Milrinone 1 mg/ml Solution for injection or infusion

Each ml contains 1 mg of the active substance milrinone.

Each 10 ml ampoule contains 10 mg milrinone.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially 'sodium- free'.

For a full list of excipients, see section 6.1.

Solution for injection or infusion.

Clear, colourless to pale yellow liquid free from visible particle.

Osmolarity: Between 230 mOsmol/L and 330 mOsmol/L pH: Between 3.20 and 4.00

Adults

Milrinone 1 mg/ml Solution for injection or infusion is indicated for the short-term treatment (48 hours) of severe congestive heart failure unresponsive to conventional maintenance therapy (glycosides, diuretics, vasodilators and/or angiotensin converting enzyme (ACE) inhibitors).

Children

In the paediatric population Milrinone 1 mg/ml Solution for injection or infusion 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.

Posology Careful monitoring should be maintained during milrinone therapy including blood pressure, heart rate, clinical state, electro-cardiogram, fluid balance, electrolytes and renal function (i.e. serum creatinine)(see section 4.4). Facilities must be available for immediate treatment of potential adverse cardiac effects (e.g. life-threatening ventricular arrhythmias). The infusion rate should be adjusted according to haemodynamic response.

Adults: Milrinone 1 mg/ml Solution for injection or infusion should be given as a loading dose of 50µg/kg administered over a period of 10 minutes usually followed by a continuous infusion at a dosage titrated between 0.375µg/kg/min and 0.75µg/kg/min (standard 0.5 µg/kg/min) according to haemodynamic and clinical response and the possible onset of undesirable effects such as hypotension and arrhythmias.

The total dose should not exceed 1.13 mg/kg/day total dose which corresponds to an infusion rate of 45.0 µg/kg/hr.

The following provides a guide to maintenance infusion delivery rate based upon a solution containing milrinone 200µg/ml prepared by adding 40ml diluent per 10ml ampoule 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

Renal Impairment: Dosage adjustment required. Dosage adjustment in patients with renal impairment is based on data obtained from patients with common renal impairment but without congestive heart failure, who show significant increases to the terminal elimination half-life of milrinone. The loading dose is not affected, but a reduction in the maintenance infusion rates may be necessary depending on the severity (creatinine clearance) of the renal impairment (see table below):.

Older people: Experience so far suggests that no special dosage recommendations are necessary in patients with normal renal function. Renal clearance may be reduced in older people, lower Milrinone 1 mg/ml Solution for injection or infusion doses may be required in such cases.

Paediatric population:

In published studies selected doses for infants and children were:

• Intravenous loading dose: 50 to 75 µg/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 µg/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 µg/kg loading dose over 60 minutes followed by a 0.75 µg/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).

Method of administration

For slow intravenous administration. To avoid local irritation, as large a vein as possible should be punctured. Extravascular injection must be avoided.

Milrinone 1 mg/ml Solution for injection or infusion may not be mixed with other diluents as stated above (see section 6.2). Solutions of different concentrations may be used according to patient fluid requirements. After dilution the solution is a clear and colourless liquid free from visible particle..

The duration of therapy should depend upon the patient's response but should not exceed 48 hours due to a lack of evidence of safety and efficacy in long-term treatment of congestive heart failure (see section 4.4).

• Hypersensitivity to milrinone (active substance) or any of the excipients listed in section 6.1

• Severe hypovolaemia.

Careful monitoring should be maintained during therapy with Milrinone 1 mg/ml Solution for injection, or infusion including blood pressure, heart rate, clinical state, electro-cardiogram, fluid balance, electrolytes and renal function (i.e. serum creatinine). Facilities must be available for immediate treatment of potential adverse cardiac effect (e.g. life threatening ventricular arrhythmias).

In patients with severe obstructive aortic or pulmonary valvular disease, or hypertrophic subaortic stenosis (KMP), Milrinone 1 mg/ml Solution for injection or infusion should not be used in lieu of surgical relief of the obstruction. As with other drugs with inotropic / vasodilator properties, it may aggravate outflow obstruction in these conditions.

