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Liquid NormalIntravenousImmunoglobulin

Liquid Harmony

octagam_Bros_0908E5B1 17.09.2008 8:56 Uhr Seite 2


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Octapharma’s Commitment to Plasma Derived Therapies

Octapharma was established in 1983 and was the first company to introduce the Solvent/Detergent (S/D) process for virus inactivation on an industrial scale for the manufacture of plasma-derived products.

To date, Octapharma’s immunoglobulin, haemophilia and intensive care productsare used in over 60 countries worldwide.

The Octapharma Group currently operates four manufacturing plants in Europe –Vienna (Austria), Lingolsheim (France), Stockholm (Sweden) and Springe (Germany).The technical set up of these plants enables manufacturing of Octapharma’s pharmaceutical products under identical standard operation procedures (SOP) on all sites. This provides Octapharma with the utmost flexibility to meet the needs of the market and backup option to secure continuous supply.


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octagam® – Tried and Trusted

Efficacy, safety and tolerability are fundamental characteristicsof an intravenous immunoglobulin (IVIG). octagam® has a trackrecord of over 13 years of use in many markets worldwide.

Following the approval of octagam® in 1995, an open prospective observational cohort study1 was initiated to observethe tolerability of octagam®.



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octagam® at a Glance

Tolerability

Open prospective observational cohort study1 to evaluate the long-term tolerability and safety profile in daily use in primary (PID) and secondary (SID) immunodeficiencies and autoimmune diseases (AID)

Experience in more than 60 countries

Safety

The octagam® manufacturing process provides significant viral reduction through three validated manufacturing steps:

Cold Ethanol fractionation Solvent/Detergent treatment Low pH incubation


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Documented Clinical Efficacy

Only 0.1 serious bacterial infections per patient per year in primary immunodeficient (PID) patients2; FDA requirement: ≤ 13

Mean half-life approximately 40 days in PID patients 2

No enzymatic or chemical cleavage during the manufacturing process, which might change the IgG molecules nativity

Fc function typically 96.7%4

IgG subclasses similar to physiological distribution 5

Typically ≥ 99.6% monomers and dimers 4

Indications for Use*

Replacement Therapy

Primary immunodeficiency syndromes:– congenital agammaglobulinaemia

and hypogammaglobulinaemia– common variable immunodeficiency– severe combined immunodeficiencies– Wiskott Aldrich syndrome

Myeloma or chronic lymphocytic leukaemia with severe secondary hypogamma-globulinaemia and recurrent infections

Children with congenital Acquired Immune Deficiency Syndrome (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

Allogenic Bone MarrowTransplantation

* This information is based on the European core summary of product characteristics for octagam®

and may deviate from the product information valid in your country. Please do refer to your national octagam®

summary of product characteristics or prescribing information.

Convenience

Liquid, ready-to-use

Storage at room temperature (up to 25 °C)

Filling sizes of: 1 g (20 ml), 2.5 g (50 ml), 5 g (100 ml), 10 g (200 ml), 25 g (500 ml)

No saccharoseNo glucoseNo preservativesLatex-free container


octagam® – Efficacy

In this study, the rate of serious bacterial infections was 0.1/patient/year. This result is markedly lowerthan the U.S. Food and Drug Administration’s efficacy requirement of ≤ 1 serious infection/subject/year.3

Efficacy was further demonstrated by the lowlevel of days missed from work or school, unplanned medical visits, and hospitalisations.2

Such sequelae would represent additional costs in the treatment of PID patients and should beavoided.

Efficacy, safety and tolerability are the most fundamental considerations when selecting anIVIG. The efficacy of octagam® was demonstratedin a multi-centre trial of 46 patients with primary immune deficiency (PID), who received654 infusions over a 12-month period.2


The efficacy of an intravenous immunoglobulinmay depend on the native properties of the preparation.

