Milrinone 1 mg/ml Solution for Injection and Infusion.

Each 10 ml vial contains 10 mg milrinone (as lactate).

Each ml of solution contains 1 mg milrinone (as lactate).

For the full list of excipients see section 6.1.

Solution for Injection and Infusion.

Clear, colourless to pale yellow solution, practically free from particles.

The pH of the solution is 3.2 - 4.0 and the osmolality is 260 - 320 mOsm/kg

Adults

Short-term therapy (up to 48 hours) of severe cardiac failure, which is not satisfactorily treatable with the usual treatment regimen (cardiac glycosides, diuretics, vasodilators, and angiotensin converting enzyme (ACE) inhibitors).

During treatment with milrinone infusion, continuous monitoring of ECG, blood pressure must be ensured.

Children

In children, milrinone is indicated for short-term therapy (up to 35 hours) of congestive heart failure that is not responsive to standard basic therapy (glycosides, diuretics, vasodilators and / or ACE inhibitors) and for short-term therapy (up to 35 hours) of children with acute cardiac failure, including states of reduced cardiac output (low-output syndrome) status post cardiac surgery.

Posology

Milrinone therapy should begin as an initial weight dependent dose reaching saturation and subsequently followed by a continuous, efficacy based maintenance dose according to the guidelines below.

Initial dose

The initial dose is 50 micrograms (0.05 mg) of milrinone/kg. It is administered slowly over a period of 10 minutes. This is usually followed by a continuous maintenance infusion. (Table 1)

Maintenance dose

The maintenance dose is generally 0.5 micrograms of milrinone /kg /minute. However, it may be between 0.375 micrograms of milrinone/kg/minute and 0.75 micrograms of milrinone/kg/minute. (Table 2)

The level of maintenance dose should be selected based on the hemodynamic effect and clinical efficacy.

The daily dose should not exceed 1.13 mg milrinone/kg.

Table 1. Initial dose (Concentration 1 mg / ml)

Body weight of the patient (kg) compared to the amount of initial dose of milrinone

Table 2. Maintenance dose (for continuous use)

* The "daily dose (24 hours)" (in mg/kg BW) is calculated from the respective dosage (minimum, standard, maximum dose) plus initial dose (0.05 mg/kg BW)

To administer the maintenance dose, prepare an infusion solution containing 200 micrograms of milrinone/ml. It is prepared by adding 40 ml of a carrier solution to 10 ml undiluted milrinone solution for injection. The diluents/carrier solutions can be 0.9% Sodium Chloride Infusion and 5% Glucose Infusion.

Depending on the required maintenance dose (in micrograms/kg/minute), the following infusion rates (in milliliters/kg/hour) are obtained for the prepared infusion solution at a concentration of 200 microgram/ml (see Table 3).

Table 3: Conversion of the maintenance dose into the corresponding infusion rate

* calculated for an infusion solution containing 200 micrograms of milrinone per milliliter.

Infants and Children

The published studies revealed that the following doses were used in infants and children:

- Intravenous initial dose: 50 to 75 microgram/kg over 30 to 60 minutes.

- Continuous intravenous infusion: administration of dose has to be carried out, with due consideration given to the hemodynamic response and possible onset of side effects; the infusion rate is 0.25 to 0.75 microgram/kg/ min over a period of up to 35 hours.

In clinical studies in infants and children under 6 years with low-cardiac output syndrome after surgical correction of congenital heart disease, the administration of an initial dose of 75 microgram/kg over 60 minutes and subsequent maintenance infusion of 0.75 microgram/kg/min over 35 hours reduced the risk of a low-cardiac output syndrome.

The results of the pharmacokinetic studies (see section 5.2) must be taken into account.

Children with renal impairment:

Since no data is available, the use of milrinone in children with impaired renal function is not recommended (see section 4.4 for more information).

Patent Ductus arteriosus:

When considering the use or risk of milrinone in preemies or neonates, infants with patent Ductal arteriosus, the therapeutic benefit should be weighed against the potential risks (see sections 4.4, 4.8, 5.2 and 5.3).

Elderly patients

Based on current knowledge, it is to be expected that in case of normal renal function no special dosage recommendations are necessary for this patient group.