Milrinone is not recommended immediately following acute myocardial infarction until safety and efficacy have been established in this situation. Use of positive inotropes such as milrinone in the acute phase of post myocardial infarction may lead to an undesirable increase in myocardial oxygen consumption (MVO2).

There is a possibility of an increased ventricular response rate in patients with atrial flutter or fibrillation. In these patients, prior digitalisation or treatment with other agents to prolong atrio-ventricular node conduction time should be considered, as milrinone produces a slight enhancement in A-V node conduction.

Supraventricular and ventricular arrhythmias have been observed in the high risk population treated with milrinone. In some patients, an increase in ventricular ectopy including non-sustained ventricular tachycardia has been observed.

Patients, especially those with complex ventricular arrhythmias, should therefore be kept under continuous ECG and clinical monitoring during Milrinone 1 mg/ml Solution for injection or infusion therapy and the dosage should be carefully adjusted.

If prior vigorous diuretic therapy is suspected of having caused significant decreases in cardiac filling pressure Milrinone 1 mg/ml Solution for injection or infusion should be cautiously administered while monitoring blood pressure, heart rate and clinical symptomatology.

Fluid and electrolyte changes, as well as serum creatinine levels should be carefully monitored during treatment. Improvement in cardiac output with resultant diuresis may necessitate a reduction in the dose of diuretic.

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, the use of Milrinone 1 mg/ml Solution for injection or infusion.

Milrinone may induce hypotension as a consequence of its vasodilatory activity; caution should therefore be exercised when Milrinone 1 mg/ml Solution for injection or infusion is administered to patients who are hypotensive prior to treatment. In patients showing excessive decreases in blood pressure after milrinone administration, the treatment should be discontinued until the hypotensive effect has been resolved and then resumed, if necessary, at a lower rate of infusion.

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 Milrinone 1 mg/ml Solution for injection or infusion (see Section 4.8). Consequently, careful monitoring of the infusion site should be maintained to avoid possible extravasation.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially 'sodium-free'.

Use in Older people: There are no special recommendations for older people. 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 older people.

Paediatric population:

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

In neonates, 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 5.3).

Use in patients with renal impairment

In patients with severe renal impairment, dosage adjustment is required (see section 4.2)

Fluid and electrolyte changes, as well as serum creatinine levels, should be carefully monitored during treatment with milrinone. The effect of milrinone and diuretics may be mutually potentiated. Additive, diuretic and hypokalaemic effects have been observed. 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. If inotropic agents (e.g. dobutamine) are co-administered, the positive inotropic effects may be potentiated.

Concomitant administration of inotropic agents increases the positive inotropic effects

For incompatibilities, reference is made to section 6.2.

Use in Pregnancy

Although animal studies have not revealed evidence of drug-induced fetal 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 fetus.

Use in Breast feeding

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

Fertility

There were no effects on fertility in male and female rats (see section 5.3).

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

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

Blood and the lymphatic system disorders:

• Uncommon: Thrombocytopenia

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

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

- Supraventricular arrhythmias¹

- Hypotension

1 The incidence of arrhythmias has not been related to dose or plasma levels of milrinone. Life threatening arrhythmias are often found to be associated with underlying risk factors such as pre- existing arrhythmias, metabolic abnormalities (e.g. hypokalaemia), elevated serum digoxin levels or catheter insertion. Clinical data suggest that milrinone-related arrhythmias are less common in children than in adults.

• Uncommon:

- Ventricular fibrillation

- Angina/chest pain

• Very rare: Torsades de pointes

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

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 the national reporting system (see details below)

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Overdose of intravenous Milrinone 1mg/ml Solution for injection or infusion may produce hypotension (because of its vasodilatory effect) and cardiac arrhythmia. If this occurs, Milrinone 1 mg/ml Solution for injection or infusion 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.

Pharmacotherapeutic group: Cardiac therapy; Phosphodiesterase inhibitor, ATC code: C01CE02

Adults:

Milrinone is a positive inotropic and vasodilator substance with little chronotropic, bathmotropic and dromotropic activity.

