KEYVENB 50 UI/ML Powder and solvent for intravenous infusion solution

Зміст інструкції

1. KEYVENB 50 UI/ml Solution for Infusion
   1. What is KEYVENB and what it is used for
   2. Cosa deve sapere prima di usare KEYVENB
   3. How to use KEYVENB
2. KEYVENB can only be administered in hospital or clinics and nursing homes by
   1. Possible side effects
   2. How to store KEYVENB
   3. Content of the pack and other information
3. KEYVENB 50 UI/ml Powder and solvent for infusion solution
   1. What is KEYVENB and what it is used for
   2. What you need to know before using KEYVENB
   3. How to use KEYVENB
   4. Possible side effects
   5. How to store KEYVENB
   6. Contents of the pack and other information

KEYVENB 50 UI/ml Solution for Infusion

Human anti-hepatitis B immunoglobulin for intravenous use

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, ask your doctor, pharmacist or nurse.
• If any side effects occur, including those not listed in this leaflet, tell your doctor, pharmacist or nurse. See section 4.

Contents of this leaflet:

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

1. What is KEYVENB and what it is used for

This medicine belongs to a pharmacotherapeutic group called immune sera and
immunoglobulins.
KEYVENB is a solution of human anti-hepatitis B immunoglobulins (proteins that function as antibodies)
for intravenous use and is used in the following therapies:
To prevent relapses of hepatitis B after liver transplantation due to liver failure
induced by the hepatitis B virus, in combination with antiviral therapy.
To rapidly provide antibodies against the hepatitis B virus in order to prevent
hepatitis B infection in the following cases:

• in case of accidental exposure in non-immunized subjects (i.e. in people who are not vaccinated against the hepatitis B virus, including people who are not fully vaccinated or whose vaccination cycle is unknown);
• in patients undergoing hemodialysis (i.e. in patients with severe kidney failure who require blood purification using an artificial kidney), until vaccination has become effective;
• in newborns with a mother carrying the hepatitis B virus;
• in subjects who have not shown an immune response after vaccination (i.e. in people in whom vaccination has not become effective) and for whom continuous prevention is necessary due to the persistent risk of contracting hepatitis B.

2. Cosa deve sapere prima di usare KEYVENB

Non usi KEYVENB
If you are allergic to human immunoglobulins or to any of the other components of this medicine (listed in section 6).
If you have antibodies against IgA-type immunoglobulins in your blood, as the 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 intravenous immunoglobulin (IVIg). Therefore, your doctor must act with particular caution when administering this medicine if you have risk factors for thrombosis.
The levels of anti-HBs antibodies in your blood should be checked regularly.
Some 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 normal human immunoglobulins for the first time;
• in rare cases where the type of human immunoglobulin medicinal product has been changed, or when a long time has passed since the previous infusion.
• In some 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 be particularly careful in the following circumstances:
• if you are overweight,
• if you are elderly,
• if you suffer from diabetes,
• if you have high blood pressure (hypertension),
• if your blood volume is too low (hypovolemia),
• if you have or have had problems with blood vessels (vascular diseases),
• if you have an increased tendency to blood clotting (inherited or acquired thrombophilic disorders),
• if you suffer from thrombotic episodes,
• if you suffer from diseases that increase blood density (viscosity),
• if you have had a prolonged period of immobility,
• if you have or have had kidney problems or if you are taking medicines that can damage the kidneys (nephrotoxic medicines), as cases of acute renal failure have been reported. In case of kidney damage, your doctor will consider interrupting treatment.
• You may be allergic (hypersensitive) to immunoglobulins (antibodies) without knowing it.This can happen even if you have previously received normal human immunoglobulins and have tolerated previous administrations. This is particularly likely if you do not have 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 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. In addition, you must be closely monitored and carefully observed during the entire infusion period to detect the onset of any symptoms.
If adverse reactions occur, your doctor may decide to reduce the infusion rate or stop the infusion. In addition, your doctor will decide the type of treatment required depending on the nature and severity of the adverse effect.
KEYVENB contains small amounts of IgA. If you have an IgA deficiency, you may be at risk of developing anti-IgA antibodies and may develop anaphylactic reactions after the administration of blood components containing IgA. Your doctor must assess the benefit of treatment with KEYVENB against the potential risk of hypersensitivity reactions.
Human anti-hepatitis B immunoglobulins can rarely induce a drop in blood pressure with anaphylactic reaction, even if you have tolerated previous treatments with immunoglobulins.
If you suffer from renal failure, your doctor should consider interrupting treatment with IVIg. Although cases of renal dysfunction and acute renal failure have been associated with the use of many IVIg-authorised products containing various excipients such as sucrose, glucose and maltose, those containing sucrose as a stabiliser represent a very high percentage of the total number. In patients at risk for acute renal failure or thromboembolic adverse reactions, IVIg-based products should be administered at the lowest practicable infusion rate and dose.
With immunoglobulin-based treatments, you may incur lung damage related to treatment, called Transfusion Related Acute Lung Injury (TRALI). If you experience shortness of breath or rapid breathing during the infusion or in the hours following the infusion, immediately inform your doctor or nurse as emergency treatment may be necessary.
Suspicion of allergic or anaphylactic reactions requires immediate interruption of the injection. In case of shock, standard medical treatment for shock must be followed.
Tell your doctor if at least one of the above conditions applies to you. Your doctor will take particular care in prescribing and administering KEYVENB to you.
Human intravenous immunoglobulin products (IVIg) may contain blood group-specific antibodies that can rarely cause destruction of red blood cells (hemolysis). For this reason, a form of anemia due to abnormal red blood cell breakdown (hemolytic anemia) may develop following IVIg therapy. Therefore, you will be monitored for clinical signs and symptoms of hemolysis during treatment with IVIg.
Blood tests
KEYVENB may interfere with some blood tests due to the temporary increase in various antibodies that are passively transferred into your blood with the immunoglobulin infusion; this increase in antibodies may cause some blood tests to have a result that may not be correct. Passive transfer of antibodies against erythrocyte antigens, e.g. A, B, D (determining the blood group), may interfere with some serological tests for red blood cell antibodies, for example the direct antiglobulin test (Coombs' test).

