ZUTECTRA 500UI injection solution in pre-filled syringe medication leaflet

Zutectra 500 IU solution for injection in pre-filled syringe

Human hepatitis B immunoglobulin

One mL contains:

Human hepatitis B immunoglobulin 500 IU (purity of at least 96 % IgG)

Each pre-filled syringe of 1 mL solution contains: 150 mg of human protein, with a content ofantibodies to hepatitis B virus surface antigen (HBs) of 500 IU.

Distribution of IgG subclasses (approx. values):

IgG1: 59 %

IgG2: 35 %

IgG3: 3 %

IgG4: 3 %

The maximum IgA content is 6,000 micrograms/mL.

Produced from the plasma of human donors.

For the full list of excipients, see section 6.1.

Solution for injection

The solution is clear to opalescent and colourless to pale yellow with a pH of 5.0-5.6 and anosmolality of 300-400 mOsm/kg.

Prevention of hepatitis B virus (HBV) re-infection in HBsAg and HBV-DNA negative adult patients atleast one week after liver transplantation for hepatitis B induced liver failure. HBV-DNA negativestatus should be confirmed within the last 3 months prior to OLT. Patients should be HBsAg negativebefore treatment start.

The concomitant use of adequate virostatic agents should be considered as standard of hepatitis B re-infection prophylaxis.

In HBV-DNA negative adults at least one week after liver transplantation subcutaneous injections of

Zutectra per week or fortnightly according to serum anti-HBs trough levels.

Prior to the initiation of subcutaneous treatment with Zutectra adequate anti-HBs serum levels shouldbe stabilised with an intravenous hepatitis B immunoglobulin to levels at or above 300-500 IU/L inorder to ensure adequate anti-HBs coverage during the transition from intravenous to subcutaneousdosing. Antibody levels > 100 IU/L should be maintained in HBsAg and HBV-DNA negative patients.

The dose can be individually established and adapted from 500 IU up to 1,000 IU (in exceptional casesup to 1,500 IU) subcutaneous injections on a weekly or fortnightly basis, according to the serum anti-

HBs concentrations and at the discretion of the physician in charge. Antibody levels > 100 IU/Lshould be maintained.

Patients must be monitored for serum anti-HBs antibody levels regularly. Serum anti-HBs antibodylevels should be measured at least every 2-4 weeks and at the discretion of the physician in charge forat least half a year.

There is no relevant indication for use of Zutectra in children under the age of 18.

For subcutaneous use only.

Injection of the medicinal product by the patient or by caregiver in a home treatment requires trainingby a physician experienced in the guidance of patients for home treatment. The patient or caregiverwill be instructed in injection techniques, the keeping of a treatment diary and measures to be taken incase of severe adverse events. A sufficient surveillance period with stable anti-HBs trough serumlevels of > 100 IU/L as well as a fixed dosage regimen is required: the monitoring schedule of patientsanti-HBs antibody levels (see above) needs to be closely followed. In addition, patient or caregivermust comply with the injection technique as well as with the dosing regimen to ensure anti-HBstrough serum levels > 100 IU/L after extended periods between level controls.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to humanimmunoglobulins. In particular, in very rare cases of IgA deficiency when the patient to be treated hasantibodies against IgA.

Zutectra must not be administered intravascularly.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded. This recommendation applies also fordocumentation in the treatment diary during self-administration of the medicinal product in a hometreatment.

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 (see section 2). Individuals who are deficient in IgA have thepotential for developing IgA antibodies and may have anaphylactic reactions after administration ofblood 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 anaphylacticreaction, 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 initially injecting the product slowly;

- are carefully monitored for any symptoms throughout the injection. In particular, patients naiveto human normal immunoglobulin, patients switched from an alternative product or when therehas been a long interval since the previous injection should be monitored during the firstinjection and for the first hour after the first injection, in order to detect potential adverse signs.

All other patients should be observed for at least 20 minutes after administration.

Suspicion of allergic or anaphylactic type reactions requires immediate discontinuation of theinjection. In case of shock, standard medical treatment for shock should be implemented.

Interference with serological testing

After injection of immunoglobulin the transitory rise of the various passively transferred antibodies inthe 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 someserological tests for red cell antibodies, for example the direct antiglobulin test (DAT, direct Coombs’test).

Transmissible agents

Standard measures to prevent infections resulting from the use of medicinal products prepared fromhuman blood or plasma include selection of donors, screening of individual donations and plasmapools for specific markers of infection and the inclusion of effective manufacturing steps for theinactivation/removal of viruses. Despite this, when medicinal products prepared from human blood orplasma 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 human immunodeficiencyvirus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV), and for the non-enveloped hepatitis

A virus (HAV). The measures taken may be of limited value against non-enveloped viruses such asparvovirus B19.

