Primacor 1mg/ml Solution for Injection

Milrinone

The following information is extracted from the SPC.

Technical information for the administration of Primacor Injection

1    NAME OF THE MEDICINAL PRODUCT

Primacor 1mg/ml Solution for Injection

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ampoule contains 1 mg/ml of the active substance Milrinone.

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM Solution for Injection.

Clear, colourless to pale yellow liquid.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Primacor Injection is indicated for the short-term treatment of severe congestive heart failure unresponsive to conventional maintenance therapy, and for the treatment of patients with acute heart failure, including low output states following cardiac surgery.

In paediatric population Primacor is indicated for the short-term treatment (up to 35 hours) of severe congestive heart failure unresponsive to conventional maintenance therapy (glycosides, diuretics, vasodilators and/or angiotensin converting enzyme (ACE) inhibitors), and for the short-term treatment (up to 35 hours) of paediatric patients with acute heart failure, including low output states following cardiac surgery.

4.2    Posology and method of administration For intravenous administration.

Adults: Primacor Injection should be given as a loading dose of 50ug/kg administered over a period of 10 minutes usually followed by a continuous infusion at a dosage titrated between

0.375pg/kg/min and 0.75pg/kg/min according to haemodynamic and clinical response, but should not exceed 1.13mg/kg/day total dose.

The following provides a guide to maintenance infusion delivery rate based upon a solution containing milrinone 200pg/ml prepared by adding 40ml diluent per 10ml ampoule (400ml diluent per 100ml Primacor Injection). 0.45% saline, 0.9% saline or 5% glucose may be used as diluents.

Solutions of different concentrations may be used according to patient fluid requirements. The duration of therapy should depend upon the patient’s response. In congestive cardiac failure, patients have been maintained on the infusion for up to 5 days, although the usual period is 48 to 72 hours. In acute states following cardiac surgery, it is unlikely that treatment need be maintained for more than 12 hours.

Renal Impairment. Dosage adjustment required. Data obtained from patients with severe renal impairment but without heart failure have demonstrated that the presence of renal impairment significantly increases the terminal elimination half-life of milrinone. For patients with clinical evidence of renal

The infusion rate should be adjusted according to haemodynamic response.

Elderly: Experience so far suggests that no special dosage recommendations are necessary.

Paediatric population:

In published studies selected doses for infants and children were:

•    Intravenous loading dose: 50 to 75 pg/kg administered over 30 to 60 minutes.

•    Intravenous continuous infusion: To be initiated on the basis of hemodynamic response and the possible onset of undesirable effects between 0.25 to 0.75 pg/kg/min for a period up to 35 hours.

In clinical studies on low cardiac output syndrome in infants and children under 6 years of age after corrective surgery for congenital heart disease 75 pg/kg loading dose over 60 minutes followed by a 0.75 pg/kg/min infusion for 35 hours significantly reduced the risk of development of low cardiac output syndrome. Results of pharmacokinetic studies (see section 5.2) have to be taken into consideration.

Renal impairment:

Due to lack of data the use of milrinone is not recommended in paediatric population with renal impairment (for further information please see section 4.4).

Patent ductus arteriosus:

If the use of milrinone is desirable in preterm or term infants at risk of/with patent ductus arteriosus, the therapeutic need must be weighed against potential risks (see section 4.4, 4.8, 5.2, and 5.3).

4.3 Contraindications

In patients with severe obstructive aortic or pulmonary valvular disease or hypertrophic subaortic stenosis, Primacor Injection should not be used in place of surgical relief of the obstruction. In these conditions it is possible that a drug with inotropic / vasodilator properties might aggravate outflow obstruction. Supraventricular and ventricular arrhythmias have been observed in the high risk population treated with milrinone. In some patients an increase in ventricular ectopy including nonsustained ventricular tachycardia has been observed which did not affect patient safety or outcome.

The potential for arrhythmia, present in heart failure itself, may be increased by many drugs or a combination of drugs. Patients receiving Primacor Injection should be closely monitored during infusion and the infusion should be stopped if arrhythmias develop.

