Report Number: S84-96-06-016, dated 28 March 1996
Methods • Objective
To evaluate the efficacy and safety of 5% w/w spironolactone cream applied three times per
day, in comparison with its vehicle, in patients with nodulocystic acne.
• Study design
Multicenter, randomized, double-blind, multidose, vehicle controlled comparison of 5%
spironolactone cream applied topically in the treatment of patients with nodulocystic acne. The duration
of treatment was to be 24 weeks with 18 weeks double-blinded and the last 6 weeks open-label with all
patients treated with active drug.
Phase: II.
Location: 8 centers in the United States.
Spironolactone Public Assessment Report RO/W/0003/pdWS/001 Page 18/42
Period: 26 January 1990 - 31 October 1990
• Study population /Sample size
A total of 80 fully evaluable outpatients between 12 and 45 years with nodulocystic acne were
to be enrolled in the study. The inclusion and exclusion criteria are described in detail in the clinical
protocol. Each center will enroll at least 20 patients. Equal treatment assignment was randomized from a
computer generated code. Patients meeting all of the inclusion criteria and having none of the exclusion
criteria will be eligible for enrollment.
During the double-blind phase, 37 patients received the vehicle cream (controls) and 39 patient
received spironolactone cream. Six of the 37 vehicle-control patients and 11 of the 39 spironolactone-
treated patients were <18 years of age at enrollment.
Of a target sample size of 80 fully evaluable patients (approximately 100 were to be enrolled),
76 patients were enrolled and received study drugs and 44 completed the study. Twenty-five patients
were withdrawn (five due to protocol violations, 15 due to noncompliance, and five due to treatment
failure) and seven were lost to follow-up.
The primary objective of the study was to compare the effectiveness of 5%
spironolactone with vehicle in the treatment of cystic acne vulgaris. Assuming a 50% success
rate (improvement of 50% in the lesion count) in those receiving spironolactone and a 20%
success rate with those receiving vehicle a total of 40 evaluable patients in each treatment
group (80 total) are required to insure a statistical power of 80% if significance is assessed at
the 0.05 level.
Patients with nodulocystic acne with a minimum of six inflamed nodular and/or cystic lesions of
the face, each lesion measuring greater than 4 mm in the largest diameter were enrolled in the study.
Facial lesions will be counted above the jawline without magnification, but
with adequate direct 1ighting.
The following lesions will be counted:
- nodules and cysts (minimum 6)
- pustules
- papules *
- open and closed comedones
Patients must have discontinued all medicated shampoos or cleansers 1
week prior to entry into the study. Patients will use soap and shampoo provided by the
sponsor at least 1 week prior to study entry.
Approximately 100 patients were enrolled into the study in order to achieve 80 fully evaluable
patients.
Patients must agree to avoid excessive sun or ultraviolet light exposure throughout the
study which may produce erythema and scaling.
All patients, and guardians when applicable, must give written informed consent prior to
entry in the study.
Patients were excluded with :
1. Acne rosacea and acne necrotica
2. Acne induced by iodides, bromides, steroids or envi ronment/occupation
3. Current significant facial skin disease other than acne, or a history of facial skin disease
which might reoccur.
4. Significant history or clinical evidence of renal, hepatic, cardiovascular, hematologic,
gastrointestinal, respiratory, metabolic, or other systemic disease.
5. Need for administration of any chronic
medications except for oral contraceptives. This includes prescription, over-the-counter or
recreational drugs. Occasional use of an analgesic, such as aspirin or acetaminophen, is
permitted.
Spironolactone Public Assessment Report RO/W/0003/pdWS/001 Page 19/42
6. Concurrent acne therapy including mechanical, nonprescription and prescription drugs, UV light,
and/or acne surgery.
7. Treatment within the last 6 months with oral isotretinoin.
8. Treatment with topical acne preparations including topical retinoids within 15 days of study
entry.
9. Treatment with systemic steroids within 30 days of enrollment and during the study.
10. Treatment with oral spironolactone within 30 days of enrollment and during the study.
11. Treatment with oral antibiotics which can affect the acne condition including
tetracyclines, minocycline, erythromycin and trimethoprim/ sulfamethoxazole within 30 days of
study entry and during the study
12. Investigational drug or device use within 30 days of drug treatment.
13. Excessive facial hair (i.e. full beards, lengthy sideburns, etc.)
14. Patient considered likely to be non-compliant in applying their medication or
in attending follow-up visits.
15. Known hypersensitivity to spironolactone.
16. Previous participation in this study.
17. Clinically significant abnormal hematology or chemistry findings.
• Treatments
During the treatment period, patients were randomized to spironolactone cream 5% or placebo
given three times daily, 24 weeks with 18 weeks double-blinded and the last 6 weeks open-label with
all patients treated with active drug.
Spironolactone was supplied as 5% w/w cream, and the comparator was the same formulation
but without spironolactone (lot number RCT 8617). Both active and vehicle medications were to be
supplied in 30 gram tubes.
The patients were requested to apply an adequate amount of cream (~1 inch) to cover the entire
face (bounded by the hairline and the borders of the mandible), three times per day after washing the face
with soap and water and patting dry. Males who shave are to apply the medication after shaving and
washing. Females who use cosmetics will be required to use oil free products and apply these products
after applying the study medication. Patients should wash their hands immediately after applying the study
medication. Patients should not wash their face for at least 3 hours after each application. This procedure
will be continued on a daily basis for the 26 weeks of the study. The first application will be done in the
presence of the clinic staff.
Tubes of cream were to be weighed prior to dispensing and again when returned.
In addition, patients were to be supplied with one bar of nonirritating soap and one bottle of
shampoo.
Patients who had used less than 10 g of medication in a three-week period were not to be
considered evaluable for efficacy. Visit compliance was defined as a minimum of six visits after
prescreening, including the Week 18 visit.
Patients were to be instructed to use the soap and shampoo beginning at least 7 days prior to
study entry and throughout the study. Additional soap was to be supplied at each visit and additional
shampoo was to be supplied as needed. Each patient was to receive one tube of spironolactone cream at
each visit beginning at Week 0, and continuing at Weeks 3, 6, 9, 12, 15, 18, and 21.
Outcomes/endpoints
CRITERIA FOR EVALUATION - dermatological examination of the face including lesion
count, Dermatological exam, clinical laboratory tests, and adverse event monitoring
Assessment of spironolactone efficacy was to be based on the reduction of nodulocystic
lesions, inflammatory, and noninflammatory lesions at the end of the study with respect to their
Spironolactone Public Assessment Report RO/W/0003/pdWS/001 Page 20/42
baseline counts. The investigator's assessment of overall clinical response to treatment was to be made and recorded on the CRF at the Week 18 and 24 visits.
Safety assessments were to be based on rate signs and symptoms of skin irritation and adverse
events. Only safety data were analyzed for this report. Rate signs and symptoms of skin irritation were defined in the clinical protocol.
• Statistical Methods
None described
Results Efficacy results:
Not assessed.
Given the large number of dropouts, only safety data were analyzed and reported.
Seventy-six patients were enrolled and received treatment. Forty-four patients completed the study. No
subjects were withdrawn due to adverse events (AEs) and no deaths occurred. Twenty-five patients (32%)
were withdrawn. Reasons for withdrawal included protocol violations, noncompliance, treatment failure,
and lost to follow-up - five due to protocol violations, 15 due to noncompliance, and five due to treatment
failure) and seven were lost to follow-up.
Safety results: Forty-six (61%) of the 76 patients enrolled in the study experienced adverse events during the double-
blind period. Of these, twenty-one (57%) were from the 37 patients who received placebo and 25 (64%) were
from the 39 patients who received spironolactone. Adverse events reported for more than three patients across
both treatment groups were headaches (eight placebo, 13 spironolactone patients), upper respiratory tract
infection (three placebo, five spironolactone), rhinitis (four placebo, four spironolactone), and coughing (three
placebo, one spironolactone). Skin disorders were reported by two placebo patients (moderate irritation,
moderate pruritus) and three spironolactone patients (moderate pain in cystic lesions, mild dry skin, and mild
fungal dermatitis).
Two patients experienced four severe events.
One patient experienced a severe infection in the genital area on Day 65 of treatment that lasted for 6
days and required hospitalization, but was not considered to be related to the study medication.
One other patient experienced three severe events during the study. A placebo patient experienced
asthenia, palpitations, and heart valve disorder (mitral valve prolapse) on Day 19 of treatment, all of which
were severe but were not considered to be related to study medication.
Adverse events reported to be moderate in severity for placebo patients were irritation (not
otherwise specified), facial edema, headache, dental abscess, bacterial infection (strep throat), pruritus,
and conjunctivitis. Events that were moderate in severity for the spironolactone group were accidental
injury (dog bite wound), pain in cystic lesions, headache, earache, tendinitis, ear infection, upper
respiratory tract infection, and pharyngitis. All other events were mild.
The only event in either treatment group that was considered probably related to study drug was
irritation (aggravated condition) in one placebo patient.
