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SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
INDOCID® PDA
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
„Indocid‟ PDA contains indometacin sodium trihydrate equivalent to 1.0 mg indometacin.
3. PHARMACEUTICAL FORM
„Indocid‟ PDA is available in vials containing a sterile, off-white to yellow lyophilised
powder for solution for injection, of indometacin sodium trihydrate.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
„Indocid‟ PDA is indicated for the closure of patent ductus arteriosus in premature infants.
4.2 Posology and method of administration
For intravenous use only.
A course of therapy is defined as three intravenous doses of „Indocid‟ PDA given at 12- to
24-hour intervals, with careful attention to urinary output.
If anuria or marked oliguria (urinary output of 0.6 ml/kg/hour) is evident at the time of the
scheduled second or third dose, „Indocid‟ PDA must not be given until laboratory studies
indicate that renal function has returned to normal.
Undesirable effects may be minimised by using the lowest effective dose for the shortest
duration necessary to control symptoms. (see section 4.4).
Dosage recommendations depend closely on the age of the infant:
Dosage (mg/kg)
Age at 1st dose 1st 2nd 3rd
Less than 48 hours 0.2 0.1 0.1
2-7 days 0.2 0.2 0.2
Over 7 days 0.2 0.25 0.25
If the ductus arteriosus closes or is significantly reduced in size 48 hours after the first course
of therapy, no further treatment is necessary. If the ductus arteriosus reopens, a second course
of 1-3 doses may be given, each dose separated by a 12-24 hours interval as described above
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If the condition is unchanged after the second course of therapy, surgery may then be
necessary. If severe adverse reactions occur, stop the treatment.
4.3 Contraindications
„Indocid‟ PDA is contra-indicated in:
infants with established or suspected untreated infection;
infants who are bleeding, especially with active intracranial haemorrhage or
gastro-intestinal bleeding;
infants with congenital heart disease in whom patency of the ductus arteriosus is
necessary for satisfactory pulmonary or systemic blood flow (e.g. pulmonary atresia,
severe tetralogy of Fallot, severe coarctation of the aorta);
infants with thrombocytopenia;
infants with coagulation defects;
infants with known or suspected necrotising enterocolitis;
infants with significant impairment of renal function.
NSAIDs (non-selective non-steroidal anti-inflammatory drugs) are contraindicated:
in patients who have previously shown hypersensitivity reactions (e.g. asthma,
rhinitis, angioedema or urticaria) in response to, indometacin, ibuprofen, aspirin, or
other non- steroidal anti-inflammatory drugs;
in patients with severe heart failure, hepatic failure and renal failure (see section 4.4);
in patients with a history of gastrointestinal bleeding or perforation, related to
previous NSAIDs therapy.
4.4 Special warnings and precautions for use
General: „Indocid‟ PDA may mask the usual signs and symptoms of infection. The drug
must therefore be used cautiously in the presence of existing controlled infection.
Because severe hepatic reactions have been reported in adults on prolonged therapy with oral
indometacin, „Indocid‟ PDA should be discontinued if signs and symptoms consistent with
liver disease develop in the neonate.
„Indocid‟ PDA may inhibit platelet aggregation. Premature infants should be observed for
signs of bleeding.
„Indocid‟ PDA should be administered carefully to avoid extravasation and resultant irritation
to tissues.
The use of „Indocid‟ PDA with concomitant NSAIDs including cyclooxygenase-2 selective
inhibitors should be avoided (see section 4.5).
Undesirable effects may be minimised by using the lowest effective dose for the shortest
duration necessary to control symptoms (see section 4.2, gastro-intestinal and cardiovascular
risks below).
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Cardiovascular and Cerebrovascular Effects
Appropriate monitoring and advice are required for patients with a history of hypertension
and/or mild to moderate congestive heart failure as fluid retention and oedema have been
reported in association with NSAID therapy.
Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high
doses and in long term treatment) may be associated with a small increased risk of arterial
thrombotic events (for example myocardial infarction or stroke). There are insufficient data
to exclude such a risk for indometacin.
Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart
disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with
NSAIDs after careful consideration. Similar consideration should be made before initiating
longer-term treatment of patients with risk factors for cardiovascular disease (e.g.
hypertension, hyperlipidaemia, diabetes mellitus, smoking.)
Gastro-intestinal bleeding, ulceration and perforation
Gastrointestinal bleeding, ulceration or perforation, which can be fatal, has been reported with
all NSAIDs at any time during treatment, with or without warning symptoms or a previous
history of serious GI events.
