Privigen 100 mg/ml solution for infusion

Human normal immunoglobulin (IVIg)

One ml contains:

Human normal immunoglobulin…………………………………………...100 mg

(purity of at least 98% IgG)

One vial of 25 ml solution contains: 2.5 g human normal immunoglobulin

One vial of 50 ml solution contains: 5 g human normal immunoglobulin

One vial of 100 ml solution contains: 10 g human normal immunoglobulin

One vial of 200 ml solution contains: 20 g human normal immunoglobulin

Distribution of the IgG subclasses (approx. values):

IgG₁.......... . 67.8%

IgG₂.......... . 28.7%

IgG₃.......... . 2.3%

IgG₄.......... . 1.2%

The maximum IgA content is 0.025 mg/ml.

Produced from the plasma of human donors.

Privigen is essentially sodium free.

For the 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 approximate osmolality of 320 mOsmol/kg.

Replacement therapy in adults, and children and adolescents (0-18 years) in:

• Primary immunodeficiency (PID) syndromes with impaired antibody production (see section 4.4).

• Hypogammaglobulinaemia and recurrent bacterial infections in patients with chronic lymphocytic leukaemia, in whom prophylactic antibiotics have failed.

• Hypogammaglobulinaemia and recurrent bacterial infections in plateau phase multiple myeloma patients who have failed to respond to pneumococcal immunisation.

• Hypogammaglobulinaemia in patients after allogeneic haematopoietic stem cell transplantation (HSCT).

• Congenital AIDS with recurrent bacterial infections.

Immunomodulation in adults, and children and adolescents (0-18 years) in:

• Primary immune thrombocytopenia (ITP), in patients at high risk of bleeding or prior to surgery to correct the platelet count.

• Guillain-Barré syndrome.

• Kawasaki disease.

Replacement therapy should be commenced and monitored under the supervision of a physician experienced in the treatment of immunodeficiency.

Posology

The dose and dose regimen is dependent on the indication.

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

Replacement therapy in primary immunodeficiency (PID) syndromes

The dose regimen should achieve a trough IgG level (measured before the next infusion) of at least 5-6 g/l. 3-6 months are required after the initiation of therapy for equilibration to occur.

The recommended starting dose is 0.4-0.8 g/kg body weight (bw) given once, followed by at least 0.2 g/kg bw every 3-4 weeks.

The dose required to achieve a trough level of 5-6 g/l is of the order of 0.2-0.8 g/kg bw/month. The dosage interval when steady state has been reached varies from 3-4 weeks.

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.

Hypogammaglobulinaemia and recurrent bacterial infections in patients with chronic lymphocytic leukaemia, in whom prophylactic antibiotics have failed; hypogammaglobulinaemia and recurrent bacterial infections in plateau phase multiple myeloma patients who have failed to respond to pneumococcal immunisation; congenital AIDS with recurrent bacterial infections.

The recommended dose is 0.2-0.4 g/kg bw every 3-4 weeks.

Hypogammaglobulinaemia in patients after allogeneic haematopoietic stem cell transplantation

The recommended dose is 0.2-0.4 g/kg bw every 3-4 weeks. The trough levels should be maintained above 5 g/l.

Primary immune thrombocytopenia (ITP)

There are two alternative treatment schedules:

• 0.8-1g/kg bw given on day 1; this dose may be repeated once within 3 days

• 0.4 g/kg bw given daily for 2-5 days.

The treatment can be repeated if relapse occurs.

Guillain-Barré syndrome

0.4 g/kg bw/day for 5 days.

Kawasaki disease

1.6-2.0 g/kg bw should be administered in divided doses over 2-5 days or 2.0 g/kg bw as a single dose.

Patients should receive concomitant treatment with acetylsalicylic acid.

The dosage recommendations are summarised in the following table:

Paediatric population

The posology in children and adolescents (0-18 years) is not different to that of adults as the posology for each indication is given by body weight and adjusted to the clinical outcome of the above mentioned conditions.

Method of administration

For intravenous use.