Only one placebo patient experienced adverse events reported as having an uncertain relationship
to study drug and these were facial edema and conjunctivitis. Pain in cystic lesions, headache, upper
respiratory tract infection, and dry skin were reported as having an uncertain relationship to study drug in
the spironolactone group.
Five events were related to the skin. One patient in placebo group experienced moderate itching
on the trunk considered not related to study medication, and another placebo patient experienced
moderate irritation considered probably related to study medication. Three patients in the active control
group experienced the following adverse events: moderate pain in cystic lesions and mild dry skin, both
with an uncertain relationship to study medication, and mild fungal dermatitis with no relationship to
study drug.
During the open-label period, seven patients (9%) experienced adverse events, which were mild or
Spironolactone Public Assessment Report RO/W/0003/pdWS/001 Page 21/42
moderate headache and mild pharyngitis.
None of the adverse events resulted in withdrawal of a patient from the study.
In conclusion, spironolactone 5% cream and its vehicle were generally well tolerated with only
five adverse events that were related to the skin (none directly attributable to spironolactone) when used
topically for 18-24 weeks to treat nodulocystic acne.
Assessor’s comments
The performed study has has several shortcomings which reduce its informative value:
- Only 11 patients with age <18 years at enrollment were included in the active group
(spironolactone-treated patients) and 6 patients out of 37 in the vehicle-control group.
- Primary endpoint was not clearly defined
- The definition for primary efficacy parameter was not given
- the report does not contain some important information of statistical methods.
- given the large number of dropouts, the sample size of 44 patients, who completed the
study, arm was not expected to provide enough statistical power to detect any difference between any two-
treatment arms.
- only safety data were analyzed and reported.
Seventy-six patients were enrolled and received treatment. Forty-four patients completed the study. No
subjects were withdrawn due to adverse events (AEs) and no deaths occurred. Twenty-five patients (32%)
were withdrawn.
Further clarifications on the reasons for withdrawal were provided by the MAH and the large majority of
discontinuations were because of loss of non-compliance.
Reasons for withdrawal included protocol violations, noncompliance, treatment failure, and lost to
follow-up:
- five due to protocol violations
- 15 due to noncompliance,
- five due to treatment failure and
- seven were lost to follow-up.
The conclusions that can be drawn are generally for safety and the study is too limited to offer any
evidence on the efficacy of spironolactone 5% cream in patients with nodulocystic acne
The findings of this study conducted approximately 15 years ago do not provide sufficient evidence to
justify any changes to the current Core Data Sheet.
The results of this study have no impact on product information
The provided data are not sufficient to include an indication for children in section 4.1. In addition, no
dose recommendation can be drawn based on the provided results. Therefore no dose recommendation
can be included in section 4.2.
The review of the literature submitted by the MAH reveals the followings:
Spironolactone is a competitive inhibitor of mineralocorticoid receptors and an aldosterone
antagonist. It reduces the reabsorption of sodium ions and excretion of potassium ions by blocking the
sodium-potassium exchange in the renal tubule.
Spironolactone, as a competitive aldosterone antagonist, increases sodium excretion whilst
reducing potassium loss at the distal renal tubule. It has a gradual and prolonged action.
Classic pharmacology ascribes the mechanism of action of spironolactone to the modulation of
ion transport in the distal tubule of the nephron by antagonism of the mineralocorticoid aldosterone.
Although classified as antagonist of the aldosterone-receptor complex on renal tubules, preventing the
Spironolactone Public Assessment Report RO/W/0003/pdWS/001 Page 22/42
activity of the hormone on the regulation of urinary electrolyte concentration, this mechanism of action
does not fully account for the antihypertensive activity.
Indeed, besides its specific action in primary and secondary hyperaldosteronism, spironolactone
is effective in lowering blood pressure in essential hypertension, despite normal levels of aldosterone
production. This implies a direct effect on cardiovascular system which is different from those on renal
tubules.
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 diabetes mellitus.
Spironolactone is indicated for the treatment of essential hypertension. It is also indicated for congestive
heart failure (alone or in combination with standard therapy), including severe heart failure (NYHA class
III- IV) to increase survival and reduce the risk of hospitalization when used in conjunction with standard
therapy. Spironolactone is further indicated for the management of hirsutism and as adjunctive therapy in
diuretic-induced hypokalemia/hypomagnesemia. Spironolactone is also indicated in establishing the
diagnosis of hyperaldosteronism, for short-term preoperative treatment of patients with primary
hyperaldosteronism, and conditions in which secondary hyperaldosteronism may be present, including
liver cirrhosis accompanied by edema and/or ascites, nephrotic syndrome, and other edematous
conditions.
Spironolactone is used primarily to treat heart failure, ascites in patients with liver disease, low-
renin hypertension, hypokalemia, secondary hyperaldosteronism (such as occurs with hepatic cirrhosis),
and Conn's syndrome (primary hyperaldosteronism). On its own, spironolactone is only a weak diuretic
because its effects target the distal nephron (collecting tubule), where urine volume can only be slightly
modified; but it can be combined with other diuretics to increase efficacy. About one person in one
hundred with hypertension has elevated levels of aldosterone; in these persons, the antihypertensive effect
of spironolactone may exceed that of complex combined regimens of other antihypertensives.
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 of Spironolactone in adult patients with CHF.822/1663 patients received
Spironolactone(25 mg daily) and 841 received placebo.
All patients were taking a loop diuretic, 97% were taking an ACE inhibitor and 78% were on
digoxin (at the time this trial was conducted, b-blockers were not widely used to treat heart failure and
only 15% were treated with a b-blocker). Patients with a baseline serum creatinine of >2.5 mg/dL or a
recent increase of 25% or with a baseline serum potassium of >5.0 mEq/L were excluded. Patients were
randomized 1:1 to spironolactone 25 mg orally once daily or matching placebo. Patients who tolerated 25
mg once daily had their dose increased to 50 mg once daily as clinically indicated. Patients who did not
tolerate 25 mg once daily had their dosage reduced to 25 mg every other day. The primary endpoint for
RALES was time to all-cause mortality. RALES was terminated early, after a mean follow-up of 24
months, because of significant mortality benefit detected on a planned interim analysis. Spironolactone
reduced the risk of death by 30% compared to placebo (p<0.001; 95% confidence interval 18% to 40%).
Spironolactone also significantly reduced the risk of cardiac death, primarily sudden death and death from
progressive heart failure as well as the risk of hospitalization for cardiac causes. Changes in NYHA class
were more favorable with spironolactone. Gynaecomastia or breast pain was reported in 10% of men who
were treated with spironolactone, as compared with 1% of men in the placebo group ( p<0.001). The
incidence of serious hyperkalaemia was low in both groups of patients.
The information regarding the benefit of spironolactone in patients with congestive heart failure
has been included in section 5.1 of the SmPC.
The administration of Spironolactone can cause side effects such as: fluid and electrolyte
imbalance (hyperkalemia, hyponatremia), mild acidosis, and transient elevation of serum urea nitrogen.
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
Spironolactone Public Assessment Report RO/W/0003/pdWS/001 Page 23/42
calcium chloride solution, sodium bicarbonate solution, and/or the oral or parenteral administration of
glucose with a rapid acting insulin preparation.
Due to its antiandrogen effect, it can also be used to treat hirsutism. It is also used for treating hair
loss and acne in women, and can be used as a topical medication for treatment of male baldness. It is
commonly used to treat symptoms of polycystic ovary syndrome (PCOS) such as excess facial hair and
acne. It can also be used as part of sex reassignment therapy by transwomen.
Spironolactone can cause gynecomastia in males and, unless regularly monitored, should not be
given with potassium supplementation for fear of development of hyperkalemia.
Spironolactone: Listed Indications and Daily Dose in Adults
Spironolactone Indication Daily Dose (mg)
Essential hypertension 50 – 200
Congestive heart failure
- severe heart failure (NYHA Class III-IV) and
mg/dL
100 - 200
25 – 50
Nephrotic syndrome 100 – 200
Hypokalemia/Hypomagnesemia 25 – 100
Diagnosis of Primary Hyperaldosteronism 400
Short-Term Preoperative Treatment of Primary
Hyperaldosteronism
100 – 400
Management of Hirsutism 100 – 200
Cirrhosis
- urinary Na+/K+ ratio ≥1.0
- urinary Na+/K+ ratio <1.0
100
200 – 400
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 metabolite and
decrease the effectiveness of Spironolactone.
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.
Although no specific study investigated the side effects of Spironolactone in children
comprehensively, because Spironolactone is a non-selective aldosterone receptor antagonist, endocrine-
related adverse effects, such as gynecomastia, are relatively common with this medicine. The side effects
of Spironolactone are related to its antagonistic action against the testosterone receptor; it causes
gynecomastia, mastalgia, impotence, and menstrual irregularities. Spironolactone side effects include:
potassium retention, GI irritation, rash, gynecomastia, hyperchloremic metabolic acidosis, amenorrhea,
anorexia, agranulocytosis, 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.
Potassium sparing diuretics can alter digoxin pharmacokinetics. 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.
Spironolactone Public Assessment Report RO/W/0003/pdWS/001 Page 24/42
Spironolactone can also interact with ACE inhibitors (can cause hyperkalemia) and potassium
supplements.
