MEGALOTECT 100 U/mL SOLUTION FOR INFUSION

2. What you need to know before you use Megalotect

Do not use Megalotect

• if you are allergicto human anti-cytomegalovirus immunoglobulin or to any of the other ingredients of this medicine (listed in section 6).
• if you have a deficiency of immunoglobulin A, in particular if you have antibodies against immunoglobulin A in your blood, because it may lead to anaphylaxis.

Warnings and Precautions

Talk to your doctor, pharmacist, or nurse before Megalotect is administered.

• if you are going to be administered human immunoglobulin for the first time or after a long interruption of treatment, or if you have changed the immunoglobulin product. In these cases, the frequency of adverse reactions may be higher and your doctor will monitor you closely.
• if you are allergicto immunoglobulins (see the section "Do not use Megalotect"). You may be allergic to immunoglobulins without knowing it, even if you have been administered them before and tolerated them well. However, hypersensitivity reactions are rare.
• if you have an untreated infection or a prolonged underlying inflammation (chronic)
• if you
• • are severely overweightor are an elderly patient,
  • have high blood pressure(hypertension), diabetes, or vasculopathy,
  • have a greater tendency to blood coagulation,
  • have been bedridden for a long time,
  • have low blood volume(hypovolemia) or higher than normal blood density,
  • have a pre-existing kidney diseaseor are taking medicines that may damage the kidneys.

In these cases, there is a higher risk of experiencing side effects. Your doctor may interrupt treatment with Megalotect or take other precautionary measures (e.g., a particularly low infusion rate).

Infusion Reactions

If you notice any of the following signs of a reaction during the infusion of Megalotect, such as headache, flushing, chills, muscle pain, wheezing, rapid heartbeat, back pain, nausea, low blood pressure, inform your doctor immediately.

Inform your doctor immediatelyif you notice these reactions during the administration of Megalotect. He will decide whether to reduce the infusion rate or stop it completely and initiate the necessary medical measures to treat these reactions.

Information on Safety with Regard to Infections

Megalotect is prepared from human plasma (the liquid part of the blood). When medicines derived from blood or human plasma are administered, certain measures must be taken to prevent infections from being transmitted to patients. The blood of all donors is tested for viruses and infections. Additionally, the processing of blood or plasma includes steps that can inactivate or eliminate viruses.

Despite these measures, when medicines derived from blood or human plasma are administered, the possibility of transmitting infectious agents cannot be completely excluded.

The measures taken are considered effective against viruses such as

• human immunodeficiency virus (HIV),
• hepatitis A virus (HAV),
• hepatitis B virus (HBV),
• hepatitis C virus (HCV).

The measures taken are of limited value against viruses such as

• parvovirus B19.

To date, immunoglobulins have not been associated with hepatitis A or parvovirus B19 infections. This is because the antibodies contained in Megalotect protect against these infections.

We strongly recommend that you note the name and batch number of each dose of Megalotect administered to you. The batch number provides information about the raw materials used in your medicine. This allows, if necessary, the relationship between you and the raw material used to be established.

Children and Adolescents

The special warnings and precautions for adults are also valid for children and adolescents.

Other Medicines and Megalotect

Tell your doctor or pharmacist if you are using, have recently used, or might use any other medicines.

Megalotect may reduce the effectiveness of certain vaccines, e.g., the effectiveness of vaccines against

• measles
• rubella
• mumps
• chickenpox

If you have been administered Megalotect, you should wait at least 3 months before receiving certain vaccines and at least one year before being vaccinated against measles.

Please avoid the simultaneous use of loop diuretics with Megalotect.

Children and Adolescents

It is expected that the interactions mentioned for adults will be the same for children and adolescents.

Pregnancy, Breast-feeding, and Fertility

If you are pregnant or breast-feeding, think you may be pregnant, or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine.

Your doctor will decide whether Megalotect can be used during pregnancy and breast-feeding.

Driving and Using Machines

Megalotect has a minor influence on the ability to drive and use machines. If you experience side effects during treatment, wait until they resolve before driving or using machines.

