Gammaplex^® is a sterile liquid of 5 % w/v normal immunoglobulin.

Human normal immunoglobulin for intravenous administration. This product is prepared from plasma from carefully screened and healthy donors. Donors are selected from the USA.

Gammaplex^® contains 5 g/100 mL of human normal immunoglobulin (i.e. 50 g/L, of which virtually 100% is IgG).

Gammaplex^® has an IgA content of less than 10 micrograms per mL (typically ~4 micrograms per mL) and a sub-class distribution of IgG1:IgG2:IgG3:IgG4 of approximately 62:31:6:1; this is similar to plasma.

For excipients see 6.1.

Gammaplex^® is a colourless sterile liquid for intravenous administration.

Replacement therapy in:

Primary immunodeficiency 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.

Posology

The dose and dosage regimen is dependent on the indication.

In replacement therapy the dosage may need to be individualised for each patient dependent 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 level of IgG (measured before the next infusion) of at least 4 - 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 - 0.8 g/kg followed by at least 0.2 g/kg every three weeks.

The dose required to achieve a trough level of 6 g/L is of the order of 0.2 - 0.8 g/kg/month. The dosage interval when steady state has been reached varies from 2 - 4 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 - 0.4 g/kg every 3 to 4 weeks.

The dosage recommendations are summarised in the following table:

Method of administration

Gammaplex^® should be infused intravenously, preferably using an intravenous infusion set fitted with an in-line 15 micron filter, at an initial rate of 0.01 - 0.02 mL/kg/minute for 15 minutes. If well tolerated, the rate of administration may be gradually increased to 0.04 mL/kg/minute up to a maximum of 0.08 mL/kg/minute, for the remainder of the infusion. Due to the absence of any anti-microbial preservatives, it is recommended that administration should begin immediately after piercing the cap.

Hypersensitivity to any of the components.

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

Fructose intolerance (see section 4.4).

Certain severe adverse drug reactions may be related to the rate of infusion. The recommended infusion rate given under “4.2 Method of administration” 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 infusion rate;

- 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 seldom 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 injecting Gammaplex^® slowly (0.01 mL/kg/min);

- that patients are carefully monitored for any symptoms throughout the infusion period. In particular, patients naïve 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;

There is clinical evidence of an association between IVIg administration and thromboembolic events such as myocardial infarction, stroke, pulmonary embolism and deep vein thrombosis which are 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 hypovolemic patients, 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, 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 beenassociated 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.

In patients at risk for 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.

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 that Gammaplex^® 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.

This medicinal product contains 50 mg of sorbitol per mL as an excipient. Patients with rare hereditary problems of fructose intolerance should not take this medicine. Special precautions should be taken with babies and young children because this fructose intolerance may not yet be diagnosed and may be fatal.

Live attenuated 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 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.

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), 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.

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

In clinical trials adverse reactions were experienced by almost 50% of the patients. The most frequent adverse reaction was headache.

Events reported for this product are (proportions of patients experiencing):

Incidence (>1/100 to <1/10) is defined as common, (>1/10) is defined as very common

Other adverse reactions associated with intravenous immunoglobulins which may occur occasionally include allergic reactions, low blood pressure. 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, isolated cases of reversible haemolytic anaemia/haemolysis and rare cases of transient cutaneous reactions, have been observed with human normal immunoglobulin.

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 4.4.

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

Gammaplex^® is in pharmacotherapeutic group: Immune sera and immunoglobulins: immunoglobulins, normal human, for intravascular administration, ATC code: J06B A02.

Gammaplex^® contains mainly immunoglobulin G (IgG) with a broad spectrum of antibodies against various infectious agents.

Gammaplex^® contains the IgG antibodies present in the normal population. It is usually prepared from pooled plasma from not fewer than 1,000 donors. Gammaplex^® 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.

Human normal immunoglobulin is immediately and completely bioavailable in the recipient's circulation after intravenous administration. It is distributed relatively rapidly between the plasma and extravascular fluid, after approximately 3 - 5 days equilibrium is reached between the intra- and extravascular compartments. The half-life of Gammaplex^® has been found to be 21.7 days (mean after single dose) and 35.5 days (median at steady state). This half-life may vary from patient to patient, in particular in primary immunodeficiency.

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

Immunoglobulins are normal constituents of human plasma and therefore toxicity testing in heterologous species is of no relevance. Gammaplex^® contains highly purified immunoglobulins and has been tested in non-clinical haemodynamic monitoring studies. There was no evidence of effects on blood pressure or heart rate at infusion rates similar to those used clinically. At higher infusion rates of approximately 2- to 7-fold those used clinically, a hypertensive effect was found. No other preclinical studies have been carried out.

D-sorbitol

Glycine

Sodium

Chloride

Acetate

Polysorbate 80

The product pH is 4.8 - 5.1.

This medicinal product must not be mixed with other medicinal products.

24 months if stored unopened at temperatures between 2ºC and 25ºC.

Gammaplex^® should be stored at temperatures between 2ºC and 25ºC in its carton.

DO NOT FREEZE.

Do not use after the expiry date printed on the label. The conditions of expired or incorrectly stored product cannot be guaranteed. Such product may be unsafe and should not be used.

Gammaplex^® is a sterile colourless liquid immunoglobulin G supplied as 2.5 g, 5 g and 10 g doses. The product is contained in a clear glass bottle, closed with a stopper and oversealed with a tamper-evident cap.

The product should be brought to room or body temperature before use.

Gammaplex^® should be clear or slightly opalescent. Do not use solutions that are cloudy or have deposits.

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

Bio Products Laboratory

Dagger Lane

Elstree

Hertfordshire

WD6 3BX

United Kingdom.

E-mail: info@bpl.co.uk

PL 08801/0053

05 October 2009