Pedea: Indications, Contraindications, and Side Effects for PDA Treatment, Study notes of Medicine

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Pedea 5 mg/ml solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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 a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

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

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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

4.2 Posology and method of administration

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 3rd^ 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.

• 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 (see section 4.4).

4.6 Pregnancy and lactation

Not relevant

4.7 Effects on ability to drive and use machines

Not relevant

4.8 Undesirable effects

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.

Blood and lymphatic system disorders Very common : Thrombocytopenia, Neutropenia Nervous system disorders Common : Intraventricular haemorrhage, Periventricular leukomalacia Respiratory, thoracic and mediastinal disorders

Very common: Bronchopulmonary dysplasia* Common : Pulmonary haemorrhage Uncommon: Hypoxemia* Gastrointestinal disorders Common : Necrotizing enterocolitis, Intestinal perforation 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, Blood sodium decreased * see below

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. There have also been post-marketing reports of pulmonary hypertension where Pedea was administered to premature neonates in the therapeutic setting.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

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: CNS depression, seizures, gastrointestinal disturbances, bradycardia, hypotension, apnoea, abnormal renal function, haematuria have been observed. Massive overdose (up to more than 1000 mg/kg) has been reported to induce coma, metabolic acidosis, and transient renal failure. All patients recovered with conventional treatment. Only one recorded death has been published: after an overdose of 469 mg/kg, a 16-month old child developed an apnoeic episode with seizures and a fatal aspiration pneumonia.

The management of ibuprofen overdose is primarily supportive.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

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 cyclo- oxygenase, 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.

5.2 Pharmacokinetic properties

Distribution 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.

As for all parenteral products, ampoules of Pedea should be visually inspected for particulate matter and the integrity of the container prior to use. Ampoules are intended for single use only, any unused portions 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 alcohol 70% is recommended. When disinfecting the neck of the ampoule with an antiseptic, to avoid any interaction with the Pedea solution, 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, and should 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 to adjust injection volume. The total volume of solution injected to preterm infants should take into account the total daily fluid volume administered. A maximal volume of 80 ml/kg/day on the first day of life should usually be respected; this should be progressively increased in the following 1-2 weeks (about 20 ml/kg birthweight/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 infusion line 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 product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Recordati Rare Diseases Immeuble “Le Wilson” 70, avenue du Général de Gaulle F-92800 Puteaux France

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/04/284/

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 29 July 2004 Date of renewal: 29 July 2009

10. DATE OF REVISION OF THE TEXT

Detailed information on this product is available on the web site of the European medicines Agency (EMEA) http://www.emea.europa.eu

ANNEX II

A. MANUFACTURER RESPONSIBLE FOR BATCH

RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY

AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE

MARKETING AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL

PRODUCT

ANNEX III

LABELLING AND PACKAGE LEAFLET

A. LABELLING

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF

APPROPRIATE

After first opening of an ampoule any unused portions must be discarded. Any unused product or waste material should be disposed of in accordance with local requirements.

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Recordati Rare Diseases Immeuble “Le Wilson” 70 avenue du Général de Gaulle F- 92800 Puteaux France

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/04/284/

13. BATCH NUMBER

Batch

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:

SN:

NN:

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

GLASS AMPOULE LABEL

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Pedea 5 mg/ml solution for injection Ibuprofen IV use

2. METHOD OF ADMINISTRATION

See leaflet

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Batch

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

10 mg / 2 ml

6. OTHER

PACKAGE LEAFLET: INFORMATION FOR THE USER

Pedea 5mg/ml solution for injection Ibuprofen

Read all of this leaflet carefully before this medicine is administered to your baby.

• Keep this leaflet. You may need to read it again.
• If you have further questions, please ask your doctor or your pharmacist.
• This medicine has been prescribed for your baby. Do not pass it on to others. It may harm them, even if their symptoms are the same as your baby’s.
• If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or your pharmacist.

In this leaflet :

1. What Pedea is and what it is used for
2. Before Pedea is administered to your baby
3. How Pedea is used
4. Possible side effects
5. How to store Pedea
6. Further information

1. WHAT PEDEA IS AND WHAT IT IS USED FOR

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 the 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 its lungs the ductus arteriosus normally closes. However, in some cases this does not happen. The medical term for this condition is ‘patent ductus arteriosus’ , i.e. an open ductus arteriosus. This can cause heart problems in your baby. This condition is much more frequent in premature newborn than in full-term newborn infants. Pedea, when given to your baby, can help to close the ductus arteriosus.

The active substance in Pedea is ibuprofen. Pedea closes the ductus arteriosus by inhibiting the production of prostaglandin, a naturally occurring chemical in the body which keeps the ductus arteriosus open.

2. BEFORE PEDEA IS ADMINISTERED TO YOUR BABY

Pedea will only be given to your baby in a special neonatal intensive care unit by qualified health care professionals.

