Gamunex^® 10%,

100 mg/ml, solution for infusion

Human normal immunoglobulin (IVIG): 1 ml Gamunex^® 10% contains 100 mg protein with an IgG content of at least 98% (IgA content: mean: 0.059 mg/ml; max.: 0.084 mg/ml; n=5).

For a full list of excipients, see section 6.1.

Solution for infusion

Replacement therapy in:

Primary immunodeficiency syndromes such as:

- congenital agammaglobulinaemia and hypogammaglobulinaemia

- common variable immunodeficiency

- severe combined immunodeficiency

- Wiskott-Aldrich syndrome

Multiple myeloma or chronic lymphocytic leukaemia with severe secondary hypogammaglobulinaemia and recurrent infections,

Children with congenital AIDS and recurrent severe bacterial infections.

Immunomodulation in:

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

Guillain-Barré syndrome (GBS),

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP),

Kawasaki disease (in conjunction with acetylsalicylic acid therapy).

Allogeneic bone marrow transplantation

The dosage and the interval between infusions are dependent on the indication. In replacement therapy, the dosage should be individually adjusted on the basis of the pharmacokinetic parameters and the clinical response. Recommended dosages are as follows:

Replacement therapy in primary immunodeficiency syndromes:

The dosage regimen should be such that a trough level of IgG of at least 4 - 6 g/l is attained. To raise an abnormally low serum IgG level to within the normal range, the recommended initial dose is 0.4 – 0.8 g/kg body weight (BW) (4 - 8 ml/kg BW), followed by a dose of at least 0.2 g/kg BW (2 ml/kg BW) at intervals of 3 to 4 weeks. The dose should be individualised and can be administered more often if the increase in serum IgG is insufficient or if the fall in serum level took place particularly quickly.

IgG trough levels should be measured in order to determine the necessary dose and the dosage interval. The time to attainment of equilibrium is 3 - 6 months from commencement of therapy. The dose required to achieve an IgG trough level of 6 g/l is of the order of 0.2 – 0.8 g/kg BW (2 - 8 ml/kg BW) every 3 - 4 weeks.

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

The recommended dose is 0.2 – 0.4 g/kg BW (2 - 4 ml/kg BW) every 3 - 4 weeks.

Replacement therapy in children with AIDS and recurrent infections:

The recommended dose is 0.2 – 0.4 g/kg BW (2 - 4 ml/kg BW) every 3 - 4 weeks.

Idiopathic thrombocytopenic purpura (ITP):

0.4 g/kg BW (4 ml/kg BW) on two to five days or, alternatively, 1 g/kg BW (10 ml/kg BW) on two consecutive days.

The treatment can be repeated if the platelet count falls again.

Guillain-Barré syndrome (GBS):

0.4 g/kg BW (4 ml/kg BW) on three to seven consecutive days. The treatment should commence within 14 days of the onset of the symptoms.

Only limited experience is available of use of intravenous immunoglobulins in children with Guillain-Barré syndrome.

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP):

2 g/kg (20 mL/kg BW) in divided doses over 2 to 4 consecutive days as loading dose. Maintenance dose of 1 g/kg administered over 1 day (10 mL/kg BW) or divided into two doses of 0.5 g/kg (5 mL/kg BW) given on two consecutive days, every 3 weeks.

Only limited experience is available of use of intravenous immunoglobulins in children with Chronic Inflammatory Demyelinating Polyneuropathy.

Clinical studies of Gamunex^® did not include sufficient numbers of subjects aged 65 and over to determine a precise treatment effect.

Kawasaki disease:

1.6 - 2 g/kg BW (16 – 20 ml/kg BW) as a single infusion or in divided doses over 2 to 5 days in conjunction with acetylsalicylic acid therapy.

Allogeneic bone marrow transplantation:

Gamunex^® 10% can be used as part of the conditioning regimen prior to surgery and after the transplant. For the treatment of infections and prophylaxis of graft-versus-host reaction, the dosage should be individually adjusted. The starting dose is normally 0.5 g/kg BW (5 ml/kg BW) per week, commencing seven days before transplantation; thereafter, 0.5 g/kg BW (5 ml/kg BW) once per week for up to 3 months after transplantation. In the event of a persistent lack of antibody production, a dose of 0.5 g/kg BW (5 ml/kg BW) per month is recommended until antibody levels have returned to normal.

