1.Name of the medical product
Intratect®
50 g/I: solution for infusion

2.Qualitative and quantitative composition
Human normal immunoglobulin for intravenous use (IVIg) 
Human protein 50 g/I of which at least 96% is IgG, derived from human blood/plasma donors.
One vial of 20 ml contains: 1 g
One vial of 50ml contains: 2,5g
One vial of 100ml contains: 5g
One vial of 200ml contains: 10g

Distribution of IgG subclasses:
IgG 1                 57%
IgG 2                 37%
IgG 3                   3%
IgG 4                   3%
IgA max. 2mg/ml

For excipients, see 6.1

3.Pharmaceutical form
Solution for infusion. 
The solution is clear to slightly opalescent and colourless to pale yellow.

4. Clinical particulars
4.1 Therapeutic indications
Replacement therapy in: 
Primary immunodeficiency syndromes such as:
  • Congenital agammaglobulinaemia and hypogammaglobulinaemia 
  • Common variable immunodeficiency
  • Severe combined immunodeficiency
  • Wiskott Aldrich syndrome

Myeloma or chronic lymphocytic leukaemia with severe secondary hypogammaglobulinemia 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-Barre syndrome
  • Kawasaki disease

Allogeneic bone marrow transplantation

4.2 Posology and method of administration 
Posology
The dose and dosage regimen is dependent on the indication. In replacement therapy the dosage may need to be individualized for each patient dependent on the pharmacokinetic and clinical response. The following dosage regimens are given as a guideline:

Replacement therapy in primary immunodeficiencies 
The dosage regimen should achieve a trough level of IgG (measured before the next infusion) of at least 4-6 g/I. Three to six months are required after the initiation of therapy for equilibration to occur. The recommended starting dose is 8-16ml (0.4-0.8)/kg followed by at least 4ml (0.2g)/kg every three weeks.

The dose required to achieve a trough level of 6g/I is of the order of 4-16 ml (0.2-0.8g) kg/month. The dosage interval when steady state has been reached varies from 2-4 weeks.

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

Replacement therapy in myeloma or chroniclymphocytic leukaemia with severe secondary hypogammaglobulinemia and recurrent infections; replacement therapy in children with AIDS and recurrent infections 

The recommended dose is 4-8 ml (0.2 - 0.4g)/kg every three to four weeks.

Idiopathic thrombocytopenic purpura
For the treatment of an acute episode, 16 - 20ml (0.8 - 1g)/kg on day one, which may be repeated once within 3 days, or 8 ml (0.4g)/kg daily for two to five days. The treatment can be repeated if relapse occurs.

Guillain-Barre syndrome 
8ml (0.4g)/kg/day for 3 to 7 days. Experience in children is limited.

Kawasaki disease
32-40ml (1.6-2g)kg should be administered in divided doses over two to five days or 40ml (2g)/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 transplantation. For the treatment of infections and prophylaxis of graft versus host disease, dosage is individually tailored. The starting dose is normally 10ml (0.5g)/kg/week, starting seven days before transplantation and for up to 3 months after transplantation.
In case of persistent lack of antibody production, dosage of 10ml (0.5g)/kg/month is recommended until antibody level returns to normal. 

The dosage recommendations are summarized in the following table:

Method of administration 
Intratect® should be infused intravenously at an initial rate of not more than 1.4ml/ kg/hr for 30 minutes. If well tolerated, the rate of administration may gradually be increased to a maximum of 1.9ml/kg/hr for the remainder of the infusion.

4.3 Contraindications
Hypersensitivity to any of the components. Hypersensitivity to homologous immunoglobuline, especially in very rare cases of IgA deficiency, when the patient has antibodies against IgA.

4.4 Special warnings and special precautions for use
Certain severe adverse drug reactions may be related to the rate of infusion. The recommended infusion rate given under "4.2 Posology and method of administration" must be closely followed. Patients must be closely monitored and carefully observed for any symptoms throughout the infusion period.

