Keyvenb: detailed information

Package leaflet: Information for the user

KEYVENB 50 IU/ml Powder and solvent for solution for infusion

Human hepatitis B immunoglobulin for intravenous use
Please read 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 questions, ask your doctor, pharmacist or nurse.
If you get any side effects, including those not listed in this leaflet, tell your doctor, pharmacist or nurse. See section 4.

Contents of this leaflet:

What KEYVENB is and what it is used for
What you need to know before using KEYVENB
How to use KEYVENB
Possible side effects
How to store KEYVENB
Contents of the pack and other information

1. What KEYVENB is and what it is used for

This medicinal product belongs to a pharmacotherapeutic group called immune sera and immunoglobulins.
KEYVENB is a solution of human immunoglobulins (proteins that function as antibodies) against hepatitis B for intravenous use, and is used in the following treatments:
To prevent recurrence of hepatitis B after liver transplantation due to liver failure caused by the hepatitis B virus, in combination with antiviral therapy.
To provide rapid availability of antibodies against the hepatitis B virus in order to prevent hepatitis B in the following cases:

following accidental exposure in non-immunized individuals (i.e., in people who have not been vaccinated against the hepatitis B virus; including those who have not completed the full vaccination course or whose vaccination status is unknown);
in patients undergoing haemodialysis (i.e., patients with severe renal failure requiring blood purification through an artificial kidney), until vaccination becomes effective;
in newborns born to mothers who are carriers of the hepatitis B virus;
in individuals who have not shown an immune response after vaccination (i.e., in people for whom vaccination has not been effective) and who require ongoing prevention due to persistent risk of contracting hepatitis B.

2. What you need to know before using KEYVENB

Do not use KEYVENB

If you are allergic to human immunoglobulins or to any of the other ingredients of this medicine (listed in section 6).
If you have antibodies in your blood directed against IgA-type immunoglobulins, as administration of a product containing IgA may cause a severe allergic reaction.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using KEYVENB.
Blockage of a blood vessel (thrombosis) has been associated with the administration of normal human immunoglobulins for intravenous use (IVIg). Therefore, your doctor must exercise particular caution when administering this medicine if you have risk factors for thrombosis.
The levels of anti-HBs antibodies in your blood should be monitored regularly.
Adverse reactions may occur more frequently:

if the infusion rate is high;
if you have uncontrolled symptoms of untreated infections (e.g. fever) or symptoms of chronic inflammation;
if you are receiving human immunoglobulins for the first time;
in rare cases when switching between different types of normal human immunoglobulin medicinal products, or after a long interval since the previous infusion.
- In certain conditions, immunoglobulins may increase the risk of myocardial infarction, stroke, pulmonary embolism, or deep vein thrombosis because they increase blood viscosity. Therefore, your doctor will pay particular attention in the following circumstances:
if you are overweight,
if you are elderly,
if you have diabetes,
if you have high blood pressure (hypertension),
if your blood volume is too low (hypovolemia),
if you have or have had blood vessel problems (vascular diseases),
if you have an increased tendency for blood to clot (inherited or acquired thrombophilic disorders),
if you have experienced thrombotic episodes,
if you suffer from diseases that increase blood density (viscosity),
if you have had prolonged periods of immobility,
if you have or have had kidney problems or are taking medicines that may damage the kidneys (nephrotoxic medicines), as cases of acute kidney failure have been reported. If kidney damage occurs, your doctor may consider stopping treatment.
- You may be allergic (hypersensitive) to immunoglobulins (antibodies) without knowing it. This may occur even if you have previously received normal human immunoglobulins and tolerated prior administrations. This possibility is particularly relevant if you lack IgA-type immunoglobulins (IgA deficiency with anti-IgA antibodies). In these rare cases, allergic (hypersensitivity) reactions such as a drop in blood pressure or shock may occur.

The recommended infusion rate described in section 3 "How to use KEYVENB" must be strictly followed
by the doctor; this is strongly recommended because some serious adverse reactions to the medicine may be related to the infusion rate. Additionally, you must be closely monitored and carefully observed throughout the entire infusion period for the appearance of any symptoms.
If adverse reactions occur, your doctor may decide whether to reduce the infusion rate or stop the infusion. Furthermore, your doctor will determine the type of treatment required depending on the nature and severity of the adverse effect.
KEYVENB contains small amounts of IgA. If you have IgA deficiency, you may be at risk of developing anti-IgA antibodies and may develop anaphylactic reactions after administration of blood components containing IgA. Your doctor must evaluate the benefit of treatment with KEYVENB against the potential risk of hypersensitivity reactions.
Human anti-hepatitis B immunoglobulins may rarely cause a drop in blood pressure with anaphylactic reaction, even if you have previously tolerated treatments with immunoglobulins.
If you suffer from kidney failure, your doctor should consider discontinuing treatment with IVIg.
Although cases of kidney dysfunction and acute kidney failure have been associated with the use of many authorized IVIg products containing various excipients such as sucrose, glucose, and maltose, those containing sucrose as a stabilizer represent a very high proportion of the total number. In patients at risk of acute kidney failure or thromboembolic adverse reactions, IVIg products should be administered at the lowest feasible infusion rate and dose.
With immunoglobulin treatments, you may experience treatment-related lung injury, known as transfusion-related acute lung injury (TRALI). If you experience shortness of breath or rapid breathing during or in the hours following the infusion, inform your doctor or nurse immediately, as emergency treatment may be required.
Suspicion of allergic or anaphylactic reactions requires immediate discontinuation of the infusion. In case of shock, standard medical treatment for shock must be followed.
Inform your doctor if any of the above conditions apply to you. Your doctor will pay particular attention when prescribing and administering KEYVENB to you.
Intravenous human immunoglobulin (IVIg) products may contain blood group-specific antibodies that may rarely cause destruction of red blood cells (hemolysis). For this reason, following IVIg therapy, you may develop a form of anemia due to abnormal breakdown of red blood cells (hemolytic anemia). Therefore, during IVIg treatment, you will be monitored for clinical signs and symptoms of hemolysis.

Blood tests
KEYVENB may interfere with certain blood tests due to the temporary increase in various antibodies passively transferred into your bloodstream through the immunoglobulin infusion; this increase in antibodies may lead to blood test results that may not be accurate. Passive transfer of antibodies against erythrocyte antigens, e.g., A, B, D (determining blood group), may interfere with certain serological tests for red blood cell antibodies, for example, the direct antiglobulin test (Coombs test).

