Octagam 10% - DIMDI · mellitus and a history of vascular disease or thrombotic episodes, patients with acquired or inherited thrombophilic disorders, patients with prolonged periods

Public Assessment Report

(according sec 34 subs 1a and 1b Medicinal Products Act)

Octagam 10% Human Normal Immunoglobulin G for Intravenous Administration

Octapharma GmbH, 40764 Langenfeld, Germany

Registration Date: 20.05.2008

Registration Number: PEI.H.03627.01.1

ENR:

Creation Date of the PAR: 14.08.2008

annex to the marketing authorisation 2/2

EUROPEAN PUBLIC ASSESSMENT REPORT (EPAR)

Octagam 10%

DE/H/479/001/DC

TABLE OF CONTENTS MODULE 1: INFORMATION ABOUT THE INITIAL PROCEDURE 3 MODULE 2: SUMMARY OF PRODUCT CHARACTERISTICS 5 MODULE 3: PACKAGE LEAFLET 15 MODULE 4: LABELLING 21 MODULE 5: SCIENTIFIC DISCUSSION 23 MODULE 6: STEPS ARE TAKEN AFTER THE INTITIAL PROCEDURE 35

Octagam 10% DE/H/479/001/DC PAR MODULE 1 3

MODULE 1: INFORMATION ABOUT THE INITIAL PROCEDURE

Octagam 10%

DE/H/479/001/DC

Concerning the name of the product for Austria, Hungary, Estonia and Sweden the name of the medicinal product will be Octagam 100 mg/ml. In the RMS and all other Concerned Member States the name of the medicinal product will be Octagam 10%.

1. Type of application:

Full application according article 8.3 (i) Directive 2001/83/EC

2. Active Substance:

Human Normal Immunoglobulin

3. Form:

Solution for infusion

4. Strength:

100 mg/ml

5. Marketing Authorisation Holder:

• Octapharma GmbH, 40764 Langenfeld, Germany

• Octapharma Pharmazeutika Produktionsges.m.b.H., 1100 Vienna, Austria

• Octapharma AB, 11275 Stockholm, Sweden

• Octapharma (IP) Limited, Coventry CV59RG, UK

• Octapharma Benelux S.A./N.V.1180 Brussels, Belgium

• Octapharma Produtos Farmeceuticous Lda, 1170-169 Lisboa, Portugal

• Octapharma AG, 8853 Lachen, Switzerland

6. Reference Member State:

Paul-Ehrlich-Institut, Germany

7. Concerned Member State:

AT, UK, DK, SE, PT, LU, EE, HU, NO


8. Procedure-number:

DE/H/479/001/DC

9. Timetable:

Start of procedure d0: 21.11.2007

Assessment report d70: 30.01.2008

Comments d100: 29.02.2008

End of procedure d150: 20.04.2008

20080416_spc_853_DCP_05.04_en.doc PAR MODULE 2 5

MODULE 2: SUMMARY OF PRODUCT CHARACTERISTICS

SUMMARY OF PRODUCT CHARACTERISTICS Human normal immunoglobulin for intravenous administration (IVIg)

NAME OF THE MEDICINAL PRODUCT OCTAGAM 10%

OCTAGAM 100 mg/ml

[country specific] solution for infusion

QUALITATIVE AND QUANTITATIVE COMPOSITION

Active ingredients Human normal immunoglobulin (IVIg)

Quantitative composition: 1 ml solution contains:

Protein 100 mg of which ≥ 95% is human Immunoglobulin G IgA ≤ 0.4 mg IgM ≤ 0.3 mg

Distribution of IgG subclasses: IgG1 ca. 60% IgG2 ca. 32% IgG3 ca. 7% IgG4 ca. 1%

For a full list of excipients, see section 6.1.

PHARMACEUTICAL FORM Solution for infusion

The liquid preparation is clear to slightly opalescent and colourless to slightly yellow. The pH of the liquid preparation is 4.5 – 5.0, the osmolality is ≥ 240 mosmol/kg.

CLINICAL PARTICULARS

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 lymphatic leukaemia 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

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 equilibration 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 to 4 weeks.

• Trough levels should be measured in order to adjust the dose and dosage interval.

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

Idiopathic Thrombocytopenic Purpura:

• For the treatment of an acute episode, 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 for 3 to 7 days. Experience in children is limited.

Kawasaki disease:

• 1.6 - 2 g/kg should be administered in divided doses over two to five days or 2 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 the 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 injection

Replacement therapy in primary immunodeficiency

- Starting dose: 0.4 - 0.8 g/kg

- Thereafter: 0.2 - 0.8 g/kg

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

Replacement therapy in secondary immunodeficiency Children with AIDS

0.2 - 0.4 g/kg 0.2 – 0.4 g/kg

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

Immunomodulation: Idiopathic Thrombocytopenic Purpura

0.8 - 1 g/kg or 0.4 g/kg/day

on day 1, possibly repeated once within 3 days for 2-5 days

Guillain Barré syndrome 0.4 g/kg/day for 3-7 days

Kawasaki syndrome 1.6 - 2 g/kg or

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

2 g/kg in one dose in association with acetylsalicylic acid

Allogeneic bone marrow transplantation: - treatment of infections and prophylaxis of graft versus host disease

0.5 g/kg

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

- Persistent lack of antibody production

0.5 g/kg every month until IgG levels return to normal

Method of administration Octagam 10% [100 mg/ml] should be infused intravenously at an initial rate of 0.01 to 0.02 mL/kg body weight per minute for 30 minutes. If well tolerated, the rate of administration may gradually be increased to a maximum of 0.12 mL/kg/ body weight per minute.


Contraindications Hypersensitivity to the active substance or to any of the excipients of Octagam 10% [100 mg/ml].

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

Special warnings and precautions for use Certain severe adverse drug reactions may be related to the rate of infusion. 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 agammaglobulinaemia, with or without IgA deficiency

• 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

True hypersensitivity reactions are rare. They can occur in very seldom cases of IgA deficiency with anti-IgA antibodies.

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

Potential complications can often be avoided by ensuring:

• that patients are not sensitive to human normal immunoglobulin by initially injecting the product slowly (0.01 to 0.02 mL/kg body weight per minute);

• that patients are carefully monitored for any symptoms throughout the infusion period; in particular, patients naive to human normal immunoglobulin, patients switched from an alternative IVIg product to Octagam 10% [100 mg/ml] 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.

There is clinical evidence of an association between IVIg administration 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 advanced age, hypertension, diabetes mellitus and a history of vascular disease or thrombotic episodes, patients with acquired or inherited thrombophilic disorders, patients with prolonged periods of immobilisation, severely hypovolemic patients, patients with diseases which increase blood viscosity).

Cases of acute renal failure have been reported in patients receiving IVIg therapy. In most cases, risk factors have been identified, such as pre-existing renal insufficiency, diabetes mellitus, hypovolemia, overweight, concomitant nephrotoxic medicinal products or age over 65.


In case 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 containing various excipients such as sucrose, glucose and maltose, those containing sucrose as a stabiliser accounted for a disproportionate share of the total number. In patients at risk, the use of IVIg products not containing such excipients 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 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.

Some types of blood glucose testing systems may falsely interpret the maltose (90 mg/ml) contained in Octagam 10% [100 mg/ml] as glucose. This may result in falsely elevated glucose readings and, consequently, in the inappropriate administration of insulin and cases of true hypoglycaemia may go untreated if the hypoglycaemic state is masked by falsely elevated glucose readings. For further details see Section 4.5.

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 HIV, HBV and HCV.

The measures taken may be of limited value against non-enveloped viruses such as HAV and parvovirus B19. There is a 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 Octagam 10% [100 mg/ml] 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.

Interaction with other medicinal products and other forms of interactions In order to infuse any product that may remain in the infusion tubing at the end of the infusion the tubing may be flushed with either 0.9% saline or 5% dextrose solution.

Live attenuated virus vaccines


Immunoglobulin administration may impair for a period of at least 6 weeks and up to 3 months the efficacy of live attenuated virus vaccines such as measles, rubella, mumps and varicella. After administration of this product, an interval of 3 months should elapse before vaccination with live attenuated virus vaccines. In the case of measles, this impairment may persist for up to 1 year. Therefore, patients receiving measles vaccine should have their antibody status checked.