As milrinone produces a slight enhancement in A-V node conduction, there is a possibility of an increased ventricular response rate in patients with uncontrolled atrial flutter / fibrillation. Consideration should therefore be given to digitalisation or treatment with other agents to prolong A-V node conduction time prior to starting Primacor Injection therapy, and to discontinuing the therapy if arrhythmias occur. Milrinone may induce hypotension as a consequence of its vasodilatory activity, therefore caution should be exercised when Primacor Injection is administered to patients who are hypotensive prior to treatment. The rate of infusion should be slowed or stopped in patients showing excessive decreases in blood pressure.

If prior vigorous diuretic therapy is suspected of having caused significant decreases in cardiac filling pressure Primacor Injection should be cautiously administered while monitoring blood pressure, heart rate and clinical symptomatology. Improvement in cardiac output with resultant diuresis may necessitate a reduction in the dose of diuretic. Potassium loss due to excessive diuresis may necessitate a reduction in the dose of diuretic. Potassium loss due to excessive diuresis may redispose digitalised patients to arrhythmias. Therefore, ypokalaemia should be corrected by potassium supplementation in advance of, or during, the use of Primacor Injection.

Decrease in haemoglobin, including anaemia, often takes place in the setting of cardiac failure. Due to the risk of thrombocytopenia or anaemia, careful monitoring of the corresponding laboratory parameters is required in patients with decreased platelet count or decreased haemoglobin.

There is no experience in controlled trials with infusions of milrinone for periods exceeding 48 hours.

Cases of infusion site reaction have been reported with Primacor Injection (see Section 4.8, Undesirable effects). Consequently, careful monitoring of the infusion site should be maintained so as to avoid possible extravasation.

Use in the elderly: There are no special recommendations for elderly patients. No age-related effects on the incidence of adverse reactions have been observed. Controlled pharmacokinetic studies have not shown changes in the pharmacokinetic profile of milrinone in the elderly.

In patients with severe renal impairment dosage adjustment is required (see section 4.2 Posology and method of administration).

Paediatric population:

The following should be considered in addition to the warnings and precautions described for adults:

In neonates, following open heart surgery during Primacor therapy, monitoring should include heart rate and rhythm, systemic arterial blood pressure via umbilical artery catheter or peripheral catheter, central venous pressure, cardiac index, cardiac output, systemic vascular resistance, pulmonary artery pressure, and atrial pressure. Laboratory values that should be followed are platelet count, serum potassium, liver function, and renal function. Frequency of assessment is determined by baseline values, and it is necessary to evaluate the neonate’s response to changes in therapy.

Literature revealed that in paediatric patients with impaired renal function, there were marked impairment of milrinone clearance and clinically significant side effects, but the specific creatinine clearance at which doses must be adjusted in paediatric patients is still not clear, therefore the use of milrinone is not recommended in this population (see section 4.2).

In paediatric patients milrinone should be initiated only if the patient is hemodynamically stable.

Caution should be exercised in neonates with risk factors of intraventricular haemorrhage (i.e. preterm infant, low birth weight) since milrinone may induce thrombocytopenia. In clinical studies in paediatric patients, risk of thrombocytopenia increased significantly with duration of infusion. Clinical data suggest that milrinone-related thrombocytopenia is more common in children than in adults (see section 4.8).

In clinical studies milrinone appeared to slow the closure of the ductus arteriosus in paediatric population. Therefore, if the use of milrinone is desirable in preterm or term infants at risk of/with patent ductus arteriosus, the therapeutic need must be weighed against potential risks (see section 4.2, 4.8, 5.2, and

4.5    Interaction with other medicinal products and other forms of interactions

Furosemide or bumetanide should not be administered in intravenous lines containing milrinone lactate in order to avoid precipitation.

Milrinone should not be diluted in sodium bicarbonate intravenous infusion.

Whilst there is a theoretical potential interaction with calcium channel blockers, there has been no evidence of a clinically significant interaction to date.

Milrinone has a favourable inotropic effect in fully digitalised patients without causing signs of glycoside toxicity.