Viral safety
When medicines are prepared from human blood or plasma, certain measures are taken 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 to confirm the absence of infectious agents and/or viruses;
inclusion during manufacturing processes of steps capable of inactivating or removing viruses. Despite these measures, when administering medicines prepared from human blood or plasma, the possibility of transmitting infectious agents cannot be completely excluded. This also applies to emerging or unknown viruses or other types of 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 the non-lipid-enveloped hepatitis A virus (HAV).

The measures taken may have limited effectiveness against non-lipid-enveloped viruses such as parvovirus B19.
Immunoglobulins have not been associated with hepatitis A or parvovirus B19 infections, probably because the antibodies against these infections contained in the product have protective properties.
It is strongly recommended that each time you are administered KEYVENB, the name and batch number of the product are recorded to ensure traceability of the batch used.

Children
No specific measures or monitoring are required.

Other medicines and KEYVENB
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
Human anti-hepatitis B immunoglobulins for intravenous use must not be mixed with other medicinal products.

Live attenuated virus vaccines
KEYVENB may interfere with the development of an immune response to live attenuated virus vaccines, such as those for rubella, mumps, measles, and varicella. Administration of immunoglobulins may alter the effectiveness of these vaccines for a period lasting up to 3 months. At least three months must elapse after administration of KEYVENB before vaccination with live attenuated virus vaccines.
Human anti-hepatitis B immunoglobulins should be administered three or four weeks after vaccination with live attenuated virus vaccines; if administration of human anti-hepatitis B immunoglobulins is required within three or four weeks after vaccination, revaccination should be performed three months after administration of the human anti-hepatitis B immunoglobulins.

Loop diuretics (a group of medicines that increase urine production)
Concomitant use of loop diuretics together with KEYVENB should be avoided.

Pregnancy, breastfeeding, and fertility

If you are pregnant, suspect you may be pregnant, planning to become pregnant, or breastfeeding, consult your doctor or pharmacist before using this medicine. Your doctor will decide whether it is appropriate to use KEYVENB during pregnancy and breastfeeding.
Clinical studies with KEYVENB in pregnant women have not been conducted. It has been shown that intravenous human immunoglobulin products cross the placenta increasingly during the third trimester. However, medicines containing antibodies have been used for years in pregnant women and have been shown not to be expected to cause harmful effects on the course of pregnancy, the fetus, or the newborn.
If you are breastfeeding and receiving treatment with KEYVENB, the antibodies contained in the product may pass into breast milk. Therefore, your baby may be protected from certain infections.
Clinical experience with immunoglobulins suggests that harmful effects on fertility are not expected.

KEYVENB contains sodium and sucrose.
This medicine contains up to a maximum of 39 mg of sodium (a main component of table salt) per 10 ml vial and 175.5 mg of sodium per 45 ml vial. The amounts stated correspond to 1.9% and 8.7%, respectively, of the maximum daily dietary intake recommended for an adult.
The medicine contains up to 92 mg of sucrose per ml (91.9 mg/ml). This should be taken into consideration in patients at risk of acute kidney failure.

3. How to use KEYVENB

KEYVENB can only be administered in hospitals or clinics and healthcare facilities by physicians or
healthcare professionals.
The dosage and treatment schedule depend on the indication; your doctor will determine the appropriate dose and
treatment regimen for you.
At the beginning of the infusion, you will receive KEYVENB at the minimum infusion rate. If you tolerate the
infusion rate well, your doctor may gradually increase the infusion speed.
For further instructions, refer to the section “ The following information is intended exclusively for
physicians or healthcare professionals ”.
If you use more KEYVENB than you should
The consequences of overdose are unknown.
If you are administered more KEYVENB than intended, protein overload in body fluids may occur, and the blood may become too thick (hyperviscous); this is particularly observed in patients at risk, especially elderly patients or those with impaired cardiac or renal function.
If you have any further questions about the use of this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody will experience them.
If you notice any of the following side effects, consult your doctor immediately or contact the nearest
hospital:

Allergic reactions (hypersensitivity). In some cases, this side effect may progress to an acute allergic reaction (anaphylactic shock): for example, itching, skin reactions, swelling of the lips, face and tongue, difficulty swallowing, breathing difficulties, fainting.
Acute kidney failure (e.g. decreased or absent urine flow, fluid retention, shortness of breath).

The following side effects have generally been reported after treatment with
intravenous immunoglobulins:

bradycardia (slow heart rate), feeling of warmth, syncope (fainting), bronchospasm (narrowing of the airways), cough, tachypnea (rapid breathing), hyperhidrosis (excessive sweating), tachycardia (fast heart rate), chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia (joint pain), hypotension (low blood pressure), moderate lower back pain and generalized musculoskeletal pain have been reported occasionally;
isolated cases of temporary reduction in red blood cells (reversible haemolytic anaemia/haemolysis), especially in patients with blood groups A, B and AB, and (rarely) haemolytic anaemia requiring transfusion;
a sudden drop in blood pressure has been reported rarely and, in some isolated cases, hypersensitivity reactions (anaphylactic shock) may occur, even when the patient has not previously shown reactions to earlier administrations;
rare cases of transient skin reactions have been observed;
very rare reports of thromboembolic reactions (blood clot formation), which may lead to myocardial infarction, stroke, blockage of the pulmonary arteries (pulmonary embolism) and deep vein thrombosis;
cases of transient non-infectious meningitis (reversible aseptic meningitis);
cases of increased blood creatinine levels and/or acute kidney failure;
cases of transfusion-related acute lung injury (TRALI).

The following side effects have been reported following administration of KEYVENB
after the medicine was placed on the market (frequency cannot be estimated from the available data):

Hypersensitivity
Anaphylactic shock
Nausea
Vomiting
Fever
Malaise
Chills
Dyspnea
Chest discomfort or pain

For information regarding safety with respect to transmissible agents, see section 2 "What you need to know before using KEYVENB."
Additional side effects in children
Specific data in the paediatric population are not available.
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist or nurse. You may 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 KEYVENB

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 outer packaging.
The expiry date refers to the last day of that month.
Do not store above 25°C.
Store in the outer packaging to protect the medicine from light.
Do not freeze.
KEYVENB must be used immediately after reconstitution with the solvent.
Do not use this medicine if you notice that the solution is cloudy or contains deposits or shows any change in colour (see also “Description of the appearance of KEYVENB and contents of the pack” in section 6).
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Contents of the pack and other information

What KEYVENB contains
The active substance is human hepatitis B immunoglobulin.

