PEDEA 5mg / ml injectible solution medication leaflet

Pedea 5 mg/ml solution for injection

Each ml of the solution contains 5 mg ibuprofen.

Each ampoule of 2 ml contains 10 mg ibuprofen.

Excipients: each ml contains 7.5 mg of sodium.

For the full list of excipients, see section 6.1.

Solution for injection.

Clear, colourless to slightly yellow solution.

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

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

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

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

- 1st injection: 10 mg/kg,

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

If anuria or manifest oliguria occurs after the first or second dose, the next dose should be withhelduntil 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 courseof 3 doses, as above, may be given.

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

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 forinjection or glucose 50 mg/ml (5%) solution for injection. Any unused portion of the solution shouldbe discarded.

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

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1;

- 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 satisfactorypulmonary or systemic blood flow (e.g. pulmonary atresia, severe tetralogy of Fallot, severecoarctation of the aorta);

- Known or suspected necrotising enterocolitis;

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

Since prophylactic use in the first 3 days of life (starting within 6 hours of birth) in preterm newborninfants less than 28 weeks of gestational age was associated with increased pulmonary and renaladverse events, Pedea should not be used prophylactically at any gestational age (see sections 4.8 and5.1). In particular, severe hypoxemia with pulmonary hypertension was reported in 3 infants withinone hour of the first infusion and was reversed within 30 min after start of inhaled nitric oxide therapy.

If hypoxaemia occurs during or following Pedea infusion, close attention should be paid to pulmonarypressure.

Since ibuprofen was shown in vitro to displace bilirubin from its binding site to albumin, the risk ofbilirubin encephalopathy in premature newborn infants may be increased (see section 5.2). 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 andsymptoms of infection. Pedea must therefore be used cautiously in the presence of an infection (seealso section 4.3).

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

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

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

Careful monitoring of both renal and gastrointestinal function is recommended.

Severe skin reactions

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnsonsyndrome, and toxic epidermal necrolysis have been reported rarely in association with the use of

NSAIDSs (see section 4.8). Patients appear to be at highest risk of these reactions early in the courseof therapy, the onset of the reaction occurring in the majority of cases within the first month oftreatment. Acute generalised exanthematous pustulosis (AGEP) and drug reaction with eosinophiliaand systemic symptoms (DRESS syndrome) have been reported in relation to ibuprofen-containingproducts. Ibuprofen should be discontinued, at the first appearance of signs and symptoms of severeskin reactions, such as skin rash, mucosal lesions, or any other sign of hypersensitivity.

In preterm newborn infants less than 27 weeks of gestational age, the closure rate of the ductusarteriosus (33 to 50%) was shown to be low at the recommended dose regimen (see section 5.1).

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 ofnephrotoxicity of NSAIDs in dehydrated patients.

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

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

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

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

- aminoglycosides: since ibuprofen may decrease the clearance of aminoglycosides, their co-administration may increase the risk of nephrotoxicity and ototoxicity (see section 4.4).

Not relevant

Not relevant

Data are currently available on approximately 1,000 preterm newborn from both the literatureconcerning ibuprofen and clinical trials with Pedea. Causality of adverse events reported in thepreterm newborn is difficult to assess since they may be related to the haemodynamic consequences ofthe 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 aredefined 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.

Blood and lymphatic system disorders Very common: Thrombocytopenia, Neutropenia

Nervous system disorders Common: Intraventricular haemorrhage,

Periventricular leukomalacia

Respiratory, thoracic and mediastinal Very common: Bronchopulmonary dysplasia*disorders Common: Pulmonary haemorrhage

Uncommon: Hypoxemia*

Gastrointestinal disorders Common: Necrotizing enterocolitis, Intestinalperforation

Uncommon: Gastrointestinal haemorrhage

Unknown: Gastric perforation

Renal and urinary disorders Common: Oliguria, Fluid retention, Haematuria

Uncommon: Acute renal failure

Investigations Very Common: Blood creatinine increased, Bloodsodium decreased

Skin and subcutaneous tissue disorders N o t known: Acute generalised exanthematouspustulosis (AGEP), drug reaction with eosinophiliaand systemic symptoms (DRESS syndrome)

* see below

In a clinical curative trial involving 175 preterm newborn infants less than 35 weeks of gestationalage, 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, severehypoxemia with pulmonary hypertension was reported in 3 newborn infants less than 28 weeks ofgestational age. This occurred within one hour of the first infusion and was reversed within 30 minutesafter the inhalation of nitric oxide. There have also been post-marketing reports of pulmonaryhypertension where Pedea was administered to premature neonates in the therapeutic setting.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No case of overdose has been reported with intravenous ibuprofen in preterm newborn infants.

However, overdose has been described in infants and children administered oral ibuprofen: CNSdepression, seizures, gastrointestinal disturbances, bradycardia, hypotension, apnoea, abnormal renalfunction, haematuria have been observed.