Blood glucose tests
Some blood glucose measurement systems (for example, those based on pyrroloquinoline quinone glucose dehydrogenase (GDH-PQQ) or the colorimetric glucose-oxidase method) falsely recognize maltose (100 mg/ml) contained in KEYVENB as glucose. This can result in a reading of falsely elevated blood glucose values during the infusion and for a period of approximately 15 hours after the end of the infusion and, consequently, in inadequate insulin administration, causing a life-threatening or even fatal hypoglycemia. In addition, real hypoglycemia may not be treated if the hypoglycemic state is masked by falsely elevated glucose values. Consequently, during the 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 blood glucose measurement system, including those of the test strips, must be carefully checked to establish whether the system is appropriate for use in patients treated with parenteral products containing maltose. If in doubt, contact the manufacturer of the measurement system to determine the appropriateness of use in conjunction with parenteral products containing maltose.
Viral safety
When medicines are prepared from human blood or plasma, certain measures are taken to prevent the transmission of infections to patients.
These measures include:

• careful selection of blood and plasma donors to ensure that potentially infected individuals are excluded;
• testing of each donation and plasma pool to ensure the absence of infectious agents and/or viruses;
• the inclusion, during the manufacturing processes, of steps capable of inactivating or removing viruses. Despite these measures, the possibility of transmission of infectious agents cannot be completely excluded when administering medicines prepared from human blood or plasma. This also applies to viruses, or other types of infectious agents, emerging or unknown. The measures taken are considered effective for enveloped viruses such as the human immunodeficiency virus (HIV), the hepatitis B virus (HBV), the hepatitis C virus (HCV) and the non-enveloped hepatitis A virus (HAV). The measures taken may have limited value 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, which are contained in the product, have protective capacity.

It is strongly recommended that each time you are administered KEYVENB, the name and lot number of the product are recorded, so as to maintain traceability of the lot used.

Children
No specific measures or monitoring are required.

Other medicines and KEYVENB
Tell 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. The administration of immunoglobulins may alter the effectiveness of these vaccines for a period that can last up to 3 months. At least three months must elapse after the administration of KEYVENB before proceeding with 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 the administration of human anti-hepatitis B immunoglobulins is necessary within three or four weeks of vaccination, revaccination should be done three months after the administration of human anti-hepatitis B immunoglobulins.
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 are pregnant, are planning to become pregnant, or are breastfeeding, ask your doctor or pharmacist for advice before using this medicine. The 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 human intravenous immunoglobulin-based products cross the placenta in increasing amounts 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 have adverse effects on the course of pregnancy, the fetus or the newborn.
• If you are breastfeeding and are being treated with KEYVENB, the antibodies contained in the product may pass into breast milk. Therefore, your baby may be protected from some infections.
• Clinical experience with immunoglobulins suggests that no adverse effects on fertility are expected.

Driving and using machines
KEYVENB does not alter or negligibly alters the ability to drive and use machines. Patients who experience adverse reactions during treatment should wait for their resolution before driving vehicles or using machines.

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 is equivalent to 1.9% and 9.7% of the recommended daily intake with the diet of an adult, respectively.

3. How to use KEYVENB

KEYVENB can only be administered in hospital or clinics and nursing homes by

doctors or healthcare professionals.
The dosage and treatment regimen depend on the indication; the 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, please refer to the section “ The following information is intended

exclusively for doctors or healthcare professionals”.

If you use more KEYVENB than you should
The consequences of an overdose are unknown.
If you are given more KEYVENB than you should, a protein overload may occur
in the fluids and the blood may become too dense (hyperviscous); this is particularly
manifest in at-risk patients, especially elderly patients or those with impaired cardiac or renal function.
If you have any further doubts about 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.

If you notice any of the following side effects, consult your doctor immediately or contact the nearest hospital:

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

The side effects reported below may generally occur after treatment with intravenous immunoglobulin:

• chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia (joint pain), decreased blood pressure and moderate back pain have been reported occasionally;
• isolated cases of temporary reduction of 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 presented reactions to previous administrations;
• rare cases of transient skin reactions have been observed;
• very rarely, thromboembolic reactions (blood clot formation) have been reported, which can cause myocardial infarction, stroke, pulmonary artery obstruction (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 renal failure;
• cases of acute lung injury associated with transfusion (TRALI).