Interference with serological testing

After injection of immunoglobulin the transitory rise of 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 or D may interfere with some serological tests for red cell allo-antibodies, for example the antiglobulin test (e.g. Coombs Test).

Blood Glucose Testing Some types of blood glucose testing systems (for example, those based on the glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ) or glucose-dye-oxidoreductase methods) falsely interpret the maltose (90 mg/ml) contained in Octagam 10% [100 mg/ml] as glucose. This may result in falsely elevated glucose readings during an infusion and for a period of about 15 hours after the end of the infusion and, consequently, in the inappropriate administration of insulin, resulting in life-threatening or even fatal hypoglycemia. Also, cases of true hypoglycemia may go untreated if the hypoglycemic state is masked by falsely elevated glucose readings. Accordingly, when administering Octagam 10% [100 mg/ml] or other parenteral maltose- containing products, the measurement of blood glucose must be done with a glucose-specific method. The product information of the blood glucose testing system, including that of the test strips, should be carefully reviewed to determine if the system is appropriate for use with maltose-containing parenteral products. If any uncertainty exists, contact the manufacturer of the testing system to determine if the system is appropriate for use with maltose- containing parenteral products.

Pregnancy and lactation The safety of this medicinal product for use in human pregnancy has not been established in controlled clinical trials and therefore should only be given with caution to pregnant women and breast-feeding mothers. Clinical experience with immunoglobulins suggests that no harmful effects on the course of pregnancy, or on the foetus and the neonate are to be expected. Immunoglobulins are excreted into the milk and may contribute to the transfer of protective antibodies to the neonate.

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

Undesirable effects In general, various allergic and hypersensitivity type of reactions and headache, chills, back pain, chest pain, fever, cutaneous reactions, vomiting, arthralgia, low blood pressure and nausea may occasionally occur. Reactions to intravenous immunoglobulins tend to be related to the dose and the rate of infusion.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.


MedDRA 8.1 Coded Common >1% - <10%

Uncommon >0.1% - <1%

Very Rare < 0.01%

Blood and lymphatic system disorders

leukopenia; haemolytic anaemia

Immune system disorders hypersensitivity anaphylactic shock; anaphylactic reaction; anaphylactoid reaction; angioneurotic oedema; face oedema

Psychiatric disorders agitation

Nervous system disorders headache cerebrovascular accident; meningitis aseptic; migraine; dizziness; paraesthesia

Cardiac disorders myocardial infarction; tachycardia; palpitations; cyanosis

Vascular disorders thrombosis; peripheral circulatory failure; hypotension; hypertension

Respiratory, thoracic and mediastinal disorders

respiratory failure; pulmonary embolism; pulmonary oedema; bronchospasm; dyspnoea; cough

Gastrointestinal disorders nausea vomiting; diarrhoea; abdominal pain

Skin and subcutaneous tissue disorders

eczema; urticaria; rash; rash erythematous; dermatitis; pruritus; alopecia

Musculoskeletal and connective tissue disorders

back pain arthralgia; myalgia

Renal and urinary disorders renal failure acute

General disorders and administration site conditions

fever; fatigue; injection site reaction

chills; chest pain

hot flush; flushing; hyperhidrosis; malaise

Investigations hepatic enzymes increased; blood glucose false positive

Cases of reversible aseptic meningitis, isolated cases of reversible haemolytic anaemia/haemolysis and rare cases of transient cutaneous reactions, have been observed with human normal immunoglobulin.

Increase in serum creatinine level and/or acute renal failure have been observed.

Very rarely: Thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism, deep vein thromboses.


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.

Standard measures are taken to prevent infections resulting from the use of medicinal products prepared from human blood or plasma. 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. For safety with respect to transmissible agents, see 4.4.

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

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties Pharmacotherapeutic group: immune sera and immunoglobulins: immunoglobulins, normal human, for intravascular administration,

ATC-Code: J06B A02

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

Human normal immunoglobulin contains the IgG antibodies present in the normal population.

It is prepared from pooled plasma from not fewer than 3500 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 level to the normal range.

The mechanism of action in indications other than replacement therapy is not fully elucidated, but includes immunomodulatory effects. Clinical Studies

In a prospective, open-label, multicentre phase III trial, the efficacy and safety of Octagam 10% [100 mg/ml] was studied in patients suffering from idiopathic (immune) thrombocytopenic purpura (ITP). Octagam 10% [100 mg/ml] was infused on 2 consecutive days at a dose of 1 gram/kg/day, and patients were observed for a period of 21 days and at a follow-up visit on Day 63 post-infusion. Haematology parameters were assessed on Days 2 to 7, 14 and 21.

A total of 31 subjects were included in the analysis; 15 were subjects with chronic ITP, 15 were newly-diagnosed, and 1 subject was incorrectly enrolled in the study (had no ITP) and was therefore excluded from the efficacy analysis.

In total, 25 subjects (83%) showed a clinical response. A higher clinical response rate was seen in the newly-diagnosed cohort (93%) than in the chronic ITP cohort (73%). In subjects with a response, the median time to platelet response was 2 days, with a range of 1 to 5 days.

In 24 subjects (77%), Octagam 10% [100 mg/ml] was given at the maximum allowed infusion rate of 0.06 mL/kg/min. Following a Protocol Amendment, 2 patients of the


presented analysis received the product at a rate of 0.08 mL/kg/min which was uneventful in both cases. In the continuation of this on-going study, 22 subjects have been treated with the maximum allowed infusion rate of 0.12 mL/kg/min.

In 9 of 62 infusions (14.5%) treatment-related infusional AE were observed. The most common drug-related AE was headache, followed by tachycardia and pyrexia. There was no case of haemolysis related to the study drug. Pre-treatment to alleviate infusion-related intolerability was not given.

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 extravascular compartments.

Human normal immunoglobulin has an average half life ranging from 26 to 41 days, as measured in immunodeficient patients. 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.

Preclinical safety data Immunoglobulins are normal constituents of the human body. In animals, acute toxicity testing is of no relevance because of the excessive dose required. Repeated dose toxicity testing and embryo-foetal toxicity studies are impracticable. Effects of the product on the immune system of the newborn have not been studied.

Virus inactivation by solvent/detergent treatment is carried out with Tri-n-butyl phosphate (TNBP) and Octoxynol (Triton X-100). The maximum permitted amounts in the final product are 1 µg/ml TNBP and 5 µg/ml Octoxynol. In the doses in which Octagam 10% [100 mg/ml] is administered, these substances have been found to have no toxic effects in animal tests concerning acute and chronic toxicity, teratogenicity and embryotoxicity.

Since clinical experience provides no hint for tumorigenic or mutagenic effects of immunoglobulins, experimental studies, particularly in heterogolous species, are not considered necessary.

PHARMACEUTICAL PARTICULARS

List of excipients Maltose Water for injections

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

Shelf-life 2 years

Special precautions for storage Store in a refrigerator (2°C – 8°C).

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


Do not freeze.

Do not use after expiry date.

Because of the possibility of bacterial contamination, any remaining contents must be discarded.

Within its shelf-life, the product may be stored below 25 °C for up to 3 months, without being refrigerated again during this period, and must be withdrawn if not used after this.

Nature and contents of container

Package size Contents Container

Octagam 20 ml 2 g 30 ml injection vial

Octagam 50 ml 5 g 70 ml infusion bottle



Not all pack sizes may be marketed.

The primary container is made of type II glass closed with bromobutyl rubber stopper.

Components used in the packaging of Octagam 10% [100 mg/ml] are latex-free.

Special precautions for disposal and other handling The product should be brought to room or body temperature before use.

The solution should be clear or slightly opalescent.

Do not use solutions that are cloudy or have deposits.

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

MARKETING AUTHORISATION HOLDER To be completed nationally

MARKETING AUTHORISATION NUMBER(S)

DATE OF AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation:

Date of last renewal:

DATE OF REVISION OF THE TEXT April 2008

LEGAL CATEGORY For prescription only.

