1. Name Of The Medicinal Product
Zutectra
2. Qualitative And Quantitative Composition
One pre-filled syringe of 1 ml contains Human hepatitis B immunoglobulin 500 IU.
Human protein 150 mg/ml of which at least 96 % is IgG, with a content of antibodies to hepatitis B virus surface antigen (HBs) of 500 IU/ml.
Distribution of IgG subclasses:
IgG1: 59 %
IgG2: 35 %
IgG3: 3 %
IgG4: 3 %
IgA content max. 6 mg/ml.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Solution for injection in pre-filled syringe.
The solution is clear and pale yellow or light brown.
4. Clinical Particulars
4.1 Therapeutic Indications
Prevention of hepatitis B virus (HBV) re-infection in HBV-DNA negative patients
Zutectra is indicated in adults only.
The concomitant use of adequate virostatic agents should be considered, if appropriate, as standard of hepatitis B re-infection prophylaxis.
4.2 Posology And Method Of Administration
Posology
In HBV-DNA negative adults
- patients with bodyweight < 75 kg: 500 IU (1 ml)/week
- patients with bodyweight
Prior to the initiation of subcutaneous treatment with Zutectra, anti-HBs serum levels should be stabilised with an adequate intravenous hepatitis B immunoglobulin to levels at or above 300
Patients must be monitored for serum anti-HBs antibody levels regularly.
There is no relevant indication for use of Zutectra in children.
Method of administration
Zutectra should be administered via the subcutaneous route.
Zutectra is accompanied by a package leaflet with detailed instruction for use to be followed. Injection of the medicinal product by the patient or by caregiver in a home treatment requires training by a physician experienced in the guidance of patients for home treatment. The patient or caregiver will be instructed in injection techniques, the keeping of a treatment diary and measures to be taken in case of severe adverse events. A sufficient surveillance period with stable anti-HBs trough serum levels of> 100 IU/l as well as a fixed dosage regimen is required. In addition patient or caregiver must comply with the injection technique as well as with the dosing regimen to ensure anti-HBs trough serum levels> 100 IU/l after extended periods between level controls.
4.3 Contraindications
Hypersensitivity to any of the components.
Hypersensitivity to human immunoglobulins.
Zutectra must not be administered intravascularly.
4.4 Special Warnings And Precautions For Use
Ensure that Zutectra is not administered into a blood vessel, because of the risk of shock.
If the recipient is a carrier of HBsAg, there is no benefit in administering this medicinal product.
There is no data about efficacy in post-exposure prophylaxis.
True hypersensitivity reactions are rare.
Zutectra contains a small quantity of IgA. Individuals who are deficient in IgA have the potential for developing IgA antibodies and may have anaphylactic reactions after administration of blood components containing IgA. The physician must therefore weigh the benefit of treatment with Zutectra against the potential risk of hypersensitivity reactions.
Rarely, human hepatitis B immunoglobulin can induce a fall in blood pressure with anaphylactic reaction, even in patients who have tolerated previous treatment with human immunoglobulin.
Potential complications can often be avoided by ensuring that:
- patients are not sensitive to human normal immunoglobulin, by first injecting the medicinal product slowly;
- patients are carefully monitored for any symptoms throughout the injection. The patients should be observed for at least 20 minutes after administration.
Suspicion of allergic or anaphylactic type reactions requires immediate discontinuation of the injection. In case of shock, standard medical treatment for shock should be implemented.
Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.
The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV, and for the non-enveloped virus HAV. The measures taken may be of limited value against non-enveloped viruses such as parvovirus B19.
There is reassuring clinical experience regarding the lack of hepatitis A or parvovirus B19 transmission with immunoglobulins and it is also assumed that the antibody content makes an important contribution to the viral safety.
It is strongly recommended that every time that Zutectra is administered to a patient, the name and batch number of the medicinal product are recorded in order to maintain a link between the patient and the batch of the medicinal product. This recommendation applies also for documentation in the treatment diary during self-administration of the medicinal product in a home treatment.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Live attenuated virus vaccines
Immunoglobulin administration may interfere with the development of an immune response to live attenuated virus vaccines such as rubella, mumps, measles and varicella for a period of 3 months. After administration of this medicinal product, an interval of at least 3 months should elapse before vaccination with live attenuated virus vaccines.
Human hepatitis B immunoglobulin should be administrated three to four weeks after vaccination with such a live attenuated vaccine; in case administration of human hepatitis B immunoglobulin is essential within three to four weeks after vaccination, then revaccination should be performed three months after the administration of human hepatitis B immunoglobulin.