Conditions to be treated –
Treatment of Primary Hyperaldosteronism in Pediatric Patients
Primary hyperaldosteronism is characterized by hypertension, potassium depletion,
hypervolemia, decreased plasma renin activity, and other clinical manifestations. In adults, spironolactone
may be used to establish the diagnosis of primary hyperaldosteronism by therapeutic trial, or in the short-
term or long-term treatment of primary hyperaldosteronism in certain clinical situations. Six pediatric
cases of primary hyperaldosteronism or apparent mineralocorticoid excess syndrome were identified
during searches of the biomedical literature. The patients ranged in age from 3 to 10 years. In all cases
spironolactone therapy was effective in lowering blood pressure and treating hyperkalemia.
Treatment of Hyperaldosteronism Secondary to Effective Diuretic Therapy in Pediatric
Patients
Spironolactone counteracts secondary aldosteronism induced by volume depletion and
associated with sodium loss caused by active diuretic therapy.
Treatment of Hypertension in Pediatric Patients
Hypertension and its management in pediatric patients were reviewed in several publications.
Hypertension appears to be present in 1 to 3% of the pediatric population, with greater likelihood in
certain pediatric patients, including those with renal or cardiac disease, diabetes mellitus, parents with
hypertension, or obesity. Unlike adults, an underlying cause for hypertension is often found in younger
pediatric patients, including cardiovascular, renal parenchymal or reno-vascular, endocrine (e.g.
corticosteroid excess, hyperaldosteronism), and neoplastic causes. In adolescents essential hypertension
accounts for the majority of cases. Thus, most pediatric patients, with exception of adolescents, will have
hypertension secondary to other causes.
The choice of initial agents for the pharmacological management of hypertension in pediatric
patients depends on several factors; however diuretics are part of the stepped-care approach.
Spironolactone is the only potassium-sparing diuretic commonly given to children and its principal
indication is hypertension due to mineralocorticoid excess. It may also be effective in cases of essential
hypertension, when aldosterone secretion may be within normal limits, as adjunctive therapy with loop
and/or thiazide diuretics to minimize potassium loss. The recommended starting dosage of spironolactone
in pediatric patients for treatment of hypertension is 1 mg/kg/day as a single dose or divided, with the
maximum dose being 3.3 mg/kg/day up to 100 mg/day. Potassium-sparing diuretics should be used with
caution in hypertensive pediatric patients with renal insufficiency because of the risk of hyperkalemia.
Treatment of Edematous States Secondary to Hyperaldosteronism in Pediatric Patients
Edema and Ascites in Heart Failure
In infants ranging in age from 1 week to 10 months and presenting congestive heart failure, mean serum
aldosterone concentration was significantly elevated [151 + 38 ng/dL (mean + SE); n = 15] compared with
aldosterone concentration in normal infants (29 + 7 ng/dL; n = 20). Increased serum aldosterone was
related to increased plasma renin; aldosterone augments fluid and sodium retention. The natriuretic
response to furosemide (1 mg/kg) was inversely proportional to the aldosterone concentration, and
additional administration of spironolactone (1 to 3 mg/kg/day) resulted in an increased diuretic effect and
a decrease in mineralocorticoid concentrations.
The value of the combined administration of spironolactone has been confirmed in an open label,
randomized study that followed 21 children under 1 year of age who presented with stable cardiac failure
secondary to congenital malformations.9 All the patients received treatment with digoxin and
chlorothiazide. Ten subjects were included in a group who were also treated with oral potassium
supplementation while the other 11 subjects received spironolactone at 1 to 2 mg/kg/day divided into two
daily doses. Clinical observations included vital signs, weight, hepatomegaly, and incidence of vomiting.
Spironolactone Public Assessment Report RO/W/0003/pdWS/001 Page 25/42
Significant reductions (p<0.05) occurred in liver size, weight, and respiratory rate in spironolactone
treated
pediatric patients, with a lower incidence of vomiting. There were no significant inter- or intra-group
differences in plasma digoxin concentrations. The authors concluded that spironolactone hastens and
enhances the response to standard treatment with digoxin and chlorothiazide in infants with congestive
heart failure.
In a review of congestive heart failure in infants and children, Sharma et al. noted the importance of renal
retention of fluid, renin-angiotensin mediated vasoconstriction, and sympathetic over activity as
physiological responses to heart failure. Hepatomegaly is usually present and hepatic enlargement
regresses quickly in response to therapy and is a useful indicator of treatment. Diuretics reduce pulmonary
or systemic congestion and afford quick relief of congestion. Furosemide is the agent of choice. Secondary
hyperaldosteronism occurs in infants with CHF and addition of spironolactone to other diuretics conserves
potassium. Recommended dosages of spironolactone in neonatal and infant patients with congestive heart
failure are 1 to 3 mg/kg/day. Even higher dosages have been reported by Buchhorn et al. (3 to 5
mg/kg/day) and Chéron and Le Masne (3 to 10 mg/kg/day) in treating congestive heart failure in infants.
Wimmer et al. recommended initial dosages of 4 to 5 mg/kg/day for 3 to 5 days followed by 2 to 3
mg/kg/day thereafter for childhood pediatric patients.
Nephrotic Syndrome
The SmPC in France for Aldactone (spironolactone 25 mg, scored, film-coated tablet) states that for
nephrotic syndrome in children, spironolactone is not an anti-inflammatory and its use is only
recommended if glucocorticoids are insufficiently active.
Kapur et al. studied the effects of diuretics in 11 children with nephrotic syndrome with volume expansion
and severe edema (pitting edema and ascites). The mean age of the subjects was 9.1 years. The patients
received furosemide and spironolactone; the dosage of spironolactone was 2.5 mg/kg/day divided twice
daily to maximum of 100 mg twice daily.
The efficacy endpoints were percentage weight loss and duration of hospitalization.
Percentage weight loss after 1 day of hospitalization was 4.06 +
a cohort of pediatric patients with nephrotic syndrome and volume contraction who were treated with
albumin and furosemide. A suboptimal response was described for only one of the 11 children treated with
furosemide and spironolactone.
Adverse effects were observed in two patients, one of whom experienced a >50% increase in serum
creatinine concentration along with increased serum BUN and decrease sodium concentration. A second
patient experienced an increase in serum creatinine concentration from 0.7 mg/dL to 0.9 mg/dL. The
authors concluded that diuretic therapy is safe in pediatric patients with nephrotic syndrome presenting
with severe edema.
Cirrhotic Ascites
Spironolactone therapy for patients with cirrhotic ascites is appropriate because aldosterone concentrations
are increased with cirrhosis. Combination therapy with a thiazide or loop diuretic increases the initial
diuretic response.
Yachha and Khama reviewed the clinical aspects of ascites in childhood liver disease and its
management. Diuretics are used in treating pediatric patients with cirrhotic ascites and the authors
recommended an initial daily dose of 0.3 to 3 mg/kg of spironolactone in combination with furosemide.
Dual therapy was recommended as furosemide has an early mobilizing effect on fluid while the
therapeutic response to spironolactone is gradual. Dual diuretic therapy can be changed to monotherapy
with spironolactone while obtaining satisfactory diuretic responses. Potential adverse effects of
spironolactone noted by the authors include hyperkalemia and gynecomastia. General diuretic-induced
complications in patients with cirrhosis are hepatic encephalopathy, increased serum creatinine
concentration, hyponatremia, and hypokalemia or hyperkalemia.
Adjuvant Treatment in Myasthenia in Pediatric Patients
Spironolactone Public Assessment Report RO/W/0003/pdWS/001 Page 26/42
The current SmPC in France for Aldactone - -coated tablet)
describes the following use of spironolactone in pediatric patients with myasthenia: adjuvant treatment in
myasthenia; spironolactone spares potassium and decreases the exaggerated requirements for potassium.
The searches of the biomedical literature data bases yield no publications on the use of spironolactone in
pediatric patients for myasthenia. However, Gottlieb and Laurent reported on the beneficial effects of
spironolactone in seven patients with myasthenia gravis, including one adult patient diagnosed at 19 years
of age. The authors observed definite improvement in six of the seven patients, including ability to walk in
a previously bedridden woman. The patient who experienced no apparent benefit had previously
responded well to pyridostigmine therapy and spironolactone provided no additional benefit.
Adjuvant Treatment in Hirsutism The aldosterone antagonist, spironolactone, has been used for many years as an orally administered
antihypertensive agent and diuretic. Spironolactone has also been shown to have antiandrogenic
properties. In clinical trials, orally administered spironolactone in doses of 50-200 mg/day has been shown
to decrease hirsutism in women with elevated or normal androgen levels, as well as improve acne and
seborrhea. The precise mechanism of the antiandrogenic effect has not been fully elucidated, but is
probably multi factorial involving competitive interaction with androgen receptors, competitive
displacement of testosterone from plasma proteins, interference with the peripheral conversion of
testosterone to its active metabolite, dehydrotestosterone, through an inhibitory effect on 5-alpha reductase
in androgen dependent tissue, or interference with testosterone synthesis itself.