Clinical results indicate that major gastro-intestinal bleeding was no more common in those
infants receiving indometacin than those receiving placebo. However, minor gastro-intestinal
bleeding (i.e. chemical detection of blood in the stool) was more common in infants treated
with indometacin.
The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in
patients with a history of ulcer, particularly if complicated with haemorrhage or perforation
(see section 4.3) and in the elderly. These patients should commence treatment on the lowest
dose available. Combination therapy with protective agents (e.g misoprostol or proton pump
inhibitors) should be considered for these patients, and also for patients requiring concomitant
low dose aspirin, or other drugs likely to increase gastrointestinal risk (see below and section
4.5)
In patients with a history of GI toxicity any unusual symptoms (especially GI bleeding) should
be reported particularly in the initial stages of treatment.
Caution should be advised in patients receiving concomitant medications which could
increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as
warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin (see
section 4.5)
Should GI bleeding or ulceration occur in a patient receiving “Indocid” PDA, treatment
should be withdrawn.
NSAIDs should be given with care to patients with a history of gastrointestinal disease
(ulcerative colitis, Crohn‟s disease) as these conditions may be exacerbated (see section 4.8)
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CNS reactions
Prematurity per se is associated with an increased incidence of spontaneous intraventricular
haemorrhage. Because indometacin may inhibit platelet aggregation, the potential for
intraventricular bleeding may be increased.
Renal effects
„Indocid‟ PDA may cause significant reduction in urine output (50% or more) with elevated
blood urea and creatinine, and reduced GFR and creatinine clearance. In most infants, these
effects are transient and disappear when therapy with „Indocid‟ PDA is stopped. However,
because adequate renal function can depend on renal prostaglandin synthesis, „Indocid‟ PDA
may precipitate renal insufficiency including acute renal failure. This is most likely in infants
with conditions such as extracellular volume depletion from any cause, impaired renal
function, cardiac impairment, congestive heart failure, sepsis, or hepatic dysfunction, in those
taking diuretics or who are undergoing therapy with nephrotoxic drugs which may affect renal
function. Renal function and serum electrolytes should be monitored in these infants (see also
section 4.3)
Whenever a significant suppression of urine volume occurs with treatment, treatment with
„Indocid‟ PDA must stop until urine output returns to normal.
„Indocid‟ PDA may suppress water excretion in premature infants to a greater extent than the
excretion of sodium. This may result in hyponatraemia. Renal function and plasma
electrolytes should be monitored.
Dermatological
Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson
syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with
the use of NSAIDs (see section 4.8). Patients appear to be at highest risk for these reactions
early in the course of therapy: the onset of the reaction occurring in the majority of cases
within the first month of treatment.
„Indocid‟ PDA should be discontinued at the first appearance of skin rash, mucosal lesions, or
any other sign of hypersensitivity.
4.5 Interaction with other medicinal products and other forms of interaction
Other analgesics including cyclooxygenase-2 selective inhibitors: Avoid concomitant use of
two or more NSAIDs (including aspirin) as this may increase the risk of adverse effects (see
section 4.4)
Cardiac Glycosides: The half-life of digitalis in premature infants with patent ductus
arteriosus and with cardiac failure is often prolonged by indometacin. When both drugs are
used concomitantly, frequent monitoring of ECG and serum digitalis may help prevention or
early detection of digitalis toxicity.
NSAIDs may exacerbate cardiac failure, reduce GRF and increase plasma glycoside levels.
Aminoglycosides: In a study of premature infants treated with „Indocid‟ PDA and also
receiving gentamicin or amikacin, both peak and trough levels of these aminoglycosides were
significantly elevated.
Methotrexate: Decreased elimination of methotrexate.
Ciclosporin: Increased risk of nephrotoxicity.
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Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with
tacrolimus.
Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding (see section 4.4)
Anti-platelet agents: Increased risk of gastrointestinal bleeding (see section 4.4).
Diuretics: „Indocid‟ may reduce diuretic effects, including the diuretic effect of furosemide.
Diuretics can increase the risk of nephrotoxicity of NSAIDs.
Antihypertensives: Reduced anti-hypertensive effect. In addition, in some patients with
compromised renal function, the co-administration of an NSAID and an ACE inhibitor or
angiotensin II antagonist may result in further deterioration of renal function, including
possible acute renal failure, which is usually reversible.
