GAMMAGARD S/D IMMUNE GLOBULIN I.V. 2.5 G

Baxter

SUMMARY OF PRODUCT CHARACTERISTICS

" עעבקנהזןולעטמרופ " רשואוקדבנונכותותואירבהדרשמי ." רשואמןולע : טסוגוא 2011

“This leaflet format has been determined bythe Ministryof Healthand the content thereof has been checked and

approved.” Dateof approval:August2011.

1. NAME OF THE MEDICINAL PRODUCT

IMMUNE GLOBULIN I.V.GAMMAGARD S/D 2.5 g, 5.0 g, 10.0 g, Powder for Solution for Injection.

(GAMMAGARD S/D {Solvent/Detergent}).

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Human normal immunoglobulin (IVIg).

IMMUNE GLOBULIN I.V.GAMMAGARD S/D (Solvent/Detergent) maybe reconstitutedwithsterilised

waterforinjectionstoa5%(50mg/ml)solution or a 10 % (100mg/ml) solution of protein of which at least

90 %is gammaglobulin.

Distribution of IgG subclasses: IgG

≥63.0 %

IgG

≥21.8 %

IgG

≥5.4 %

IgG

≥0.2 %

MaximumIgA content: not more than 3 microgramper ml

Excipients: human albumin, glycine, sodiumchloride, glucose, polyethylene glycol 3350.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder and solvent for solution for infusion.

IMMUNE GLOBULIN I.V.GAMMAGARD S/D (Solvent/Detergent) is a lyophilised, white orveryfaint

yellow powder/cake, substantiallyfree of foreign visible particles.

4. CLINICAL PARTICULARS

4.1. Therapeutic indications

Replacement therapyin:

primaryimmunodeficiencysyndromes (PID) such as:

congenital agammaglobulinaemia and hypogammaglobulinaemia;

common variable immunodeficiency;

severe combined immunodeficiency;

Wiskott Aldrich syndrome.

myeloma or chronic lymphocytic leukaemia (CLL) with severe secondary

hypogammaglobulinaemia and recurrent infections.

children with congenital AIDSand recurrent infections.

Immunomodulation

idiopathic thrombocytopenic purpura (ITP), in childrenor adults at high risk of bleeding orpriorto

surgeryto correct the platelet count.

Baxter

SUMMARY OF PRODUCT CHARACTERISTICS

Guillain Barré syndrome. In this caseGAMMAGARDS/D (Solvent/Detergent) is onlyindicated in

patients showing one of the following symptoms:

progressive paresis (the patient cannotwalk more than 10 mon his own);

signs of a respiratorydisorder (clinicallyobserved or demonstrated bymeasuringthevital

capacityat the patient’s bed);

signs of oropharyngeal paresis.

Kawasaki disease.

Allogeneic bone marrow transplantation

4.2.Posology and method of administration

Posology

The dose and dosage regimen are dependent on the indication.

In replacement therapythe dosagemayneedtobeindividualised for each patient depending on the

pharmacokinetic and clinical response. The following dosage regimens are given as a guideline.

Replacement therapyin primaryimmunodeficiencysyndromes

Thetherapyshouldachievea trough level of IgG (measuredbefore the next infusion) of at least 4 – 6 g/l.

Threeto six months are required after the initiation oftherapyfor equilibration to occur. The recommended

starting dose is 0.4 – 0.8 g/kg, followed byat least 0.2 g/kg everythree weeks.

The dose required to achieve a trough level of 6 g/l is ofthe order of 0.2 – 0.8g/kg/month. The frequencyof

administration when steadystate hasbeen reached varies fromtwo to four weeks. Trough levels should be

measured in order to adjust the dose and administration interval.

Replacement therapyin myeloma or chronic lymphocytic leukaemia(CLL)withseveresecondary

hypogammaglobulinaemia and recurrent infections; replacement therapyin children with congenital AIDS

and recurrent infections

The recommended dose is 0.2 – 0.4 g/kg everythree to four weeks.