Fluid and electrolyte changes, as well as serum creatinine levels should be carefully monitored during treatment with milrinone. Improvement in cardiac output and consequently, diuresis, may require reduction in the dose of a diuretic agent. Potassium loss due to excessive diuresis may predispose digitalised patients to arrhythmias. Therefore, hypokalaemia should be corrected by potassium supplementation in advance of, or during milrinone use.

4.6    Fertility, pregnancy and lactation

Use in Pregnancy

Although animal studies have not revealed evidence of drug-induced foetal damage or other deleterious effects on reproductive function, the safety of milrinone in human pregnancy has not yet been established. It should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Use in Lactation

There is insufficient information on the excretion of milrinone in human milk. A decision must be made whether to discontinue breast-feeding or discontinue milrinone therapy taking into account the benefit of breast-feeding for a child and the benefit of therapy for the woman.

4.7    Effects on ability to drive and to use machines

No studies on the effect on the ability to drive and use machinery have been performed.

4.8    Undesirable effects

Adverse reactions have been ranked under heading of system-organ class and frequency using the following convention: very common (>1/10); common (>1/100, <1/10); uncommon (>1/1,000, < 1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Blood and the lymphatic system _i disorders:

•    Uncommon: Thrombocytopenia*

•    Not known: reduction of red blood count and/or haemoglobin concentration

*In infants and children, risk of thrombocytopenia increased significantly with duration of infusion. Clinical data suggest that milrinone-related thrombocytopenia is more common in children than in adults (see section 4.4).

Immune system disorders:

•    Very rare: Anaphylactic shock Metabolism and nutrition disorders:

•    Uncommon: Hypokalaemia Nervous system disorders:

•    Common: Headaches, usually mild to moderate in severity

•    Uncommon: Tremor Cardiac disorders:

•    Common:

-    Ventricular ectopic activity

-    Non sustained or sustained ventricular tachycardia (see section 4.4)

-    Supraventricular arrhythmias

-    Hypotension

•    Uncommon:

-    Ventricular fibrillation

-    Angina/chest pain

•    Very rare: Torsades de pointes

The incidence of arrhythmias has not been related to dose or plasma levels of milrinone. These arrhythmias are rarely life threatening. If present, they are often associated with certain underlying factors such as pre-existing arrhythmias, metabolic abnormalities (e.g. hypokalaemia) abnormal digoxin levels and catheter insertion. Clinical data suggest that milrinone-related arrhythmias are less common in children than in adults. Respiratory, thoracic and mediastinal disorders:

•    Very rare: Bronchospasm Hepato-biliary disorders:

•    Uncommon: Liver function tests abnormal Skin and subcutaneous tissue disorders:

•    Very rare: Skin reactions such as rash Renal and urinary disorders

•    Not known: Renal failure, secondary to a concomitant hypotension.

General disorders and administration site conditions:

•    Not known: Infusion site reaction Paediatric population:

Nervous system disorders:

•    Not known: Intraventricular haemorrhage (see section 4.4) Congenital, familial, and genetic disorders:

•    Not known: Patent ductus arteriosus*** (see section 4.2, 4.4, 5.2, and 5.3)

***The critical consequences of the patent ductus arteriosus are related to a combination of pulmonary overcirculation with consecutive pulmonary oedema and haemorrhage and of reduced organ perfusion with consecutive intraventricular haemorrhage and necrotizing enterocolitis with possible fatal outcome as described in literature.

Long-term safety data for paediatric population are not yet available.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

4.9 Overdose

Overdose of intravenous Primacor may produce hypotension (because of its vasodilatory effect) and cardiac arrhythmia. If this occurs, Primacor injection administration should be reduced or temporarily discontinued until the patient’s condition stabilises. No specific antidote is known, but general measures for circulatory support should be taken.