3. How to Use Megalotect

Your treating doctor will administer Megalotect to you.

The recommended dose is 1 ml per kg of body weight and day for adults, children, and adolescents.

The medicine will be administered at least a total of 6 times, at intervals of 2 or 3 weeks. Your doctor will decide on the exact number of infusions you need and when to start treatment.

Megalotect is administered through an infusion device (infusion) into a vein. This medicine should be at room temperature or body temperature before use.

If you use more Megalotect than you should

An overdose of Megalotect may cause fluid overload and hyperviscosity (thickening) of the blood, especially if you are over 65 years old and/or have heart or kidney failure.

If you think you have received more Megalotect than you should, contact your doctor as soon as possible.

In case of overdose or accidental ingestion, call the Toxicology Information Service immediately, telephone 915620420.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist, or nurse.

4. Possible Side Effects

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

The following side effects have been reported spontaneously with Megalotect:

Not known: Frequency cannot be estimated from the available data

• Anemia (hemolytic anemia)
• Severe allergic reactions, such as anaphylactic shock, anaphylactic reactions, anaphylactoid reactions, hypersensitivity
• Headache, dizziness
• Vomiting
• Skin reactions such as rash, abnormal skin redness, itching
• Joint pain
• Blood test results indicating impaired renal function (increased serum creatinine level) and/or acute renal failure
• Chills, fever, fatigue

Normally, preparations of normal human immunoglobulins can cause the following adverse reactions (in decreasing frequency):

• chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, joint pain, low blood pressure, and moderate back pain
• decrease in the number of red blood cells due to their destruction in the blood vessels (hemolytic reactions [reversible]) and (rarely) hemolytic anemia requiring blood transfusion
• (rarely) sudden drop in blood pressure and in isolated cases anaphylactic shock
• (rarely) transient skin reactions (including cutaneous lupus erythematosus, frequency not known)
• (very rarely) thromboembolic reactions such as heart attack (myocardial infarction), stroke, blood clots in the lungs (pulmonary embolism), blood clots in a vein (deep vein thrombosis)
• cases of acute transient inflammation of the protective membranes covering the brain and spinal cord (aseptic meningitis)
• cases of blood test results indicating renal dysfunction and/or sudden renal failure
• cases of transfusion-related acute lung injury (TRALI). This causes non-cardiogenic fluid accumulation in the lung airspaces (non-cardiogenic pulmonary edema). You would experience significant difficulty breathing (respiratory distress), rapid breathing (tachypnea), abnormally low oxygen levels in the blood (hypoxia), and increased body temperature (fever).

Reporting of Side Effects

If you experience any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly through the Spanish Pharmacovigilance System for Human Use Medicines: https://www.notificaram.es. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Megalotect

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.

Store in a refrigerator (between 2°C and 8°C). Store in the original packaging to protect from light.

Do not freeze.

The product should be inspected visually before use: the solution should be clear or slightly opalescent (with a milky appearance) and colorless or pale yellow. Do not use Megalotect if the solution is cloudy or sediment has formed.

The medicine should be used immediately after opening.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Container Content and Additional Information

Megalotect Composition

The active ingredient is human anti-cytomegalovirus immunoglobulin (CMVIG).

1 ml of the solution contains:

50 mg of human plasma proteins, of which at least 96% is immunoglobulin G (IgG), with an antibody content against cytomegalovirus (CMV) of 100 U*.

Each vial with 10 ml contains: 500 mg of human plasma proteins (of which at least 96% is immunoglobulin G), with an antibody content against CMV of 1,000 U*.

Each vial with 50 ml contains: 2,500 mg of human plasma proteins (of which at least 96% is immunoglobulin G), with an antibody content against CMV of 5,000 U*.

The distribution of IgG subclasses is approximately 65% IgG1, 30% IgG2, 3% IgG3, 2% IgG4.

The maximum content of immunoglobulin A (IgA) is 2,000 micrograms/ml.

• units of the Paul Ehrlich Institute reference preparation

The other components are glycine and water for injectable preparations.

Product Appearance and Container Content

Megalotect is a clear or slightly opalescent (with a milky appearance), colorless or slightly yellowish solution in vials made of colorless glass.