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

• Headache
• Fast heartbeat (tachycardia)
• Low blood pressure (hypotension)
• Nausea
• Vomiting
• Skin reactions, redness (erythema), tingling, itching
• Joint pain (arthralgia)
• Fever
• Feeling unwell
• Chills

For information regarding safety in relation to transmissible agents, see paragraph 2 “What you need to know before using KEYVENB”.

Additional side effects in children
No specific data are available for the paediatric population.

Reporting of side effects
If you get any side effects, even those not listed in this leaflet, tell your doctor, pharmacist or nurse. You can also report side effects directly via web: 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 which is stated on the label and the outer
packaging.
The expiry date refers to the last day of that month.
Store in a refrigerator (2°C - 8°C).
Store in the outer packaging to protect the medicine from light.
Do not freeze.
Once the container is opened, the product must be administered immediately.
Do not use this medicine if you notice that the solution is cloudy or contains deposits or presents
a change in color (see also the “Description of the appearance of KEYVENB and contents of the

pack”in paragraph 6).
Do not dispose of any medicine in wastewater or household waste. Ask your pharmacist how to
dispose of medicines you no longer use. This will help protect the environment.

6. Content of the pack and other information

What KEYVENB contains
The active ingredient is human anti-hepatitis B immunoglobulin.

The IgG subclasses (type G immunoglobulins) 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 content of IgA is 0.05 mg/ml
Product from human donor plasma.
The 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 presented as a clear or slightly opalescent, colorless or
pale yellow preparation.
Before administration, visually inspect the solution for the presence of
particles in suspension, corpuscles or chromatic alterations. Do not use turbid solutions or those
that present deposits.
KEYVENB 50 IU/ml solution for infusion: vial with 500 IU in 10 ml
KEYVENB 50 IU/ml solution for infusion: vial with 2500 IU in 50 ml + infusion set.

Marketing Authorisation 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 (Napoli).

The following information is intended exclusively for doctors or healthcare professionals:
Instructions for correct use
Before use, bring the product to room or body temperature.
KEYVENB must be infused intravenously at an initial rate of 0.46 – 0.92 ml/kg/h
(for example for a patient of 65 kg at a rate of 10 - 20 drops per minute) for 20 - 30
minutes. In case of adverse reaction, the administration rate must be reduced or the
infusion stopped. If well tolerated, the administration rate may be gradually increased
up to a maximum of 1.85 ml/kg/h (for example for a patient of 65 kg at a rate of 40
drops/minute) for the remainder of the infusion.
Do not use turbid solutions or those that present deposits.
Reconstituted products must be visually checked for the possible presence of particles in
suspension or chromatic alterations before administration.
The solution is presented as a clear or slightly opalescent, colorless or
pale yellow preparation.
Unused medicinal product and waste derived from such medicinal product must be disposed of in
accordance with local regulations.

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

• that patients are not sensitive to normal human immunoglobulin by administering the product slowly at the beginning (with an infusion rate between 0.46 and 0.92 ml/kg/h);
• that patients are carefully monitored for any symptom during the entire infusion period. In particular, patients receiving human normal immunoglobulin for the first time, patients who have changed the type of IVIg-based product, or patients for whom a long interval has elapsed since the previous infusion, must be monitored during the first infusion and for the first hour after the first infusion, to identify potential signs of adverse reactions. All other patients must be observed for at least 20 minutes after administration.

In all patients, the administration of IVIg requires:

• adequate hydration before the start of IVIg infusion;
• monitoring of urine volume;
• monitoring of serum creatinine levels;
• avoiding the concomitant use of loop diuretics.

In case of adverse reaction, the administration rate must be reduced or the infusion must
be interrupted. The necessary treatment depends on the nature and severity of the adverse
effect. In case of shock, standard medical treatment for shock must be performed.
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 strictly monitored and carefully observed for any symptom during
the entire infusion period.
Adverse reactions may occur more frequently:

• in case of high infusion rate;
• in patients with hypo- or agammaglobulinemia with or without IgA deficiency.