Massive overdose (up to more than 1000 mg/kg) has been reported to induce coma, metabolicacidosis, and transient renal failure. All patients recovered with conventional treatment. Only onerecorded death has been published: after an overdose of 469 mg/kg, a 16-month old child developedan apnoeic episode with seizures and a fatal aspiration pneumonia.

The management of ibuprofen overdose is primarily supportive.

Prolonged use at higher than recommended doses or overdose may result in renal tubular acidosis andhypokalaemia.

Pharmacotherapeutic group: other cardiac preparations, ATC code: C01 EB16

Ibuprofen is a NSAID that possesses anti-inflammatory, analgesic and antipyretic activity. Ibuprofenis 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 cyclo-oxygenase, leading to reduced synthesis of prostaglandins.

Since prostaglandins are involved in the persistence of the ductus arteriosus after birth, this effect isbelieved 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 rateassociated to the 10-5-5 mg/kg dose regimen was 75% (6/8) in neonates of 27-29 weeks’ gestation and33% (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 pretermnewborn infants less than 28 weeks of gestational age was associated with increased incidence of renalfailure and pulmonary adverse events including hypoxia, pulmonary hypertension, pulmonaryhaemorrhage, as compared to curative use. Conversely, a lower incidence of neonatal grade III-IVintraventricular 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 aremeasured around 35-40 mg/l after the initial loading dose of 10 mg/kg as well as after the lastmaintenance 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, whichreflects 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 ductuscloses.

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 %). Ibuprofencompetes with bilirubin for albumin binding in newborn infant serum and, as a consequence, the freefraction of bilirubin may be increased at high ibuprofen concentrations.

Elimination rate is markedly lower than in older children and adults, with an elimination half-lifeestimated at approximately 30 hours (16-43). The clearance of both enantiomers increases withgestational age, at least in the range of 24 to 28 weeks.

In preterm newborns ibuprofen significantly reduced plasma concentrations of prostaglandins andtheir metabolites, particularly PGE2 and 6-keto-PGF-1-alpha. Low levels were sustained up to72 hours in neonates who received 3 doses of ibuprofen, whereas subsequent re-increases wereobserved at 72 hours after only 1 dose of ibuprofen.

There are no preclinical data considered relevant to clinical safety beyond data included in othersections of this Summary of Product Characteristics. With the exception of an acute toxicity study, nofurther studies have been carried out in juvenile animals with Pedea.

Trometamol,sodium chloride,sodium hydroxide (for pH adjustment),hydrochloric acid 25% (for pH adjustment),water for injections.

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Pedea solution must not be in contact with any acidic solution such as certain antibiotics or diuretics.

A rinse of the infusion line must be performed between each product administration (see section 6.6).

4 years.

To avoid any possible microbiological contamination, the product should be used immediately afterfirst opening.

This medicinal product does not require any special storage conditions.

2 ml solution in a colourless type 1 glass ampoule.

Pedea is supplied in packs of 4 x 2 ml ampoules.

As for all parenteral products, ampoules of Pedea should be visually inspected for particulate matterand the integrity of the container prior to use. Ampoules are intended for single use only, any unusedportions must be discarded.

Chlorhexidine must not be used to disinfect the neck of the ampoule as it is not compatible with the

Pedea solution. Therefore, for asepsis of the ampoule before use, ethanol 60% or isopropyl alcohol70% is recommended.

When disinfecting the neck of the ampoule with an antiseptic, to avoid any interaction with the Pedeasolution, the ampoule must be completely dry before it is opened.

The required volume to be given to the infant should be determined according to body weight, andshould be injected intravenously as a short infusion over 15 minutes, preferably undiluted.

Use only sodium chloride 9 mg/ml (0.9%) solution for injection or glucose 50 mg/ml (5%) solution toadjust injection volume.

The total volume of solution injected to preterm infants should take into account the total daily fluidvolume administered. A maximal volume of 80 ml/kg/day on the first day of life should usually berespected; this should be progressively increased in the following 1-2 weeks (about 20 ml/kgbirthweight/day) up to a maximal volume of 180 ml/kg birthweight/day.

Before and after administration of Pedea, to avoid contact with any acidic solution, rinse the infusionline over 15 minutes with 1.5 to 2 ml of either sodium chloride 9 mg/ml (0.9%) or glucose 50 mg/ml(5%), solution for injection.

After first opening of an ampoule, any unused portions must be discarded.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Recordati Rare Diseases

Tour Hekla52, avenue du Général de Gaulle

F-92800 Puteaux

France

EU/1/04/284/001

Date of first authorisation: 29 July 2004

Date of renewal: 29 July 2009

Detailed information on this product is available on the web site of the European medicines Agencyhttps://www.ema.europa.eu