Indomethacin Agila

New Zealand - English - Medsafe (Medicines Safety Authority)

Active ingredient:
Indometacin sodium trihydrate 1.061 mg Equivalent to Indomethacin 1 mg
Available from:
Viatris Limited
INN (International Name):
Indometacin sodium trihydrate 1.061 mg (Equivalent to Indomethacin 1 mg)
Dosage:
1 mg
Pharmaceutical form:
Powder for injection
Composition:
Active: Indometacin sodium trihydrate 1.061 mg Equivalent to Indomethacin 1 mg
Prescription type:
Prescription
Manufactured by:
Sequent Scientific Limited
Therapeutic indications:
Indomethacin is indicated for the closure of patent ductus arteriosus in premature babies. Clear-cut clinical evidence of a haemodynamically significant patent ductus arteriosus should be present, such as respiratory distress, a continuous murmur, a hyperactive precordium, cardiomegaly and pulmonary plethora on chest x-ray. Indomethacin should only be used in a hospital under supervision of a specialist neonatologist.
Product summary:
Package - Contents - Shelf Life: Vial, glass, 2 mL USP Type l tubular flint vial, rubber stopper, 3 vials/carton - 3 dose units - 18 months from date of manufacture stored at or below 25°C protect from light and moisture
Authorization number:
TT50-9562
Authorization date:
2014-05-26

Read the complete document

Page 1 of 2

NEW ZEALAND CONSUMER MEDICINE INFORMATION

INDOMETHACIN AGILA

Indomethacin sodium trihydrate Powder for Injection 1 mg

What is in this leaflet

This leaflet answers some common

questions about Indomethacin

Agila.

It does not contain all the available

information. It does not take the

place of talking to your baby’s

doctor.

All medicines have risks and

benefits. Your baby’s doctor has

weighed the risks of using

Indomethacin Agila against the

benefits they expect it will have for

your baby.

If you have any concerns about

this medicine, talk to your baby’s

doctor.

Keep this leaflet. You may need to

read it again.

What Indomethacin

Agila is used for

Indomethacin Agila contains the

active ingredient indomethacin

sodium trihydrate.

While a baby is inside its mother's

womb it does not need to use its

lungs. An unborn baby has a blood

vessel called a ductus arteriosus

near the heart which allows the

baby's blood to bypass the lungs

and circulate to the rest of the body.

When the baby is born and starts

using his/her lungs, the ductus

arteriosus spontaneously closes up.

However, in some cases this does

not happen. The medical term for

this condition is 'patent ductus

arteriosus', i.e. an open ductus

arteriosus. If the ductus arteriosus is

not closed it can cause problems for

your baby. Indomethacin Agila,

when given to your baby, can help

to close the ductus arteriosus.

It is not known exactly how

indomethacin works, but it is

believed that it closes a ductus

arteriosus by inhibiting the

production of prostaglandin, a

naturally occurring chemical in the

body which keeps the ductus

arteriosus open.

This medicine is used only in a

hospital under the supervision of a

specialist neonatologist.

Before being given

Indomethacin Agila

When it must not be

used

Indomethacin Agila should not be

given to babies if:

they have a suspected or

established untreated

infection

they are bleeding,

especially if the bleeding is

inside the skull or the

intestines

they have other heart

problems which require the

ductus arteriosus to remain

open so circulation is

maintained

they have problems with

blood clotting

they have certain problems

with their intestines

they have significant kidney

problems.

Use with caution

Indomethacin Agila should be

used with caution in babies with:

dehydration or salt

imbalances in the body

heart failure or fluid

retention

liver problems

high blood pressure.

Taking other medicines

Do not give any medicines,

including any that you get

without a prescription, to your

baby without first discussing

with your baby’s doctor.

Some medicines and Indomethacin

Agila may interfere with each other.

These include:

digitalis - used for the heart

gentamicin or amikacin -

antibiotics used to treat

certain infections

furosemide - a diuretic

anticoagulants - used to

prevent or treat blood clots

ACE inhibitors - used for

the heart

aspirin or other salicylates

non-steroidal anti-

inflammatory drugs - used

for pain and inflammation

corticosteroids - used for

certain inflammatory

conditions.

These medicines may be affected

by Indomethacin Agila or may affect

how well it works. Your baby may

need different amounts of these

medicines, or may need to be given

different medicines.

Your baby’s doctor has more

information on medicines to be

careful with or avoid while using

Indomethacin Agila.

How Indomethacin

Agila is given

Babies with patent ductus arteriosus

will be cared for in a neonatal

intensive care unit where your

baby's condition will be closely

monitored. A healthcare

professional in the unit will know

how to prepare and administer the

injection.

Page 2 of 2

Indomethacin Agila is usually given

as a course of three injections, each

injection given at 12 to 24 hour

intervals. The dose of Indomethacin

Agila given depends on the age and

weight of your baby.

If your baby's ductus arteriosus is

closed or significantly reduces in

size 48 hours after the first course

of therapy (i.e. three injections), no

further treatment is necessary. If

your baby's ductus arteriosus

reopens, a second course of

therapy may be given.

If your baby’s ductus arteriosus

remains open after two courses of

therapy, surgery may be necessary.

If too much is given

(overdose)

Indomethacin Agila should be

administered in a neonatal

intensive care unit. Your baby

will be closely monitored to

prevent or detect the possibility

of overdose.

If you have any concerns about the

dose of Indomethacin Agila being

given to your baby, talk to the

doctor treating your baby.

Side effects

Indomethacin Agila may cause

unwanted side effects in some

babies. All medicines can have

side effects.

Do not be alarmed by the

following list of side effects. Your

baby may not experience any of

them.

Ask your baby’s doctor to answer

any questions you may have.

The following side effects have

been reported with indomethacin

use in infants:

kidney problems such as

reduced volumes of urine

and kidney failure

problems with the digestive

system such as vomiting,

perforation of the intestine

problems with blood clotting

resulting in bleeding

disorders

slow heart rate, high blood

pressure, heart failure

weight gain due to fluid

retention

allergic reactions

severe skin reactions

worsening of infections

changes to blood sodium,

potassium and sugar levels

changes to the acid/base

balance in the body.

Storage

Indomethacin Agila should be

stored in a cool dry place where

the temperature stays below

25°C, protected from light and

moisture.

This medicine should be kept out

of the reach of children.

Disposal

Indomethacin Agila should only be

made up for use as needed. This

will be done by a healthcare

professional. Any unused material

remaining in the open vial should be

discarded.

Indomethacin Agila injection should

not be used after the expiry date

marked on the pack.

Product description

What it looks like

Before being made up, each vial of

Indomethacin Agila contains a

sterile white to yellow powder or

plug.

Once made up, the solution is a

clear, yellow colour solution.

Ingredients

Indomethacin Agila contains

indomethacin sodium trihydrate

equivalent to 1 mg of indomethacin

as the active ingredient.

This medicine does not contain

lactose, sucrose, gluten, tartrazine

or any other azo dyes.

If you want to know

more

Should you have any questions

regarding this product, please

contact your pharmacist or doctor.

Who supplies this

medicine

Distributed in New Zealand by:

Mylan New Zealand Ltd,

PO Box 11183,

Ellerslie,

Auckland.