Efficacy Conclusions
Searches of the biomedical literature found published references reporting the efficacy of spironolactone
in pediatric patients, and confirming that the use of spironolactone is well established in current pediatric
clinical practice. Established dosing regimens generally range from 1 to 4 mg/kg/day. However, the MAH
has no new efficacy studies on file to support the beneficial effects of spironolactone for this population.
Assessor’s comment:
The articles refer to a review of spironolactone.
No new information on spironolactone is concerned.
The recommended daily dose differs in adults, children, and other patient populations.
The recommended daily dose differs based on indication for use
In the line listing there are many other supportive studies on the confirmed therapeutic indications, which
have already been included in the current Company Core Data Sheet.
While the MAH has no specific efficacy data on file to support the beneficial effects of spironolactone for
children, several publications are available to support the use of spironolactone in pediatric patients for
various indications. Pertinent publications are summarized Clinical Overview.
The Company Core Data Sheet has detailed information on these indications and posology:
4.1. Therapeutic indications
Spironolactone is indicated for the following:
- essential hypertension
- short-term preoperative treatment of patients with primary hyperaldosteronism
- congestive heart failure (alone or in combination with standard therapy), including
severe heart failure (NYHA class III- IV) to increase survival and reduce the risk of hospitalization when
used in addition to standard therapy.
- conditions in which secondary hyperaldosteronism may be present, including liver
cirrhosis accompanied by edema and/or ascites, nephrotic syndrome, and other
edematous conditions (alone or in combination with standard therapy)
- diuretic-induced hypokalemia/hypomagnesemia as adjunctive therapy
Spironolactone Public Assessment Report RO/W/0003/pdWS/001 Page 27/42
- establishing a diagnosis of primary hyperaldosteronism
- management of hirsutism.
4.2. Posology and method of administration
For adults, the daily dose may be given in divided doses or as a single daily dose.
Essential Hypertension
The usual adult dose is 50 to 100 mg per day, which for difficult or severe cases may be gradually
increased at intervals of two weeks up to 200 mg/day. Treatment should be continued for at least two
weeks to ensure an adequate response to therapy. Dose should be adjusted as necessary.
Congestive Heart Failure
The usual adult dose is 100 mg/day. In difficult or severe cases the dose may be increased up to 200
mg/day. Maintenance dose should be individually determined.
For severe heart failure (NYHA Class III-IV). In the Randomized Aldactone Evaluation Study (RALES),
treatment with spironolactone was initiated at a dose of 25 mg once daily when used in conjunction with
standard therapy in patients with a serum potassium ≤ 5.0 mEq/L and serum creatinine ≤ 2.5 mg/dL.
Patients who tolerated 25 mg once daily had their dose increased to 50 mg once daily as clinically
indicated. Patients who did not tolerate 25 mg once daily had their dosage reduced to 25 mg every other
day. See section 4.4 Special warnings and precautions for use: Hyperkalemia in Patients with Severe
Heart Failure for advice on monitoring serum potassium and serum creatinine.
Cirrhosis
If urinary Na+/K+ ratio is greater than 1.0, the usual adult dose is 100 mg/day. If the ratio is less than 1.0,
the usual adult dose is 200 to 400 mg/day. Maintenance dose should be individually determined.
Nephrotic Syndrome
The usual adult dose is 100 to 200 mg/day. Spironolactone has not been shown to affect the basic
pathological process, and its use is advised only if other therapy is ineffective.
Edema in Children
Initial dosage is 3 mg/kg body weight daily in divided doses. Dosage should be adjusted on the basis of
response and tolerance. If necessary a suspension may be prepared by pulverizing spironolactone tablets
with a few drops of glycerine and adding cherry syrup.
Such a suspension is stable for one month when refrigerated.
Hypokalemia/Hypomagnesemia
25 to 100 mg daily may be useful in treating diuretic-induced hypokalemia and/or hypomagnesemia when
oral potassium and/or magnesium supplements are considered inappropriate.
Diagnosis and Treatment of Primary Hyperaldosteronism
Spironolactone may be employed as an initial diagnostic measure to provide presumptive evidence of
primary hyperaldosteronism while patients are on normal diets.
Long test: Daily adult dose of 400 mg for 3 to 4 weeks. Correction of hypokalemia and of hypertension
provides presumptive evidence or the diagnosis of primary hyperaldosteronism.
Short test: Daily adult dose of 400 mg for four days. If serum potassium increases during spironolactone
administration, but drops when spironolactone is discontinued, a presumptive diagnosis of primary
hyperaldosteronism should be considered.
Short-Term Preoperative Treatment of Primary Hyperaldosteronism
After the diagnosis of hyperaldosteronism has been established by more definitive testing procedures,
spironolactone may be administered in daily doses of 100 to 400 mg in preparation for surgery. For
patients who are considered unsuitable candidates for surgery, spironolactone may be employed for long-
term maintenance therapy at the lowest effective dosage determined for the individual patient.
Management of Hirsutism
The usual dose is 100 to 200mg per day, preferably in divided dose.
In Europe, only the current French Summary of Product Characteristics (SmPC) for Aldactone -
(spironolactone 25 mg, scored, film-coated tablet) contains therapeutic indications in children which are:
Spironolactone Public Assessment Report RO/W/0003/pdWS/001 Page 28/42
Treatment of primary hyperaldosteronism
- Hyperaldosteronism secondary to effective diuretic treatment
- Essential hypertension
- Edematous states that may accompany hyperaldosteronism:
o Edema and ascites in heart failure
o Nephrotic syndrome
o Cirrhotic ascites
- Adjuvant treatment in myasthenia; spironolactone spares potassium and decreases the exaggerated
requirements for potassium.
For all the others available products, spironolactone is authorised in several indications for adults
including recommended posology in children.
The national labeling currently approved for spironolactone in France, Germany and Italy include the use
in children with adapted posology.
Currently no specific paediatric formulation is available.
For children the Core Data Sheet states that if necessary a suspension may be prepared by pulverizing
spironolactone tablets with a few drops of glycerin and adding cherry syrup. Such a suspension is stable
for 1 month when refrigerated. The current SmPC in France states that in children <6 years of age, the 25
mg spironolactone tablet (or part of the table) is to be crushed and suspended in a liquid and the liquid will
preferably be a syrup or 20% methylcellulose solution in order to promote suspension.
The company’s proposal regarding the administration of spironolactone in children aged less than 6 years
has to be included in section 4.2 . Posology and method of administration.
“In children aged less than 6 years, the tablet is to be crushed (or the part of the tablet) and suspended in a
liquid (the liquid will preferably be a syrup or 20% methylcellulose solution in order to promote
suspension).
The dosage is 1 to 4 mg/kg/day as 1 or 2 divided intakes daily.
peraldosteronism: adjust dosage to the patient's requirements.
otic syndromes: spironolactone is not an anti-inflammatory and its use is only recommended if
glucocorticoids are insufficiently active.
Rapporteur’s recommendation
Usually, oral solid formulations should normally be contra-indicated in children under 6 years of age,
which is the case for the oral tablets of spironolactone. A more appropriate and suitable oral formulation
for this paediatric population may be further taken under consideration in the scope of a further article
46.
Also, the MAH submitted the Periodic Safety Update Report (PSUR) for spironolactone
covering the period 08 June 2008 through 09 November 2009.
Worldwide, spironolactone has received marketing authorization in 85 countries and is currently
marketed in 65 countries. From the second quarter of 2008 through the second quarter of 2009, there have
Spironolactone Public Assessment Report RO/W/0003/pdWS/001 Page 29/42
been worldwide sales of over 900 million standard dosage units of spironolactone corresponding to
approximately 2.5 million patient-years of exposure.
Some changes were made to the reference safety document, the spironolactone Core Data Sheet
(CDS), during the reporting period.
The Core Data Sheet (CDS), last revised on 09 March 2009, serves as the reference safety
document (RSD).
Based on information received by Safety and Risk Management at the time this PSUR was
prepared, there were no actions taken regarding spironolactone for safety reasons either by a healthy
authority (HA) or by the MAH during the reporting period.
The following safety-related changes were made to the RSD on 09 March 2009:
Under Posology and method of administration, the underlined section below was added to the congestive
heart failure indication:
Congestive Heart Failure
The usual adult dose is 100 mg/day. In difficult or severe cases the dose may be increased up to
200 mg/day. Maintenance dose should be individually determined.
For severe heart failure (NYHA Class III-IV). In the Randomized Aldactone Evaluation Study
(RALES), treatment with spironolactone was initiated at a dose of 25 mg once daily when used in
conjunction with standard therapy in patients with a serum potassium
their dose increased to 50 mg once daily as
clinically indicated. Patients who did not tolerate 25 mg once daily had their dosage reduced to 25 mg
every other day. See section 4.4 Special warnings and precautions for use: Hyperkalemia in Patients
with Severe Heart Failure for advice on monitoring serum potassium and serum creatinine.
