HEPATECT 50 IU/ml SOLUTION FOR INFUSION

2. What you need to know before you use Hepatect

Do not use Hepatect,

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

Warnings and precautions

Consult your doctor, pharmacist, or nurse before using Hepatect

• if you have not received this medicine before or if it has been a long time (e.g., several weeks) since you last received it (you will need close monitoring during infusion and for at least one hour after infusion).

• if you have recently received Hepatect (you will need observation during infusion and for at least 20 minutes after infusion).

• if you have an untreated infection or underlying chronic inflammation.

• if you have had a reaction to other antibodies (in rare cases, you may be at risk of an allergic reaction).

• if you have kidney disease.

• if you have received medicines that can harm your kidneys (if kidney function worsens, it may be necessary to discontinue treatment with Hepatect).

Your doctor will be particularly careful if you are overweight, elderly, have diabetes, or suffer from hypertension, decreased blood volume (hypovolemia), if your blood is thicker than normal (increased blood viscosity), you are bedridden or have been immobile for some time (immobilization), or have vascular problems or other risks of thrombotic events (blood clots).

Remember: reactions

During the Hepatect infusion period, you will be closely monitored to ensure you do not experience any reactions (e.g., anaphylaxis). Your doctor will ensure that the infusion rate of Hepatect is suitable for your case.

If you notice any of the following signs of a reaction, such as headache, flushing, chills, muscle pain, wheezing, rapid heartbeat, back pain, nausea, or low blood pressure during Hepatect infusion, inform your doctor immediately. The infusion rate may be reduced or stopped completely.

Information on transmission of infectious agents

When administering medicines derived from human plasma or blood, certain measures must be taken to prevent the transmission of infections to patients. These measures include:

• careful selection of donors to exclude those at risk of carrying infectious diseases.
• testing for specific infection markers in individual donations and plasma pools.
• inclusion of steps in the manufacturing process to eliminate/inactivate viruses.

Despite these measures, when administering medicines derived 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 infections.

These measures 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 value against non-enveloped viruses, such as hepatitis A virus and parvovirus B19.

Immunoglobulins have not been associated with the transmission of hepatitis A or parvovirus B19 infections, possibly due to the protective effect of the antibody content against these infections in the medicine.

It is strongly recommended that each time a dose of Hepatect is administered, the name of the medicine and batch number administered should be recorded to maintain a record of the batches used.

Using Hepatect with other medicines

Tell your doctor or pharmacist if you are taking or have recently taken any other medicines.

Hepatect may reduce the effectiveness of some vaccines, such as:

• measles vaccine
• rubella vaccine
• mumps vaccine
• varicella vaccine

You may need to wait 3 months before receiving certain vaccines or up to 1 year for measles vaccination.

Avoid concomitant use of loop diuretics with Hepatect.

Pregnancy, breastfeeding, and fertility

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

Your doctor will decide whether you can use Hepatect during pregnancy or breastfeeding.

Driving and using machines

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

3. How to use Hepatect

Hepatect is intended for intravenous administration (infusion into a vein). It will be administered by your doctor or nursing staff. The recommended dose will depend on your condition and body weight. Your doctor will know the appropriate amount to administer.

At the start of the infusion, Hepatect will be administered at a slow rate. Then, your doctor may gradually increase the infusion rate.

If you have any further questions on the use of this product, ask your doctor or nursing staff.

If you use more Hepatect than you should:

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

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 in clinical trials with Hepatect:

Not known: frequency cannot be estimated from the available data

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

Human normal immunoglobulin preparations may generally cause the following side effects (in decreasing frequency):

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

If you experience any side effects, the infusion rate will be reduced or stopped.

Reporting of side effects

If you experience any side effects, talk to your doctor, pharmacist, or nurse, even if they are not listed in this leaflet. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines: https://www.notificaram.es.

By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Hepatect

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 outer packaging and on the label of the vial.

Store the vial in the outer packaging to protect it from light.

Store in a refrigerator (between 2°C and 8°C). Do not freeze.

The solution should be clear or slightly opalescent and colorless to pale yellow. Do not administer solutions that are cloudy or have deposits.

The solution should be administered immediately after opening the container. The product should be at room temperature or body temperature before administration.

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

6. Container Content and Additional Information

Hepatect Composition:

• The active ingredient of Hepatect is human anti-hepatitis B immunoglobulin for intravenous administration.

Hepatect contains 50 mg/ml of human plasma protein, of which at least 96% is immunoglobulin G (IgG). The content of anti-hepatitis B antibodies is 50 IU/ml. The maximum content of immunoglobulin A (IgA) is 2,000 micrograms/ml. The approximate distribution by IgG subclasses is: 59% IgG1, 35% IgG2, 3% IgG3, and 3% IgG4.

• The other components are glycine and water for injectable preparations.

Product Appearance and Container Content

Hepatect is a solution for infusion. The solution is transparent or slightly opalescent (milky color like opal) and colorless or pale yellow.

Container size of 1 vial with 2 ml, 10 ml, 40 ml, or 100 ml of solution.

Marketing Authorization Holder and Manufacturer:

Biotest Pharma GmbH

Landsteinerstrasse 5

63303 Dreieich

Germany

Phone: +49 6103 801-0

Fax: +49 6103 801-150

e-mail: [email protected]

For more information about this medication, please contact the local representative of the marketing authorization holder:

Grifols Movaco, S.A.

Can Guasc, s/n – Parets del Vallès

08150 Barcelona

Spain

Date of the Last Revision of this Prospectus: 11/2019

Detailed and updated information about this medication is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.gob.es/

This information is intended only for healthcare professionals:

Administration Route

Intravenous route

Hepatect should be infused intravenously at an initial rate of 0.1 ml/kg body weight/hour for 10 minutes. In case of adverse reactions, the administration rate will be reduced or the infusion will be interrupted. If well tolerated, the administration rate can be gradually increased up to a maximum of 1 ml/kg body weight/hour.

