PATIENT INFORMATION LEAFLET

Requires 5 mg/ml injectable solution

Ibuprofen

Read this leaflet carefully before administering this medicine to your baby.

• Keep this leaflet, as you may need to read it again.
• If you have any doubts, consult your doctor or pharmacist.
• This medicine has been prescribed for your baby and should not be given to other people, even if they have the same symptoms as your baby, as it may harm them.
• Inform your doctor or pharmacist if you consider any of the side effects your baby is experiencing to be severe or if you notice any side effects not mentioned in this leaflet.

While the baby is inside the mother's uterus, it does not need to use the lungs. Fetal blood vessels called the ductus arteriosus are near the heart, allowing the baby's blood not to enter the lungs and circulate through the rest of the body.

When the baby is born, and begins to use the lungs, the ductus arteriosus normally closes.

However, in some cases, this does not occur. The medical term for this condition is 'persistent ductus arteriosus', that is, an open ductus arteriosus. This can produce heart problems in the baby. This condition is much more frequent in premature newborns than in those born at term.

Pedea, when administered to the baby, may help to close the ductus arteriosus.

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

Pedea will only be administered to your baby in a neonatal intensive care unit by qualified healthcare professionals.

Do not use Pedea

• if your baby is allergic (hypersensitive) to ibuprofen or any of the other components of Pedea;

• if your baby has a life-threatening infection that has not been treated;
• if your baby experiences bleeding, especially if the bleeding is inside the skull or in the intestines;
• if your baby has a decrease in platelet cells (thrombocytopenia) or other blood clotting problems;
• if your baby has kidney problems;
• if your baby has other heart problems that require the ductus arteriosus to remain open to maintain adequate blood circulation;
• if your baby has or is suspected to have certain intestinal problems (a disease called necrotizing enterocolitis).

Be especially careful with Pedea

• Before starting treatment with Pedea, an echocardiogram of the baby will be performed to confirm that the ductus arteriosus is open.
• Pedea should not be administered in the first 6 hours of life.
• - Treatment with Pedea should not be used if it is suspected that the baby has liver disease, whose signs and symptoms include yellow skin and eyes.
• - If the baby already has an infection being treated, the doctor will treat the baby with Pedea only after carefully evaluating the baby's condition.
• - Healthcare personnel should administer Pedea with caution to the baby, in order to avoid damage to the skin and surrounding tissues.
• - Ibuprofen may reduce the baby's blood clotting ability. Therefore, the baby should be monitored for signs of prolonged bleeding.
• - The baby may develop some bleeding in the intestines and kidneys. In order to detect this, the baby's stool and urine may be analyzed to determine the presence of blood in them.
• - Pedea may reduce the amount of urine expelled by the baby. If it is significant, treatment may be interrupted until the urine volume returns to normal levels.
• Pedea may be less effective in very premature babies less than 27 weeks of gestational age.

Use of other medications

Inform your doctor or pharmacist if your baby is using or has recently used other medications, including those obtained without a prescription.

Certain medications, if administered with Pedea, may produce adverse reactions. These are listed below:

• Your baby may have difficulty expelling urine and may have been prescribed diuretics. Ibuprofen may reduce the effect of these medications.
• Your baby may be receiving anticoagulants (medications that prevent blood from clotting). Ibuprofen may increase the anticoagulant effect of this medication.
• Your baby may be receiving nitric oxide to improve blood oxygenation. Ibuprofen may increase the risk of bleeding.
• Your baby may be receiving corticosteroids to prevent inflammation. Ibuprofen may increase the risk of bleeding in the stomach and intestines.
• In order to treat an infection, it is possible that your baby will be administered aminoglycosides (a family of antibiotics). Ibuprofen may increase the concentrations of these in the baby's blood and thus increase the risk of kidney and ear toxicity.

Important information about some of the components of Pedea

This medication contains less than 1 mmol of sodium (15 mg) per 2 ml, that is, it is essentially 'sodium-free'.

Only a qualified healthcare professional in a neonatal intensive care unit will administer Pedea to your baby.

A cycle of therapy is defined as three intravenous injections of Pedea administered at 24-hour intervals. The dose to be administered will be calculated based on your baby's weight. The initial dose is 10 mg/kg, and the second and third doses are 5 mg/kg.

The calculated amount will be administered through a 15-minute intravenous infusion.

If, after the first treatment cycle, the ductus arteriosus remains open or reopens, your baby's doctor may decide to administer a second treatment cycle.

If, after the second treatment cycle, the ductus arteriosus continues to remain open, surgery may then be proposed.

Like all medications, Pedea can produce adverse effects, although not all people will experience them. However, it is difficult to distinguish them from frequent complications that occur in premature babies and complications due to the disease.

