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

Human normal immunoglobulin (IVIg)

One mL contains: Human normal immunoglobulin 50 mg (purity of at least 95% IgG).

Each 2.5 g vial of 50 mL contains: 2.5 g of Human normal immunoglobulin.

Each 5 g vial of 100 mL contains: 5 g of Human normal immunoglobulin.

Each 10 g vial of 200 mL contains: 10 g of Human normal immunoglobulin.

Distribution of the IgG subclasses (approximate values):

The maximum IgA content is 10 micrograms per mL (typically ~4 micrograms per mL).

Produced from the plasma of human donors.

For a full list of excipients, see section 6.1.

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

Replacement therapy in adults, and children and adolescents in:

- Primary immunodeficiency 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 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 initiated and monitored under the supervision of a physician experienced in the treatment of immunodeficiency. Treatment at home should be similarly supervised, with the patient fully assessed and trained in hospital prior to self-infusion at home.

Posology

The dose and dose regimen is dependent on the indication.

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

Replacement therapy in primary immunodeficiency syndromes

The dose regimen should achieve a trough level of IgG (measured before the next infusion) of at least 5 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 - 0.8 g/kg given once, followed by at least 0.2 g/kg given every three to four 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/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 incidence of infection. To reduce the rate of infection, it may be necessary to increase the dosage and 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 every three to four weeks.

Hypogammaglobulinaemia in patients after allogeneic haematopoietic stem cell transplantation

The recommended dose is 0.2 - 0.4 g/kg every three to four weeks. The trough levels should be maintained above 5 g/L.

Primary immune thrombocytopenia

There are two alternative treatment schedules:

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

- 0.4 g/kg given daily for two to five days.

The treatment can be repeated if relapse occurs.

Guillain Barré syndrome

0.4 g/kg/day over 5 days.

Kawasaki Disease

1.6 - 2.0 g/kg should be administered in divided doses over two to five days or 2.0 g/kg 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 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.

Gammaplex^® should be infused intravenously, preferably using an intravenous infusion set, at an initial rate of 0.01 - 0.02 mL/kg/minute (0.6 - 1.2 mL/kg/hour) for 15 minutes. If well tolerated (see section 4.4), the rate of administration may be increased to 0.04 mL/kg/minute (2.4 mL/kg/hour) for 15 minutes, then to 0.06 mL/kg/minute (3.6 mL/kg/hour) for 15 minutes, followed by a maximum of 0.08 mL/kg/minute (4.8 mL/kg/hour) 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.

Hereditary fructose intolerance (see section 4.4).

Babies and young children (see section 4.4).

Hypersensitivity to the active substance or to any of the excipients (see section 4.4).

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

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. In babies and young children hereditary fructose intolerance may not yet be diagnosed, as they may not yet have been exposed to fructose-containing foods such as fruit or sucrose and infusion of sorbitol may be fatal. Therefore, babies and young children who have not been exposed to fructose containing foods or sucrose should not receive this medicine until it is known whether they can metabolise fructose.

In other patients, in case of inadvertent administration and suspicion of fructose intolerance, the infusion has to be stopped immediately, normal glycaemia has to be re-established and organ function has to be stabilised by means of intensive care.

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 injecting Gammaplex^® slowly (0.01 – 0.02 mL/kg/min);

- 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.

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.

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 anaphylactic reaction, even in patients who had tolerated previous treatment with human normal immunoglobulin.

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.

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, those 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 these excipients may be considered. Gammaplex^® does not contain sucrose, maltose or glucose.

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

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.

Haemolytic anaemia

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

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

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 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.

Paediatric population

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.

Home therapy

Gammaplex^® must only be used by patients themselves at home after thorough training in hospital by a qualified health care professional, expert in infusion of IVIg products. The patient should first be stabilised on the product under supervision in hospital.

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.

Paediatric population

There are no known interactions that are specific to the paediatric population or any subset of the paediatric population.

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 fetus 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 Gammaplex^®. 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 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, deep vein thromboses.

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

Tabulated list of adverse reactions

The table presented below is according to the MedDRA system organ classification (SOC and Preferred Term Level).

Frequencies have been evaluated according to the following convention: 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), not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Frequency of Adverse Reactions (ADRs) in clinical studies with Gammaplex^®

Description of selected adverse reactions

None of the reported adverse reactions to Gammaplex^® warrant separate description.

Paediatric population

Of the 50 patients in the clinical study of Gammaplex^® in primary immunodeficiency, seven were aged less than 18 years (age range 9 to 17 years). Of the 29 patients in the clinical study of Gammaplex^® in chronic immune thrombocytopenia (ITP), three were aged less than 18 years (age range 6 to 17 years). The frequency, type and severity of adverse reactions in children are expected to be the same as in adults.

Other special populations

Certain patient groups may be at increased risk of hypersensitivity reactions, thromboembolism or acute renal failure. Caution should be exercised when infusing IVIg in obese patients or those with advanced age, hypertension, diabetes mellitus, history of vascular disease or thrombotic episodes, acquired or inherited thrombophilic disorders, prolonged periods of immobilisation, severe hypovolaemia, diseases which increase blood viscosity, pre-existing renal insufficiency or those receiving concomitant nephrotoxic medicinal products; see Section 4.4 for details.

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

Gammaplex^® is in pharmacotherapeutic group: immune sera and immunoglobulins: immunoglobulins, normal human, for intravascular administration, ATC code: J06BA02.

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 donations 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.

A phase III, multicentre, non-randomized, open-label study in 50 subjects with primary immunodeficiency diseases (PID), where Gammaplex^® was infused at a dose of 300 to 800 mg/kg every 21 or 28 days, concluded that Gammaplex^® was well tolerated and efficacious and therefore suitable for the management of subjects with PID. There were no serious acute bacterial infections during the 12 months of treatment, and the most commonly reported adverse reactions were headache (9 patients), nausea (6 patients), pyrexia (6 patients) and fatigue (6 patients).

A later Phase III, open-label, multicentre clinical study investigating the safety and efficacy of Gammaplex^® infused at a dose of 1 g/kg/day for two consecutive days in 29 subjects with chronic immune thrombocytopenia (ITP) showed Gammaplex^® to be an effective treatment, and hence its efficacy in immunomodulation. The most commonly reported adverse reactions were headache (18 patients), vomiting (5 patients) and pyrexia (4 patients).

Paediatric population

The above study on Gammaplex^® in PID included seven patients aged less than 18 years (9-17 years inclusive). There were no reports of serious adverse reactions in any of the paediatric subjects.

The above study on Gammaplex^® in ITP included three subjects aged less than 18 years (6-17 years inclusive). One of the paediatric subjects (aged six years) experienced a serious adverse reaction (headache, with vomiting and dehydration).

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, and after approximately 3 - 5 days equilibrium is reached between the intra- and extravascular compartments. Gammaplex^® has a half-life of 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.

Paediatric population

Two children participated in a PK sub-study as part of the study in subjects with PID. Gammaplex^® was shown to have a half-life of 33.9 to 69.7 days, confirming variability between patients.

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.

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

24 months if stored unopened in the dark at temperatures between 2°C and 25°C.

Gammaplex should be used immediately after opening (see Section 4.2).

Gammaplex^® should be stored at temperatures between 2°C and 25°C 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 with an integral sling, closed with a stopper and oversealed with a tamper-evident cap.

The product should be brought to room temperature before use.

Gammaplex^® should be clear or slightly opalescent and colourless. Solutions that are cloudy or have deposits should not be used.

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