Hypersensitivity
True hypersensitivity reactions are rare.
KEYVENB contains small amounts of IgA. Individuals who have an IgA deficiency may
develop antibodies against IgA and may have anaphylactic reactions after administration of
blood components containing IgA. The doctor must therefore assess the benefit of
treatment with KEYVENB against the potential risk of hypersensitivity reactions.
Rarely, human anti-hepatitis B immunoglobulins may induce a drop in
blood pressure with anaphylactic reaction, even in patients who have tolerated previous treatments
with immunoglobulins.
Patients must be informed about the early signs of hypersensitivity reactions such as urticaria,
generalized urticaria, feeling of tightness in the chest, wheezing, hypotension and anaphylaxis. The
treatment required depends on the nature and severity of the adverse reaction.
Suspicion of allergic or anaphylactic reactions requires immediate interruption
of the injection. In case of shock, standard medical treatment for shock must be followed.
Interference with serological tests
After the injection of immunoglobulins, the transient increase of various passively transferred antibodies
in the patient's blood may give falsely positive results in serological tests.
Passive transfer of antibodies against erythrocyte antigens, e.g. A, B, D may interfere with
some serological analyses for red blood cell antibodies, for example the antiglobulin
test (Coombs' test).
Transmissible agents
Standard measures to prevent infections resulting from the use of medicinal products prepared from
human blood or plasma include the selection of donors, the screening of individual donations
and plasma pools for specific infection markers and the inclusion of effective production steps for the inactivation/removal of viruses.
However, when administering medicinal products prepared from human blood or plasma,
the possibility of transmitting infectious agents cannot be totally excluded. This applies
also to viruses and other pathogens that are emerging or unknown.
The measures taken are considered effective for enveloped viruses such as the human immunodeficiency virus (HIV), the hepatitis B virus (HBV) and the hepatitis C virus (HCV) and
for the non-enveloped hepatitis A virus (HAV).
The measures taken may have limited value against non-enveloped viruses such as the
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 makes 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 are recorded, in order to maintain traceability between the
patient and the batch of the product.
Important information about the 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 respectively 1.9% and 9.7%
of the maximum recommended daily intake by the WHO which corresponds to 2 g of sodium for an
adult.
This medicinal product contains up to a maximum of 91.9 mg of maltose per ml as excipient.
Interference of maltose with blood glucose tests may lead to an overestimation of glucose values and, consequently, to inadequate insulin administration, which may cause a
life-threatening hypoglycemic state and the death of the patient. In addition, cases of real hypoglycemia
may not be treated if the hypoglycemic state is masked by falsely elevated glucose values. 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
There is clinical evidence demonstrating a relationship between the administration of IVIg and thromboembolic events such as myocardial infarction, stroke (including stroke), pulmonary embolism and deep vein thrombosis which are presumed to be related to a relative increase in
blood viscosity due to a high influx of immunoglobulin in patients at risk.
Caution should be exercised in 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
and a history of vascular diseases or thrombotic episodes, patients with acquired or
congenital thrombophilic disorders, patients immobilized for a prolonged period, severely hypovolemic patients,
patients with diseases that increase blood viscosity).
In patients at risk for thromboembolic adverse reactions, IVIg-based products must be
administered at the minimum practicable infusion rate and dose.
Acute renal failure
Cases of acute renal failure have been reported in patients undergoing therapy with IVIg.
In most cases, risk factors such as pre-existing renal insufficiency, diabetes mellitus, hypovolemia, overweight, concomitant use of nephrotoxic drugs or age over 65 years have been identified.
Renal function should be monitored before administering IVIg, particularly in patients
with a potentially increased risk of developing acute renal failure, and at appropriate intervals
after administration.
In patients at risk of acute renal failure, IVIg-based products must be
administered at the minimum practicable infusion rate and dose. In case of renal damage, interruption of IVIg should be considered.
Although cases of renal dysfunction and acute renal failure have been linked to
the use of many licensed IVIg medicinal 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, the use of IVIg-based products that do not
contain these excipients may be considered. KEYVENB contains maltose (see paragraph “Important

information about the ingredients of KEYVENB”).
Aseptic meningitis syndrome (AMS)
Aseptic meningitis syndrome may occur in combination with IVIg treatment.
Generally the syndrome begins after a period ranging from several hours to 2 days after treatment
with IVIg. Studies on the cerebrospinal fluid often are positive for pleocytosis up to several
thousand cells per mm , especially granulocytes, and elevated protein levels, up to several
hundred mg/dl.
Patients presenting with such signs and symptoms should receive a complete neurological examination,
including CSF studies, to exclude other causes of meningitis.
Discontinuation of IVIg treatment has led to remission of AMS within a few days
without consequences.
Hemolytic anemia
IVIg-based medicinal products contain specific blood group antibodies that may
act as hemolysins and induce, in vivo, the binding of red blood cells with immunoglobulins, causing
a positive direct antiglobulin reaction (Coombs' test) and rarely, hemolysis. Following
IVIg therapy, hemolytic anemia may develop due to increased red blood cell capture.
Subjects 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 treatment with IVIg. This usually occurs within a few hours or days
after IVIg administration and resolves spontaneously within 7-14 days.
Acute lung injury associated with transfusion (TRALI)
Some 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 appear during the transfusion or within 6 hours of the transfusion, often within 1-2 hours.
Therefore, patients receiving IVIg should be monitored and the infusion with the product must
be immediately interrupted in case of the appearance of pulmonary adverse reactions. TRALI is
a condition that may put the patient in a life-threatening situation requiring immediate admission
to intensive care.
Pediatric population
No specific measures or monitoring are required.

Dosage recommendations
Posology
The dose and treatment regimen depend on the indication. The doses indicated below should be
understood as a guideline.
To prevent relapses of hepatitis B after liver transplantation due to liver failure
induced by hepatitis B.

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 patients negative for HBV- DNA and above 500 IU/l in patients positive for HBV-DNA. Paediatric population:The dosage should be adjusted according to body surface area, based on 10,000 IU/1.73 m².

Hepatitis B immunoprophylaxis

• Prevention of hepatitis B in case of accidental exposure in non-immunized subjects: at least 500 IU, based on the intensity of exposure, as soon as possible after exposure, and preferably within 24 - 72 hours.
• Hepatitis B immunoprophylaxis in patients undergoing hemodialysis: 8-12 IU/kg up to a maximum of 500 IU, every 2 months until vaccination has become effective.
• Prevention of hepatitis B in the newborn with a mother carrying the hepatitis B virus, at birth or as soon as possible after birth: 30-100 IU/kg. In clinical practice, the intramuscular route of administration is preferred whenever repeated administrations are necessary to achieve seroconversion after vaccination. The administration of anti-hepatitis B immunoglobulin may be repeated until seroconversion following vaccination.