Patients with renal impairment:

In patients with renal impairment, excretion of milrinone is limited. Therefore, a dose adjustment is required. The following recommendation is based on data from patients with renal impairment without cardiac insufficiency, in whom a significant prolongation of terminal half-life of milrinone was observed.

The initial dose is unchanged. The maintenance dose should be reduced depending on the extent of functional impairment (see Table 4).

Table 4: Conversion of the reduced maintenance dose in renal impairment patients to the corresponding infusion rate

* calculated for an infusion solution containing 200 micrograms of milrinone per milliliter

Method of administration

Milrinone is administered by slow intravenous injection or intravenous infusion.

Milrinone must not be mixed with carrier solutions other than those mentioned above (see also section 6.2). Depending on the fluid requirements of the patient, solutions of different concentrations can be used.

If no immediate usage is possible, the diluted solution should not be used after 24 hours (see also section 6.3).

For injection, the largest possible vein should be punctured to avoid local irritation. An extravascular injection must be avoided. The duration of treatment should not exceed 48 hours due to a lack of evidence of safety and efficay in long-term treatment of congestive heart failure. In children, the treatment duration is up to 35 hours.

So far, results have been available on the treatment of heart failure with milrinone only with concomitant administration of a diuretic.

- Hypersensitivity to milrinone or any of the excipients listed in section 6.1,

- Severe obstructive aortic or pulmonary valve disease,

- Hypertrophic obstructive cardiomyopathy,

- Ventricular aneurysm,

- Severe, previously untreated hypovolemia,

- Acute myocardial infarction.

Milrinone must not be used in patients with cardiac failure due to hyperthyroidism, acute myocarditis or Amyloid cardiomyopathy, as there is insufficient therapy experience.

Patients with atrial flutter / fibrillation should always be digitalized or treated with other effective antiarrhythmic drugs prior to administration of milrinone, unless no other contraindications exist, as milrinone accelerates AV node conduction and thus may favor the ventricular arrhythmia.

Patients with severe cardiac failure often have risk of supraventricular or ventricular arrhythmias or are particularly susceptible to their occurrence In some patients, milrinone increased ventricular ectopia, including non-sustained ventricular tachycardia (see section 4.8). Therefore, patients especially those with complex ventricular arrhythmias, should be continuously monitored electrocardiographically and clinically during milrinone therapy and the dosage must be carefully adjusted.

If cardiac filling pressures are suspected to have decreased (eg due to previous treatment with diuretics), then milrinone may be administered only after previous measurement and correction of ventricular filling pressures (ZVD, PCWP) and patients are to be administered under clinical observation.

Milrinone injection should be used with caution in patients with severe renal impairment. Renal impairment requires dose adjustment (see section 4.2).

During therapy with milrinone, both renal function (serum creatinine) and fluid and electrolyte status should be checked.

It should also be considered that the improvement in cardiac output induced by milrinone which in turn associated with improvement in renal perfusion with increased diuresis may require a reduction in diuretics. Potassium loss due to excessive diuresis may favor the onset of arrhythmias. At low potassium levels, potassium replacement should be performed before or during milrinone therapy.

Milrinone may be hypotensive because of its vasodilatory activity. Therefore, the use of milrinone injection in hypotensive patients should be considered carefully and therapy should be started with a low dose. If there is excessive hypotension during milrinone therapy, the infusion should be stopped until the blood pressure returns to normal. If re-use of milrinone injection is considered, a lower dose should be chosen.

In patients with a decreased platelet count (<100,000 / microliter), milrinone injection should only be used under close lab monitoring, as in some cases further decreases in platelet count could occur (see section 4.8). In patients with decreased hemoglobin concentrations (<10 g/l), milrinone injection should only be used with careful monitoring of the red blood cell count, as there may be a further decrease in hemoglobin concentration (and erythrocyte count).

There are no controlled clinical studies on the use of milrinone beyond 48 hours of use.

Cases of infusion site reactions have been reported with intravenous milrinone therapy (see section 4.8). Consequently, the infusion site should be carefully monitored to avoid a possible extravasation.

Milrinone injection should not be used in patients with rare glucose-galactose malabsorption.