Idiopathic thrombocytopenic purpura (ITP)

For the treatment of an acute episode, 0.8 –1.0g/kgon dayone, which maybe repeated once within three

days, or 0.4 g/kg/dayfor two to five days. Thetreatment can be repeated if a relapse occurs.

Guillain Barré syndrome

A dose of 0.4 g/kg/daywill be administered for three to seven days. Experience in children is limited.

Kawasaki disease

1.6 – 2.0 g/kg should be administered in divided dosesovertwotofive daysor 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 aspartof the conditioning regimen and after a bone

marrow transplant.

Baxter

SUMMARY OF PRODUCT CHARACTERISTICS

For the treatment of infections and prophylaxis of graftversushostdisease, dosage is individuallytailored.

The starting dose is normally0.5 g/kg/week, starting sevendaysbeforetransplantation and for up to three

months after transplantation.

In case of persistent lack of antibodyproduction,a dose of 0.5 g/kg/month is recommended until antibody

level returns to normal.

The dosage recommendations are summarised in the following table.

Indication Dosage Frequency of injections

Replacement therapyin primary

immunodeficiencysyndromes

Replacement therapyin secondary

immunodeficiencysyndromes

Children with AIDS

- loading dose:

0.4 – 0.8 g/kg

- maintenance dose:

0.2 – 0.8 g/kg

0.2 – 0.4 g/kg

0.2 – 0.4 g/kg

every2 – 4 weeks to obtain IgG trough

level of at least 4 – 6 g/l

every3 – 4 weeks to obtain IgG trough

level of at least 4 – 6 g/l

every3 – 4 weeks

Immunomodulation:

- idiopathic thrombocytopenic purpura

- Guillain Barré syndrome

0.8 – 1.0 g/kg

or

0.4 g/kg/day

0.4 g/kg/day

1.6 – 2.0 g/kg

or

on day1, possiblyrepeated once

within 3 days

for 2 – 5 days

for 3 – 7 days

in several doses for 2 – 5 daysin

association with acetylsalicylic acid

single dose in association with

acetylsalicylic acid

Allogeneic bone marrow

transplantation:

- treatment of infections and

prophylaxis of graft versus host

disease

- persistent lack of antibodyproduction

0.5 g/kg

0.5 g/kg

everyweek fromday-7 up to 3

months after transplantation

everymonth until antibodylevels

return to normal

Method of administration

At the beginning the therapy,GAMMAGARD S/D (Solvent/Detergent)5%(50mg/ml)shouldbeinfused

intravenouslyat a rate of 0.5ml/kg/h. If well toleratedbythe patient, the dose maygraduallybe increased to

amaximumof8ml/kg/h.Patientswho tolerate GAMMAGARD S/D (Solvent/Detergent) 5 %, can be

infused with GAMMAGARD S/D (Solvent/Detergent) 10 % at a maximumrate of 8 ml/kg/h.

Baxter

SUMMARY OF PRODUCT CHARACTERISTICS

4.3. Contraindications

Hypersensitivityto the active substance or to anyof the excipients.

Hypersensitivityto homologous immunoglobulins, especiallyin veryrare cases of selective IgA

deficiencywhen the patient has anti-IgAantibodies. However, GAMMAGARD S/D

(Solvent/Detergent)contains onlytrace amounts of IgA (maximumIgA content: not more than

3 microgramper ml).

4.4.Special warnings and precautions for use

Certain severe adverse events maybe related totherate of infusion. The recommended infusion rate given

undersection4.2.,“Method of administration” must be closelyfollowed. Patients must be carefullyobserved

for anysigns of intolerance throughout the infusion period.

Certain adverse events mayoccur more frequently:

in case of high rate of infusion;

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

in patients who receive human normal immunoglobulinforthefirst time or, in rare cases, when the

human normal immunoglobulin product is switchedorwhen there has beena long interval since

the previous infusion.

True hypersensitivityreactions are rare. Theycan occurintheveryseldomcases of selective IgA deficiency

with anti-IgA antibodies.