In all these situations, vaccination against the hepatitis B virus is strongly recommended.
The first dose of vaccine and human anti-hepatitis B immunoglobulins can be injected on the
same day, but in different sites.
In subjects who have not shown an immune response after vaccination (anti-HBs antibodies not
measurable) and for whom continuous prevention is necessary, the administration of 500 IU in adults and 8 IU/kg in children, every 2 months may be considered; it is considered that a minimum protective antibody titer is 10 mUI/ml.
The dose and dosage schedule for the use of human anti-hepatitis B immunoglobulins for intravenous use recommended in other official guidelines should also be considered.

KEYVENB 50 UI/ml Powder and solvent for infusion solution

Human anti-hepatitis B immunoglobulin for intravenous use

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, ask your doctor, pharmacist or nurse.
• If any side effects occur, including those not listed in this leaflet, tell your doctor, pharmacist or nurse. See section 4.

Contents of this leaflet:

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

1. What is KEYVENB and what it is used for

This medicine belongs to a pharmacotherapeutic group called immune sera and
immunoglobulins.
KEYVENB is a solution of human anti-hepatitis B immunoglobulins (proteins that function as antibodies)
for intravenous use and is used in the following therapies:
To prevent relapses of hepatitis B after liver transplantation due to liver failure
induced by the hepatitis B virus in combination with antiviral therapy.
To rapidly provide antibodies against the hepatitis B virus in order to prevent
hepatitis B in the following cases:

• in case of accidental exposure in non-immunized subjects (i.e., in people who are not vaccinated against the hepatitis B virus; including people who are not fully vaccinated or whose vaccination cycle is unknown);
• in patients undergoing hemodialysis (i.e., in patients with severe kidney failure who require blood purification using an artificial kidney), until vaccination has become effective;
• in newborns with a mother carrying the hepatitis B virus;
• in subjects who have not shown an immune response after vaccination (i.e., in people in whom vaccination has not become effective) and for whom continuous prevention is necessary due to the 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 directed against IgA-type immunoglobulins in your blood, as the administration of a product containing IgA may cause a severe allergic reaction.

Warnings and precautions
Consult your doctor, pharmacist or nurse before using KEYVENB.
Blockage of a blood vessel (thrombosis) has been associated with the administration of
normal intravenous immunoglobulin (IVIg). Therefore, your doctor must act with particular
caution when administering this medicine if you have risk factors for thrombosis.
The levels of anti-HBs antibodies present in your blood must be checked regularly.
Some 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 normal human immunoglobulin for the first time;
• in rare cases where the type of human immunoglobulin medicinal product has been changed, or when a long interval has elapsed since the previous infusion.
• In some conditions, immunoglobulins may increase the risk of myocardial infarction, stroke, pulmonary embolism or deep vein thrombosis because they increase theviscosity of the blood.Therefore, your doctor will be particularly careful in the following circumstances:
• if you are overweight,
• if you are elderly,
• if you suffer from diabetes,
• if you have high blood pressure (hypertension),
• if your blood volume is too low (hypovolemia),
• if you have or have had problems with blood vessels (vascular diseases),
• if you have an increased tendency to blood clotting (inherited or acquired thrombophilic disorders),
• if you suffer from thrombotic episodes,
• if you suffer from diseases that increase blood density (viscosity),
• if you have had a prolonged period of immobility,
• if you have or have had kidney problems or if you are taking medicines that can damage the kidneys (nephrotoxic medicines), as cases of acute renal failure have been reported. In case of kidney damage, your doctor will consider interrupting the treatment.
• You may be allergic (hypersensitive) to immunoglobulins (antibodies) without knowing it.This can happen even if you have received normal human immunoglobulin in the past and have tolerated previous administrations. This is particularly likely if you do not have IgA-type 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 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 during the entire infusion period to detect the
appearance of any symptoms.
In case of adverse reactions, your doctor may decide to reduce the infusion rate or stop
the infusion. Furthermore, your doctor will decide the type of treatment required depending on the nature and
severity of the undesirable effect.
KEYVENB contains small amounts of IgA. If you have an IgA deficiency, you may be at risk of
developing anti-IgA antibodies and may develop anaphylactic reactions after the administration of
blood components containing IgA. Your doctor must assess the benefit of treatment with
KEYVENB versus the potential risk of hypersensitivity reactions.
Human anti-hepatitis B immunoglobulins may rarely induce a drop in blood
pressure with anaphylactic reaction, even if you have tolerated previous treatments with
immunoglobulins.
If you suffer from renal failure, your doctor should consider interrupting treatment
with IVIg. Although cases of renal dysfunction and acute renal failure have been linked to the use of many licensed 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 patients at risk for acute renal failure
or thromboembolic adverse reactions, IVIg-based products should be
administered at the lowest practicable infusion rate and dose.
With immunoglobulin-based treatments, you may experience lung damage related to
treatment, called Transfusion Related Acute Lung Injury (TRALI). If you experience shortness of breath, or rapid breathing during the infusion or in the hours
following the infusion, immediately inform your doctor or nurse as emergency treatment may be
necessary.
Suspicion of allergic or anaphylactic reactions requires immediate interruption
of the injection. In case of shock, standard medical treatment for shock must be followed.
Tell your doctor if at least one of the conditions mentioned above applies to you. Your doctor
will take particular care in prescribing and administering KEYVENB to you.
Human intravenous immunoglobulin (IVIg) products may contain
blood group-specific antibodies that can rarely cause the destruction of red blood cells
(hemolysis). For this reason, a form of anemia due to abnormal red blood cell breakdown (hemolytic anemia) may develop following IVIg therapy. Therefore, during treatment
with IVIg, you will be monitored for clinical signs and symptoms of hemolysis.
Blood tests
KEYVENB may interfere with some blood tests due to the temporary increase in various
antibodies that are passively transferred into your blood with the immunoglobulin infusion;
this increase in antibodies may cause some blood tests to have a result that may
not be correct. Passive transfer of antibodies against erythrocyte antigens, e.g. A, B, D
(determining the blood group), may interfere with some 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 the transmission of infections to patients. These measures include:

