Milrinone zentiva

Package leaflet: Information for the user

Milrinone Zentiva, 1 mg/ml, solution for injection/infusion
Milrinonum
Please read all of this leaflet carefully before using this medicine, because it contains
important information for you.

• 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 a specific individual. Do not pass it on to others. It may harm other people, even if their symptoms are the same.
• If you experience any adverse reactions, including any not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of the leaflet

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

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

Milrinone Zentiva is a medicine that increases cardiac output. The active substance is
milrinone. Milrinone is a compound that affects the cardiovascular system and dilates blood vessels.
Milrinone Zentiva is used in adults for:
Short-term treatment (up to 48 hours) of severe heart failure not responding adequately to conventional therapies (cardiac glycosides, diuretics, angiotensin-converting enzyme [ACE] 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 sufficient blood to the rest of the body), when other medications have proven ineffective;
• Short-term treatment (up to 35 hours) of acute heart failure, for example following heart surgery, i.e. when the heart has difficulty pumping blood through the body. During milrinone infusion, cardiac function and arterial pressure must be continuously monitored.

2. Important information before using Milrinone Zentiva

When not to use Milrinone Zentiva:

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

Milrinone Zentiva should also not be used in patients with heart failure
caused by hyperthyroidism, acute myocarditis, or amyloid heart disease (amyloid cardiomyopathy), due to insufficient experience with treatment in these conditions.
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 certain ventricular arrhythmias), as milrinone administration may worsen some types of arrhythmias. Therefore, the doctor may consider giving additional antiarrhythmic drugs, adjusting the dose, or monitoring with electrocardiography.
• if low cardiac filling pressure is suspected (e.g. due to prior diuretic treatment). The doctor will assess cardiac filling pressure before administering the medicine and, if necessary, correct it.
• if the patient has kidney disease or low arterial blood pressure. The doctor will perform appropriate tests before and during treatment to evaluate the treatment effect and dosing of milrinone and other medications.
• if the patient has low platelet count (thrombocytes), low red blood cell count (erythrocytes), or low hemoglobin levels. The doctor will continue milrinone administration only under strict monitoring of platelet levels, as further reduction in platelet count may occur.

Infusion site reactions have been observed. Therefore, during milrinone infusion, the site where the infusion solution enters the venous blood via the catheter should be carefully monitored 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 several parameters, such as heart rhythm and blood pressure, and perform blood tests.
Milrinone Zentiva will not be administered to children with unstable heart rhythm or blood pressure.
Inform the doctor if:

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

In such cases, the doctor will decide whether the child can be treated with milrinone.
Cases of heart defects in premature infants have been reported.
Elderly patients
There are no special dosage recommendations for elderly patients.
Controlled pharmacokinetic studies have not so far demonstrated age-related changes in distribution and/or elimination of milrinone – the active substance in Milrinone Zentiva.
Milrinone Zentiva and other medicines
Inform the doctor or pharmacist about all medicines the patient is currently taking or has recently taken, as well as any medicines the patient plans to take.
In patients receiving diuretics and milrinone simultaneously, enhanced diuretic effect and potassium-lowering effect may occur. Resulting potassium loss may predispose to cardiac arrhythmias. The effect of milrinone may also be stronger.
Concomitant administration of milrinone and other cardioprotective drugs (e.g. dobutamine) may enhance the cardiotonic effect (positive inotropic effect).
Pregnancy, breastfeeding and fertility
If the patient is pregnant or breastfeeding, suspects she may be pregnant, or is planning to have a child, she should consult a doctor before using this medicine.
Currently, there is no experience with the use of milrinone in pregnant women. Animal studies have not shown direct or indirect harmful effects on embryonic or fetal development.
Due to the need for caution, pregnant women should avoid using milrinone.
It is not known whether milrinone passes into human milk. A risk to the newborn or child cannot be excluded. Breastfeeding must be discontinued during treatment with milrinone.
Driving and operating machinery
No influence on the ability to drive or operate machinery.
Milrinone Zentiva contains glucose
If the doctor has diagnosed intolerance to certain sugars in the patient, inform the doctor before administering milrinone.
Milrinone Zentiva contains sodium
This medicine contains less than 1 mmol sodium (23 mg) per 1 ml, meaning 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. Below are dosage recommendations that the physician will consider when making their decision.
Dosage
Initial dose:
The initial dose is 50 micrograms (0.05 mg) of milrinone per kilogram of body weight (kg). This dose is administered over 10 minutes. Subsequently, a maintenance dose is usually given as a continuous infusion (Table 1).
Maintenance dose:
Generally, the continuous maintenance infusion is administered at a rate of 0.5 micrograms of milrinone per kg of body weight per minute. However, this value may range from 0.375 micrograms of milrinone/kg body weight per minute to 0.75 micrograms of milrinone/kg body weight per minute, depending on the cardiovascular response (Table 2).
The total daily dose of milrinone should not exceed 1.13 mg of milrinone per kg of body weight.
To administer the maintenance dose, prepare an infusion solution containing 200 micrograms of milrinone per ml. Add 40 ml of diluent to 10 ml of undiluted milrinone injection solution. As diluents, 0.9% sodium chloride solution or 5% glucose solution for infusion may be used.
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 kg body weight per minute), the prepared infusion solution at a concentration of 200 micrograms/ml is administered at the following infusion rate (in milliliters per kg 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 millilitre.
Use in children and adolescents
As the initial dose for a child, the doctor should administer 50 to 75 micrograms per kilogram of the child's body weight over a period of 30 to 60 minutes.
Subsequently, a maintenance dose of 0.25 to 0.75 microgram per kilogram of body weight per minute should be administered, depending on the child's response to treatment and the occurrence of adverse effects. Milrinone may be administered for up to a maximum of 35 hours.
During the infusion, the child will be closely monitored: the doctor will check various parameters, such as heart rhythm and blood pressure. Blood samples will also be taken to assess response to treatment and the occurrence of adverse effects.