IgG subclassesAntibodies of the different IgG subclasses are specifically directed at different types of pathogens, e.g., antiviral antibodies mainly belong to the IgGsubclasses 1 and 3. A physiological distribution of the subclasses is one of the prerequisites for optimal therapeutic efficiency. The IgG subclassdistribution of octagam® is similar to the normalphysiological distribution in human plasma.5

octagam® Normal values

IgG1 ~ 60 % ~ 60 %

IgG2 ~ 32 % ~ 29 %

IgG3 ~ 7 % ~ 7 %

IgG4 ~ 1 % ~ 4 %

Summary of Secondary Efficacy Endpoints 2

Events per subject Total days or visits Percent of days or visitsmean (range) mean (range)

Work or school days missed 5.0 (0–22) 1.5 (0–6)

Days of hospitalisation 0.3 (0–6) 0.1 (0–2)

Visits to physician or emergency room 2.0 (0–11) 0.6 (0–3)

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Fc-functionIn an IVIG product, the IgG molecules should be retained in their full native biological state.Changes in the IgG molecule, e.g., its Fc-part,caused by the production process, may result in restricted in vivo function. This may have consequences for both the use of IVIG for replacement in antibody deficiency syndromes aswell as for their immunomodulatory applications.6

The production process of octagam® does not contain enzymatic or chemical cleavage steps(e.g., by pepsin). The Fc-function remains intact.

Half-lifePrevious clinical studies of various IVIG productshave reported IgG half-life values of 2 to 40 days.7, 8

In the case of octagam®, in patients with antibodydeficiency syndrome, a mean half-life of approxi-mately 40 days has been observed.2

Monomers/DimersMonomers and dimers of IgG exhibit an immunomodulatory action. However, polymersand aggregates increase the risk of undesirableeffects. The total concentration of monomers and dimers in octagam® is high, typically ≥ 99.6 %.4

Parvovirus B19 Antibodies Immunoglobulin preparations should containeffective concentrations of antibodies againstParvovirus B19 which contribute to the neutralisation of these viruses. Octapharma routinely determines the titer of Parvovirus B19antibodies in octagam® batches. octagam®

typically contains ≥ 180 I.U./ml Parvovirus B19antibodies which is several times the antibodytiter stipulated in numerous countries.4

Seru

m C

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(m

g/d

l)

0

500

0 7 14 21 28

1000

1500

2000

Time (days post infusion)

21-Day Infusion ScheduleDose: 0,30 – 0,45 g/kg28-Day Infusion ScheduleDose: 0,4 – 0,6 g/kg

A production process that maintains the physiologicproperties of the IgG molecule contributes to optimal efficacy of an IVIG product

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Median IgG plasma concentration after administration of octagam® in PID patients 2



octagam® – Virus InactivationTrust in Expertise and Experience

Pathogen safety of IVIG products depends on a multitude of factors.

The manufacture of octagam® includes multistep safety measures to ensure that thepatients receive an IVIG that meets national and international guidelines.9,10,11

The risk of viral transmission is minimised by:

Donor selection criteria

Starting plasma control

Testing of individual units, mini-pools and final product

Cold Ethanol fractionation

Solvent/Detergent treatment

pH4 incubation

Quality of virus validation studies – Good Laboratory Practice (GLP) and Re-Validation

All phases of the virus validation studies foroctagam® have been performed under strict adherence to Good Laboratory Practice.

Over the past years and for octagam®, numerous virus validation studies were carried out underthese strict regulations. Although validation isperformed, transmission of infectious agents cannot be totally excluded.

As Octapharma adheres to the latest guidelinesregarding virus validation studies, Octapharmaproactively invests in re-validation of virus validation studies.

Since the first launch of octagam® in Europe in1993, more than 45 million grams of octagam®

have been infused worldwide to approximately2.5 million patients equivalent.4

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Solvent/Detergent TreatmentThe S/D treatment is a highly effective step for the inactivation of viruses with lipid envelope, such as Hepatitis B, Hepatitis C and HIV-1/-2. It destroys their lipid envelopes in a reliable manner. The FDA regards the S/D treatment to be moreeffective at inactivating the hepatitis C virus than pasteurisation.12 Furthermore, newly emerging pathogens like West Nile virus (WNV) or Severe Acute Respiratory Syndrome virus (SARS-coronavirus) are lipid-enveloped viruses.Kinetic studies 4,13 have shown that these two viruses are completely and reliably inactivated within the first few minutes. Robustness studieshave shown that process changes such as variations in temperature and concentration do not adversely affect the effectiveness of the

procedure. The octagam® S/D process with TNBPand Triton-X 100 has therefore been shown tohave a margin of safety. 4, 14

pH4 Incubation In a second and independent virus inactivationstep the intermediary product is incubated at pH4for 24 hours. Under these conditions both lipid enveloped and several non-enveloped virusesare inactivated.