Under Special warnings and precautions for use, the following section was added:
Hyperkalemia in Patients with Severe Heart Failure
Hyperkalemia may be fatal. It is critical to monitor and manage serum potassium in patients with
severe heart failure receiving spironolactone. Avoid using other potassium-sparing diuretics. Avoid using
oral potassium supplements in patients with serum potassium >3.5 mEq/L. The recommended monitoring
for potassium and creatinine is one week after initiation or increase in dose of spironolactone, monthly for
the first 3 months, then quarterly for a year, and then every 6 months. Discontinue or interrupt treatment
for serum potassium >5 mEq/L or for serum creatinine >4 mg/dL. (See section 4.2 Posology and method
of administration; Severe heart failure).
A total of 476 cases from health care professionals and any other medically confirmed cases
(containing 923 events) fulfilled criteria for inclusion in this 17-month safety update report.
In addition, there were 266 medically confirmed, spontaneously reported cases containing only
non-serious listed AEs and 151 cases containing only non-medically confirmed serious and non-serious
(listed and unlisted) AEs.
The most commonly reported adverse events were encoded to the Preferred Terms (PTs):
Hyperkalaemia, Renal failure acute, Drug interaction, Hyponatraemia, Renal failure, Gynaecomastia,
Dehydration, Hypotension, and Bradycardia.
Upon review, the majority of the most frequently reported events were related to the patients’
underlying illnesses, an intercurrent disorder, or the reported events were specifically listed or consistent
with the current CDS.
In the previous PSUR (08 June 2005 through 07 June 2008), the MAH committed to review and
discuss in the next PSUR PTs contained in the MedDRA Severe Cutaneous Adverse Reactions
Standardized MedDRA Query, and the PTs Diarrhoea, Breast cyst, Breast mass, and Breast cancer male.
These topics/events are reviewed and discussed in this PSUR and no new safety issues were identified.
Cumulative review of cases reporting Upper gastrointestinal haemorrhage and related events was
performed because, during the reporting period, Gulmez et al.1 reported on the use of spironolactone and
the risk of upper gastrointestinal bleeding. Review of cases in the MAH’s safety data base did not identify
any significant new safety information.
Spironolactone Public Assessment Report RO/W/0003/pdWS/001 Page 30/42
Analysis of 476 cases received by the MAH, between 08 June 2008 and 09 November 2009
identified no new safety information that altered the benefit-risk assessment of spironolactone. The current
CDS appropriately reflects the safety experience with this product and, based on this review, no actions
are recommended.
Assessor’s comment
It is reassuring that no new safety issues were observed in children during PSURs.
The MAH had updated the CDS with core safety wording in the “Dosage and Administration” and in the
“Special warnings and precautions for us” sections concerning Patients with congestive Heart Failure
and the risk of Hyperkalemia in Patients with Severe Heart Failure.
The implementation of these proposed changes has been carried out follow the submission of national
variation.
B) Summary of clinical program sponsored by MAH
The MAH did not carry out any paediatric study for spironolactone in paediatric population, in
accordance with Article 45 of the Regulation (EC) No 1901/2006, as amended on medicinal products for
paediatric use.
The MAH submitted an extensive review of the clinically relevant information on efficacy and
safety clinical studies relating to spironolactone for the use in children from the published international
literature documented in the clinical overview.
The supportive documentation available for this purpose was the following:
- A short critical expert overview;
- Literature searches on standard medical databases (1986-2009);
- Company Core Safety Information.
The MAH, did propose some minor change to the approved SmPC in conjunction with the
submitted paediatric data.
The MAH submitted 59 articles related to paediatric studies for spironolactone, in accordance
with Article 45 of the Regulation (EC) No 1901/2006, as amended on medicinal products for paediatric
use.
This review is based on the results of a bibliographic research performed through Medline,
Embase and Derwent databases up to September 2009. The relevant published and non-published trials
that assess the clinical efficacy of spironolactone in different indications are summarized hereunder.
No pharmacokinetic and/or pharmacodynamic studies concerning pediatric population have been
performed by the MAH .
The review of available clinical data concerning the paediatric use of spironolactone has provided
the information on its use in the following indications: bronchopulmonary dysplasia, arterial hypertension,
hyperaldosteronism and edematous conditions.
1 Abman SH, Mourani PM, Sontag M. Bronchopulmonary dysplasia: a genetic disease. Pediatrics
2008; 122(3): 658-9.
2 Ehrenkranz RA, Walsh MC, Vohr BR, Jobe AH, Wright LL, Fanaroff AA, et al. National
Institutes of Child Health and Human Development Neonatal Research Network. Validation of the
National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics 2005;
116(6): 1353-60.
3 Kantak AD, McBride JT. Bronchopulmonary Dysplasia (BPD): Respiratory Disorders in
Neonates, Infants, and Young Children. Merck Manual Professional [online]. Last full review/revision
March 2009. Available from URL:
4 Deakins KM. Bronchopulmonary dysplasia. Respir Care 2009; 54(9): 1252-62.
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5 Sweet D, Bevilacqua G, Carnielli V, Greisen G, Plavka R, Saugstad OD, et al; Working Group on
Prematurity of the World Association of Perinatal Medicine, European Association of Perinatal Medicine.
European consensus guidelines on the management of neonatal respiratory distress syndrome. J Perinat
Med 2007; 35(3): 175-86.
6 Tin W, Wiswell TE. Adjunctive therapies in chronic lung disease: examining the evidence. Semin
Fetal Neonatal Med 2008; 13(1): 44-52.
7 National High Blood Pressure Education Program (NHBPEP). The Fourth Report on the
diagnosis, valuation, and treatment of high blood pressure in children and adolescents. NIH publication.
No 05 - 5267. Originally printed September 1996 (96 - 3790). Revised May 2005.
8 Williams B, Poulter NR, Brown MJ, Davis M, McInnes GT, Potter JF, et al. British Hypertension
Society. Guidelines for management of hypertension: report of the fourth working party of the British
Hypertension Society, 2004-BHS IV. J Hum Hypertens 2004; 18(3): 139-85.
9 Working Group on Management of Congenital Heart Diseases in India (WGMCHDI), Saxena A,
Juneja R, Ramakrishnan S. Drug therapy of cardiac diseases in children. Indian Pediatr 2009; 46(4):
310-38.
10 Flynn JT, Daniels SR. Pharmacologic treatment of hypertension in children and adolescents. J
Pediatr 2006; 149(6): 746-54.
11 Grossman. Primary Aldosteronism: Adrenal Disorders: Merck Manual Professional [online]. Last
full review/revision November 2007.
12 Assadi F. Diagnosis of hypokalemia: a problem-solving approach to clinical cases. Iran J Kidney
Dis 2008; 2(3): 115-22.
13 Funder JW, Carey RM, Fardella C, Gomez-Sanchez CE, Mantero F, Stowasser M, et al.;
Endocrine Society. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an
endocrine society clinical practice guideline. J Clin Endocrinol Metab. 200; 93(9): 3266-81.
14 Canadian Hypertension Education Program (CHEP). 2009 CHEP Recommendations for the
Management of Hypertension. 2009.
15 Grossman. Secondary Aldosteronism: Adrenal Disorders: Merck Manual Professional [online].
Last full review/revision November 2007.
16 O'Brien JG, Chennubhotla SA, Chennubhotla RV. Treatment of edema. Am Fam Physician 2005 ;
71(11): 2111-7.
17 Mandal AK. Generalized edema: guidelines for effective treatment. Consultant 2004; 44(9): 1245-
50.
18 Beggs S, Thompson A, Nash RE, Tompson AJ, Peterson, GM. Cardiac failure in children. 17th
Expert Committee on the Selection and Use of Essential Medicines; Geneva, March 2009.
19 Kay JD, Colan SD, Graham TP Jr. Congestive heart failure in pediatric patients. Am Heart J 2001;
142(5): 923-8.
20 Yachha SK, Khanna V. Ascites in childhood liver disease. Indian J Pediatr 2006; 73(9): 819-24.
21 Noerr B. Spironolactone. Neonatal Netw 1999; 18(3): 43-6.
22 van der Vorst MM, Kist JE, van der Heijden AJ, Burggraaf J. Chapter 2: Diuretics in pediatrics :
current knowledge and future prospects. Paediatr Drugs 2006; 8(4): 245-64.
23 Bartter Syndrome: Abnormal Renal Transport Syndromes: Merck Manual Professional
24 Frassetto LA. Bartter Syndrome. Hereditary Kidney Disorders. Nephrology. eMedicine
Specialties. Updated: Sep 18, 2009. Available from URL:
http://emedicine.medscape.com/article/238670-print
25 Jospe N. Precocious Puberty: Endocrine Disorders in Children: Merck Manual Professional
[online]. Last full review/revision May 2009. Available from URL:
http://www.merck.com/mmpe/print/sec19/ch282/ch282h.html
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Spironolactone is a potassium-sparing diuretic and is marketed as a competitive aldosterone
antagonist. It is indicated for the treatment of oedema and ascites, nephrotic syndrome, congestive heart
failure and primary hyperaldosteronism. The use of spironolactone in infants and children was first
reported in 1964 when administration of the drug to three infants produced a moderate diuresis. Since then
spironolactone has been widely used in the management of congestive heart failure associated with
congenital heart disease, BPD or CLD and paediatric ascites. Although frequently prescribed, there is a
lack of published research documenting the safety and efficacy of spironolactone in the paediatric
population.