Elderly patients
Based on current knowledge, no specific dosage recommendations are expected to be necessary for elderly patients with normal renal function.

Patients with renal impairment
In patients with impaired renal function, milrinone elimination is reduced. Therefore, the maintenance dose should be reduced according to the degree of renal dysfunction (see Table 4).

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

*calculated for an infusion solution with a concentration of 200 micrograms of milrinone per millilitre.
Method of administration
Milrinone Zentiva is administered as a slow intravenous injection or intravenous infusion.
Milrinone Zentiva must not be mixed with any substances other than the carrier solutions listed above.
Furosemide shows chemical incompatibilities with many substances, including milrinone. Therefore, when co-administering furosemide or bumetanide with milrinone, alternative intravenous routes should be chosen, or furosemide should be administered orally in tablet form.
Milrinone must not be mixed with sodium bicarbonate solutions.
Depending on the patient's fluid requirements, infusion solutions of various concentrations may be used.
For injection, the largest possible vein should be selected to avoid local irritation. Injection into perivascular tissues must be avoided.
Duration of treatment:
The duration of treatment should not exceed 48 hours, as controlled clinical trials evaluating treatment longer than 48 hours have not been conducted.
In children, the duration of treatment is up to 35 hours.
Use of a higher than recommended dose of Milrinone Zentiva
This may lead to a drop in arterial blood pressure and cardiac arrhythmias.
In case of overdose, the physician will discontinue the milrinone infusion or reduce the infusion rate and may apply other appropriate measures. No specific antidote is known.
If you have any further questions about the use of this medicine, consult your doctor or pharmacist.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everybody will experience them.

Common (in no more than 1 in 10 people)

• Headaches of mild to moderate intensity,
• Irregular heartbeat due to extra heartbeats,
• Tachycardia,
• Heart rhythm disorders,
• Low blood pressure (hypotension).

Uncommon (in no more than 1 in 100 people)

• Decreased platelet count,
• Decreased potassium levels in blood,
• Tremors,
• Ventricular fibrillation,
• Severe chest pain, often accompanied by pressure and shortness of breath,
• Increased liver function tests due to impaired liver function.

Rare (in no more than 1 in 1,000 people)

• Decreased red blood cell count,
• Decreased blood pigment concentration.

Very rare (in no more than 1 in 10,000 patients)

• Anaphylactic shock (anaphylaxis),
• Torsade de pointes – severe heart rhythm disturbances. Symptoms include very rapid, irregular or forceful heartbeat (palpitations), dizziness and loss of consciousness. The patient may also experience malaise, cold sweats, shortness of breath, unusual paleness of the skin, and chest pain,
• Bronchospasm,
• Skin reactions such as rash.

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

• Kidney failure caused by concomitant low blood pressure,
• Irritation at the infusion site.

Life-threatening heart rhythm disturbances have particularly occurred in the presence of concomitant cardiac arrhythmias and/or metabolic disturbances (e.g. low potassium levels) and/or increased digoxin levels.

In addition to adverse reactions observed in adults, the following adverse reactions have been observed in children:

• Bleeding into the fluid-filled spaces in the brain (intraventricular haemorrhage),
• A heart condition known as patent ductus arteriosus, i.e. a connection between two major blood vessels (aorta and pulmonary artery) that remains open although it should have closed. This may lead to excess fluid in the lungs and bleeding or damage to the intestines or gastrointestinal tract. This condition may lead to death.

Furthermore, in children, decreased platelet count occurs more frequently than in adults. The risk of this adverse reaction increases with the duration of milrinone treatment. Heart rhythm disturbances appear to occur less frequently in children than in adults.

