Privigen^® 100 mg/ml solution for infusion

Human normal immunoglobulin (IVIg).

One ml contains:

human plasma protein…………………………………………………………...100 mg

(purity of at least 98% IgG)

One vial of 25 ml contains: 2.5 g

One vial of 50 ml contains: 5 g

One vial of 100 ml contains: 10 g

One vial of 200 ml contains: 20 g

Distribution of the IgG subclasses (average values):

IgG₁........... . 67.8%

IgG₂........... . 28.7%

IgG₃........... . 2.3%

IgG₄........... . 1.2%

The maximum IgA content is 0.025 mg/ml.

For a full list of excipients, see section 6.1.

Solution for infusion.

The solution is clear or slightly opalescent and colourless to pale yellow.

Privigen is isotonic, with an osmolality of 320 mOsmol/kg.

Replacement therapy in

• Primary immunodeficiency (PID) syndromes such as:

– congenital agammaglobulinaemia and hypogammaglobulinaemia

– common variable immunodeficiency

– severe combined immunodeficiency

– Wiskott Aldrich syndrome

• Myeloma or chronic lymphocytic leukaemia with severe secondary hypogammaglobulinaemia and recurrent infections.

• Children with congenital AIDS and recurrent infections.

Immunomodulation

• Immune thrombocytopenic purpura (ITP), in children or adults at high risk of bleeding or prior to surgery to correct the platelet count.

• Guillain-Barré syndrome.

• Kawasaki disease.

Allogeneic bone marrow transplantation

Posology

The dose and dosage regimen is dependent on the indication.

In replacement therapy the dosage may need to be individualised for each patient depending on the pharmacokinetic and clinical response. The following dosage regimens are given as a guideline.

Replacement therapy in primary immunodeficiency syndromes

The dosage regimen should achieve a trough IgG level (measured before the next infusion) of at least 4 to 6 g/l. Three to six months are required after the initiation of therapy for equilibration to occur.

The recommended starting dose is 0.4 to 0.8 g/kg body weight (bw) followed by at least 0.2 g/kg bw every three weeks.

The dose required to achieve a trough level of 6 g/l is of the order of 0.2 to 0.8 g/kg bw/month. The dosage interval when steady state has been reached varies from two to four weeks.

Trough levels should be measured in order to adjust the dose and dosage interval.

Replacement therapy in myeloma or chronic lymphocytic leukaemia with severe secondary hypogammaglobulinaemia and recurrent infections; replacement therapy in children with AIDS and recurrent infections

The recommended dose is 0.2 to 0.4 g/kg bw every three to four weeks.

Immune thrombocytopenic purpura

For the treatment of an acute episode, 0.8 to 1 g/kg bw on day one, which may be repeated once within three days, or 0.4 g/kg bw daily for two to five days. The treatment can be repeated if relapse occurs.

Guillain-Barré syndrome

0.4 g/kg bw/day for three to seven days.

Experience in children is limited.

Kawasaki disease

1.6 to 2.0 g/kg bw should be administered in divided doses over two to five days or 2.0 g/kg bw as a single dose.

Patients should receive concomitant treatment with acetylsalicylic acid.

Allogeneic bone marrow transplantation:

Human normal immunoglobulin treatment can be used as part of the conditioning regimen and after the transplantation.

For the treatment of infections and prophylaxis of graft versus host disease, dosage is individually tailored. The starting dose is normally 0.5 g/kg bw/week, starting seven days before transplantation and continued for up to three months after the transplantation.

In case of persistent lack of antibody production, a dose of 0.5 g/kg bw/month is recommended until antibody levels return to normal.

The dosage recommendations are summarised in the following table:

Method of administration

Human normal immunoglobulin should be infused intravenously. The initial infusion rate is 0.3 ml/kg bw/hr. If well tolerated, the rate of administration may gradually be increased to 4.8 ml/kg bw/hr.

In PID patients who have tolerated the infusion rate of 4.8ml/kg bw/hr well, the rate may be further increased gradually to 7.2 ml/kg bw/hr.

If dilution prior to infusion is desired, Privigen may be diluted with 5% glucose solution to a final concentration of 50 mg/ml (5%). For instruction, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients.

Hypersensitivity to homologous immunoglobulins, especially in the very rare cases of IgA deficiency when the patient has antibodies against IgA.