The recommended dose of spironolactone in infants and children is 1 to 4 mg/kg/day up to 100
mg/day administered as a single dose or in two divided doses. Some references list a dose of 3.3
mg/kg/day, based on conversion of an older recommendation of body weight in pounds (1.5 mg/lb/day).
Bronchopulmonary Dysplasia
In 4 out of 7 studies selected in patients with BPD and the Cochrane review, the use of
spironolactone appears effective and safe.
The conflicting findings from these studies make interpretation difficult, however, few
pharmacologic therapies have been shown conclusively to affect lung function in neonates with CLD
because of the large number of variables affecting outcome. In clinical practice, most institutions continue
to use long-term combination diuretic therapy in the management of neonatal CLD.
Clinical data are limited but showed an improvement of lung function with the use of the
combination of spironolactone and thiazide in neonates.
Whereas oxygen, continuous positive airway pressure and mechanical ventilation are the
mainstays of treatment of pulmonary conditions such as BPD in newborns, there is a number of
adjunctive therapies that may improve the pulmonary function of these infants. These include the use of
Spironolactone Public Assessment Report RO/W/0003/pdWS/001 Page 34/42
diuretics, often used in these patients to accelerate lung fluid reabsorption and therefore to improve
pulmonary mechanisms. Diuretics are therefore generally recommended for severe chronically ill patients
for the management of accumulation of interstitial lung fluid, such as in cases of pulmonary edema.
Spironolactone in combination with a thiazide diuretic are often used for the control of
pulmonary oedema in preterm infants with severe CLD, and this is felt to be the safest diuretic
combination for long-term use.
Hypertension
Recent review and guidelines from expert groups recommend that the management of the
hypertensive child include pharmacotherapy for those who are unresponsive to lifestyle changes or who
have end organ damage or other compelling indications. However, most antihypertensive agents currently
used in children are administered off-label, and there is a lack of information about long-term safety and
impact of outcomes such as cardiovascular morbidity and mortality.
Recommendations in children are extrapolated from results obtain in adults patients. Acceptable
treatments for use in children include ACE inhibitors, angiotensin receptor blockers, calcium channel
blockers, beta-blocking agents and diuretics.
To date, the benefits of spironolactone in the treatment of pediatric hypertension have not been
clearly established, mainly due to the lack of clinical studies in the pediatric population.
However, among all the drugs cited, spironolactone is recommended in the International clinical
guidelines. Spironolactone may be used alone or in combination, and may be useful as add-on therapy in
children with resistant hypertension.
Primary Aldosteronism
Primary aldosteronism is a rare disease and particularly uncommon in childhood, therefore,
clinical data are very limited, with only a few case reports available.
Spironolactone, as an aldosterone antagonist is given to lower the blood pressure and to normalize
the serum potassium.
Although treatment of primary hyperaldosteronism may include unilateral adrenalectomy,
administration of the potassium-sparing diuretic, spironolactone, and sodium restriction are used to control
hyperaldosteronism without surgery. For bilateral adrenal hyperplasia, spironolactone remains the drug of
choice.
Edema
Treatment of edema consists of reversing the underlying disorder (when possible) and restricting
dietary sodium to minimize fluid retention. This approach highlights the need to establish a diagnosis and
to use non-pharmacologic approach when appropriate. However, diuretics are required in most patients.
The choice of diuretic, route of administration and dosing regimen will vary based on the underlying
disease, its severity and the urgency of the problem. Actually, edema may be of renal, cardiac and hepatic
origin.
The potassium-sparing diuretic spironolactone competes with aldosterone for receptor sites in the
distal renal tubules, increasing sodium chloride and water excretion while conserving potassium and
hydrogen ions.
Spironolactone is indicated in children for the treatment of edema associated with excessive
aldosterone excretion (secondary hyperaldosteronism) such as ascites or nephrotic syndrome.
The safety data collected from clinical trials for the treatment in infants and children with
bronchopulmonary dysplasia, primary hyperaldosteronism, edematous state, and different others
indications as acne, hirsutism, and precocious puberty showed that the safety profile of spirolactone does
not differ from what is already known. Adverse effects of spironolactone are primarily related to fluid or
electrolyte disturbances arising from the diuretic action of the drug, and include serum sodium, potassium,
phosphorus, creatinine. Most of the laboratory events resolved after corrective supplementations.
Gastrointestinal complaints also may occur.
The analysis of the published safety data and data reported to the MAH did not identify any
safety concern specific to the pediatric population. Nevertheless, considering the paucity of the available
Spironolactone Public Assessment Report RO/W/0003/pdWS/001 Page 35/42
information, the safety profile of the administration of spironolactone in the pediatric population cannot
be definitely established.
A cumulative updated review of safety is included and recently submitted as part of the most
recent periodic safety update review covering the period 19 October 2009 to 31 July 2011.
A search from the global MAH pharmacovigilance database and of the scientific literature was
performed using Medline, Embase, Derwent Drug File, and Biosis Previews medical databases from
October 2009 to July 2011, in order to retrieve all publications providing relevant safety data of
spironolactone use in children and/or adolescents, whatever the nature of the publication (ie, interventional
and non-interventional studies, and case reports).
Postmarketing data in children is limited. No specific safety issue in the paediatric population was
identified in the Periodic Safety Update Reports.
No solicited serious cases involving spironolactone in children or adolescents age groups were
reported in the MAH global pharmacovigilance database, for the period between 19 October 2009 and 31
July 2011.
The analysis of the published safety data and cases reported to the company during the reporting
period did not identify any safety concern specific to the pediatric population. Nevertheless, considering
the paucity of the available information, the safety profile of the administration of spironolactone in the
pediatric population cannot be definitely established.
Adverse effects of spironolactone are primarily related to fluid or electrolyte disturbances arising
from the diuretic action of the drug: the safety data collected from one clinical trial in infants to determine
the pharmacokinetics of vancomycin in co-administration with amoxicillin-clavulanic acid and
spironolactone documented possible interaction with vancomycin due to decreased volume of distribution
of vancomycin as a consequence of changes in the total body water due to spironolactone.
The data presented in these reports are consistent with the known safety profile of
spironolactone.
There is no evidence of new types of substance-related adverse drug reactions. The data do not
suggest a change of the favorable benefit-risk ratio of this product.
Thus, the PSUR confirms the good benefit/risk ratio of spironolactone in the labeled indications.
Rapporteur’s comment
In Europe, spironolactone is currently registered (by national procedures) and marketed by the MAH in
three countries, as follows:
- France:
Spironolactone Winthrop 25 mg tablets (recently approved)
Spironolactone Winthrop 50 mg and 75 mg film-coated tablets
- Germany:
Osyrol 50 mg and 100 mg film-coated tablets
- Italy:
Aldactone 25 mg capsules
Aldactone 100 mg tablets
The therapeutic indications are as follows:
France:
- Primary hyperaldosteronism
- Reactional hyperaldosteronism in an effective diuretic treatment
- Essential arterial hypertension
- Oedema associated with secondary hyperaldosteronism.
- Adjuvant therapy in myasthenia
Spironolactone Public Assessment Report RO/W/0003/pdWS/001 Page 36/42
- Treatment of the cardiac insufficiency stage III or IV according to the classification of the NYHA
fraction of systolic ejection ≤ 35 %), in association with a treatment including a loop diuretic, a converting
enzyme inhibitor, and a digitalic in the majority of the cases (25 mg and in adults only).
Germany:
- Primary hyperaldosteronism unless an operation is indicated
- Oedema and/or ascites occurring with disorders associated with secondary hyperaldosteronism.
Italy:
Treatment of primary or secondary hyperaldosteronism and of essential arterial
hypertension when other treatments have not been sufficiently effective or tolerated.
The national labelings include the use in children with adapted posology. There are some differences with
respect to indications and dosage recommendations of spironolactone in different SmPC.
Only the current French Summary of Product Characteristics (SmPC) for Aldactone- (spironolactone 25
mg, scored, film-coated tablet) contains therapeutic indications in children which are:
- Treatment of primary hyperaldosteronism
- Hyperaldosteronism secondary to effective diuretic treatment
- Essential hypertension
- Edematous states that may accompany hyperaldosteronism:
o Edema and ascites in heart failure
o Nephrotic syndrome
o Cirrhotic ascites
- Adjuvant treatment in myasthenia; spironolactone spares potassium and decreases
the exaggerated requirements for potassium
Spironolactone has been widely used in the management of congestive heart failure associated with
congenital heart disease, BPD or CLD. Although frequently prescribed, there is a lack of published
research documenting the safety and efficacy of spironolactone in the paediatric population.
The recommended dose of spironolactone in infants and children is 1 to 4 mg/kg/day up to 100 mg/day
administered as a single dose or in two divided doses. Some references list a dose of 3.3 mg/kg/day, based
on conversion of an older recommendation of body weight in pounds (1.5 mg/lb/day).
One change was proposed by the company in section 4.2 to include the following wording, to be in line
with the information available in the clinical overview and Aldactone SmPC, France.