Reporting of adverse reactions

If any adverse reactions occur, including any adverse reactions not listed in this leaflet, inform your doctor or pharmacist. Adverse reactions can be reported directly to the Department of Monitoring of Adverse Drug Reactions of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products.

Al. Jerozolimskie 181 C
02 - 222 Warsaw
Tel.: + 48 22 49 21 301
Faks: + 48 22 49 21 309
Website: https://smz.ezdrowie.gov.pl

Adverse reactions can also be reported to the marketing authorisation holder or its representative in Poland.

Reporting adverse reactions helps provide more information on the safety of this medicine.

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 stated on the carton and vial after "EXP".
The expiry date refers to the last day of the stated month.
Storage conditions
No special requirements for storage conditions.
Do not freeze. Store in the original packaging.
This product is usually a clear, colourless to pale yellow liquid. The vial should be discarded if
precipitates or changes in colour of the product are observed.
Storage conditions after dilution:
Chemical and physical stability of the product after dilution in 0.9% sodium chloride solution or
5% glucose solution for infusion has been demonstrated 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 excludes the risk of microbiological contamination. If not used immediately, the user is
responsible for ensuring appropriate storage conditions and duration before administration.
Infusion solutions at the recommended dilutions with 0.9% sodium chloride solution or 5% glucose
solution should be prepared immediately before use.
Vials are for single use only. Any unused product or waste material should be disposed of in
accordance with local regulations.

6. Contents of the pack and other information

What Milrinone Zentiva contains

• The active substance is milrinone. One 10 ml vial of concentrate for solution for injection and infusion contains 10 mg of milrinone.
• The other ingredients are: (L)-lactic acid, glucose, water for injections, 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, colourless to pale yellow solution, practically free from
particulate matter. The medicine is supplied in colourless glass vials (type I) closed with a bromobutyl rubber stopper and a flip-off seal, packed in a cardboard box. Each vial contains 10 ml of solution.
Pack sizes: 1 or 10 vials.

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

Manufacturer
Tillomed Malta Limited,
Malta Life Sciences Park,
LS2.01.06 Industrial Estate,
San Gwann, SGN 3000, Malta

This medicinal product is authorised in the member countries of the European Economic Area under the following names:
Austria: Milrinone Tillomed 1 mg/ml Injektionslösung/Infusionslӧsung
Germany: Milrinon Tillomed 1 mg/ml Injektionslösung/Infusionslӧsung
France: MILRINONE TILLOMED 1 mg/mL, solution injectable/pour perfusion
Netherlands: Milrinone Tillomed 1 mg/ml oplossing voor injectie/infusie
Poland: Milrinone Zentiva

To obtain further information about this medicine, please contact the representative of the Marketing Authorisation Holder in Poland:
Zentiva Polska Sp. z o.o.
ul. Bonifraterska 17
00-203 Warsaw
tel.: +48 22 375 92 00

INFORMATION INTENDED FOR HEALTHCARE PROFESSIONALS

Pharmaceutical incompatibilities
Furosemide and bumetanide should not be administered through the same intravenous line as milrinone due to precipitation occurring after their addition. Milrinone should not be diluted in sodium bicarbonate solution.
Due to the lack of available data on pharmaceutical compatibility, this medicinal product must not be mixed with other medicinal products.

Shelf life:
3 years for unopened product.
After dilution: Chemical and physical stability has been demonstrated for the product diluted 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 excludes the risk of microbiological contamination. If not used immediately, responsibility for appropriate storage conditions and duration prior to administration lies with the user, provided that storage does not exceed 24 hours at 2 to 8°C, unless dilution was performed under controlled and validated aseptic conditions.
Do not store in the refrigerator.

Special precautions during storage:
No special storage precautions required.
Do not freeze. Store in the original packaging.

Recommendations for dilution and method of administration:
Infusion solutions should be freshly prepared prior to use.
The following diluents may be used to prepare infusion solutions:

• 0.9% sodium chloride solution for infusion
• 5% glucose solution for infusion

Initial dose
The initial dose is 50 micrograms (0.05 mg) of milrinone per kg body weight. This dose should be administered slowly over 10 minutes. Subsequently, a maintenance dose is usually administered as a continuous infusion.

Maintenance dose
The maintenance dose is typically 0.5 microgram of milrinone per kg body weight per minute. However, it may range from 0.375 micrograms milrinone/kg body weight/min to 0.75 micrograms milrinone/kg body weight/min. To administer the maintenance dose, prepare an infusion solution containing 200 micrograms of milrinone per ml. Add 40 ml of diluent to 10 ml of undiluted milrinone injection solution. The following infusion solutions may be used as diluents for this purpose: 0.9% sodium chloride solution or 5% glucose solution for infusion.

Rate of administration:
Adults
Below are recommendations for the maintenance infusion rate for the solution containing 200 micrograms of milrinone per ml.

Patients with renal function impairment:
Below are recommendations for the maintenance infusion rate for the solution described
above.

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