Octagam

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT OCTAGAM

Composition:

Active substance: normal human immunoglobulin;

1 ml of infusion solution contains total protein 50 mg (including immunoglobulin G (IgG) not less than 95 % and immunoglobulin A (IgA) not more than 0.2 mg);

Excipients: maltose, octoxynol (Triton X-100), tri-n-butyl phosphate, water for injections.

Distribution of immunoglobulin G (IgG) subclasses (approximate values): IgG1 − 60 %, IgG2 − 32 %, IgG3 − 7 %, IgG4 − 1 %.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: liquid, clear, colorless or slightly opalescent solution.

Pharmacotherapeutic group. Immune sera and immunoglobulins. Normal human immunoglobulin for intravenous administration. ATC code J06B A02.

Pharmacological properties.

Pharmacodynamics.

Normal human immunoglobulin contains predominantly immunoglobulin G (IgG) with a broad spectrum of antibodies against infectious agents.

Normal human immunoglobulin contains IgG antibodies present in the healthy organism.

It is obtained from pooled material derived from at least 3500 donors. The distribution of immunoglobulin G subclasses is approximately proportional to that in native human plasma. Appropriate doses of this medicinal product can restore pathologically low levels of immunoglobulin G to normal values.

The mechanism of action in indications other than replacement therapy has not been fully elucidated.

Clinical studies

A prospective, open-label, multicenter Phase III study evaluated the efficacy and safety of Octagam 10% (100 mg/mL) in patients with idiopathic (immune) thrombocytopenic purpura (ITP). Octagam 10% (100 mg/mL) was administered at a dose of 1 g/kg/day for 2 consecutive days; patients were followed for 21 days and during a subsequent visit on day 63 after infusion. Hematological parameters were assessed on days 2–7, 14, and 21.

A total of 116 subjects were included in the analysis: 66 with chronic ITP, 49 with newly diagnosed ITP, and 1 subject incorrectly enrolled (without ITP), who was excluded from the efficacy analysis.

The overall response rate in the full analysis set was 80% (95% confidence interval: 73–87%). The frequency of clinical response was similar in the two cohorts: 82% in the chronic ITP cohort and 78% in the newly diagnosed ITP cohort. Among responders, the median time to platelet response was 2 days (range: 1–6 days).

The maximum infusion rate was generally 0.12 mL/kg/min. In the group of patients for whom the maximum infusion rate of 0.12 mL/kg/min was allowed (n = 90), the maximum rate of 0.12 mL/kg/min was achieved, with a median of 0.10 mL/kg/min.

Overall, 55% of patients experienced an adverse reaction related to the medicinal product, with a similar frequency of occurrence in patients with chronic ITP and those with newly diagnosed ITP. All drug-related adverse reactions were mild or moderate in intensity, and all resolved.

The most common adverse reactions were headache, tachycardia (reported as pulse rate changes of less than 10 beats/min), and hyperthermia (elevated body temperature).

Adverse reactions related to the medicinal product occurring during infusion or within 1 hour after infusion administered at a rate ≤ 0.08 mL/kg/min were observed in 32 of 116 patients (28%), whereas only 6 of 54 patients (11%) experienced such reactions at an infusion rate of 0.12 mL/kg/min (if an adverse reaction started after the end of infusion, it was attributed to the last infusion rate applied).

No cases of hemolysis caused by the investigational product were reported. Patients were not pre-treated to reduce infusion intolerance, except for one patient.

Chronic inflammatory demyelinating polyneuropathy (CIDP)

A retrospective study included data from 46 patients with chronic inflammatory demyelinating polyneuropathy (CIDP) who received treatment with Octagam. The efficacy analysis included data from 24 patients: 11 untreated patients (Group 1) and 13 patients who had not received immunoglobulins within 12 weeks prior to starting Octagam therapy (Group 2). Group 3 consisted of 13 other patients who had previously received immunoglobulin treatment (immunoglobulins administered within 12 weeks prior to starting Octagam). Treatment was considered effective if there was a reduction of at least 1 point on the Overall Neuropathy Limitations Scale (ONLS) within 4 months after starting therapy. In Groups 1 and 2, the score significantly decreased in 41.7% of patients (p = 0.02). Only 3 of 13 patients (23.08%) in Group 3 (previously treated with intravenous immunoglobulin) showed improvement in ONLS; in 10 patients, the condition remained unchanged. No significant improvement in ONLS was expected in patients previously treated with intravenous immunoglobulin.