	KEYVENB 500 IU	KEYVENB 2500 IU
Human proteins	50 g/l	50 g/l
consisting of human immunoglobulins of at least	95%	95%
Antibodies against HBs antigen (anti-HBs) in an amount not less than	500 IU/vial	2500 IU/vial
Antibodies against HBs antigen (anti-HBs) after reconstitution with solvent in an amount not less than	50 IU/ml	50 IU/ml

The IgG (immunoglobulin G) subclasses have the following distribution:
IgG 26.0 - 40.0 mg/ml
IgG 13.0 - 25.0 mg/ml
IgG 1.20 - 2.50 mg/ml
IgG 0.15 - 0.50 mg/ml
The maximum IgA content is 0.05 mg/ml.
Produced from plasma of human donors.
Other components are sucrose, sodium chloride, and water for injections.
The vial of powder contains human anti-hepatitis B immunoglobulins, sucrose, and sodium chloride.
The solvent vial contains sodium chloride and water for injections.
Description of the appearance of KEYVENB and contents of the pack
The KEYVENB pack contains one vial of powder and one vial of solvent used to prepare the solution for administration.
The powder is white or slightly yellow, or appears as a friable solid mass.
After reconstitution, the product is a transparent or slightly opalescent liquid, colorless or slightly yellow.
Before administration, reconstituted products must be visually inspected for the presence of suspended particles or abnormal discoloration. Do not use cloudy solutions or those containing deposits.
KEYVENB 50 UI/ml powder and solvent for solution for infusion
Vial of 500 UI powder + 10 ml solvent vial + infusion set (1 syringe with needle + 1 administration needle).
Vial of 2500 UI powder + 45 ml solvent vial + infusion set.
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).
This summary of product characteristics was last approved on

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

Instructions for Proper Use
Before use, bring the product to room or body temperature.
Complete reconstitution must be achieved within 30 minutes.
KEYVENB must be administered by intravenous infusion at an initial rate of 0.46–0.92 mL/kg/h (e.g., for a 65 kg patient, at a rate of 10–20 drops per minute) for 20–30 minutes. If an adverse reaction occurs, reduce the infusion rate or interrupt the infusion. If well tolerated, the infusion rate may be gradually increased up to a maximum of 1.85 mL/kg/h (e.g., for a 65 kg patient, at a rate of 40 drops per minute) for the remainder of the infusion.

Reconstitution of Solution, 500 IU Vial:

Draw the solvent into the injection syringe;
Inject the solvent with the same syringe into the vial containing the powder;
Gently shake the vial until the powder is completely dissolved;
Do not shake vigorously; foam formation must be avoided;
Aspirate the resulting solution with the syringe;
Replace the needle and administer to the patient.

Reconstitution of Solution, 2500 IU Vial:

Remove the protective caps from the powder and solvent vials;
Clean the stopper surfaces of both vials with alcohol;
Insert the smaller needle of the double-ended needle into the solvent vial;
Remove the needle cap from the other end of the double-ended needle, taking care not to touch the second needle;
Invert the solvent vial with the double-ended needle and insert the second needle into the powder vial; at the moment of piercing the powder vial stopper, the needle tip in the solvent vial must be in contact with the liquid, not with air;
Gently shake the vial at room temperature until the powder is completely dissolved;
Do not shake vigorously: foam formation must be avoided;
Remove the solvent vial with the double-ended needle;
Attach the infusion set and administer intravenously.

Reconstituted products must be visually inspected for particulate matter and discoloration prior to administration.
After reconstitution, the product is a clear or slightly opalescent, colorless or pale yellow liquid.
Turbid solutions or those with deposits must not be used.
KEYVENB must be used immediately after reconstitution with the solvent.
Unused medicine and waste materials derived from this medicine must be disposed of in accordance with local regulations.

Special Precautions
Some serious adverse reactions to the product may be related to the infusion rate.
Potential complications can often be avoided by ensuring:

that patients are not sensitive to normal human immunoglobulin by initially administering the product slowly (with an infusion rate between 0.46 and 0.92 mL/kg/h);
that patients are closely monitored for any symptoms throughout the entire infusion period. In particular, patients receiving normal human immunoglobulin for the first time, patients switching from another IVIg product, or patients with a long interval since their last infusion should be monitored during the first infusion and for the first hour after the first infusion to detect potential signs of adverse reactions. All other patients should be observed for at least 20 minutes after administration.

In all patients, IVIg administration requires:

adequate hydration before starting IVIg infusion;
monitoring of urinary output;
monitoring of serum creatinine levels;
avoidance of concomitant use of loop diuretics. If an adverse reaction occurs, the infusion rate must be reduced or the infusion interrupted. Required treatment depends on the nature and severity of the adverse effect. In case of shock, standard medical treatment for shock must be initiated.

Infusion Reaction
Some adverse reactions (e.g., headache, flushing, chills, myalgia, wheezing, tachycardia, back pain, nausea, and hypotension) may be related to the infusion rate. The recommended infusion rate must be carefully followed. Patients must be closely monitored and carefully observed for any symptoms throughout the entire infusion period.
Adverse reactions may occur more frequently:

with high infusion rates;
in patients with hypo- or agammaglobulinemia, with or without IgA deficiency.

Hypersensitivity
True hypersensitivity reactions are rare.
KEYVENB contains small amounts of IgA. Individuals with IgA deficiency may potentially develop antibodies against IgA and may experience anaphylactic reactions after administration of blood components containing IgA. Therefore, the physician must evaluate the benefit of treatment with KEYVENB against the potential risk of hypersensitivity reactions.
Rarely, anti-hepatitis B human immunoglobulins may induce a drop in blood pressure with anaphylactic reaction, even in patients who have previously tolerated immunoglobulin treatments.
Patients must be informed about the early signs of hypersensitivity reactions, such as urticaria, generalized hives, chest tightness, wheezing, hypotension, and anaphylaxis. The required treatment depends on the nature and severity of the adverse reaction.
Suspected allergic or anaphylactic reactions require immediate interruption of the infusion. In case of shock, standard medical treatment for shock must be followed.

Interference with Serological Tests
After immunoglobulin administration, the transient increase in various passively transferred antibodies in the patient's blood may lead to false-positive results in serological tests.
Passive transfer of antibodies against erythrocyte antigens, e.g., A, B, D, may interfere with certain serological tests for red blood cell antibodies, such as the antiglobulin test (Coombs test).

