other cardiac preparations - ATC code: C01 EB16

ibuprofen

Each ml of the solution contains 5 mg ibuprofen. Each ampoule of 2 ml contains 10 mg ibuprofen.

Solution for injection. Clear, colourless to slightly yellow solution.

Treatment of a haemodynamically significant patent ductus arteriosus in preterm newborn infants less than 34 weeks of gestational age

Treatment with Pedea should only be carried out in a neonatal intensive care unit under the supervision of an experienced neonatologist.

Posology

A course of therapy is defined as three intravenous injections of Pedea given at 24-hour intervals. The first injection should be given after the first 6 hours of life.

The ibuprofen dose is adjusted to the body weight as follows:

- 1^st injection: 10 mg/kg,

- 2^nd and 3^rd injections: 5 mg/kg.

If anuria or manifest oliguria occurs after the first or second dose, the next dose should be withheld until urine output returns to normal levels.

If the ductus arteriosus does not close 48 hours after the last injection or if it re-opens, a second course of 3 doses, as above, may be given.

If the condition is unchanged after the second course of therapy, surgery of the patent ductus arteriosus may then be necessary.

Method of administration

For intravenous use only.

Pedea should be administered as a short infusion over 15 minutes, preferably undiluted. If necessary, the injection volume may be adjusted with either sodium chloride 9 mg/ml (0.9%) solution for injection or glucose 50 mg/ml (5%) solution for injection. Any unused portion of the solution should be discarded.

The total volume of solution injected should take into account the total daily fluid volume administered.

- Hypersensitivity to the active substance or to any of the excipients;

- Life-threatening infection;

- Active bleeding, especially intracranial or gastrointestinal haemorrhage;

- Thrombocytopenia or coagulation defects;

- Significant impairment of renal function;

- Congenital heart disease in which 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);

- Known or suspected necrotising enterocolitis;

Before administration of Pedea an adequate echocardiographic examination should be performed in order to detect a haemodynamically significant patent ductus arteriosus and to exclude pulmonary hypertension and ductal-dependent congenital heart disease.

Since prophylactic use in the first 3 days of life (starting within 6 hours of birth) in preterm newborn infants less than 28 weeks of gestational age was associated with increased pulmonary and renal adverse events, Pedea should not be used prophylactically at any gestational age. In particular, severe hypoxemia with pulmonary hypertension was reported in 3 infants within one hour of the first infusion and was reversed within 30 min after start of inhaled nitric oxide therapy.

Since ibuprofen was shown in vitro to displace bilirubin from its binding site to albumin, the risk of bilirubin encephalopathy in premature newborn infants may be increased. Therefore, ibuprofen should not be used in infants with marked elevated bilirubin concentration.

As a non-steroidal anti-inflammatory drug (NSAID), ibuprofen may mask the usual signs and symptoms of infection. Pedea must therefore be used cautiously in the presence of an infection.

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

As ibuprofen may inhibit platelet aggregation, premature neonates should be monitored for signs of bleeding.

As ibuprofen may decrease the clearance of aminoglycosides, strict surveillance of their serum levels is recommended during co-administration with ibuprofen.

Careful monitoring of both renal and gastrointestinal function is recommended.

In preterm newborn infants less than 27 weeks of gestational age, the closure rate of the ductus arteriosus (33 to 50%) was shown to be low at the recommended dose regimen.

This medicinal product contains less than 1 mmol sodium (15 mg) per 2 ml, i.e. essentially 'sodium-free'.

The concomitant use of Pedea with the following medicinal products is not recommended:

- diuretics: ibuprofen may reduce the effect of diuretics; diuretics can increase the risk of nephrotoxicity of NSAIDs in dehydrated patients.

- anticoagulants: ibuprofen may increase the effect of anticoagulants and enhance the risk of bleeding.

- corticosteroids: ibuprofen may increase the risk of gastrointestinal bleeding.

- nitric oxide: since both medicinal products inhibit platelet function, their combination may in theory increase the risk of bleeding.

- other NSAIDs: the concomitant use of more than one NSAID should be avoided because of the increased risk of adverse reactions.

- aminoglycosides: since ibuprofen may decrease the clearance of aminoglycosides, their co-administration may increase the risk of nephrotoxicity and ototoxicity

Data are currently available on approximately 1,000 preterm newborn from both the literature concerning ibuprofen and clinical trials with Pedea. Causality of adverse events reported in the preterm newborn is difficult to assess since they may be related to the haemodynamic consequences of the patent ductus arteriosus as well as to direct effects of ibuprofen.

Reported adverse reactions are listed below, by system organ class and by frequency. Frequencies are defined as: very common ( 1/10), common (1/100, <1/10) and uncommon (1/1,000, <1/100).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

In a clinical curative trial involving 175 preterm newborn infants less than 35 weeks of gestational age, the incidence of bronchopulmonary dysplasia at 36 weeks post-conceptional age was 13/81 (16%) for indomethacin versus 23/94 (24%) for ibuprofen.

In a clinical trial where Pedea was administered prophylactically during the first 6 hours of life, severe hypoxemia with pulmonary hypertension was reported in 3 newborn infants less than 28 weeks of gestational age. This occurred within one hour of the first infusion and was reversed within 30 minutes after the inhalation of nitric oxide.

Orphan Europe (UK) Limited

(POM)

14 February 2012