Hizentra 200 mg/ml solution for subcutaneous injection

Human normal immunoglobulin (SCIg)

One ml contains:

human plasma protein 200 mg

(purity of at least 98% IgG)

One vial of 5 ml solution contains: 1 g of human plasma protein

One vial of 10 ml solution contains: 2 g of human plasma protein

One vial of 15 ml solution contains: 3 g of human plasma protein

One vial of 20 ml solution contains: 4 g of human plasma protein

Approximate distribution of the IgG subclasses:

IgG1.......... 62-74%

IgG2.......... 22-34%

IgG3.......... 2-5%

IgG4.......... 1-3%

The maximum IgA content is 0.050 mg/ml.

Produced from the plasma of human donors.

Hizentra is essentially sodium free.

For the full list of excipients, see section 6.1.

Solution for subcutaneous injection.

The solution is clear and pale-yellow or light-brown.

Hizentra has an approximate osmolality of 380 mOsmol/kg.

Replacement therapy in adults and children in primary immunodeficiency syndromes such as:

− congenital agammaglobulinaemia and hypogammaglobulinaemia

− common variable immunodeficiency

− severe combined immunodeficiency

− IgG subclass deficiencies with recurrent infections

Replacement therapy in myeloma or chronic lymphocytic leukaemia with severe secondary hypogammaglobulinaemia and recurrent infections.

Treatment should be commenced and initially monitored under the supervision of a healthcare professional experienced in the treatment of immunodeficiency.

Posology

Adults and children

The dose may need to be individualised for each patient dependent on the pharmacokinetic and clinical response and serum IgG trough levels. The following dose regimens are given as a guideline.

The dose regimen using the subcutaneous route should achieve a sustained level of IgG. A loading dose of at least 0.2 to 0.5 g/kg (1.0 to 2.5 ml/kg) body weight may be required. This may need to be divided over several days. After steady state IgG levels have been attained, maintenance doses are administered at repeated intervals to reach a cumulative monthly dose of the order of 0.4 to 0.8 g/kg (2.0 to 4.0 ml/kg) body weight.

Trough levels should be measured and assessed in conjunction with the patient's clinical response. Depending on the clinical response (e.g. infection rate), adjustment of the dose and/or the dose interval may be considered in order to aim for higher trough levels.

As the posology is given by body weight and adjusted to the clinical outcome of the above mentioned conditions, the posology in the paediatric population is not considered to be different to that of adults.

Hizentra was evaluated in 33 paediatric subjects (21 children [3 to 11 years] and 12 adolescents [12 to 16 years]) with primary immunodeficiency disease (PID). No paediatric-specific dose requirements were necessary to achieve the desired serum IgG levels.

Method of administration

The medicinal product must be administered via the subcutaneous route only. Hizentra may be injected into sites such as abdomen, thigh, upper arm, and lateral hip. If large doses are given (> 25 ml), it is advisable to administer them at multiple sites.

The recommended initial infusion rate depends on individual needs of the patient and should not exceed 15 ml/hour/site (see also section 4.4). If well-tolerated, the infusion rate can then gradually be increased to 25 ml/hour/site.

Infusion pumps appropriate for subcutaneous administration of immunoglobulins can be used.

Up to 4 injection sites can be used simultaneously, provided that the maximum infusion rate for all sites combined does not exceed 50 ml/hour. Injection sites should be at least 5 cm apart.

Subcutaneous infusion for home treatment should be commenced and initially monitored by a healthcare professional experienced in the guidance of patients for home treatment. The patient or a caregiver will be instructed in infusion techniques, the keeping of a treatment diary and measures to be taken in case of severe adverse reactions.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Patients with hyperprolinaemia.

Hizentra must not be given intravascularly.

Hizentra is for subcutaneous use only. If Hizentra is accidentally administered into a blood vessel, patients could develop shock.

The recommended infusion rate given under section 4.2 should be adhered to. Patients should be closely monitored and carefully observed for any adverse events throughout the infusion period.

Certain adverse reactions may occur more frequently in patients who receive human normal immunoglobulin for the first time or, in rare cases, when the human normal immunoglobulin product is switched or when treatment has been stopped for more than eight weeks.

True allergic reactions are rare. They can particularly occur in patients with anti-IgA antibodies who should be treated with particular caution. Patients with anti-IgA antibodies, in whom treatment with subcutaneous IgG products remains the only option, should be switched to Hizentra only under close medical supervision.

Rarely, human normal immunoglobulin can induce a fall in blood pressure with anaphylactic reaction, even in patients who had tolerated previous treatment with human normal immunoglobulin.

Potential complications can often be avoided by ensuring that patients:

− are not sensitive to human normal immunoglobulin, by initially injecting the product slowly (see section 4.2);

− are carefully monitored for any symptoms throughout the infusion period. In particular, patients naive to human normal immunoglobulin, patients switched from an alternative product or when there has been a long interval since the previous infusion should be monitored during the first infusion and for the first hour after the first infusion, 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 the injection. In case of shock, standard medical treatment should be administered.

Information on safety with respect to transmissible agents

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 viruses HAV and 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 Hizentra 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.

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 allo-antibodies (Coombs test).

Live attenuated virus vaccines

Immunoglobulin administration may impair for a period of at least 6 weeks and up to 3 months the efficacy of live attenuated virus vaccines such as measles, rubella, mumps and varicella. After administration of this medicinal product, an interval of 3 months should elapse before vaccination with live attenuated virus vaccines. In the case of measles, this impairment may persist for up to 1 year. Therefore patients receiving measles vaccine should have their antibody status checked.