Additionally, extensive virus validation studieshave confirmed that the Cold Ethanol fractionation method used for octagam® is a step that removes viruses.4

Furthermore, due to the pooling of plasma from individual donors, octagam® contains a wide spectrum of neutralising antibodies. Theseprotective antibodies, e.g., against HAV andParvovirus B19, make an additional contribution to virus safety.4

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Infe

ctiv

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(%)

0

0 5 10 15 20 25 30 240

25

50

75

100

Time of S/D treatment (min)

Below the limit of detection

Kinetics of SARS-CoV and WNV inactivation by S/D treatment

Virus reduction factors: > 5 log

octagam® – Virus Validation Data4

Enveloped Viruses Non-Enveloped Viruses

Process Step HIV-1 SBV PRV MEV PPV

S/D Treatment ≥ 6.0 ≥ 7.8 ≥ 7.8 n. a. n. a.

pH 4 Incubation ≥ 8.6 ≥ 8.9 ≥ 7.7 ≥ 6.2 2.9

Cold Ethanol ≥ 5.5 ≥ 6.4 ≥ 7.3 ≥ 5.8 ≥ 7.8

Total Virus Reduction ≥ 20.1 ≥ 23.1 ≥ 22.8 ≥ 12.0 ≥ 10.7

HIV-1 = Human Immunodeficiency Virus Type 1

SBV = Sindbis Virus

(Model for Hepatitis C virus)

PRV = Pseudorabies Virus

(Model for large DNA viruses,

e.g. for Hepatitis B virus)

MEV = Murine Encephalomyelitis Virus

(Model for small non-enveloped viruses,

e.g. for Hepatitis A virus, Parvovirus B19)

PPV = Porcine Parvovirus

(Model for small non-enveloped viruses,

e.g. for Hepatitis A virus, Parvovirus B19)



octagam® – Reassurance for the Patient and the Physician

Adverse reactions to IVIG solutions can seriouslyimpact the health and comfort of patients. In general, there is a wide range of potential side effects that may occur in IVIG therapy.16

This makes tolerability both during and after infusion a major consideration when prescribingor selecting an IVIG brand. Literature suggeststhat there may be significant differences betweenbrands with respect to overall incidence of adversereactions.17, 18, 19 These differences may be due tovariance in pharmacological parameters such asconcentration, osmolarity, sodium content, sugarcontent, pH of the final formulation, isoagglutinintiter, and IgA content.

Tolerability of octagam® – Clinical Trials

The tolerability of octagam® has been evaluatedin an observational study1 and in clinical trials.15,20

In a study in 46 patients 2 with primary immunedeficiency (PID), adverse events (AE) potentiallyrelated to octagam® occurred in only 5% of allinfusions. No serious AE related to octagam®

occurred. All AE were mild or moderate in severity. Most frequently reported AE were headache, chills and fever.

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Precaution: 21

Maltose is used in octagam® as an osmolality regulator. When some blood glucose monitoringsystems are used, specifically those that use test strips containing the enzymes glucose dehydrogenase-pyrroloquinolinequinone or glucose dye oxidoreductase in patients receivingmaltose-containing products, interference of bloodglucose levels can occur. Maltose is misinterpretedas glucose, which can result in erroneously elevated serum glucose levels. This interferencecan result in the unnecessary administration of insulin, which may lead to hypoglycaemia.Clinicians must review the package inserts of all test strips to determine the type of glucose monitoring system being used and to use onlythose systems whose tests strips contain glucoseoxidase, glucose dehydrogenase-nicotinamide adenine dinucleotide, or glucose dehydrogenase-flavin adenine dinucleotide.


octagam® – Ten-Year Observational Study 1

Following the approval of octagam® in 1995, anopen prospective observational cohort study wasinitiated to evaluate the long-term safety profileof octagam® in daily use in the treatment of various primary (PID) and secondary (SID) immu-nodeficiencies and autoimmune diseases (AID).

Within a time period of 10 years, data was collected in 310 study sites. The treating physicians documented patient characteristics,treatment parameters and the occurrence of anadverse drug reaction (ADR) by using detailedcase record forms (CRF).

A total of 6357 patients of all ages received92,958 infusions of octagam®. ADRs occurred in 4.2% of the patients and in 0.35% of all infusions. Most of them (94.8%) were classifiedas non-serious, the majority (90.2%) were of mildor moderate intensity.