The mean age of the studied patients was 65 years, which is higher than in other CIDP studies. Patients aged 65 years and older showed a lower response rate compared to younger patients.

Children

A prospective, open-label, Phase III study of Octagam was conducted in 17 pediatric patients with primary immunodeficiency. Previously treated patients received 0.2 g/kg every 3 weeks for 6 months of the study period. Patients who were previously untreated received 0.4 g/kg every 3 weeks for the first 3 months, followed by 0.2 g/kg until the end of the study. Dosing adjustments were required to maintain a minimum IgG level of at least 4 g/L in patients.

Severity of infections was assessed as mild. No serious infections requiring hospitalization were observed.

Pharmacokinetics.

After intravenous administration, the bioavailability of normal human immunoglobulin in the recipient's circulation is immediate and complete. It rapidly distributes between plasma and extravascular fluid, with equilibrium between intravascular and extravascular compartments reached after approximately 3–5 days.

The mean half-life of normal human immunoglobulin ranges from 26 to 41 days, as indicated by corresponding measurements in patients with immunodeficiency. This half-life may vary among individual patients, especially in those with primary immunodeficiency. IgG and IgG complexes are catabolized in cells of the reticuloendothelial system.

Children

A prospective, open-label, Phase III study of Octagam was conducted in 17 children (mean age 14.0 years, range 10.5–16.8 years) with primary immunodeficiency. Patients were treated for 6 months.

During the treatment period, the mean steady-state Cmax was 11.1 ± 1.9 g/L; the mean trough level was 6.2 ± 1.8 g/L. The mean half-life of total IgG was 35.9 ± 10.8 days, with a mean interval of 34 days. The mean volume of distribution of total IgG was 3.7 ± 1.4 L, and total clearance was 0.07 ± 0.02 L/day.

Clinical characteristics.

Indications.

Replacement therapy in adults and children (aged 0 to 18 years):

• Primary immunodeficiency syndromes (PIS) with impaired antibody production.
• Secondary immunodeficiencies (SID) in patients with severe or recurrent infections, ineffective antimicrobial therapy, established specific antibody deficiency (ESAD)*, or serum IgG level below 4 g/L.

* ESAD – inability to achieve at least a 2-fold increase in IgG antibody titers against pneumococcal polysaccharide vaccine and polyvalent antigen.

Immunomodulatory therapy in adults and children (0–18 years):

• Idiopathic thrombocytopenic purpura (ITP) in patients with high risk of bleeding or prior to surgery – for platelet count correction.
• Guillain-Barré syndrome.
• Kawasaki disease (in combination with acetylsalicylic acid, see "Method of administration and dosage").
• Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).
• Multifocal motor neuropathy (MMN).

Contraindications.

Hypersensitivity to the active substance (human immunoglobulins) or to any of the excipients (see sections "Special precautions", "Composition").

In patients with selective IgA deficiency who have developed antibodies against IgA, administration of a product containing IgA may lead to anaphylaxis.

Special precautions.

The product should reach room or body temperature before administration.
The solution should be clear, colorless, or slightly opalescent.
Do not use cloudy solutions or solutions with sediment.

Due to the risk of bacterial contamination, any unused portion of the product must be discarded.

Unused medicinal product or waste material must be disposed of in accordance with local requirements.

Interaction with other medicinal products and other forms of interaction.

Live attenuated viral vaccines

Administration of immunoglobulins may reduce the efficacy of live attenuated viral vaccines against measles, rubella, mumps, and varicella for a period ranging from 6 weeks to 3 months. A minimum interval of 3 months should elapse between administration of this product and vaccination with live attenu游戏副本

Special precautions for use.

50 ml of solution contains 2.5 g of normal human immunoglobulin.

100 ml of solution contains 5 g of normal human immunoglobulin.

200 ml of solution contains 10 g of normal human immunoglobulin.

This medicinal product is manufactured from human donor plasma.