• careful selection of blood and plasma donors to ensure that those potentially infected are excluded;
• testing of each donation and plasma pool to ensure the absence of infectious agents and/or viruses;
• the inclusion, during the 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 transmission of infectious agents cannot be totally excluded. This also applies to viruses, or other types of infectious agents, emerging or unknown. The measures taken are considered effective for enveloped viruses such as the human immunodeficiency virus (HIV), the hepatitis B virus (HBV), the hepatitis C virus (HCV) and the non-enveloped hepatitis A virus (HAV). The measures taken may have limited value 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 capacity.

It is strongly recommended that each time you are administered KEYVENB, the name and lot
number of the product are recorded, in order to maintain traceability of the lot used.

Children
No specific measures or monitoring are required.

Other medicines and KEYVENB
Tell 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 vaccines based on
live attenuated viruses, such as those for rubella, mumps, measles and varicella. The administration
of immunoglobulins may alter the effectiveness of these vaccines for a period that may last up to 3
months. At least three months must elapse after the administration of KEYVENB before
proceeding with 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 the administration
of human anti-hepatitis B immunoglobulins is necessary within three or four weeks of
vaccination, revaccination should be carried out three months after the administration of
human anti-hepatitis B immunoglobulins.
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 are pregnant, are planning to become pregnant, or are breastfeeding, ask your doctor or pharmacist for advice before using this medicine. The 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. Human intravenous immunoglobulin products have been shown to 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 have harmful effects on the course of pregnancy, the fetus or the newborn.
• If you are breastfeeding and are being treated with KEYVENB, the antibodies contained in the product may pass into breast milk. Therefore, your baby may be protected from some infections. Clinical experience with immunoglobulins suggests that no harmful effects on fertility are to be expected.

Driving and using machines
KEYVENB does not impair or negligibly impairs the ability to drive and operate machinery.
Patients who experience adverse reactions during treatment should wait for their
resolution before driving vehicles or operating machinery.

KEYVENB contains sodium and sucrose.
This medicine contains up to a maximum of 39 mg of sodium (the main component of table
salt) per 10 ml vial and 175.5 mg of sodium per 45 ml vial. The amounts
indicated correspond to 1.9% and 8.7% of the recommended daily intake
of salt with the diet of an adult, respectively.
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 renal failure.

3. How to use KEYVENB

KEYVENB can only be administered in hospital or clinics and nursing homes by doctors or healthcare professionals.
The dosage and treatment regimen depend on the indication; the 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, please refer to the section “ The following information is intended

exclusively for doctors or healthcare professionals”.

If you use more KEYVENB than you should
The consequences of an overdose are unknown.
If you are given more KEYVENB than you should, protein overload may occur
in the fluids and the blood may become too thick (hyperviscous); this is particularly
evident in at-risk patients, especially elderly patients or those with impaired cardiac or renal function.
If you have any further doubts about 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 everyone gets them.

If you notice any of the following side effects, consult your doctor immediately or contact the nearest hospital:

• Allergic reactions (hypersensitivity). This side effect can in some cases progress to acute allergic reaction (anaphylactic shock): for example, itching, skin reactions, swelling of the lips, face and tongue, difficulty swallowing, difficulty breathing, fainting.
• Acute renal failure (for example, decreased or absent urine flow, fluid retention, shortness of breath).

The side effects reported below may generally occur after treatment with intravenous immunoglobulin:

• chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia (joint pain), decreased blood pressure and moderate back pain have been reported occasionally;
• isolated cases of temporary reduction of 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 presented 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 cause myocardial infarction, stroke, pulmonary artery obstruction (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 renal failure;
• cases of acute lung injury associated with transfusion (TRALI).

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

• Headache
• Fast heartbeat (tachycardia)
• Low blood pressure (hypotension)
• Nausea
• Vomiting
• Skin reactions, redness (erythema), tingling, itching
• Joint pain (arthralgia)
• Fever
• General feeling of discomfort
• Chills

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 on the pediatric population.

