SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Subgam®, Human normal immunoglobulin solution 160g/L, solution for injection.

2.    Qualitative and Quantitative Composition

Human normal immunoglobulin Ph.Eur. (SC/IMIg)

Subgam is presented as two vial sizes of 750 mg and 1,500 mg of protein. Each millilitre contains: nominal 160 mg human protein of which at least 95% is immunoglobulin G (gammaglobulin). The sub-class distribution of IgG1:IgG2:IgG3:IgG4 is approximately 64:29:6:1, which is similar to plasma. The IgA content is less than 0.04% w/w of the total protein. This product is prepared from plasma from screened donors. Donors are selected from the USA.

For excipients see 6.1.

3    PHARMACEUTICAL FORM

Solution for injection.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Replacement therapy in adults and children in primary immunodeficiency syndromes such as:

a.    Congenital agammaglobulinaemia and hypogammaglobulinaemia,

b.    Common variable immunodeficiency,

c.    Severe combined immunodeficiency,

d.    IgG subclass deficiencies with recurrent infections

Replacement therapy in myeloma or chronic lymphatic leukaemia with severe secondary hypogammaglobulinaemia and recurrent infections.

4.2 Posology and method of administration Replacement therapy

The product should be administered via the subcutaneous or intramuscular route.

Treatment should be initiated and monitored under the supervision of a physician experienced in the treatment of immunodeficiency.

The dosage may need to be individualised for each patient dependent on the pharmacokinetic and clinical responses. The following dosage regimens are given as a guideline.

The dosage regimen using the subcutaneous route should achieve a sustained trough level of IgG. A loading dose of at least 0.2 - 0.5 g/kg may be required. After steady state IgG levels have been attained, maintenance doses are administered at repeated intervals to reach a cumulative monthly dose of the order of 0.4 - 0.8 g/kg.

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

Subgam® should be administered via the subcutaneous or intramuscular route.

Subcutaneous infusion for home treatment should be initiated by a physician experienced in the guidance of patients for home treatment. The patient will be instructed in the use of a syringe driver, infusion techniques, the keeping of a treatment diary and measures to be taken in case of severe adverse events. The amount of Subgam® infused subcutaneously per injection site will vary depending on the patient’s age and amount of subcutaneous tissue. Initially the infusion rate should be no more than 10 mL/hour for each syringe driver. If well tolerated it can be increased at weekly intervals by 2 mL/hour per syringe driver to a maximum of 20 mL/hour. The administration can be performed at two or more different sites simultaneously to reduce infusion time.

Intramuscular injection must be given by a physician or nurse.

Contraindications

Hypersensitivity to any of the components. Subgam^® must not be given intravenously.

Subgam® must not be administered intramuscularly in cases of severe thrombocytopenia and in other disorders of haemostasis.

4.4 Special warnings and special precautions for use

If Subgam® is accidentally administered into a blood vessel, patients could develop shock.

The recommended infusion rate given under “4.2 Method of administration” should be adhered to. Patients should be closely monitored and carefully observed for any adverse events throughout the infusion period.

Certain adverse reactions may occur more frequently 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 treatment has been stopped for more than eight weeks.

True hypersensitivity reactions are rare. They can particularly occur in the very rare cases of IgA deficiency with anti-IgA antibodies and these patients should be treated with caution.

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 first injecting the product slowly (see 4.2);

■    patients are carefully monitored for any symptoms throughout the infusion period. In particular, patients naive to human normal immunoglobulin, patients switched from an alternative 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.

Suspicion of allergic or anaphylactic type reactions requires immediate discontinuation of the injection. In case of shock, standard medical treatment should be administered.

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 human immunodeficiency virus, hepatitis B virus and hepatitis C virus and for the non-enveloped hepatitis A and parvovirus B19 viruses.

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 Subgam^® 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.

4.5 Interaction with other medicinal products and other forms of interaction 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 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 (reticulocyte count, haptoglobin and Coombs’ test).

4.6 Pregnancy and lactation

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.

Effects on ability to drive and use machines

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

4.8 Undesirable effects

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. Local reactions at infusion sites: swelling, soreness, redness, induration, local heat, itching, bruising and rash.

With intramuscular administration, local pain and tenderness can be observed at the injection site.