Telephone: (09) 579 2792

Date of Information

3 November 2014

(Based on datasheet dated 18

September 2014)

Read the complete document

Page 1 of 18

NEW ZEALAND DATA SHEET

INDOMETHACIN AGILA

Indomethacin sodium trihydrate Powder for Injection 1 mg

Description

Indomethacin Agila (indomethacin sodium trihydrate (also known as indometacin sodium trihydrate)) for

intravenous administration is lyophilised indomethacin sodium trihydrate.

Indomethacin sodium trihydrate is designated chemically as 1H-Indole-3-acetic acid, 1-(4-chlorobenzoyl)-5-

methoxy-2-methyl-, sodium salt, trihydrate.

Its molecular weight is 433.82 g/mol.

Its molecular formula is C

ClNNaO

O and

Its structural formula is:

CAS Number:

74252-25-8

Each vial contains indomethacin sodium trihydrate equivalent to 1 mg indomethacin as a sterile white to yellow

lyophilised powder or plug. Variations in the size of the lyophilised plug and the intensity of colour have no

relationship to the quality or amount of indomethacin present in the vial.

pKa value for Indomethacin is 4.5.

Indomethacin Agila contains no other excipients.

Pharmacology

Indomethacin is a non-steroidal anti-inflammatory agent which inhibits prostaglandin synthesis. Although the

exact mechanism of action through which indomethacin causes closure of a patent ductus arteriosus is not

known, it is believed to be through inhibition of prostaglandin synthesis. Indomethacin 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 fetal and newborn lambs, E type

prostaglandins have also been shown to maintain the patency of the ductus, and as in human newborns,

indomethacin causes its constriction.

Studies in premature infants with patent ductus arteriosus indicated that, after the first dose of intravenous

indomethacin, 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

has not been established.

Page 2 of 18

Pharmacokinetics

Absorption: The disposition of indomethacin following intravenous administration (0.2 mg/kg) in pre-term

neonates with patent ductus arteriosus has not been extensively evaluated. Even though the plasma half-life

of indomethacin was variable among premature infants, it was shown to vary inversely with postnatal age and

weight. In one study of 28 evaluated infants, the plasma half-life in those infants less than 7 days old averaged

20 hours (range: 3-60 hours, n=18). In infants older than 7 days, the mean plasma half-life was 12 hours

(range: 4-38 hours, n=10). Grouping the infants by weight, the mean plasma half-life in those weighing less

than 1000 g was 21 hours (range: 9-60 hours, n=10) and in those infants weighing more than 1000 g, was 15

hours (range: 3-52 hours, n=18).

Distribution: In adults, about 99 percent of indomethacin is bound to protein in plasma over the expected range

of therapeutic plasma concentrations. The percent bound in neonates has not been studied. In controlled trials

in premature infants, however, no evidence of bilirubin displacement has been observed as evidenced by an

increased incidence of bilirubin encephalopathy (kernicterus).

Excretion: Following intravenous administration in adults, indomethacin is eliminated via renal excretion,

metabolism, and biliary excretion. Indomethacin undergoes appreciable enterohepatic circulation. The mean

plasma half-life of indomethacin is estimated to be about 4.5 hours. In the absence of enterohepatic circulation,

it is 90 minutes.

Clinical Trials

Systematic Reviews Comparing Different Dosing Schedules of Indomethacin for Symptomatic PDA

To date three systematic reviews on indomethacin in symptomatic PDA have been performed comparing:

1. Intermittent prolonged courses (6-8 doses) to intermittent short courses (2-3 doses)

Herrera, Cochrane Database of

Systematic Reviews 2007, Issue 2

2. Continuous infusion (36 hrs) to intermittent bolus injection (3 doses)

Görk, Cochrane Database of Systematic Reviews 2008,

Issue 1

3. Intermittent slow infusion (3 doses, 1-2 courses) to intermittent bolus injection (3 doses, 1-2 courses)

Merck

Sharp & Dohme, 2008

The following table summarises the key selection criteria and findings for each of these reviews:

Table 1

Key selection criteria and findings for systematic reviews on indomethacin in symptomatic PDA

Herrera 2008

Objectives & Inclusion

Criteria

Treatments, Studies & Patients

Primary Results by Endpoint

To determine the effect of a

prolonged course of

indomethacin (compared to

a short course) on the rate

of treatment failure without

unwanted side-effects in

preterm infants with PDA.

Randomised or quasi-

randomised controlled trials

including preterm infants

with PDA, diagnosed on

clinical and/or

echocardiographic

examination that evaluated

indomethacin treatment.

Treatment by any route given as a

long course (four or more doses) vs.

a short course (three or fewer

doses).

Five RCTs/quasi RCTs met inclusion

criteria and included 431 infants.

PDA closure was only reported in 4

trials (361 infants).

To compare intermittent prolonged

courses to short courses (Relative

Risk [RR], Risk Difference [RD],

Number Needed to Treat [NNT]

were reported).

No significant difference in failure

of PDA closure [typical RR 0.82

(95% CI 0.51, 1.33); typical RD -

0.03 (95% CI -0.11, 0.04)].

The prolonged course was

associated with an increased risk

of NEC [typical RR 1.87 (95% CI

1.07, 3.27), typical RD 0.08 (95%

CI 0.01, 0.15); NNT 13 (7, 100)]

decreased incidence of renal

function impairment, as evidenced

Page 3 of 18

by a lower proportion of infants

having diminished urine output

[typical RR 0.27 (95% CI 0.13,

0.6); typical RD -0.19 (95% CI -

0.28, -0.09); NNT 5 (4, 11)] and

increased serum creatinine level

[typical RR 0.51 (95% CI 0.33,

0.77); typical RD -0.14 (95% CI -

0.23, -0.06); NNT 7 (4, 16)].

RR>1 favours short course IV

indomethacin.

Authors' conclusions - Implications for practice

Prolonged indomethacin course does not appear to have a significant effect on improving

important outcomes, such as PDA treatment failure, CLD, IVH, or mortality. The reduction of

transient renal impairment does not outweigh the increased risk of NEC associated with the

prolonged course. Based on these results, the author cannot recommend a prolonged course of

indomethacin for the routine treatment of PDA in preterm infants.

Görk 2008

Objectives & Inclusion

Criteria

Treatments, Studies & Patients

Primary Results by Endpoint

To compare the efficacy

and safety of continuous

infusion vs. bolus

administration of

indomethacin in closing a

symptomatic PDA in

preterm infants.

Review included

randomised and quasi-

randomised controlled

trials comparing

continuous indomethacin

infusion to bolus doses for

closure of a symptomatic

PDA in preterm infants

with a symptomatic PDA

diagnosed clinically and/or

by echocardiography.

Experimental group: Continuous

infusion of indomethacin given after

24 hours of life for closure of a

symptomatic PDA. All doses and

durations of any continuous infusion

were included.

Control group: Indomethacin

administered as a bolus dose of no

longer than 20 minutes in any dosing

schedule after 24 hours of life for

closure of a symptomatic PDA.

2 RCTs/quasi RCTs met inclusion

criteria including 40 preterm infants

(25 to 32 weeks gestational age) less

than 1750 g birth weight.

To compare continuous infusion to

intermittent bolus injection (Relative

Risk [RR] was reported).

PDA closure at day 2 (RR 1.57,

95% CI 0.54, 4.60).

PDA closure at day 5 (RR 2.77,

95% CI 0.33, 23.14).

