This information is intended for use by health professionals

1. Name of the medicinal product

GAMMAGARD1 S/D 10 g powder and solvent for solution for infusion

1 GAMMAGARD is a trademark of Baxalta Incorporated.

2. Qualitative and quantitative composition

Active Ingredient Human normal immunoglobulin G (IgG)

Quantitative Composition Human Normal Immunoglobulin for Intravenous Administration, GAMMAGARD S/D, may be reconstituted with solvent [Water for Injections, Ph. Eur. (EP)] to a 5% (50 mg/mL) solution or a 10 % (100 mg/mL) solution of protein of which at least 90% is gamma globulin.

GAMMAGARD S/D contains only trace amounts of IgA.

Maximum immunoglobulin A (IgA) content: not more than 3 microgram per mL in a 5% solution.

Excipients: Human Albumin, Glycine, Sodium Chloride, Glucose Monohydrate.

For a full list of excipients, see section 6.1.

3. Pharmaceutical form

A sterile, purified, lyophilised powder for reconstitution with solvent prior to intravenous administration (Lyophilisate for injection).

4. Clinical particulars
4.1 Therapeutic indications

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 leaukaemia with severe secondary hypogammaglobulinaemia and recurrent infections

Children with congenital AIDS and recurrent infections

Immunomodulation:

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

Guillain-Barré syndrome

Kawasaki disease

Allogeneic bone marrow transplantation

4.2 Posology and method of administration

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 equilibrium 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 hypogammaglobulinemia and recurrent infections; replacement therapy in children with AIDS and recurrent infections

The recommended dose is 0.2- 0.4 g/kg every three to four weeks to obtain trough levels of at least 4-6g/L.

Idiopathic thrombocytopenic purpura

For the treatment of an acute episode, the required dose is 0.8-1 g/kg on day one, which may be repeated once within 3 days, or 0.4 g/kg daily for two to five days. The treatment can be repeated if relapse occurs.

Guillain-Barré syndrome

0.4 g/kg/day administered for 5 consecutive days. Experience in children is limited.

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.

Allogeneic Bone Marrow Transplantation

Human normal immunoglobulin treatment can be used as part of the conditioning regimen and after the transplant. For the treatment of infections and prophylaxis of graft versus host disease, dosage is individually tailored. The starting dose is normally 0.5 g/kg/week, starting seven days before transplantation and for up to 3 months after transplantation. In case of persistent lack of antibody production, dosage of 0.5 g/kg/month is recommended until antibody level returns to normal.

The dosage recommendations are summarised in the following table.

Indication

Dose

Frequency of injections

Replacement therapy in primary immunodeficiency

Replacement therapy in secondary immunodeficiency

Children with AIDS

-starting dose: 0.4-0.8 g/kg.

-thereafter: 0.2-0.8 g/kg

0.2-0.4 g/kg

0.2-0.4 g/kg

every 2-4 weeks to obtain IgG trough level of at least 4-6 g/L

every 3-4 weeks to obtain IgG trough level of at least 4-6 g/L

every 3-4 weeks

Immunomodulation:

Idiopathic Thrombocytopenic Purpura

Guillain-Barré syndrome

Kawasaki disease

0.8-1 g/kg

or

0.4 g/kg/d

0.4 g/kg/day

1.6-2 g/kg

or

2 g/kg

on day 1, possibly repeated once within 3 days

for 2-5 days

for 3-7 days

in several doses for 2-5 days in association with acetylsalicylic acid

in one dose in association with acetylsalicylic acid

Allogeneic Bone Marrow Transplantation:

treatment of infections and prophylaxis of graft versus host disease

-persistent lack of antibody production

0.5 g/kg

0.5 g/kg

every week from day –7 up to 3 months after transplantation

every month until antibody level returns to normal

Method of Administration

For intravenous use.

It is recommended that antecubital veins be used for GAMMAGARD S/D 10% solutions, if possible. This may reduce the likelihood of the patient experiencing discomfort at the infusion site.

In general, it is recommended that patients beginning therapy with GAMMAGARD S/D or switching from one Intravenous Immunoglobulin (IVIG) brand to another be started at the lower rates and then advanced to the maximal rate if they have tolerated several infusions at intermediate rates of infusion. Please also see 4.4

Adverse reactions may occur more frequently in patients especially those with immune deficiency who receive human normal immunoglobulin for the first time, or when they switch from another IVIG brand, or when there has been a long interval since the previous infusion. (See Section 4.8)

The rate of administration is individualised based on the tolerability of the patient.

