PACKAGE LEAFLET: INFORMATION FOR THE USER

MILRINONE 1 MG/ML SOLUTION FOR INJECTION/INFUSION

Milrinone

(Referred to Milrinone in this leaflet)

Read all of this leaflet carefully before you start using this medicine.

-    Keep this leaflet. You may need to read it again.

-    If you have any further questions, ask your doctor or pharmacist.

-    This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.

-    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 pharmacist.

In this leaflet:

1.    What Milrinone is and what it is used for

2.    Before you use Milrinone

3.    How to use Milrinone

4.    Possible side effects

5.    How to store Milrinone

6.    Further information

1. WHAT MILRINONE IS AND WHAT IT IS USED FOR

Milrinone is a medicine used to increase cardiac output (heart performance). The active substance is called milrinone. It is a substance with properties that increase the strength of heart contractions and dilate the blood vessels.

Milrinone can be used in adults for:

-    Short-term treatment of severe congestive heart failure (where the heart cannot pump enough blood to the rest of the body) when other medicines have not worked

Milrinone can be used in children for:

-    Short-term treatment (up to 35 hours) of severe congestive heart failure (where the heart cannot pump enough blood to the rest of the body) when other medicines have not worked.

-    Short-term treatment (up to 35 hours) of acute heart failure after a heart operation i.e. when your heart is having difficulty pumping blood around your body.

Whilst using Milrinone, constant monitoring of heart

function and blood pressure must be ensured.

2. BEFORE YOU USE MILRINONE

Do not use Milrinone

-    if you are allergic (hypersensitive) to milrinone (active substance) or any of the other ingredients of Milrinone,

-    if your heart failure is due to abnormal enlargement of the heart muscle cells (hypertrophic obstructive cardiomyopathy),

-    if you have been diagnosed with ventricular aneurysm (localised expansion of the heart's ventricle wall),

-    if you are suffering from severe, as-yet untreated dehydration (hypovolaemia),

-    if you have suffered an acute heart attack (myocardial infarction).

In addition, do not use Milrinone

if your heart failure is due to

-    an overactive thyroid (hyperthyroidism),

-    acute heart muscle inflammation (myocarditis) or

-    a certain type of heart muscle disease (amyloid cardiomyopathy),

duetothelack of sufficient therapeutic experience available.

Take special care with Milrinone

-    if you have severe narrowing of the heart valves (obstructive aortic or pulmonary valve disease),

-    if you have been, or if you are expected to be diagnosed with certain forms of heart rhythm disorders (e.g. atrial flutter, atrial fibrillation or certain other types of heart rhythm disorders originating from the lower chamber (ventricle) of the heart), as Milrinone may promote certain heart rhythm disorders. Your doctor will therefore check whether additional antiarrhythmic treatment, a dose adjustment or electrocardiogram monitoring is required.

-    if your heart is suspected of having low filling pressures (e.g. due to previous treatment with water tablets). Before use, your doctor will check your filling pressures and correct them if necessary.

-    if you suffer from a kidney disorder or low blood pressure. Before and during treatment, your doctor will carry out appropriate checks and take these into account during treatment, as well as when determining the dose of Milrinone and other medicines.

-    if you have been diagnosed with a reduced number of blood platelets (thrombocytes) or red blood cells (erythrocytes) or a low haemoglobin level, Milrinone may only be used with careful blood platelet monitoring, as this might lead to a further decrease in these blood components.

Cases of reactions at the infusion site have been reported. Whilst using Milrinone, careful monitoring is therefore required at the puncture site, in order to prevent ex-travascular administration of the infusion (i.e. accidental administration outside the vein).

Children and adolescents

The following should be considered in addition to warnings and precautions described for adults: Before giving Milrinone infusion, your doctor will check a lot of parameters such as heart rhythm and blood pressure. He/she will order blood tests as well.

The infusion will not start if your child's heart rhythm and blood pressure is not stable.

Please tell your doctor if:

-    Your child has kidney problems

-    Your child is a preterm infant or has a low birth weight Your child has a certain heart problem named Patent Ductus Arterisus: a connection between 2 major blood vessels (aorta and pulmonary artery) which persists though it should be closed.