RR>1 favours IV indomethacin

bolus.

Authors' conclusions

Due to a paucity of events and lack of precision, the available data was found to be insufficient to

draw conclusions regarding the efficacy of continuous indomethacin infusion versus bolus

injections for the treatment of PDA. Although continuous indomethacin seems to cause less

alterations in cerebral, renal and mesenteric circulations, the clinical meaning of this effect is

unclear. Definitive recommendations about the preferred method of indomethacin administration

i.e. continuous versus bolus infusions for the treatment of PDA in premature infants cannot be

made based on the current findings of this review.

Page 4 of 18

Merck, Sharp & Dohme (MSD) 2008

Objectives & Criteria

Treatments, Studies &

Patients

Primary Results by Endpoint

To compare the efficacy

and safety of bolus

injection to slow infusion

of indomethacin on the

intermittent dosing

protocols in common

practice (0.2, 0.1-

0.25x2mg/kg/12-24hr x1-

2 courses).

This systematic literature

review includes reported

randomised, quasi-

randomised controlled

trials and retrospective &

prospective cohort-series

on the use of intermittent

slow infusion and

intermittent bolus

injection of indomethacin

for closure of a

haemodynamic PDA in

preterm infants

diagnosed clinically

and/or by

echocardiography.

A total of 99 distinct clinical

study reports were included in

the review, 46 reporting on

bolus and 53 on slow infusion

dosing. There were:

35 RCTs including

1185 subjects: 474

treated by bolus and

711 by slow infusion;

32 prospective case

series studies

including 860 subjects:

272 treated by bolus

and 588 by slow

infusion;

32 retrospective case

series studies

including 2218

subjects: 595 treated

by bolus and 1623 by

slow infusion.

Some of the studies

had “titrated to

response schedules”,

the latter schedules

employing

echocardiography to

confirm that the PDA

had not closed prior to

each dose.

To compare intermittent bolus injection to

slow infusion (rate of PDA closure after 1

course, rate of PDA closure after allocated

treatment, rate of surgical ligation after

allocated treatment were reported for each

method of administration).

For the pooled efficacy estimates there are

no significant differences between the bolus

and slow infusion groups (p>0.05). Rate

estimates (95%CI) for all studies included in

the review on the primary outcome of PDA

closure after 1

course (bolus vs slow) were

72.2% (67.4% to 77.0%) vs 70.7% (63.8%

to 77.6%), p=0.728. Estimates for all studies

included in the review on the secondary

outcomes of PDA closure and surgical

ligation after allocated treatment (bolus vs

slow) were 79.9% (76.1% to 83.7%) vs

78.8% (75.0% to 82.6%), p=0.687 and

12.7% (8.5% to 16.9%) vs 12.7% (9.3% to

16.1%), p=1.000.

Estimates for the primary and secondary

outcomes by treatment regimen and mean

cumulative dose are provided in Table 2.

Of the key toxicity measures reported from

a reasonable number of studies, the

following measures occurred less frequently

in the Bolus group, NEC [5.0% (2.7% to

7.3%) vs 10.4% (7.1% to 13.7%), p=0.012],

Any ICH [2.0% (0.4% to 5.8%) vs 9.0%

(4.3% to 13.7%); p=0.002] and ventilatory

support [5.0% (1.4% to 12.3%) vs 35.9%

(24.6% to 47.2%), p<0.001].

Estimates for key toxicity outcomes by

treatment regimen are provided in Tables 3

and 4.

The review did not find differences between

bolus and slow infusions for decreases in

cerebral or mesenteric blood flow. There

was no deterioration in cerebral function

demonstrated for either method of

administration.

Summary of Authors' conclusions

The review indicated that the infusion of indomethacin over 15 to 30 minutes in doses of 0.2, 0.1-

0.25 every 12-24hrs was at least as effective as bolus administration in promoting ductal closure in

preterm infants and does not increase the risk of any of the monitored complications.

Company Comment

Page 5 of 18

The conclusions of the authors that slow infusion of indomethacin does not increase the risk of

any of the monitored complications is an opinion based on the strength of the available data but,

as indicated in the table above, some of the key toxicity measures (NEC, ICH & ventilator support)

reported did occur less frequently in the bolus group.

Estimates for the primary (PDA closure after first treatment course) and secondary (PDA closure and surgical

ligation after allocated treatment) outcomes by treatment regimen and mean cumulative dose arising from the

Merck, Sharp & Dohme 2008 review are provided in Table 2. The results for all studies (observational + RCTs)

within the dose range recommended for prescribing are shown non-bolded while the results for pooled RCTs

are shown bolded. The studies which examined the use of indomethacin titrated to response (indomethacin

treatment guided by the PDA flow pattern) were reviewed separately to the standard 3 dose course schedules.

Table 2

Comparative efficacy results (% event rate of PDA closure or surgical ligation, with corresponding 95% CI) for

each method of administration: MSD 2008 review

Treatment Regimen

Closure after 1

st

Course

Closure after Allocated Treatment

(assessed at end of treatment)

Surgical Ligation after

Allocated Treatment

Bolus

Slow

Bolus

Slow

Bolus

Slow

Dose range covered by Product Information

0.2,0.1-0.25mg/kg/12h-

0.66(0.56,0.75)

0.67(0.57,0.78)

**

0.70(0.62,0.77*

0.68(0.52,0.83)

0.76(0.68,0.85)

0.75(0.68,0.81)

[0.61/0.65mg/kg]

0.78(0.74,0.82)

0.80(0.75,0.85)

[0.67/0.70mg/kg]

0.17(0.09,0.26)

0.12(0.03,0.22)

[0.62/0.68mg/kg]

0.13(0.10,0.17)

0.10(0.07,0.13)

[0.66/0.70mg/kg]

Dose schedules covered by Product Information

0.2mg/kg/12h (

3 doses)

0.60(0.43,0.77)

0.58(0.42,0.75)*

0.68(0.58,0.78) *

0.67(0.50,0.85)

0.75(0.68,0.82)

0.75(0.47,93)

[0.62/0.75mg/kg]

0.72(0.67,0.77)

0.74(0.67,0.81)

[0.61/0.63mg/kg]

0.20(0.07,0.34)

[0.61mg/kg]

0.14(0.03,0.25)

0.06(0.008,0.21)

[0.60/0.60mg]

0.2mg/kg/12h (3 doses

0.69(0.42,0.96)

0.64(0.54,0.75)

[0.76/0.79mg/kg]

0.79(0.73,0.84)

0.82(0.75,0.88)

++

[0.71/0.75mg/kg]

0.18(0.00,0.41)

0.04(0.00,0.08)

[0.76/0.69mg/kg]

0.16(0.10,0.22)

0.11(0.06,0.15)

[0.69/0.71mg/kg]

0.2mg/kg/24h (

3 doses)

0.78(0.65,0.90)

0.73(0.47,0.98)

0.92(0.86,0.98)

[0.62mg/kg]

0.77(0.72,0.72)

[0.78mg/kg]

0.07(0.01,0.12)

[0.60mg/kg]

0.2mg/kg/24h (3 doses

0.81(0.73,0.89)

[0.52mg/kg]

0.12(0.00,0.28)

[0.47mg/kg]

0.08(0.00,0.17)

[0.81mg/kg]

0.2mg/kg/12-24h (

3 doses)