It differs from both digitalis glycosides and catecholamines in terms of its structure and mode of action.

At inotropic and vasorelaxant concentrations, milrinone is a selective inhibitor of the peak III cAMP phosphodiesterase isoenzyme in cardiovascular muscles. In the myocardial cell, this inhibitory effect leads to a cAMP-mediated increase in intracellular ionised calcium and myocardial contractility, as well as a cAMP-dependent phosphorylation of contractile proteins. In the vascular muscle cell, there is a cAMP-mediated decrease in intracellular ionised calcium and hence a relaxation of vascular muscles. Further experimental findings indicate that milrinone is not a beta-receptor agonist and, unlike digitalis glycosides, it does not inhibit Na+/Ka+-ATPase activity.

Clinical studies in patients with heart failure have shown that milrinone, depending on the dose and its plasma concentration, leads to an increase in the maximum rate of increase of left-ventricular pressure. Studies in healthy subjects have shown that the slope of the left-ventricular pressure/volume relationship increases during milrinone therapy. This indicates a direct inotropic effect of the substance. In patients with heart failure, milrinone also led to a dose-related and plasma concentration-related increase in forearm blood flow, indicating a direct vasodilator effect on the arteries.

In addition to the increase in myocardial contractility, milrinone improves diastolic function, as demonstrated by improvements in left-ventricular diastolic relaxation.

In patients with impaired myocardial function, injection of milrinone within the usual dosage range led to a rise in the cardiac index and a reduction in pulmonary capillary pressure and vascular resistance. The heart rate increased by 3% to 10%, depending on the dose. Mean arterial blood pressure fell dose-dependently by 5% to 17%. The haemodynamic improvements correlated with the dose and milrinone plasma concentration and were accompanied by an improvement in clinical symptoms. The vast majority of patients showed improvements in haemodynamic parameters within five to fifteen minutes after the start of treatment.

Milrinone also shows a positive inotropic effect in digitalised patients. There are no indications that milrinone increases the toxicity of glycosides. Close to maximum effects of milrinone on cardiac output and pulmonary capillary pressure are seen at milrinone plasma concentrations within the range of 150 ng/ml to 250 ng/ml.

Paediatric population:

Literature review identified clinical studies with patients treated for low cardiac output syndrome following cardiac surgery, septic shock or pulmonary hypertension. The usual dosages were a loading dose of 50 to 75 μg/kg administered over 30 to 60 minutes followed by an intravenous continuous infusion of 0.25 to 0.75 μg/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.

Distribution

In vitro protein binding assays revealed that milrinone, depending on the assay method used, is 70– 91% protein-bound at therapeutically relevant plasma concentrations. Six to twelve hours after a constant maintenance infusion of 0.50 micrograms/kg BW/min, steady-state plasma concentrations of milrinone are approximately 200 ng/ml..

Following intravenous injections of 12.5 micrograms/kg BW to 125 micrograms/kg BW in patients with heart failure, milrinone had a volume of distribution of 0.38 l/kg BW, a mean terminal elimination half-life of 2.3 hours and a clearance of 0.13 l/kg BW/h. Following intravenous infusions of 0.20 micrograms/kg BW/min to 0.7 micrograms/kg BW/min in patients with heart failure, the substance had a volume of distribution of approximately 0.45 l/kg BW, the mean terminal elimination half-life was 2.4 hours and clearance was 0.14 l/kg BW/h. These pharmacokinetic parameters were not dose-dependent. Conversely, the area under the plasma concentration-time curve after the injections was significantly dose-dependent. Via ultracentrifugation, milrinone was shown to be up to 70% bound to human plasma proteins at plasma concentrations between 70 and 400 nanograms/ml. Both clearance and half-life were prolonged in patients with heart failure in relation to their degree of renal impairment compared to healthy subjects. Data from patients with severe renal insufficiency (creatinine clearance less than 30 ml/min) showed that the terminal elimination half-life is prolonged in cases of renal insufficiency.