Rarely,theuseofhumannormal 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 byensuring:

that patients are not sensitive to human normal immunoglobulin byfirst infusing the product

slowly(0.5 to 1 ml/kg/h).

that patients are carefullymonitored for anysymptomsthroughout theinfusionperiod.In

particular, patients naive to human normal immunoglobulin, patients switched fromanalternative

IVIgpreparationor when there has been a long interval since the previous administration with

humannormal immunoglobulin, should be monitored during the first infusion and for the first hour

after the first infusion, in order to detect potential adverse events. All otherpatientsshouldbe

observed for at least 20 minutes after administration of the product.

that the glucose content (0.43g/g ofIgG)istaken into account in case of latent diabetes (where

transient glycosuria could appear), diabetes or in patients on a low sugar diet.

There is clinical evidence of an associationbetweenIVIg administration and thromboembolic events such as

myocardial infarction, cerebrovascular accident, pulmonaryembolismand deep vein thrombosis which is

assumed to be caused bya relative increase in blood viscositythroughthehigh influx of immunoglobulin in

at-risk patients. Caution shall be exercised in prescribingandinfusing IVIg in obese patients, in patients with

pre-existing risk factors for thromboticeventssuchas advanced age, hypertension and diabetes, in patients

with a historyof vascular disease orthromboticepisodes, in patients with acquired or inherited

thrombophilic reactions, in patients with prolonged periodsofimmobilisation, in severelyhypovolemic

patients and in patients with diseases which increase blood viscosity.

Cases of acute renal insufficiencyhave been reported inpatients receiving IVIg therapy.In most cases, risk

factors have been identified, such as pre-existingrenalinsufficiency,diabetes, hypovolaemia, overweight,

concomitant nephrotoxic medicinal products or age over 65.

Baxter

SUMMARY OF PRODUCT CHARACTERISTICS

In case of renal impairment, IVIg discontinuation should be considered. While reports of renal dysfunction

and acute renal insufficiencyhavebeenassociatedwiththe use of manyof 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 thatdonotcontain sucrose maybe considered. GAMMAGARD S/D

(Solvent/Detergent) does not contain sucrose.

Inpatients at risk for acute renal insufficiencyorthromboembolic adverse events, IVIg products should be

administered at the minimumrate of infusion and dose practicable.

In all patients, IVIg administration requires:

adequate hydration prior to the initiation of the infusion of IVIg;

monitoring of diuresis;

monitoring of serumcreatinine levels;

avoidance of concomitant use of loop diuretics.

In case of adverse events, either the rate of infusionmust be reduced or the infusion stopped. The treatment

required depends on the nature and severityof the side effect.

In case of shock, the applicable medical guidelines for the treatment of shock should be implemented.

GAMMAGARD S/D (Solvent/Detergent) is made fromhuman plasma. Standard measures to prevent

infections resulting fromthe use of medicinal products prepared fromhuman bloodorplasmainclude

selection of donors, screening of individual donations and plasma pools for specific markersofinfectionand

the inclusion of effective manufacturing steps for theinactivation/removal of viruses. Despite this, when

medicinal products prepared fromhuman blood or plasma are administered,thepossibilityoftransmitting

infectiveagents cannot be totallyexcluded. Thisalso applies to unknown or emerging viruses and other

pathogens.

The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV, andforthe

non-enveloped viruses HAV and parvovirus B19.

There is reassuring clinical experience regarding the lack of hepatitis A or parvovirus B19 transmission with

immunoglobulins. It is also assumed that the antibodycontent makes an important contribution to the viral

safety.

It is stronglyrecommended that everytime that GAMMAGARD S/D (Solvent/Detergent) isadministeredto

a patient, the nameand batch number (lot) of the product are recorded in ordertomaintainalinkbetweenthe

patient and the batch of the product.