0.79(0.70,0.87)

0.82(0.67,0.97)

0.90(0.82,0.99)

[0.81mg/kg]

0.06(0.05,0.07)

Page 6 of 18

0.2,0.1,0.1mg/kg/12h (

doses)

0.73(0.67,0.80)

0.2,0.1,0.1mg/kg/12h (3

doses

0.88(0.80,0.95)

[0.48mg/kg]

0.07(0.03,0.12)

0.06(0.01,0.21)

[0.48mg/kg]

Titrated to response

dose schedules

0.77(0.70,0.83)

0.88(0.79,0.96)

[0.37/0.33mg/kg]

0.83(0.70,0.99)

0.81(0.72,0.90)

[0.31/0.275mg]

0.81(0.77,0.85)

[0.37mg/kg]

0.91(0.83,1.0)

+

[0.30mg/kg]

0.09(0.03,0.15)

[0.42mg/kg]

0.006(0.11,0.22)

[0.30mg/kg]

*p < 0.05 (relative to titrated schedule on equivalent outcome),

p < 0.01 (relative to titrated schedule on equivalent outcome);

p<0.05

(relative to equivalent schedule and outcome, Bolus),

p<0.01 (relative to equivalent schedule and outcome, Bolus); Square brackets

(mean doses used in the comparisons); Shaded box: not applicable or insufficient data. >3 doses

6 means the number of doses

administered was more than 3 and 6 doses or less.

There were no significant differences between the two methods of administration (bolus and slow infusion) on

all studies combined for the dose range and treatment schedules recommended for prescribing. This pattern

is consistent for the primary and secondary outcomes.

Of the efficacy measures reported from a reasonable number of studies on the pooled subset of RCT studies

(bolded), comparability between the bolus and slow infusion groups on the primary outcome (PDA closure

after 1st course) was demonstrated for all studies combined, the standard treatment regimen 0.2mg/kg/12h (

3 doses) and titrated schedules. With respect to the secondary outcomes (PDA closure and surgical ligation

after completion of allocated treatment result) comparability between the bolus and slow infusion groups was

observed on all studies combined and the treatment schedules 0.2mg/kg/12h (

3 doses) for PDA closure after

allocated treatment and on the 0.2mg/kg/12h (3 < doses

6) schedule for ligation after allocated treatment. A

statistically superior result on PDA closure after allocated treatment was found for the slow infusion group on

the 0.2mg/kg/12h (3 doses

6). The precision of this finding does require some caution due to the small

number of studies (low statistical power) included in this comparison (bolus, n=3 studies, 91 patients) vs (slow,

n=12, 437 patients).

The titrated dosage treatment schedules yielded statistically superior primary treatment outcome (closure after

course) on all studies combined compared to non-titrated bolus (p<0.01) and slow infusion (p<0.05) for the

dose range prescribed in the Product Information.

Systematic Review Comparing Prophylactic Indomethacin Therapy to Indomethacin Therapy for

Symptomatic PDA

A previous meta-analysis of randomised studies comparing prophylactic indomethacin therapy versus

indomethacin therapy for symptomatic PDA

Fowlie

2003

demonstrated short-term benefits with prophylactic

therapy. These benefits included a reduction in the incidence of PDA, need for surgical ligation of a PDA, and

severe IVH without increased risk of intestinal or renal side effects. Despite these reported short-term benefits,

published survey findings on clinical practice

Amin SB, 2007

suggest that about seventy five percent of NICUs use

indomethacin therapy for symptomatic PDA and not prophylactically for asymptomatic PDA. One plausible

explanation for this difference could be the perceived possibility by the physician of spontaneous closure of

asymptomatic PDA and lack of long-term benefits with prophylactic indomethacin. Further RCTs have been

recommended

assess

more

precisely

beneficial

adverse

effects

short

long-term

outcomes

Fowlie 2003

Overall, the findings from the systematic reviews on Indomethacin therapy for symptomatic PDA

Herrera 2007, Görk

2008, MSD 2008

indicated:

Prolonged indomethacin course does not appear to have a significant effect on improving important

outcomes, such as PDA treatment failure, CLD, IVH, or mortality. The reduction of transient renal

Page 7 of 18

impairment does not outweigh the increased risk of NEC associated with the prolonged course. Based

on these results, a prolonged course of indomethacin cannot be recommended for the routine

treatment of PDA in preterm infants (Herrera 2008).

The available data was found to be insufficient to draw conclusions regarding the efficacy of

continuous indomethacin infusion

versus

bolus

injections

treatment

PDA. Although

continuous

indomethacin

seems

cause

less

alterations

cerebral,

renal

mesenteric

circulations, the clinical meaning of this effect is unclear. Definitive recommendations about the

preferred method of indomethacin administration i.e. continuous versus bolus infusions for the

treatment of PDA in premature infants could not be made based on the current findings of this review

(Görk 2008).

The infusion of indomethacin over 15 to 30 minutes in doses of 0.2, 0.1-0.25, 0.1-0.25 every 12-24hrs

was at least as effective as bolus administration in promoting ductal closure in preterm infants and

does not increase the risk of any of the monitored complications (MSD 2008).

Indomethacin treatment guided by the PDA flow pattern (titrated to response) is as good as the

standard indomethacin treatment protocol in terms of ductal closure and is associated with significantly

fewer doses of indomethacin than normal. Furthermore, fewer doses were associated with a reduced

rate of complications - hypoglycaemia, impaired urine output, and gastrointestinal bleeding. There was

no obvious effect on neonatal morbidity or the incidence of chronic lung disease (MSD 2008).

Evidence from controlled trials comparing outcomes on infants treated after or in adjunct to conservative

treatment with infants whose treatment was commenced early with indomethacin suggests no advantage is

conferred by delaying indomethacin treatment. A haemodynamically significant PDA in extremely preterm

infants can lead to serious respiratory, intestinal and neurological morbidities, and a delay in indomethacin

therapy needs careful justification (MSD 2008).

Significant differences in mortality rate and transient urine output for the pooled randomised clinical

trials for the dose range recommended for prescribing were observed with bolus treatment as

compared to slow infusion, with a higher incidence of mortality (and an improved incidence of transient

urine output) observed on bolus injection. No significant difference is demonstrated when the same

analysis is further broken down into treatment dosage schedules as measured for any of the safety

outcomes including mortality, transient renal output and transient Serum Creatinine. On the dose

range recommended for prescribing for all studies combined, the measures NEC, GI Perforation and

GI Bleeding were shown to occur less frequently on the bolus delivery. Of the toxicity measures

reported from an adequate number of studies, the following measures occurred less frequently in the

Bolus group: NEC, Any ICH and ventilatory support.

Indications

Indomethacin Agila is indicated for the closure of patent ductus arteriosus in premature babies. Clear-cut

clinical evidence of a haemodynamically significant patent ductus arteriosus should be present, such as

respiratory distress, a continuous murmur, a hyperactive precordium, cardiomegaly and pulmonary plethora

on chest x-ray. Indomethacin Agila should only be used in a hospital under supervision of a specialist

neonatologist.

Contraindications

Indomethacin Agila is contraindicated 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.

Page 8 of 18

Precautions

Gastrointestinal Effects

Clinical results indicate that major gastrointestinal bleeding was no more common in those infants receiving

indomethacin than in those infants on placebo. However, gastrointestinal bleeding (i.e. chemical detection of

blood in the stool) was more commonly noted in those infants treated with indomethacin.