Human normal immunoglobulin should be infused intravenously at an initial infusion rate of 0.3 ml/kg bw/hr for approximately 30 min. If well tolerated (see section 4.4), the rate of administration may gradually be increased to a maximum of 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 listed in section 6.1 (see also section 4.4).

Hypersensitivity to human immunoglobulins, especially in patients with antibodies against IgA.

Patients with hyperprolinaemia.

Certain severe adverse reactions may be related to the rate of infusion. The recommended infusion rate given under section 4.2 must be closely followed.

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 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.

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 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.

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 adverse reaction.

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

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.

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.

Hypersensitivity

True hypersensitivity reactions are rare. They can occur in patients with anti-IgA antibodies.

IVIg is not indicated in patients with selective IgA deficiency where the IgA deficiency is the only abnormality of concern.

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

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.

Isolated cases of haemolysis-related renal dysfunction/renal failure or disseminated intravascular coagulation have occurred.

The following risk factors are associated with the development of haemolysis: high doses, whether given as a single administration or divided over several days; non-0 blood group; and underlying inflammatory state. Increased vigilance is recommended for non-0 blood group patients receiving high doses for non-PID indications. Haemolysis has rarely been reported in patients given replacement therapy for PID.

IVIg recipients should be monitored for clinical signs and symptoms of haemolysis (see also section 4.8).

Aseptic meningitis syndrome (AMS)

Aseptic meningitis syndrome has been reported to occur in association with IVIg treatment.

Discontinuation of IVIg treatment has resulted in remission of AMS within several days without sequelae. The syndrome usually begins within several hours to 2 days following IVIg treatment. Cerebrospinal fluid studies are frequently positive with pleocytosis up to several thousand cells per mm³, predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dl.

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

Thromboembolism

There is clinical evidence of an association between IVIg administration and thromboembolic events such as myocardial infarction, cerebral vascular accident (including 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, patients with diseases which increase blood viscosity).

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

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 for example the direct antiglobulin test (DAT, direct Coombs' test).Transmissible agentsStandard 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 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.

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, hypovolaemia, 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 containing various excipients such as sucrose, glucose and maltose, 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, maltose or glucose.

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

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

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. IVIg products have been shown to cross the placenta, increasingly after the third trimester.

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.

Breast-feeding

Immunoglobulins are excreted into the milk and may contribute to protecting the neonate from pathogens which have a mucosal portal of entry.

Fertility

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

The ability to drive and operate machines may be impaired by some adverse reactions associated with Privigen. Patients who experience adverse reactions during treatment should wait for these to resolve before driving or operating machines.

Summary of the safety profile

Adverse reactions such as chills, headache, dizziness, 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 non-0 blood groups in immunomodulatory treatment. 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.

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

Tabulated list of adverse reactions

Three clinical studies with Privigen were performed, two in PID patients and one in ITP patients.

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 reactions (ARs) observed in the three clinical studies were mild to moderate in nature.

The ARs reported in the three studies are presented in the table below according to the MedDRA System organ classification (SOC and Preferred Term Level).

Frequencies have been evaluated using the following convention: very common (1/10), common (1/100 to <1/10), uncommon (1/1 000 to <1/100).

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

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 1000 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).

Absorption

Human normal immunoglobulin is immediately and completely bioavailable in the recipient's circulation after intravenous administration.

Distribution

It is distributed relatively rapidly between plasma and extravascular fluid, after approximately 3-5 days equilibrium is reached between the intra- and extravascular compartments.

Elimination

The pharmacokinetic parameters for Privigen were determined in a clinical study in PID patients (see section 5.1). Twenty-five patients (aged 13-69 years) participated in the pharmacokinetic (PK) assessment. In this study, the median half-life of Privigen in PID patients was 36.6 days. In an extension of this study, 13 PID patients (aged 3-65 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 PID.

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

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.

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.

For storage conditions after first opening of the diluted medicinal product, see section 6.3.

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-to-use solution in single-use vials. The product should be brought to 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 and colourless or pale yellow. Solutions that are cloudy or have deposits should not be used.

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.

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

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

19 March 2012

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