Anticoagulants: Indometacin usually does not influence the hypoprothrombinemia produced
by anticoagulants. When indometacin is added to anticoagulants, prothrombin time should be
monitored closely. In post marketing experience, bleeding has been reported in patients on
concomitant treatment with anticoagulants and „Indocid‟. Caution should be exercised when
„Indocid‟ and anticoagulants are administered concomitantly.
NSAIDs may enhance the effects of anti-coagulants, such as warfarin (see section 4.4)
Quinolone antibiotics: Animal data indicate that NSAIDs can increase the risk of convulsions
associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an
increased risk of developing convulsions.
Zidovudine: Increased risk of haematological toxicity when NSAIDs are given with
zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in
HIV(+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.
4.6 Pregnancy and lactation
Pregnancy:
Not applicable
Lactation:
Not applicable
4.7 Effects on ability to drive and use machines
Not applicable.
4.8 Undesirable effects
Haemorrhagic: gross or microscopic bleeding into the gastro-intestinal tract, oozing from the
skin after needle puncture, pulmonary haemorrhage, and disseminated intravascular
coagulopathy.
Gastro-intestinal: The most commonly-observed adverse events associated with NSAIDs are
gastrointestinal in nature. Abdominal distension, transient ileus, necrotising enterocolitis,
peptic ulcers, perforation or GI bleeding, sometimes fatal, may occur (see section 4.4).
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Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melena,
haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn‟s disease (see section
4.4) have been reported following administration. Less frequently, gastritis has been observed.
Pancreatitis has been reported very rarely.
Renal: Renal failure, renal dysfunction including one or more of the following: reduced
urinary output, reduced urine sodium, chloride or potassium, urine osmolality, free water
clearance, or glomerular filtration rate, uraemia, transient oliguria, and hypercreatinaemia.
Hypersensitivity: Hypersensitivity reactions have been reported following treatment with
NSAIDs. These may consist of (a) non-specific allergic reactions and anaphylaxis (b)
respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea,
or (c) assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura,
angiodema and, more rarely exfoliative and bullous dermatoses (including epidermal
necrolysis and erythema multiforme).
Metabolic: hyponatraemia, elevated serum creatinine, elevated plasma potassium, elevated
blood urea, hypoglycaemia.
Cardiovascular and cerebrovascular: pulmonary hypertension, intracranial bleeding.
Oedema, hypertension and cardiac failure have also been reported in association with NSAID
treatment.
Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high
doses and in long term treatment) may be associated with a small increased risk of arterial
thrombotic events (for example myocardial infarction or stroke) (see section 4.4).
Coagulation: decreased platelet aggregation.
General: weight gain (fluid retention), and exacerbation of infection.
Other adverse reactions associated with NSAIDs reported less commonly include:
Renal: Nephrotoxicity in various forms, including interstitial nephritis, nephritic syndrome
and renal failure.
Hepatic: abnormal liver function, hepatitis and jaundice.
Neurological and special senses: Visual disturbances, optic neuritis, headaches, paraesthesia,
reports of aseptic meningitis (especially in patients with existing auto-immune disorders, such
as systematic lupus erythematosus, mixed connective tissue disease), with symptoms such as
stiff neck, headache, nausea, vomiting, fever or disorientation (see section 4.4), depression,
confusion, hallucinations, tinnitus, vertigo, dizziness, malaise, fatigue and drowsiness.
Haematological: Thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia and
haemolytic anaemia.
Dermatological: Bullous reactions including Stevens Johnson syndrome and Toxic Epidermal
Necroloysis (very rare). Photosensitivity.
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Causal relationship unknown:
Although the following reactions have been reported in infants, a definite causal relationship
has not been established.
Cardiovascular: bradycardia.
Respiratory: apnoea, exacerbation of pre-existing pulmonary infection.
Haematological: disseminated intravascular coagulation.
Metabolic: acidosis, alkalosis.
Ophthalmic: retrolental fibroplasia.
4.9 Overdose
It is recommended that „Indocid‟ PDA should be administered only in a neonatal
intensive-care unit.
Dosage is critical.
The following signs and symptoms have occurred in individuals (not necessarily in premature
infants) following overdose of NSAIDs: headache, nausea, vomiting, epigastric pain,
gastrointestinal bleeding, rarely diarrhoea, disorientation, mental confusion, paraesthesiae,
numbness, excitation, coma, drowsiness, dizziness, tinnitus, fainting, occasionally
convulsions. In cases of significant poisoning acute renal failure and liver damage are
possible.