Severe gastrointestinal effects have been reported in adults with various arthritic disorders treated chronically

with oral indomethacin. These include gastrointestinal bleeding, vomiting, abdominal distention, melaena,

transient ileus, gastric perforation, localised perforation(s) of the small and/or large intestine, necrotising

enterocolitis.

Data in adults indicate that all NSAIDs can cause gastrointestinal discomfort and serious, potentially fatal

gastrointestinal effects such as ulcers, bleeding and perforation which may increase with dose or duration of

use, but can occur at any time without warning. Upper gastrointestinal ulcers, gross bleeding or perforation

caused by NSAIDs occur in approximately 1% of patients treated for 3 – 6 months and in about 2 – 4% of

patients treated for one year.

These trends continue with longer duration of use, increasing the likelihood of developing a serious

gastrointestinal event at some time during the course of therapy. However, even short term therapy is not

without risk.

Caution is advised in patients with risk factors for gastrointestinal events who may be at greater risk of

developing serious gastrointestinal events, e.g. the elderly, those with a history of serious gastrointestinal

events, smoking and alcoholism. When gastrointestinal bleeding or ulcerations occur in patients receiving

NSAIDs, the drug should be withdrawn immediately. Doctors should warn patients or their guardians about the

signs and symptoms or serious gastrointestinal toxicity.

The concurrent use of aspirin and NSAIDs also increases the risk or serious gastrointestinal adverse events.

Should GI bleeding or ulceration occur in a patient receiving indomethacin, treatment should be withdrawn.

CNS Effects

Prematurity per se, is associated with an increased incidence of spontaneous intraventricular haemorrhage.

Because indomethacin may inhibit platelet aggregation, the potential for intraventricular bleeding may be

increased.

Renal Effects

Indomethacin may cause significant reduction in urine output with concomitant elevations of blood urea

nitrogen and creatinine, and reductions in glomerular filtration rate and creatinine clearance. These effects in

most infants are transient, disappearing with cessation of therapy with indomethacin. However, because

adequate renal function can depend upon renal prostaglandin synthesis, indomethacin may precipitate renal

insufficiency, including acute renal failure, especially in infants with conditions such as extracellular volume

depletion from any cause, congestive heart failure, sepsis, concomitant use of nephrotoxic drugs or hepatic

dysfunction. When significant suppression of urine volume occurs after treatment no additional dose should

be given until the urine output returns to normal levels.

Indomethacin in pre-term infants may suppress water excretion to a greater extent than sodium excretion. This

may result in hyponatraemia. Renal function and plasma electrolytes should be monitored (see Precautions,

Drug Interactions and Dosage and Administration).

Cardiovascular Thrombotic Events

Observational studies in adults have indicated that non-selective NSAIDs may be associated with an increased

risk of serious cardiovascular events, including myocardial infarction and stroke, which may increase with dose

or duration of use. Patients with cardiovascular disease or cardiovascular risk factors may also be at greater

risk. To minimise the potential risk of an adverse cardiovascular event in patients taking an NSAID, especially

in those with cardiovascular risk factors, the lowest effective dose should be used for the shortest possible

duration (see Dosage and Administration).

Page 9 of 18

There is no consistent evidence that the concurrent use of aspirin mitigates the possible increased risk of

serious cardiovascular thrombotic events associated with NSAID use.

Hypertension

Studies in adults have indicated that NSAIDs may lead to the onset of new hypertension or worsening of pre-

existing hypertension and patients taking anti-hypertensives with NSAIDs may have an impaired anti-

hypertensive response. Caution is advised when prescribing NSAIDs to patients with hypertension. Blood

pressure should be monitored closely during initiation of NSAID treatment and at regular intervals thereafter.

Heart failure

Fluid retention and oedema have been observed in some patients taking NSAIDs, therefore caution is advised

in patients with fluid retention or heart failure. This information is based on data in adult patients.

Severe Skin Reactions

Data in adults indicate that NSAIDs may very rarely cause serious cutaneous adverse events such as

exfoliative dermatitis, toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), which can be

fatal and occur without warning. These serious adverse events are idiosyncratic and independent of dose or

duration of use. Patients or their guardians should be advised of the signs and symptoms of serious skin

reactions and to consult their doctor at the first appearance of a skin rash or any other sign of hypersensitivity.

General

Indomethacin may mask the usual signs and symptoms of infection. Therefore, the physician must be

continually on the alert for this and should use the drug with extra care in the presence of existing controlled

infection.

Severe hepatic reactions including jaundice and hepatitis have been reported on rare occasions in adults

treated chronically with oral indomethacin for arthritic disorders. If clinical signs and symptoms consistent with

liver disease develop in the neonate, or if systemic manifestations occur, indomethacin should be discontinued.

Indomethacin may inhibit platelet aggregation and therefore premature infants receiving the drug should be

observed closely for signs of bleeding.

Indomethacin should be administered carefully to avoid extravasation and resultant irritation to tissues.

Interactions with other Medicines

Cardiac Glycosides

Since renal function may be reduced by indomethacin, consideration should be given to reduction in dosage

of those medications that rely on adequate renal function for their elimination. The half-life of digitalis in

premature babies with patent ductus arteriosus and with cardiac failure can be prolonged by indomethacin.

When both drugs are used concomitantly, frequent monitoring of ECG and serum digitalis may help prevention

or early detection of digitalis toxicity.

Aminoglycosides

In a study of premature infants treated with indomethacin and also receiving either gentamicin or

amikacin,

both peak and trough levels of these aminoglycosides were significantly elevated.

Diuretics

Indomethacin may reduce diuretic effects, including the diuretic effect of furosemide.

Therapy with indomethacin may blunt the natriuretic effect of furosemide and help maintain renal function in

the premature infant when indomethacin is added to the treatment of patent ductus arteriosus. This response

has been attributed to inhibition of prostaglandin synthesis by nonsteroidal anti-inflammatory drugs. This effect

however has not been consistently observed with some studies suggesting that furosemide may not prevent

deterioration in renal function when administered with indomethacin

(Romagnoli 1997, Struis 2003)

. Romagnoli (1997)

found that furosemide cannot prevent indomethacin-induced renal failure, but it does not have any negative

influence on its therapeutic effectiveness. Struis (2003) concluded that the additional use of furosemide to

indomethacin did not compromise ductal closure, but did result in a significant hyponatremia and in an

unexpected increase of serum creatinine without marked influence on the urine output. By contrast, in a study

Page 10 of 18

of 19 premature infants with patent ductus arteriosus treated with either indomethacin alone or a combination

of indomethacin and frusemide, results showed that infants receiving both indomethacin and frusemide had

significantly higher urinary output, higher levels of sodium and chloride excretion, and higher glomerular

filtration rates than did those infants receiving indomethacin alone. In this study, the data suggested that

therapy with frusemide helped to maintain renal function in the premature infant when indomethacin was added

to the treatment of patent ductus arteriosus

Yeh 1982

Indomethacin causes marked reduction of glomerular filtration rate and creatinine clearance for 24-96 hours.

All drugs relying on renal excretion should be avoided during this period or should be monitored with plasma

levels and dose modification accordingly.

Anticoagulants

Indomethacin usually does not influence the hypoprothrombinemia produced by anticoagulants. When

indomethacin 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

indomethacin.