Paediatric population
In general, the daily dose in children is 1 to 4 mg per kg body weight up to 100 mg/day administered as a
single dose or two divided doses.
The company’s proposal is currently not agreed and the issue on standard initial dose range
recommendation needs to be further discussed and justified before a change in the SmPC can be
considered.
The conflicting findings from published studies in patients with bronchopulmonary dysplasia (BPD)
make interpretation difficult, however, few pharmacologic therapies have been shown conclusively to
affect lung function in neonates with CLD because of the large number of variables affecting outcome. In
clinical practice, most institutions continue to use long-term combination diuretic therapy in the
management of neonatal CLD.
Clinical data are limited but showed an improvement of lung function with the use of the combination of
spironolactone and thiazide in neonates.
Whereas oxygen, continuous positive airway pressure and mechanical ventilation are the mainstays of
treatment of pulmonary conditions such as BPD in newborns, there is a number of adjunctive therapies
that may improve the pulmonary function of these infants. These include the use of diuretics, often used in
these patients to accelerate lung fluid reabsorption and therefore to improve pulmonary mechanisms.
Spironolactone Public Assessment Report RO/W/0003/pdWS/001 Page 37/42
Diuretics are therefore generally recommended for severe chronically ill patients for the management of
accumulation of interstitial lung fluid, such as in cases of pulmonary edema.
Spironolactone in combination with a thiazide diuretic are often used for the control of pulmonary oedema
in preterm infants with severe CLD, and this is felt to be the safest diuretic combination for long-term use.
Although the use of spironolactone appears effective and safe in this condition the provided data
are insufficient for granting a new specific indication. However, in clinical practice, most institutions
continue to use long-term combination diuretic therapy in the management of neonatal CLD.
The literature published during the reporting period did not provide new or additional
information on adverse events related to spironolactone. In literature no publications on serious,
unexpected adverse drug reactions have been identified.
V. RAPPORTEUR’S OVERALL CONCLUSION AND RECOMMENDATION
It is agreed that the data from the submitted studies do not specifically indicate any need of
major change of the current paediatric information in the SmPCs.
Only one change on dose recommendation in paediatric population has been proposed into the
European SmPC text by one MAH based on the data presented. The company’s proposal is currently not
agreed and the issue on standard initial dose range recommendation needs to be further discussed and
justified before a change in the SmPC can be considered.
Spironolactone has been registered on a national basis in the EU member states and currently
there are some divergences between member states in regard to indications and dosage recommendations
of oral formulations of spironolactone. There is no agreement between the MSs on therapeutic indications
and the initial dose range of spironolactone in children 1 month-12 years of aged.
On the basis of the submitted data as part of this worksharing procedure no recommendation could
be made.
The indications and recommended doses are largely based on expert opinion and clinical
experience (spironolactone has been used for more than 50 years in children and adults).
There is a lack of comprehensive studies evaluating the therapeutic effects of Spironolactone in
children.
Physicians have established treatment protocols for paediatric use based on experience and the
available literature. Consensus seems to exist that dosing for the younger paediatric population should be
calculated per body weight.
Since the pathology of different types of conditions for the use of spironolactone in adults and
children is not similar, the extrapolation of the efficacy in adults to all conditions in children is not
considered acceptable and separate indications for the paediatric population are recommended, when
appropriate.
An explicit wording in section 4.1, respective 4.2 for paediatric population is considered
necessary.
Having regard to the differences between member states in respect to the therapeutic indications
and dose posology for the originator medicinal product (Aldactone), it would be appropriate for the
Applicant to submit this product for a SmPC harmonisation procedure.
Considering that spironolactone is acknowledged for the potential serious risk of hyperkalaemia,
which could be more severe in children, it should be ensured that all authorised SmPCs and PLs are
updated to contain adequate information. Such information may be required by prescribers and carers in
order to properly consider the benefits and risks in the different situations for which spironolactone is
taken into consideration for use in paediatric population. This will help to ensure that spironolactone is
Spironolactone Public Assessment Report RO/W/0003/pdWS/001 Page 38/42
used safely in children. For these reasons the Rapporteur would like to recommend that spironolactone be
considered for a SmPC harmonisation procedure.
The current paediatric posology, as described in local SmPCs and as approved by national
competent authorities, is based on historical use and text book knowledge that involved long time before
there were any requirements of clinical study documentation on a paediatric population. Additional
research is needed to define the pharmacokinetics and optimal dosing interval of Spironolactone in
paediatric population, as well as to determine its long-term effects on potassium. Based on the available data the dosing information included in section 4.2 regarding paediatric
population is not very clear.
No liquid formulation of spironolactone suitable for young children is available. A liquid
formulation would be useful to overcome the difficulties of administering the correct dose to small
children especially during the initial period of dose titration.
The applicants are encouraged to consider developing age appropriate paediatric formulations for
spironolactone in order to minimize the risk of dosing errors.
Oral solid formulations should normally be contra-indicated in children under 6 years of age,
which is the case for the oral tablets of spironolactone, due to the risk of inadvertent aspiration. A more
appropriate and suitable oral formulation for this paediatric population may be further taken under
consideration in the scope of a further article 46.
From the submitted data there is no clinical evidence restricting the use of spironolactone to
specific paediatric subpopulations and no age restriction should be applied. According to the available
data, an extemporaneously liquid oral formulation of spironolactone may be suitable for use in pediatric
patients.
The current SmPCs for Aldactone (spironolactone 25 mg, scored, film-coated tablet) contain in
section 4.2 the following dosing recommendation covering younger patients “If necessary a suspension
may be prepared by crushing tablets” (the 25 mg spironolactone tablet (or part of the table) is to be
crushed and suspended in a liquid and the liquid will preferably be a syrup or 20% methylcellulose
solution in order to promote suspension).
It should be clearly mentioned in the product information that only the 25 mg strength, tablets is
specifically indicated in children.
It should also be emphazised that the 25 mg strength, capsules is not to be crushed and suspended
in a liquid.
The data presented by the MAH (s) do not reveal any new information on the safety and efficacy
for the use of spironolactone for the paediatric population.
Indeed, no specific recommendations regarding developing age appropriate paediatric
formulations are endorsed to appear in the SmPC.
The authorised SmPCs need to be updated to contain more comprehensive information regarding
spironolactone for the benefit of the prescriber using this product in the paediatric population.
Taking into consideration that the key objective of the Paediatric Regulation is to improve the
information available on the use of medicinal products in the various paediatric populations, it is
suggested by the Rapporteur in the Day 90 draft final paediatric assessment report that the following
amendments should be implemented in the countries where the respective wordings have not already been
included in the SmPCs using variation procedures. PROPOSED CHANGES IN THE SmPC
“Sections 4.1 and 4.2: it is the Rapporteur's opinion that the SmPCs should be amended including a
specific paediatric indication for the products containing spironolactone and no age restriction should be
applied where applicable (i.e if the tablet can be crushed/suspended).
Based on the available evidence, the rapporteur is the opinion that the therapeutic indications and
the dosage in paediatric population should be in line with the current recommendations of the available
guidelines for Spironolactone:
BNF for children, 2009 and WHO model formulary for children 2010, as follows:
Spironolactone Public Assessment Report RO/W/0003/pdWS/001 Page 39/42
According to BNFC 2009 and WHO model formulary for children 2010 recommendations, spironolactone
may be given to neonates, infants and children for the treatment of heart failure, oedema and ascites,
nephrotic syndrome, reduction of hypokalemia induced by diuretics or amphotericin and primary
hyperaldosteronism.
Dosage should be individually determined and the following is only a guide:
The following posology for the paediatric population based on age is recommended:
- Neonate: 1-2mg/kg daily in 1-2 divided doses; up to 7mg/kg daily in resistant ascites.
- Child 1 month-12years: 1-3mg/kg daily in 1-2 divided doses; up to 9mg/kg daily in resistant ascites.
- Child 12-18years: 50-100mg daily in 1-2 divided doses; up to 9mg/kg daily (max. 400mg daily) in
resistant ascites.”
Further to the circulation of the Day 90 draft final paediatric assessment report, we received
comments from United Kingdom, the Netherlands, Hungary and France.
The UK and HU agreed with the overall conclusions of the Rapporteur and had no further comments. NL
in general supported the Rapporteur’s recommendation for section 4.2, but also asked for appropriate text
proposals for the package leaflet in sections 4.1 and 4.2, that should be agreed before finalisation of the
procedure.
FR does not support the latest amendments for section 4.2. The French proposal for the section 4.2 is the
following:
“4.2. Posology and method of administration
In children
For children under 6 years, it is necessary to crush the tablet (or fraction of a tablet) to make a suspension
in a liquid (the liquid will preferably be a syrup or a solution of methyl cellulose 20% in order to facilitate
the suspension).
Dosage should be individually determined and the following is only a guide: The dose is 1 to 4 mg / kg / day as 1 or 2 divided intakes daily up to 100 mg/day.
• Treatment of hyperaldosteronism: the doses are tailored to the needs of the patient.
• High blood pressure: a dose of 1 to 4 mg / kg / day should be administered once daily.
• Heart failure: spironolactone can be administered alone or combined with another diuretic.