The following list shows the frequency of possible adverse effects using the following convention:

very frequent (affects more than 1 user in 10)

frequent (affects 1 to 10 users in 100)

infrequent (affects 1 to 10 users in 1,000)

very rare (affects less than 1 user in 10,000)

unknown frequency (cannot be estimated from available data)

Very frequent:

• Decrease in the number of platelets in the blood (thrombocytopenia)
• Decrease in the number of white blood cells called neutrophils (neutropenia)
• Increased level of creatinine in the blood
• Decrease in the level of sodium in the blood
• Respiratory problems (bronchopulmonary dysplasia)

Frequent:

• Internal skull hemorrhage (intraventricular hemorrhage) and brain injury (periventricular leukomalacia)
• Pulmonary hemorrhage
• Intestinal perforation and intestinal tissue injury (necrotizing enterocolitis)
• Decreased urine output, blood in the urine, fluid retention

Infrequent:

• Acute renal insufficiency
• Intestinal hemorrhage
• Arterial blood oxygen levels below normal (hypoxemia)

Unknown:

• Stomach perforation

If you consider any of the adverse effects you are experiencing to be severe or if you notice any adverse effect not mentioned in this prospectus, inform your baby's doctor or pharmacist.

Keep out of reach and sight of children.

Do not use Pedea after the expiration date that appears on the box and the label after CAD. The expiration date is the last day of the month indicated.

No special storage conditions are required.

Once opened, Pedea must be administered immediately.

Medicines should not be disposed of through drains or in the trash. Ask your pharmacist how to dispose of the containers and medicines you no longer need. This will help protect the environment.

Composition of Pedea

• The active principle is ibuprofen. Each ml contains 5 mg of ibuprofen. Each ampoule of 2 ml contains 10 mg of ibuprofen.
• The other components are trometamol, sodium chloride, sodium hydroxide (to adjust the pH), hydrochloric acid 25% (to adjust the pH), and water for injections.

Appearance of the product and contents of the pack

Pedea 5 mg/ml injectable solution is a transparent, colourless to pale yellow solution.

Pedea 5 mg/ml injectable solution is presented in boxes of four ampoules of 2 ml.

Marketing Authorisation Holder

Orphan Europe SARL

Immeuble “Le Wilson”

70, avenue du Général de Gaulle

F- 92800 Puteaux,

France

Responsible Person

Orphan Europe SARL

Immeuble “Le Wilson”

70, avenue du Général de Gaulle

92800 Puteaux

France

or

Orphan Europe SARL

Eco River Parc

30, rue des Peupliers

F-92000 Nanterre

France

You can request more information about this medicine by contacting the local representative of the marketing authorisation holder.

This leaflet was approved in {Month/year}.

The detailed information on this medicine is available on the website of the European Medicines Agency (EMEA)http://www.emea.europa.eu/.

This information is intended solely for medical professionals or healthcare professionals:

Like all parenteral products, Pedea ampoules should be visually inspected for particles and to check the integrity of the container before use. The ampoules are for single use only, discard any unused part.

Dosage and administration (see also section 3)

Only for intravenous use. Treatment with Pedea can only be carried out in a neonatal intensive care unit under the supervision of an experienced neonatologist. A treatment cycle is defined as three intravenous doses of Pedea administered at intervals of 24 hours.

The dose of ibuprofen is adjusted according to body weight as follows:

- 1st injection: 10 mg/kg,

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

If the ductus arteriosus does not close within 48 hours after the last injection or if it reopens, a second cycle of 3 doses may be administered in the same way.

If the disorder continues after a second cycle of treatment, surgical intervention on the persistent ductus arteriosus may be necessary.

In case of manifest anuria or oliguria after the first or second dose, the next dose should be postponed until urine excretion returns to normal levels.

Administration:

Pedea should be administered as a short infusion over 15 minutes, preferably undiluted. To facilitate administration, a infusion pump may be used.

If necessary, the injection volume may be adjusted with sodium chloride solution 9 mg/ml (0.9%) or glucose solution 50 mg/ml (5%). Discard any unused part of the solution.

The total volume of the injected solution in preterm newborns should take into account the total daily volume of liquids administered. Normally, a maximum volume of 80 ml/kg/day should be respected on the first day of life; this volume will be gradually increased over the next 1-2 weeks (approximately 20 ml/kg of birth weight/day) to a maximum volume of 180 ml/kg of birth weight/day.

Incompatibilities

Chlorhexidine should not be used to disinfect the neck of the ampoule because it is not compatible with the Pedea solution. Therefore, to perform the asepsis of the ampoule before use, it is recommended to use ethanol 60% or isopropyl alcohol 70%.

To avoid any interaction with the Pedea solution during the disinfection of the neck of the ampoule with an antiseptic, the ampoule should be completely dry before opening.

This medicine should not be mixed with other medicines except with sodium chloride solution 9 mg/ml (0.9%) or glucose solution 50 mg/ml (5%).

To avoid any significant pH variation due to the presence of acidic medicines that may remain in the infusion line, the line should be flushed before and after the administration of Pedea with 1.5 to 2 ml of sodium chloride solution 9 mg/ml (0.9%) or glucose solution 50 mg/ml (5%).