Indications for subcutaneous administration (SCIg)

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

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

• Hypogammaglobulinaemia and recurrent bacterial infections in patients with chronic lymphocytic leukaemia (CLL), in whom prophylactic antibiotics have failed or are contra-indicated.

• Hypogammaglobulinaemia and recurrent bacterial infections in multiple myeloma (MM) patients.

• Hypogammaglobulinaemia in patients pre- and post-allogeneic haematopoietic stem cell transplantation (HSCT).

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

Posology

Replacement therapy

The product should be administered via the subcutaneous route.

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.

The dose regimen should achieve a trough level of IgG (measured before the next infusion) of at least 6 g/l and aim to be within the reference interval of serum IgG for age. A loading dose of at least 0.2 to 0.5 g/kg (1.25 to 3.13 ml/kg) may be required. This may need to be divided over several days, with a maximal daily dose of 0.1 to 0.15 g/kg.

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. Each single dose may need to be injected at different anatomic sites.

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 dose and aim for higher trough levels.

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 in replacement therapy indications.

Method of administration

For subcutaneous use only.

Subcutaneous infusion for home treatment should be initiated and monitored by a physician experienced in the guidance of patients for home treatment. The patient will be instructed in the use of appropriate infusion devices, or other infusion techniques, the keeping of a treatment diary and measures to be taken in case of severe adverse reactions.

Subgam may be injected into sites such as abdomen, thigh, upper arm, and lateral hip by

(a) an infusion device or

(b) manual push using a syringe and needle

Infusion device

It is recommended to use an initial administration speed of between 10 to 20 ml/h/site.

If well tolerated (see section 4.4), the infusion speed can be increased to a recommended maximum speed of 30 ml/h/site. More than one infusion device can be used simultaneously. The amount of product infused into a particular site varies. In infants and children, infusion site may be changed every 5-15 ml. In adults, doses over 30 ml may be divided according to patient preference. There is no limit to the number of infusion sites.

Manual push using a syringe and needle

For practical reasons, a single site per syringe is recommended. The rate of administration should be adjusted for each patient's local tolerance which may depend on the volume and site of each subcutaneous injection and the amount of the individual patient's subcutaneous tissue at that site. If well tolerated, the infusion rate can be increased with subsequent doses.

An appropriate choice of needle size may facilitate achievement of infusion rate.

Frequency of infusions

When tailoring the dosage regimen for an individual, the following are recommended dosage administrations (see section 5.2).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see section 4.4).

Subgam must not be given intravenously.

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

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

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 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:

• initially injecting the product slowly (0.002 ml/kg/min)

• ensuring that patients are carefully monitored for any symptoms throughout the infusion period. In particular, patients naï ve to human normal immunoglobulin, patients switched from an alternative immunoglobulin 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 should be administered.

Hypersensitivity

True allergic reactions are rare. They can particularly occur in patients with anti-IgA antibodies who should be treated with particular caution. Patients with anti-IgA antibodies, in whom treatment with subcutaneous IgG products remains the only option, should be treated with Subgam only under close medical supervision.

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

Arterial and venous thromboembolic events including myocardial infarction, stroke, deep venous thrombosis and pulmonary embolism have been associated with the use of immunoglobulins. Patients should be sufficiently hydrated before use of immunoglobulins. Caution should be exercised 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 events, patients with acquired or inherited thrombophilic disorders, patients with prolonged periods of immobilisation, severely hypovolemic patients, patients with diseases which increase blood viscosity).

Patients should be informed about first symptoms of thromboembolic events including shortness of breath, pain and swelling of a limb, focal neurological deficits and chest pain and should be advised to contact their physician immediately upon onset of symptoms.

Aseptic Meningitis Syndrome (AMS)

Aseptic meningitis syndrome has been reported to occur in association with subcutaneous immunoglobulin treatment; the symptoms usually begin within several hours to 2 days following treatment. Discontinuation of immunoglobulin treatment may result in remission of AMS within several days without sequelae.

Patients should be informed about first symptoms which encompass severe headache, neck stiffness, drowsiness, fever, photophobia, nausea and vomiting.

Important information about some of the ingredients of Subgam

Sodium

This medicinal product contains up to 4.6 mg sodium per mL, equivalent to 2.5% of the WHO recommended maximum daily intake of 2 g sodium for an average 80kg adult.

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 anti-globulin 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 human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) 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.

Paediatric population

The listed warnings and precautions apply to both adults and children.

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

The listed interactions apply to both adults and children.

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. Immunoglobulin products have been shown to cross the placenta, increasingly during 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 are to be expected.

The ability to drive and operate machines may be impaired by some adverse reactions associated with Subgam. 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, 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 may frequently occur.

For safety information 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 <1,1000); 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 Subgam

Description of selected adverse reactions

Although infusion site reactions are very common initially, their frequency usually reduces with continued treatment aided by changing the sites of infusions.

Paediatric population

Frequency, type and severity of adverse reactions in children are the same as in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard

Consequences of an overdose are not known.

Pharmacotherapeutic group: immune sera and immunoglobulins: immunoglobulins, normal human, for extravascular administration, ATC code: J06BA01.

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 less than 1,000 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.

