Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Recordati Rare Diseases, Immeuble Le Wilson, 70, avenue du Général de Gaulle, F-92800 Puteaux, France
Pharmacotherapeutic group: other cardiac preparations
ATC code: C01EB16
Ibuprofen is a NSAID that possesses anti-inflammatory, analgesic and antipyretic activity. Ibuprofen is a racemic mixture of S ( + ) and R(-) enantiomers. In vivo and in vitro studies indicate that the S ( + ) isomer is responsible for the clinical activity. Ibuprofen is a non selective inhibitor of cyclooxygenase, leading to reduced synthesis of prostaglandins. Since prostaglandins are involved in the persistence of the ductus arteriosus after birth, this effect is believed to be the main mechanism of action of ibuprofen in this indication.
In a dose-response study of Pedea in 40 preterm newborn infants, the ductus arteriosus closure rate associated to the 10-5-5 mg/kg dose regimen was 75% (6/8) in neonates of 27-29 weeks' gestation and 33% (2/6) in neonates of 24-26 weeks' gestation.
Prophylactic use of Pedea 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 incidence of renal failure and pulmonary adverse events including hypoxia, pulmonary hypertension, pulmonary haemorrhage, as compared to curative use. Conversely, a lower incidence of neonatal grade III-IV intraventricular haemorrhage and of surgical ligation was associated with prophylactic use of Pedea.
Although a great variability is observed in the premature population, peak plasma concentrations are measured around 35-40 mg/l after the initial loading dose of 10 mg/kg as well as after the last maintenance dose, whatever gestational and postnatal age. Residual concentrations are around 10-15 mg/l 24 hours after the last dose of 5 mg/kg.
Plasma concentrations of the S-enantiomer are much higher than those of the R-enantiomer, which reflects a rapid chiral inversion of the R- to the S-form in a proportion similar to adults (about 60%).
The apparent volume of distribution is on average 200 ml/kg (62 to 350 according to various studies). The central volume of distribution may depend on the status of the ductus and decrease as the ductus closes.
In vitro studies suggest that, similarly to other NSAIDs, ibuprofen is highly bound to plasma albumin, although this seems to be significantly lower (95%) compared with adult plasma (99%). Ibuprofen competes with bilirubin for albumin binding in newborn infant serum and, as a consequence, the free fraction of bilirubin may be increased at high ibuprofen concentrations.
Elimination rate is markedly lower than in older children and adults, with an elimination half-life estimated at approximately 30 hours (16–43). The clearance of both enantiomers increases with gestational age, at least in the range of 24 to 28 weeks.
In preterm newborns ibuprofen significantly reduced plasma concentrations of prostaglandins and their metabolites, particularly PGE2 and 6-keto-PGF-1-alpha. Low levels were sustained up to 72 hours in neonates who received 3 doses of ibuprofen, whereas subsequent re-increases were observed at 72 hours after only 1 dose of ibuprofen.
There are no preclinical data considered relevant to clinical safety beyond data included in other sections of this Summary of Product Characteristics. With the exception of an acute toxicity study, no further studies have been carried out in juvenile animals with Pedea.
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