Neohepatect

Patient Information Leaflet

neoHepatect 50 IU/ml infusion solution

Human anti-hepatitis B immunoglobulins for intravenous administration
Information for healthcare professionals is provided at the end of this leaflet, in a separate section.
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.
• This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, as it may be harmful.
• If you experience any adverse reaction, including those not listed in this leaflet, consult your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet:

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

1. What neoHepatect is and what it is used for

neoHepatect contains as its active substance human hepatitis B immunoglobulins, which can
protect against hepatitis B. Hepatitis B is an inflammation of the liver caused by the hepatitis
B virus. neoHepatect is a solution for infusion (into a vein) and is available in vials containing 2
ml (100 international units [IU]), 10 ml (500 IU), 40 ml (2000 IU), and 100 ml (5000 IU).
neoHepatect is used to provide immediate and long-term immunity (protection) to:

• prevent hepatitis B infection in patients who are unvaccinated or not yet fully vaccinated against hepatitis B and who are at risk of hepatitis B infection.
• prevent infection of a transplanted liver in patients who test positive for hepatitis B.
• newborns whose mothers are infected with the hepatitis B virus.
• protect patients for whom hepatitis B vaccination has not provided adequate protection.

2. What you need to know before using neoHepatect

Do not use neoHepatect

• if you are allergic to human immunoglobulins or to any of the other ingredients of this medicine (listed in section 6).
• if you have immunoglobulin A (IgA) deficiency, especially if you have antibodies against IgA in your blood, as this may cause anaphylaxis.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using neoHepatect if

• you have not previously received this medicine or if there has been a long interval (e.g. several weeks) since your last dose (you will need to be closely monitored during the infusion and for one hour after the infusion has ended)
• you have recently received neoHepatect (you will need to be monitored during the infusion and for at least 20 minutes after the infusion)
• you have an untreated infection or an underlying chronic inflammation
• you have previously experienced a reaction to other antibodies (in rare cases, you may be at risk of allergic reactions)
• you have or have had kidney disease
• you have received medicines that may damage the kidneys (if kidney function worsens, treatment with neoHepatect may need to be discontinued). Your doctor will pay particular attention if you are overweight, elderly, diabetic, have high blood pressure, low blood volume (hypovolemia), increased blood viscosity (thick blood), have been bedridden or immobile for a period (immobilization), or have blood vessel disorders (vascular diseases) or other risk factors for thrombotic events (blood clots).

Caution – Reactions
You will be closely monitored during the infusion with neoHepatect to ensure that you do not have a reaction (e.g. anaphylaxis). Your doctor will ensure that the infusion rate of neoHepatect is appropriate for you.
If any of the following signs of a reaction occur, such as headache, flushing, chills, muscle pain, wheezing, rapid heartbeat, back pain, nausea, or low blood pressure during the infusion of neoHepatect, inform your doctor immediately. The infusion rate may be reduced or the infusion may be stopped completely.

Information on transmission of infectious agents
neoHepatect is derived from human plasma (the liquid part of blood).
For medicines derived from human blood or plasma, certain measures are taken to prevent transmission of infections to patients. These include:

• careful selection of plasma and blood donors to exclude individuals who may carry infections,
• testing of each donation and pooled plasma for signs of viruses/infection,
• inclusion of manufacturing steps capable of inactivating or removing viruses during blood or plasma processing.

Despite these measures, when medicines derived from human blood or plasma are administered, the risk of transmitting infections cannot be completely excluded. This also applies to unknown or new viruses or other types of infections.
The measures taken are considered effective against enveloped viruses, such as human immunodeficiency virus (HIV), hepatitis B virus, and hepatitis C virus.
The measures taken may have limited effectiveness against non-enveloped viruses, such as hepatitis A virus and parvovirus B19.
Immunoglobulins have not been associated with hepatitis A or parvovirus B19 infection, likely because the antibodies directed against these infections contained in the product are protective.
It is strongly recommended to record the name and batch number of the medicine each time a patient receives a dose of neoHepatect, in order to maintain documentation of the batches used.

Other medicines and neoHepatect
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
neoHepatect may reduce the effectiveness of certain vaccines, such as those against:

• measles
• rubella
• mumps
• varicella

It may be necessary to wait up to 3 months before receiving a vaccination and up to 1 year before receiving the measles vaccine.

Avoid concomitant use of loop diuretics with neoHepatect.

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 taking this medicine.
Your doctor will decide whether neoHepatect can be used during pregnancy and breastfeeding.