Elderly patients

There are special dosage recommendations for elderly patients. Controlled pharmacokinetic studies have so far shown no age-dependent effect on the distribution and/or excretion of milrinone, the active substance of Milrinone.

Using other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

If you are taking water tablets (diuretics) at the same time as Milrinone, their effect may be enhanced in terms of increasing urine output and lowering potassium. The resulting potassium loss may promote the onset of heart rhythm disorders, especially if you are taking concomitantly digoxin (used for heart problems). The effect of Milrinone may also be stronger.

When given at the same time as cardiotonic medicines (i.e. that increase the strength of heart contractions, e.g. dobutamine), Milrinone can enhance the cardiotonic (positive inotropic) effects of these medications and vice versa.

Please note that all this information may also apply to recently-used medicines.

Pregnancy and breast-feeding

For milrinone, no clinical data are available regarding use in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, prenatal development (i.e. before the birth), delivery or postnatal development (i.e. after the birth).

Caution should be exercised during use in pregnancy. As it is unknown whether milrinone is excreted in human milk, breast-feeding must be discontinued in the event of treatment.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

There is no available experience regarding adverse effects on the ability to drive and use machines.

Important information about some of the ingredients of Milrinone

This medicine contains glucose. If you have been told thatyou have an intolerance to some sugars,you should tell your doctor before Milrinone is used.

3. HOWTO USE MILRINONE

Your doctor will determine the dosage and how to administer Milrinone. In general, he/she will be guided by the following dosage recommendations:

Dosage

Starting dosage:

Milrinone should be administered at a loading dose of 50 micrograms of milrinone/kg body weight (BW) over a 10-minute period; this is normally followed by a continuous maintenance infusion.

Maintenance dosage:

In general, the continuous maintenance infusion is 0.5 micrograms of milrinone/kg BW/min; however, it can range between 0.375 micrograms of milrinone/kg BW/min and 0.75 micrograms of milrinone/kg BW/min, depending on the effects on the cardiovascular system.

The total dose should not exceed 1.13 mg milrinone/kg BW/day.

For administering the maintenance dose, a solution for infusion is prepared at a concentration of 200 micrograms of milrinone/ml. It is made by adding 40 ml of a carrier solution to 10 ml undiluted solution for injection/ infusion. As carrier solutions, 0.9% saline solution or 5% glucose solution can be used.

Depending on the required maintenance dose (in micrograms per kg BW per minute), this gives the following infusion rates (in millilitres per kg BW per hour) for the prepared solution for infusion, at a concentration of 200 micrograms/ml (see Table 1).

Table 1: Converting the maintenance dose to the equivalent infusion rate * calculated for a solution for infusion with 200 micrograms of milrinone per millilitre

Children and adolescents

Your doctor should give your child a first dose ranging between 50 and 75 micrograms for every kilogram of his weight, over a period of 30 to 60 minutes.

This is then followed by a dose ranging from 0.25 to 0.75 micrograms for every kilogram of his/her weight per minute according to your child's response to the treatment and occurrence of side effects.

Milrinone can be given for up to 35 hours.

During infusion, your child will be closely monitored: your doctor will check a lot of parameters such as heart rhythm and blood pressure and blood will be taken to evaluate the response to therapy and occurrence of side effects.

Elderly patients

Based on the current state of knowledge, it is assumed that no special dosage recommendations are necessary for this patient group if kidney function is normal. Patients with impaired kidney function If your kidney function is severely impaired, the excretion of milrinone will be reduced. The maintenance dose should therefore be reduced, depending on the extent of kidney dysfunction (see Table 2).

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* calculated for a solution for infusion with 200 micrograms of milrinone per millilitre

Method of administration:

Milrinone is administered by slow intravenous injection or by intravenous infusion.

Milrinone must not be mixed with carrier solutions other than those mentioned above (5% glucose solution or 0.9% saline solution).

Furosemide is chemically incompatible with a range of substances including milrinone. If Milrinone is administered at the same time as furosemide or bumetanide, different intravenous accesses should therefore be selected or furosemide should be taken as a tablet, for example. Milrinone must not be mixed with sodium bicarbonate solutions for infusion.

Depending on fluid requirements, solutions for infusion with various concentrations can be used.

For the injection, as large a vein as possible should be chosen to avoid local irritation.

