Milrinone Zentiva

Leaflet attached to the packaging: information for the user

Milrinone Zentiva, 1 mg/ml, solution for injection/infusion

Milrinonum

Read the leaflet carefully before using the medicine, as it contains important information for the patient.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor, pharmacist, or nurse.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
• If you experience any side effects, including any not listed in this leaflet, please tell your doctor or pharmacist. See section 4.

Table of contents of the leaflet

• 1. What is Milrinone Zentiva and what is it used for
• 2. Important information before using Milrinone Zentiva
• 3. How to take Milrinone Zentiva
• 4. Possible side effects
• 5. How to store Milrinone Zentiva
• 6. Contents of the pack and other information

1. What is Milrinone Zentiva and what is it used for

Milrinone Zentiva is a medicine that increases the minute volume of the heart. The active substance of the medicine is milrinone. Milrinone is a compound that affects the cardiovascular system and dilates blood vessels.
Milrinone Zentiva is used in adults for the short-term treatment (up to 48 hours) of severe heart failure that is not effectively treated with conventional products (cardiac glycosides, diuretics, angiotensin-converting enzyme inhibitors, and vasodilators).
Milrinone Zentiva is used in children in the following situations:

• Short-term treatment (up to 35 hours) of severe heart failure (when the heart cannot pump enough blood to the rest of the body), when other medicines have been ineffective;
• Short-term treatment (up to 35 hours) of acute heart failure, for example after heart surgery, i.e. when the heart has difficulty pumping blood in the body. During treatment with milrinone infusion, heart function and arterial pressure should be constantly monitored.

2. Important information before using Milrinone Zentiva

When not to use Milrinone Zentiva:

• if the patient is hypersensitive to milrinone or any of the other ingredients of this medicine (listed in section 6),
• in patients with severe aortic or pulmonary valve stenosis,
• in patients with heart failure caused by abnormal thickening of the heart muscle cells (hypertrophic obstructive cardiomyopathy),
• in patients with localized enlargement of the heart chamber wall (ventricular aneurysm),
• in patients with severe, previously untreated fluid volume depletion,
• in patients after acute myocardial infarction.

Milrinone Zentiva should not be used in patients with heart failure caused by hyperthyroidism, acute myocarditis, or amyloid cardiomyopathy due to insufficient experience with such treatment.

Warnings and precautions

Before using Milrinone Zentiva, consult a doctor or nurse.

• if the patient has certain heart rhythm disorders (e.g. atrial flutter, atrial fibrillation, or other ventricular rhythm disorders), as milrinone administration may exacerbate some forms of arrhythmia. In this regard, the doctor will consider the administration of additional anti-arrhythmic drugs, dose modification, or monitoring using electrocardiography.
• if it is suspected that the ventricular filling pressure is low (e.g. due to previous treatment with diuretics). The doctor will assess ventricular filling pressure before using the medicine and, if necessary, correct it.
• if the patient has kidney disease or low blood pressure. The doctor will perform appropriate tests before and during treatment to assess the effect of treatment and milrinone dosing.
• if the patient has a low platelet count or low red blood cell count or low hemoglobin level. The doctor will continue milrinone administration only under strict monitoring of platelet count, as it may lead to further reduction.

There have been reports of reactions at the infusion site. Therefore, during milrinone administration, the site where the infusion solution passes from the catheter into the vein should be carefully observed to avoid accidental extravasation.

Children and adolescents

In children, the following additional warnings and precautions should be considered, in addition to those described for adults:
Before administering milrinone, the doctor will check various parameters, such as heart rate and blood pressure, and perform blood tests.
Milrinone Zentiva will not be administered to children with unstable heart rate and blood pressure.
Tell your doctor if:

• the child has kidney problems,
• the child is premature or has low birth weight,
• the child has a heart defect known as patent ductus arteriosus, i.e. a connection between the two large blood vessels (aorta and pulmonary artery) that remains open, although it should be closed.

In such cases, the doctor will decide whether the child can be treated with milrinone.
There have been reports of heart defects in premature infants.

Elderly patients

There are no special dosage recommendations for elderly patients.
Based on current knowledge, it is expected that in patients with normal renal function, no special dosage recommendations will be necessary in this patient group.