Patients with hyperprolinaemia.

Certain severe adverse drug reactions may be related to the rate of infusion. The recommended infusion rate given under section 4.2 "Method of administration" must be followed closely. Patients must be closely monitored and carefully observed for any symptoms throughout the infusion period.

Certain adverse reactions may occur more frequently:

– in case of high rate of infusion,

– in patients with hypo- or agammaglobulinaemia with or without IgA deficiency,

– 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 there has been a long interval since the previous infusion.

True hypersensitivity reactions are rare. They can occur in the very rare cases of IgA deficiency with anti-IgA antibodies.

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 infusing the product slowly (0.3 ml/kg bw/hr);

– are carefully monitored for any symptoms throughout the infusion period. In particular, patients naive to human normal immunoglobulin, patients switched from an alternative IVIg product or when there has been a long interval since the previous infusion should be monitored during the first infusion and for one hour after, in order to detect potential adverse signs. All other patients should be observed for at least twenty minutes after administration.

Haemolytic anaemia

IVIg products can contain blood group antibodies which may act as haemolysins and induce in vivo coating of red blood cells (RBC) with immunoglobulin, causing a positive direct antiglobulin reaction (Coomb's test) and, rarely, haemolysis. Haemolytic anaemia can develop subsequent to IVIg therapy due to enhanced RBC sequestration. IVIg recipients should be monitored for clinical signs and symptoms of haemolysis (see also Section 4.8).

There is clinical evidence of an association between IVIg administration and thromboembolic events such as myocardial infarction, stroke, pulmonary embolism and deep vein thromboses which is assumed to be related to a relative increase in blood viscosity through the high influx of immunoglobulin in at-risk patients. Caution should be exercised in prescribing and infusing IVIg in obese patients and in patients with pre-existing risk factors for thrombotic events (such as advanced age, hypertension, diabetes mellitus and a history of vascular disease or thrombotic episodes, patients with acquired or inherited thrombophilic disorders, patients with prolonged periods of immobilisation, severely hypovolaemic patients and patients with diseases which increase blood viscosity).

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, hypovolaemia, being overweight, concomitant nephrotoxic medicinal products or age over 65.

In case of renal impairment, IVIg discontinuation should be considered.

While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IVIg products, those containing sucrose as a stabiliser accounted for a disproportionate share of the total number. In patients at risk, the use of IVIg products that do not contain sucrose may be considered. Privigen does not contain sucrose or other sugars.

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

In all patients, IVIg administration requires:

– adequate hydration prior to the initiation of the infusion of IVIg

– monitoring of urine output

– monitoring of serum creatinine levels

– avoidance of concomitant use of loop diuretics.

In case of adverse reaction, either the rate of administration must be reduced or the infusion stopped. The treatment required depends on the nature and severity of the side effect.

In case of shock, standard medical treatment for shock should be implemented.

For patients suffering from diabetes mellitus and requiring dilution of Privigen to lower concentrations, the presence of glucose in the recommended diluent should be taken into account.

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 B19V.

There is reassuring clinical experience regarding the lack of hepatitis A or B19V 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 Privigen is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

Live attenuated virus vaccines

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

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 (e.g. Coombs test).

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.

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

No effects on ability to drive and use machines have been observed.

With human normal immunoglobulin for intravenous administration, 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.

Cases of reversible aseptic meningitis and rare cases of transient cutaneous reactions, have been observed with human normal immunoglobulin. Reversible haemolytic reactions have been observed in patients, especially those with blood groups A, B, and AB. Rarely, haemolytic anaemia requiring transfusion may develop after high dose IVIg treatment (see also Section 4.4).

Increase in serum creatinine level and/or acute renal failure have been observed.

Very rarely: Thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism and deep vein thromboses.

Three clinical studies with Privigen were performed, two in patients with primary immunodeficiency (PID) and one in patients with immune thrombocytopenic purpura (ITP). In the pivotal PID study 80 subjects were enrolled and treated with Privigen. Of these, 72 completed the twelve months of treatment. In the PID extension study 55 subjects were enrolled and treated with Privigen. The ITP study was performed in 57 patients.

Most adverse drug reactions (ADRs) observed in the three clinical studies were mild to moderate in nature.