5 PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties Pharmacotherapeutic group: Cardiac therapy; phosphodiesterase inhibitor, ATC code: C01CE02

Milrinone is a positive inotrope and vasodilator, with little chronotropic activity. It also improves left ventricular diastolic relaxation. It differs in structure and mode of action from the digitalis glycosides, catecholamines or angiotensin converting enzyme inhibitors. It is a selective inhibitor of peak III phosphodiesterase isoenzyme in cardiac and vascular muscle. It produces slight enhancement of A-V node conduction, but no other significant electro-physiological effects.

In clinical studies Primacor Injection has been shown to produce prompt improvements in the haemodynamic indices of congestive heart failure, including cardiac output, pulmonary capillary wedge pressure and vascular resistance, without clinically significant effect on heart rate or myocardial oxygen consumption. Haemodynamic improvement during intravenous Primacor therapy is accompanied by clinical symptomatic improvement in congestive cardiac failure, as measured by change in New York Heart Association classification.

Paediatric population:

Literature review identified clinical studies with patients treated for low cardiac output syndrome following cardiac surgery, septic shock or pulmonaryhypertension. The usual dosages were a loading dose of 50 to 75 jig/kg administered over 30 to 60 minutes followed by an intravenous continuous infusion of 0.25 to 0.75 jg/kg/min for a period up to 35 hours. In these studies, milrinone demonstrated an increase of cardiac output, a decrease in cardiac filling pressure, a decrease in systemic and pulmonary vascular resistance, with minimal changes in heart rate and in myocardial oxygen consumption.

Studies of a longer use of milrinone are not sufficient to recommend an administration of milrinone during a period of more than 35 hours.

Some studies explored the paediatric use of milrinone in patients with nonhyperdynamic septic shock (Barton et al 1996; Lindsay et al., 1998); the effect of milrinone on postbypass pulmonary hypertension after tetralogy of Fallot repair (Chu et al., 2000); the combined effect of nitric oxide and milrinone on pulmonary circulation after Fontan-type procedure (Cai et al.,

The results of these studies were inconclusive. Therefore, the use of milrinone in these indications cannot be recommended.

5.2    Pharmacokinetic properties

Following intravenous injections of 12.5 to 125mcg/kg to congestive heart failure patients, Primacor Injection had a volume of distribution of 0.38 l/kg/hr, a mean terminal elimination half-life of 2.3 hours, and a clearance of 0.13 l/kg/hr. Following intravenous infusions of 0.2 to

0.7mcg/kg/min to congestive heart failure patients, the drug had a volume of distribution of about 0.45 l/kg, a mean terminal elimination half-life of 2.4 hours, and a clearance of 0.14 l/kg/hr. These pharmacokinetic parameters were not dose-dependent, and the area under the plasma concentration versus time curve following injection was significantly dose-dependent. The primary route of excretion of milrinone in man is via the urine. Elimination in normal subjects via the urine is rapid, with approximately 60% recovered within the first two hours following dosing, and approximately 90% recovered within the first eight hours following dosing. The mean renal clearance of milrinone is approximately 0.3 l/min, indicative of active secretion.

Paediatric population:

Milrinone is cleared more rapidly in children than in adults, but infants have significantly lower clearance than children, and preterm infants have even lower clearance. As a consequence of this more rapid clearance compared to adults, steady-state plasma concentrations of milrinone were lower in children than in adults. In paediatric population with normal renal function steady-state milrinone plasma concentrations after 6 to 12 hours continuous infusion of 0.5 to 0.75 pig/kg/min were about of 100 to 300 ng/ml.

Following intravenous infusion of 0.5 to 0.75 pg/kg/min to neonates, infants and children after open heart surgery, milrinone has a volume of distribution ranging from 0.35 to 0.9 litres/kg with no significant difference across age groups. Following intravenous infusion of 0.5 pg/kg/min to very preterm infants to prevent low systemic outflow after birth, milrinone has a volume of distribution of about 0.5 litres/kg. Several pharmacokinetic studies showed that, in paediatric population, clearance increases with increasing age. Infants have significantly lower clearance than children (3.4 to 3.8 ml/kg/min versus 5.9 to 6.7 ml/kg/min). In neonates milrinone clearance was about 1.64 ml/kg/min and preterm infants have even lower clearance (0.64 ml/kg/min).