Intravenous infusions of GAMMAGARD S/D 5% (50 mg/mL) solutions at 0.5 mL/kg/hr are recommended initially. In general, it is recommended that patients beginning treatment with GAMMAGARD S/D or switching from one IVIg brand to GAMMAGARD S/D be started at a lowest rate and then increased to the maximal rate if they have tolerated several infusions at intermediate rates of infusion (please also see Section 4.4). If well tolerated , the administration rate may be gradually increased to a maximum rate of 4 mL/kg/hr. Patients who tolerate GAMMAGARD S/D 5% solutions can be infused with 10% GAMMAGARD S/D solutions starting at 0.5ml/kg BW/hour, increasing gradually to a maximum rate of 8 mL/kg/hr.

When switching from the 5% solution to the 10% solution, the rate of the 10% solution should be initially reduced to keep the rate of IgG protein administration comparable.

4.3 Contraindications

Hypersensitivity or known anaphylactic reactions to the active substance or to any of the excipients.

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

GAMMAGARD S/D contains not more than 3 microgram IgA per mL in a 5% solution.

4.4 Special warnings and precautions for use

GAMMAGARD S/D is not indicated in patients with selective IgA deficiency where the IgA deficiency is the only abnormality of concern.

GAMMAGARD S/D should only be administered intravenously.

GAMMAGARD S/D is reconstituted to provide a protein solution of 5 g per 100 mL of solvent. This fluid volume will result in blood volume expansion with the extent dependent on the dose administered. When administered in high dose over a relatively short period of time, signs and symptomatology of fluid overload may result, especially in susceptible patients such as small children, elderly individuals or patients with renal impairment.

Certain severe adverse drug reactions such as headache and flushing may be related to the rate of infusion. Slowing or stopping the infusion usually allows the symptoms to disappear promptly. The infusion may then be resumed at a rate that does not result in recurrence of the symptoms. (See Section 4.8).

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 rate of infusion;

- in patients with hypo- or agammaglobulinemia with or without IgA deficiency;

- in immunodeficient 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.

Hypersensitivity

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 an anaphylactic reaction with a fall in blood pressure with anaphylactic reaction, even in patients who had tolerated previous treatment with human normal immunoglobulin.

Patients with antibodies to IgA or with IgA deficiencies that are a component of an underlying primary immunodeficiency disease for which IVIG treatment is indicated may be at increased risk of anaphylactic reaction. Anaphylaxis has been reported with the use of GAMMAGARD S/D even though it contains low levels of IgA. (see section 4.8)

GAMMAGARD S/D is not indicated in patients with selective IgA deficiency where the IgA deficiency is the only abnormality of concern. These patients should be treated only if their IgA deficiency is associated with an immune deficiency for which therapy with intravenous immune globulin is clearly indicated.

Patients who have had a severe hypersensitivity reaction to other intravenous gammaglobulin preparations should only receive GAMMAGARD S/D with utmost caution and in a setting where supportive care is available for treating life-threatening reactions (see section 4.8).

Potential complications can often be avoided by ensuring:

- that patients are not sensitive to human normal immunoglobulin by initially injecting the product slowly (0.5 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;

- that the glucose content (max. content of 0.4g/g of IgG) is taken into account in case of latent diabetes (where transient glycosuria could appear), diabetes, or in patients on a low sugar diet.

Thromboembolis

There is clinical evidence of an association between IVIG treatment (including GAMMMAGARD S/D), 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 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 history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, known or suspected hyperviscosity, for example dehydration or paraproteins, hypercoagulable disorders, prolonged period of immobilization, obesity, diabetes mellitus, patients using estrogens, patients with an indwelling vascular catheter acquitted or inherited thrombophilic disorder, a dose and rapid infusion.).

In patients at risk of hyperviscosity monitor for signs and symptoms of thrombosis and assess blood viscosity.

Acute renal failure

Severe renal adverse reactions have been reported in patients receiving IVIG treatment, particularly those products containing sucrose (GAMMAGARD S/D does not contain sucrose). These include

- acute renal failure (reported with GAMMAGARD S/D)

- acute tubular necrosis

- proximal tubular nephropathy

- osmotic nephrosis

In most cases, risk factors have been identified, such as pre-existing renal insufficiency, diabetes mellitus, hypovolemia, hyperviscosity, concomitant nephrotoxic medicinal products age over 65, sepsis or paraprotinaemia.

In cases 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 sucrose as a stabilizer 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 and after 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.