4.5.Interaction with other medicinal products and other forms of interaction

Live attenuated virus vaccines

Human normal immunoglobulin administration mayimpair for a period of six weeks uptothreemonthsthe

efficacyof live attenuated virusvaccinessuchasmeasles, rubella, mumps and varicella. After administration

of this product, an interval of three months shouldbetaken into account before vaccination with live

attenuated virus vaccines. In the case of measles, thisimpairedefficacymaypersist for up to one year.

Therefore, patients receiving measles vaccine should have their antibodystatus checked.

Interference with serological testing

Afterinfusionof human normal immunoglobulin the transitoryrise of the various passivelytransferred

antibodies in the patient’s blood mayresult in false positive results in serological testing.

Passive transmission of antibodies to erythrocyte antigens,e.g.A,Band D, mayinterfere with some

serological tests for red cell allo-antibodies (e.g. Coombs test), reticulocyte count and haptoglobin.

Baxter

SUMMARY OF PRODUCT CHARACTERISTICS

4.6.Pregnancy and lactation

Todate,the safetyof GAMMAGARD S/D (Solvent/Detergent) for use in human pregnancyhas not been

established in controlled trials. Therefore, the productshould onlybe given withcautionto pregnant women

and breast-feeding mothers. However, clinical experience with immunoglobulins suggests thatnoharmful

effects on the course of pregnancy,the fetus and the neonate are to be expected.

Immunoglobulins are excreted into the milk and maycontribute to the transfer of protective antibodies to the

neonate.

4.7.Effects on ability to drive and use machines

No effects on abilityto drive anduse machines have been observed.

4.8. Undesirable effects

Adverse events such as chills, headache, fever, vomiting,allergic reactions, nausea, arthralgia,hypotension

and moderate low back pain mayoccur occasionally.

Rarelythe use of human normal immunoglobulins maycause a sudden fall in blood pressure and, in isolated

cases, anaphylactic shock, even when the patient hasshown no hypersensitivityto previous administration.

Cases of reversible lymphocytic meningitis, isolatedcasesofreversible haemolytic anaemia/haemolysis and

rare cases of transient cutaneous reactions, have beenobservedwith products containing human normal

immunoglobulin.

Increase in serumcreatinine level and/or acuterenal insufficiencyhave been observed.

Thromboembolic events such as myocardial infarction,cerebrovascularaccident, pulmonaryembolismand

deep vein thrombosis have been observed.

There is clinical evidence of a possibleassociationbetween IVIg administration and thrombotic events. The

exactcauseof this association is unknown. Therefore,caution should be exercised in the prescribing and

infusion of IVIg in patients withpredisposingfactors towards cardiovascular disease or thrombotic reactions.

Analysis of adverse event reports has indicated that anincreased rate of infusion maybe ariskfactorfor

thrombosis.

With GAMMAGARD S/D (Solvent/Detergent), the adverseevents reported in the listinghereafterarebased

on reports frompost-marketing experience.

Nervous systemdisorders: headache, dizziness, paraesthesia anddysaesthesia, tremor, convulsions, aseptic

meningitis, central nervous systemhaemorrhages and cerebrovascular accidents.

Eye disorders: photophobia, visual disturbance, eye pain, retinal vein thrombosis.

Psychiatric disorders: anxiety,agitation (restlessness).

Blood and lymphaticsystemdisorders: direct positive Coombs test, haemolysis, anaemia, thrombocytopenia,

lymphadenopathy.

Immune systemdisorders: hypersensitivity, anaphylactic or anaphylactoid reaction, anaphylactic shock.

Cardiac disorders: palpitations, tachycardia, cyanosis, myocardial infarction.

Vascular disorders: flushing, hypertension, pallor, hypotension, thrombophlebitis, deep vein thrombosis.

Baxter

SUMMARY OF PRODUCT CHARACTERISTICS

Respiratory,thoracic andmediastinaldisorders: cough, throat tightness, hypoxia, hyperventilation,

dyspnoea, wheezing, bronchospasm, pulmonaryembolism.

Gastrointestinal disorders: nausea, vomiting, dyspepsia, abdominal pain, diarrhoea.