Remark: prospective observational cohort studieshave to be differentiated from pharmacovigilancestudies for their methodology and for their predictive value. Furthermore, their value can only be applied in the field of the registered indications of the product evaluated.

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Frequency of adverse drug reactions in octagam® ten-year observational study1



Factors Affecting Tolerability

pH

Neonates or those with electrolyte imbalance may not be able to properly buffer low pH products, especially when large doses are required 22

octagam® has a pH of 5.1-6.0. Products with a more acidic pH may produce irritation, thrombophlebitis and/or necrosis at the infusionsite.17,18

Stabilisers

octagam® contains: No sucroseNo saccharoseNo preservatives

Concentration

Higher osmolarity may present problems for patients with underlying renal complications or diabetes, in neonates, and patients over 60 years of age19,22,23

Hyperosmolar products may also be responsible for thrombotic events including cerebral and myocardial infarction 24–29

octagam® is supplied at a 5% concentration. The osmolality of octagam® (≥ 240 mOsmol/kg 4)is similar to the physiologic range (280-300 mOsmol/kg).

IgA

Anaphylactic reactions, although rare, have beenassociated with the formation of antibodiesagainst IgA in patients with selective IgA deficiency 16, 30–32

In such cases, antibodies in the serum of the patient form an immune complex with the traces of IgA in the infused immunoglobulin

The IgA content of octagam is ≤ 0.2 mg/ml 5

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octagam® 4 Units Specification Typical Value

IgG (nephelometry) mg/ml 42.8–55.0 49.9

Immunoglobulin G ≥ 96% ≥ 98.0%

Monomers and dimers ≥ 90% ≥ 99.6%

Prekallikrein activator I.U./ml ≤ 35 3.6

Fc-Function ≥ 60% ≥ 96.7%

pH value 5.1–6.0 5.4

Anti-HBsAg I.U./g IgG ≥ 1 36

Anti-HAV I.U./ml ≥ 10 19.1

Anti-Parvo B19 I.U./ml ≥ 60 196

Anti-Diphtheria Ab I.U./ml 2.6


Indications

Primary Immunodeficiency Syndromes

Congenital agammaglobulinaemia and hypogammaglobulinaemiaCommon variable immunodeficiencySevere combined immunodeficienciesWiskott Aldrich syndrome

The dosage may need to be individualised for each patient dependant on the pharmacokineticresponse. A plasma trough level of IgG of at least4-6 g/l should be achieved. The recommendedstarting dose is 0.4-0.8 g/kg. The dose required tomaintain a trough level of 6 g/l is of the order of0.2-0.8 g/kg/month. The dosage interval in steadystate varies from 2-4 weeks.

Immunomodulation

Idiopathic Thrombocytopenic PurpuraFor the treatment of an acute episode, 0.8-1.0 g/kg on day one, repeated on day three if necessary, or 0.4 g/kg daily for two to five days. The treatment can be repeated if relapse occurs.

Guillain-Barré Syndrome0.4 g/kg/day for 3 to 7 days.

Kawasaki Disease1.6-2.0 g/kg should be administered in divided doses over two to five days. Patients should receive concomitant treatment with aspirin.

Allogenic Bone Marrow Transplantation

Intravenous immunoglobulin treatment may be used as part of the conditioning regimen and after the transplant. For the treatment of infections and prophylaxis of graft versus hostdisease, dosage is individually tailored. The starting dose is normally 0.5 g/kg/week, startingseven days before transplantation and for up to 3 months after transplantation.

Myeloma or chronic lymphatic leukaemia with severe secondary hypogamma-globulinaemia and recurrent infectionsChildren with congenital AIDS who have repeated bacterial infections

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

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Replacement Therapy



1 Debes A, Tolerability and safety of the intravenous immunoglobulin octagam®: a 10-year prospective observational study, Pharmacoepidemiol Drug Saf. 2007 Sep;16(9):1038-47

2 Ochs H, Pinciaro PJ & the octagam® Study Group. octagam®, an intravenous IgG product, is efficacious and well tolerated in subjects with primary immunodeficiency diseases. J Clin Immunol, 2004; 3:309-314.

3 Department of Health and Human Services, Food and Drug Administration Center for Biologics Evaluation and Research: Blood Products Advisory Committee, 65th Meeting, Washington, March 17, 2000. Washington, Miller Reporting Company Inc.