Transfusion Related Acute Lung Injury

There have been reports of noncardiogenic pulmonary edema (Transfusion Related Acure Lung Injury, TRALI) in patients administered IVIG.

Interference with Laboratory Tests

After infusion 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 for example Hepatitis A, Hepatitis B, measles and varicella.

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 antiglobulin test (direct Coombs test).

Administration of GAMMAGARD S/D can lead to false positive readings in assays that depend on detection of beta-D-glucans for diagnosis of fungal infections; this may persist during the weeks following infusion of the product.

Transmissible agents

GAMMAGARD S/D is made from human plasma. 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, such as the Creutzfeldt-Jacob disease (CJD) agent.

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 viruses hepatitis A (HAV) 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.

Further precautions

Hyperproteinemia and increased serum viscosity may occur in patients receiving IVIG therapy.

The amount of sodium in the maximum daily dose may add materially to the recommended daily allowance of dietary sodium for patients in a low sodium diet. In these patients, the amount of sodium from the product should be calculated and taken into account when determinating dietary sodium intake.

GAMMAGARD S/D contains 0.85% NaCl, or approximately 3340 mg sodium per liter at a 5% concentration. A 70Kg patient receiving 1g/kg (1.4L)) would receive 4676mg of sodium

Gammagard S/D , contains blood group antibodies that may act as hemolysins and induce in vivo coating of red blood cells (RBC) with immune globulin. This may cause a positive direct antiglobulin test [DAT (Coomb's test)]. Delayed hemolytic anemia can develop subsequent to GAMMAGARD S/D therapy due to enhanced RBC sequestration; acute hemolysis, consistent with intravascular hemolysis, has been reported.

The following risk factors may be related to the development of hemolysis: high doses (single administration or divided over several days) and non-O blood group.

Underlying inflammatory state in an individual patient may increase the risk of hemolysis but its role is uncertain.

Hyperproteinemia and increased serum viscosity may occur in patients receiving IVIG therapy.

It is strongly recommended that every time that GAMAGARD S/D 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

1. Live Attenuated Vaccines

Immunoglobulin administration may impair the efficacy of live attenuated virus vaccines such as measles, rubella, mumps, varicella and yellow fever for a period of at least 6 weeks and up to 3 months following the infusion. 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.

2. 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.

4.6 Fertility, pregnancy and lactation

The safety of this medicinal product for use in human pregnancy has not been established in controlled clinical trials: therefore it should only be given with caution to pregnant women and breast-feeding mothers.

Maternally administrated IVIG products have been shown to cross the placenta, increasing during the third trimester.

Breast feeding

Immunoglobulins are excreted into the milk. Maternally administrated IVIG products have been shown to cross the placenta, increasingly during the third trimester.

Fertility

The effects of GAMMAGARD S/D on fertility have not been established.

4.7 Effects on ability to drive and use machines

There is no information on the effects of GAMMAGARD S/D on the ability to drive or operate an automobile or other heavy machinery.

4.8 Undesirable effects

Summary of the safety profile

With human normal immunoglobulin for intravenous administration, 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 (including cutaneous lupus erythematosus - frequency unknown) have been observed with human 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 events such as myocardial infarction, stroke, pulmonary embolism, deep vein thrombosis have been observed.

There is clinical evidence of a possible association between IVIg administration and the potential for the development of thrombotic events. The exact cause of this is unknown; therefore, caution should be exercised in the prescribing and infusion of IVIg in patients with a history of and predisposing factors towards cardiovascular disease or thrombotic episodes. Analysis of adverse event reports has indicated that a rapid rate of infusion may be a risk factor for vascular occlusive events.

Haemolytic anaemia can develop subsequent to IVIG (including GAMMAGARD S/D) therapy. IVIG products can contain blood group antibodies that may act as haemolysins and induce in vivo coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, haemolysis.

Noncardiogenic pulmonary edema (Transfusion Related Acute Lung Injury, TRALI) have been observed in patients administered IVIG (see section 4.4).

Adverse reactions were pooled from a pivotal clinical study of GAMMAGARD S/D and phase 4 study assessing the acute and mid-term safety of GAMMAGARD . ADRs reported in the two studies and post-marketing are summarized and categorized according to the MedDRA System organ class and frequency in the table below.

Tabulated list of adverse reactions

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

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), not known (cannot be estimated from available data)

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

Adverse drug reactions (ADRs) with Gammagard S/D

MedDRA

system organ class

MedDRA preferred term

ADR frequency category*

Infections and infestations

Influenza

Uncommon

Meningitis aseptic

Not known

Blood and lymphatic system disorders

Haemolysis, Anaemia, Thrombocytopenia, Lymphadenopathy.