Certain adverse reactions may occur more frequently
 • in case of high rate of infusion,
 • in patients with hypo-or agammaglobulinemia with or without IgA deficiency, 
 • in 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 the 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 infusing the product slowly (0.024ml/kg//min), 
- 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 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 ad 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 history of vascular disease or thrombotic episodes, patients with acquired or inherited thrombophilic disorders, patients with prolonged periods of immobilization, 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, those containing sucrose as a stabilizer accounted for disproportionate share of the total number. In patients at risk, the use of IVIg products that do not contain sucrose may be considered.

In patients at risk for acute renal failure of 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 initiation of the infusion of IVIg,
 • monitoring of urine output,
 • monitoring of serum creatinine levels,
 • avoidance of concomitant use of loop diuretics.

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

In case of shock, standard medical treatment for shock should be implemented.

Standard measured 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 pathogen.

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 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 Intratect^® is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

4.5 Interaction with other medicinal products and other forms of interaction

Live attenuated virus vaccines
Immunoglobulin administration may impair for a period of at least 6 week 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 the various passively transferred antibodies in the patients blood may result in misleading positive results in serological testing. Passive transmission of antibodies to erythrocyte antigens, e.g., A,B,D may interfere with some serological tests including the antiglobulin test (Coomb's test).

4.6 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. 

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

4.8 Undesirable effects
Adverse reactions such as chills, headache, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure and mild back pain may occur occasionally. Rarely, human normal immunoglobulins may cause a sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even when the patient has shown no hypersensitivity to previous administration. 

Cases of reversible aseptic meningitis, 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. 

Details of the spontaneously reported adverse reactions: Cardiac disorders: Angina pectoris (very rare) General disorders and administration site conditions: Rigors (very rare) Immune system disorders: Anaphylactoid shock (very rare), hypersensitivity (very rare) Investigation: Blood pressure decreased (very rare). Musculoskeletal and connective tissue disorders: Back pain (very rare) Respiratory, thoracic and mediastinal disorders: Dyspnoe NOS (very rare). For safety with respect to transmissible agents, see 4.4

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

5.1 Pharmacodynamic properties 
Pharmacotherapeutic group: Immune sera and immunoglobulins: Immunoglobulins, normal human, for intravascular administration, ATC code: J06BA02 Human normal immunoglobulin contains mainly immunoglobulin G (IgG) with a broad spectrum of antibodies against infectious agents. 

Human normal immunoglobulin contains the IgG antibodies present in the normal population. It is usually prepared from pooled plasma from not fewer than 1000 donations. It has a distribution of IgG subclasses closely proportional to that in native human plasma. Adequate doses of this medicinal product may restore abnormally low IgG levels to the normal range. The mechanism of action in indications other than replacement therapy is not fully elucidated, but includes immunomodulatory effect.

5.2 Pharmacokinetic properties 
Human normal immunoglobulin is immediately and completely bioavailable in the recipient's circulation after intravenous administration. It is distributed relatively rapidly between plasma and dextravascular fluid, after approximately 3-5 days equilibrium is reached between the intra and extravascular compartments. Intratect^® has a half-life of about 27 days. This half-life may vary from patient to patient in particular in primary immunodeficiency. 

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

5.3 Preclinical safety data
Immunoglobulins are normal constituents of the human body. In animals, single dose toxicity testing is of no relevance since higher doses result in over loading. Repeated doses toxicity testing and embryo-foetal toxicity studies are impracticable due to induction of, and interference with antibodies. Effects of the product on the immune system of the new-born have not been studied.
Since clinical experience provides no hint for tumorigenic and mutagenic effects of immunoglobulins, experimental studies, particularly in heterologous species, are not considered necessary.

6.1 List of excipients 
Glycine, water for injections.

6.2 Incompatibilities 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 

6.3 Shelf-life
2 years.
After first opening, an immediate use is recommended.

6.4 Special precautions for storage
Do not store above 25⁰C. Do not freeze. Keep the container in the outer carton.

6.5 Nature and contents of container 
20ml or 50ml or 100ml or 200ml of solution in a vial (Type II glass) with a stopper (chlorobutyl) and a cap (aluminium) - pack size of one vial.

6.6 Instruction for use, handling and disposal 
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.

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