20080408_pil_853_DCP_05.04_en.doc PAR MODULE 3 15

MODULE 3: PACKAGE LEAFLET

PACKAGE LEAFLET: INFORMATION FOR THE USER OCTAGAM 10% [100 mg/ml], solution for infusion Human Normal Immunoglobulin (IVIg) Read all of this leaflet carefully before you start using this medicine. − Keep this leaflet. You may need to read it again. − If you have any further questions, ask your doctor or pharmacist. − This medicine has been prescribed for you. Do not pass it on to others. It may harm

them, even if their symptoms are the same as yours. − If any of the side effects gets serious, or if you notice any side effects not listed in this

leaflet, please tell your doctor or pharmacist. In this leaflet: 1. What Octagam 10% [100 mg/ml] is and what it is used for 2. Before you use Octagam 10% [100 mg/ml] 3. How to use Octagam 10% [100 mg/ml] 4. Possible side effects 5. How to store Octagam 10% [100 mg/ml] 6. Further information

WHAT OCTAGAM 10% [100 MG/ML] IS AND WHAT IT IS USED FOR

What Octagam 10% [100 mg/ml] is: Octagam 10% [100 mg/ml] is a human normal immunoglobulin (IgG) solution (i.e. solution of human antibodies) for intravenous administration (i.e. infusion into a vein). Immunoglobulins are normal constituents of the human body and support the immune defence of your body. Octagam 10% [100 mg/ml] contains all IgG activities which are present in the normal population. Adequate doses of this medicinal product may restore abnormally low IgG levels to the normal range.

Octagam 10% [100 mg/ml] has a broad spectrum of antibodies against various infectious agents. What Octagam 10% [100 mg/ml] is used for: Octagam 10% [100 mg/ml] is used

* as replacement therapy in patients who do not have sufficient amounts of own antibodies.

* in certain inflammatory diseases

* to prevent or treat infections after a bone marrow transplantation

Octagam 10% [100 mg/ml] is used as replacement therapy. There are 3 groups of replacement therapy:

- Patients with inborn deficiency of antibodies (primary immunodeficiency syndromes: congenital agammaglobulinaemia and hypogammaglobulinaemia,


common variable immunodeficiency, severe combined immunodeficiencies, Wiskott Aldrich syndrome)

- Patients with diseases of the blood that lead to a lack of antibodies and to recurrent infections (Myeloma or chronic lymphatic leukaemia with severe secondary hypogammaglobulinaemia and recurrent infections)

- Children with congenital AIDS who have repeated bacterial infections Octagam 10% [100 mg/ml] can be used in the following inflammatory diseases:

- In adults or children who do not have a sufficient number of platelets (idiopathic thrombocytopenic purpura) and who have a high risk of bleeding or prior to surgery to correct the platelet count

- In patients with a disease that leads to inflammation of various organs (Kawasaki disease)

- In patients with a disease that can lead to inflammation of certain parts of the nervous system (Guillain Barré syndrome)

BEFORE YOU USE OCTAGAM 10% [100 MG/ML]

Do not use Octagam 10% [100 mg/ml]:

- if you are allergic to human immunoglobulin or any of the other ingredients contained in Octagam 10% [100 mg/ml].

- if you have a deficiency of immunoglobulin A (IgA deficiency) with anti-IgA antibodies.

Take special care with Octagam 10% [100 mg/ml]: Tell your doctor if you have any other illnesses.

In the case of an adverse reaction, either the rate of administration must be reduced or the infusion must be stopped. The treatment of the adverse event required will depend on the nature and severity of the side effect.

Virus safety When medicines are made from human blood or plasma, certain measures are put in place to prevent infections being passed on to patients. These include: • careful selection of blood and plasma donors to make sure those at risk of carrying

infections are excluded • testing of each donation and pools of plasma for signs of virus/infections • steps included by the manufacturers in the processing of the blood or plasma that can

inactivate or remove viruses.

Despite these measures, when medicines prepared from human blood or plasma are administered, the possibility of passing on infection cannot be totally excluded. This also applies to any unknown or emerging viruses or other types of infections.

The measures taken are considered effective for encapsulated viruses such as human immunodeficiency virus (HIV), hepatitis B virus and hepatitis C virus.

The measures taken may be of limited value against non-encapsulated viruses such as hepatitis A virus and parvovirus B19.


Immunoglobulins have not been associated with hepatitis A or parvovirus B19 infections possibly because the antibodies against these infections, which are contained in the product, are protective.

It is strongly recommended that every time you receive a dose of Octagam 10% [100 mg/ml] the name and batch number of the product are recorded in order to maintain a record of the batches used.

Using other medicines: The infusion line may be flushed before and after administration of Octagam 10% [100 mg/ml] with either normal saline or 5% dextrose in water. Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription, or if you have received a vaccination in the last three months.

Octagam 10% [100 mg/ml] may impair the effect of live attenuated virus vaccines such as measles, rubella, mumps and varicella.

After administration of this product, an interval of 3 months should elapse before vaccination with live attenuated virus vaccines. In the case of measles, this impairment may persist for up to 1 year.

Inform your doctor that you are taking immunoglobulin when you give a blood sample, as this treatment may affect the results. Blood Glucose Testing Some types of blood glucose testing systems (so called glucometers) falsely interpret the maltose contained in Octagam 10% [100 mg/ml] as glucose. This may result in falsely elevated glucose readings during an infusion and for a period of about 15 hours after the end of the infusion and, consequently, in the inappropriate administration of insulin, resulting in life-threatening hypoglycaemia (i.e. a decreased blood sugar level).

Also, cases of true hypoglycaemia may go untreated if the hypoglycaemic state is masked by falsely elevated glucose readings.

Accordingly, when administering Octagam 10% [100 mg/ml] or other maltose-containing products, the measurement of blood glucose must be done with a test-system using a glucose-specific method. Systems based on the glucose dehydrogenase pyrroloquinolinequinone (GDH PQQ) or glucose-dye-oxidoreductase methods should not be used. Review carefully the product information of the blood glucose testing system, including that of the test strips, to determine if the system is appropriate for use with maltose-containing parenteral products. If any uncertainty exists, please ask your treating physician to determine if the glucose testing system you are using is appropriate for use with maltose-containing parenteral products.

Pregnancy and breast-feeding: Ask your doctor or pharmacist for advice before taking any medicine.

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


that no harmful effects on the course of pregnancy, or on the foetus and the neonate are to be expected.

Immunoglobulins are excreted into the milk and may contribute to the transfer of protective antibodies to the newborn.

Driving and using machines: There are no indications that immunoglobulin preparations may impair the ability to drive and use machines.

HOW TO USE OCTAGAM 10% [100 MG/ML]

Your doctor will decide if you need Octagam 10% [100 mg/ml] and at what dose. Octagam 10% [100 mg/ml] is administered as an intravenous infusion (infusion into a vein) by healthcare personnel. The dose and dosage regimen is dependent on the indication and may need to be individualised for each patient.

• If you have any further questions on the use of this product, ask your doctor or pharmacist.

POSSIBLE SIDE EFFECTS Like all medicines, Octagam 10% [100 mg/ml] can cause side effects, although not everybody gets them. Adverse reactions which may occur occasionally:

Chills, headache, fever, vomiting, allergic reactions, nausea, joint pain, changes in blood pressure (low/high blood pressure) and moderate low back pain

Adverse reactions which may occur rarely and in isolated cases:

Human normal immunoglobulins may cause a fall in blood pressure and an anaphylactic shock, even when the patient has shown no hypersensitivity to previous administration.

The following cases, isolated cases and rare cases have been observed with human normal immunoglobulin: • reversible aseptic meningitis (inflammation of the tissue surrounding the brain) • reversible haemolytic anaemia/haemolysis (destruction of red blood cells) • transient increases in liver transaminases (blood markers that indicate temporarily

impaired liver function) • regressive cutaneous reactions (reactions of the skin), often eczema-like • increase in creatinine (blood marker that indicates impaired function of the kidneys)

and/or acute renal failure

• thrombotic events (formation of blood clots) have been reported - in elderly patients

- in patients with signs of cerebral or cardiac ischemia (impaired blood circulation in the brain or heart vessels)

- in overweight and overly volume depleted patients


If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

HOW TO STORE OCTAGAM 10% [100 MG/ML] Store in a refrigerator (2°C – 8°C). Keep the container in the outer carton in order to protect from light. Do not freeze. Within its shelf-life, the product may be stored below 25 °C for up to 3 months, without being refrigerated again during this period, and must be withdrawn if not used after this.