Skin and subcutaneous tissue disorders: erythema, pruritus, rash, urticaria,dermatitis,hyperhidrosis,

angioneurotic oedema.

Musculoskeletal and connective tissue disorders: arthralgia, myalgia, back pain, muscle spasms.

Renal and urinarydisorders: renal failure.

General disorders and administrationsiteconditions: chills, pyrexia, asthenia, fatigue, chest pain, oedema,

influenza like illness, injection and infusion site reactions.

For safetywith respect to transmissible agents see section 4.4.

4.9. Overdose

Overdose maylead to fluid overload and hyperviscosity, particularlyin 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, human normal, for

intravascular administration.

ATC code: J06BA02.

GAMMAGARD S/D (Solvent/Detergent) contains mainlyfunctionallyintact immunoglobulin G (IgG)with

a broad spectrumof antibodies against infectious agents.

Humannormalimmunoglobulin contains the IgG-antibodies present in the normal population. It is usually

prepared frompooled plasma fromnot fewer than 1000donations. It has a distributionofimmunoglobulinG

subclasses closelyproportional to that in normal humanplasma. Adequate doses ofthismedicinalproduct

mayrestore abnormallylow immunoglobulin G levels to the normal range.

The mechanismof action in indications other than replacementtherapyis not fullyelucidated, but includes

immunomodulatoryeffects.

5.2. Pharmacokinetic properties

GAMMAGARD S/D (Solvent/Detergent) is immediatelyand completelybioavailable in therecipient’s

circulation after intravenous administration. It isdistributed relativelyrapidlybetweenplasmaand

extravascular fluid. After approximatelythree to fivedaysequilibriumis reached between the intra- and

extravascular compartments.

The half-life of GAMMAGARD S/D (Solvent/Detergent)is about 24 days. This half-life mayvaryfrom

patient to patient, in particular in primaryimmunodeficiency.

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

5.3.Preclinical safety data

Immunoglobulins are normal constituents of the human body.

Baxter

SUMMARY OF PRODUCT CHARACTERISTICS

Single dose toxicitytesting is of no relevance sincehigher doses result in systemoverload. Repeated dose

toxicitytesting in animals are impractical due to interference bydevelopment of antibodies.

Since clinical experience provide no hint foroncogenic or mutagenic effects of human normal

immunoglobulin, experimental studies, particularlyinheterologous species, are not considered imperative.

6. PHARMACEUTICAL PARTICULARS

6.1.List of excipients

Powder:

human albumin ;

glycine;

sodiumchloride;

glucose ;

polyethylene glycol 3350.

Solvent:

sterilised water for injections, USP.

6.2. Incompatibilities

GAMMAGARD S/D (Solvent/Detergent) must notbe mixed with other medicinal products.

Itis recommended that GAMMAGARD S/D (Solvent/Detergent) be administered separatelyfromother

medicinal products that the patient maybe receiving.

6.3.Shelf life of reconstituted product

GAMMAGARD S/D should be administered as soon after reconstitution as possible.

The reconstituted material should be atroomtemperature during administration.

When reconstitution is performed asepticallyoutside ofa sterile laminar air flow hood, administrationshould

begin as soon as possible, but not more than 2 hours at temperature not exceeding 25 C after reconstitution.

When reconstitution is performed asepticallyinside ofa sterile laminar air flow hood, the reconstituted

product maybe either maintained in the original glasscontainer,orpooled into infusion bags and stored

under constant refrigeration (2-8 C), for up to 24 hours. (The date and time of reconstitution /pooling should

be recorded). If these conditions are not met, sterilityof the reconstituted product cannot be maintained.

Partiallyused vials should be discarded.

6.4.Special precautions for storage

Do not store above 25°C.

Do not freeze.

Do not use GAMMAGARD S/D (Solvent/Detergent) afterthe expirydate which is stated on the label after

“EXP”. The expirydate refers to the last dayof that month.

Keep out of the reach and sight of children.