Transmissible Agents
Standard measures to prevent infections from medicinal products derived from human blood or plasma include donor selection, screening of individual donations and plasma pools for specific infection markers, and inclusion of manufacturing steps effective for virus inactivation/removal.
Nevertheless, when administering medicinal products derived from human blood or plasma, the possibility of transmitting infectious agents cannot be completely excluded. This applies also to emerging or unknown viruses and pathogens.
The measures taken are considered effective against enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), and against the non-enveloped hepatitis A virus (HAV).
The measures taken may have limited effectiveness against non-enveloped viruses such as parvovirus B19.
Clinical experience is reassuring regarding the absence of transmission of hepatitis A and parvovirus B19 with immunoglobulins, and it can be assumed that the antibody content provides an important contribution to viral safety.
It is strongly recommended that each time KEYVENB is administered to a patient, the product name and batch number be recorded to ensure traceability between the patient and the product batch.

Important Information on Ingredients of KEYVENB
This medicinal product contains up to a maximum of 39 mg of sodium per 10 mL vial and 175.5 mg of sodium per 45 mL vial, equivalent to 1.9% and 8.7%, respectively, of the maximum daily intake recommended by the WHO, which corresponds to 2 g of sodium for an adult. This medicinal product contains up to 92 mg of sucrose per mL (91.9 mg/mL). This should be taken into account in patients at risk of acute renal failure.

The following adverse reactions have been associated with the use of normal human immunoglobulins for intravenous use (IVIg):

Thromboembolism
Clinical evidence shows an association between IVIg administration and thromboembolic events such as myocardial infarction, cerebrovascular accident (including stroke), pulmonary embolism, and deep vein thrombosis, presumed to be related to a relative increase in blood viscosity due to a high influx of immunoglobulin in at-risk patients. Caution is required when prescribing and infusing IVIg in obese patients and in patients with pre-existing risk factors for thrombotic events (such as advanced age, hypertension, diabetes mellitus, history of vascular disease or thrombotic episodes, patients with acquired or congenital thrombophilic disorders, patients immobilized for prolonged periods, severely hypovolemic patients, or patients with conditions increasing blood viscosity).
In patients at risk for thromboembolic adverse reactions, IVIg-based products should be administered at the lowest feasible infusion rate and dose.

Acute Renal Failure
Cases of acute renal failure have been reported in patients undergoing IVIg therapy.
In most cases, risk factors have been identified, such as pre-existing renal insufficiency, diabetes mellitus, hypovolemia, overweight, concomitant use of nephrotoxic drugs, or age over 65 years.
Renal function must be checked before administering IVIg, particularly in patients potentially at increased risk of developing acute renal failure, and at appropriate intervals after administration.
In patients at risk of acute renal failure, IVIg-based products should be administered at the lowest feasible infusion rate and dose. In case of renal damage, discontinuation of IVIg should be considered.
Although cases of renal dysfunction and acute renal failure have been associated with the use of many authorized IVIg products containing various excipients such as sucrose, glucose, and maltose, those containing sucrose as a stabilizer represent a very high percentage of the total number.
In at-risk patients, consideration should be given to using IVIg-based products that do not contain these excipients. KEYVENB contains sucrose (see section 2, "KEYVENB contains sodium and sucrose").

Aseptic Meningitis Syndrome (AMS)
Aseptic meningitis syndrome may occur in association with IVIg treatment.
The syndrome typically begins several hours to 2 days after IVIg treatment. Cerebrospinal fluid (CSF) studies often show pleocytosis up to several thousand cells/mm³, predominantly granulocytes, and elevated protein levels up to several hundred mg/dL.
Patients presenting with such signs and symptoms should undergo a complete neurological examination, including CSF studies, to exclude other causes of meningitis.
Discontinuation of IVIg treatment has led to resolution of AMS within several days without sequelae.

Hemolytic Anemia
IVIg medicinal products contain blood group-specific antibodies that may act as hemolysins and induce, in vivo, binding of red blood cells to immunoglobulins, causing a positive direct antiglobulin reaction (Coombs test) and, rarely, hemolysis. Hemolytic anemia may develop following IVIg therapy due to increased red blood cell uptake. Patients receiving IVIg 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 IVIg treatment. This typically occurs within hours or days after IVIg administration and resolves spontaneously within 7–14 days.

Transfusion-Related Acute Lung Injury (TRALI)
A few cases of acute non-cardiogenic pulmonary edema (transfusion-related acute lung injury, TRALI) have been reported in patients receiving IVIg. TRALI is characterized by severe hypoxia, dyspnea, tachypnea, cyanosis, fever, and hypotension. Symptoms associated with TRALI typically occur during or within 6 hours of transfusion, often within 1–2 hours. Therefore, patients receiving IVIg must be monitored, and infusion with the product must be immediately interrupted if pulmonary adverse reactions occur. TRALI is a condition that may be life-threatening and requires immediate admission to an intensive care unit.

Pediatric Population
No specific measures or monitoring are required.

Dosage Recommendations
Dosage
The dose and treatment regimen depend on the indication. The doses indicated below are intended as guidelines.

For the prevention of hepatitis B recurrence after liver transplantation due to hepatitis B-induced liver failure.

Adults:
10,000 IU on the day of transplantation, peri-operatively;
followed by 2,000–10,000 IU/day for 7 days,
and as needed to maintain antibody levels above 100–150 IU/L in HBV-DNA negative patients and above 500 IU/L in HBV-DNA positive patients.

Pediatric Population:
Dosage should be adjusted according to body surface area based on 10,000 IU/1.73 m².

Hepatitis B Immunoprophylaxis

Prevention of hepatitis B following accidental exposure in non-immunized individuals: at least 500 IU, depending on the intensity of exposure, as soon as possible after exposure, preferably within 24–72 hours.
Hepatitis B immunoprophylaxis in hemodialysis patients: 8–12 IU/kg up to a maximum of 500 IU, every 2 months until seroconversion following vaccination.
Prevention of hepatitis B in newborns born to hepatitis B virus carrier mothers: 30–100 IU/kg at birth or as soon as possible after birth. In clinical practice, the intramuscular route is preferred whenever repeated administrations are required to achieve seroconversion after vaccination. Administration of hepatitis B immunoglobulin may be repeated until post-vaccination seroconversion.

In all these situations, vaccination against hepatitis B virus is strongly recommended. The first dose of vaccine and hepatitis B immunoglobulins can be administered on the same day, but at different sites.
In individuals who have not shown an immune response after vaccination (non-measurable anti-HBs antibodies) and for whom continuous prevention is required, administration of 500 IU in adults and 8 IU/kg in children every 2 months may be considered; a minimum protective antibody titer is considered to be 10 mIU/mL.
The dose and dosing regimen for the use of hepatitis B human immunoglobulins for intravenous use recommended in other official guidelines should also be taken into account.