Keep out of the reach and sight of children.

Do not use Octagam 10% [100 mg/ml] after the expiry date which is stated on the label and the carton.

Do not use Octagam 10% [100 mg/ml] if you notice that the solution is cloudy, has deposits or is coloured intensively.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

FURTHER INFORMATION What Octagam 10% [100 mg/ml] contains: − The active substance is human normal immunoglobulin 10% [100 mg/ml] (at least 95%

is immunoglobulin G). − The other ingredients are maltose and water for injections. − Components used in the packaging of Octagam 10% [100 mg/ml] are latex-free. What Octagam 10% [100 mg/ml] looks like and contents of the pack: Octagam 10% [100 mg/ml] is a solution for infusion and is available as: 20 ml of solution in a 30 ml injection vial (Type II glass) - pack size of 1 50 ml of solution in a 70 ml infusion bottle (Type II glass) - pack size of 1 100 ml of solution in a 100 ml infusion bottle (Type II glass) - pack size of 1 200 ml of solution in a 250 ml infusion bottle (Type II glass) - pack size of 1 The solution is clear or slightly opalescent, colourless or slightly yellow.

Not all pack sizes may be marketed. Marketing authorisation holder: To be completed nationally Manufacturers: Octapharma Pharmazeutika Produktionsges.m.b.H. Oberlaaer Strasse 235, A-1100 Vienna, Austria Tel: +43 1 61032 0 Fax: +43 1 61032 9300


Octapharma S.A.S. 70-72 rue de Marèchal Foch, BP 33, F-67380 Lingolsheim, France Tel: +33 3 88 78 89 89 Fax +33 3 88 78 89 78

Octapharma AB SE-112 75 Stockholm, Sweden Tel: +46 8 566 430 00 Fax: +46 8 133045 This medicinal product is authorised in the member states of the EEA under the following names: Octagam 10% Octagam 100 mg/ml This leaflet was last approved in MM/YYYY. The following information is intended for medical or healthcare professionals only:

• The product should be brought to room or body temperature before use.

• The solution should be clear and should not have a deposit.

• Any remaining fraction should be discarded.

• Human normal immunoglobulin for intravenous administration (IVIg) should not be mixed with other medicinal products.

• In order to infuse any product that may remain in the infusion tubing at the end of the infusion the tubing may be flushed with either 0.9% saline or 5% dextrose solution.

20080408_lab_853_DCP_03.02_en.doc PAR MODULE 4 21

MODULE 4: LABELLING PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING Immediate Packaging (Label) for: 20 ml solution in a 30 ml bottle, 50 ml solution in a 70 ml bottle, 100 ml solution in a 100 ml bottle or 200 ml solution in a 250 ml bottle – pack size of 1 1. NAME OF THE MEDICINAL PRODUCT Octagam 100 mg/ml, solution for infusion Human Normal Immunoglobulin (IVIg) 2. STATEMENT OF ACTIVE SUBSTANCE(S) 1 ml of solution contains:

Protein 100 mg of which ≥ 95% is human normal immunoglobulin G 3. LIST OF EXCIPIENTS 1 ml of solution contains:

Maltose 90 mg Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS 1 vial, 2 g/20 ml or: 1 bottle, 5 g/50 ml or: 1 bottle, 10 g/100 ml or: 1 bottle, 20 g/200 ml 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Intravenous use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE

STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Do not use turbid solutions. 8. EXPIRY DATE Exp. date:

20080303_lab_853_DCP_02.01_en.doc PAR MODULE 4 22

9. SPECIAL STORAGE CONDITIONS Store in a refrigerator (2°C – 8°C). Do not freeze! Keep the bottle in the outer carton. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER <[To be completed nationally]> Manufacturer: OCTAPHARMA 12. MARKETING AUTHORISATION NUMBER(S) <[To be completed nationally]> 13. BATCH NUMBER Batch-No.: 14. GENERAL CLASSIFICATION FOR SUPPLY For prescription only. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Justification for not including Braille: According to Article 56a of Directive 2001/83/EC as amended, labelling in Braille is not applicable. Self treatment is not indicated for the blind or partially sighted patients since the preparation is administered as an intravenous infusion and applied by health care professionals only.


MODULE 5: SCIENTIFIC DISCUSSION

Octagam 10%

DE/H/479/001/DC

I. INTRODUCTION Octagam 10% is a human normal immunoglobulin for intravenous administration (IVIg) presented in liquid form. It is prepared from human plasma and contains mainly IgG. The viral safety of Octagam 10% is mainly based on the solvent-detergent treatment, the pH4 treatment and the cold ethanol fractionation that further contributes to the viral safety. Octagam 10% is classified in the following pharmacotherapeutic group: immune sera and immunoglobulins: immunoglobulins, normal human, for intravascular administration, ATC code: J06B A02. Octagam 10% is indicated for replacement therapy in patients with primary and secondary immunodeficiency syndromes or in children with congenital AIDS. Furthermore the product can be used for immunomodulation in children or adults with idiopathic thrombocytopenic purpura, or in patients with Kawasaki disease or Guillain Barré syndrome. The product can also be used to prevent or treat infections after an allogeneic bone marrow transplantation.

II. QUALITY ASPECTS II.1 Introduction Octagam 10% is a virus inactivated, human normal immunoglobulin for intravenous use (IVIg), formulated in a liquid presentation. Octagam is a clear or slightly opalescent and colourless or slightly coloured solution of the normal immunoglobulin G fraction (> 95%) from human blood containing 100 mg of protein per ml. The pH of the preparation is 4.5 – 5.0. The removal of product related impurities such as IgA, IgM and other impurities is reproducible. A very low level of IgA, low content of polymers and aggregates, and low isoagglutinin titre are accomplished by the manufacturing process. The IgG molecules are in their native form which is necessary for the biological activity. It has a distribution of immunoglobulin G subclasses closely proportional to that in native human plasma and is classified in the following pharmacotherapeutic group: immune sera and immunoglobulin: immunoglobulin, normal human, for intravascular administration, ATC code: J06B A02.

Octagam 10% is manufactured at Octapharma’s facilities in Vienna (Austria), Lingolsheim (France) and Stockholm (Sweden). All three sites are responsible for the whole manufacturing process, i.e. from plasma starting material through to be labelled, packaged, quality control tested and batch released finished product. For German use only is the site Octapharma – Dessau for final packaging, labelling, batch release responsible. All three manufacturing sites have been inspected recently.

II.2 Drug substance The drug substance human immunoglobulin is not manufactured or added but isolated during manufacture, a fractionation process based on the Cohn method, of the drug product directly.

All plasma used for the manufacture of Octagam 10% complies with the current version of the approved Plasma Master File EMEA/H/PMF/000008/05/AU/003. The human plasma used for the manufacture of Octagam 10% comes from the Austria, Germany, Sweden, Switzerland, USA and Poland. Octagam 10% is prepared from plasma obtained from voluntary, non-remunerated and paid donors.


II.3 Drug Product

Description and Composition of the Drug Product

The active component, immunoglobulin G, is purified from human blood and the final product contains residues of other plasma proteins. Maltose is added to achieve iso-osmolality. Octagam is a clear or slightly opalescent and colourless or slightly coloured solution of the normal immunoglobulin G fraction from human blood containing 100 mg of protein per ml. The pH of the preparation is 4.5 – 5.0. The removal of product related impurities such as IgA, IgM and other impurities is reproducible. A very low level of IgA is accomplished by the manufacturing process. The IgG molecules are in their native form which is necessary for the biological activity.

Pharmaceutical Development

The basis of Octagam 10% is Octagam 5%, a product which is on the market since 1993 and is already registered in 60 countries all over the world. Octagam 10% contains twice as much protein as Octagam 5% which leads to a content of 100 mg/ml of total protein, of which > 95% are immunoglobulins, and a content of < 0.4 mg/ml IgA. The active component, immunoglobulin G, is purified from human blood and the final product contains residues of other plasma proteins. Maltose is added to achieve iso-osmolality.