Milrinone has a mean terminal half-life of 2 to 4 hours in infants and children and a mean terminal elimination half-life of 10 hours in preterm infants.

It was concluded that the optimal dose of milrinone in paediatric patients in order to obtain plasma levels above the threshold of pharmacodynamic efficacy appeared higher than in adults, but that optimal dose in preterms in order to obtain plasma levels above the threshold of pharmacodynamic efficacy appeared lower than in children.

Patent ductus arteriosus:

Milrinone is cleared by renal excretion and has a volume of distribution that is restricted to extracellular space which suggests that the fluid overload and hemodynamic changes associated with patent ductus arteriosus may have an effect on distribution and excretion of milrinone (see section 4.2, 4.4, 4.8, and 5.3).

5.3 Preclinical safety data

Juvenile animals:

A preclinical study was performed to clarify the ductus-dilating effects of PDE 3 inhibitors in near-term rat pups and their differential effects in near-term and preterm foetal rats. Postnatal ductus arteriosus dilatation by milrinone was studied with three doses (10, 1 and 0.1 mg/kg). The dilating effects of milrinone in the foetal ductus constricted by indomethacin were studied by simultaneous administration of milrinone (10, 1 and 0.1 mg/kg) and indomethacin (10 mg/kg) to the mother rat at D21 (near-term) and D19 (preterm). This in vivo study has shown that milrinone induces dose-dependent dilation of the foetal and the postnatal constricted ductus arteriosus. Dilating effects were more potent with injection immediately after birth than at

I    hour after birth. In addition, the study showed that the premature ductus arteriosus is more sensitive to milrinone than the mature ductus arteriosus (see section 4.2, 4.4, 4.8, and 5.2).

6    PHARMACEUTICAL PARTICULARS

6.1    List of Excipients Lactic Acid Glucose Anhydrous Water for Injection

Sodium Hydroxide (for pH adjustment)

6.2    Incompatibilities

Furosemide or bumetanide should not be administered in intravenous lines containing Primacor Injection since precipitation occurs on admixture. Sodium Bicarbonate Intravenous infusion should not be used for dilution.

Other drugs should not be mixed with Primacor Injection until further compatibility data are available.

6.3    Shelf life

48 months when unopened. A diluted solution of Primacor Injection should be used within 24 hours.

6.4    Special precautions for storage Store below 25°C. Do not freeze.

6.5    Nature and contents of container

Type I colourless, glass ampoules 10ml or 20ml packed in lots of 10.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

Infusion solutions diluted as recommended with 0.45% saline, 0.9% saline or 5% glucose should be freshly prepared before use. Parenteral drug products should be examined visually and should not be used if particulate matter or discolouration are present.

7    MARKETING AUTHORISATION HOLDER

Aventis Pharma Limited

One Onslow Street

Guildford

Surrey

GU14YS

United Kingdom

Or trading as:

Sanofi

One Onslow Street Guildford Surrey GU1 4YS United Kingdom

8    MARKETING AUTHORISATION NUMBER

PL 04425/0646

9    Date of First Authorisation / Renewal of the Authorisation

Date of first authorisation: 11 October 1989 Date of latest renewal: 7 April 2004

10    Date of Revision of Text

II    January 2016 LEGAL STATUS

POM

PACKAGE LEAFLET: INFORMATION FOR THE USER

Primacor 1mg/ml Solution for Injection

Milrinone

Is this leaflet hard to see or read?

Phone 0845 372 7101 for help Read all of this leaflet carefully before you start taking this medicine

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

•    If you have any further questions, ask your doctor, nurse 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, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1.    What Primacor is and what it is used for

2.    What you need to know before you take Primacor

3.    How to take Primacor

4.    Possible side effects

5.    How to store Primacor

6.    Contents of the pack and other information_

1. What Primacor is and what it is used for

The name of your medicine is Primacor 1mg/ml Solution for Injection (called Primacor in this leaflet). Primacor contains a medicine called milrinone. This belongs to a group of medicines called phosphodiesterase inhibitors.