Pregnancy

Data from prospective clinical trials on the use of human normal immunoglobulin in pregnant women is limited. Therefore, Hizentra 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 or the neonate are to be expected.

Continued treatment of the pregnant woman ensures a passive immunity for the neonate.

Breast-feeding

Immunoglobulins are excreted into the milk and may contribute to the transfer of protective antibodies to the neonate.

Fertility

Clinical experience with immunoglobulins suggests that no harmful effects on fertility are to be expected.

Hizentra has no or negligible influence on the ability to drive and use machines.

Summary of safety profile

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 infusion sites: swelling, soreness, redness, induration, local heat, itching, bruising and rash.

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

Tabulated summary of adverse reactions

Adverse Reactions (ARs) have been collected from one phase I study with healthy subjects (n = 28) and two phase III studies in patients with primary immunodeficiency (n = 100) with Hizentra.

The ARs reported in these three clinical studies are summarised and categorised according to the MedDRA System Organ Class and frequency below. Frequency per infusion has been evaluated using the following criteria: very common (1/10), common (1/100 to <1/10), uncommon (1/1,000 to <1/100), and rare (1/10,000 to <1/1,000).

Frequency of Adverse Reactions (ARs) in clinical studies with Hizentra

Consequences of an overdose are not known.

Pharmacotherapeutic group: immune sera and immunoglobulins: immunoglobulins, normal human, for extravascular administration, ATC code: J06BA01.

Human normal immunoglobulin contains mainly immunoglobulin G (IgG) with a broad spectrum of antibodies against infectious agents.

Human normal immunoglobulin contains the IgG antibodies present in the normal population. It is usually prepared from pooled plasma from not fewer than 1,000 donors. It has a distribution of immunoglobulin G subclasses closely proportional to that in native human plasma. Adequate doses of this medicinal product may restore abnormally low immunoglobulin G levels to the normal range.

In the European study, a total of 51 subjects with primary immunodeficiency syndromes aged between 3 and 60 years old were treated with Hizentra for up to 41 weeks. The mean dose administered each week was 0.12 g/kg body weight. Sustained IgG trough levels with mean concentrations of 7.99 – 8.25 g/l were thereby achieved throughout the treatment period. Subjects received in total 1,831 weekly Hizentra infusions.

In the US study, a total of 49 subjects with primary immunodeficiency syndromes aged between 5 and 72 years old were treated with Hizentra for up to 15 months. The mean dose administered each week was 0.23 g/kg body weight. Sustained IgG trough levels with a mean concentration of 12.53 g/l were thereby achieved throughout the treatment period. Subjects received in total 2,264 weekly Hizentra infusions.

No serious bacterial infections were reported during the efficacy period in subjects receiving Hizentra during clinical studies.

Following subcutaneous administration of Hizentra, peak serum levels are achieved after approximately 2 days.

In a clinical trial with Hizentra (n = 46), the subjects achieved sustained trough levels (median 8.1 g/l) over a period of 29 weeks when receiving median weekly doses of 0.06 to 0.24 g/kg body weight.

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

Paediatric population

No differences were seen in the pharmacokinetic parameters between adult and paediatric study patients.

Immunoglobulins are a normal constituent of the human body. L-proline is a physiological, non-essential amino acid.

The safety of Hizentra has been assessed in several preclinical studies, with particular reference to the excipient L-proline. Non-clinical data reveal no special risk for humans based on safety pharmacology and toxicity studies.

L-proline

Polysorbate 80

Water for injections

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

30 months.

Once a vial has been opened, the solution should be used immediately.

Do not store above 25 °C.

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

5, 10, 15 or 20 ml of solution in a vial (type I glass), with a stopper (halobutyl), a cap (aluminium crimp) and a flip off disc (plastic).

Pack sizes of 1, 10 or 20 vials:

1 g / 5 ml

2 g / 10 ml

3 g / 15 ml

4 g / 20 ml

Not all pack sizes may be marketed.

Hizentra comes as a ready-to-use solution in single-use vials. Because the solution contains no preservative, Hizentra should be used / infused as soon as possible after opening the vial.

The medicinal product should be at room or body temperature before use.

The solution should be clear and pale-yellow or light-brown.

Do not use if the solution is cloudy or has particulate matter.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

CSL Behring GmbH

Emil-von-Behring-Strasse 76

D-35041 Marburg

Germany

EU/1/11/687/001: 1g / 5ml, 1 vial

EU/1/11/687/002: 1g / 5ml, 10 vials

EU/1/11/687/003: 1g / 5ml, 20 vials

EU/1/11/687/004: 2g / 10ml, 1 vial

EU/1/11/687/005: 2g / 10ml, 10 vials

EU/1/11/687/006: 2g / 10ml, 20 vials

EU/1/11/687/007: 3g / 15ml, 1 vial

EU/1/11/687/008: 3g / 15ml, 10 vials

EU/1/11/687/009: 3g / 15ml, 20 vials

EU/1/11/687/010: 4g / 20ml, 1 vial

EU/1/11/687/011: 4g / 20ml, 10 vials

EU/1/11/687/012: 4g / 20ml, 20 vials

14 April 2011

18 October 2011

Detailed information on this product is available on the website of the European Medicines Agency: http://www.ema.europa.eu/