The fraction II (paste II) derived from human plasma by conventional Cohn fractionation (Cohn et al.; 1946) is taken as raw material for Octagam 10%. Fraction II (paste II) is a common starting material for production of immunoglobulins. It has been shown that fractionation according to Cohn removes and inactivates various viruses. The following process from fraction II to the final product was developed at acidic pH to inhibit the development of multimers. IgG has an isoelectric point at about 7, at pH 4 the single molecule has a high charge and therefore is less prone to form aggregates. The fraction II is suspended in Water for Injections and the pH is adjusted to 4.6. At this pH immunoglobulins are very stable. After suspension of the fraction II the solution is ultrafiltered in order to remove the ethanol and to reduce the volume of the solution. A subsequent diafiltration removes the residues of ethanol.

To achieve virus safety, the preparation is treated by the Solvent/Detergent (SD) method. The preparation is exposed to 0.3% TNBP and 1% Octoxynol (Triton X-100). The virus inactivation is carried out at a pH-value of 5.3. At this pH-value the TNBP and the immunoglobulins are stable. Strength of the detergent was adapted to the amount of lipid components in the preparation. Octoxynol was chosen, because it is the most effective detergent in disrupting the lipid envelopes which preserve the “integrity” of lipid enveloped viruses. TNBP (tri-n-butyl-phosphate) is the standard solvent used in SD treatment of plasma products. The removal of the SD reagents is carried out by castor oil extraction to remove TNBP and solid phase extraction to remove Octoxynol. Castor oil was chosen because it is suitable for this function and it is described in the European Pharmacopoeia at a quality suitable for use in parenterals. Solid phase removes Octoxynol efficiently. The physical properties of the material Prep C-18 were considered most advantageous.

The treatment of immunoglobulins at pH 4 is known to reduce the amount of aggregates without changing the structure of the immunoglobulin molecule. The solution is adjusted in pH (3.95) and maltose is added to a final concentration of 10%. Then the solution is agitated for at least 24 hours at 37°C without addition of pepsin or other enzymes. The treatment performed in this way is effective in reducing the amount of aggregates and it should be noted that this treatment was shown to have virucidal effect.

A second ultra/diafiltration was introduced to adjust the final protein and maltose concentrations. Maltose is added to a final concentration of 8.7 % and the preparation is sterile filtered before filling. Octagam 10% is dispensed in colourless 30 ml, 70 ml, 100 ml, 250 ml glass bottles, glass type II (Ph. Eur.). The stability studies show that the container closure system is suitability for storage and


that the Octagam 10% container/closure system is able to maintain the sterility of the biologic product.

Manufacture

As manufacture facilities, Octapharma -Vienna, -Lingolsheim and -Stockholm are indicated. The additional contract laboratories are listed.

The ranges of batch size are indicated. One batch fraction II can be produced from either an equivalent of approximately 2,500 – 3,100 kg of plasma (Vienna and Lingolsheim) or an equivalent of 2200 to 4000 kg (± 10%) of plasma (Stockholm). Furthermore, several Fraction II pastes from one or more production sites may be combined / mixed to a batch size of 20 – 30 kg IgG for further purification. Excipients and raw materials were listed. Specifications of substances not described in Pharmacopoeia were provided. In all cases, Octapharma performs a test for identity.

Octagam 10%/ Octagam 5% is prepared by Cohn-Oncley cold ethanol fractionation process from human plasma of at least 1,000 donations. The manufacturing process comprises the Solvent/Detergent (S/D) virus inactivation method and a pH 4 treatment, a virus inactivating step that is also reducing anti-complementary activity. The whole manufacturing process is carried out at a low pH to maintain the nativity of the IgG molecules. The S/D method is highly effective against enveloped viruses, while the Cohn fractionation and the pH 4 treatment are effective against both, enveloped and non-enveloped viruses. The manufacture of Octagam 10%/ Octagam 5% involves two parts. The process from Plasma to Fraction II paste and the process from Fraction II paste to Final Container. The first part of the manufacturing procedure of Octagam 10% (from plasma to Fraction II paste) is completely identical to the process approved for Octagam 5%. The differences between 5% and 10% take place after pH 4 treatment.

Difference between manufacture of Octagam 5% and Octagam 10%

Reason

pH adjustment after pH 4 treatment is 4.6 ± 0.2 instead of 5.3 ± 0.2

Increase of stability

addition of maltose to 8.7% instead of 10%

since the higher amount of proteins in Octagam 10% contributes to a rise in osmolality, the amount of maltose had to be reduced for achieving the same osmolality as Octagam 5%.

subsequent pH adjustment: 4.7 ± 0.2 instead of 5.3 ± 0.2

Increase of stability

adjustment of contents of protein 90-120 g/l instead of 45 –55 g/l

Due to doubling of strength

The active substance human normal immunoglobulin is isolated and purified by the Cohn ethanol fractionation process from a pool of human plasma. The production of Octagam 10% from plasma to Final Container is identical at the Octapharma manufacturing sites in Vienna (OPG) and in Lingolsheim (OSA). The production process of fraction II+III starting from plasma at the Stockholm (OAB) site slightly differs. The manufacturing process from fraction (I+)II+III to the final product Octagam 10% is identical at all three production sites.

The process starts with the Reconstitution of fraction II and then filtered through a cellulose depth filter. The pH-value is adjusted to 4.6 ± 0.2 and the solution is filtered followed by ultrafiltration and diafiltration step. For the Virus inactivation by SD – treatment, the pH-value is adjusted to 5.3 ± 0.2 and Octoxynol (Triton X-100) and TNBP are added The mixture is agitated For the Removal of virus inactivation reagents castor oil is added under agitation. The aqueous phase is filtered through and the oily phase is discarded. The solution is passed through a C-18 chromatography column. For the pH treatment the pH is adjusted to pH 4. Maltose is added under agitation. The solution is filtered and kept for 24 - 26 hours at 37 ± 1 °C. The pH-value of the preparation is adjusted to 4.6. During the Second ultrafiltration and diafiltration the solution is concentrated and the protein concentration is then adjusted to 105 – 115 g/L in the final solution. For the Preparation


of final solution Maltose is added under agitation to a final concentration of 8.7 % (w/w). The pH-value is adjusted to 4.7 ± 0.2. Then the solution is adjusted to 100 g/L by addition of a 8.7 % maltose solution. The solution is filtered through a membrane with a pore size of ≤ 0.2 µm. Before and after use, the sterile filter is tested for integrity according to an appropriate test method. The Octagam bulk preparation is stored for a maximum of 14 days (+2 C to +8°C). Up to four (4) bulk solutions may be pooled prior final sterile filtration. Immediately before filling under aseptic conditions the solution is sterile filtered again through an inline sterilizing grade filter membrane. The sterile filter is tested for integrity before and after use. The product is filled into sterile, siliconized and pyrogen free infusion bottles which are closed with sterile, siliconized rubber stoppers. The filling volume is monitored throughout the filling process. Random samples are drawn from the preparations and their compliance with the specifications is verified. The finished preparations are visually inspected for particulate contamination, defects of vials and closures. Defective preparations are rejected. The accepted final containers are stacked into storage containers, which are closed, sealed and labelled with product name, fill size and lot number. They are transported back into the storage area and kept at 2°C – 8°C pending labelling and packaging.

As intermediates for Octagam the Fraction (I+) II+III and Fraction II were defined. The specifications for Fraction II were provided and are acceptable. In general for fraction II the three different storage temperatures and times are proposed at all three fractionation sites: 6 months at ≤ -25 °C, 24 months at -18 °C ± 2 °C and 12 months at ≤ -70 °C.

For fraction II+III manufactured at Octapharma Stockholm and Fraction I+II+III manufactured at Octapharma Lingolsheim or Vienna a shelf life of 2 years when stored at ≤ −25 °C or at −18 °C ± 2 °C were defined.

An indication of the critical steps was given, these steps are monitored with the in-process controls listed in the relevant operating procedures. The test methods for in-process controls were provided.