• Nephrotic syndrome: Spironolactone is not an anti-inflammatory; its use is recommended only if the
glucocorticoids are insufficiently active. In children: 2 mg/kg on average per 24 hours.
• Myasthenia gravis: the doses are tailored to the needs of the patient.”
Overall conclusion Based on the review of the presented paediatric data on spironolactone, the rapporteur considers
that the data from the submitted studies do not specifically indicate any need of major change of the
current paediatric information in the SmPCs.
The submitted paediatric studies do not influence the benefit-risk and that there is no
consequential regulatory action. However, in connection with this PdWS procedure the Rapporteur may
suggest that an update of the SPCs and PILs regarding paediatric population for all formulations which
contain spironolactone is needed in order to be in line with the revised SPC guideline (September 2009)
and QRD template to improve the information available on the use of medicinal products in the paediatric
population.
Spironolactone has been registered on a national basis in the EU member states and currently
there are some divergences between member states in regard to indications and dosage recommendations
of oral formulations of spironolactone. There is no agreement between the MSs on therapeutic indications
and the initial dose range of spironolactone in children 1 month-12 years of aged.
Since the pathology of different types of conditions for the use of spironolactone in adults and
children is not similar, the extrapolation of the efficacy in adults to all conditions in children is not
Spironolactone Public Assessment Report RO/W/0003/pdWS/001 Page 40/42
considered acceptable and separate indications for the paediatric population are recommended, when
appropriate.
An explicit wording in section 4.1, respective 4.2 for paediatric population is considered
necessary.
Based on the review of the available data there is no clinical evidence to restrict the use of
spironolactone to specific paediatric population. No age restriction should be applied.
However, no specific paediatric formulation is available.
A liquid formulation would be useful to overcome the possible difficulties of administering the
correct dose to small children especially during the initial period of dose titration.
Currently, in Europe products containing spironolactone are available only as 25 mg, 50 mg, 75
mg, and 100 mg tablets, capsules and film-coated tablets.
It should be clearly mentioned in the product information that only 25 mg dosage as tablets is
specifically use in children.
If necessary in younger children, a suspension may be prepared by crushing tablets.
As part of the SmPC there is the following wording:
“in children < 6 years of age, the 25 mg spironolactone tablet (or part of the table) is to be crushed
and suspended in a liquid and the liquid will preferably be a syrup or 20% methylcellulose solution in
order to promote suspension”
From the performed studies such a suspension is stable for 1 month when refrigerated.
There are no data available regarding the stability of a potential solution by crushing 25 mg
capsules.
There is no agreement between the MSs on therapeutic indications and the initial dose range of
spironolactone in children 1 month-12 years of aged.
Based on the evidence submitted through this worksharing procedure no recommendation could
be made and the Rapporteur would recommend appropriately national variation procedure.
The proposed amendment by one MAH for section 4.2, to change the initial dose range for
children from 1.5 -3 mg/kg/day to 1-4 mg/kg/day cannot be supported, based on the submitted data
package for this procedure.
The company’s proposal in section 4.2 of the SmPC was to change the initial recommended
dosage in children for spironolactone
“Paediatric population
In general, the daily dose in children is 1 to 4 mg per kg body weight up to 100 mg/day administered as a
single dose or two divided doses.”
The justification given was to be in line with the information available in Clinical Overview,
dated 06-Nov-2009 and with the Aldactone SmPC from France.
No clarification regarding the discrepancy in paediatric posology and therapeutic indications for
the originator product Aldactone 25 mg has been provided.
The current data do not support any specific changes in section 4.1 and 4.2 regarding paediatric
population.
From the provided data there is a discrepancy regarding the therapeutic indications and the initial
recommended doses in children for Aldactone 25 mg referred to French Summary of Product
Characteristics (SmPC) and Core Data Sheet text. The Myasthenia gravis indication “Adjuvant treatment
in myasthenia” and the initial recommended posology in children up to 1 to 4 mg/kg/day, included in the
French SmPC for Aldactone 25 mg were not stated in the provided Core Data Sheet.
Considering that there are significant differences in the product information of the originator
medicinal product registered in different MS, it is the responsibility of the MAH to consider how to
address this situation, taking into account that it is an objective of the Paediatric Regulation to give
children the same access to authorised medicinal products suitable for their use across the European
Community. The MAH may consider a range of regulatory options including submission of a series of
variations or initiation of a referral procedure in order to achieve a harmonised position.
Spironolactone Public Assessment Report RO/W/0003/pdWS/001 Page 41/42
Please note that in RO we don’t have registered the originator product Aldactone.
Recommendation
Having regard to the differences between member states in respect to the therapeutic indications
and dose posology for the originator medicinal product (Aldactone), it would be appropriate for the MAH
to submit this product for a SmPC harmonisation procedure.
Taking into consideration that spironolactone is acknowledged for the potential serious risk of
hyperkalaemia, which could be more severe in children, it should be ensured that all authorised SmPCs
and PLs are updated to contain adequate information. Such information may be required by prescribers
and carers in order to properly consider the benefits and risks in the different situations for which
spironolactone is taken into consideration for use in paediatric population. This will help to ensure that
spironolactone is used safely in children. For these reasons the Rapporteur would like to recommend that
spironolactone be considered for a SmPC harmonisation procedure.
X. LIST OF MEDICINCAL PRODUCTS AND MARKETING AUTHORISATION
HOLDERS INVOLVED
The list can be taken from the spreadsheet compiled from the EMA
EU Regulatory status for Spironolactone - National approvals only
ALL TRADE NAMES, STRENGTHS, DOSAGE FORMS by Pfizer Limited
Member
State
Initials
Name of MAH Name of Product National
Authorisation
Number(s)
Pharmaceutical
form(s)
Strength(s)
BE CONTINENTAL
PHARMA,
Belgium
Aldactone
Aldactone
Aldactone
BE033476
BE177484
BE109024
Film Coated Tablet
25mg
50mg
100mg
EL Pfizer Hellas A.E.,
Greece
Aldactone
Aldactone
4259/2.2.95
4258/2.2.95
Film Coated Tablet
25mg
100mg
ES Pfizer S.A.
Avda.
Alcobendas
(Madrid)
Aldactone 25 mg comprimidos
recubiertos con película
Aldactone 100 mg comprimidos
recubiertos con película
39.059
54.900
Film Coated Tablet
(scored tablets can be
divided in two
identical
halves)
25mg
100mg
FR PFIZER HOLDING
FRANCE
Aldactone 25 mg, comprimé
sécable
Spironolactone Pfizer 25mg,
comprimé sécable
Aldactone 50 mg, comprimé
sécable
Spironolactone Pfizer 50mg,
comprimé sécable
Aldactone 75 mg, comprimé
sécable
Spironolactone Pfizer 75mg,
comprimé
NL 22667
NL 23638
V01265
NL 23357
NL12882
NL 21073
Scored Tablet
25mg
25mg
50mg
50mg
75mg
75mg
IE Pharmacia Ireland
Limited
Dublin 24
Ireland
Aldactone
Aldactone
Aldactone
PA 936/16/1
PA 936/16/2
PA 936/16/3
Film Coated Tablet
25mg
50mg
100mg
IS Pfizer ApS Aldactone 640211 (IS) Film Coated Tablet 25mg
Spironolactone Public Assessment Report RO/W/0003/pdWS/001 Page 42/42
Denmark Aldactone 792398 (IS) 100mg
LU CONTINENTAL
PHARMA,
Belgium
Aldactone
Aldactone
Aldactone
0136/98/02/43
17
0136/97/01/01
27
0136/95/04/31
40
Film Coated Tablet
25mg
50mg
100mg
MT Pfizer Hellas S.A.,
Greece
Aldactone MA505/00701 Film Coated Tablet
25mg
NO Pfizer AS
Lysaker
Norge
Aldactone
Aldactone
Aldactone
4550
6533
6191
Film Coated Tablet
25mg
50mg
100mg
PT Laboratórios Pfizer,
Lda.
Aldactone
Aldactone
4657490,
4657391,
9046755,
5726799
9046714,
4657599
Tablet, Uncoated 25mg
100mg
SE Pfizer AB Aldactone
Spironolakton Pfizer
Aldactone
Spironolakton Pfizer
Aldactone
Spironolakton Pfizer
7223
9766
9519
9899
9357
900
Film Coated Tablet
Uncoated Tablet
Film Coated Tablet
Uncoated, Tablet
Film Coated Tablet
Uncoated, Tablet
25mg
25mg
50mg
50mg
100mg
100mg
UK Pharmacia Limited
United Kingdom
Aldactone
Aldactone
Aldactone
PL 00032/0394
PL 00032/0395
PL 00032/0393
Film Coated Tablet
25mg
50mg
100mg
ALL TRADE NAMES, STRENGTHS, DOSAGE FORMS by the other MAH(s)
France Spironolactone Winthrop 25 mg tablets
Spironolactone Winthrop 50 mg and 75 mg film-coated tablets
Germany - Osyrol 50 mg and 100 mg film-coated tablets
Italy - Aldactone 25 mg capsules
Aldactone 100 mg tablets