Clinical experience with newborns of mothers carrying the hepatitis B virus has shown that intravenous infusion of Hepatect at a rate of 2 ml in 5 to 15 minutes is well tolerated.

Special Precautions

Monitoring of anti-HBs antibody levels:

Serum levels of anti-HBs antibodies in patients should be periodically monitored. The dose should be adjusted to maintain therapeutic levels of antibodies and to avoid insufficient dosing (see the posology section).

Especially when applying higher doses, the administration of human intravenous immunoglobulin requires:

• adequate hydration before starting the infusion of human immunoglobulins
• monitoring of diuresis
• monitoring of serum creatinine levels
• avoiding concomitant use of loop diuretics

In case of an adverse reaction, the infusion rate will be reduced or the infusion will be suspended. Treatment depends on the nature and intensity of the adverse reaction.

Hypersensitivity

Hypersensitivity reactions are rare. Rarely, human anti-hepatitis B immunoglobulin may induce a drop in blood pressure with anaphylactic reaction, even in patients who have tolerated previous treatments with immunoglobulin.

Suspicion of an allergic or anaphylactic reaction requires immediate interruption of the infusion. In case of shock, standard medical guidelines for shock treatment should be followed.

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

Thromboembolism

There is clinical evidence of the association between the administration of IVIg and the occurrence of thromboembolic events, such as myocardial infarction, stroke (including stroke), pulmonary embolism, and deep vein thrombosis, which is believed to be related to a relative increase in blood viscosity due to the high flow of immunoglobulin in patients at risk. Caution should be exercised when prescribing and administering IVIg in obese patients and in patients with pre-existing risk factors for thrombotic events (such as advanced age, hypertension, diabetes mellitus, and history of vascular disease or thrombotic episodes, patients with acquired or hereditary thrombophilic disorders, patients with prolonged periods of immobilization, patients with severe hypovolemia, patients with diseases that increase blood viscosity).

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

Acute Renal Failure

Cases of acute renal failure have been reported in patients receiving IVIg therapy. In most cases, risk factors have been identified, such as pre-existing renal insufficiency, diabetes mellitus, hypovolemia, overweight, concomitant nephrotoxic medications, or age over 65.

Before IVIg infusion, renal parameters should be evaluated, especially in patients considered to be at higher 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 minimum infusion rate and viable dose. In case of renal failure, IVIg suspension should be considered.

Although reports of renal dysfunction and acute renal failure have been associated with the administration of many authorized IVIg products containing various excipients such as sucrose, glucose, and maltose, those containing sucrose as a stabilizer account for a disproportionate part of the total number. In patients at risk, the use of human immunoglobulin products that do not contain these excipients could be considered. Hepatect does not contain sucrose, maltose, or glucose.

Aseptic Meningitis Syndrome (AMS)

The occurrence of aseptic meningitis syndrome associated with IVIg treatment has been reported.

The syndrome usually begins several hours to 2 days after IVIg treatment. Cerebrospinal fluid studies are often positive, revealing pleocytosis of up to several thousand cells per mm³, predominantly of the granulocytic series, and elevated protein levels of up to several hundred mg/dl.

AMS may occur more frequently in association with high-dose IVIg treatments (2 g/kg).

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

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

Hemolytic Anemia

IVIg products may contain antibodies against blood groups that could act as hemolysins and induce the coating of red blood cells with immunoglobulin in vivo, resulting in a positive direct antiglobulin test (Coombs test) and, rarely, hemolysis. Hemolytic anemia may develop after IVIg treatment due to increased red blood cell sequestration. Clinical signs and symptoms of hemolysis should be monitored in IVIg recipients.

Neutropenia/Leukopenia

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

Transfusion-Related Acute Lung Injury (TRALI)

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

Interference with Serological Tests

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

Posology

Unless otherwise prescribed, these recommendations will be followed:

Prevention of hepatitis B reinfection after liver transplantation due to hepatitis B-induced liver failure:

In adults:

10,000 IU on the day of transplantation, during the perioperative period

continuing with 2,000-10,000 IU (40-200 ml)/day for 7 days,

and as necessary to maintain antibody levels above 100-150 IU/l in HBV-DNA negative patients and above 500 IU/l in those HBV-DNA positive.

In children:

The posology will be adjusted according to body surface area based on 10,000 IU/1.73 m².

Hepatitis B Immunoprophyllaxis:

• Prevention of hepatitis B in case of accidental exposure of non-immunized subjects:

As soon as possible after exposure, preferably within the first 24-72 hours, at least 500 IU (10 ml) will be administered, depending on the intensity of the exposure.

• Hepatitis B immunoprophyllaxis in hemodialysis patients:

8-12 IU (0.16-0.24 ml)/kg with a maximum of 500 IU (10 ml) will be administered every 2 months until seroconversion occurs after vaccination.

• Prevention of hepatitis B in newborns of mothers carrying the hepatitis B virus at birth or as soon as possible after birth: 30-100 IU (0.6-2 ml)/kg. Human anti-hepatitis B immunoglobulin may be administered repeatedly until seroconversion occurs after vaccination.

In all these situations, vaccination against the hepatitis B virus is strongly recommended. The first dose of the vaccine can be injected on the same day as the human anti-hepatitis B immunoglobulin, although at different sites.

In subjects who did not show an immune response (unmeasurable anti-hepatitis B antibodies) after vaccination and who require continuous prevention, administration of 500 IU (10 ml) in adults and 8 IU (0.16 ml)/kg in children every 2 months may be considered; the minimum protective antibody titre is considered 10 mIU/ml.