There is reassuring clinical experience regarding the lack of hepatitis A or parvovirus B19transmission with immunoglobulins and it is also assumed that the antibody content makes animportant contribution to the viral safety.

Live attenuated virus vaccines

Immunoglobulin administration may interfere with the development of an immune response to liveattenuated 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 beforevaccination with live attenuated virus vaccines.

Human hepatitis B immunoglobulin should be administrated three to four weeks after vaccination withsuch a live attenuated vaccine; in case administration of human hepatitis B immunoglobulin isessential within three to four weeks after vaccination, then revaccination should be performed threemonths after the administration of human hepatitis B immunoglobulin.

The safety of this medicinal product for use in human pregnancy has not been established in controlledclinical trials and therefore should only be given with caution to pregnant women. Clinical experiencewith immunoglobulins suggests that no harmful effects on the course of pregnancy, or on the foetusand the neonate are to be expected.

The safety of this medicinal product for use in breast-feeding has not been established in controlledclinical trials and therefore should only be given with caution to breast-feeding mothers.

No fertility studies have been performed (see section 5.3).

Hepatitis B immunoglobulin has no or negligible influence on the ability to drive and use machines.

Most adverse drug reactions (ADRs) were mild to moderate in nature. In isolated cases human normalimmunoglobulins may cause an anaphylactic shock.

The following adverse reactions have been reported in the context of 4,810 subcutaneous applicationsof Zutectra during four completed clinical trials and 1,006 applications during a non-interventionalpost marketing safety study (PASS).

The ADRs reported in four trials are summarised and categorised according to the MedDRA systemorgan class and frequency below. Frequency per injection has been evaluated using the followingconvention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100),rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from theavailable data). Within each frequency grouping the adverse reactions are presented in decreasingseriousness.

MedDRA System Adverse reactions Frequency

Organ Class

Infections and infestations Nasopharyngitis Rare*

Immune system disorders Hypersensitivity Rare*

Nervous system disorders Headache Uncommon

Cardiac disorders Palpitations, cardiac discomfort Rare*

Vascular disorders Hypertension Rare*

Respiratory, thoracic and Oropharyngeal pain Rare*mediastinal disorders

Gastrointestinal disorders Upper abdominal pain Uncommon

Skin and subcutaneous tissue Pruritus, rash Rare*disorders

Musculoskeletal and connective Muscle spams Rare*tissue disorders

General disorders and Injection site pain, injection site Commonadministration site conditions urticaria, injection sitehaematoma, injection siteerythema

Fatigue, tiredness Rare*

* single case reports

Adverse reactions observed with other human immunoglobulin preparations

With normal immunoglobulins adverse reactions such as chills, headache, dizziness, fever, vomiting,allergic reactions, nausea, arthralgia, low blood pressure and moderate low back pain may occuroccasionally.

Rarely human normal immunoglobulins may cause a sudden fall in blood pressure and, in isolatedcases, anaphylactic shock, even when the patient has shown no hypersensitivity to previousadministration.

Swelling, soreness, redness, induration, local heat, itching, bruising and rash.

For safety information with respect to transmissible agents, see section 4.4.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Consequences of an overdose are not known.

Pharmacotherapeutic group: Immune sera and immunoglobulins, Specific immunoglobulins, Hepatitis

B immunoglobulin, ATC code: J06BB04

Hepatitis B immunoglobulin contains mainly immunoglobulin G (IgG) with a specifically high contentof antibodies against hepatitis B virus surface antigen (HBs).

The open, prospective, single-arm clinical trial enrolled 23 liver transplant recipients, who had beenreceiving intravenous hepatitis B immunoglobulin prophylaxis and subsequently switched tosubcutaneous Zutectra. The weekly subcutaneous dose was 500 IU for patients with bodyweight< 75 kg (a dose increase to 1,000 IU was allowed, if medically required to maintain a safety level of> 100 IU) and 1,000 IU for patients with bodyweight ≥ 75 kg. 2 patients received a higher and2 patients received a lower dose than recommended by the weight based dosing regimen. Serum anti-

HBs trough levels of 100 IU/L and higher (primary efficacy endpoint) were maintained for all patientsduring the 18 to 24 week trial period. The > 100 IU/L safety margin is the generally accepted level ofeffective prevention against HBV re-infection in liver transplant patients at risk. No patientexperienced HBV re-infection. Self-administration was feasible for most patients.

The mean anti-HBs serum level before switching was 393 ± 139 IU/L. All patients used antiviralmedicine.

