Plasmasafe

Package leaflet: Information for the user

PLASMASAFE infusion solution

Human plasma, frozen
AB0 group specific
solvent-detergent treated
Please read all of this leaflet carefully before you start using this medicine because it contains
important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or nurse.
• If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of this leaflet:

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

1. What PLASMASAFE is and what it is used for

PLASMASAFE is a frozen, blood group-specific human plasma solution containing all the normal
plasma components such as albumin, immunoglobulins and other globulins, coagulation factors,
complement factors and their inhibitors. The content and distribution of plasma proteins in
PLASMASAFE are comparable to those of fresh frozen plasma (FFP), i.e. 45–70 mg/ml.
PLASMASAFE shows coagulation activity levels close to those of normal human FFP, with each
coagulation factor present at a minimum concentration of 0.5 IU/ml.
Furthermore, as a result of the solvent-detergent (SD) treatment and purification process, the lipid
and lipoprotein content is reduced. This does not affect the indications for PLASMASAFE.
PLASMASAFE has the same indications as FFP and is used in the following therapies:

• Combined deficiencies of coagulation factors, as seen in consumption coagulopathies (disorders of the blood coagulation mechanism), such as disseminated intravascular coagulation (DIC, an acquired thrombo-hemorrhagic syndrome), or coagulopathies due to severe liver failure or massive transfusions;

• Replacement therapy in coagulation factor deficiencies, in emergency situations when a specific coagulation factor concentrate (e.g. factor V or factor XI) is not available, or when specific laboratory diagnosis is not possible;

• Reversal of fibrinolytic activity (breakdown of fibrin clots which may cause bleeding) and rapid reversal of the effect of oral anticoagulants (such as coumarin or
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  indanedione derivatives) when vitamin K action is insufficient due to impaired liver function or in emergency situations;

• Thrombotic Thrombocytopenic Purpura (TTP, a severe acute blood disorder), usually in association with plasmapheresis (a therapeutic procedure allowing separation of the liquid component of blood, i.e. plasma, from the cellular components, and removal of harmful substances from the plasma);

• In intensive plasmapheresis procedures, PLASMASAFE should be used exclusively to correct coagulation abnormalities during severe bleeding.

2. What you should know before using PLASMASAFE

Do not use PLASMASAFE
if you are allergic (hypersensitive) to plasma proteins or to any of the other components
of this medicine (listed in section 6);
if you know you have antibodies against IgA immunoglobulins (IgA deficiency with documented
presence of anti-IgA antibodies);
if you know you have low levels of protein S (a vitamin K-dependent protein in the blood);
if you have previously experienced reactions to human plasma products or fresh frozen plasma.

Warnings and precautions
Talk to your doctor or nurse before using PLASMASAFE.
Exercise particular caution with PLASMASAFE if:

• you have low blood levels of immunoglobulin A;
• you have previously had allergic reactions to plasma proteins, including fresh frozen plasma;
• you suffer from heart failure or pulmonary edema (fluid in the lungs);
• you have an increased risk of thrombotic complications (blood clots), due to a potential increased risk of venous thromboembolism (partial or complete blockage of a vein by a blood clot).

PLASMASAFE must not be used:

• as a plasma expander in patients where no deficiency of coagulation factors has been documented;
• in bleeding caused by von Willebrand disease (vWD, a genetic disorder characterized by spontaneous bleeding) or other coagulation deficiencies when specific factor concentrates are available;
• to correct hyperfibrinolysis (massive uncontrolled dissolution of fibrin clots that may cause bleeding) due to plasmin inhibitor (alpha2 antiplasmin) deficiency, since dilution with treated SD plasma, which contains low levels of alpha2 antiplasmin, might reduce alpha2 antiplasmin levels.