Children and adolescents

Beyond the precautions and warnings for adults, the following should be considered for children:

When undergoing milrinone therapy after open-heart surgery, the following values should be monitored in neonates: heart rate and heart rhythm, systemic arterial blood pressure by means of umbilical artery catheter or peripheral catheter, central venous pressure, cardiac index, cardiac output, systemic vascular resistance, pulmonary artery pressure and atrial pressure. The following laboratory values should be monitored: platelet count, serum potassium, liver and kidney function.

The frequency of the determination depends on baseline levels and it is necessary to monitor the neonatal response to any therapy changes. It is known from the literature that in pediatric patients with impaired renal function, the clearance of milrinone was significantly reduced and clinically relevant side effects occurred.

However, it is not yet clear from which specific creatinine clearance in pediatric patients, a dose adjustment is required. Therefore, the use of milrinone in these patients is not recommended (see section 4.2).

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

Caution should be exercised in neonates with risk factors for intraventricular hemorrhage (i.e. preterm or low birth weight) as milrinone may induce thrombocytopenia. In clinical trials in pediatric patients, the risk of thrombocytopenia increased significantly with the duration of infusion.

Clinical data suggest that milrinone induced thrombocytopenia is more common in children than in adults (see section 4.8). In clinical studies on children, milrinone apparently delayed the occlusion of the ductus arteriosus. Therefore, in premature and neonates at risk for or with a patent ductus arteriosus, the therapeutic benefit must be weighed against potential risks (see sections 4.2, 4.8, 5.2 and 5.3).

Elderly patients

No special dosage recommendations are available for elderly patients. Controlled, pharmacokinetic studies have not shown any age related effects on the distribution and/or elimination of milrinone.

This medicine contains less than 1 mmol sodium (23 mg) per 1 mL, that is to say essentially “sodium free”.

Fluid and electrolyte changes should be monitored as carefully as the serum creatinine level during Milrinone therapy. Milrinone and diuretics can mutually reinforce their effects. Cumulative diuretic and hypokalemic effects were observed. Milrinone enhances renal perfusion by increasing cardiac output, increasing the effect of diuretics and may thus require a reduction in diuretic dosing.

Potassium loss due to excessive diuresis favor the onset of arrhythmias in digitalized patients. Therefore, hypokalemia should be corrected before or during milrinone therapy.

Co-administration of inotropic agents (e.g. dobutamine) may increase the positive inotropic effects.

For incompatibilities with other solutions see section 6.2.

Pregnancy

Currently there is little or no experience with the use of milrinone in pregnant women. Animal studies have not indicated any direct or indirect harmful effects to reproductive toxicity (see section 5.3). As a precautionary measure, use of milrinone during pregnancy should be avoided.

Breast feeding

It is unknown if milrinone or its metabolites are excreted in breast milk. A risk for the newborn / child cannot be excluded. A decision must be made whether to discontinue breastfeeding or to refrain from milrinone therapy. One should take into account both the benefit of breastfeeding for the child and the benefits of the therapy for the woman.

There is no impact on the driving or the ability to operate machines.

The frequencies for side effects are based on the following categories:

Very common (≥1/10)

Common (≥1/100 to <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)

¹⁾ In infants and children, the risk of thrombocytopenia increased significantly with the duration of infusion. Clinical data suggest that milrinone associated thrombocytopenia is more common in children than in adults (see section 4.4).

²⁾ The frequency of supraventricular and ventricular arrhythmias did not appear to be dose or plasma concentration related. Life threatening arrhythmias occurred in particular due to history of arrhythmias and/or metabolic abnormalities (eg, hypokalemia) and/or increased digitalis levels or catheterization.

Clinical data suggest that milrinone related arrhythmias are less common in children than in adults.

Milrinone leads to a slight shortening of the AV conduction time. This can lead to an increased ventricular rate in patients with atrial flutter/fibrillation.

Children and adolescents:

Diseases of the nervous system

Frequency not Known: intraventricular hemorrhage (see section 4.4).

Congenital, familial and genetic disorders

Frequency not Known: persistent ductus arteriosus (see sections 4.2, 4.4, 5.2 and 5.3).

According to literature the critical consequences of a persistent ductus arteriosus based on the combination of pulmonary hyperperfusion with pulmonary edema and pulmonary hemorrhage and reduced organ perfusion followed by intraventricular hemorrhage and necrotizing enterocolitis, may be fatal.