This medicinal product contains maltose as an excipient: 100 mg per 1 ml. The presence of maltose may interfere with blood glucose measurements, leading to falsely elevated glucose readings and, consequently, inappropriate insulin administration, which may result in life-threatening hypoglycemia. Additionally, episodes of true hypoglycemia may remain undetected if masked by falsely elevated glucose readings. See information below regarding acute renal failure.

Traceability

To improve the traceability of biological medicinal products, the name and batch number of the administered product should be clearly recorded.

Precautions for use

Potential complications can often be avoided by ensuring that:

• patients are tolerant to normal human immunoglobulin, verified by administering the first injection slowly (1 ml/kg/hour);
• patients are closely monitored for any symptoms throughout the entire injection period. In particular, if a patient has switched from an alternative intravenous immunoglobulin-containing product to Octagam, or if there has been a prolonged interval since the last injection, the patient should be monitored during and for 1 hour after the first injection to detect potential adverse signs. For all other patients, monitoring should continue for at least 20 minutes after administration.

If an adverse reaction occurs, the infusion rate should be reduced or the infusion stopped. Required treatment depends on the nature and severity of the adverse reaction.

In case of shock, standard anti-shock treatment should be administered.

Administration of intravenous immunoglobulin (IVIG) requires:

• adequate patient hydration prior to the start of IVIG infusion;
• monitoring of diuresis;
• monitoring of serum creatinine levels;
• avoidance of concomitant use of loop diuretics (see section "Interaction with other medicinal products and other forms of interaction").

Infusion reactions

Some adverse reactions (e.g., headache, flushing, chills, myalgia, wheezing, tachycardia, back pain, nausea, and hypotension) may be related to the infusion rate. The recommended infusion rate specified in the section "Posology and method of administration" must be strictly followed. Patients should be closely monitored throughout the infusion period for the development of any symptoms.

Adverse reactions may occur more frequently:

• in patients receiving normal human immunoglobulin for the first time, or in rare cases when switching from another normal human immunoglobulin product, or when there is a long interval between previous and subsequent infusions;
• in patients with untreated infection or concomitant chronic inflammation.

Hypersensitivity

Hypersensitivity reactions are rare.

Anaphylactic reactions may occur in patients:

• with undetected IgA deficiency who have antibodies against immunoglobulin A (IgA);
• who have undergone prior treatment with normal human immunoglobulin.

In case of shock, standard anti-shock medical treatment should be administered.

Excipients with known effect

This medicinal product contains 35 mg of sodium per 100 ml, which corresponds to 1.75% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

This should be taken into account if the patient is on a sodium-controlled diet.

Thromboembolism

There are clinical indications of an association between IVIG administration and thromboembolic complications such as myocardial infarction, acute cerebrovascular accident (including stroke), pulmonary artery embolism, and deep vein thrombosis, which are believed to be related to relative increase in blood viscosity due to high immunoglobulin load in at-risk patients. IVIG should be prescribed and administered with caution in obese patients and in patients with risk factors for thrombotic complications (such as advanced age, hypertension, diabetes mellitus, vascular disease, history of thrombotic events, acquired or inherited thrombophilic disorders, prolonged immobilization, hypovolemia, or conditions increasing blood viscosity).

For patients at risk of thromboembolic adverse reactions, IVIG products should be administered at the lowest possible infusion rate and at the minimal effective dose.

Acute renal failure

Cases of acute renal failure have been reported in patients receiving IVIG therapy. In most cases, risk factors such as pre-existing renal impairment, diabetes mellitus, hypovolemia, obesity, concomitant use of nephrotoxic drugs, or age over 65 years were present.

If renal function deteriorates, discontinuation of IVIG therapy should be considered. Reports of renal dysfunction and acute renal failure have been associated with the use of various IVIG products containing different excipients such as sucrose, glucose, and maltose, particularly those using sucrose as a stabilizer. For patients at risk, IVIG products not containing these excipients may be considered.

For patients at risk of acute renal failure, IVIG products should be administered at the lowest possible infusion rate and at the minimal effective dose.

Renal function should be assessed before IVIG infusion, especially in patients at increased risk of acute renal failure, and monitored at regular intervals. IVIG should be administered at the lowest infusion rate and minimal possible doses in patients at risk of acute renal failure.