Summary of dosage recommendations:

*The dose is based on the dose used in the clinical study conducted with Gamunex^® 10%.

The duration of treatment beyond 48 weeks should be subject to the physicians discretion based upon the patient response and maintenance response in the long-term.

The dosing and intervals may have to be adopted according to the individual course of the disease.

Infuse clear solutions only. Prior to infusion, bring Gamunex^® 10% up to room temperature or body temperature (possibly in a water bath at a temperature no higher than 37°C).

Gamunex^® 10% should initially be administered at an infusion rate of 0.01 – 0.02 ml/kg BW per minute (corresponding to approx. 0.75 – 1.5 ml per minute for a patient weighing 75 kg). If the product is well tolerated, the rate of infusion may gradually be increased after approximately 30 minutes to a maximum of 0.08 – 0.14 ml/kg BW per minute (corresponding to 6 – 10.5 ml per minute for a patient weighing 75 kg). All patients should be closely monitored when high rates of infusion (0.14 ml/kg BW) are used. In children or patients at risk of renal failure, the maximum infusion rate should not exceed 0.08 ml/kg BW per minute.

Gamunex^® 10% must not be mixed with other solutions for infusion and other medicinal products. If dilution is necessary prior to infusion, 5% glucose solution may be used for this purpose. Gamunex^® 10% is not compatible with saline solution.

Hypersensitivity to the active substance or to any of the excipients. This applies in particular to extremely rare cases of selective IgA deficiency when the patient has antibodies against IgA.

Certain undesirable effects may be related to the rate of infusion. The recommended infusion rate (see 4.2) should therefore be followed and the patient should be carefully observed during the infusion and for at least 20 minutes afterwards.

Certain undesirable effects may occur more frequently:

- with a high infusion rate,

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

- in patients who are receiving human normal immunoglobulin for the first time or, in rare cases, when the immunoglobulin product is switched or after a prolonged interval without treatment.

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

In rare instances, immunoglobulins can cause a fall in blood pressure with anaphylactic reactions, even if the patient has tolerated previous treatment with normal human immunoglobulin.

Potential complications can often be avoided by ensuring:

- that patients are not hypersensitive to normal human immunoglobulin by initially infusing Gamunex^® 10% slowly (0.1 ml/kg BW per hour),

- that patients are carefully monitored for any symptoms throughout the infusion period. In particular, patients receiving human immunoglobulin for the first time and those switched from a different immunoglobulin or not having received treatment for some time should be monitored for possible undesirable effects during the first infusion and for one hour afterwards.

- the use of glucose solution for dilution prior to infusion should be carefully considered for patients suffering from latent diabetes, diabetes or in patients on a low sugar diet.

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 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 prolonged periods of immobilization, severely hypovolaemic patients, patients with diseases which increase blood viscosity).

If undesirable effects occur, the infusion rate should be reduced or the infusion should be suspended until the symptoms have disappeared.

If the symptoms persist even after suspending the infusion, suitable treatment should be instituted. In the event of anaphylactic shock, treatment with the product should be discontinued immediately and the current standard medical treatment for shock should be implemented.

Cases of renal dysfunction and acute renal failure have been reported in connection with administration of intravenous immunoglobulins. Those particularly at risk are patients with risk factors such as pre-existing renal insufficiency, diabetes mellitus, hypovolaemia, overweight, concomitant treatment with nephrotoxic medicinal products and age over 65. When such patients receive intravenous immunoglobulin treatment,

- adequate fluid intake must be ensured prior to commencement of therapy,

- urine output and serum creatinine levels must be monitored and

- concomitant use of loop diuretics must be avoided.

If renal dysfunction occurs, discontinuation of the immunoglobulin therapy should be considered.

While the reports of renal dysfunction and acute renal failure have been associated with use of many of the licensed immunoglobulin products, products containing sucrose as a stabiliser accounted for a disproportionate share of the total number. At-risk patients should therefore receive immunoglobulin products that do not contain sucrose. In patients at risk for acute renal failure or thromboembolic adverse reactions Gamunex^® 10% should be administered at the minimum rate of infusion and dose practicable.

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. The measures taken may be of limited value against non-enveloped viruses such as HAV and/or 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 Gamunex^® 10% is administered to a patient, the name and batch number of the product are recorded using the supplied tear-off labels in order to maintain a link between the patient and the batch of the product.