Data on long-term use in children 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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects you can help provide more information on the safety of this medicine.

Symptoms of intoxication

Hypotension and cardiac arrhythmias can occur if milrinone is overdosed.

Overdose Therapy

Currently there is no specific antidote that is known.

In case of overdose, stop the infusion or reduce the infusion rate until the condition of the patient has stabilized. Symptomatic measures and support for circulatory function may be indicated. If necessary, antiarrhythmic therapy should be considered.

Pharmacotherapeutic group: phosphodiesterase inhibitors.

ATC code: C01CE02.

Milrinone is a positive inotropic and vasodilating substance with low chronotropic, bathmotropic and dromotropic effects.

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

Milrinone is a selective inhibitor of the peak-III- cAMP -phosphodiesterase -isoenzyme in myocardium and the tunica media at inotropic and vasorelaxant concentrations. This inhibitory effect leads to a cAMP-mediated increase in intracellular Ca²⁺ in the myocardial cell and the contraction force of the myocardium as well as cAMP dependent phosphorylation of the contractile proteins.

In the tunica media cells, there is a cAMP mediated decrease of the intracellular Ca²⁺ and thus leads to a relaxation of the vascular musculature. Further experimental evidence suggests that milrinone is neither a beta-receptor agonist nor does it resemble the Na⁺/Ka⁺ ATPase inhibitory effect of digitalis glycosides.

Clinical trials in cardiac failure patients have shown that milrinone increases the rate of maximum left ventricular pressure rise as a function of the dose and its plasma concentration. Studies in healthy volunteers have shown an increase in left ventricular pressure-volume relationship during milrinone therapy. This indicates a direct inotropic effect of the substance. Milrinone also resulted in a dose and plasma concentration dependent increase in forearm blood flow in patients with cardiac failure, indicating a direct vasodilatory effect on the arteries.

In addition to increasing myocardial contractility, milrinone improves diastolic function. This was demonstrated by improvements in left ventricular diastolic relaxation.

In patients with impaired myocardial function, milrinone injection in the usual dose range increased cardiac index and decreased pulmonary capillary pressure and vascular resistance. The heart rate increased by 3% to 10% depending on the dose. The mean arterial blood pressure fell dose dependently by 5% to 17%. The hemodynamic improvements correlated with dose and milrinone plasma concentration and were accompanied by improvement in clinical symptoms. The vast majority of patients showed improvements in hemodynamic parameters within five to fifteen minutes of treatment initiation.

Milrinone also has a positive inotropic effect in digitalized patients. There is no evidence that milrinone increases the toxicity of glycosides. Approximately maximum effects of milrinone on cardiac output and pulmonary capillary pressure are attained at milrinone plasma concentrations ranging from 150 ng/ml to 250 ng/ml.

Children and adolescents:

Upon reviewing the literature, there were clinical studies in patients treated for low-cardiac output syndrome status post cardiac surgery due to septic shock or pulmonary hypertension. The usual dosage consisted of an initial dose from 50 to 75 microgram/kg for 30 to 60 minutes followed by a continuous intravenous infusion of 0.25 to 0.75 microgram/kg / min for up to 35 hours. In these studies, milrinone showed an increase in cardiac output, a decrease in cardiac filling pressure, and a decrease in systemic and pulmonary vascular resistance, along with a minimal change in heart rate and myocardial oxygen consumption.

There are inadequate studies on prolonged use of milrinone to recommend a duration of more than 35 hours.

Some studies have investigated the use of milrinone in children with non-hyperdynamic septic shock, the effect of milrinone on postsurgical pulmonary hypertension after bypass to correct a Tetralogy of Fallot and the combined effect of nitric oxide and milrinone on pulmonary circulation after Fontan surgery. The study results were not conclusive. Therefore, milrinone cannot be recommended for these indications.

In vitro protein binding studies revealed that depending on the method of determination, milrinone is 70-91% protein bound at therapeutically relevant plasma concentrations. The steady-state plasma concentrations of milrinone is approximately 200 ng/ml, six to twelve hours after a steady maintenance infusion of 0.50 micrograms/kg/ min.