Fifty subjects were treated in an open, non-comparative clinical study to evaluate the efficacy and safety of Subgam in primary immunodeficiency (PID). Subgam was initially given weekly at a starting dose of 100 mg/kg and dose and frequency adjusted if required. The majority of patients adhered to a once a week dosing schedule. Fifteen subjects were children aged <12 years (12 male, 3 female), 7 were adolescents aged 12.1 to 18.0 years (3 male, 4 female) and 28 were adults (10 male, 18 female). A mean of 147.7 (22 to 317) infusions were given during an average 147.5 (24 to 208) weeks of treatment. All subjects completed approximately 6 months in the study (Stage 1: safety and efficacy) and 32 (64%) subjects participated for at least 3 years (Stage 2: long-term follow-up). The majority of infusions (93.6%) were infused at home. The primary endpoint of the study was the proportion of trough levels at each time point where serum IgG was ≥ 4 g/l for children and ≥ 6 g/l for teenagers and adults. In Stage 1 of the study, target serum IgG levels were met in 14 of the 15 children (93%) and in 119 of 122 observations (98%) in this patient subgroup. Target serum IgG levels were met at all observations in 29 of the 34 teenagers and adults (85%) and in 447 of 463 observations (97%) in this patient subgroup. There were 513 infections during the 51,655 study days (mean of 3.62 infections per subject per year) recorded by the subjects in their diary cards and there was no difference apparent between age groups. Fifteen subjects (out of 49) were on long-term antibiotic prophylaxis for 26.6% of study days. Of those for whom data are available (n = 33), children (n = 10) had a mean of 3.7% (median = 2.3%) of days off school, teenagers (n = 7) had a mean of 1.8% (median = 1.6%) of days off work/school and adults (n = 16) had a mean of 2.9% (median = 0.5%) of days off work.

Paediatric population

A total of 15 children (<12 years) were recruited to the study; all remained on the study for at least 18 months and 12 were on study for at least 30 months. All 7 teenagers (< 18 years) remained on the study for at least 30 months. No differences were seen in the pharmacodynamic properties of Subgam between the age groups.

In a clinical study to evaluate the pharmacokinetics and safety of Subgam in PID, 38 subjects aged 2-72 years received weekly doses of Subgam for a median of 26 weeks). Of the 38 subjects, 24 (63.2%) were ≥ 18 years and 14 (36.8%) were 2 to 17 years old with four aged 2– 5 years, five aged 6– 11 years and five aged 12– 17 years). The study determined the pharmacokinetic (PK) profile of Subgam. Secondary objectives were to assess the safety of Subgam, including the incidence of adverse events and site infusion reactions in subjects with PID. There were no serious acute bacterial infections.

Absorption and Distribution

Following subcutaneous administration of Subgam, peak serum levels are achieved after approximately 2 to 3 days. Steady state was reached after approximately 6 to 7 weekly infusions of Subgam in both adult and paediatric patients.

Metabolism and Elimination

The extravascular systemic clearance (i.e. dose/AUC_0-t) was similar for adults and children (respectively 0.194 and 0.197 dl/day/kg).

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

Weight/ BMI

BMI had marginal difference on the IgG AUC_0-t after Subgam over the range 14.2 to 32.6 kg/m².

Gender

Systemic exposure to IgG (e.g. AUC) after administration of Subgam was not appreciably different between males and females.

Trough concentrations

The median trough level of IgG was 9.21 g/l in 49 patients during a period of 26 weeks when receiving median weekly doses 0.102 g/kg. When the median weekly dose was 0.171 g/kg (range 0.102 to 0.349 g/kg, the median trough level was 12.25 g/l (range 8.19 to 19.72 g/l) in 38 patients. Serum trough levels of IgG antibodies to specific antigens, e.g. Haemophilus influenzae and Streptococcus pneumoniae, tended to increase throughout the study in line with total IgG levels.

Doses Once Weekly, every Two Weeks or more Frequent Dosing.

Population PK data showed that, for the same total weekly dose, Subgam infusions given 2-7 times per week also results in comparable IgG exposure across a 1-week interval. In addition, Subgam administered every 14 days at double the weekly dose results in comparable IgG exposure across the entire 2-week interval.

Missed doses

Simulations have been made for potential missed doses on a weekly or daily regimen. The results are shown in the following table. These examples provide a measure of the decrease in the trough IgG at worst and, where appropriate depending on the replacement strategy, the increase in the maximum IgG concentration. These illustrative examples can help recommendations to patients for missed doses.

N/A Not appropriate

Paediatric population

The pharmacokinetics of IgG after administration of Subgam were not appreciably different between age categories.

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.

Sodium chloride

Glycine

Sodium acetate

Polysorbate 80

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

2 years.

Once a vial has been opened, the solution should be used immediately.

Store in a refrigerator (2° C – 8° C).

Do not freeze.

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

When stored between 2° C – 8° C Subgam has a shelf-life of 24 months.

At any time within this shelf life:

- Subgam may be stored for one period of up to 2 months at room temperature (up to 25° C). After 2 months at room temperature unused product should be discarded.

- Alternatively, one short period (up to 1 week) at room temperature (up to 25° C) will not compromise product stability. The product may be returned to a refrigerator with no change to the expiry date.

If the carton is removed from the refrigerator the date of removal should be recorded on the carton.

Subgam is supplied in type I or II glass vials, closed with a halobutyl stopper and over-sealed with a tamper-evident cap.

Pack sizes

1 vial of 750 mg contains 5 ml solution for injection

1 vial of 1 g contains 6.25 ml solution for injection

1 vial of 1500 mg contains 10 ml solution for injection

1 vial of 2 g contains 12.5 ml solution for injection

1 vial of 4 g contains 25 ml solution for injection

Not all pack sizes may be marketed.

The medicinal product should be brought to room or body temperature before use. Products should be inspected visually for particulate matter and discolouration prior to administration.

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.