Specific interaction studies with Gamunex^® 10% have not been performed. Clinically relevant interactions with other medicinal products on concomitant use of Gamunex^® 10% have nevertheless not been described to date.

Live attenuated vaccines: the effect of active immunisation may be impaired by concomitant treatment with immunoglobulins for at least 6 weeks and up to 3 months. Live attenuated virus vaccines, such as those against mumps, rubella or varicella, should therefore not be administered for three months after infusion of Gamunex^® 10%. In the case of vaccines against measles, this effect may persist for up to a year after intravenous administration of immunoglobulin. Such patients' antibody status should therefore be checked.

Interference with serological testing: After injection of immunoglobulin the transitory rise of the various passively transferred antibodies in the patients 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), reticulocyte count and haptoglobin.

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 fetus 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.

There are no indications that immunoglobulins impair the ability to drive or use machines.

Chills, headache, dizziness, fever, nausea and vomiting, diarrhoea, low blood pressure, allergic reactions such as urticaria, skin rash and pruritus, arthralgia, weakness, mild back pain and reactions at the injection site have been reported occasionally.

Rarely, hypersensitivity reactions with a sudden fall in blood pressure, to the point of anaphylactic reactions even anaphylactic shock in isolated instances, may occur, even if the patient has shown no reaction to previous administration.

In isolated instances, particularly on administration of immunoglobulins at high doses, signs of aseptic meningitis such as severe headache, nausea, vomiting, fever, neck stiffness or diminished consciousness have been described. These were fully reversible on ceasing treatment.

In isolated instances, impairment of renal function with elevation of serum creatinine, to the point even of acute renal failure, may occur in the context of administration of immunoglobulins.

Very rarely: Thromboembolic reactions, such as myocardial infarction, stroke, pulmonary embolism and deep vein thromboses have been reported in patients at risk such as elderly patients, patients with ischaemic cerebrovascular or cardiovascular disease, overweight and severely hypovolaemic patients.

Furthermore, reversible haemolytic anaemia / haemolysis have been observed in isolated instances and transient skin reactions have been observed rarely.

The ADRs reported in clinical trials with Gamunex^® 10% are summarised and categorised according to MedDRA System Organ Classes. The Frequency has been evaluated using the following criteria:

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) and not known (cannot be estimated from available data).

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

ADRs which have been reported in clinical trials with Gamunex^® 10% in rare frequencies:

Haemolytic anaemia, dyspnoe, sinusitis, skin exfoliation, anxiety, myalgia, haemoglobin decreased, dyspepsia, contusion, dermatitis, flushing, musculoskeletal stiffness, palmar erythema, aphonia.

Frequency of Adverse Drug Reactions (ADRs) in clinical trials with Gamunex^® 10%

For safety with respect to transmissible agents, see 4.4.

Overdose may lead to hypervolaemia or a hyperviscosity syndrome, particularly in elderly patients and patients with impaired renal function.

Pharmacotherapeutic group: human normal immunoglobulin for intravenous administration. ATC code: J06B A02

Clinical trials conducted with Gamunex^® 10% on patients with Chronic Inflammatory Demyelinating Polyneuropathy (CIDP):

The IVIG-C CIDP efficacy trial (ICE study), a double-blind, randomised, placebo-controlled study investigated the efficacy and safety of Gamunex^® 10% in the treatment of CIDP. A total of 117 CIDP patients were randomised to receive either Gamunex^® 10% or placebo every three weeks. Loading dose was 2 g/kg BW; maintenance dose was 1 g/kg BW.

Responder rates (determined by improvement in INCAT disability score and maintenance of 1 improvement over the 24 week efficacy period) were significantly higher in the Gamunex^® 10% group (54%), compared to the placebo group (21%, p=0.0002). Muscle strength as measured by the MRC score and grip strength, as well as sensation as measured by the ISS score improved significantly more in the Gamunex^® 10% group compared to placebo.

In view of the limited number of patients 65 years included in the study, a precise treatment effect could not be determined with regard to the INCAT score; for grip strength, a statistically significant treatment effect was shown in favour of Gamunex^® 10%.

Of the responders, less than half responded after the loading dose (by week 3), but most responded after the second dose (by week 6) Non-responders were crossed over to the alternative treatment, for again up to a maximum of 24 weeks of therapy.