Caution

should

exercised

when

indomethacin

anticoagulants

administered

concomitantly.

Antihypertensive medications

In some patients with compromised renal function, the co-administration of an NSAID and an ACE inhibitor

may result in further deterioration of renal function, including possible acute renal failure, which is usually

reversible.

Aspirin

The use of indomethacin with aspirin or other salicylates is not recommended.

Other NSAIDs

The concomitant use of indomethacin with other NSAIDs is not recommended due to the increased possibility

of gastro-intestinal toxicity, with little or no increase in efficacy.

Corticosteroids

In a study of premature infants treated with indomethacin, concurrent use of corticosteroids appeared to

increase the risk of NEC.

Neonatal Effects

There is a lack of long-term follow-up studies of babies who have received indomethacin in controlled trials.

Further studies examining the long-term safety of indomethacin are required. In view of the widespread

prostaglandin inhibiting effects of indomethacin, and immaturity of the very low birthweight population, the

results of any studies need to be interpreted with caution, especially in comparison with surgical ligation.

In rats and mice, oral indomethacin 4.0 mg/kg/day given during the last three days of gestation caused a

decrease in maternal weight gain and some maternal and fetal deaths. An increased incidence of neuronal

necrosis in the diencephalon in the liveborn fetuses was observed. At 2.0 mg/kg/day, no increase in neuronal

necrosis was observed as compared to the control groups. Administration of 0.5 or 4.0 mg/kg/day during the

first three days of life did not cause an increase in neuronal necrosis at either dose level.

Pregnant rats, given 2.0 mg/kg/day and 4.0 mg/kg/day during the last trimester of gestation, delivered offspring

whose pulmonary blood vessels were both reduced in number and excessively muscularised. These findings

are similar to those observed in the syndrome of persistent pulmonary hypertension of the newborn.

Adverse Effects

The following tables compare the toxicities of indomethacin bolus vs slow infusion (15-30mins) for the

individual dose schedules and overall dose range (0.2, 0.1-0.25x2mg/kg/12-24hr x1-2 courses) recommended

for prescribing arising from the Merck, Sharp & Dohme 2008 review.

Aggregate results for all studies or pooled estimates (observational + RCTs) on the dose range recommended

for prescribing are shown non bolded while the results for pooled RCTs are shown bolded.

Page 11 of 18

Table 3

Comparative safety results on Mortality & Renal Toxicity (% event rate or mean estimate, with

corresponding 95% CI) for each method of administration: MSD 2008 review

Treatment Regimen

Mortality Rate

Transient Urine Output

(mL/kg/hr)

Transient SeCr

(mg/dL)

Bolus

Slow

Bolus

Slow

Bolus

Slow

Dose range covered by Product Information

0.2,0.1-0.25mg/kg/12h-

0.10(0.06,0.15)

0.13(0.06,0.21)

0.08(0.05,0.10)

0.05(0.02,0.08)

***

1.79(0.57,3.01)

2.48(0.95,4.01)

2.25(1.94,2.56)

2.25(1.94,2.56)

**

0.98(0.47,1.48)

1.19(0.92,1.45)

1.07(0.97,1.17)

1.19(1.03,1.34)

Dose schedules covered by Product Information

0.2x3mg/kg/12h-

doses

0.06(0.00,0.19)

0.00(0.00,0.20)

0.04(0.01,0.08)

0.04(0.0,0.09)

0.88(0.39,1.36)

1.13(0.34,1.92)

0.2x3mg/kg/12h-3 <

doses

0.09(0.00,0.18)

0.11(0.0,0.26)

0.08(0.04,0.11)

0.04(0.01,0.07)

2.25(1.94,2.56)

2.25(1.94,2.56)

1.11(1.06,1.16)

1.16(1.06,1.26)

0.2x3mg/kg/24h-

doses

0.17(0.00,0.38)

0.31(0.09,0.61)

0.2,0.1,0.1mg/kg/12h 3 <

doses-

0.26(0.12,0.45)

Titrated to response

dose schedules

0.13(0.06,0.21)

0.10(0.00,0.21)

p < 0.01 (relative to Bolus equivalent schedule);

p < 0.001 (relative to Bolus equivalent schedule). >3 doses

6 means the

number of doses administered was more than 3 and 6 doses or less.

The pooled safety results on all studies combined for the dose range recommended for prescribing showed

comparability between the bolus and slow infusion groups for mortality and renal toxicity. By treatment

regimen, comparability on mortality rates between the bolus and slow infusion groups was observed for all

studies for the schedules 0.2x3mg/kg/12h-

3 doses and 0.2x3mg/kg/24h-

3 doses.

Significant differences in mortality rate and transient urine output for the pooled RCTs (highlighted in bold) for

the dose range recommended for prescribing were observed with bolus treatment as compared to slow infusion

with a higher incidence of mortality (and an improved incidence of transient urine output) observed on bolus

injection. The difference in the mortality analysis can be attributed to the change in treatment protocols since

the introduction of the bolus modality in the 1970’s which have since been superseded by more modern

practice. In particular we refer to the time lag bias arising from significant technological improvements to the

present slow infusion era and the delayed pharmacological treatment of the Bolus infants until after Usual

Management Therapy has failed (on average 8 days from birth). Examination of the baseline characteristics

of the RCTs included in the mortality analysis show significant differences between the infants in the Bolus

and Slow groups for age at 1st dose, gestational age and mean cumulative dose. Of these the difference of

most clinical relevance was age at 1st dose (increased for Bolus, p<0.0001).

No significant difference is demonstrated when the same analysis is further broken down into treatment dosage

schedules as measured for any of the safety outcomes including mortality, transient renal output and transient

Serum Creatinine.

Page 12 of 18

Table 4

Comparative safety results on Gastrointestinal Toxicity (% event rate with corresponding 95% CI) for each

method of administration: MSD 2008 review

Treatment Regimen

NEC

GI Perforation

GI Bleeding

Bolus

Slow

Bolus

Slow

Bolus

Slow

Dose range covered by Product Information

0.2,0.1-0.25mg/kg/12h-

0.05(0.02,0.07)

0.07(0.04,0.10)

0.10(0.07,0.13)

0.07(0.03,0.11)

0.00(0.00,0.02)

0.03(0.00,0.07)

0.04(0.03,0.06)

0.02(0.00,0.04)

0.08(0.00,0.18)

0.07(0.00,0.22)

0.13(0.06,0.21)

0.06(0.00,0.12)

Dose schedules covered by Product Information

0.2x3mg/kg/12h-

doses

0.00(0.00,0.20)

0.07(0.00,0.15)

0.07(0.00,0.15)

0.00(0.00,0.21)

0.0(0.0,0.20)

0.2x3mg/kg/12h-3 <

doses

0.05(0.02,0.09)

0.23(0.08,0.38)

0.04(0.00,0.09)

0.03(0.00,0.11)

0.04(0.02,0.06)

0.03(0.02,0.04)

0.15(0.07,0.23)

0.14(0.07,0.26)

0.11(0.03,0.19)

0.03(0.00,0.05

**

0.2x3mg/kg/24h-

doses

0.00(0.00,0.21)

0.2x3mg/kg/12-24h-

doses

0.06(0.00,0.12)

0.08(0.04,0.12)

0.04(0.01,0.10)

0.2x3mg/kg/12-24h 3 <

doses-

0.11(0.01,0.33)

0.10(0.01,0.33)

0.10(0.05,0.15)

0.07(0.02,0.12)

0.2,0.1,0.1mg/kg/12-24h

-3 < doses

0.17(0.02,0.31)

0.26(0.12,0.45)

Titrated to response

dose schedules

0.06(0.00,0.13)

0.10(0.02,0.17)

0.10(0.05,0.14)

0.12(0.05,0.23)

0.00(0.00,0.10)

0.08(0.03,0.19)

0.14(0.00,0.35)

0.17(0.10,0.24)

0.17(0.08,0.29)

p < 0.05 (relative to Bolus equivalent schedule);

p < 0.01 (relative to Bolus equivalent schedule)

NEC, necrotising enterocolitis. >3 doses

6 means the number of doses administered was more than 3 and 6 doses or less.