Not known

Immune system disorders

Anaphylactic or Anaphylactoid reaction, Anaphylactic shock, Hypersensitivity.

Not known

Metabolism and Nutritional Disorders

Anorexia

Uncommon

Psychiatric disorders

Anxiety, Agitation

Uncommon

Restlessness

Not known

Nervous system disorders

Headache

Common

Lethargy

Uncommon

Cerebrovascular accident, Stroke, transient ischemic attack, convulsions , Migrane, Dizziness, Paraesthesia, Syncope, Tremor, Central nervous system haemorrhages.

Not known

Eye disorders

Vision blurred

Uncommon

Retinal vein thrombosis ,visual impairment, eye pain,, Photophobia

Not known

Cardiac disorders

Palpitations

Uncommon

Myocardial infarction, Cyanosis, Tachycardia, Bradycardia

Not known

Vascular disorders

Flushing

Common

Blood pressure fluctuations

Uncommon

Hypertension, Pallor, Hypotension, Thrombophlebitis, Deep Vein Thrombosis, Vena Cava Thrombosis, Arterial Thrombosis,

Not known

Respiratory, thoracic and mediastinal disorders

Dyspnoea, Epistaxis

Uncommon

Pulmonary embolism, Pulmonary edema, Hypoxia, Bronchospasm, Wheezing, Throat tightness ,Cough

Not known

Gastrointestinal disorders

Vomiting ,Nausea,

Common

Diarrhoea, Stomatitis, Abdominal pain upper, Abdominal discomfort

Uncommon

Abdominal pain

Not known

Hepatobiliary Disorders

Hepatitis (non-infectious hepatitis)

Not known

Skin and subcutaneous tissue disorders

Utricaria, Pruritis, Cold sweat , hyperhidrosis

Uncommon

Erythema, Rash, , Dermatitis Allergic, Angioedema

Not known

Musculoskeletal and connective tissue disorders

Back pain, Muscle spasm, Pain in extremity

Uncommon

Arthralgia, Myalgia

Not known

Renal and urinary disorders

Renal failure.

Not known

General disorders and administration site conditions

Fatigue, chills, pyrexia

Common

Chest pain, Malaise, Pain , Chest discomfort, Feeling abnormal, Feeling cold, Feeling hot, Influenza-like illness, Infusion site erythema, Infusion site extravasation, Infusion site pain

Uncommon

Asthenia, Oedema, Injection and Infusion site reactions, Rigors

Not known

Investigations

Blood pressure increased

Uncommon

Coombs direct test positive

Not known

*Based on percentage per infusions.

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

4.9 Overdose

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

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: immune sera and immunoglobulins: immunoglobulins, normal human, for intravascular administration, ATC code: J06BA02.

Human normal immunoglobulin contains mainly immunoglobulin G (IgG) with a broad spectrum of antibodies against infectious agents.

GAMMAGARD S/D contains the IgG antibodies present in the normal population. It is usually prepared from pooled plasma from not fewer than 1000 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. The mechanism of action in indications other than replacement therapy is not fully elucidated, but includes immunomodulatory effects.

5.2 Pharmacokinetic properties

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, after approximately 3-5 days equilibrium is reached between the intra- and extra-vascular compartments.

GAMMAGARD S/D has a half-life of approximately 37.7 ± 15 days. 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. Fever and infection have been seen to coincide with a shortened half-life of IgG.

5.3 Preclinical safety data

Toxicological properties

Immunoglobulins are normal constituents of the human body. Single dose toxicity testing is of no relevance since higher doses result in overloading the system. Repeated dose toxicity testing in animals is impractical due to interference with developing antibodies.

Since clinical experience provides no hint for tumorigenic and mutagenic effects of human normal immunoglobulins, experimental studies, particularly in heterologous species, are not considered imperative.

6. Pharmaceutical particulars
6.1 List of excipients

Stabilising agents in a typical batch of GAMMAGARD S/D (in grams per 100 mL reconstituted product, at 5 %) are present in the following amounts:

0.225

g human albumin (pasteurised), EP

1.5

g glycine, EP

0.9

g sodium chloride, EP

1.7

g glucose monohydrate, EP

6.2 Incompatibilities

GAMMAGARD S/D preparations should not be mixed with other pharmaceutical products. Administer separately from other medications.