4 Octapharma Data on File.5 octagam® Summary of Product Characteristics6 Dalakas MC. Mechanism of action of intravenous immunoglobulin and therapeutic considerations in the treatment of

autoimmune neurologic diseases. Neurology 1998; 51: S2-87 Borte M; Davies SV; Touraine JL; Farber CM; Lipsic T; Adams C; Späth P; Bolli R; Morell A; Andresen I. Clinical properties

of a novel liquid intravenous immunoglobulin: studies in patients with immune thrombocytopenic purpura and primary immunodeficiencies. Transfusion Medicine and Hemotherapy 2004; 31, 126-134

8 Theobald K; Högy B. Pharmacokinetics of single and multiple infusions of 5S intravenous immunoglobulin. Vox sanguinis 1995; 68, 5-8

9 Guidelines on Assessing the Risk for Virus Transmission – New Chapter 6 of the Note for Guidance on Plasma-Derived Medicinal Products – CPMP/BWP/269/95 from the 21st of October 2004.

10 « Plasma Master File » (PMF) from the EMEA, EMEA/H/PMF/000008/05/AU/002.11 EMEA. CPMP/BWP/269/95 rev. 3. Note for guidance on plasma-derived medicinal products. 25 January 2001.12 FDA Violative Advertising and Promotional Labelling Letter, January 23, 200313 Rabenau HF, Biesert L, Schmidt T, Bauer G, Cinatl J, Doerr HW. SARS-coronavirus (SARS-Co V) and the safety of a solvent/

detergent (S/D) treated immunoglobulin preparation. Biologicals 33 (2005): 95-9914 Loewer J. Paul-Ehrlich-Institute, Langen, Germany. April 11, 2003, http://www.who.int15 Brenner B. Clinical experience with octagam®, a solvent detergent(SD) virus inactivated gammaglobulin. Clin Experimental

Rheumatol 1996;14 (Suppl.15): S115-S119

16 Wells JV, Buckley RH, Schanfield MS. Anaphylactoid reactions to plasma infusions in patients with hypogammaglobulinemia and anti-IgA antibodies. Clin Immunol Immunopathol, 1971; 8:265-271.

17 Martin TD. Safety & tolerability of intravenous immunoglobulin. Clin Neurophysiol, 1999; (Suppl 50): 514-520.18 Nydegger UE, Sturzenegger. Adverse effects of intravenous immunoglobulin therapy. Drug Safety, 1999; 3:171-185.19 Haskin JA, Warner DJ, Blank DU. Acute renal failure after large dose of intravenous immunoglobulin. Ann Pharm 1999;

33(7-8): 800-320 Bauer M, Schultz C. Immunoglobulins for the treatment of patients with secondary immunodeficiency: long-term investigation

confirms excellent tolerability of octagam®. European Journal of Hospital Pharmacy; 2004:4:76-7721 Schleis TG, Interference of maltose, icodextrin, galactose, or xylose with some blood glucose monitoring systems,

Pharmacotherapy. 2007 Sep;27(9):1313-2122 Brannagan TH III, Nagle KJ, Lange DJ, Rowland LP. Complications of intravenous immune globulin in neurologic disease.

Neurology, 1996; 47:674-7.23 Stangel M, Hartung H-P, Marx P, Gold R. Side effects of high dose intravenous immunoglobulins. Clinical Neuropharmacology,

1997; 20; 5:385-393.24 Fisman DN, Smilovitch M. Intravenous immunoglobulin, blood viscosity and myocardial infarction. Can J Cardiol, 1997; 13:775-7.25 Silbert PL, Knezevic WV, Bridge DT. Cerebral infarction complicating intravenous immunoglobulin therapy for polyneuritis

cranialis. Neurology, 1992; 49:257-8.26 Thornton CA, Ballow M. Safety of intravenous immunoglobulin. Arch Neurol, 1993; 50: 135- 6.27 Steg RE, Lefkowitz DM. Cerebral infarction following intravenous immunoglobulin therapy for myasthenia gravis.

Neurology, 1994; 44:1180.28 Dalakas MC. High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events.

