Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Aventis Pharma Limited, 410 Thames Valley Park Drive, Reading, Berkshire, RG6 1PTUK Trading as: Sanofi, 410 Thames Valley Park Drive, Reading, Berkshire, RG6 1PTUK
The use of inotropic agents such as milrinone during the acute phase of a myocardial infarction may lead to an undesirable increase in myocardial oxygen consumption (MVO2). Primacor Injection is not recommended immediately following acute myocardial infarction until safety and efficacy have been established in this situation.
Careful monitoring should be maintained during Primacor Injection therapy including blood pressure, heart rate, clinical state, electro-cardiogram, fluid balance, electrolytes and renal function (i.e. serum creatinine).
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 non-sustained 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 predispose digitalised patients to arrhythmias. Therefore, hypokalaemia 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). Consequently, careful monitoring of the infusion site should be maintained so as to avoid possible extravasation.
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).
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 sections 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 sections 4.2, 4.8, 5.2, and 5.3).
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.
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.
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.
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 (≥1/100, ≤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).
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).
Very rare: anaphylactic shock
Uncommon: hypokalaemia
Common: headaches, usually mild to moderate in severity
Uncommon: tremor
Common:
Uncommon:
Very rare:
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.
Very rare: bronchospasm
Uncommon: liver function tests abnormal
Very rare: skin reactions such as rash
Not known: renal failure, secondary to a concomitant hypotension.
Not known: infusion site reaction
Not known: interventricular haemorrhage (see section 4.4)
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 interventricular haemorrhage and necrotizing enterocolitis with possible fatal outcome as described in literature.
Long-term safety data for paediatric population are not yet available.
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 or search for MHRA Yellow Card in the Google Play or Apple App Store.
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.
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