Package leaflet: information for the user

KEYVENB 50 UI/ml Infusion Solution

Human hepatitis B immunoglobulin for intravenous use
Please read this leaflet carefully before using this medicine as it contains important information for you.

Keep this leaflet. You may need to read it again.
If you have any questions, consult your doctor, pharmacist, or nurse.
If you experience any side effects, including those not listed in this leaflet, tell your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet:

What KEYVENB is and what it is used for
What you need to know before using KEYVENB
How to use KEYVENB
Possible side effects
How to store KEYVENB
Contents of the pack and other information

1. What KEYVENB is and what it is used for

This medicinal product belongs to a pharmacotherapeutic group called immune sera and immunoglobulins.
KEYVENB is a human anti-hepatitis B immunoglobulin solution for intravenous use and is used in the following treatments:
To prevent recurrence of hepatitis B after liver transplantation due to liver failure caused by the hepatitis B virus, in combination with antiviral therapy.
To provide rapid availability of antibodies against the hepatitis B virus in order to prevent hepatitis B infection in the following cases:

following accidental exposure in non-immunized individuals (i.e., individuals who have not been vaccinated against the hepatitis B virus; including those who have not been fully vaccinated or whose vaccination status is unknown);
in patients undergoing haemodialysis (i.e., patients with severe renal failure requiring blood purification through an artificial kidney), until vaccination becomes effective;
in newborns born to mothers who are carriers of the hepatitis B virus;
in individuals who have not shown an immune response after vaccination (i.e., individuals in whom vaccination has not been effective) and who require ongoing prevention due to persistent risk of contracting hepatitis B.

2. What you need to know before using KEYVENB

Do not use KEYVENB

If you are allergic to human immunoglobulins or to any of the other ingredients of this medicine (listed in section 6).
If you have antibodies in your blood directed against IgA immunoglobulins, as administration of a product containing IgA may cause a severe allergic reaction.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using KEYVENB.
Blockage of a blood vessel (thrombosis) has been associated with the administration of
intravenous normal human immunoglobulins (IVIg).
Therefore, your doctor must exercise particular caution when administering this medicine if you have
thrombotic risk factors.
The levels of anti-HBs antibodies in your blood should be monitored regularly.
Adverse reactions may occur more frequently:

if the infusion rate is high;
if you have uncontrolled symptoms of untreated infections (e.g. fever) or symptoms of chronic inflammation;
if you are receiving human normal immunoglobulins for the first time;
in rare cases when switching to a different type of human normal immunoglobulin medicinal product, or after a long interval since the last infusion.
- In certain conditions, immunoglobulins may increase the risk of myocardial infarction, stroke, pulmonary embolism, or deep vein thrombosis because they increase blood viscosity. Therefore, your doctor will pay special attention in the following circumstances:
if you are overweight,
if you are elderly,
if you have diabetes,
if you have high blood pressure (hypertension),
if your blood volume is too low (hypovolemia),
if you have or have had blood vessel problems (vascular diseases),
if you have an increased tendency for blood to clot (inherited or acquired thrombophilic disorders),
if you have had thrombotic episodes,
if you have diseases that increase blood density (viscosity),
if you have had prolonged immobility,
if you have or have had kidney problems or if you are taking medicines that may damage the kidneys (nephrotoxic medicines), as cases of acute renal failure have been reported. In case of kidney damage, your doctor may consider stopping treatment.
- You may be allergic (hypersensitive) to immunoglobulins (antibodies) without knowing it. This may occur even if you have previously received normal human immunoglobulins and tolerated prior administrations. This possibility is particularly relevant if you lack IgA immunoglobulins (IgA deficiency with anti-IgA antibodies). In these rare cases, allergic (hypersensitivity) reactions such as low blood pressure or shock may occur.

The recommended infusion rate described in section 3 “How to use KEYVENB” must be strictly followed
by the doctor; this is strongly recommended because some serious adverse reactions to the
medicine may be related to the infusion rate. Furthermore, you must be closely monitored
and carefully observed throughout the entire infusion period for the appearance of any
symptoms.
In case of adverse reactions, your doctor may decide whether to reduce the infusion rate or stop
the infusion. Your doctor will also determine the type of treatment required depending on the nature and
severity of the adverse effect.
KEYVENB contains small amounts of IgA. If you have IgA deficiency, you may be at risk of developing
anti-IgA antibodies and may experience anaphylactic reactions after administration of blood components
containing IgA. Your doctor must evaluate the benefit of treatment with KEYVENB versus the potential
risk of hypersensitivity reactions.
Hepatitis B-specific human immunoglobulins may rarely cause a drop in blood pressure with anaphylactic
reaction, even if you have previously tolerated immunoglobulin treatments.
If you have renal insufficiency, your doctor should consider discontinuing treatment with IVIg.
Although cases of renal dysfunction and acute renal failure have been associated with the use of
many authorized IVIg products containing various excipients such as sucrose, glucose, and
maltose, products containing sucrose as a stabilizer represent a very high proportion of the total number
of cases. In patients at risk for acute renal failure or thromboembolic adverse reactions,
IVIg products should be administered at the lowest feasible infusion rate and dose.
With immunoglobulin-based treatments, you may develop treatment-related lung injury, known as transfusion-related acute lung injury (TRALI). If you experience shortness of breath or rapid breathing during or in the hours following the infusion, notify your doctor or nurse immediately, as emergency treatment may be required.
Suspected allergic or anaphylactic reactions require immediate discontinuation of the infusion. In case of shock, standard medical treatment for shock should be followed.
Inform your doctor if any of the above conditions apply to you. Your doctor
will pay particular attention when prescribing and administering KEYVENB to you.
Intravenous human immunoglobulin (IVIg) products may contain blood group-specific antibodies that may rarely cause destruction of red blood cells (hemolysis). For this reason, hemolytic anemia (anemia due to abnormal breakdown of red blood cells) may develop after IVIg therapy. Therefore, during IVIg treatment, you will be monitored for clinical signs and symptoms of hemolysis.

Blood tests
KEYVENB may interfere with certain blood tests due to a temporary increase in various antibodies
passively transferred into your bloodstream via immunoglobulin infusion; this increase in
antibodies may cause some blood tests to yield incorrect results. Passive transfer of antibodies against erythrocyte antigens, e.g., A, B, D (determining blood group), may interfere with certain serological tests for red blood cell antibodies, for example, the direct antiglobulin test (Coombs test).