Interference with serological testing
After injection of immunoglobulin the transitory rise of the various passively transferred antibodies in the patient's blood may result in misleading positive results in serological testing.
Passive transmission of antibodies to erythrocyte antigens, e.g. A, B, D may interfere with some serological tests for red cell antibodies, for example the antiglobulin test (Coombs' test).
4.6 Pregnancy And Lactation
The safety of this medicinal product for use in human pregnancy has not been established in controlled clinical trials and therefore should only be given with caution to pregnant women and breast-feeding mothers. Clinical experience with immunoglobulins suggests that no harmful effects on the course of pregnancy, or on the foetus and the neonate are to be expected.
4.7 Effects On Ability To Drive And Use Machines
No effects on ability to drive and use machines have been observed.
4.8 Undesirable Effects
The following undesirable effects have been reported in the context of 697 subcutaneous applications of Zutectra during two completed clinical trials.
Most adverse drug reactions (ADRs) observed in the two clinical trials were mild to moderate in nature.
The ADRs reported in the two trials are summarised and categorised according to the MedDRA system organ class and frequency below. Frequency per injection has been evaluated using the following criteria: very common (
The effects were grouped by system organ classes under relevant medical headings.
Unspecific hypersensitivity reactions:
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Injection site reactions:
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Other:
Additionally the following single case reports have been received from completed clinical trials:
General disorders and administration site conditions: fatigue, tiredness.
With normal immunoglobulins adverse reactions such as chills, headache, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure and moderate low back pain may occur occasionally.
Rarely human normal immunoglobulins may cause a sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even when the patient has shown no hypersensitivity to previous administration.
Local reactions at injection sites: swelling, soreness, redness, induration, local heat, itching, bruising and rash.
For safety with respect to transmissible agents, see section 4.4.
4.9 Overdose
Consequences of an overdose are not known.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Specific immunoglobulins, ATC code: J06BB04
Zutectra contains mainly immunoglobulin G (IgG) with a specifically high content of antibodies against hepatitis B virus surface antigen (HBs).
Clinical experience
The open, prospective, single-arm clinical trial (Biotest 958) enrolled 23 liver transplant recipients, who had been receiving intravenous hepatitis B immunoglobulin prophylaxis and subsequently switched to subcutaneous Zutectra. The weekly subcutaneous dose was 500 IU for patients with bodyweight < 75 kg (a dose increase to 1000 IU was allowed, if medically required to maintain a safety level of> 100 IU) and 1000 IU for patients with bodyweight
The mean anti-HBs serum level before switching was 393±139 IU/l. All patients used antiviral medication.
Using the Clopper Pearson method, the failure rate after 18 weeks was 0 % for patients of the ITT set (95 % CI: [0, 14.8 %]). A failure rate of 0 % was also found for the facultative extension phase (week 24) (95 % CI: [0, 20.6 %])
5.2 Pharmacokinetic Properties
Zutectra is slowly absorbed into the recipient's circulation and reaches a maximum after a delay of 2
Zutectra has a half-life of about 3
IgG and IgG-complexes are broken down in the reticuloendothelial system.
5.3 Preclinical Safety Data
Immunoglobulins are normal constituents of the human body, therefore toxicity testing in heterologous species is of no relevance.
In a local tolerance trial in rabbits, there was no evidence of irritation attributable to Zutectra.
No other non-clinical trials have been carried out.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Glycine
Water for injections
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products.
No other preparations may be added to the Zutectra solution as any change in the electrolyte concentration or the pH may result in precipitation or denaturisation of the proteins.
6.3 Shelf Life
18 months.
The solution should be administered immediately after opening the syringe.
6.4 Special Precautions For Storage
Store and transport refrigerated (2°C
Do not freeze.
Keep the container in the outer carton in order to protect from light.
6.5 Nature And Contents Of Container
One ml solution in a pre-filled syringe (Type I glass) with a stopper (bromobutyl) and a tip cap (bromobutyl rubber).
Pack size of five syringes in a blistered pack.
6.6 Special Precautions For Disposal And Other Handling
This medicinal product should be brought to room temperature (approx. 23°C
The solution can vary from colourless to pale-yellow up to light brown.
Solutions that are cloudy or have deposits should not be used.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. Marketing Authorisation Holder
Biotest Pharma GmbH
Landsteinerstrasse 5
D-63303 Dreieich
Germany
Tel.: +49 6103 801
Telefax: +49 6103 801
8. Marketing Authorisation Number(S)
EU/1/09/600/001
9. Date Of First Authorisation/Renewal Of The Authorisation
30/11/2009
10. Date Of Revision Of The Text
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web site: http://www.emea.europa.eu/.
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