Therapeutic measure: Patients should be treated symptomatically as required. Good urine
output should be ensured. Renal and liver function should be observed for at least four hours
after ingestion of potentially toxic amounts. Frequent or prolonged convulsions should be
treated with intravenous diazepam. Other measures may be indicated by the patient‟s clinical
condition.
The patient should be monitored for several days because gastro-intestinal ulceration and
haemorrhage have been reported as adverse reactions of indometacin. Any complications
occurring in the gastro-intestinal, renal and central nervous systems should be treated
symptomatically and supportively.
Plasma half-life of intravenous indometacin was inversely variable to the post-natal age and
weight of the baby. In one study, a mean plasma half-life in infants less than a week old
averaged 20 hours, while older infants showed a 12-hour average. Grouping the same infants
by weight, the mean plasma half-life seen in infants under 1,000 g was 21 hours, in heavier
infants the half-life was reduced to an average of 15 hours.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
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Although the exact mechanism of action through which indometacin causes closure of patent
ductus arteriosus is not known, it is believed to be through inhibition of prostaglandin
synthesis. Indometacin has been shown to be a potent inhibitor of prostaglandin synthesis,
both in vitro and in vivo. In human newborns with certain congenital heart malformations,
PGE 1 dilates the ductus arteriosus. In foetal and newborn lambs, E type prostaglandins have
also been shown to maintain the patency of the ductus; as in human newborns, indometacin
causes its constriction.
Studies in healthy young animals and in premature infants with patent ductus arteriosus
indicated that, after the first dose of intravenous indometacin, there was a transient reduction
in cerebral blood flow velocity and cerebral blood flow. Similar decreases in mesenteric
blood flow and velocity have been observed. The clinical significance of these effects have
not been established.
5.2 Pharmacokinetic properties
The disposition of indometacin following intravenous administration in preterm neonates with
patent ductus arteriosus has not been extensively evaluated. Even though the plasma half-life
of indometacin was variable among premature infants, it was shown to vary inversely with
post-natal age and weight. In one study of 28 evaluable infants, the plasma half-life in those
infants less than 7 days old averaged 20 hours, and in infants older than 7 days, the mean
plasma half-life was 12 hours. Grouping the infants by weight, the mean plasma half-life in
those weighing less than 1,000 g was 21 hours, and in those weighing more than 1,000 g was
15 hours.
5.3 Preclinical safety data
No relevant information.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Water for injection.
6.2 Incompatibilities
None reported.
6.3 Shelf life
18 months.
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6.4 Special precautions for storage
Store and transport refrigerated (2C – 8C). Keep in outer carton. Intravenous solution
should be prepared just prior to use and any unused portion remaining in the opened vial
should be discarded.
When reconstituted, „Indocid‟ PDA is acceptable for use only when clear and free from
particulate matter.
Further dilution with intravenous infusion solutions is not recommended. „Indocid‟ PDA is
not buffered, and reconstitution at pH levels below 6 may cause precipitation of insoluble
indometacin.
6.5 Nature and contents of container
Available in cartons of three Type I glass vials each containing 1 mg.
6.6 Instructions for use and handling
The solution should be prepared only with 1 to 2 ml 0.9% Sodium Chloride Injection BP or
Water for Injections Ph Eur. Preparations containing dextrose must not be used.
Preservatives should be carefully avoided at every stage because of the risk of toxicity in the
newborn; any unused portion remaining in the opened vial should be discarded.
A fresh solution should be prepared just prior to each administration according to the dilution
table below:
Amount of diluent used Concentration achieved
for each vial
1 ml 0.1 mg/0.1 ml
2 ml 0.05 mg/0.1 ml
While the optimal rate of injection has not been established, published literature suggests an
infusion rate over 20-30 minutes.
Further dilution with intravenous infusion solutions is not recommended.
7. MARKETING AUTHORISATION HOLDER
Lundbeck Pharmaceuticals Ireland Ltd.
14 Lower Pembroke Street
Dublin 2
Ireland.
8. MARKETING AUTHORISATION NUMBER(S)
PL 27628/0001
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9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
14 January 1986/13 May 1997
10. DATE OF REVISION OF THE TEXT
Jan 2011
LEGAL CATEGORY
POM
®
Registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.,
Whitehouse Station, NJ, USA
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