Reporting of side effects
If you get any side effects, even those not listed in this leaflet, tell your doctor, pharmacist or nurse. You can also report side effects directly to the Italian Medicines Agency (AIFA) through its 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 which is stated on the label and the outer
packaging.
The expiry date refers to the last day of that month.
Do not store at a temperature 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 presents
a change in color (see also the “Description of the appearance of KEYVENB and contents of the

pack”in paragraph 6).
Do not dispose of any medicine in 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 ingredient is human anti-hepatitis B immunoglobulin.
The IgG (type G immunoglobulins) 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 content of IgA is 0.05 mg/ml
Produced from plasma of human donors.
The other components are sucrose, sodium chloride and water for injections.
The powder vial 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 pack of KEYVENB contains a powder vial and a solvent vial with which the solution for administration is prepared.
The powder is white or slightly yellow, or as a friable solid mass.
After reconstitution, the product appears as a clear or slightly opalescent liquid, colorless or slightly yellow.
Before administration, reconstituted products must be visually checked for the presence of suspended particles or abnormal coloration. Do not use turbid solutions or those with deposits.
KEYVENB 50 IU/ml powder and solvent for solution for infusion
Powder vial of 500 IU + solvent vial of 10 ml + infusion set (1 syringe with needle + 1 administration needle).
Powder vial of 2500 IU + solvent vial of 45 ml + infusion set.

Marketing Authorisation 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 (Napoli).

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The following information is intended exclusively for doctors or healthcare professionals:
Instructions for correct use
Before use, bring the product to room or body temperature.
Complete reconstitution must be achieved within 30 minutes.
KEYVENB must be infused intravenously at an initial 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 administration rate must be reduced or the infusion stopped. If well tolerated, the administration rate may be gradually increased to a maximum of 1.85 ml/kg/h (for example for a 65 kg patient at a rate of 40 drops/minute) for the remainder of the infusion.
Reconstitution of the solution, 500 IU vial:

• 1. draw up the solvent with the injection syringe;
• 2. inject the solvent with the same syringe into the vial containing the powder;
• 3. gently shake the vial until the powder is completely dissolved; do not shake vigorously, foam formation should be avoided;
• 4. draw up the resulting solution with the syringe;
• 5. replace the needle and infuse to the patient.

Reconstitution of the solution, 2500 IU vial:

• 1. remove the protective caps from the powder and solvent vials;
• 2. clean the surfaces of the stoppers of the two vials with alcohol;
• 3. insert the smaller needle of the double needle into the vial containing the solvent;
• 4. remove the cap covering the needle on the other side of the double needle, being careful not to touch the second needle;
• 5. invert the solvent vial with the double needle and insert the second needle into the powder vial; when piercing the stopper of the vial containing the powder, the end of the needle in the solvent vial must be in contact with the liquid and not with the air;
• 6. gently shake the vial at room temperature until the powder is completely dissolved;;
• 7. do not shake vigorously: foam formation must be avoided;
• 8. remove the solvent vial with the double needle;
• 9. apply the infusion set and infuse intravenously.

Reconstituted products must be visually inspected for the presence of corpuscles and alterations in color before administration.
After reconstitution, the product is a clear or slightly opalescent liquid and colorless or light yellow.
Turbid solutions or those with deposits must not be used.
KEYVENB must be used immediately after reconstitution with the solvent.
Unused medicinal product and waste derived from such medicinal product must be disposed of in accordance with local regulations.

Precauzioni speciali
Some serious adverse reactions to the product may be due to the rate of infusion.
Potential complications can often be avoided by ensuring:

• that patients are not sensitive to normal human immunoglobulin by administering the product slowly at the beginning (with an infusion rate between 0.46 and 0.92 ml/kg/h);
• that patients are carefully monitored for any symptoms throughout the entire infusion period. In particular, patients receiving normal human immunoglobulin for the first time, patients who have changed the type of IVIg-based product, and patients for whom a long interval has elapsed since the previous infusion, must be monitored during the first infusion and for the first hour after the first infusion, to identify potential signs of adverse reactions. All other patients should be observed for at least 20 minutes after administration.

In all patients, the administration of IVIg requires:

• adequate hydration before the start of IVIg infusion;
• monitoring of urine output;
• monitoring of serum creatinine levels;
• avoiding the concomitant use of loop diuretics. In case of an adverse reaction, the administration rate must be reduced or the infusion must be stopped. The necessary treatment depends on the nature and severity of the undesirable effect. In case of shock, standard medical treatment for shock must be performed.

Infusion reaction
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 carefully followed. Patients
must be closely monitored and carefully observed for any symptoms during
the entire infusion period.
Adverse reactions may occur more frequently:

• in case of a high infusion rate;
• in patients with hypo- or agammaglobulinemia with or without IgA deficiency.