On the dose range recommended for prescribing for all studies combined, the measures NEC, GI Perforation

and GI Bleeding were shown to occur less frequently on the bolus delivery. The findings were statistically

significant for the NEC and GI perforation measures (p<0.05). By treatment regimen, for all studies combined

there was comparability between the bolus and slow infusion groups on GI toxicity measures for all treatment

schedules on which a reasonable number of studies were available. Within the subset of RCTs, comparability

was observed between the bolus and slow infusion groups on all measures for all studies combined on the

dose range recommended for prescribing. GI bleeding was observed in the RCT subset at a higher incidence

in the bolus injection group on the 0.2x3mg/kg/12h 3 < doses

6 schedule. This finding should be viewed

cautiously due to the small number of studies (low statistical power) included in this comparison (Bolus, n=1

studies, 62 patients) vs (Slow, n=3, 113 patients).

Page 13 of 18

The following adverse reactions in infants treated with indomethacin have been reported in the

medical

literature, regardless of the route of administration.

Renal

(Incidence rates from literature - acute renal failure 3.2%; oliguria 44%)

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. Electrolyte disturbances are common following indomethacin in preterm

neonates. The risk of renal impairment appears to be dose related. The impaired renal function usually

resolves over 24 hours following discontinuation.

Gastrointestinal

(Incidence rates from literature – GI bleeding 3.9% to 7.6%; Perforation 2.2%; NEC 4.6% to 7.7%)

Gastrointestinal bleeding, vomiting, abdominal distention, melaena, transient ileus, gastric perforation and,

localised perforations of the small and/or large intestine, necrotising enterocolitis.

Haemorrhagic

(Incidence rates from literature – bleeding 10%).

Gross or microscopic bleeding into the gastro-intestinal tract, oozing from the skin after needle puncture,

pulmonary haemorrhage, and disseminated intravascular coagulopathy.

Cerebral

(Incidence rates from literature – PVL 6.5%; ICH 7.1% to 10.5%; IVH 8.6% to 14.3%)

Periventricular leukomalacia, intracranial haemorrhage, intraventricula haemorrhage have been reported in

Randomised Clinical Trials with the slow infusion regimen.

Metabolic

Hypersensitivity, hyponatraemia, elevated plasma potassium, elevated blood urea, hypoglycaemia, decreased

platelet aggregation and reduction in blood sugar, including hypoglycaemia.

Coagulation

Decreased platelet aggregation.

Cardiovascular

Pulmonary hypertension; intracranial bleeding.

Severe Skin Reactions

Data in adults indicate that NSAIDs may very rarely cause serious cutaneous adverse events such as

exfoliative dermatitis, toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), which can be

fatal and occur without warning. These serious adverse events are idiosyncratic and independent of dose or

duration of use. Patients should be advised of the signs and symptoms of serious skin reactions and to consult

their doctor at the first appearance of a skin rash or any other sign of hypersensitivity.

General

Exacerbation of infection and weight gain (fluid retention).

Causal relationship unknown

Although the following adverse reactions have been reported in infants treated with indomethacin, a causal

relationship to therapy with indomethacin has not been established.

Cardiovascular - bradycardia.

Respiratory - Apnoea, exacerbation of pre-existing pulmonary infection.

Page 14 of 18

Metabolic - Acidosis/alkalosis.

Haematologic - Disseminated intravascular coagulation.

Ophthalmic (incidence ROP 11.7% to 21.1%; blindness <1%) - Retrolental fibroplasia.

Oedema, hypertension and cardiac failure, have 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).

A variety of adverse experiences has been reported in adults treated with oral indomethacin for moderate to

severe rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute painful shoulder and acute gouty

arthritis (see section Additional Adverse Effects - Oral Indomethacin - Adults). Their relevance to the pre-term

neonate receiving indomethacin for patent ductus arteriosus is unknown.

Additional Adverse Effects - Oral Indomethacin - Adults

The following adverse reactions have been reported in adults treated with oral indomethacin for moderate to

severe rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute painful shoulder and acute gouty

arthritis. Complaints not of relevance in the treatment of the premature infant, such as anorexia, psychic

disturbances, and blurred vision, are not listed.

Gastrointestinal

(Incidence 1% to 3%)

Diarrhoea; Constipation

(Incidence less than 1%)

Bloating (includes distention), epigastric distress, abdominal pain, flatulence, peptic ulcer, gastroenteritis,

rectal bleeding, proctitis; single or multiple ulcerations, including perforation and haemorrhage of the

oesophagus, stomach, duodenum or small and large intestines; intestinal ulceration associated with stenosis

and obstruction; gastrointestinal bleeding without obvious ulcer formation and perforation of pre-existing

sigmoid lesions; development of ulcerative stomatitis; gastritis, toxic hepatitis and jaundice (some fatal cases

have been reported).

Central Nervous System

(Incidence less than 1%)

Central nervous system adverse effects are headache, dizziness, light-headedness, depression, vertigo and

fatigue (including malaise and listlessness). Reactions reported infrequently include mental confusion, anxiety,

syncope, drowsiness, convulsions, coma, peripheral neuropathy, muscle weakness, involuntary muscle

movements, insomnia, psychic disturbances such as depersonalisation, psychotic episodes and rarely

paraesthesias, dysarthria, aggravation of epilepsy and parkinsonism. These are often transient and disappear

frequently with continued treatment or with a reduction in dosage. However, the severity of these may, on

occasion, require stopping therapy.

Special Senses

(Incidence less than 1%)

Hearing disturbances, deafness, tinnitus.

Cardiovascular

(Incidence less than 1%)

Hypertension, hypotension, tachycardia, arrhythmia, congestive heart failure, thrombophlebitis, palpitations,

chest pain.

Metabolic

Page 15 of 18

(Incidence less than 1%)

Oedema, weight gain, flushing, hyperglycaemia, glycosuria, hyperkalaemia.

Integumentary

(Incidence less than 1%)

Rash, pruritus, urticaria, angiitis, petechiae or ecchymosis, exfoliative dermatitis, erythema nodosum, loss of

hair, Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis.

Haematologic

(Incidence less than 1%)

Leucopenia, bone marrow depression, anaemia secondary to obvious or occult gastrointestinal bleeding,

aplastic anaemia, haemolytic anaemia agranulocytosis, thrombocytopenic purpura, thrombocytopenia and

disseminated intravascular coagulation. There have been several reports of leukaemia. The supporting

information is weak.