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 %])

The objectives of the open, prospective, single-arm clinical trial were the investigation of feasibility ofhome self-administration (including patient compliance), efficacy and safety of subcutaneousapplication of Zutectra in a population of stable patients during long-term treatment for prophylaxisagainst re-infection of a transplanted liver in 66 patients. All patients included in this study had to runthrough a training period of at least 29 days and home self-administration could start on day 36 at theearliest. With the exception of 6 patients who withdrew prior to day 36, all patients achieved completehospital and home self-administration. No patient prematurely discontinued the study due to lack offeasibility of home self-treatment. During the 48-weeks treatment phase constant serum HBs antibodyconcentrations ≥ 100 IU/L were measured in all patients at all assessments with mean values of312.0 ± 103.5 IU/L at the end of the treatment period. In total, 53/66 patients (80.3 %) used antiviralmedication and 13 patients received monotherapy with Zutectra during this study. No hepatitis B re-infection was reported and no patient was tested HBsAg positive during the treatment period of48 weeks. No serious adverse events were reported to be related to study medication. No fatal casewas observed during the study.

The objective of the open, prospective, single-arm clinical trial was the investigation of efficacy andsafety of Zutectra for prevention of hepatitis B virus (HBV) re-infection ≥ one week after orthotopicliver transplantation in HBsAg and HBV-DNA negative patients. At the time of transplantation21 patients (42.9 %) were tested positive for HDV, patients with a positive HIV or HCV test wereexcluded from study participation. 49 patients received subcutaneous injections of Zutectra of 500 IU(1 mL) or 1,000 IU (2 mL) (dose adaptation in exceptional cases up to 1,500 IU) per week orfortnightly according to serum anti-HBs trough levels. The individual treatment duration per patientwas planned to be up to 24 weeks after transplantation. No treatment failures occurred during the 6-month study period. Serum HBs antibody concentrations above the minimum safety trough level of> 100 IU/L were measured in all patients at all timepoints independent of the type of administration(investigator, caregiver or self-injection), the dose regimen (500 IU, 1,000 IU, 1,500 IU) or thetreatment intervals. No clinical signs of a hepatitis B re-infection were observed and no patient wastested HBsAg positive or HBV-DNA positive during the study which confirms that effectiveprotection against Hepatitis B virus re-infection was provided by subcutaneous administration of

Zutectra as part of the combination treatment with HBV virostatic therapy 8 - 18 days after orthotopicliver transplantation. One non-serious adverse event was reported to be related to Zutectra (injectionsite haematoma). No fatal case was observed during the study.

The non-interventional post authorization safety study (PASS 978) enrolled 61 adult patients≥ 6 months after liver transplantation for hepatitis B induced liver failure. The objective of the studywas to evaluate the level of compliance of patients using subcutaneous Zutectra as home self-treatment for preventing hepatitis B re-infection. Patients were to be treated with Zutectra inaccordance with the information and dosage given in the SPC. Compliance according to anti-HBsserum levels could be shown for 57 (of 61) patients (93 %), with no values below 100 IU/L and amean anti-HBs serum level of 254.3 IU/L at the final visit. In total, 42/61 patients (68.9 %) usedantiviral medication and 19 patients received monotherapy with Zutectra during this study. Notreatment failure defined as positive HBV-DNA and HBsAg findings occurred during the entireobservation period. No re-infection was observed. No serious adverse reaction was reported. No fatalcase was observed during the study.

Zutectra is slowly absorbed into the recipient’s circulation and reaches a maximum after a delay of2-7 days.

IgG and IgG-complexes are broken down in the reticuloendothelial system.

Zutectra has a half-life of about 3-4 weeks. This half-life may vary from patient to patient.

Immunoglobulins are normal constituents of the human body, therefore toxicity testing inheterologous 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.

Glycine

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

No other preparations may be added to the Zutectra solution as any change in the electrolyteconcentration or the pH may result in precipitation or denaturisation of the proteins.

2 years.

Once the protective cap has been removed from the pre-filled syringe, the solution should beadministered immediately.

Store and transport refrigerated (2 °C-8 °C).

Do not freeze.

Keep the pre-filled syringe in the outer carton in order to protect from light.

One mL solution for injection in a pre-filled syringe (Type I glass) with a stopper (bromobutyl) and atip cap (bromobutyl rubber).

Pack size of five pre-filled syringes in a blistered pack.

This medicinal product should be brought to room temperature (approx. 23 °C-27 °C) before use.

The solution can vary from clear to opalescent and colourless to pale yellow.

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 localrequirements.

Biotest Pharma GmbH

Landsteinerstrasse 5

D-63303 Dreieich

Germany

Tel.: +49 6103 801-0

Fax: +49 6103 801-150

Email: mail@biotest.com

EU/1/09/600/001

Date of first authorisation: 30 November 2009

Date of latest renewal: 16 September 2014

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.