Blood glucose testing
Some blood glucose monitoring systems (e.g., those based on pyrroloquinoline quinone glucose dehydrogenase (GDH-PQQ) or the glucose oxidoreductase colorimetric method) may falsely recognize the maltose (100 mg/ml) contained in KEYVENB as glucose. This may result in falsely elevated blood glucose readings during the infusion and for approximately 15 hours after the end of the infusion, potentially leading to inappropriate insulin administration, which may be life-threatening or even result in fatal hypoglycemia. Additionally, actual cases of hypoglycemia may remain untreated if the hypoglycemic state is masked by falsely elevated glucose readings. Therefore, during administration of KEYVENB or other parenteral products containing maltose, blood glucose measurement must be performed using glucose-specific methods. The instructions for use of the glucose monitoring system, including those for test strips, must be carefully reviewed to determine whether the system is suitable for use in patients receiving parenteral products containing maltose. If in doubt, contact the manufacturer of the glucose monitoring system to determine its suitability for use with parenteral products containing maltose.

Viral safety
When medicines are prepared from human blood or plasma, certain measures are taken 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 to detect the presence of infectious agents and/or viruses;
inclusion during manufacturing processes of steps capable of inactivating or removing viruses. Despite these measures, when administering medicines prepared from human blood or plasma, the possibility of transmitting infectious agents cannot be completely ruled out. This also applies to emerging or unknown viruses or other infectious agents. The measures taken are considered effective against lipid-enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), and the non-lipid-enveloped hepatitis A virus (HAV). The measures taken may have limited effectiveness against non-enveloped viruses such as parvovirus B19. Immunoglobulins have not been associated with hepatitis A or parvovirus B19 infections, probably because the antibodies against these infections contained in the product have protective properties.

It is strongly recommended that each time you are administered KEYVENB, the name and batch number
of the product be recorded to ensure traceability of the batch used.
Children
No specific measures or monitoring are required.
Other medicines and KEYVENB
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any
other medicines.
Hepatitis B-specific human immunoglobulins for intravenous use must not be mixed with other
medicinal products.
Live attenuated virus vaccines
KEYVENB may interfere with the development of an immune response to live attenuated virus vaccines, such as those for rubella, mumps, measles, and varicella. Administration of immunoglobulins may alter the effectiveness of these vaccines for a period lasting up to 3 months. At least three months should elapse after administration of KEYVENB before vaccination with live attenuated virus vaccines.
Hepatitis B-specific human immunoglobulins should be administered three or four weeks after vaccination with live attenuated virus vaccines; if administration of hepatitis B-specific human immunoglobulins is required within three or four weeks after vaccination, revaccination should be performed three months after immunoglobulin administration.
Loop diuretics (a group of medicines that increase urine production)
Concomitant use of loop diuretics with KEYVENB should be avoided.
Pregnancy, breastfeeding, and fertility

If you are pregnant, suspect you may be pregnant, planning pregnancy, or breastfeeding, consult your doctor or pharmacist before using this medicine. Your doctor will decide whether it is appropriate to use KEYVENB during pregnancy and breastfeeding.
Clinical studies with KEYVENB have not been conducted in pregnant women. It has been shown that intravenous human immunoglobulin products cross the placenta increasingly during the third trimester. However, antibody-containing medicines have been used for years in pregnant women, and no harmful effects on the course of pregnancy, the fetus, or the newborn are expected.
If you are breastfeeding while being treated with KEYVENB, the antibodies contained in the product may pass into breast milk. Therefore, your baby may be protected from certain infections.
Clinical experience with immunoglobulins suggests that no harmful effects on fertility are expected.

Driving and using machines
KEYVENB does not affect or has a negligible effect on the ability to drive and use machines. Patients who experience adverse reactions during treatment should wait until symptoms resolve before driving or operating machinery.
KEYVENB contains sodium
This medicine contains up to a maximum of 39 mg of sodium (the main component of table salt) per 10 ml vial and 195 mg of sodium per 50 ml vial. This corresponds to 1.9% and 9.7%, respectively, of the maximum daily dietary intake recommended for an adult.

3. How to use KEYVENB

KEYVENB can only be administered in hospitals or clinics and care facilities by physicians or
healthcare professionals.
The dosage and treatment schedule depend on the indication; your doctor will determine the appropriate dose and
treatment for you.
At the beginning of the infusion, you will receive KEYVENB at the minimum infusion rate. If you tolerate the
applied rate well, your doctor may gradually increase the infusion rate.
For further instructions, refer to the section “ The following information is intended exclusively for
physicians or healthcare professionals ”.
If you use more KEYVENB than you should
The consequences of overdose are unknown.
If you are administered more KEYVENB than required, a protein overload in body fluids may occur, and the blood may become too thick (hyperviscous); this is particularly evident in patients at risk, especially elderly patients or those with impaired cardiac or renal function.
If you have any further doubts about the use of this medicine, consult your doctor, pharmacist, or
nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
If you notice any of the following side effects, consult your doctor immediately or contact the nearest hospital:

Allergic reactions (hypersensitivity). In some cases, this side effect may progress to an acute allergic reaction (anaphylactic shock): for example, itching, skin reactions, swelling of the lips, face and tongue, difficulty swallowing, breathing difficulties, fainting.
Acute kidney failure (for example, reduced or absent urine flow, fluid retention, shortness of breath).

The following side effects have generally been reported after treatment with intravenous immunoglobulins:

bradycardia (slow heart rate), feeling of warmth, syncope (fainting), bronchospasm (airway narrowing), cough, tachypnea (rapid breathing), hyperhidrosis (excessive sweating), tachycardia (fast heart rate), chills, headache, dizziness, fever, vomiting, nausea, allergic reactions, arthralgia (joint pain), drop in blood pressure, moderate lower back pain and generalized musculoskeletal pain have been reported occasionally;
isolated cases of temporary reduction in red blood cells (reversible hemolytic anemia/hemolysis), especially in patients with blood groups A, B and AB, and (rarely) hemolytic anemia requiring transfusion;
a sudden drop in blood pressure has been reported rarely and, in some isolated cases, hypersensitivity reactions (anaphylactic shock) may occur, even when the patient has not had reactions to previous administrations;
rare cases of transient skin reactions have been observed;
very rarely, thromboembolic reactions (blood clot formation) have been reported, which may lead to myocardial infarction, stroke, blockage of the pulmonary arteries (pulmonary embolism), and deep vein thrombosis;
cases of transient non-infectious meningitis (reversible aseptic meningitis);
cases of increased creatinine levels in the blood and/or acute kidney failure;
cases of transfusion-related acute lung injury (TRALI).