Neurology, 1994; 44:223-6.29 Rosenbaum JT. Myocardial infarction as a complication of immunoglobulin therapy. Arthritis Rheum, 1997; 40:1732-3.30 Vyas GN, Perkins HA, Fundenberg HH. Anaphylactoid transfusion reaction associated with anti-IgA. Lancet, 1971; 2:312-4.31 Schmidt AP, Taswell HF, Gleich GJ. Anaphylactic transfusion reactions associated with anti-IgA antibody. N Engl J Med, 1969;

280:188-192.32 Cunningham-Rundles C, Zhou Z, Mankarious S, Courter S. Long-term use of IgA-depleted intravenous immunoglobulin

in immunodeficient subjects with anti-IgA antibodies. J Clin Immunol 1993,13;4:272-8

References

Liquid Harmony

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octagam®

Abbreviated Prescribing Information

QUALITATIVE AND QUANTITATIVE COMPOSITION: Human normal immunoglobulin for intravenous administration (IVIG). One mlof solution contains: 50 mg human protein of which ≥ 95% is immunoglobulin G (IgG). IgG subclasses (approx. percent of totalIgG):IgG1 60%, IgG2 32%, IgG3 7%, IgG4 1%. IgA ≤ 0.2 mg.Maltose for adjustment of osmolality: 100 mg. THERAPEUTIC INDICATIONS: Replacement therapy: Primaryimmunodeficiency syndromes: congenital agammaglobulinaemia andhypogammaglobulinaemia, common variable immunodeficiency,severe combined immunodeficiency, Wiskott Aldrich syndrome.Myeloma or chronic lymphatic leukaemia with severe secondaryhypogammaglobulinaemia and recurrent infections, children withcongenital AIDS who have repeated bacterial infections.Immunomodulation: Immune (idiopathic) thrombocytopenic purpura in adults or children with a high risk of bleeding or prior tosurgery to correct the platelet count, Guillain-Barré syndrome,Kawasaki disease, allogenic bone marrow transplantation. POSOLOGY: In replacement therapy the dosage may need to beindividualised for each patient dependant on the pharmacokineticresponse. Replacement therapy in primary immunodeficiencies:a plasma trough level of IgG of at least 4-6g/l should be achieved.The recommended starting dose is 0.4-0.8g/kg, the dose required tomaintain a trough level of 6 g/l is of the order of 0.2-0.8g/kg/month.The dosage interval in steady state varies from 2-4 weeks.Replacement therapy in myeloma or chronic lymphatic leukaemia; replacement therapy in children with AIDS andrecurrent infections: The recommended dose is 0.2-0.4g/kg everythree to four weeks. Immune (Idiopathic) Thrombocytopenic Purpura: For the treatment of an acute episode, 0.8-1g/kg on day one, repeated on day three if necessary, or 0.4g/kg daily for two to five days. The treatment can be repeated if relapse occurs.

Guillain-Barré Syndrome: 0.4 g/kg/day for 3 to 7 days. Experiencein children is limited. Kawasaki Disease: 1.6-2.0g/kg should be administered in divideddoses over two to five days. Patients should receive concomitanttreatment with aspirin. Allogenic Bone Marrow Transplantation: For the treatment ofinfections 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 monthsafter transplantation. METHOD OF ADMINISTRATION: Human normal immunoglobulinshould be infused intravenously at an initial rate of 1 ml/kg/hour for 30 minutes. If well tolerated, the rate of administration may gradually be increased to a maximum of 5 ml/kg/hour. CONTRAINDICATIONS: History of an allergic reaction to any humanimmunoglobulin preparation or to any constituent of octagam®.Hypersensitivity to homologous immunoglobulins, especially in veryrare cases of immunoglobulin A (IgA) deficiency, when the patienthas antibodies against IgA. SPECIAL WARNINGS AND PRECAUTIONS FOR USE: The recommended infusion rate must be closely followed as adverse drugreactions may be related to the infusion rate. Patients must be closelymonitored and carefully observed for any symptoms throughout theinfusion. True hypersensitivity reactions are rare. They can occur inthe very seldom cases of IgA deficiency with anti-IgA antibodies.Rarely, human normal immunoglobulin can induce a fall in bloodpressure with anaphylactic reaction. Potential complications can oftenbe avoided by ensuring: that patients are not sensitive to human normal immunoglobulin by first injecting the product slowly (1 ml/kg/min); that patients are carefully monitored for any symptomsthroughout the infusion period. In particular, patients naive to humannormal immunoglobulin, patients switched from an alternative IVIGproduct or when treatment has been stopped for more than eightweeks should be monitored during the first infusion and for the firsthour after the first infusion. All other patients should be observed forat least 20 minutes after administration. Cases of renal dysfunctionand acute renal failure have been reported in patients receiving IVIG