All responders were re-randomised in an extension phase for another 6 months period of maintenance therapy with either Gamunex^® 10% or placebo. Of the former responders to Gamunex^® 10%, the actual relapse rate was significantly higher in the patients randomised to placebo (42%) than in those randomised to Gamunex^® 10% (13%, p=0.012).

The ICE study has shown short-term and long-term efficacy of Gamunex^® 10% in the treatment of CIDP.

Table 1: Primary endpoint and other results of the ICE study

¹ Improvement indicated by positive figure

²Improvement indicated by negative figure

^aMRC: Medical Research Council

^bISS: INCAT Sensory Sum Score

Gamunex^® 10% contains unmodified immunoglobulin G (IgG) with a broad spectrum of antibodies against various infectious agents. Opsonisation and neutralisation of microbes and toxins by specific antibodies has been demonstrated.

Gamunex^® 10% contains the IgG antibodies present in the normal population. It is prepared from plasma from at least 1,000 donors. Its subclass distribution corresponds to that of human plasma. Abnormally low serum IgG levels can be restored to normal with appropriate doses of Gamunex^® 10%. The mechanism of action in indications other than replacement therapy has not yet been fully investigated but includes immunomodulatory effects.

The proprietary product is adjusted to a weakly acidic pH. Since Gamunex^® 10% has a low buffering capacity, it is rapidly neutralised by the blood during the infusion. Even after administration of high doses of Gamunex^® 10%, no change in the pH of the blood was recorded. Osmolality is 258 mOsm/kg solution and thus approximates to the normal range (285-295 mOsm/kg).

Immunoglobulins are immediately and completely bioavailable in the recipient's circulation after intravenous administration. They are distributed relatively rapidly between plasma and extravascular fluid; after approximately 3 – 5 days, equilibrium is reached between the intravascular and extravascular compartments.

The in vivo half-life of Gamunex^® 10%, determined in patients with a primary antibody deficiency syndrome, is 35 days and therefore exceeds that of 21 days described in the literature in healthy subjects. The half-life of IgG may vary from patient to patient, however, particularly in patients with primary immunodeficiency syndromes.

Immunoglobulins and IgG complexes are broken down in the cells of the mononuclear phagocytic system.

Immunoglobulins are normal components of the human body. Because administration of immunoglobulins in animal studies may lead to the formation of antibodies, preclinical safety data are limited. In the acute and sub-acute animal studies that were performed, Gamunex^® 10% did not show special risks for humans.

Glycine

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

3 years

Store at +2 °C to +8 °C (in a refrigerator). Do not freeze.

The product may be stored in its outer carton for a one-off period of up to 6 months at room temperature (not above 25°C). In that case, the shelf life of the product expires at the end of this 6-month period. The new expiry date must be noted on the outer carton and the vial label. The new expiry date must be no later than the printed expiry date. Thereafter, it must be used or destroyed. Subsequent refrigeration is not possible.

Solution for intravenous infusion in clear Type I or II glass vials with halobutyl/isoprene rubber stoppers or chlorobutyl stoppers.

Pack sizes: 10 ml, 50 ml, 100 ml, 200 ml; hospital packs. Not all pack sizes may be marketed.

For intravenous administration. Infuse clear solutions only. Prior to infusion, Gamunex^® 10% must be brought up to room temperature or body temperature, possibly in a water bath at a temperature no higher than 37 °C. Once the container has been opened, the contents should be infused immediately. Subsequent storage, even in a refrigerator, is not permitted on account of possible microbial colonisation.

If dilution is necessary prior to infusion, 5% glucose solution may be used for this purpose. Gamunex^® 10% is not compatible with saline solution.

Talecris Biotherapeutics GmbH

Lyoner Strasse 15

D-60528 Frankfurt

Germany

PL 29527/0001

09.02.2004

September 2009

POM.

COUNTRY OF ORIGIN OF THE BLOOD PLASMA USED

USA

Instructions for use of the vials (50 ml, 100 ml and 200 ml vials only)

The vials are supplied with a hanger label (Fig. 1). After inserting the giving set (Fig. 2), invert the vial and fold back the loop section of the label (Fig. 3). Use firm finger pressure to create a crease on each side where the loop section joins the rest of the label (Fig. 4). Suspend the vial from the infusion stand by the resulting loop (Fig. 5).