The following adverse events have been reported following administration of KEYVENB after the medicine was placed on the market (frequency cannot be estimated from the available data):

Hypersensitivity
Anaphylactic shock
Nausea
Vomiting
Fever
Malaise
Chills
Dyspnea
Chest discomfort or pain

For information regarding safety with respect to transmissible agents, see section 2 “What you need to know before using KEYVENB”.
Additional side effects in children
No specific data are available in the paediatric population.
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist or nurse. You can also report side effects directly via the following website: 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 KEYVENB

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 outer packaging.
The expiry date refers to the last day of that month.
Store in a refrigerator (2°C - 8°C).
Keep in the outer packaging to protect the medicine from light.
Do not freeze.
Once the container has been opened, the product must be administered immediately.
Do not use this medicine if you notice that the solution is cloudy or contains deposits or shows any change in colour (see also “Description of the appearance of KEYVENB and contents of the pack” in section 6).
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Contents of the pack and other information

What KEYVENB contains
The active substance is human hepatitis B immunoglobulin.

	KEYVENB 500 UI	KEYVENB 2500 UI
Human proteins	50 g/l	50 g/l
consisting of human immunoglobulins of at least	95%	95%
Antibodies against HBs antigen (anti-HBs) in a quantity not less than	50 IU/ml 500 IU/vial	50 IU/ml 2500 IU/vial

The IgG (immunoglobulin G) subclasses have the following distribution:
IgG 26.0 - 40.0 mg/ml
IgG 13.0 - 25.0 mg/ml
IgG 1.20 - 2.50 mg/ml
IgG 0.15 - 0.50 mg/ml
Maximum IgA content is 0.05 mg/ml.
Produced from plasma of human donors.
Other components are maltose, sodium chloride, and water for injections.
Description of the appearance of KEYVENB and contents of the pack
KEYVENB is a solution for infusion.
The solution is a clear or slightly opalescent, colourless or pale yellow liquid.
Before administration, visually inspect the solution for the presence of suspended particles, foreign matter, or colour changes. Do not use cloudy solutions or those containing deposits.
KEYVENB 50 IU/ml solution for infusion: vial containing 500 IU in 10 ml
KEYVENB 50 IU/ml solution for infusion: vial containing 2500 IU in 50 ml + infusion set.
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:

Instructions for Proper Use
Before use, bring the product to room or body temperature.
KEYVENB must be administered intravenously at an initial infusion rate of 0.46 – 0.92 ml/kg/h (for
example, for a 65 kg patient, at a rate of 10 – 20 drops per minute) for 20 – 30 minutes. In case of
an adverse reaction, the infusion rate should be reduced or the infusion stopped. If well tolerated,
the infusion rate may be gradually increased up to a maximum of 1.85 ml/kg/h (for example, for a 65 kg patient, at a rate of 40 drops per minute) for the remainder of the infusion.
Do not use solutions that are cloudy or contain deposits.
Reconstituted products must be visually inspected for the presence of particulate matter or discoloration prior to administration.
The solution appears as a clear or slightly opalescent, colorless or pale yellow preparation.
Any unused medicinal product and waste material derived from this medicinal product must be disposed of in accordance with current local regulations.

Special Precautions
Some adverse reactions to the product may be related to the rate of infusion.
Potential complications can often be avoided by ensuring:

that patients are not sensitive to normal human immunoglobulin by initially administering the product slowly (at an infusion rate between 0.46 and 0.92 ml/kg/h);
that patients are closely monitored for any symptoms throughout the entire infusion period. In particular, patients receiving normal human immunoglobulin for the first time, patients switching from another IVIg product, or patients who have had a long interval since their last infusion should be monitored during the first infusion and for the first hour after the first infusion to detect potential signs of adverse reactions. All other patients should be observed for at least 20 minutes after administration.

In all patients, administration of IVIg requires:

adequate hydration prior to the start of IVIg infusion;
monitoring of urinary output;
monitoring of serum creatinine levels;
avoidance of concomitant use of loop diuretics. In case of an adverse reaction, the infusion rate must be reduced or the infusion stopped. The necessary treatment depends on the nature and severity of the adverse effect. In case of shock, standard medical treatment for shock must be initiated.

Infusion Reactions
Some adverse reactions (e.g., headache, flushing, chills, myalgia, wheezing, tachycardia, back pain, nausea, and hypotension) may be related to the rate of infusion. The recommended infusion rate must be strictly followed. Patients must be closely monitored and carefully observed for any symptoms throughout the entire infusion period.
Adverse reactions may occur more frequently:

with high infusion rates;
in patients with hypo- or agammaglobulinemia, with or without IgA deficiency.

Hypersensitivity
True hypersensitivity reactions are rare.
KEYVENB contains small amounts of IgA. Individuals with IgA deficiency may develop antibodies against IgA and may experience anaphylactic reactions after administration of blood components containing IgA. Therefore, the physician must evaluate the benefit of treatment with KEYVENB against the potential risk of hypersensitivity reactions.
Rarely, anti-hepatitis B human immunoglobulins may induce a drop in blood pressure with anaphylactic reaction, even in patients who have previously tolerated immunoglobulin treatments.
Patients should be informed about early signs of hypersensitivity reactions such as urticaria, generalized hives, chest tightness, wheezing, hypotension, and anaphylaxis. The required treatment depends on the nature and severity of the adverse reaction.
Suspected allergic or anaphylactic reactions require immediate discontinuation of the infusion. In case of shock, standard medical treatment for shock must be initiated.

Interference with Serological Tests
Following immunoglobulin injection, transient increases in various passively transferred antibodies in the patient's blood may lead to false-positive results in serological tests.
Passive transfer of antibodies against erythrocyte antigens, e.g., A, B, D, may interfere with certain serological tests for red blood cell antibodies, for example, the antiglobulin test (Coombs test).

Transmissible Agents
Standard measures to prevent infections from medicinal products derived from human blood or plasma include donor selection, screening of individual donations and plasma pools for specific infection markers, and inclusion of effective manufacturing steps for virus inactivation/removal.
Nevertheless, when administering medicinal products derived from human blood or plasma, the possibility of transmitting infectious agents cannot be completely ruled out. This also applies to emerging or unknown viruses and pathogens.
The measures implemented are considered effective against lipid-enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV), as well as against the non-lipid-enveloped hepatitis A virus (HAV).
The measures may have limited effectiveness against non-lipid-enveloped viruses such as parvovirus B19.
There is reassuring clinical experience regarding the absence of transmission of hepatitis A and parvovirus B19 with immunoglobulins, and it can be assumed that the antibody content provides an important contribution to viral safety.
It is strongly recommended that each time KEYVENB is administered to a patient, the name and batch number of the product be recorded to ensure traceability between the patient and the product batch.