From clinical trials with Subgam® the following side effects have been reported. The frequencies relate to the proportion of patients developing each side effect at some time during the trial, but not with every infusion:

Very common >1/10; Common >1/100 to <1/10

Psychiatric disorders: Common Anxiety

Nervous system disorders:    Very common Headache

Common Dizziness

Common    Migraine

Common Paraesthesia

Vascular disorders:    Common    Flushing

Respiratory, thoracic and mediastinal disorders:

Common    Wheezing/asthma

Gastrointestinal disorders:    Common    Nausea

Common	Vomiting
Common	Diarrhoea
Common	Mouth ulcer
Common	Abdominal pain upper
Skin and subcutaneous tissue disorders:
Common	Pruritus
Common	Sweating increased
Common	Rash
Muscular skeletal, Connective tissue and bone disorders:
Common	Arthralgia
Common	Musculoskeletal pain/stiffness
General disorders and administration site conditions:
Very common	Infusion site reaction
Common	Chest pain/tightness
Common	Fatigue
Common	Pyrexia

Common    Shivering/feeling cold

Investigations: Common Blood pressure increased

For information on viral safety see 4.4.

4.9 Overdose

Consequences of an overdose are not known.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: immune sera and immunoglobulins: immunoglobulins, normal human, for extravascular administration, ATC code: J06B A02.

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 donations. 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.

5.2 Pharmacokinetic properties

With subcutaneous administration of Subgam®, peak levels are achieved in the recipient’s circulation after a delay of 3 to 4 days.

Data from clinical trials show that trough levels of Subgam® can be maintained by doses of 100 (90 to 115) mg/kg. usually given once weekly.

With intramuscular administration, human normal immunoglobulin is bioavailable in the recipient’s circulation after a delay of 2 to 3 days.

5.3 Preclinical safety data

Human normal immunoglobulin is a preparation of human plasma proteins, so safety testing in animals is not particularly relevant to the safety of use in man. However, acute toxicity studies in rat and mouse showed no minimum lethal dose with the clinical strength product used at approximately 1,250 mg/kg. This is equivalent to approximately 10 times the dose in man. Repeated dose testing is impracticable due to induction of, and interference with antibodies, to human protein. Clinical experience provides no evidence of tumourigenic and mutagenic effects.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Sodium chloride, Glycine, Sodium acetate trihydrate, Sodium hydroxide, Polysorbate 80, Hydrochloric acid (if required)

6.2 Incompatibilities

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

6.3 Shelf life

Stored at 2°C - 8°C (in the dark):    2 years

Stored at 25°C (in the dark):    1 week

6.4 Special precautions for storage

Subgam^® should be stored in its carton to protect it from light, between 2°C and 8°C. DO NOT FREEZE. Storage for up to one week (within the overall shelf-life) at ambient temperatures (25°C) is not detrimental. Product that has been stored out of a fridge for one period of up to one week at temperatures up to 25 °C may be returned to the fridge with no change to the expiry date.

6.5    Nature and contents of container

The containers are:

1500 mg - 26 mL brimful glass vial with a 20 mm neck and closure,

750 mg - 12 mL brimful glass vial with a 13 mm neck and closure.

The closure on the vials consists of a halobutyl rubber stopper with an overseal consisting of a clear lacquered aluminium skirt and a snap-off polypropylene cap.

6.6    Special precautions for disposal and handling

Detailed infusion technique:

The syringe driver should be checked and the appropriate rate set for the patient. A suitable size syringe should be selected and the IgG solution drawn up aseptically. Attach the ‘butterfly’ or other infusion system and prime tubing with the solution. Cleanse the injection site and insert the needle into the subcutaneous tissue. Ensure that the needle tip is not in a blood vessel. Switch on the syringe driver. The usual sites of infusion are the subcutaneous tissues over the anterior abdominal wall or the anterior aspect of the thigh(s). When the end-of-infusion signal sounds, remove the needle.

The dose volume for each size is specified on the label. The product should be brought to room or body temperature before use.

The solution 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.

7. MARKETING AUTHORISATION HOLDER

Bio Products Laboratory Limited

Dagger Lane

Elstree

Hertfordshire

WD6 3BX

United Kingdom.

8    MARKETING AUTHORISATION NUMBER(S)

PL 08801/0050

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

9 June 2004

DATE OF REVISION OF THE TEXT

03/11/2014