The ADRs reported in the three 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).

Within each frequency grouping, undesirable effects are presented in order of decreasing severity.

Frequency of Adverse Drug Reactions (ADRs) in clinical studies with Privigen

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

Overdose may lead to fluid overload and hyperviscosity, particularly in patients at risk, including elderly patients or patients with renal impairment.

Pharmacotherapeutic group: immune sera and immunoglobulins: immunoglobulins, normal human, for intravascular administration, ATC code: J06BA02.

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.

The mechanism of action in indications other than replacement therapy is not fully elucidated, but includes immunomodulatory effects.

The safety and efficacy of Privigen was evaluated in three prospective, open-label, single-arm, multicenter studies performed in Europe (ITP and PID studies) and the USA (PID study).

Human normal immunoglobulin is immediately and completely bioavailable in the recipient's circulation after intravenous administration. It is distributed relatively rapidly between plasma and extravascular fluid, equilibrium between the intra- and extravascular compartments is reached after approximately three to five days.

The pharmacokinetic parameters for Privigen were determined in a clinical study in PID patients (see section 5.1). Twenty-five patients (aged 13 to 69 years) participated in the pharmacokinetic (PK) assessment. In this study, the median half-life of Privigen in primary immunodeficiency patients was 36.6 days. In an extension of this study, thirteen PID patients (aged 3 to 65 years) participated in a PK sub-study. The results of this study show the median half-life of Privigen to be 31.1 days (see table below). The half-life may vary from patient to patient, particularly in primary immunodeficiency.

Pharmacokinetic parameters of Privigen in PID patients

C_max, maximum serum concentration; C_{min ,} trough (minimum level) serum concentration; t_½, elimination half-life

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

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

The safety of Privigen has been assessed in several preclinical studies, with particular reference to the excipient L-proline. Some published studies pertaining to hyperprolinaemia have shown that long-term, high doses of L-proline have effects on brain development in very young rats. However, in studies where the dosing was designed to reflect the clinical indications for Privigen, no effects on brain development were observed. Non-clinical data reveal no special risk for humans based on safety pharmacology and toxicity studies.

L-proline

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

3 years

If the product is diluted to lower concentrations (see section 6.6), immediate use after dilution is recommended. The in-use stability of Privigen after dilution with a 5% glucose solution to a final concentration of 50 mg/ml (5%) has been demonstrated for 10 days at 30°C; however, the microbial contamination aspect was not studied.

Do not store above 25 °C.

Do not freeze.

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

25 ml of solution in a single vial (type I glass), with a stopper (elastomeric), a cap (aluminium crimp), a flip off disc (plastic), label with integrated hanger.

50 or 100 ml of solution in a single vial (type I or II glass), with a stopper (elastomeric), a cap (aluminium crimp), a flip off disc (plastic), label with integrated hanger.

200 ml of solution in a single vial (type II glass), with a stopper (elastomeric), a cap (aluminium crimp), a flip off disc (plastic), label with integrated hanger.

Pack sizes:

1 vial (2.5 g/25 ml, 5 g/50 ml, 10 g/100 ml, 20 g/200 ml),

3 vials (10 g/100 ml, 20 g/200 ml).

Not all pack sizes may be marketed.

Privigen comes as a ready-for-use solution in single-use vials. The product should be at room or body temperature before use. A vented infusion line should be used for the administration of Privigen. Always pierce the stopper at its centre, within the marked area.

The solution should be clear or slightly opalescent. Do not use solutions that are cloudy or have particulate matter.

If dilution is desired, 5 % glucose solution should be used. For obtaining an immunoglobulin solution of 50 mg/ml (5%), Privigen 100 mg/ml (10%) should be diluted with an equal volume of the 5% glucose solution. Aseptic technique must be strictly observed during the dilution of Privigen.

Once the vial has been entered under aseptic conditions, its contents should be used promptly. Because the solution contains no preservative, Privigen should be infused as soon as possible.

Any unused 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

2.5g: EU/1/08/446/004

5g: EU/1/08/446/001

10g: EU/1/08/446/002

20g: EU/1/08/446/003

10g x 3: EU/1/08/446/005

20g x 3: EU/1/08/446/006

001-003: 25 April 2008

004: 07 May 2009

005-006: 30 June 2009

26 August 2010

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