Milrinone Zentiva and other medicines

Tell your doctor or pharmacist about all medicines you are taking, have recently taken, or might take.
In patients using diuretics and milrinone, there may be an increased diuretic effect and hypokalemia. The resulting potassium loss may contribute to the occurrence of arrhythmias. The effect of milrinone may also be enhanced.
Concomitant administration of milrinone and other cardioprotective drugs (e.g. dobutamine) may potentiate the cardiopressant effect (positive inotropic effect).

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, think you may be pregnant, or are planning to have a baby, ask your doctor for advice before taking this medicine.
There is currently no experience with the use of milrinone in pregnant women. In animal studies, no direct or indirect harmful effects on embryonic or fetal development have been observed.
As a precaution, pregnant women should avoid using milrinone.
It is not known whether milrinone passes into breast milk. A risk to the newborn or child cannot be excluded. During treatment with milrinone, breastfeeding should be discontinued.

Driving and using machines

No effect on the ability to drive and use machines.

Milrinone Zentiva contains glucose

If your doctor has told you that you have an intolerance to some sugars, tell your doctor before taking milrinone.

Milrinone Zentiva contains sodium

This medicine contains less than 1 mmol of sodium (23 mg) per 1 ml, i.e. the medicine is considered "sodium-free".

3. How to take Milrinone Zentiva

The dosage and method of administration of Milrinone Zentiva will be determined by your doctor. The following are recommendations for dosing that the doctor will base their decision on.

Dosage

Initial dose:
The initial dose is 50 micrograms (0.05 mg) of milrinone per kilogram of body weight. This dose is administered over 10 minutes. Subsequently, a maintenance dose is usually administered by continuous infusion (Table 1).
Maintenance dose:
Generally, the continuous maintenance infusion is administered at a rate of 0.5 micrograms of milrinone per kilogram of body weight per minute. However, this value may range from 0.375 micrograms of milrinone per kilogram of body weight per minute to 0.75 micrograms of milrinone per kilogram of body weight per minute, depending on the cardiovascular response (Table 2).
The daily dose of milrinone should not exceed 1.13 mg of milrinone per kilogram of body weight.
To administer the maintenance dose, a solution for infusion containing 200 micrograms of milrinone per milliliter should be prepared. 40 ml of the diluent should be added to 10 ml of the undiluted milrinone injection solution. The following diluents can be used for dilution: 0.9% sodium chloride solution or 5% glucose solution for infusion.
Table 1. Initial dose (concentration 1 mg/ml)

Table 2. Maintenance dose (for continuous administration)
*The daily dose (in mg/kg body weight) is calculated from the corresponding dose (minimum, standard, maximum) plus the initial dose (0.05 mg/kg body weight)
Depending on the required maintenance dose (in micrograms per kilogram of body weight per minute)
the prepared infusion solution with a concentration of 200 micrograms/ml is administered at the following infusion rate (in milliliters per kilogram of body weight per hour) (see Table 3).
Table 3. Maintenance dose and corresponding infusion rate
*calculated for an infusion solution with a concentration of 200 micrograms of milrinone per milliliter.

Use in children and adolescents

As the first dose for a child, the doctor should administer 50 to 75 micrograms per kilogram of body weight over 30 to 60 minutes.
Subsequently, a dose of 0.25 to 0.75 micrograms per kilogram of body weight per minute is administered, depending on the child's response to treatment and the occurrence of side effects. Milrinone may be administered for up to 35 hours.
During the infusion, the child will be closely monitored: the doctor will check various parameters, such as heart rate and blood pressure. Blood samples will also be taken to assess the response to treatment and the occurrence of side effects.
Elderly patients
Based on current knowledge, it is expected that in patients with normal renal function, no special dosage recommendations will be necessary in this patient group.

Patients with renal impairment
The elimination of milrinone is decreased in patients with renal impairment. Therefore, the maintenance dose should be reduced depending on the degree of renal impairment (see Table 4).
Table 4: Conversion of reduced maintenance dose in patients with renal impairment to corresponding infusion rate
*calculated for an infusion solution with a concentration of 200 micrograms of milrinone per milliliter.