The manufacturing process of Octagam 10% has been validated at the Octapharma production site in Vienna. Two validation reports were provided. The manufacture of fraction II was validated in the year 2001 and revalidated in the year 2004 at the Vienna site. Routine in-process analytics and additional biochemical parameters were determined to show process reproducibility. The protein content was determined in several samples and demonstrated good batch-to-batch reproducibility. All determined biochemical and physical parameters of the revalidation performed in 2004 are comparable to the results of the validation 2001. Consistency of the process as described in the actual Methods of Manufacturing for fraction II has been demonstrated. The production of Octagam 10% from fraction II was validated in 2003 at the Vienna site (080RPQ04046.103). Routine in-process analytics and additional biochemical parameters were determined and process reproducibility was demonstrated.

The manufacturing process of Octagam 10%, as performed at Octapharma Vienna has been transferred to Octapharma Lingolsheim and Octapharma Stockholm. The Intersite Validation Report, Octagam 10% (120P52_01_05_00) summarises the performed validation activities including a comparison between the three sites. All steps of the production were validated and with a risk assessment critical operations identified. The submitted analytical data of the in process controls demonstrate a good process consistency at the Vienna site to Octapharma Lingolsheim and Octapharma Stockholm. Physical and biochemical results of the final product demonstrate a good batch to batch reproducibility and good biochemical comparability between the Octapharma sites. Analytical testing methods are validated. Transfer of methods to the different sites is documented in the Method Transfer Summary Reports.

Control of excipients

The used chemical raw materials were listed and comply with the European Pharmacopoeia (Ph. Eur.) or the National Formulation (NF). Quality control and compliance are guaranteed by the respective manufacturers, or the required tests are performed by Octapharma. In all cases, Octapharma performs a test for identity.

Control of Drug Product


Specifications for the drug product comply with the requirements of Ph Eur. fixed in the monograph “Human normal immunoglobulin for intravenous administration”. The final product specification is a corporate document and valid at all three manufacturing sites. Taking into account the higher protein content of Octagam 10% the specifications for additional tests are comparable to the specifications of Octagam 5%, which is on the market for a number of years. For all analytical procedures the relevant SOPs were provided. A number of validation studies have been submitted. In some cases no validation data have been presented, because test methods are used according to Ph. Eur. The used reference standards and materials were listed

For the batch analysis three batches produced at the Vienna site and two batches each produced at the Lingolsheim site and Stockholm site were analyzed. All measured parameter meet the specifications. Octagam is a clear or slightly opalescent and colourless or slightly coloured solution of the normal immunoglobulin G fraction from human blood containing 100 mg of protein per ml. The pH of the preparation is 4.5 – 5.0. The removal of product related impurities such as IgA, IgM and other impurities is reproducible. A low level of IgA is accomplished by the manufacturing process. The IgG molecules are in their native form which is necessary for the biological activity.

TNBP and Triton X-100 should be also indicated as product related impurities.

Container closure system

The final container for Octagam 10% are colourless 30 ml, 70 ml, 100 ml, 250 ml glass bottles, glass type II (Ph. Eur.). As Stoppers infusion stoppers 20 mm (30 ml bottle) and 32 mm (70 ml, 100 ml, 250 ml bottles) from bromobutyl rubber according Ph. Eur. are used. The bottles are sealed with aluminium flip-off caps. The outer packaging is a standard carton for 1 bottle.

Stability

The proposed shelf-life and storage conditions are “2 years stored at +2°C to +8°C protected from light. Within its shelf-life, the product may be stored below +25°C for up to 3 months, without being refrigerated again during this period, and must be withdrawn if not used after this.” To support this shelf life two stability studies were done and one is still ongoing.

The final 30 months data of Octagam 10% produced in Vienna stored at +5°C exhibited no observable trend over the entire period. At +25°C/60% RH the product stability is restricted to 6 months. Short-term temperature excursion studies, performed between months 21 and 24 at +25°C/60%RH also support that the product does not undergo any quality changes before it expired. The shelf-life and storage conditions recommended in final product specification were demonstrated for batches produced in Vienna.

For batches produced in Stockholm and Lingolsheim no temperature transition studies were conducted. The comparability of the stability of batches produced in Stockholm to batches produced in Vienna was demonstrated. 9 months data from the ongoing stability study 06P025 of Octagam 10% produced in Stockholm and Lingolsheim are available. The storage at +5 °C and +30 °C/65 % RH revealed no deviation over the period of 9 months and could be well compared to batches produced in Vienna. The proposed shelf life and storage condition are acceptable, the applicant committed to submit all outstanding stability data of the current study in time and to submit any OOS result immediately to the RMS.

Virus safety

Octagam 10% is a normal human immunoglobulin for intravenous use that is manufactured from human plasma. Plasma is collected in Austria, Germany, Sweden, Switzerland, the USA and Poland. In the case of Poland, plasma is collected from repeat donors or from first time donors where confirmatory testing is available. The viral safety strategy includes the selection of qualified donors and testing of plasma donations. Individual donations are tested serologically for anti-HIV-


1 and 2 antibodies, HBs antigen and anti-HCV antibodies. Manufacturing plasma pools are tested for HIV-1 and 2 antibodies, HBs antigen and HCV RNA. Donors with an increased risk for sporadic or variant Creutzfeldt-Jakob-Disease are excluded. The donor selection and plasma donation testing strategy for viral markers is considered adequate.

Octagam 10% is manufactured from fraction-II paste, prepared from pooled human plasma by conventional Cohn-Oncley fractionation and is produced at three different sites in Europe; Lingolsheim in France; Vienna in Austria; and Stockholm in Sweden. The production process differs slightly at the Stockholm site for the production of fraction II+III. The process from fraction (I)+II+III is identical at all three sites.

No animal-derived TSE risk material is used during production. Effective reduction of prion protein during down-scaled manufacture of Octagam 10% has been demonstrated for both the Cohn-fractionation steps and the production of the final bulk from the fraction II paste. In addition, several manufacturing steps have been validated for their capacity to inactivate or remove viruses: (1) Cohn-fractionation, (2) solvent/detergent (S/D) treatment and (3) low pH treatment. Effective inactivation of enveloped viruses by S/D treatment and at low pH 4 has been demonstrated. Effective removal of non-enveloped viruses has been demonstrated for the Cohn-fractionation step, removing Fraction III precipitate from the product intermediate. In summary, the requirements of Guideline CPMP/BWP/269/95 on the inactivation/removal of viruses have been fulfilled.


III. NON-CLINICAL ASPECTS Octagam 10% can be defined as belonging to the well known and characterized biological product family of human immunoglobulins. Hence, the standard pharmacodynamic and toxicity studies normally carried out for new substances in commonly used species, are not generally applicable to this product. However, a study on local tolerance after intravenous, intra-arterial and paravenous administration in rabbits was provided.

The excipient used (maltose) is very common in such pharmaceutical formulations. Taking into account its amount in the final formulation, no toxicity is expected following the intended therapeutic use of OCTAGAM 10%.

The production process of Octagam 10 % leaves residual amounts of TNBP and Triton X-100 of maximally 1µg/ml and 5µg/ml in the product. Therefore the pharmacokinetic and toxicity of TNBP + Triton X-100 was determined experimentally by means of a series of key investigations. In addition, literature data were provided. Two dose regimens were used for risk assessment (concerning TNBP and Triton X-100):

• 600 mg/kg BM OCTAGAM 10% (corresponding to ≤ 6 µg/kg TNBP and ≤ 30 µg/kg Triton X-100) every 4 weeks (for the whole life) in replacement therapy,

• 2 g/kg BM OCTAGAM 10% in one dose (corresponding to ≤ 20 µg/kg TNBP and ≤ 100 µg/kg Triton X-100) in Kawasaki disease.

A pharmacokinetic study in rats will cover plasma levels and concentrations in urine and faeces after a combined intravenous application of TNBP and Triton X-100 (1+5). TNBP and Triton X-100, separately or in combination, were tested in single dose toxicity studies: rats were treated intravenously, mice and rats (adult and new-born) were treated intraperitoneally. Repeat-dose toxicity studies were performed in rats and dogs with daily intravenous dosing of TNBP and Triton X-100 over 13 weeks in different doses at the ratio 1+5. Genotoxicity studies were presented for both substances (in combination):

− reverse mutation test with Salmonella typhimurium strains,

− HPRT test in V 79 cells,

− chromosomal analysis from rat bone marrow and

− micronucleus test on rats.