Biotransformation and Elimination

In man, milrinone is mainly excreted in the urine. The main excretory products in humans are milrinone (83%) and its O-glucuronide metabolite (12%). In healthy subjects, excretion in the urine is rapid; approximately 60% is recovered in the urine within the first two hours after administration and approximately 90% of the dose within the first eight hours after administration. Mean renal clearance of milrinone IV is approximately 0.3 l/min; this is 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 µg/kg/min were about of 100 to 300 ng/ml.

Following intravenous infusion of 0.5 to 0.75 µg/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 µg/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.

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).

Acute toxicity

After oral administration, the LD50 for male mice is 137 mg/kg and for female mice 170 mg/kg, while the LD50 for male rats is 91 mg/kg and for female rats 153 mg/kg. After intravenous administration of milrinone, focal epicardial and endocardial haemorrhages and focal myocardial fibroses (particularly in the papillary muscle and in the endocardial areas) occur in rabbits.

Subacute toxicity

Subacute toxicity was examined in rats and dogs. In dogs, endocardial haemorrhages and myocardial fibroses occurred in all treated groups after cumulative and fractioned administration of milrinone in quantities just above the therapeutic dose.

Subchronic and chronic toxicity

Oral and intravenous application of milrinone to rats, dogs and monkeys lead in therapeutic doses, or in doses just above the therapeutic dose, to myocardial degenerations, fibroses and, particularly in the region of the papillary muscles of the left ventricle, to subendocardial haemorrhages. Lesions of the coronary vessels, characterised by a periarterial oedema and inflammation, were only observed in dogs.

Carcinogenicity

In long-term trials, no tumour-producing potential was detected in rats and mice. Endocardial haemorrhages and myocardial necroses and fibroses occurred in rats. At the highest dosage, myocardial degenerations and fibroses were detected in mice. In the stomachs of mice, necroses and ulcers were detected.

Mutagenicity

A detailed in vitro and in vivo test on mutagenicity produced negative results.

Fertility/reproductive toxicology

Milrinone, at oral doses of up to 40 times the usual human therapy dose, did not have an effect on the fertility of male and female rats. Studies of the reproductive toxicology in rats and rabbits did not produce any evidence of a teratogenic action at doses of up to 10 times (oral) and 2.5 times (i.v.) of the usual human therapy dose.

In a study spanning 3 generations (P, F1, F2 generation) of rats treated orally with milrinone, no effect on the development of the animals and their reproductive capacity was detected in the mothers or the descendents, even at the highest dose (40 times the usual human therapy dose).

Embryonic/fetal dose in relation to the mother's serum concentration:

A diaplacental transmission of milrinone to the fetus is documented in a study of pregnant monkeys which had human therapy doses administered intravenously. The ratio of maternal serum values to fetal serum levels was 4:1.

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 fetal rats. Postnatal ductus arteriosus dilatation by milrinone was studied with three doses (10, 1 and 0.1mg/kg). The dilating effects of milrinone in the fetal ductus constricted by indomethacin were studied by simultaneous administration of milrinone (10, 1 and 0.1mg/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 fetal and the postnatal constricted ductus arteriosus. Dilating effects were more potent with injection immediately after birth than at 1 hour after birth. In addition, 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).

Lactic Acid

Glucose Anhydrous

Water for Injections

Sodium Hydroxide (for pH adjustment)

Furosemide or bumetanide should not be administered in intravenous lines containing Milrinone 1 mg/ml Solution for injection or infusion since precipitation occurs on admixture. Sodium Bicarbonate Intravenous infusion should not be used for dilution.

The medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Unopened: 30 months

After dilution: A diluted solution of Milrinone 1 mg/ml Solution for injection or infusion should be used within 24 hours.

From a microbiological point of view, unless the method of opening and dilution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

Do not store above 25°C. Do not freeze.

Discard any unused product.

For storage after dilution of the medicinal product, see section 6.3.

10 ml clear glass ampoule (type I), with a blister pack size of 5, 10 and 25 ampoules. Not all pack sizes may be marketed.

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.

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

Baxter Healthcare Limited Caxton Way

Thetford, Norfolk IP24 3SE

PL 00116/0692

15/05/2019

15/05/2019