Your doctor or another healthcare professional will closely monitor and observe you throughout the entire infusion period with PLASMASAFE to ensure no reactions occur.
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As with any intravenous protein product, allergic-type hypersensitivity reactions may occur.
Occasionally, symptoms such as fever, skin manifestations (rash, erythematous rash, and urticaria), chills/cold sensation with or without fever, nausea with or without vomiting, local edema (swelling), and allergic or anaphylactic reactions (severe and rapid allergic reaction) may occur.
If you notice any of the listed symptoms during administration of the product, you must inform the doctor or healthcare professional immediately, as these symptoms may be the first signs of an allergic reaction.
In case of adverse reactions, the doctor will decide whether the infusion rate should be reduced or the infusion stopped, depending on the type and severity of the adverse events.
In case of shock, standard medical treatment for shock must be initiated.

Children
The safety and efficacy of PLASMASAFE in children have not yet been established.
Available data on the use of PLASMASAFE in premature newborns are very limited; therefore, the product should be administered only if the benefits clearly outweigh the potential risks.

Viral safety of PLASMASAFE
Medicines prepared from human blood or plasma are subject to a number of safety measures to prevent transmission of infections to patients. These measures include:

• careful selection of blood and plasma donors to ensure potentially infected donors are excluded;
• testing of each donation and plasma pool for the presence of viruses;
• inclusion of manufacturing steps capable of inactivating or removing viruses. Despite these measures, when administering medicines prepared from human blood or plasma, the possibility of transmitting infection cannot be completely ruled out. This also applies to emerging or unknown viruses or other infectious agents. The measures adopted are considered effective against lipid-enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), and against the non-lipid-enveloped hepatitis A virus (HAV). The measures adopted may have limited effectiveness against non-lipid-enveloped viruses such as parvovirus B19. Parvovirus B19 infection may be severe in pregnant women (fetal infection) and in individuals with a weakened immune system or certain types of anemia (e.g., sickle cell anemia or hemolytic anemia).

It is strongly recommended that each time you receive a dose of PLASMASAFE, the name and batch number of the product be recorded, in order to maintain traceability between the patient and the batch of product used.
Your doctor may recommend vaccination against hepatitis A and B if you receive medicines derived from human blood or plasma regularly or repeatedly.
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Other medicines and PLASMASAFE
Inform your doctor or nurse if you are taking, have recently taken, or might take any other medicines.
During clinical studies, the human plasma protein solution, having the same pharmaceutical form and qualitative-quantitative composition as PLASMASAFE, was administered concomitantly with various medications and no interactions were identified.
PLASMASAFE must not be mixed with other drugs due to the possibility of inactivation or precipitation.
The product may be mixed with red blood cells and platelets.
To avoid clot formation, solutions containing calcium must not be administered through the same infusion line.
No interactions with other medicines are known.

PLASMASAFE with food, drinks, and alcohol
No effects have been observed.

Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, planning to become pregnant, or are breastfeeding, consult your doctor or pharmacist before using this medicine.
The safety of using PLASMASAFE during pregnancy has not been established in controlled clinical studies. Therefore, the product should be administered during pregnancy or breastfeeding only if clearly indicated.
Due to the potential risk of transmission of parvovirus B19, please refer to the section "Warnings and precautions".

Driving and using machines
After an outpatient infusion with PLASMASAFE, the patient should rest for one hour.
PLASMASAFE does not affect, or affects negligibly, the ability to drive vehicles or operate machinery.

PLASMASAFE contains sodium
This medicine contains up to a maximum of 0.92 g of sodium (main component of table salt) per 200 ml bag.
This corresponds to 46% of the maximum recommended daily dietary intake for an adult.

3. How to use PLASMASAFE

PLASMASAFE may only be used in hospitals or clinics by medical professionals or other healthcare providers.

• Administration of PLASMASAFE must be based on ABO blood group compatibility.
• In emergency situations, AB group PLASMASAFE may be considered as universal plasma, as it can be administered to any patient.

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For instructions on correct use and dosage, refer to the section “The following information is intended exclusively for doctors or healthcare professionals”.
Treatment must be initiated under the supervision of a physician.
The dose and treatment regimen depend on the individual clinical condition and underlying diseases, but 12–15 ml of PLASMASAFE/kg body weight generally represents an accepted initial dose (corresponding to an increase of approximately 25% in the levels of the deficient coagulation factor).
Your doctor will determine the appropriate dose and treatment regimen for you.