Aseptic Meningitis Syndrome (AMS)

Aseptic meningitis syndrome has been reported in association with IVIG treatment. The syndrome typically begins within several hours to 2 days after IVIG administration. Cerebrospinal fluid analysis often shows pleocytosis of up to several thousand cells/mm³, predominantly granulocytes, and elevated protein levels up to several hundred mg/dL.

AMS may occur more frequently with high-dose IVIG treatment (2 g/kg).

Patients presenting signs and symptoms of AMS should undergo thorough neurological evaluation, including cerebrospinal fluid analysis, to exclude other causes of meningitis.

Discontinuation of IVIG treatment has led to resolution of AMS within several days without sequelae.

Hemolytic anemia

Immunoglobulin products may contain blood group antibodies that can act as hemolysins and induce in vivo coating of red blood cells with immunoglobulin, resulting in a positive direct antiglobulin reaction (Coombs test) and, less frequently, hemolysis. Hemolytic anemia may develop after IVIG therapy due to enhanced erythrocyte lysis. Risk factors for hemolysis include: high-dose immunoglobulin administered over several days; blood groups other than group O; and inflammatory conditions. Hemolysis has rarely been observed in patients receiving replacement therapy for primary immunodeficiency. Clinical signs of hemolysis should be monitored in patients receiving IVIG.

Neutropenia/leukopenia

Transient decreases in neutrophil count and/or episodes of neutropenia, sometimes severe, have been reported after IVIG treatment. These typically occur within hours or days after IVIG administration and resolve spontaneously within 7–14 days.

Acute transfusion-related lung injury (TRALI)

There have been several reports of acute non-cardiogenic pulmonary edema, known as acute transfusion-related lung injury (TRALI), in patients receiving IVIG. Therefore, this adverse effect cannot be completely excluded with the use of Octagam.

TRALI is characterized by severe hypoxia, dyspnea, tachypnea, cyanosis, fever, and hypotension. TRALI symptoms usually develop during or within 6 hours after infusion, often within 1–2 hours. Therefore, recipients of IVIG should be monitored, and IVIG infusion should be stopped immediately in case of pulmonary adverse reactions. TRALI is a potentially life-threatening condition requiring immediate treatment in an intensive care unit.

Effect on serological test results

Following immunoglobulin injection, transient elevation in blood levels of various passively transferred antibodies may lead to pseudopositive results in serological tests.

Passive transfer of antibodies against erythrocyte antigens, such as A, B, and D, may affect certain serological tests for red cell antibodies, for example, the direct antiglobulin test (direct Coombs test).

Transmission of infectious agents

Standard precautions to prevent infections from medicinal products derived from human blood or plasma include donor selection, testing of individual donations and plasma pools for specific infection markers, and inclusion of effective manufacturing steps for virus inactivation/removal. Despite these measures, the possibility of transmitting infection cannot be completely excluded when administering products derived from human blood or plasma. This also applies to any unknown or emerging viruses or other infectious agents.

The measures taken are considered effective against enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus, and hepatitis C virus. However, the measures may be less effective against non-enveloped viruses such as hepatitis A virus and parvovirus B19.

Available clinical experience indicates no transmission of hepatitis A or parvovirus B19 with immunoglobulins, and the antibody content is expected to contribute to viral safety.

Pseudoelevated erythrocyte sedimentation rate (ESR)

In patients receiving IVIG therapy, erythrocyte sedimentation rate (ESR) may be pseudoelevated (non-inflammatory elevation).

Volume overload

Volume overload is possible when the volume of IVIG (or any other product derived from human blood or plasma) infused, along with other concurrent infusions, leads to acute hypervolemia and acute pulmonary edema.

Injection site reactions

Reactions at the injection site have been observed, which may include extravasation, erythema at the infusion site, swelling at the infusion site, and similar symptoms.

Children

There are no specific or additional warnings or precautions applicable to children.

Use during pregnancy or breastfeeding.

Pregnancy

The safety of using this medicinal product during pregnancy has not been established in controlled clinical trials; therefore, it should be used with caution in pregnant women and in women who are breastfeeding. IVIG products have been shown to cross the placenta, particularly during the third trimester. Clinical experience with immunoglobulin use suggests no harmful effects on pregnancy, the fetus, or the newborn are expected.