In addition, two studies were conducted with TNBP alone:

− micronucleus test in mice and

− SCE in CHO cells.

Pharmacology

Due to the fact that the Octagam 10% can be defined as belonging to the well known and characterized biological product family it is acceptable that no pharmacodynamic studies in animals were performed. Effective parameter were provided, such as the antibody spectrum, in-vitro opsonizing effects and in vivo a mouse protection assay.

A pharmacokinetic study with 300 μg of TNBP + 1,500 μg of Triton X-100/kg BM was conducted in rats and revealed no risk for accumulation. Literature data were provided concerning Pharmacokinetic and safety pharmacology of TNBP and Triton X-100. Nevertheless Tri-n-butyl-phosphate (TNBP) and Triton X-100 (Octoxynol) are widely used for the viral inactivation of immunoglobulin preparations and in general will be removed from the product throughout the manufacturing process. Therefore TNBP and Triton X-100 commonly defined as process-related impurity with low specifications.

Pharmacokinetics


Due to the fact that Octagam 10% can be defined as belonging to the well known and characterized biological product family it is acceptable that no Pharmakokinetic study was performed with Octagam 10% itself. The production of Octagam 10% leads to residual amounts of TNBP and Triton X-100 of maximally 1 µg/ml and 5 µg/ml, respectively in the product. Therefore a pharmacokinetic study with 300 μg of TNBP + 1,500 μg of Triton X-100/kg BM was conducted in rats and revealed no risk for accumulation. The results of the pharmacokinetic study carried out in rats (Report No. 6149/90), reflect the pharmacokinetic profile of TNBP and Triton X-100 which is already known in the literature. No further studies are required to gain more information.

Toxicology

The basis for the development of Octagam 10% was Octagam 5%. Based on the clinical experience with Octagam 5% only one none-clinical study was conduct with OCTAGAM 10% a local tolerance study in rabbits. This study revealed Octagam 10% is well tolerated intravenously and intra-arterially and caused a minimal to mild local irritation, when given paravenously.

The production of Octagam 10% leads to residual amounts of TNBP and Triton X-100 of maximally 1 µg/ml and 5 µg/ml, respectively in the product (comparable to Octagam 5%). Therefore the toxicity of these two chemicals by means of a series of key investigations was determined.

TNBP and Triton X-100 were tested mainly in the same combination (1 + 5) as present in OCTAGAM 10%. The lowest toxic sum dose of TNBP and Triton X-100 (1+5) was 10,000 μg/kg in acute intravenous single dose toxicity tests in rats. Based on this value the following “therapeutic windows” might be calculated for OCTAGAM 10% in humans:

• ≥ 277.8 for a single dose of 600 mg/kg (once in four weeks) containing ≤ 36 μg/kg TNBP plus Triton X-100 at the ratio 1 + 5,

• ≥ 83.3 for one single injection of 2 g/kg containing ≤ 120 μg/kg TNBP plus Triton X-100.

With the intraperitoneal administration the determined lowest toxic dose was higher. There were no indications in this test with regard to differences in the susceptibility, symptoms and mortality data of newborn rats compared with mature animals. Comparison of the toxicity of the combination (TNBP + Triton X-100) with that of the individual substances reveals no indication of synergistic effects in the case of combined administration. The repeat dose toxicity revealed a lowest toxic dose level for TNPB + Triton X-100 well below the lowest dose level of the single dose toxicity study. Even if OCTAGAM 10% treatment should be repeated in shorter intervals, there is no accumulation of TNBP and Triton X-100 because of the short half-life of these chemicals.

TNBP and Triton X-100 were tested in combination in genotoxicity studies in vitro and in vivo. The mutagenicity studies with TNBP + Triton X-100 in combination, as well as TNBP alone, revealed no indications of gene or chromosomal damage this is in accordance with the presented literature data. The (negative) results are in good agreement with the existing literature. No carcinogenicity studies were performed for TNBP and Triton X-100, because the use of TNBP and Triton X-100 in humans has a long history without any reports on carcinogenicity. The subchronic tests and the mutagenicity studies performed by the applicant did not reveal any evidence of carcinogenic properties.

Again high doses were used in the embryo-foetal development studies in rats and rabbits. In rats malformations were observed to a small extent in the dose-groups (TNBP + Triton X-100; μg/kg day –1) 100 + 500 and 300 + 1,500 but not in the highest dosegroup (900 + 4,500). This lack of a dose-response relationship is a strong argument that these findings are not drug-related but spontaneous in nature. According to the results presented, there is no teratogenic effect of TNBP plus Triton X-100 and this is in good agreement with the results published for the single substances.

The in vivo toxicological studies conducted by the applicant provided no evidence of haemolytic properties of TNBP + Triton X-100 (1 + 5). There was no evidence of toxicologically significant


cell damage with TNBP + Triton X- 100 either in the in vivo subchronic tests carried out or the cytotoxicity tests conducted within the preliminary experiments for mutagenicity studies. In the HPRT Test (V79 cells) with TNBP + Triton X-100 (1 + 5), cytotoxic effects were determined.

Effects on embryo-foetal development were examined in rats and rabbits, intravenously dosed with combinations of TNBP and Triton X-100.

The haemolytic potential of both substances in combination was tested in vitro using human blood.

In summary, the toxicology studies performed with TNBP and Triton X-100 did not indicate an impact on the safety and tolerance of OCTAGAM 10%.


IV. CLINICAL ASPECTS The company Octapharma AG has submitted Marketing Authorisation Application (MAA) via the Decentralised Procedure (DCP) for the successor product to Octagam 5 %, namely Octagam 10%. Octagam 5% was first registered in 1995 and is currently registered in about 65 countries.

The biochemical characteristics of both products are essentially similar. As no relevant changes in the manufacturing process have been introduced, no additional studies are deemed necessary and are not required according to the current Note for Guidance on the Clinical Investigation of Human Normal Immunoglobulin for Intravenous Administration (IVIg), (CPMP/BPWG/388/95 rev. 1). Nevertheless, the applicant has submitted efficacy data derived from an ongoing efficacy and safety study in 116 ITP patients (GAM10-02). A descriptive interim analysis on 31 patients has been performed and its evaluation is presented here. The applicant has committed to providing the data and analysis from the ongoing study when available.

Pharmacokinetics

N.a.

Pharmacodynamics

N.a.

Clinical efficacy

The trial design comprised an open-label, non-controlled, multi-centre, phase III study in subjects with ITP. Of the 31 patients, treatment response and safety were assessed in 15 subjects with chronic ITP (i.e. platelets < 150 x 109/L for > than 6 months duration) and 15 newly-diagnosed subjects. (One patient was falsely diagnosed as having ITP). Clinical response was defined as an increase in platelets to ≥50 x 109/L within 7 days after treatment and duration of response was the number of days the platelet count remained above 50 x 109/L. Octagam 10% was infused on 2 consecutive days at a dose of 1 gram/kg/day, and patients were observed for a period of 21 days and at a follow-up visit on Day 63 post-infusion.

The chronic subset, sample size and endpoints comply with the current recommendations of the Note for Guidance on the Clinical Investigation of Human Normal Immunoglobulin for Intravenous Administration (IVIg), (CPMP/BPWG/388/95 rev. 1). Thus, this trial design is adequate.

In total, 25/30 patients (83%) showed a clinical response (platelets ≥50 x 109/L). A higher clinical response rate was seen in the newly-diagnosed cohort (93%) than in the chronic ITP cohort (73%). The response rates are in keeping with those expected in chronic and acute cohorts of ITP patients and correspond to relevant clinical treatment recommendations where a response can be expected in ~75% of patients. Normal platelet levels (150 – 450 x 109/L) were achieved in 71-72% of the responders, which is a good rate for this parameter.

In subjects with a response, the median time to platelet response was 2 days, with a range of 1 to 5 days; this is also in keeping with data from the literature and other products recently assessed.