For storage conditions of the reconstituted medicinal product, see section 6.3.

Baxter

SUMMARY OF PRODUCT CHARACTERISTICS

6.5.Nature and contents of container

Both lyophilised concentrate and solvent are provided insingledoseclearglass vials (type I, EP). Each vial

is closed with a rubber stopper and an aluminiumcap with a flip-off central portion.

GAMMAGARD S/D (Solvent/Detergent) is available in vials of 2.5 g, 5.0 g and 10.0 g.

Each package of 2.5g, 5.0g and 10.0g contains thesolvent (50 ml, 96 ml and 192 ml, respectively), a sterile

transfer device and a sterile administration set with filter.

6.6.Special precautions for disposal and other handling

The product should be brought to roomor bodytemperature before use.

The product should be administeredwithin two hours of reconstitution.

Reconstituted material should be clear or slightlyopalescent,whereas the solution is colourless to pale

yellow. Do not use solutions thatarecloudyorhave deposits. Reconstituted products should be inspected

visuallyfor particulate matter and discoloration prior to administration.

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

Before intravenous administration GAMMAGARD S/D (Solvent/Detergent) should be reconstituted withthe

appropriate volume of sterilised water for injections (solvent) provided in each package.

Reconstitution – Use aseptic technique.

2.5 g, 5.0 g, 10.0 g Sizes

Bring GAMMAGARD S/D (Solvent/Detergent) and Sterilized Water for Injections (solvent) to room

temperature. This temperature needs tobe maintained until dissolution is complete.

A. 5% Solution:

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

2. Remove spike cap fromone 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 center of

the stopper

Caution: Failure to insert spike into center of the

stopper may result in dislodging of the stopper.

3b. Ensure that the collar collapses fullyinto the device by

pushing down on the transfer device firmly.

While holding onto transfer device, remove remaining spike

cover. Do not touch spike.

Baxter

SUMMARY OF PRODUCT CHARACTERISTICS

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 center of the

stopperwhile quickly inverting the solvent vialto

avoid spilling out solvent.

CAUTION: Failure to insert the spike into the center

of the stopper may result in dislodging of the stopper

and loss of vacuum.

5b. Ensure that the collar collapses fullyinto the device

bypushing down on the solvent bottle firmly.

6. After transfer of solvent is complete, remove

transfer device and emptysolvent bottle. Immediatelyinvert gentlythe

bottle so the content can dissolve completely.

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 necessaryto removehalfofthe volume of solvent. Consult table 2 to

know the volume of solventbeforeremoving fromthe vialbefore attaching the transfer device to produce

a 10% concentration. Using aseptic technique, withdraw the unnecessaryvolume ofsolventusingasterile

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 previouslydescribed in A.

TABLE 2

Required Solvent Volume to be Removed

2.5 g 5.0 g 10.0 g

Concentration bottle bottle bottle

5%

Do not remove any solvent for reconstitution of 5% Solution

10% 25 ml 48 ml 96 ml

Baxter

SUMMARY OF PRODUCT CHARACTERISTICS

Injection – Use aseptic technique – 2.5 g, 5.0 g and 10.0 g sizes

Use the administration set provided in each package.

7. DRUG REGISTRATION NUMBERS

IMMUNE GLOBULIN I.V.GAMMAGARD S/D 2.5 g, Powder for Solution for Injection: 065 07 25271 01.

IMMUNE GLOBULIN I.V.GAMMAGARD S/D 5.0 g, Powder for Solution for Injection: 067 28 28301 01.

IMMUNE GLOBULIN I.V.GAMMAGARD S/D 10 g, Powder for Solution for Injection: 067 42 28300 01.

8MANUFACTURED BY:

Baxter Healthcare Corporation

CA, USA

9LICENCE HOLDER:

Teva Medical Marketing Ltd.

P.O. Box 2, Ashdod 77100,

Israel.

Revised: March 2010.

Baxter and GAMMAGARD are trademarks of Baxter International Inc.