therapy. Products containing sucrose as a stabiliser accounted for adisproportionate share of these reports. octagam does not containsucrose. In all patients, IVIG administration requires: adequate hydration prior to the initiation of the infusion of IVIG, monitoring ofurine output, monitoring of serum creatinine levels, avoidance ofconcomitant use of loop diuretics. If renal function deteriorates, IVIGdiscontinuation should be considered. In case of adverse reaction,either the rate of administration must be reduced or the infusionstopped. The treatment required in case of side effects depends onthe nature and severity of the side effect. In patients with cerebro-vascular or cardiovascular diseases or other vascular risk factors,immunoglobulins should be administered with care, particularly ifhigh doses are used, due to potential increases in plasma viscosity.When medicinal products prepared from human blood or plasma areadministered, infectious diseases due to transmission of infectiveagents cannot be totally excluded. This also applies to pathogens ofhitherto unknown nature. The risk of transmission of infective agentsis however reduced by: selection of donors by a medical interviewand screening of donations for the three major pathogenic viruses,HIV, HCV, HBV; testing of plasma pools for HCV genomic material;removal/inactivation procedures included in the production processthat have been validated using model viruses and are consideredeffective for HIV, HCV and HBV. The viral removal/inactivation proce-dures may be of limited value against non-enveloped viruses such ashepatitis A virus or parvovirus B19. INTERACTIONS: Immunoglobulin administration may impair for aperiod of at least 6 weeks and up to 3 months the efficacy of liveattenuated virus vaccines such as measles, rubella, mumps and varicella. Blood Glucose Testing: Some types of blood glucose testingsystems falsely interpret the maltose contained in octagam as glucose. This may result in falsely elevated glucose readings leadingto inappropriate administration of insulin, resulting in life-threateninghypoglycaemia. Also, cases of true hypoglycaemia may go untreateddue to falsely elevated glucose readings. The measurement of bloodglucose must be done with a glucose-specific method. Please reviewthe product information of the blood glucose testing system todetermine if it is appropriate for use with maltose-containing parenteral products. In case of uncertainty contact the manufacturerof the glucose testing system.

INTERFERENCE WITH SEROLOGICAL TESTING: Passive transmissionof antibodies to erythrocyte antigens, e.g. A, B or D may interferewith some serological tests for red cell allo-antibodies (e.g. CoombsTest), haptoglobin and reticulocyte count. octagam® contains maltose, which could interfere with blood and urinary glucose tests.PREGNANCY AND LACTATION: The safety of this medicinal product for use in human pregnancy has not been established incontrolled clinical trials. UNDESIRABLE EFFECTS: Adverse reactions such as chills, headache,fever, vomiting, allergic reactions, nausea, arthralgia, changes inblood pressure and moderate low back pain may occur occasionally.Rarely human normal immunoglobulins may cause a fall in bloodpressure and, in isolated cases, anaphylactic shock. Cases of reversible aseptic meningitis, isolated cases of reversible haemolyticanaemia/haemolysis, transient increases in liver transaminases andrare cases of regressive cutaneous reactions have been observed withhuman normal immunoglobulins. Increase in creatinine and/or acuterenal failure have been observed with IVIG preparations. Thromboticevents have been reported in the elderly, in patients with signs ofcerebral or cardiac ischemia, and in overweight and overly volume-depleted patients with IVIG preparations. OVERDOSE: Overdose may lead to fluid overload and hyperviscosity,particularly in patients at risk, including elderly patients or patientswith renal impairment. SPECIAL PRECAUTIONS FOR STORAGE: Do not store or transportabove 25°C. Do not freeze. Protect from light. Do not use after expiry date indicated on the bottle. INSTRUCTIONS FOR USE AND HANDLING: The product should bebrought to room or body temperature before use.

This information is designed for international use and may deviatefrom the product information valid in your country. Please do refer to your national Octagam® summary of product characteristics orprescribing information.

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Liquid Harmony

Octapharma AGSeidenstrasse 2CH-8853 LachenSwitzerland

www.octapharma.comGA

MF-

BRO

C-0

9/08

-01-

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