The median duration of response which was 13 days (range: 1 day - 64 days), was assessed by a more conservative approach by only counting up to the last visit when the count was still ≥ 50 x 109/L. The duration of response may be slightly affected in those cases where corticosteroids were given soon after Day 7 (four newly diagnosed patients received corticosteroids on Day 8, Day8, Day 10 and Day 11 respectively). Given the otherwise stringent evaluation of duration of response this is not likely to result in a major change and is therefore considered acceptable. The approaches in other studies are variable: either the count is taken on the following visit after the platelets have fallen below 50 x 109/L, or the duration is calculated as an interpolation of the 2 values, or the count is taken


after the platelets have fallen below 20 x 109/L again. Taking this into consideration the value achieved is good and in keeping with other products centrally assessed.

The incidence/resolution of haemorrhages is also in keeping with that reported in the literature. However, the haemostatic agent etamsylate was given immediately prior to or early in the study to treat or prevent a bleeding episode in 5 patients, making the assessment slightly difficult in these cases. Nevertheless, as etamsylate does not alter platelet count (and is used in other IVIG trials), the primary endpoint was not affected.

Clinical safety

Thirty-one patients were included in the safety evaluation. For both the chronic and the newly diagnosed patient groups the mean and median doses given on both treatment days were 1 g/kg.

This is the standard dosing for IVIGs in the patient population.

For both the chronic and the newly diagnosed patient groups the mean and median doses given on both treatment days were 1 g/kg. This is considered the correct dosing of IVIG for this clinical picture.

In total, 28 patients experienced an AE, with the same incidence in the 2 cohorts (93.3%). Overall, 45.2% of patients experienced a drug-related AE. This incidence was higher in the chronic ITP cohort (66.7%) than in the newly-diagnosed cohort (26.7%). One patient in the chronic ITP cohort and 3 patients in the newly-diagnosed cohort had a severe AE, which was not related to the study drug. Over half of the AEs occurred during an infusion or within 1 hour after the end of an infusion, and 58% of patients had an AE (serious or non-serious) that led to an intervention. Just over half of the patients had a significant AE (a non-serious AE with a corrective action such as a change in the dose or infusion rate or start of a drug therapy).

The most common AEs were headache in 11 patients, increased heart rate in 10 patients, and decreased heart rate in 6 patients. The most common infusional AEs were heart rate increased in 9 patients and heart rate decreased in 6 patients. Infusional drug-related AEs occurred in 9 (14.5%) of the 62 infusions administered in this study.

There were 5 SAEs, the incidence was higher in the newly-diagnosed cohort, with 4 patients (26.7%) with SAEs, compared with 1 patient (6.7%) in the chronic ITP cohort. None were considered related to Octagam 10%. There were no AEs leading to discontinuation of Octagam 10% and there were no fatal AEs. One patient (0106) had an SAE of severely decreased platelet count due to ITP that led to withdrawal from the study 17 days after the first dose of Octagam 10%.

Vital signs and physical examination findings were unremarkable for the given population. All viral markers were negative.

In summary, no new safety signals could be discerned from this interim analysis. As mentioned above data from the ongoing trial in the remaining patients is awaited.

Pharmacovigilance system

The applicant has provided documents that set out a description of the system of pharmacovigilance. A statement signed by the applicant and the qualified person for pharmacovigilance, indicating that the applicant has the services of a qualified person responsible for pharmacovigilance and the necessary means for the notification of any adverse reaction occurring either in the Community or in a third country has been provided.

Electronic transmission of individual case safety reports has been implemented with the European Medicines Agency (EMEA) and various E2B- ready competent authorities of EU Member States.

The RMS considers that the Pharmacovigilance system as described by the applicant mainly fulfils the requirements, provides sufficient information about the qualified person responsible for


pharmacovigilance and seems to have the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country.

The Pharmacovigilance issues raised in the first round of questions of this procedure were adequately addressed by the applicant and the required information was submitted (i.e. SOP of Qualified Person, computerised systems used in pharmacovigilance, brief description of the Quality management system).

Risk Management Plan

The applicant state: safety information from any source including spontaneous reports, post-approval clinical trials, Health Authorities reports and literature is collected, reviewed and analysed on an ongoing basis so that benefit risk assessment of his products is regularly monitored.

The Risk management plan issues raised in the first round of questions of this procedure were addressed (i.e. information about prion safety, "blood glucose false positive" is listed under "investigations"); remaining minor points were clarified.

The company committed to collecting safety data of Octagam 10% in the paediatric population. These data will be presented with the first periodic safety update report. This study was also integrated into the Risk Management Plan (RMP).

V. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION The results for the clinical study are in keeping with those reported in the literature and in other studies with similar products. They also fully comply with the current standards requested by the European Note for Guidance for the clinical investigation of IVIG (CPMP/BPWG/388/95 rev. 1). The correct patient population (15 adult patients with chronic ITP) was included in the studies. The doses administered to the ITP patients complied with those laid down in the core SPC.

In total, 25/30 patients (83%) showed a clinical response (platelets ≥50 x 109/L); 93% in the newly-diagnosed cohort and (73%) in the chronic ITP cohort. Platelets were maintained above this level for 13 days. The values obtained in the ITP study for the number of responders, platelet levels, and duration correspond to those cited in the recent literature.

No new safety signals could be discerned from the submitted data; the adverse reactions to IVIGs are well known and have been described in the SPC.

The overall benefit risk assessment is positive

According to new legislative requirements a user testing of the package leaflet has been performed.

Based on the review of data on quality, safety and efficacy, the Reference Member State Germany considered that the application could be approved.


MODULE 6: STEPS ARE TAKEN AFTER THE INITIAL PROCEDURE

Scope Procedure number Product information affected

Start End Approval

Assessment report attached

Alternative manufacturing process including Octapharma Springe as new manufacturing site from plasma to fraction II

DE/H/479/001/II/001 N 24.07.2008 24.10.2008 Y N

MRP repeat Use 1st Wave DE/H/479/001/E01 N 24.02.2009 25.05.2009 Y N Revision of SPC, PIL and labelling DE/H/479/001/II/003 Y 16.11.2009 19.02.2010 Y N Change of manufacturing process including increase of batch size

DE/H/479/001/II/004 N 18.01.2010 12.05.2010 Y N

Alternative Stoppers DE/H/479/001/II/006 N 07.05.2010 09.08.2010 Y N Article 107 of directive 2001/83/EC Increased risk of thromboembolic events

EMEA/H/A-107/1278 N 17.09.2010 23.09.2011 temporary suspension of marketing authorization

N

Article 31 referral of Council Directive 2001/83/EC

EMEA/H/A-31/1281 22.10.2010 31.05.2011 lifting of suspension of marketing authorization

N

Implementation of outcome of Article 31 referral EMEA/H/A-31/1281

DE/H/479/001/IA/009 N 01.06.2011 03.06.2011 Y N

Review under Article 5(3) of Regulation No 726/2004 reworking of specific Octagam batches

EMEA/H/A-5(3)/1309 21.07.2011 15.03.2012 recommendation N

Extension of shelf life at room temperature from 3 to 6 months

DE/H/479/001/II/011 Y 24.11.2011 30.03.2012 N N


Tightening of in process limits, change in address secondary packaging site

DE/H/0479/001/IA/012/G

N 21.03.2012 20.04.2012 Y N

Renewal of the marketing authorization Common renewal date: 20.05.2013

DE/H/479/001/R/001 Y 19.09.2012 23.03.2013 Y next renewal date: 20.05.2018

N

Increase batch size at Octapharma Vienna

DE/H/479/001/II/014 N 03.01.2013 03.04.2013 Y N

Change in the limits of anti A and anti B heamagglutinins in the finished product in order to comply with the requirements of Ph.Eur.

DE/H/479/001/IB/015 N 08.03.2013 07.04.2013 Y N

Substantial change to the manufacturing process of the active substance-Octagam rework

DE/H/479/001/II/016 N 05.04.2013 05.07.2013 Y N

New filling size 6g in 60ml New Pack sizes (3x10g, 3x20g)

DE/H/479/001/II/018/G Y 02.09.2013 02.01.2014 Y N

Alternative visual inspection sites DE/H/479/001/IB/020 N 08.01.2014 07.02.2014 Y N renouncement of rework during manufacturing (variation II/16)

DE/H/479/001/IB/021 N 08.01.2014 07.02.2014 Y N

Documents

Octagam 10% - DIMDI · mellitus and a history of vascular disease or thrombotic episodes, patients with acquired or inherited thrombophilic disorders, patients with prolonged periods