Method of administration

Milrinone Zentiva is administered by slow intravenous injection or intravenous infusion.
Milrinone Zentiva should not be mixed with substances other than the above-mentioned diluents.
Furosemide has been shown to be incompatible with many substances, including milrinone. Therefore, during concomitant use of furosemide or bumetanide with milrinone, a different intravenous route should be chosen or furosemide should be administered orally.
Milrinone should not be mixed with sodium bicarbonate solutions.
Depending on the patient's fluid requirements, infusions with different concentrations can be used.
In the case of injection, the largest possible vein should be chosen to avoid local irritation. Administration of the medicine into tissues adjacent to the blood vessel should be avoided.

Duration of treatment:

The duration of treatment should not exceed 48 hours, as no controlled clinical trials have been conducted to evaluate treatment lasting longer than 48 hours.
In children, the duration of treatment is up to 35 hours.

Overdose of Milrinone Zentiva

There may be a decrease in blood pressure and arrhythmias.
In case of overdose, the doctor will discontinue the milrinone infusion or reduce the infusion rate and may take other appropriate measures. There is no specific antidote known.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

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

Frequent(in up to 1 in 10 people)

• mild to moderate headaches,
• irregular heartbeat due to the occurrence of extra heartbeats,
• tachycardia,
• arrhythmias,
• low blood pressure (hypotension).

Uncommon(in up to 1 in 100 people)

• decreased platelet count,
• decreased potassium levels in the blood,
• tremors,
• ventricular fibrillation,
• severe chest pain, often with accompanying pressure and shortness of breath,
• increased liver function due to liver dysfunction.

Rare(in up to 1 in 1,000 people)

• decreased red blood cell count,
• decreased hemoglobin level.

Very rare(in up to 1 in 10,000 patients)

• anaphylactic shock (anaphylaxis),
• torsade de pointes- severe arrhythmias. Symptoms include very rapid, irregular, or strong heartbeat (palpitations), dizziness, and loss of consciousness. The patient may also experience malaise, cold sweats, shortness of breath, unusual pallor, and chest pain.
• bronchospasm,
• skin reactions, such as rash.

Frequency not known(frequency cannot be estimated from the available data)

• renal failure caused by concurrent low blood pressure,
• irritation at the infusion site.

Life-threatening arrhythmias have occurred, particularly in the presence of arrhythmias and/or metabolic disorders (e.g. low potassium levels) and/or increased digitalis levels.
In addition to the side effects observed in adults, the following side effects have been observed in children:

• bleeding into the brain's fluid-filled spaces (intraventricular hemorrhage),
• a heart defect known as patent ductus arteriosus, i.e. a connection between the two large blood vessels (aorta and pulmonary artery) that remains open, although it should be closed. This can cause excess fluid in the lungs and bleeding or damage to the intestines or digestive tract. This condition can lead to death.

In addition, children are more likely to experience a decrease in platelet count than adults. The risk of this side effect increases with the duration of treatment with milrinone.
It appears that arrhythmias occur less frequently in children than in adults.

Reporting side effects

If you experience any side effects, including any not listed in this leaflet, please tell your doctor or pharmacist. Side effects can be reported directly to the Department of Drug Safety Monitoring of the Office for Registration of Medicinal Products, Medical Devices, and Biocidal Products.
Jerozolimskie Avenue 181 C, 02-222 Warsaw, Tel.: +48 22 49 21 301, Fax: +48 22 49 21 309, Website: https://smz.ezdrowie.gov.pl Side effects can also be reported to the marketing authorization holder or its representative in Poland. By reporting side effects, you can help provide more information on the safety of this medicine.

• Zentiva Polska Sp. z o.o., Bonifraterska 17, 00-203 Warsaw, tel.: +48 22 375 92 00

5. How to store Milrinone Zentiva

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and vial after "EXP".
The expiry date refers to the last day of that month.
Storage conditions
There are no special storage requirements.
Do not freeze. Store in the original package.
This product is usually a clear, colorless to pale yellow solution, practically free from particulate matter. The vial should be discarded if precipitates or a change in color of the product is observed.