Do not use Pedea

• if your baby is allergic (hypersensitive) to ibuprofen or any of the other ingredients of Pedea;
• if your baby has a life-threatening infection which has not been treated;
• if your baby is bleeding, especially if the bleeding is inside the skull or in the intestines;
• if your baby has a decrease of blood cells called platelets (thrombocytopenia) or other problems with their blood clotting;
• if your baby has kidney problems;
• if your baby has other problems with their heart which require the ductus arteriosus to remain open so that adequate circulation of the blood is maintained;
• if your baby has or is suspected to have certain problems with their intestines (a condition called necrotising enterocolitis);

Take special care with Pedea

• Before treatment with Pedea, your baby’s heart will be examined to confirm that the ductus arteriosus is open.
• Pedea should not be given in the first 6 hours of life.
• If your baby is suspected of having liver disease, signs and symptoms of which include yellowing of the skin and eyes.
• If your baby is already suffering from an infection that is being treated, the doctor will treat your baby with Pedea only after careful consideration of your baby’s condition.
• Pedea should be carefully administered to your baby by the healthcare professional, to avoid damage to the skin and surrounding tissues.
• Ibuprofen may reduce the ability of your baby’s blood to clot. Your baby should therefore be watched for signs of prolonged bleeding.
• Your baby may develop some bleeding from the intestines and the kidneys. To detect this, your baby’s stools and urine may be tested to determine if there is any blood present in them.
• Pedea may reduce the amount of urine your baby passes. If this is significant, your baby’s treatment may be stopped until the volume of urine returns to normal.
• Pedea may be less effective in very premature babies less than 27 weeks of gestational age.

Using other medicines Please tell your doctor or pharmacist if your baby is taking or has recently taken any other medicines, including medicines obtained without a prescription.

Certain medicines, if given together with Pedea, may cause side effects. These are detailed below:

• your baby may have problems passing urine and may have been prescribed diuretics. Ibuprofen may reduce the effect of these medicines.
• your baby may be given anticoagulants (medicine preventing blood clotting). Ibuprofen may increase the anti-clotting effect of this product.
• your baby may be given nitric oxide to improve blood oxygenation. Ibuprofen may increase the risk of bleeding.
• your baby may be given corticosteroids to prevent inflammation. Ibuprofen may increase the risk of bleeding in the stomach and intestines.
• your baby may be given aminosides (one family of antibiotics) to treat infection. Ibuprofen may increase blood concentrations and thus increase the risk of toxicity on kidney and ear

Important information about some of the ingredients of Pedea This medicinal product contains less than 1 mmol sodium (15 mg) per 2 ml, i.e. essentially ‘sodium- free’.

3. HOW PEDEA IS USED

Pedea will only be given to your baby in a special neonatal intensive care unit by qualified healthcare professional.

A course of therapy is defined as three intravenous injections of Pedea given at 24 hour intervals. The dose to be administered will be calculated from the weight of your baby. It is 10 mg/kg for the first administration and 5 mg/kg for the second and the third administrations.

This calculated amount will be given by infusion in a vein over a period of 15 minutes. If after this first course of treatment, the ductus arteriosus is not closed or re-opens, your baby’s doctor may decide to give a second course of treatment.

6. FURTHER INFORMATION

What Pedea contains

• The active substance is ibuprofen. Each ml contains 5 mg ibuprofen. Each 2 ml ampoule contains 10 mg ibuprofen.
• The other ingredients are trometamol, sodium chloride, sodium hydroxide (for pH adjustment), hydrochloric acid 25% (for pH adjustment) and water for injections.

What Pedea looks like and contents of the pack Pedea 5mg/ml solution for injection is a clear, colourless to slightly yellow solution. Pedea 5mg/ml solution for injection is supplied in cartons of four 2 ml ampoules.

Marketing Authorisation Holder Recordati Rare Diseases Immeuble “Le Wilson” 70, avenue du Général de Gaulle F- 92800 Puteaux France

Manufacturer

Recordati Rare Diseases Immeuble “Le Wilson” 70, avenue du Général de Gaulle F-92800 Puteaux France

or

Recordati Rare Diseases Eco River Parc 30, rue des Peupliers F-92000 Nanterre France

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder.

Belgique/België/Belgien Recordati Tél/Tel: +32 2 46101 36

Lietuva Recordati AB. Tel: + 46 8 545 80 230 Švedija

България Recordati Rare Diseases Tel: +33 (0)1 47 73 64 58 Франция

Luxembourg/Luxemburg Recordati Tél/Tel: +32 2 46101 36 Belgique/Belgien

Česká republika Recordati Rare Diseases Tel: +33 (0)1 47 73 64 58 Francie

Magyarország Recordati Rare Diseases Tel: +33 (0)1 47 73 64 58 Franciaország

Danmark Recordati AB. Tlf : +46 8 545 80 230 Sverige

Malta Recordati Rare Diseases Tel: +33 1 47 73 64 58 Franza

Deutschland Recordati Rare Diseases Germany GmbH Tel: +49 731 140 554 0

Nederland Recordati Tel: +32 2 46101 36 België

Eesti Recordati AB. Tel: + 46 8 545 80 230 Rootsi

Norge Recordati AB. Tlf : +46 8 545 80 230 Sverige

Ελλάδα Recordati Rare Diseases Tηλ: +33 (0)1 47 73 64 58 Γαλλία

Österreich Recordati Rare Diseases Germany GmbH Tel: +49 731 140 554 0 Deutschland

España Recordati Rare Diseases Spain S.L.U. Tel: + 34 91 659 28 90

Polska Recordati Rare Diseases Tel: +33 (0)1 47 73 64 58 Francja

France Recordati Rare Diseases Tél: +33 (0)1 47 73 64 58

Portugal Jaba Recordati S.A. Tel: +351 21 432 95 00

Hrvatska Recordati Rare Diseases Tél: +33 (0)1 47 73 64 58 Francuska

România Recordati Rare Diseases Tél: +33 (0)1 47 73 64 58 Franţa

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Ísland Recordati AB. Simi:+46 8 545 80 230 Svíþjóð

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