It works by making your heart muscle contract more strongly and your blood vessels become wider. This means blood can flow more easily making your heart pump blood more successfully. Primacor can be used 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

•    Treatment after a heart operation for when your heart is having difficulty pumping blood around your body

Primacor 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._

2. What you need to know before you take Primacor

Do not take Primacor:

x You are allergic (hypersensitive) to milrinone or any of the other ingredients of Primacor (listed in Section 6 below)

Signs of an allergic reaction include: a rash, swallowing or breathing problems, swelling of your lips, face, throat or tongue. x You have lost body fluids and are severely dehydrated.

Do not have this medicine if any of the above apply to you. If you are not sure, talk to your doctor, nurse or pharmacist before having Primacor.

Warnings and precautions

Talk to your doctor, nurse or pharmacist before taking Primacor

▲    You are having or have just had a heart attack

▲    You have severe heart valve problems such as narrowing, thickening or blockage of your heart valves

▲    You have uneven or uncontrolled fast heartbeats. You may also be experiencing pounding in your chest, light-headedness, fainting and shortness of breath

▲    You have low blood pressure which may make you feel dizzy, light-headed or faint

▲    You have previously taken water tablets (diuretics) which caused you to have heart problems

▲    You have low levels of potassium in your blood. Your doctor may do blood tests to check this

▲    You have kidney problems

If you are not sure if any of the above apply to you, talk to your doctor, nurse or pharmacist before having Primacor.

The following should be considered in addition to warnings and precautions described for adults:

Children and adolescents

Before giving Primacor 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 Arteriosus: a connection between 2 major blood vessels (aorta and pulmonary artery) which persists though it should be closed.

In these cases, your doctor will decide if your child will be treated with Primacor.

Other medicines and Primacor

Please tell your doctor, nurse or pharmacist if you are taking or have recently taken any other medicines. This includes medicines you buy without a prescription, including herbal medicines. This is because Primacor can affect the way some other medicines work. Also some medicines can affect the way Primacor works.

In particular, tell your doctor, nurse or pharmacist if you are taking:

•    Digoxin - used for heart problems

•    Water tablets (diuretics)

•    Medicines used to treat high blood pressure or angina (chest pain) such as amlodipine, nifedipine or felodipine

Pregnancy and breast-feeding

Talk to your doctor, nurse or pharmacist before having this medicine if you are pregnant, might become pregnant, or think you may be pregnant.

If you are breast-feeding or planning to breast-feed, talk to your doctor or pharmacist before taking any medicine._

3. How to take Primacor

Primacor will normally be given by your doctor or nurse. This is

because it needs to be given as an injection.

Having this medicine

•    This medicine is usually given in a ‘drip’ after being diluted using either a sugar or salt solution

•    If you feel the effect of your medicine is too weak or too strong, tell your doctor or nurse

How much will be given to you

•    Your doctor will decide how much medicine you should have based on your body weight

•    If you have problems with your kidneys, you may be given a lower dose

Adults and the elderly

•    Your doctor should give you a first dose of 50 micrograms for every kilogram of your weight over 10 minutes

•    This is then followed by a smaller dose between 0.375 and 0.75 micrograms for every kilogram of body weight per minute as needed

•    The medicine is usually given for 2 to 3 days, but it may be given for up to 5 days

•    If you are having this medicine after a heart operation, it will usually only be given for up to 12 hours

Use in 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. Primacor 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.

If you have more Primacor than you should It is unlikely that your doctor or nurse will give you too much of this medicine. Your doctor and nurse will check your progress and the medicine that you are given. Always ask if you are not sure why you are getting a dose of medicine. The following effects may happen if you have too much Primacor: feeling dizzy, light-headedness and fainting (due to low blood pressure) and an uneven heartbeat.

If you forget to have Primacor

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 do think you have missed a dose, tell your doctor or nurse.

If you stop having Primacor

Keep having Primacor until your doctor tells you to stop. Do not stop having Primacor just because you feel better. If you stop, your illness may get worse.