Hypersensitivity
True hypersensitivity reactions are rare.
KEYVENB contains small amounts of IgA. Individuals who have an IgA deficiency may
potentially develop antibodies against IgA and may have anaphylactic reactions after
administration of blood components containing IgA. The doctor must therefore assess the
benefit of treatment with KEYVENB against the potential risk of hypersensitivity reactions.
Rarely, human anti-hepatitis B immunoglobulins may induce a drop in
blood pressure with anaphylactic reaction, even in patients who have tolerated previous treatments
with immunoglobulins.
Patients must be informed about the early signs of hypersensitivity reactions, such as urticaria,
generalized urticaria, a feeling of tightness in the chest, wheezing, hypotension and anaphylaxis. The treatment
required depends on the nature and severity of the adverse reaction.
Suspicion of allergic or anaphylactic reactions requires immediate interruption
of the injection. In case of shock, standard medical treatment for shock must be followed.
Interference with serological tests
After injection of immunoglobulins, the transient increase of various passively transferred antibodies
in the patient's blood may give falsely positive results in serological tests.
Passive transfer of antibodies against erythrocyte antigens, e.g. A, B, D may interfere with
some serological analyses for red blood cell antibodies, for example the antiglobulin
test (Coombs' test).
Transmissible agents
Standard measures to prevent infections resulting from the use of medicinal products prepared from
human blood or plasma include donor selection, screening of individual donations
and plasma pools for specific infection markers and the inclusion of effective production steps for
virus inactivation/removal.
However, when administering medicinal products prepared from human blood or plasma,
the possibility of transmitting infectious agents cannot be completely excluded. This applies
also to viruses and other emerging or unknown pathogens.
The measures taken are considered effective for enveloped viruses such as the human immunodeficiency virus (HIV), the hepatitis B virus (HBV) and the hepatitis C virus (HCV) and
for the non-enveloped hepatitis A virus (HAV).
The measures taken may have limited value against non-enveloped viruses such as the
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 contributes significantly to viral safety.
It is strongly recommended that whenever KEYVENB is administered to a patient, the
name and batch number of the product are recorded, in order to maintain traceability between the
patient and the product batch.
Important information about the ingredients of KEYVENB
This medicine 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 recommended daily intake by the WHO which corresponds to 2 g of sodium for an
adult. This medicine contains up to 92 mg of sucrose per ml (91.9 mg/ml). To be taken into
consideration in patients at risk of acute renal failure.

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

for

intravenous use:
Thromboembolism
There is clinical evidence demonstrating a relationship between the administration of IVIg and thromboembolic events such as myocardial infarction, stroke (including stroke), pulmonary embolism and deep vein thrombosis which are 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
and a history of vascular diseases or thrombotic episodes, patients with acquired or
congenital thrombophilic disorders, patients immobilized for a prolonged period, patients severely hypovolemic,
patients with diseases that increase blood viscosity).
In patients at risk for thromboembolic adverse reactions, IVIg-based products must be
administered at the minimum infusion rate and dose practicable.
Acute renal insufficiency
Cases of acute renal insufficiency 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 should be monitored before administering IVIg, particularly in patients
with a potentially increased risk of developing acute renal insufficiency, and at adequate intervals
after administration.
In patients at risk of acute renal insufficiency, IVIg-based products should be
administered at the minimum infusion rate and dose practicable. In case of renal damage, it
should be considered to discontinue IVIg.
Although cases of renal dysfunction and acute renal failure have been linked to
the use of many licensed IVIg medicinal 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, the use of IVIg products that do not
contain these excipients should be considered. KEYVENB contains sucrose (see paragraph 2, “KEYVENB

contains sodium and sucrose”).
Aseptic meningitis syndrome (AMS)
Aseptic meningitis syndrome may occur in combination with IVIg treatment.
Generally the syndrome begins after a period ranging from several hours to 2 days after treatment
with IVIg. Studies on cerebrospinal fluid often are positive for pleocytosis up to several
thousands of cells per mm3, especially granulocytes, and high protein levels, up to several
hundreds of mg/dl.
Patients presenting with such signs and symptoms should receive a complete neurological examination,
including CSF studies, to exclude other causes of meningitis.
Discontinuation of treatment with IVIg has led to remission of AMS within a few days
without consequences.
Hemolytic anemia
IVIg-based medicinal products contain blood group-specific antibodies that may
act as hemolysins and induce, in vivo, the binding of red blood cells with immunoglobulins, causing
a positive direct antiglobulin reaction (Coombs' test) and rarely, hemolysis. Following
IVIg therapy, hemolytic anemia due to increased red blood cell uptake may develop. Subjects 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 usually 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 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 appear during the transfusion or within 6 hours of the transfusion, often within 1-2 hours.
Therefore, patients receiving IVIg should be monitored and the infusion with the product must
be immediately stopped if adverse pulmonary reactions occur. TRALI is
a life-threatening condition requiring immediate admission to
intensive care unit.
Pediatric population
No specific measures or monitoring are required.

Raccomandazioni sul dosaggio
Dosage
The dose and treatment regimen depend on the indication. The doses indicated below are to
be understood as a guideline.
To prevent recurrence of hepatitis B 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 patients negative for HBV- DNA and above 500 IU/l in patients positive for HBV-DNA. Pediatric population:The dosage should be adjusted according to body surface area, based on 10,000 IU/1.73 m .

Immunoprophylaxis of hepatitis B

• Prevention of hepatitis B in case of accidental exposure in non-immunized subjects: at least 500 IU, based on the intensity of exposure, as soon as possible after exposure, and preferably within 24 - 72 hours.
• Immunoprophylaxis of hepatitis B in patients undergoing hemodialysis: 8-12 IU/kg up to a maximum of 500 IU, every 2 months until seroconversion following vaccination. • Prevention of hepatitis B in the newborn with a mother carrier of the hepatitis B virus, at birth or as soon as possible after birth: 30-100 IU/kg. In clinical practice, the intramuscular route is preferred whenever repeated administrations are necessary to achieve seroconversion after vaccination. The administration of anti-hepatitis B human immunoglobulin may be repeated until seroconversion following vaccination.

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