6.3 Shelf life

The shelf-life is 24 months providing the unit has not been opened.

When reconstitution is performed aseptically outside of a sterile laminar airflow hood, administration should begin as soon as possible, but not more than 2 hours after reconstitution. When reconstitution is performed aseptically in a sterile laminar airflow hood, the reconstituted product may be stored under constant refrigeration (2-8°C), for up to 24 hours. If these conditions are not met, sterility of the reconstituted product cannot be maintained.

6.4 Special precautions for storage

Store at room temperature not to exceed 25°C. Do not freeze since the solvent bottle might break. Do not use after the expiration date. Any unused solution must be discarded due to the risk of bacterial contamination. Keep the vial in the outer carton in order to protect from light. Store out of reach of children.

For storage after reconstitution refer to 6.3.

6.5 Nature and contents of container

Both product and solvent are provided in Type I EP, clear glass bottles, with rubber stoppers, aluminium cap with flip-off tops.

6.6 Special precautions for disposal and other handling

When reconstitution is performed aseptically outside of a sterile laminar airflow hood, administration should begin as soon as possible, but not more than 2 hours after reconstitution. When reconstitution is performed aseptically in a sterile laminar airflow hood, the reconstituted product may be stored under constant refrigeration (2-8°C), for up to 24 hours. If these conditions are not met, sterility of the reconstituted product cannot be maintained. Partially used vials should be discarded.

Total dissolution should be obtained within 30 minutes. The product should be brought to room or body temperature before use.

Reconstituted material should be a clear to slightly opalescent and colourless to pale yellow solution. Do not use solutions that are cloudy or have deposits. Reconstituted products should be inspected visually for particulate matter and discolouration prior to administration.

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

Reconstitution - use aseptic technique:

5.0 g, 10.0 g Sizes

Bring GAMMAGARD S/D and Sterilized Water for Injections (solvent) to room temperature. This temperature needs to be maintained until dissolution is complete.

A. 5% Solution:

1. Remove bottle caps and clean stoppers with germicidal solution.

2. Remove spike cap from one end of the transfer device.

Do not touch spike.

3a. Place the solvent vial on a flat surface. Use exposed end of transfer device to spike solvent vial through centre of the stopper.

Caution: Failure to insert spike into centre of the stopper may result in dislodging of the stopper.

3b. Ensure that the collar collapses fully into the device by pushing down on the transfer device firmly.

While holding onto transfer device, remove remaining spike cover. Do not touch spike.

4. Hold solvent bottle with attached transfer device at an angle to the concentrate bottle to prevent spilling the solvent.

Note: Do not hold solvent bottle upside down, for this can lead to solvent spillage.

5a. Spike concentrate bottle through the centre of the stopper while quickly inverting the solvent vial to avoid spilling out solvent.

CAUTION: Failure to insert spike into the centre of the stopper may result in dislodging of the stopper and loss of vacuum.

5b. Ensure that the collar collapses fully into the device by pushing down on the solvent bottle firmly.

6. After transfer of solvent is complete, remove transfer device and empty solvent bottle. Immediately swirl the concentrate bottle gently to thoroughly mix contents.

CAUTION: Do not shake. Avoid foaming.

Discard transfer device after single use.

B. 10% Solution:

1. Remove bottle caps and clean stoppers with germicidal solution.

2. To prepare a 10% solution, it is necessary to remove half of the volume of solvent. Table 2 indicates the volume of solvent that should be removed from the vial before attaching the transfer device to produce a 10% concentration. Using aseptic technique, withdraw the unnecessary volume of solvent using a sterile hypodermic syringe and needle. Discard the filled syringe and the needle.

3. Using the residual solvent in the solvent vial, follow steps 2-6 as previously described in A.

TABLE 2

Required Solvent Volume to be Removed

5.0 g

10.0 g

Concentration

bottle

bottle

5 %

Do not remove any solvent for reconstitution of 5 % solution

10 %

48 mL

96 mL

Administration – use aseptic technique

5.0 g, 10.0 g Sizes

Follow the direction insert for use, which accompanies the administration set provided in each package. If another administration set is used, ensure that the set contains a similar filter.

7. Marketing authorisation holder

Baxalta Innovations GmbH

Industriestrasse 67

A-1221 Vienna

Austria

8. Marketing authorisation number(s)

PL 34078/0006

9. Date of first authorisation/renewal of the authorisation

July 1994

Renewed: 28 October 2008

10. Date of revision of the text

23 October 2018