Storage conditions after dilution:

Chemical and physical stability of the product has been demonstrated after dilution in 0.9% sodium chloride solution or 5% glucose solution for infusion for 24 hours at a temperature of 20 to 25°C.
From a microbiological point of view, the product should be used immediately, unless the method of dilution precludes the risk of microbial contamination. If the product is not used immediately, the user is responsible for the storage conditions and storage time before administration, which should not exceed 24 hours at 2 to 8°C, unless the dilution has taken place in controlled and validated aseptic conditions.
Do not store in a refrigerator.
Special precautions for storage:
There are no special precautions for storage.
Do not freeze. Store in the original package.
Recommendations for dilution and administration:

• 0.9% sodium chloride solution for infusion
• 5% glucose solution for infusion The dose of milrinone is administered as follows:

Infusion solutions should be freshly prepared before use.
The following diluents can be used for dilution:

6. Contents of the pack and other information

What Milrinone Zentiva contains

• The active substance of the medicine is milrinone. One vial with 10 ml of solution for injection and infusion contains 10 mg of milrinone.
• The other ingredients are: L-lactic acid, glucose, water for injection, lactic acid (for pH adjustment), and sodium hydroxide (for pH adjustment). See section 2.

What Milrinone Zentiva looks like and contents of the pack

Milrinone Zentiva is a clear, colorless to pale yellow solution, practically free from particulate matter. The medicine is available in vials made of colorless glass (type I) with a bromobutyl rubber stopper and a flip-offseal in a cardboard box. Each vial contains 10 ml of solution.
Available pack sizes: 1 or 10 vials.

Marketing authorization holder

Zentiva, k.s., U kabelovny 130, Dolní Měcholupy, 102 37 Prague 10, Czech Republic

Manufacturer

MIAS Pharma Limited, Suite 2, Stafford House, Strand Road, Portmarnock, Co. Dublin, Ireland
Tillomed Malta Limited, Malta Life Sciences Park, LS2.01.06 Industrial Estate, San Gwann, SGN 3000, Malta

This medicinal product is authorized in the Member States of the European Economic Area under the following names:

Austria: Milrinone Tillomed 1 mg/ml Injektionslösung/Infusionslösung
Germany: Milrinon Tillomed 1 mg/ml Injektionslösung/Infusionslösung
France: MILRINONE TILLOMED 1 mg/mL, solution injectable/pour perfusion
Netherlands: Milrinone Tillomed 1 mg/ml oplossing voor injectie/infusie
Poland: Milrinone Zentiva

For more information on this medicine, please contact the representative of the marketing authorization holder in Poland:

Zentiva Polska Sp. z o.o., ul. Bonifraterska 17, 00-203 Warsaw, tel.: +48 22 375 92 00
Date of last revision of the leaflet:December 2023

INFORMATION INTENDED FOR HEALTHCARE PROFESSIONALS

Incompatibilities
Furosemide and bumetanide should not be administered with milrinone through the same intravenous line due to precipitation. Milrinone should not be diluted in sodium bicarbonate solution.
Due to the lack of available compatibility studies, this medicinal product should not be mixed with other medicinal products.
Shelf life:
3 years for the unopened product.
After dilution: Chemical and physical stability of the product has been demonstrated after dilution in 0.9% sodium chloride solution or 5% glucose solution for infusion for 24 hours at a temperature of 20 to 25°C.
From a microbiological point of view, the product should be used immediately, unless the method of dilution precludes the risk of microbial contamination. If the product is not used immediately, the user is responsible for the storage conditions and storage time before administration, which should not exceed 24 hours at 2 to 8°C, unless the dilution has taken place in controlled and validated aseptic conditions.
Do not store in a refrigerator.
Special precautions for storage:
There are no special precautions for storage.
Do not freeze. Store in the original package.
Recommendations for dilution and administration:

• 0.9% sodium chloride solution for infusion
• 5% glucose solution for infusion The dose of milrinone is administered as follows:

Infusion solutions should be freshly prepared before use.
The following diluents can be used for dilution:

Rate of administration:
Adults
The following are recommendations for the rate of maintenance infusion for a solution containing 200 micrograms of milrinone per milliliter.

Patients with renal impairment:
The following are recommendations for the rate of maintenance infusion for the solution described above.

The infusion rate should be adjusted according to the hemodynamic response. See section 4.2.
The vials are for single use only; after use, they should be discarded immediately.