Tests

Your doctor or nurse will use an electrocardiogram (ECG) to check how well your heart works. They will also carry out blood tests and check your blood pressure and pulse rate.

If you have any further questions on the use of this product, ask your doctor or nurse._

4. Possible side effects

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

Stop having Primacor and tell you doctor straight away if:

•    You have an allergic reaction. The signs may include: a rash, swallowing or breathing problems, swelling of your lips, face, throat or tongue, fainting or losing consciousness. The chances of this happening are very rare

Tell a doctor or nurse straight away if you notice any of the following side effects:

Common (affects less than 1 in 10 people)

•    Uneven, increased or fast heartbeats. You may also experience pounding in your chest, feel light-headed, faint or short of breath

Uncommon (affects less than 1 in 100 people)

•    Ventricular fibrillation - a serious hearth rhythm problem. Signs of this include very fast, uneven or forceful heartbeat (palpitations), dizziness and loss of consciousness. You may also feel sick, have cold sweats, shortness of breath and chest pain

•    Thrombocytopenia - a blood problem. Signs of this are that you may bruise more easily than usual

•    Chest pain

Very rare (affects less than 1 in 10,000 people)

•    Torsades de Pointes - a serious heart rhythm problem. Signs of this include very fast, uneven or forceful heartbeat (palpitations), dizziness and loss of consciousness. You may also feel sick, have cold sweats, shortness of breath, unusual pale complexion and chest pain

•    Difficulty breathing, wheezing or tightness in the chest

Tell a doctor or nurse as soon as possible if you notice any of the following side effects:

Common (affects less than 1 in 10 people)

•    Low blood pressure. Signs of this include feeling dizzy, lightheaded or fainting. If you also notice signs like a fast or uneven heartbeat or chest pain this could be a more serious side effect (see above)

•    Headache

Uncommon (affects less than 1 in 100 people)

•    Feeling shaky

•    Low levels of potassium in your blood. Signs of this are tiredness, confusion, muscle weakness and muscle cramps. This may be due to low levels of potassium in your body

Tell a doctor or nurse if any of the following side effects gets

serious or lasts longer than a few days

Very Rare (affects less than 1 in 10,000 people)

•    Skin rashes including at the site of the injection Uncommon (affects less than 1 in 100 people)

•    A blood test may show changes in the way the liver is working Talk to your doctor, nurse or pharmacist if any of the side effects gets serious or lasts longer than a few days, or if you notice any side effects not listed in this leaflet.

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

Frequency not known:

•    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 andpulmo-nary 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.

•    Changes in the way the kidneys are working if you already have low blood pressure.

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

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard By reporting side effects you can help provide more information on the safety of this medicine._

5. How to store Primacor

This medicine will be kept by your doctor or pharmacist in a safe place where children cannot see or reach it.

Do not use Primacor after the expiry date, which is stated on the ampoule and the carton. The expiry date refers to the last day of the month.

Primacor should be stored below 25°C. Do not freeze.

Medicines should not be disposed of via wastewater or household waste. Your doctor or nurse will dispose of medicines no longer required.

These measures will help to protect the environment._

6. Contents of the pack and other information

What Primacor contains

•    Each 1 ml of injection contains 1 mg of the active substance, milrinone

•    The other ingredients are lactic acid, glucose anhydrous, water for injection and sodium hydroxide (for pH adjustment)

What Primacor looks like and contents of the pack

Primacor is a clear, colourless to pale yellow liquid and is available as 10 ml or 20 ml glass ampoules in boxes of 10.

Not all pack sizes may be marketed.

Marketing Authorisation Holder Sanofi, One Onslow Street,

Guildford, Surrey, GU14YS, UK Tel: 0845 372 7101

email: uk-medicalinformation@sanofi.com Manufacturer

Delpharm Dijon, 6 Boulevard

de l'Europe, 21800 Quetigny, France

This leaflet does not contain all the information about your

medicine. If you have any questions or are not sure about

anything, ask your doctor or pharmacist.

This leaflet was last revised in April 2016 2 © Sanofi, 1989 - 2016