Megalotect is available in the following package sizes:

A box contains 1 vial with 10 ml (1,000 U) of solution for infusion

A box contains 1 vial with 50 ml (5,000 U) of solution for infusion

Only some package sizes may be marketed.

Marketing Authorization Holder and Manufacturer

Biotest Pharma GmbH

Landsteinerstraße 5

63303 Dreieich

Germany

Tel.: + 49 6103 801-0

Fax: + 49 6103 801-150

E-mail: [email protected]

For further information on this medicinal product, please contact the local representative of the marketing authorization holder:

Grifols Movaco, S.A.

Can Guasc, s/n – Parets del Vallès

08150 Barcelona

Spain

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

Croatia, Germany, Hungary: Cytotect CP Biotest

Austria: Cytotect CP Biotest 100 E/ml Infusionslösung

Italy: Cytomegatect

Spain: Megalotect 100 U/ml solution for infusion

Greece, Poland, Portugal: Megalotect CP

Belgium, Netherlands: Megalotect 100 E/ml

Slovenia: Megalotect 100 e./ml raztopina za infundiranje

Date of last revision of this leaflet:05/2023.

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This information is intended for healthcare professionals only:

Posology and method of administration

Administration should be started on the day of transplantation. If the transplant is bone marrow, prophylaxis can also be planned up to 10 days before the intervention, especially in CMV seropositive patients. At least a total of 6 doses should be administered at intervals of 2 to 3 weeks.

Method of administration

Intravenous route.

Megalotect is infused intravenously at an initial rate of 0.08 ml/kg body weight/h for 10 minutes. In case of an adverse reaction, the administration rate should be reduced or the infusion stopped. If well tolerated, the administration rate can be gradually increased up to a maximum of 0.8 ml/kg body weight/h for the remaining infusion time.

Warnings and precautions

The infusion rate may be related to certain serious drug reactions. The recommended infusion rate should be followed in detail. Patients will be closely monitored and carefully observed for any symptoms during the infusion period.

Some adverse reactions may occur more frequently

• in case of high infusion rate
• in patients receiving human immunoglobulin for the first time or, in rare cases, in those who have replaced the immunoglobulin product or cases where a long time has passed since the last infusion.

Often, possible complications can be avoided by ensuring that patients

• are not sensitive to human immunoglobulin. To do this, the product should be injected initially slowly (0.08 ml/kg body weight/hour).
• are carefully monitored during the infusion period to detect any symptoms. In particular, cases of patients not previously treated with human immunoglobulin, patients coming from other treatments with human intravenous immunoglobulin (IgIV) products or when a long time has passed since the last infusion, they should be monitored in the hospital during the first infusion and during the first hour after the first infusion to detect possible adverse effects. Other patients should be observed for at least 20 minutes after administration.

In case of an adverse reaction, the infusion rate should be reduced or the infusion stopped. The necessary treatment depends on the type of adverse reaction and the nature and severity of the reaction.

In case of shock, the usual medical treatment should be applied.

In all patients, treatment with immunoglobulin requires

• adequate hydration before starting immunoglobulin infusion,
• monitoring of diuresis,
• monitoring of serum creatinine levels,
• avoiding the simultaneous use of loop diuretics.

Hypersensitivity

Hypersensitivity reactions are rare. They may occur in patients with anti-IgA antibodies.

Anaphylaxis may develop in patients

• with undetectable IgA who have anti-IgA antibodies
• who have tolerated previous treatment with human immunoglobulin

In case of shock, the usual medical treatment should be applied.

Thromboembolism

There is clinical evidence of an association between the administration of intravenous immunoglobulin (IgIV) and thromboembolic events, such as myocardial infarction, stroke, pulmonary embolism, and deep vein thrombosis. These events are thought to be related to a relative increase in blood viscosity due to the high influx of immunoglobulin in at-risk patients. Caution should be exercised when prescribing and infusing immunoglobulins to obese patients and patients with pre-existing risk factors for thrombotic events (such as advanced age, hypertension, diabetes mellitus, and a history of vasculopathy or thrombotic events, patients with acquired or hereditary thrombophilic diseases, patients immobilized for prolonged periods, severely hypovolemic patients, patients with diseases that increase blood viscosity).