Use in children
The dosage in children and adolescents (0–18 years) is not different from that in adults, as the dosage for each indication is based on body weight and adjusted according to the individual's clinical response.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Adverse reactions known to be associated with Fresh Frozen Plasma (FFP) administration may also occur with PLASMASAFE and include:

Common:

• allergic reactions ranging from acute to mild (e.g., urticaria, fever, chills, nausea, vomiting, abdominal or back pain) due to hypersensitivity to the infused proteins.

Uncommon:

• citrate toxicity manifested by the following symptoms: fatigue, paresthesia (altered sensitivity of limbs or other body parts), tremors, and hypocalcemia (reduced blood calcium levels) during plasma exchange procedures.

Rare:

• immediate or delayed transfusion-related hemolytic reactions due to incompatibility between antibodies present in FFP and erythrocyte antigens of the recipient (therefore, administration of PLASMASAFE must be based on AB0 blood group compatibility);
• acute lung injury (a syndrome known as transfusion-related acute lung injury, TRALI), characterized by chills, fever, non-productive cough, and dyspnea (difficulty breathing), caused by high-activity anti-leukocyte antibodies;
• post-transfusion purpura (PTP), induced by high-activity specific anti-platelet antibodies, characterized by dyspnea (difficulty breathing), skin rash, fever, generalized purpura (a severe acute blood disorder), and marked thrombocytopenia (platelet count below normal);
• allergic reactions ranging from acute to severe, such as anaphylactic or anaphylactoid reactions, characterized for example by skin redness, hypotension, substernal pain, bronchospasm, dyspnea (difficulty breathing), and cardiorespiratory collapse, due to hypersensitivity to infused proteins or anti-IgA antibodies.

Since PLASMASAFE does not contain whole cells (red blood cells, white blood cells, and platelets), the risk of immunization is reduced.
Infusion of PLASMASAFE may lead to the formation of antibodies against coagulation factors.
High infusion rates may cause cardiovascular effects as a result of citrate toxicity (decrease in ionized calcium plasma levels), especially in patients with impaired liver function.

The following data are based on adverse reactions observed in clinical studies conducted in a population of 199 patients treated with human plasma proteins having the same pharmaceutical form and qualitative and quantitative composition as PLASMASAFE:

Common:

• skin manifestations (rash, erythematous rash, and urticaria)
• chills with or without fever
• fever
• local edema (localized swelling)
• nausea with or without vomiting

Uncommon:

• pruritus
• pulmonary manifestations (cough, asthma, and polypnea)
• hypocalcemia (reduced blood calcium levels)
• anaphylactoid reactions (severe and rapid allergic reaction)

Additional side effects in children
Specific data for the pediatric population are not available.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, please inform your doctor or nurse. You can also report side effects directly via
https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store PLASMASAFE

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label and on the carton.
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The expiry date refers to the last day of that month.
The product must be stored at a temperature not exceeding -18°C and protected from light.
The product must be used within 4 hours after thawing if kept at 20°C÷25°C, or within 8 hours if kept at 4°C.
See the expiry date printed on the packaging.
The expiry date refers to the product in its original, undamaged packaging and properly stored.
After opening the bag, the product must be used immediately.
Do not dispose of any medicine via wastewater or household waste.
Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

6. Package contents and other information

What PLASMASAFE contains
In a 200 ml bag, the active substance consists of human plasma proteins 9 - 14 g
The other components are: disodium citrate dihydrate, sodium dihydrogen phosphate, glycine.

Description of the appearance of PLASMASAFE and package contents
Solution for exclusive intravenous use.
The PLASMASAFE package consists of a 200 ml bag.

Marketing Authorization Holder
Kedrion S.p.A. - Loc. Ai Conti, 55051 Castelvecchio Pascoli, Barga (Lucca).