Hypersensitivity

(Incidence less than 1%)

Acute anaphylaxis, acute respiratory distress, rapid fall in blood pressure resembling a shock-like state,

dyspnoea, asthma, purpura, angiitis, pulmonary oedema, angioneurotic oedema.

Genitourinary

(Incidence less than 1%)

Haematuria, vaginal bleeding, renal insufficiency including renal failure, proteinuria, nephrotic syndrome,

interstitial nephritis, urinary frequency.

Miscellaneous

(Incidence less than 1%)

Epistaxis, breast changes (including enlargement and tenderness, or gynaecomastia), ulcerative stomatitis,

sweating.

Dosage and Administration

INDOMETHACIN AGILA IS FOR INTRAVENOUS ADMINISTRATION ONLY.

It is recommended that Indomethacin Agila be administered only in a neonatal intensive care-unit.

Indomethacin Agila should not be given without echocardiographic confirmation that symptoms are due to a

patent ductus arteriosus and that no other significant cardiac defect exists.

A course of therapy is defined as three intravenous doses of Indomethacin Agila given at 12-24 hour intervals,

with careful attention to urinary output. For advice on the rate of infusion see under ‘Directions for Use’.

After assessing the risk/benefit ratio in each individual patient, the lowest effective dose for the shortest

possible duration should be used.

If anuria or marked oliguria (urinary output < 0.6 mL/kg/hr) is evident at the scheduled time of the second or

third dose, Indomethacin Agila must not be given until laboratory studies indicate that renal function has

returned to normal.

It is likely that a single standard indomethacin regime may not be the ideal for every premature infant.

Therefore, individual patient response should be considered and evaluated, in particular in the high risk group

of extremely low birth weight babies.

Page 16 of 18

Dosage recommendations for closure of the ductus arteriosus depend closely on the age and weight of the

infant at the time of therapy.

DOSAGE (mg/kg)

AGE at 1st Dose

1st

2nd

3rd

Less than 48 hours (<1,000 g)

2-7 days (>1,000 g)

Over 7 days (>1,000 g)

0.25

0.25

If the patent ductus arteriosus closes or is significantly reduced in size 48 hours after the first course of

Indomethacin Agila, no further doses are necessary. If the ductus arteriosus re-opens, a second course of 1-

3 doses may be given, each dose separated by a 12-24 hour interval as described above.

NCIUs with skilled operators in the use of colour Doppler echocardiography may be guided on indomethacin

dosage by the PDA flow pattern arising from echocardiographic examinations performed 12–24 hours daily

after birth until the ductus arteriosus closes

MSD 2008, systematic review

This approach resulted in outcomes as good as the standard indomethacin treatment protocol in terms of

ductal closure and was associated with significantly fewer doses of indomethacin than normal (mean

cumulative dose: 0.32mg/kg). Furthermore, fewer doses were associated with a reduced rate of complications

- hypoglycaemia, impaired urine output, and gastrointestinal bleeding. There was no obvious effect on neonatal

morbidity or the incidence of chronic lung disease).

If the infant remains unresponsive to therapy with Indomethacin Agila after 2 courses, surgery may be

necessary.

Directions for Use

Parenteral drug products should be inspected visually for particulate matter and discolouration prior to

administration whenever solution and container permit.

THE SOLUTION SHOULD BE PREPARED ONLY WITH 1 TO 2 mL OF PRESERVATIVE-FREE STERILE

SODIUM CHLORIDE INJECTION BP OR WATER FOR INJECTIONS PH EUR. Preparations containing

glucose must not be used.

A fresh solution should be prepared just prior to each administration according to the dilution table below:

Amount of diluent used for each vial

Concentration achieved

1 mL

0.1 mg/0.1 mL

2 mL

0.05 mg/0.1 mL

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.

Further dilution with intravenous infusion solutions is not recommended. Indomethacin Agila is not buffered,

and reconstitution with solutions at pH values below 6 may result in precipitation of the insoluble indomethacin

free acid moiety.

While the optimal rate of injection of Indomethacin Agila has not been established, current published literature

suggests slow infusion over 20-30 minutes.

Page 17 of 18

Overdosage

Contact the Poisons Information Centre (In NZ telephone: 0800 764 766 or 0800 POISON) for information

regarding overdose management.

The following signs and symptoms have occurred in individuals (not necessarily in premature infants) following

an overdose of oral

indomethacin: nausea, vomiting, intense headache, dizziness, mental confusion,

disorientation, lethargy, paraesthesias, numbness and convulsions. There are no specific measures to treat

acute overdosage with Indomethacin Agila. The patient should be followed for several days as gastrointestinal

ulceration and haemorrhage have been reported as adverse reactions of indomethacin. Any complications

occurring in the gastro-intestinal, renal and central nervous system should be treated symptomatically and

supportively.

Presentation and Storage Conditions

Indomethacin

Agila

presented

single

glass

vials

containing

sterile

lyophilised

powder

reconstitution. Each vial contains indomethacin sodium trihydrate, equivalent to 1 mg indomethacin.

Indomethacin Agila 1 mg powder for injection is available in cartons containing 3 vials.

Store below 25°C. Protect from light and moisture. Keep in outer carton.

Indomethacin Agila powder for injection is for single use in one patient only. Discard any residue.

Medicine Classification

Prescription Medicine

Name and Address of Sponsor

Mylan New Zealand Ltd

PO Box 11-183

Ellerslie

AUCKLAND

Telephone: 09-579-2792

Date of Preparation

18 September 2014

References

Amin SB et al. Indomethacin Use for the Management of Patent Ductus Arteriosus in Preterms: A Web-Based

Survey of Practice Attitudes Among Neonatal Fellowship Program Directors in the United States. Pediatr

Cardiol (2007) 28:193–200.

Fowlie PW, Davis PG (2003) Prophylactic indomethacin for preterm infants: a systematic review and meta-

analysis. Arch Dis Child Fetal Neonatal Ed 88:F464–F466.

Görk AS, RA Ehrenkranz, MB Bracken. Continuous infusion versus intermittent bolus doses of indomethacin

for patent ductus arteriosus closure in symptomatic preterm infants. Cochrane Database of Systematic

Reviews 2008 Issue 1.

Herrera C, J Holberton, P Davis. Prolonged versus short course of indomethacin for the treatment of patent

ductus arteriosus in preterm infants. Cochrane Database of Systematic Reviews 2007 Issue 2.

Page 18 of 18

Merck Sharp & Dohme. A systematic review on intermittent short versus intermittent bolus courses of

indomethacin for the treatment of patent ductus arteriosus in preterm infants. Data on file 2008.

Romagnoli C, Zecca E, Papacci P, De Carolis M P, Giannini R, Gallini F, Tortorolo G. Furosemide does not

prevent indomethacin-induced renal side effects in preterm infants.Clin Pharmacol Ther 1997;62:181-6.

Struis N, Andriessen, Overmeire B V. Furesemide in Preterm Infants Treated with Indomethacin for Patent

Ductus Arteriosus.

Wadhawan R, Rubin LP. Early versus late treatment of PDA with indomethacin. J Pediatr 2002;140:487-8.

Yeh TF et al. Furosemide prevents the renal side effects of indomethacin therapy in premature infants with

patent ductus arteriosus. J Pediatr 1982; 101(3):433-7.

Similar products

Search alerts related to this product

View documents history

Share this information