Driving and using machines
neoHepatect may slightly impair the ability to drive or operate machinery. If adverse reactions occur during treatment, you should wait until they resolve before driving or operating machinery.

3. How to use neoHepatect

neoHepatect is intended for intravenous administration (infusion into a vein). The product is administered by a doctor or a nurse. The recommended dose will depend on clinical conditions and body weight. The doctor will determine the correct amount to administer.
Initially, the infusion rate of neoHepatect will be low, but later the doctor may gradually increase it.
If you wish to ask further questions about the use of this product, please consult your doctor or nurses.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
The following side effects have been reported spontaneously with neoHepatect:
Frequency not known: frequency cannot be estimated from the available data

• severe allergic reactions (anaphylactic shock)
• hypersensitivity reactions
• headache
• dizziness
• increased heart rate (tachycardia)
• low blood pressure (hypotension)
• nausea
• skin reactions such as rash, itching
• fever
• malaise

Normal human immunoglobulin preparations may cause the following side effects
(in decreasing order of frequency):

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

If a side effect occurs, the infusion should be slowed down or stopped completely.
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 national reporting system at 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 neoHepatect

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the outer carton and on the label
of the vial.
Keep the vial in the outer packaging to protect the medicine from light. Store in the
refrigerator (2 °C – 8 °C). Do not freeze.
The solution should be clear or slightly opalescent and colourless to pale yellow. Do not
use solutions that are cloudy or contain deposits.
The solution should be administered immediately after opening the container. The product must be brought to room temperature or body temperature before use.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

6. Package contents and other information

What neoHepatect contains:

• The active substance of neoHepatect is human anti-hepatitis B immunoglobulins for intravenous administration. neoHepatect contains 50 mg/ml of human plasma proteins, of which at least 96% are immunoglobulin G (IgG). The anti-hepatitis B antibody content is at least 50 IU/ml. The maximum content of immunoglobulin A (IgA) is 2,000 micrograms/ml. The distribution of IgG subclasses is approximately 59% IgG1, 35% IgG2, 3% IgG3 and 3% IgG4.
• The excipients are glycine and water for injections.

Description of the appearance of neoHepatect and contents of the pack
neoHepatect is a solution for infusion. The solution is clear or slightly opalescent (milky appearance similar to opal) and colourless or pale yellow.
Pack containing 1 vial of 2 ml, 10 ml, 40 ml or 100 ml of solution.
Marketing Authorisation Holder and Manufacturer:
Biotest Pharma GmbH
Landsteinerstrasse 5
63303 Dreieich
Germany
Tel.: +49 6103 801-0
Fax: +49 6103 801-150
Email: [email protected]

The following information is intended exclusively for physicians or healthcare professionals:
Method of administration
For intravenous use
neoHepatect should be administered by intravenous infusion at an initial rate of 0.1 ml/kg body weight/hour for 10 minutes. In case of adverse reaction, reduce the infusion rate or stop the infusion. If well tolerated, the infusion rate may be gradually increased up to a maximum of 1 ml/kg/hour.
Clinical experience in neonates born to hepatitis B virus carrier mothers has shown that intravenous administration of neoHepatect at an infusion rate of 2 ml over 5–15 minutes is well tolerated.
Special precautions
Monitoring of anti-HBs antibody levels
Patients must be regularly monitored to check serum levels of anti-HBs antibodies. The dosage should be adjusted to maintain therapeutic antibody levels and to avoid underdosing (see Dosage section).
Particularly when administered at high doses, intravenous administration of human immunoglobulins requires:

• adequate hydration before starting immunoglobulin infusion
• monitoring of urinary output
• monitoring of serum creatinine levels
• avoidance of concomitant use of loop diuretics.