Manufacturer
Kedrion S.p.A. - S.S. 7 bis Km 19.5, S. Antimo (Naples).

The following information is intended exclusively for physicians or healthcare professionals:

Warnings and Precautions
Administration of PLASMASAFE must be based on ABO group compatibility. In emergency situations, AB group PLASMASAFE may be considered as universal plasma, as it can be administered to any patient.

PLASMASAFE must be used with caution in the following conditions:

• IgA deficiency;

• Latent or manifest cardiac failure;

• Pulmonary edema;

• In patients at increased risk of thrombotic complications due to a potential increase in the risk of venous thromboembolism resulting from reduced protein S activity in PLASMASAFE compared to single-donor fresh frozen plasma;

• In patients who may require massive transfusion, such as in liver transplantation or other conditions with complex coagulation disorders, particular attention should be paid to symptoms indicating a tendency toward excessive bleeding.

PLASMASAFE must not be used:

• As a plasma expander in patients in whom no deficiency of coagulation factors has been documented;
• In bleeding caused by von Willebrand disease or other coagulation deficiencies when specific factor concentrates are available;
• To correct hyperfibrinolysis due to alpha2-antiplasmin deficiency, as dilution with SD-treated plasma may reduce alpha2-antiplasmin levels.

Patients must be monitored for at least 20 minutes after administration.

Dosage
It is important to monitor the response both clinically and through measurements of:

• Prothrombin time (PT),
• Partial thromboplastin time (PTT),
• and/or assay of specific coagulation factors.

Dosage for coagulation factor deficiency:
An adequate hemostatic effect in mild to moderate bleeding or minor surgery in patients with coagulation factor deficiency is normally achieved after infusion of 5–20 ml of PLASMASAFE/kg body weight (resulting in a 10–33% increase in the level of the deficient coagulation factor).
In cases of severe bleeding or major surgery, consultation with a specialist hematologist is required.

Dosage for TTP and bleeding during intensive plasmapheresis procedures:
In patients with TTP, the entire plasma volume should be replaced with PLASMASAFE.
In cases of severe bleeding during intensive plasmapheresis procedures, consultation with a specialist hematologist is required.

Pediatric population
The dosage in children and adolescents (0–18 years) is not different from that in adults, as the dosage for each indication is based on body weight and adjusted according to the clinical outcome of the respective conditions.

Method of administration
PLASMASAFE must be administered by intravenous infusion after thawing, as described in the following section “Instructions for correct use”, using an infusion set with a filter. Aseptic technique must be maintained throughout the infusion.

Due to the risk of citrate toxicity, the infusion rate must not exceed 0.020–0.025 mmol of citrate/kg body weight/minute.
Citrate-related toxic effects can be minimized by administering calcium gluconate through a separate intravenous line.

Instructions for correct use

• Thaw the product by placing the bag in a water bath with good circulation at a temperature between 35°C and 37°C. Care must be taken to ensure that water does not contaminate the opening site of the bag.
• The water bath temperature must never exceed 37°C and must never fall below 35°C. Allow the contents of the bag to reach approximately 37°C before infusion.
• The temperature of PLASMASAFE must not exceed 37°C.
• Thawing should not take longer than 30 minutes.
• Remove the outer wrapper and check that the bag shows no leaks or damage.
• Do not shake.
• Do not use cloudy solutions or those containing deposits.

Thawed product must not be refrozen. Unused product must be discarded.

If more PLASMASAFE is administered than intended
High doses or infusion rates may cause hypervolemia, pulmonary edema, and/or cardiac failure.
High infusion rates may cause cardiovascular effects as a result of citrate toxicity (decrease in plasma ionized calcium levels), especially in patients with impaired liver function.

Emergency measures for adverse reactions
Depending on the type and severity of adverse reactions, the infusion may be stopped and appropriate resuscitation measures applied, as defined by general guidelines for shock therapy:

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Following the instructions in the package leaflet reduces the risk of adverse effects.
Disposal
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
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