Breastfeeding

Immunoglobulins are excreted in breast milk. A negative effect on breastfed newborns/infants is not expected.

Fertility

Clinical experience with immunoglobulin treatment allows the assumption that no harmful effect on fertility is expected.

Ability to affect reaction speed when driving or operating machinery.

Octagam has no effect or a negligible effect on the ability to drive or use machinery.

Patients who experience adverse reactions during treatment should wait until these symptoms resolve before driving or operating machinery.

Administration and Dosage

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

The dosage and dosing regimen depend on the indication.

The dose must be individually adjusted for each patient according to clinical response. For patients with low or high body weight, dose adjustments should be based on body weight. For patients with excess body weight, dose selection should be based on physiological standards of body weight.

The following are dosing regimens according to indications.

Replacement therapy in primary immunodeficiency syndromes

The treatment regimen should ensure achievement of a minimum IgG level of at least 6 g/L (level measured prior to the next intravenous infusion). After initiation of therapy, it may take 3 to 6 months to reach a steady state. The recommended initial dose is 0.4–0.8 g/kg as a single dose, followed by 0.2 g/kg every 3–4 weeks.

The dose required to achieve levels above 6 g/L is approximately 0.2–0.8 g/kg/month.

The dosing interval at steady state ranges from 3 to 4 weeks.

To reduce infection rate, dose escalation and achievement of higher minimum IgG levels may be necessary.

Secondary immunodeficiencies

The recommended dose is 0.2–0.4 g/kg every 3–4 weeks.

Minimum IgG levels should be measured and evaluated in conjunction with the frequency of infections. The dose should be adjusted as needed to achieve optimal protection against infections. Dose increases may be necessary for patients with persistent infections; dose reduction may be considered when the patient is free of infections.

Primary immune thrombocytopenia

Two alternative treatment regimens are available:

0.8–1 g/kg on Day 1; this dose may be repeated once within 3 days

or

0.4 g/kg daily for 2–5 days.

Treatment may be repeated upon relapse.

Guillain-Barré syndrome

0.4 g/kg/day for 5 consecutive days (re-administration may be considered in case of relapse).

Kawasaki disease

A single dose of 2.0 g/kg should be administered. Patients should receive concomitant therapy with acetylsalicylic acid.

Chronic inflammatory demyelinating polyneuropathy (CIDP)

Initial dose: 2.0 g/kg, administered over 2–5 consecutive days.

Maintenance doses:

1.0 g/kg over the next 1–2 days every 3 weeks.

Therapeutic response should be evaluated after each cycle; if no therapeutic effect is observed within 6 months, treatment should be discontinued.

If treatment is effective, long-term therapy should be continued at the physician’s discretion, based on the patient’s response to maintenance doses. Dosing and intervals should be adjusted according to the individual course of the disease.

Multifocal motor neuropathy (MMN)

Initial dose: 2.0 g/kg, administered over 2–5 consecutive days.

Maintenance dose: 1.0 g/kg every 2–4 weeks or 2.0 g/kg every 4–8 weeks.

Therapeutic response should be evaluated after each cycle; if no therapeutic effect is observed within 6 months, treatment should be discontinued.

If treatment is effective, long-term therapy should be continued at the physician’s discretion, based on the patient’s response to maintenance doses. Dosing and intervals should be adjusted according to the individual course of the disease.

Table 1 provides the recommended doses and frequency of administration of Octagam in clinical studies.

Table 1

Route of administration

Normal human immunoglobulin should be administered by intravenous infusion at a rate of 1 ml/kg/hour for 30 minutes upon initial administration; see section "Special precautions for use".

If well tolerated, the infusion rate may be gradually increased up to a maximum of 5 ml/kg/hour.

The infusion system may be flushed before and after administration of Octagam with sodium chloride solution (isotonic solution) or 5% aqueous dextrose solution.

Hepatic impairment

There is insufficient available evidence to recommend dose adjustment.

Renal impairment

Dose adjustment is not required in the absence of clinical indications; see section "Special precautions for use".