In case of adverse reaction, reduce the infusion rate or stop the infusion. The required treatment depends on the nature and severity of the adverse reaction.
Hypersensitivity
Hypersensitivity reactions are rare. Rarely, human anti-hepatitis B immunoglobulins may induce a drop in blood pressure with anaphylactic reaction, even in patients who have previously tolerated immunoglobulin treatment.
Suspicion of allergic or anaphylactic-type reactions requires immediate discontinuation of the infusion. In case of shock, standard medical treatment for shock must be initiated.
The following adverse reactions have been associated with the use of normal human immunoglobulins for intravenous administration (IVIG):
Thromboembolism
There is clinical evidence of an association between IVIG administration and thromboembolic events such as myocardial infarction, cerebrovascular accidents (including stroke), pulmonary embolism and deep vein thrombosis, which are presumed to be related to a relative increase in blood viscosity caused by the high influx of immunoglobulins in at-risk patients. Prescribing and infusion of IVIG require caution 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 inherited thrombophilic disorders, patients with prolonged immobilization, patients with severe hypovolemia, patients with conditions increasing blood viscosity).
In patients at risk of 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 receiving IVIG therapy.
In most cases, risk factors were identified, such as pre-existing renal insufficiency, diabetes mellitus, hypovolemia, obesity, concomitant use of nephrotoxic medicinal products, or age over 65 years.
Renal parameters should be checked before IVIG infusion, especially in patients considered at potentially increased risk of developing acute renal failure, and again at appropriate intervals. 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 impairment, discontinuation of IVIG should be considered.
While reports 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 accounted for a disproportionate share of the total number.
In at-risk patients, use of products containing human immunoglobulins without these excipients may be considered. neoHepatect does not contain sucrose, maltose or glucose.
Aseptic Meningitis Syndrome (AMS)
Aseptic meningitis syndrome has been reported in association with IVIG treatment.
The syndrome usually begins several hours to 2 days after IVIG treatment. Cerebrospinal fluid (CSF) studies are frequently positive, showing pleocytosis up to several thousand cells/mm³, predominantly granulocytic, and elevated protein levels up to several hundred mg/dl.
AMS may occur more frequently in association with high-dose IVIG treatment (2 g/kg).
Patients presenting such signs and symptoms should undergo a thorough neurological examination, including CSF studies, to exclude other causes of meningitis.
Discontinuation of IVIG treatment has led to resolution of AMS within a few days without sequelae.
Hemolytic anemia
IVIG products may contain blood group antibodies that can act as hemolysins and induce in vivo coating of red blood cells by immunoglobulins, resulting in a positive direct antiglobulin reaction (Coombs test) and, rarely, hemolysis. Hemolytic anemia may develop following IVIG therapy due to increased sequestration of red blood cells (RBCs). Recipients of 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 hours or days after IVIG administration and resolves spontaneously within 7–14 days.
Transfusion-Related Acute Lung Injury (TRALI)
Cases of acute non-cardiogenic pulmonary edema (TRALI) have been described in patients receiving IVIG. TRALI is characterized by severe hypoxia, dyspnea, tachypnea, cyanosis, fever and arterial hypotension. TRALI symptoms usually develop during or within 6 hours after infusion, often within 1–2 hours. Therefore, recipients of IVIG should be monitored and IVIG infusion must be immediately stopped in case of pulmonary adverse reactions. TRALI is a potentially life-threatening condition requiring immediate management in an intensive care unit.
Interference with serological testing
Following immunoglobulin administration, the transient increase of various passively transferred antibodies in the patient's blood may lead to false-positive results in serological tests.
Dosage
If not otherwise prescribed, the following recommendations apply:
Prevention of hepatitis B virus reinfection after liver transplantation for liver failure caused by hepatitis B:
In adults:
Administer 10,000 IU of neoHepatect on the day of transplantation, during surgery,
followed by 2,000 to 10,000 IU (40 ml to 200 ml) daily for seven days,
and when necessary, to maintain antibody levels above 100–150 IU/l in HBV-DNA negative patients and above 500 IU/l in HBV-DNA positive patients.
In children:
The dosage is based on body surface area, at 10,000 IU/1.73 m².
Hepatitis B immunoprophylaxis:

• Prevention of hepatitis B following accidental exposure to the virus in non-immune individuals: at least 500 IU (10 ml), depending on the intensity of viral exposure, as soon as possible after exposure and preferably within 24–72 hours.
• Hepatitis B immunoprophylaxis in haemodialysis patients: 8–12 IU (0.16–0.24 ml)/kg up to a maximum of 500 IU (10 ml) every two months until seroconversion following vaccination.
• Prevention of hepatitis B in newborns of hepatitis B virus carrier mothers: 30–100 IU (0.6–2 ml)/kg at birth or as soon as possible after birth. Administration of hepatitis B immunoglobulin should be repeated until seroconversion following vaccination.

In all these situations, vaccination against hepatitis B virus is strongly recommended. The first dose of vaccine may be administered on the same day as neoHepatect but at a different injection site.
In individuals who do not show signs of immune response (indeterminate anti-hepatitis B antibodies) following vaccination and for whom continuous prevention is required, administration of 500 IU (10 ml) in adults and 8 IU (0.16 ml)/kg in children every two months may be considered; the minimum protective antibody titre against the virus is 10 mIU/mL.