After intravenous injections of 12.5 micrograms/kg to 125 micrograms/kg in patients with cardiac failure, milrinone had a volume of distribution of 0.38 l/kg, a mean terminal elimination half-life of 2.3 hours and a clearance of 0.13 l/kg/ / h.

After intravenous infusions of 0.20 microgram/kg/ min to 0.7 microgram/kg/ min in patients with cardiac failure, the volume of distribution of the substance was about 0.45 l/kg, the mean terminal elimination half-life 2.4 hours and the clearance 0.14 l/kg/ h.

These pharmacokinetic parameters were not dose dependent. The area under the plasma concentration-time curve after the injections, however, was significantly dose dependent. By ultracentrifugation, it could be shown that milrinone is present at plasma concentrations between 70 and 400 nanograms/ml and up to 70% is bound to human plasma proteins.

Both clearance and half-life were prolonged in patients with cardiac failure according to their reduced renal function compared to healthy volunteers.

Data from patients with severe renal impairment (creatinine clearance below 30 ml/min) showed that the terminal elimination half-life in renal impairment is prolonged.

Children and adolescents:

The clearance of milrinone is higher in children than in adults; however, infants have a significantly lower clearance than children, with lower premature neonatal clearance. As a result of this faster clearance compared to adults, the steady state milrinone plasma levels are lower in children than in adults.

In children with normal renal function, steady state plasma concentrations of milrinone after 6-12 hours of continuous infusion of 0.5 to 0.75 microgram/kg/min were approximately 100 to 300 ng/ml.

After intravenous infusion of 0.5 to 0.75 microgram/kg/min in neonates, infants and children status post open heart surgery, the volume of distribution of milrinone was 0.35 to 0.9 l/kg; there were no significant differences between age groups.

After intravenous infusion of 0.5 microgram/kg/min in premature infants to prevent a very low systemic blood flow postnatally, milrinone had a volume of distribution of about 0.5 l/kg.

Various pharmacokinetic studies have shown that in children, clearance increases with age. Infants have significantly lower clearance than children (3.4 to 3.8 ml/kg/min compared to 5.9 to 6.7 ml/kg/min). In neonates, the milrinone clearance is about 1.64 ml/kg/min, and premature babies 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.

From this, it was deduced that the optimal dose of milrinone appears to be higher in pediatric patients than in adults, to achieve plasma levels above the pharmacodynamic effectiveness threshold. However, in preterm infants the optimal dosage appears to be lower than in children to reach plasma levels above the pharmacodynamic efficacy threshold.

Patent ductus arteriosus:

Milrinone is eliminated by renal excretion and has a distribution volume confined to the extracellular space. This suggests that the volume load and the hemodynamic changes due to a patent ductus arteriosus could affect the distribution and excretion of milrinone (see sections 4.2, 4.4, 4.8 and 5.2).

Metabolism, excretion

Milrinone is predominantly excreted in the urine in humans. The most important products of excretion in humans are milrinone (83%) and its O-glucuronide metabolite (12%). In healthy people, urinary excretion is rapid; approximately 60% of the dose is recovered within the first two hours of administration and approximately 90% within the first eight hours of administration. The mean renal clearance of milrinone i. v. is about 0.3 l/min; this indicates an active secretion.

Acute toxicity

In the mouse, LD₅₀ after oral administration is 137 mg/kg BW for males and 170 mg/kg for females; in the rat, the LD₅₀ for the male animals was 91 mg/kg, in the female animals 153 mg/kg.

In rabbits, after intravenous milrinone, there was an onset of focal epicardial and endocardial bleeding and focal myocardial fibrosis (especially in the papillary muscle and endocardial areas).

Subacute toxicity

The subacute toxicity was tested on rat and dog. In dogs, endocardial hemorrhages and myocardial fibrosis occurred in all treated groups after cumulative and fractionated administration of milrinone in amounts just above the therapeutic dose.

Subchronic and chronic toxicity

Oral and intravenous administration of milrinone to rats, dogs and monkeys resulted in myocardial degeneration, fibrosis and subendocardial bleeding at therapeutic doses, or just above therapeutic doses respectively, especially in the area of papillary muscles of the left ventricle. Lesions of the coronary vessels, characterized by periarterial edema and inflammation, were observed only in dogs.