Important Information on Ingredients of KEYVENB
This medicinal product contains up to a maximum of 39 mg of sodium per 10 ml vial and 195 mg of sodium per 50 ml vial, equivalent to 1.9% and 9.7% of the maximum daily intake recommended by the WHO (2 g of sodium for an adult), respectively.
This medicinal product contains up to a maximum of 91.9 mg of maltose per ml as excipient.
Maltose interference with blood glucose testing may lead to overestimation of glucose values and, consequently, inappropriate insulin administration, which may cause life-threatening hypoglycemia and potentially death. Furthermore, actual hypoglycemic episodes may remain untreated if hypoglycemia is masked by falsely elevated glucose readings. See below for acute renal failure.

The following adverse reactions have been associated with the use of normal human immunoglobulins for
intravenous use (IVIg):

Thromboembolism
Clinical evidence shows an association between IVIg administration and thromboembolic events such as myocardial infarction, cerebrovascular accident (including stroke), pulmonary embolism, and deep vein thrombosis, presumed to be related to a relative increase in blood viscosity due to a high influx of immunoglobulin in at-risk patients. Caution should be exercised when prescribing and infusing IVIg in obese patients and in patients with pre-existing risk factors for thrombotic events (such as advanced age, hypertension, diabetes mellitus, history of vascular disease or thrombotic episodes, patients with acquired or congenital thrombophilic disorders, immobilized patients, severely hypovolemic patients, or patients with conditions increasing blood viscosity).
In patients at risk for thromboembolic adverse reactions, IVIg products should be administered at the lowest feasible infusion rate and dose.

Acute Renal Failure
Cases of acute renal failure have been reported in patients undergoing IVIg therapy.
In most cases, risk factors were identified, such as pre-existing renal insufficiency, diabetes mellitus, hypovolemia, obesity, concomitant use of nephrotoxic drugs, or age over 65 years.
Renal function should be monitored before administering IVIg, particularly in patients with potentially increased risk of developing acute renal failure, and at appropriate intervals after administration.
In patients at risk of acute renal failure, IVIg products should be administered at the lowest feasible infusion rate and dose. In case of renal injury, discontinuation of IVIg should be considered.
Although cases of renal dysfunction and acute renal failure have been associated with the use of many authorized IVIg products containing various excipients such as sucrose, glucose, and maltose, those containing sucrose as a stabilizer represent a very high proportion of the total number.
In at-risk patients, use of IVIg products not containing these excipients may be considered. KEYVENB contains maltose (see section "Important Information on Ingredients of KEYVENB").

Aseptic Meningitis Syndrome (AMS)
Aseptic meningitis syndrome may occur in association with IVIg treatment.
The syndrome typically begins within several hours to 2 days after IVIg administration. Cerebrospinal fluid (CSF) studies often show pleocytosis of up to several thousand cells/mm³, predominantly granulocytes, and elevated protein levels up to several hundred mg/dL.
Patients presenting with these signs and symptoms should undergo a complete neurological evaluation, including CSF studies, to exclude other causes of meningitis.
Discontinuation of IVIg treatment has led to resolution of AMS within several days without sequelae.

Hemolytic Anemia
IVIg medicinal products contain blood group-specific antibodies that may act as hemolysins and induce in vivo binding of red blood cells to immunoglobulins, resulting in a positive direct antiglobulin test (Coombs test) and, rarely, hemolysis. Hemolytic anemia may develop following IVIg therapy due to increased red blood cell sequestration. Patients receiving IVIg 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 IVIg treatment. This typically occurs within a few hours or days after IVIg administration and resolves spontaneously within 7–14 days.

Transfusion-Related Acute Lung Injury (TRALI)
A few cases of non-cardiogenic acute pulmonary edema (transfusion-related acute lung injury, TRALI) have been reported in patients receiving IVIg. TRALI is characterized by severe hypoxia, dyspnea, tachypnea, cyanosis, fever, and hypotension. TRALI-associated symptoms typically occur during or within 6 hours after transfusion, often within 1–2 hours. Therefore, patients receiving IVIg should be monitored, and infusion must be immediately stopped if pulmonary adverse reactions occur. TRALI is a potentially life-threatening condition requiring immediate admission to intensive care.

Pediatric Population
No specific measures or monitoring are required.

Dosage Recommendations
Dosage
The dose and treatment regimen depend on the indication. The doses indicated below are intended as guidelines.

For prevention of hepatitis B recurrence after liver transplantation due to hepatitis B-induced liver failure.

Adults:
10,000 IU on the day of transplantation, peri-operatively;
followed by 2,000–10,000 IU/day for 7 days,
and as needed to maintain antibody levels above 100–150 IU/L in HBV-DNA-negative patients and above 500 IU/L in HBV-DNA-positive patients.

Pediatric Population:
Dosage should be adjusted according to body surface area based on 10,000 IU/1.73 m².

Hepatitis B Immunoprophylaxis

Prevention of hepatitis B following accidental exposure in non-immunized individuals: at least 500 IU, depending on the extent of exposure, as soon as possible after exposure, preferably within 24–72 hours.
Hepatitis B immunoprophylaxis in hemodialysis patients: 8–12 IU/kg up to a maximum of 500 IU every 2 months until vaccination becomes effective.
Prevention of hepatitis B in newborns born to hepatitis B virus carrier mothers: 30–100 IU/kg at birth or as soon as possible after birth. In clinical practice, intramuscular administration is preferred whenever repeated administrations are required to achieve seroconversion after vaccination.
Administration of hepatitis B immunoglobulin may be repeated until seroconversion following vaccination.

In all these situations, vaccination against hepatitis B virus is strongly recommended.
The first dose of the vaccine and hepatitis B immunoglobulins can be administered on the same day, but at different injection sites.
In individuals who have not shown an immune response after vaccination (non-detectable anti-HBs antibodies) and for whom ongoing prevention is required, administration of 500 IU in adults and 8 IU/kg in children every 2 months may be considered; a minimum protective antibody titer is considered to be 10 mIU/ml.
The dose and dosage regimen for hepatitis B immunoglobulins for intravenous use recommended in other official guidelines should also be taken into consideration.