In patients at risk of suffering thromboembolic adverse reactions, IgIV products should be administered at the minimum infusion rate and minimum dose possible.

Acute Renal Insufficiency

Cases of acute renal insufficiency have been reported in patients treated with intravenous immunoglobulin (IgIV). In most cases, risk factors have been identified, such as pre-existing renal insufficiency, diabetes mellitus, hypovolemia, overweight, concomitant administration of nephrotoxic drugs, or age over 65.

Before IgIV infusion, renal parameters should be evaluated, especially in patients considered to be at higher risk of developing acute renal insufficiency, and again at adequate intervals. In patients at risk of acute renal insufficiency, IgIV products should be administered at the minimum infusion rate and viable dose.

In case of renal insufficiency, consideration should be given to interrupting the administration of the immunoglobulin product.

Although reports of renal dysfunction and acute renal insufficiency have been associated with the use of many authorized IgIV drugs containing different excipients such as sucrose, glucose, and maltose, those containing sucrose as a stabilizer represented a disproportionate part of the total number of cases. In at-risk patients, consideration should be given to using immunoglobulin products that do not contain these excipients. Megalotect does not contain sucrose, glucose, or maltose.

Aseptic Meningitis Syndrome (AMS)

It has been reported that AMS occurs in relation to treatment with intravenous immunoglobulins (IgIV products). The syndrome usually begins several hours to 2 days after the start of IgIV treatment. Often, cerebrospinal fluid analyses are positive with pleocytosis of up to several thousand cells per mm3, predominantly of the granulocytic series, and elevated protein concentrations of up to several hundred mg/dl. AMS occurs more frequently in association with high-dose IgIV treatment (2 g/kg)

Patients showing these signs and symptoms should undergo a thorough neurological examination, including cerebrospinal fluid (CSF) studies, to rule out other causes of meningitis.

Discontinuation of IgIV treatment has resulted in the remission of AMS within several days without sequelae.

Hemolytic Anemia

Intravenous immunoglobulins (IgIV products) may contain antibodies to blood groups that act as hemolysins and induce the in vivo coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin test (direct Coombs test) and, exceptionally, hemolysis. Hemolytic anemia may develop as a consequence of IgIV treatment and be potentiated by erythrocyte sequestration. Patients treated with IgIV should be monitored for clinical signs and symptoms of hemolysis.

Neutropenia/Leukopenia

A transient decrease in neutrophil count and/or episodes of neutropenia, sometimes severe, have been reported after IgIV treatment. This usually occurs in the hours or days following IgIV administration and resolves spontaneously within 7 to 14 days.

Transfusion-Related Acute Lung Injury (TRALI)

Non-cardiogenic acute lung injury (transfusion-related acute lung injury, TRALI) has been reported in patients who have received IgIV. TRALI is characterized by severe hypoxia, dyspnea, tachypnea, cyanosis, fever, and hypotension. Symptoms of TRALI usually develop during or within 6 hours after infusion, often within the first 1-2 hours. Therefore, IgIV recipients should be monitored and IgIV infusion should be interrupted immediately in case of pulmonary adverse reactions. TRALI is a potentially fatal disease that should be treated immediately in the intensive care unit.

Interference with serological tests

After administration of immunoglobulin, the transient increase in passively transferred antibodies to the patient's blood may cause false-positive results in serological tests.

The passive transfer of antibodies to erythrocyte antigens, e.g., A, B, and D, may interfere with some serological tests for erythrocyte antibodies, e.g., the direct antiglobulin test (DAT, direct Coombs test).

Incompatibilities and special precautions for handling

This medicinal product must not be mixed with other medicinal products or IgIV products.

The medicinal product should be used immediately after opening.

This medicinal product should be at room or body temperature before use.

Products should be inspected visually before administration. The solution should be clear or slightly opalescent and colorless or pale yellow. Do not use a solution that is turbid or has deposits.