Carcinogenicity

In long-term experiments, no tumorigenic potential was detected in rats and mice. In rats, endocardial hemorrhages and myocardial necrosis and fibrosis occurred. In mice, myocardial degeneration and fibrosis were detected at the highest dose. In mice, necrosis and ulcers were detected in the stomach.

Mutagenicity

A detailed in vitro and in vivo mutagenicity test was negative.

Fertility / reproductive toxicology

Milrinone had no effect on the fertility of male and female rats at oral doses up to 40 times the usual human therapeutic doses.

In reproductive toxicology studies in rats and rabbits, at doses up to 10-fold (oral) and 2.5-fold (i.v.) of the usual human therapeutic dose, no evidence of teratogenic effects was found.

In a 3-generation study (P, F1, F2 generation) in rats which were treated with p.o. milrinone, there was no effect on the development of animals and their reproductive capacity either in the mother or the offspring, even at the highest dose (40 times the usual human therapeutic dose).

Embryonic / fetal dose in relation to maternal serum concentration:

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

Juvenile animals:

A preclinical study was performed to investigate the dilating effects of PDE-3 inhibitors on the ductus arteriosus in full term rat cubs and their differential effects in mature and immature rat fetuses. Postnatal dilatation of the duct arteriosus by milrinone was studied at three doses (10, 1 and 0.1 mg/kg).

The dilating effects of milrinone on the fetal ductus arteriosus following indomethacin induced constriction were assessed by co-administration of milrinone (10, 1 and 0.1 mg/kg) and indomethacin (10 mg/kg) to pregnant rats on day 21 (carrying mature fetuses) and day 19 (carrying immature fetuses). This in vivo study demonstrated that milrinone causes a dose dependent dilation of the ductus arteriosus in fetus and stenosis of ductus arteriosus postnatally.

The dilating effect was more pronounced when injected immediately after birth than one-hour post-partum. In addition, the study showed that the immature ductus arteriosus is more sensitive to milrinone than the mature ductus arteriosus (see sections 4.2, 4.4, 4.8 and 5.2).

(L)-Lactic acid

Glucose anhydrous

Water for injections

Lactic acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

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

In the absence of compatibility studies, the medicinal product must note be mixed with other medicinal products.

3 years for the unopened product.

After dilution: Chemical and physical in use stability has been demonstrated for 24 hours at 20°C to 25°C when diluted with 0.9% Sodium Chloride Infusion or 5% Glucose Infusion.

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

Do not refrigerate.

This medicinal product does not require any special storage conditions.

Do not freeze. Store in the original package.

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

Milrinone 1 mg/ml solution for injection and infusion is available as a 10 ml fill volume in a 11ml clear type-I glass vial with a 20 mm dark grey bromobutyl rubber stopper and 20 mm Orange MT flip off seal and is available in pack sizes of 1 vial and 10 vials

Not all pack sizes may be marketed.

Instructions for dilution and administration:

Infusion solutions should be freshly prepared before use.

The following diluents may be used to prepare solutions for infusion:

• 0.9% Sodium Chloride Infusion

• 5% Glucose Infusion

Initial dose

The initial dose is 50 micrograms (0.05 mg) of milrinone/kg. It is administered slowly over a period of 10 minutes. This is usually followed by a continuous maintenance infusion.

Maintenance dose

The maintenance dose is generally 0.5 micrograms of milrinone /kg /minute. However, it may be between 0.375 micrograms of milrinone/kg/minute and 0.75 micrograms of milrinone/kg/minute.

To administer the maintenance dose, prepare an infusion solution containing 200 micrograms of milrinone/ml. It is prepared by adding 40 ml of a carrier solution to 10 ml undiluted milrinone solution for injection. The carrier solutions can be 0.9% Sodium Chloride Infusion or 5% Glucose Infusion.

Delivery rates:

Adults

The following provides a guide to maintenance infusion delivery rate based upon a solution containing milrinone 200microgram/ml

Patients with renal impairment:

The following maintenance infusion rates are recommended using the infusion solution described above.

The infusion rate should be adjusted according to hemodynamic response. See section 4.2.

The vials are for single use only and should be discarded immediately after initial use.

Tillomed Laboratories Limited

220 Butterfield, Great Marlings,

Luton, LU2 8DL

United Kingdom

PL 11311/0658

08/02/2021

31/05/2021