Elderly patients

Dose adjustment is not required in the absence of clinical indications; see section "Special precautions for use".

Children

The dosage for children (0–18 years) does not differ from that for adults, as the dose for each indication is based on body weight and adjusted according to clinical response.

Overdose

Overdose may lead to fluid overload and increased blood viscosity, particularly in patients with relevant risk factors, including advanced age and impaired cardiac or renal function (see section "Special precautions for use").

Adverse reactions.

Summary of safety profile

Adverse reactions associated with the administration of normal human immunoglobulins (listed in decreasing order of frequency) include the following (see also section "Special instructions for use"):

• chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia (joint pain), hypotension, and mild back pain;
• reversible hemolytic reactions; particularly in patients with blood groups A, B, and AB, and (rarely) hemolytic anemia requiring blood transfusion;
• (rarely) sudden drop in blood pressure and, in isolated cases, anaphylactic shock, even in patients who did not show hypersensitivity upon prior administration of normal human immunoglobulins;
• (rarely) transient skin reactions (including cutaneous lupus erythematosus, frequency unknown);
• (very rarely) thromboembolic complications such as myocardial infarction, stroke, pulmonary embolism, deep vein thrombosis;
• cases of reversible aseptic meningitis;
• cases of increased serum creatinine levels and/or development of acute kidney injury;
• cases of transfusion-related acute lung injury (TRALI).

List of adverse reactions in table format

Table 2 lists adverse reactions by system organ classes according to MedDRA (Medical Dictionary for Regulatory Activities). The frequency of adverse reactions is defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (frequency cannot be determined from available data).

Frequencies were derived from clinical trials of Octagam (frequencies "common" and "uncommon") and from post-marketing surveillance (frequency "not known").

Within each frequency grouping, adverse effects are listed in descending order of severity.

Table 2

Adverse reactions observed in clinical trials of Octagam, by frequency

Adverse reactions listed in Table 3 are known from post-marketing experience with the drug. The frequency of reactions reported during the post-marketing period cannot be estimated from the available data.

Table 3

Description of individual adverse reactions

For description of individual adverse events such as hypersensitivity reactions, thromboembolism, acute renal failure, aseptic meningitis syndrome, and hemolytic anemia, see section "Special precautions for use".

Children

In clinical studies of Octagam, most of the adverse reactions observed in children were considered mild, and for many children, simple measures such as reducing the infusion rate or temporarily interrupting the infusion were sufficient. Regarding the type of adverse reaction, all were recognized as those known to occur with the use of IVIG preparations. The most commonly observed adverse reaction in the pediatric population was headache.

Reporting of suspected adverse reactions

Reporting of adverse reactions following marketing authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, as well as patients or their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

2 years.

Do not use after the expiry date.

After first opening, the medicinal product should be used immediately.

Storage conditions.

Store at a temperature between 2 and 25 °C.
Do not freeze. Keep out of the reach of children. Protect from light.
Due to the possibility of bacterial contamination, any unused portion should be discarded.

Storage conditions after first opening of the medicinal product are described in the section "Shelf life".

Incompatibilities.

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

Packaging.

50 ml of solution in a 70 ml Type II glass bottle, or 100 ml of solution in a 100 ml bottle, or 200 ml of solution in a 250 ml bottle with a bromobutyl rubber stopper. One bottle per cardboard box.

Components used in the packaging of Octagam do not contain latex.

Prescription status. Prescription only.

Manufacturers.

1. Octapharma Pharmazeutika Produktionsges.m.b.H., Austria /
   Octapharma Pharmazeutika Produktionsges.m.b.H., Austria.

2. Octapharma, France / Octapharma, France.

3. OCTAPHARMA AB, Sweden / OCTAPHARMA AB, Sweden.

Manufacturer addresses and locations of operations.

1. Oberlaaer Strasse 235, 1100 Vienna, Austria /
   Oberlaaerstrasse 235, 1100 Vienna, Austria.

2. 72 rue du Marechal Foch, 67380 Lingolsheim, France /
   72 rue du Marechal Foch, 67380 Lingolsheim, France.

3. Lars Forssells gata 23, Stockholm, 11275, Sweden /
   Lars Forssells gate 23, Stockholm, 11275, Sweden.