Injections that miss the intended blood vessel must be avoided.

Duration of treatment:

The duration of treatment should not exceed 48 hours, as no controlled studies have been conducted with a treatment period of more than 48 hours.

If you are given more Milrinone than you should

A drop in blood pressure and rapid heart rhythm disorders may occur.

In the event of an overdose, your doctor will stop the infusion or reduce the infusion rate and may initiate other appropriate procedures. There is no known specific antidote.

If you forget to use Milrinone

Your doctor or nurse will have instructions on when to give you this medicine. It is unlikely that you will not be given the medicine as it has been prescribed. However, if you think you have missed a dose, tell your doctor or nurse.

Ifyou have any further questions on the use of this product, askyour doctor or pharmacist.

4. POSSIBLE SIDE EFFECTS

Like all medicines, Milrinone can cause side effects, although not everybody gets them.

The following categories are used for stating the frequency of side effects:

Common (1 to 10 out of 100 patients treated)

-    mild to moderately severe headache,

-    irregular heartbeat caused by extra beats,

-    racing heart,

-    heart rhythm disorders,

-    low blood pressure (hypotension).

Uncommon (1 to 10 out of 1,000 patients treated)

-    reduction in the number of blood platelets,

-    low potassium levels,

-    trembling,

-    ventricular fibrillation,

-    severe chest pain, often with tight-chestedness and shortness of breath,

-    increased liver values as a result of impaired liver function.

Rare (1 to 10 out of 10,000 patients treated)

-    reduction in the number of red blood cells,

-    reduced haemoglobin concentration (blood pigment), Very rare (less than 1 in 10,000 patients treated)

-    allergic (anaphylactic) shock,

-    a particularly dangerous form of racing heart (torsade de pointes),

-    spasmodic constriction of the bronchial tubes,

-    skin reactions, e.g. skin rash.

Not known (cannot be estimated from the available data)

-    irritation at the infusion site

-    reduction of red blood count and/or haemoglobin concentration.

Life-threatening heart rhythm disorders have occurred particularly in patients with pre-existing heartbeat irregularities and/or metabolic abnormalities (e.g. low potassium level) and/or high digitalis levels.

Additional side effects in children

In addition to side effects observed in adults, the following were reported in children:

Not known (cannot be estimated from the available data)

-    bleeding into the fluid-filled areas (ventricles) surrounded by the brain (intraventricular haemorrhage)

-    a heart problem known as Patent Ductus arteriosus: a connection between 2 major blood vessels (aorta and pulmonary artery) which persists though it should be closed. This can cause excess fluid in the lungs, bleedings, destruction of the bowel or part of the bowel and possibly be fatal.

Moreover, compared to adults, decrease in the number of platelets in the blood seems to occur more often in children and the riskofthisside effect in increased with the duration of the Milrinone infusion. Heart rhythm troubles seem to occur less often in children than in adults.

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 pharmacist.

5. HOW TO STORE MILRINONE

Keep out of the sight and reach of children.

Do not use Milrinone after the expiry date which is stated on the label and outer carton. The expiry date refers to the last day of that month.

Storage conditions:

This medicinal product does not require any special storage conditions.

Notes on shelf life after opening or dilution with isotonic sodium chloride or glucose 5 % solution

The chemical and physical stability of the ready-to-use preparation has been demonstrated for 24 hours at 25°C. From a microbiological point of view, the ready-to-use preparation should be used immediately.

If the ready-to-use preparation is not used immediately, storage times and conditions are the responsibility of the user.

After opening, discard any unused portion.

Any unused product or waste material should be disposed of in accordance with local requirements.

6. CONTENT OF THE PACK AND OTHER INFORMATION

What Milrinone contains

■    The active substance is milrinone.

Each ml solution for injection/infusion contains 1 mg milrinone. Each ampoule of 10 ml solution for injection/infusion contains 10 mg milrinone.

■    The other ingredients are glucose, lactic acid, sodium hydroxide and water for injections.

What Milrinone looks like and contents of the pack

Milrinone is a clear, colourless to pale yellow solution for injection/infusion.

Milrinone is available in the following pack sizes:

■    Pack of 5 or 10 clear glass ampoules of 10 ml.

Not all pack sizes may be marketed.